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CD004116	[ "9820260", "14984373", "2697693", "1985041", "19696601", "15996029" ]	[ "Treatment of irritable bowel syndrome with Chinese herbal medicine: a randomized controlled trial.", "Treatment of irritable bowel syndrome with herbal preparations: results of a double-blind, randomized, placebo-controlled, multi-centre trial.", "Irritable bowel syndrome: therapeutic evaluation of indigenous drugs.", "A controlled trial of psychological treatment for the irritable bowel syndrome.", "Symptom management for irritable bowel syndrome: a pilot randomized controlled trial of acupuncture/moxibustion.", "Acupuncture for irritable bowel syndrome: a blinded placebo-controlled trial." ]	[ "Irritable bowel syndrome (IBS) is a common functional bowel disorder for which there is no reliable medical treatment.\n To determine whether Chinese herbal medicine (CHM) is of any benefit in the treatment of IBS.\n Randomized, double-blind, placebo-controlled trial conducted during 1996 through 1997.\n Patients were recruited through 2 teaching hospitals and 5 private practices of gastroenterologists, and received CHM in 3 Chinese herbal clinics.\n A total of 116 patients who fulfilled the Rome criteria, an established standard for diagnosis of IBS.\n Patients were randomly allocated to 1 of 3 treatment groups: individualized Chinese herbal formulations (n = 38), a standard Chinese herbal formulation (n = 43), or placebo (n = 35). Patients received 5 capsules 3 times daily for 16 weeks and were evaluated regularly by a traditional Chinese herbalist and by a gastroenterologist. Patients, gastroenterologists, and herbalists were all blinded to treatment group.\n Change in total bowel symptom scale scores and global improvement assessed by patients and gastroenterologists and change in the degree of interference in life caused by IBS symptoms assessed by patients.\n Compared with patients in the placebo group, patients in the active treatment groups (standard and individualized CHM) had significant improvement in bowel symptom scores as rated by patients (P=.03) and by gastroenterologists (P=.001), and significant global improvement as rated by patients (P=.007) and by gastroenterologists (P=.002). Patients reported that treatment significantly reduced the degree of interference with life caused by IBS symptoms (P=.03). Chinese herbal formulations individually tailored to the patient proved no more effective than standard CHM treatment. On follow-up 14 weeks after completion of treatment, only the individualized CHM treatment group maintained improvement.\n Chinese herbal formulations appear to offer improvement in symptoms for some patients with IBS.", "Herbal medications have been used in many countries for the treatment of patients with irritable bowel syndrome. Controlled data supporting the efficacy of these treatments in patients with irritable bowel syndrome are lacking.\n To assess the efficacy and safety of a commercially available herbal preparation (STW 5) (nine plant extracts), the research herbal preparation STW 5-II (six plant extracts) and the bitter candytuft mono-extract in patients with irritable bowel syndrome.\n Two hundred and eight patients with irritable bowel syndrome were recruited after standardized diagnostic work-up into a double-blind, placebo-controlled, multi-centre trial and were randomly assigned to receive one of four treatments: commercially available herbal preparation STW 5 (n = 51), research herbal preparation STW 5-II (n = 52), bitter candytuft mono-extract (n = 53) or placebo (n = 52). The main outcome variables were the changes in total abdominal pain and irritable bowel syndrome symptom scores.\n Two hundred and three patients completed the trial. STW 5 and STW 5-II were significantly better than placebo in reducing the total abdominal pain score (intention-to-treat: STW 5, P = 0.0009; STW 5-II, P = 0.0005) and the irritable bowel syndrome symptom score (intention-to-treat: STW 5, P = 0.001; STW 5-II, P = 0.0003) at 4 weeks. There were no statistically significant differences between the bitter candytuft mono-extract group and the placebo group (P = 0.1473, P = 0.1207).\n The commercially available herbal preparation STW 5 and its research preparation STW 5-II are both effective in alleviating irritable bowel syndrome symptoms.", "Among 169 patients with irritable bowel syndrome (IBS), standard therapy (with clidinium bromide, chlordiazepoxide and isaphaghulla), a compound Ayurvedic preparation (with Aegle marmelos correa plus Bacopa monniere Linn) along with a matching placebo were given in a double blind randomised trial for 6 wk. The Ayurvedic preparation in 57 patients was found effective in 64.9 per cent, while standard therapy (60 patients) was useful in 78.3 per cent. Patients on placebo (52 patients) showed improvement in 32.7 per cent only. Ayurvedic therapy was particularly beneficial in diarrhoea predominant form as compared to placebo. The standard therapy was more useful in the painful form of IBS as compared to placebo and Ayurvedic preparation. In gas predominant form the effect of standard as well as Ayurvedic therapy, was similar to placebo. Long-term follow-up (greater than 6 months) showed that both forms of therapy were no better than placebo in limiting the relapse.", "One hundred two patients with irritable bowel syndrome were studied in a controlled trial of psychological treatment involving psychotherapy, relaxation, and standard medical treatment compared with standard medical treatment alone. Patients were only selected if their symptoms had not improved with standard medical treatment over the previous 6 months. At 3 months, the treatment group showed significantly greater improvement than the controls on both gastroenterologists' and patients' ratings of diarrhea and abdominal pain, but constipation changed little. Good prognostic factors included overt psychiatric symptoms and intermittent pain exacerbated by stress, whereas those with constant abdominal pain were helped little by this treatment. This study has demonstrated that psychological treatment is feasible and effective in two thirds of those patients with irritable bowel syndrome who do not respond to standard medical treatment.", "The purpose of this pilot study was to assess the effect of an individualized traditional Chinese medicine (TCM) acupuncture and moxibustion (Acu/Moxa) treatment on symptom control in patients with irritable bowel syndrome (IBS) in a preliminary, randomized, sham/placebo-controlled trial. Twenty-nine men and women with IBS were randomized to either individualized Acu/Moxa (treatment group) or sham/placebo Acu/Moxa (control group). All subjects were assessed by a diagnostic acupuncturist for a TCM evaluation and individualized point prescription. Only those subjects assigned to the experimental group received the individually prescribed treatment. The diagnostic acupuncturist did not administer treatments and was blind to treatment assignments. All subjects kept a symptom diary for the duration of the study, enabling measurement of symptom frequency, severity, and improvement. The Clinical Global Impression Scale was administered preintervention to establish baseline severity and on completion of the 4-week, eight-session treatment intervention. After 4 weeks of twice-weekly Acu/Moxa treatment, average daily abdominal pain/discomfort improved whereas the control group showed minimal reduction. This between-group difference adjusted for baseline difference was statistically significant. The intestinal gas, bloating, and stool consistency composite score showed a similar pattern of improvement. The findings indicate that Acu/Moxa treatment shows promise in the area of symptom management for IBS.", "Irritable bowel syndrome (IBS) is a common disorder and many patients fail to find adequate relief from conventional therapies for their symptoms. This study tests the claim that acupuncture is effective for a majority of these patients.\n A prospective, blinded, sham acupuncture-controlled trial of traditional Chinese acupuncture was performed at a single postgraduate teaching hospital in Europe. Sixty patients with well-established IBS were recruited. The blinded comparator was sham acupuncture administered by the second of two acupuncturists who alone was aware of the randomization, and who otherwise followed the prescription of the first. The primary end-point was a defined fall in the symptom score at 13 wk (by intention to treat). The prior expectation was a 30% placebo response, and a response rate of 70% from acupuncture, for which the study was adequately powered.\n Patients in treated and sham groups improved significantly during the study-mean improvement in scores being equal (minus 1.9) and significant for both (P<0.05; one-tailed t test). There was a small numeric but non-significant difference between the response rate in patients receiving acupuncture (40.7%) and sham treatment (31.2%). Several secondary end-points marginally favored active treatment, but an improved symptom score of any degree of magnitude occurred more often with sham therapy (65.6% vs 59.2%). For no criterion was statistical significance approached.\n Traditional Chinese acupuncture is relatively ineffective in IBS in the European hospital setting, and the magnitude of any effect appears insufficient to warrant investment in acupuncture services." ]	Some herbal medicines may improve the symptoms of irritable bowel syndrome. However, positive findings from less rigorous trials should be interpreted with caution due to inadequate methodology, small sample sizes, and lack of confirming data. Some herbal medicines deserve further examination in high-quality trials.
CD001532	[ "16510640", "18977988", "18490378", "11343739", "6981165", "18082208", "10390264", "11207174", "20478580", "18020019", "8165073", "2085989", "7324942", "12424684" ]	[ "Clinical significance of primary vesicoureteral reflux and urinary antibiotic prophylaxis after acute pyelonephritis: a multicenter, randomized, controlled study.", "Prophylaxis after first febrile urinary tract infection in children? A multicenter, randomized, controlled, noninferiority trial.", "Is antibiotic prophylaxis in children with vesicoureteral reflux effective in preventing pyelonephritis and renal scars? A randomized, controlled trial.", "Medical versus surgical treatment in children with severe bilateral vesicoureteric reflux and bilateral nephropathy: a randomised trial.", "Antimicrobial prophylaxis in children with urinary tract infection and vesicoureteral reflux.", "Antibiotic prophylaxis for the prevention of recurrent urinary tract infection in children with low grade vesicoureteral reflux: results from a prospective randomized study.", "Oral versus initial intravenous therapy for urinary tract infections in young febrile children.", "Randomised controlled trial of three day versus 10 day intravenous antibiotics in acute pyelonephritis: effect on renal scarring.", "The Swedish reflux trial in children: I. Study design and study population characteristics.", "[Endoscopic and conservative treatment of vesicoureteric reflux].", "A short-term study of nitrofurantoin prophylaxis in children managed with clean intermittent catheterization.", "Fosfomycin trometamol versus netilmicin in children's lower urinary tract infections.", "The length of antimicrobial therapy in upper vs. lower urinary tract infection of childhood.", "[Prophylaxis of recurrent urinary tract infections in children. Results of an open, controlled and randomized study about the efficacy and tolerance of cefixime compared to nitrofurantoin]." ]	[ "To evaluate the role of primary vesicoureteral reflux (VUR) in increasing the frequency and severity of urinary tract infections (UTIs) and renal parenchymal damage among patients with acute pyelonephritis and to determine whether urinary antibiotic prophylaxis reduces the frequency and/or severity of UTIs and/or prevents renal parenchymal damage among patients with mild/moderate VUR.\n Patients 3 months to 18 years of age with acute pyelonephritis, with or without VUR, were assigned randomly to receive urinary antibiotic prophylaxis or not. Patients were monitored every 3 months for 1 year. Dimercaptosuccinic acid renal scans were repeated at 6 months or if there was a recurrence of febrile UTI. Urinalysis and urine culture were performed at each clinic visit. Renal ultrasound scans and voiding cystourethrograms were repeated at the end of 1 year of follow-up monitoring.\n Of the 236 patients enrolled in the study, 218 completed the 1-year follow-up monitoring. Groups were similar with respect to age, gender, and reflux grade distribution for those with VUR. No statistically significant differences were found among the groups with respect to rate of recurrent UTI, type of recurrence, rate of subsequent pyelonephritis, and development of renal parenchymal scars.\n After 1 year of follow-up monitoring, mild/moderate VUR does not increase the incidence of UTI, pyelonephritis, or renal scarring after acute pyelonephritis. Moreover, a role for urinary antibiotic prophylaxis in preventing the recurrence of infection and the development of renal scars is not supported by this study.", "Febrile urinary tract infections are common in children and associated with the risk for renal scarring and long-term complications. Antimicrobial prophylaxis has been used to reduce the risk for recurrence. We performed a study to determine whether no prophylaxis is similar to antimicrobial prophylaxis for 12 months in reducing the recurrence of febrile urinary tract infections in children after a first febrile urinary tract infection.\n The study was a controlled, randomized, open-label, 2-armed, noninferiority trial comparing no prophylaxis with prophylaxis (co-trimoxazole 15 mg/kg per day or co-amoxiclav 15 mg/kg per day) for 12 months. A total of 338 children who were aged 2 months to <7 years and had a first episode of febrile urinary tract infection were enrolled: 309 with a confirmed pyelonephritis on a technetium 99m dimercaptosuccinic acid scan with or without reflux and 27 with a clinical pyelonephritis and reflux. The primary end point was recurrence rate of febrile urinary tract infections during 12 months. Secondary end point was the rate of renal scarring produced by recurrent urinary tract infections on technetium 99m dimercaptosuccinic acid scan after 12 months.\n Intention-to-treat analysis showed no significant differences in the primary outcome between no prophylaxis and prophylaxis: 12 (9.45%) of 127 vs 15 (7.11%) of 211. In the subgroup of children with reflux, the recurrence of febrile urinary tract infections was 9 (19.6%) of 46 on no prophylaxis and 10 (12.1%) of 82 on prophylaxis. No significant difference was found in the secondary outcome: 2 (1.9%) of 108 on no prophylaxis versus 2 (1.1%) of 187 on prophylaxis. Bivariate analysis and Cox proportional hazard model showed that grade III reflux was a risk factor for recurrent febrile urinary tract infections. Whereas increasing age was protective, use of no prophylaxis was not a risk factor.\n For children with or without primary nonsevere reflux, prophylaxis does not reduce the rate of recurrent febrile urinary tract infections after the first episode.", "There has been intense discussion on the effectiveness of continuous antibiotic prophylaxis for children with vesicoureteral reflux, and randomized, controlled trials are still needed to determine the effectiveness of long-term antibiotics for the prevention of acute pyelonephritis. In this multicenter, open-label, randomized, controlled trial, we tested the effectiveness of antibiotic prophylaxis in preventing recurrence of pyelonephritis and avoiding new scars in a sample of children who were younger than 30 months and vesicoureteral reflux.\n One hundred patients with vesicoureteral reflux (grade II, III, or IV) diagnosed with cystourethrography after a first episode of acute pyelonephritis were randomly assigned to receive antibiotic prophylaxis with sulfamethoxazole/trimethoprim or not for 2 years. The main outcome of the study was the recurrence of pyelonephritis during a follow-up period of 4 years. During follow-up, the patients were evaluated through repeated cystourethrographies, renal ultrasounds, and dimercaptosuccinic acid scans.\n The baseline characteristics in the 2 study groups were similar. There were no differences in the risk for having at least 1 pyelonephritis episode between the intervention and control groups. At the end of follow-up, the presence of renal scars was the same in children with and without antibiotic prophylaxis.\n Continuous antibiotic prophylaxis was ineffective in reducing the rate of pyelonephritis recurrence and the incidence of renal damage in children who were younger than 30 months and had vesicoureteral reflux grades II through IV.", "Nephropathy associated with vesicoureteric reflux (VUR) and urinary tract infection can result in end-stage renal failure, hypertension, or both. Whether long-term VUR contributes to these outcomes is unknown. We compared, in a randomised trial, medical with surgical management of children with bilateral severe VUR and bilateral nephropathy.\n We stratified by age and glomerular filtration rate (GFR) 25 boys and 27 girls aged 1-12 years and randomly assigned them to medical or surgical management. At enrolment and 4 years' follow-up we estimated GFR from the plasma clearance of 51Cr-labelled edetic acid (EDTA), and did intravenous urography. We also did a metastable 99mTc-labelled dimercaptosuccinic acid (DMSA) assay and contrast cystography. The change in GFR at 4 years, expressed as a percentage change between enrolment and 4 years, was available for 26 of 27 patients in the medical and 24 of 25 in the surgical group. We assessed GFR in 48 patients 10 years after enrolment.\n Mean GFR at enrolment was 72.4 mL/min per 1.73 m(2) (SD 24.1) in the medical and 71.7 mL/min per 1.73 m(2) (22.6) in the surgical group. The mean percentage change in GFR at 4 years was 2.4% (SE 4.5) versus 4.7% (5.0) in the medical and surgical groups, respectively. The difference in change in GFR at 4 years between the two groups was not significant (7.1%, 95% CI 6.4% to 20.6%).\n Our data do not lend support to the view that the outcome for renal function is improved by surgical correction of VUR in children with bilateral disease.", "Thirty children with urinary tract infection and nonobstructive vesicoureteral reflux have been followed prospectively for a mean of 17 months. After classification according to age and grade of reflux, 10 patients were assigned at random to treatment with antimicrobial prophylaxis alone or antimicrobial prophylaxis plus corrective surgery. Twenty other patients were also treated with antimicrobial prophylaxis alone. All were assigned at random to treatment with a single daily dose of trimethoprim-sulfamethoxazole or nitrofurantoin. Cultures of urine, complete blood cell counts, and determination of levels of aspartate aminotransferase in serum were performed regularly during follow-up. Both drugs proved effective in prevention of recurrent infection, and no significant hematologic or hepatic abnormalities were noted. Current results suggest that either prophylaxis or surgery may effectively prevent chronic pyelonephritis or reflux nephropathy, but only continuing evaluation of this group of patients will confirm these results.", "Antibiotic prophylaxis is given to children at risk for urinary tract infection. However, evidence concerning its effectiveness in grade I to III vesicoureteral reflux is lacking. The objective of this study was to determine whether antibiotic prophylaxis reduces the incidence of urinary tract infection in young children with low grade vesicoureteral reflux.\n Children 1 month to 3 years old with grade I to III vesicoureteral reflux were assigned randomly to receive daily cotrimoxazole or no treatment, and followed for 18 months. A urinary tract infection constituted an exit criterion. Infection-free survival rates were calculated using the Kaplan-Meier method and compared using the log rank test.\n A total of 225 children were enrolled in the study. Distribution of gender, age at inclusion and reflux grade were similar between the 2 groups. There was no significant difference in the occurrence of urinary tract infection between the 2 groups (17% vs 26%, p = 0.2). However, a significant association was found between treatment and patient gender (p = 0.017). Prophylaxis significantly reduced urinary tract infection in boys (p = 0.013), most notably in boys with grade III vesicoureteral reflux (p = 0.042).\n These data suggest that antibiotic prophylaxis does not reduce the overall incidence of urinary tract infection in children with low grade vesicoureteral reflux. However, such a strategy may prevent further urinary tract infection in boys with grade III reflux.", "The standard recommendation for treatment of young, febrile children with urinary tract infection has been hospitalization for intravenous antimicrobials. The availability of potent, oral, third-generation cephalosporins as well as interest in cost containment and avoidance of nosocomial risks prompted evaluation of the safety and efficacy of outpatient therapy.\n In a multicenter, randomized clinical trial, we evaluated the efficacy of oral versus initial intravenous therapy in 306 children 1 to 24 months old with fever and urinary tract infection, in terms of short-term clinical outcomes (sterilization of the urine and defervescence) and long-term morbidity (incidence of reinfection and incidence and extent of renal scarring documented at 6 months by 99mTc-dimercaptosuccinic acid renal scans). Children received either oral cefixime for 14 days (double dose on day 1) or initial intravenous cefotaxime for 3 days followed by oral cefixime for 11 days.\n Treatment groups were comparable regarding demographic, clinical, and laboratory characteristics. Bacteremia was present in 3.4% of children treated orally and 5.3% of children treated intravenously. Of the short-term outcomes, 1) repeat urine cultures were sterile within 24 hours in all children, and 2) mean time to defervescence was 25 and 24 hours for children treated orally and intravenously, respectively. Of the long-term outcomes, 1) symptomatic reinfections occurred in 4.6% of children treated orally and 7.2% of children treated intravenously, 2) renal scarring at 6 months was noted in 9.8% children treated orally versus 7.2% of children treated intravenously, and 3) mean extent of scarring was approximately 8% in both treatment groups. Mean costs were at least twofold higher for children treated intravenously ($3577 vs $1473) compared with those treated orally.\n Oral cefixime can be recommended as a safe and effective treatment for children with fever and urinary tract infection. Use of cefixime will result in substantial reductions of health care expenditures.", "Acute pyelonephritis often leaves children with permanent renal scarring.\n To compare the prevalence of scarring following initial treatment with antibiotics administered intravenously for 10 or three days.\n In a prospective two centre trial, 220 patients aged 3 months to 16 years with positive urine culture and acute renal lesions on initial DMSA scintigraphy, were randomly assigned to receive intravenous ceftriaxone (50 mg/kg once daily) for 10 or three days, followed by oral cefixime (4 mg/kg twice daily) to complete a 15 day course. After three months, scintigraphy was repeated in order to diagnose renal scars.\n Renal scarring developed in 33% of the 110 children in the 10 day intravenous group and 36% of the 110 children in the three day group. Children older than 1 year had more renal scarring than infants (42% (54/129) and 24% (22/91), respectively). After adjustment for age, sex, duration of fever before treatment, degree of inflammation, presence of vesicoureteric reflux, and the patients' recruitment centres, there was no significant difference between the two treatments on renal scarring. During follow up, 15 children had recurrence of urinary infection with no significant difference between the two treatment groups.\n In children with acute pyelonephritis, initial intravenous treatment for 10 days, compared with three days, does not significantly reduce the development of renal scarring.", "We compared the rates of febrile urinary tract infection, kidney damage and reflux resolution in children with vesicoureteral reflux treated in 3 ways, including antibiotic prophylaxis, endoscopic therapy and surveillance with antibiotics only for symptomatic urinary tract infection.\n Children 1 to younger than 2 years with grade III-IV reflux were recruited into this prospective, open, randomized, controlled, multicenter study and followed for 2 years after randomization. The main study end points were recurrent febrile urinary tract infection, renal status on dimercapto-succinic acid scintigraphy and reflux status. Outcomes were analyzed by the intent to treat principle.\n During a 6-year period 128 girls and 75 boys entered the study. In 96% of cases reflux was detected after urinary tract infection. The randomization procedure was successful and resulted in 3 groups matched for relevant factors. Recruitment was slower than anticipated but after patients were entered adherence to the protocol was good. Of the children 93% were followed for the intended 2 years without a treatment arm change. All except 2 patients completed 2-year followup scintigraphy.\n Recruitment was difficult but a substantial number of children were entered and randomly assigned to 3 groups with similar basic characteristics. Good adherence to the protocol made it possible to address the central study questions.\n Copyright (c) 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.", "The aim of study is to evaluate the results of endoscopic treatment of vesicoureteric reflux (VUR) comparing with conservative mode.\n In the years 2003-2006 there were forty for children in prospective randomised study enrolled and divided into two groups. Twenty two children 1-40 months old (22.9 months) were operated. Dx/Ha (Deflux) was instilled for VUR grade 3-5. The results of treatment were compared with outcome of twenty two conservatively treated randomly assigned children aged 1-32 months (mean age 13.5 months) Postoperative videourodynamic study was used to evaluate for the presence of VUR and function of the bladder and ultrasound investigation was performed too (exclusion of obstructive megaureter in operated group). There were 22 children controled after instillation. The children were followed 11-24 months. VUR was cured in 12 cases (54.5%) and improved (grade 1-2) in 5 children (66.7%). All children absolved treatment without any complications, excluding one case with obstructive megaureter after pyelonephritis diagnosed. There were 22 children evaluated in conservative group. Five children were cured (22.7%) and VUR was improved (grade 1-2) in four (18.2%)\n Endoscopic miniinvasive instillation of dextranomer is safe and effective treatment of VUR in all age groups with good therapeutical outcome and minimum of adverse effects.", "Because there is no evidence for the effectiveness of antibiotic prophylaxis in children with neurogenic bladder, the value of once-daily nitrofurantoin macrocrystals was assessed in a selected population with neurogenic bladder due to meningomyelocele. METHODS AND TRIAL POPULATION: Children with significant urinary tract abnormalities other than neurogenic bladder were excluded. A urinary tract \"infection\" was defined as > or = 10(8) colony forming units of bacteria/L of urine together with pyuria of > or = 50 x 10(6) leukocytes/L, and/or symptoms consistent with an urinary tract infection. Fifty-six children participated in a 24-week double-blinded, placebo-controlled cross-over study. The infection status was assessed at two weekly intervals or if relevant clinical manifestations occurred.\n For the whole trial the average percentage of \"infections\" per urine sample for each patient was reduced from 39% on placebo to 19% on single daily dose prophylaxis (P < .0003). For the first 12 weeks of the trial corresponding figures were 45% on placebo and 22% on prophylaxis (P < .0018). There was evidence for a marked carryover protective effect of nitrofurantoin into the placebo arm of the trial.\n Nitrofurantoin is an effective prophylactic agent during a 3-month period. Long-term studies are needed to confirm the reasonable expectation of a beneficial effect on urinary tract damage.", "Fosfomycin trometamol (FT), an antibiotic active against the common urinary pathogens, may be demonstrated in adequate urine concentrations up to 36-48 h after a single oral dose of 1-2 g. This pharmacokinetic peculiarity seems to indicate that this antibiotic may be used in single doses in the therapy of lower urinary tract infections (UTIs) in infants and children. The efficacy and safety of FT in single oral doses was compared with those of netilmicin (NM), an aminoglycoside antibiotic with a demonstrated efficacy in bolus doses against UTIs, shown in a multicentric study. One hundred and thirty-five children with lower UTI, diagnosed on the basis of fever (less than 38 degrees C), erythrocyte sedimentation rate (less than 25 mm/l h) and C-reactive protein (less than 20 micrograms/ml), were included in the study: 71 received 2 g of FT, 64 5 mg/kg of NM. Cure, defined as persistence of sterile urine up to 30 days after therapy, was reached in 80.2% of children in the FT group and in 81.2% of children in the NM group. Persistence of infection was demonstrated in 7 and in 3 children, respectively. Recurrence of infection was noticed in 7 patients in the FT group and in 9 in the NM group. No differences between FT- and NM-treated children are demonstrable even if the patient population is analyzed according to the higher risk of UTI because of the presence of an anatomical and/or functional abnormality of the urinary tract or due to a previous tendency to recurrent UTIs. FT is as effective as NM in the treatment of lower UTIs in infants and children.", "235 infants and children were randomized to a 10-day and 42-day treatment group and followed-up for 12 months after their first urinary tract infection. The anatomical level of each symptomatic infection was determined using simple laboratory criteria. The two regimens prescribed were equally effective in eradicating the infection, but after the discontinuation of the 10-day treatment with sulfafurazole, 17 (23%) of 73 patients with their upper urinary tract infection experienced a recurrence within one month, as compared to only one (1) of 76 subjects in the 42-day therapy group. After the phase of early recurrence, there was no difference in recurrence rate between these groups. The early recurrences were associated with the patient's early age and a short duration of symptoms before therapy. The recurrence rate of first lower UTI after 10-day therapy was significantly lower than that after 42-day treatment. The duration of antimicrobial therapy for childhood urinary tract infection should be adjusted according to the patient's age and the anatomical level of the infection. 10-day treatment may not be sufficient to prevent early recurrence of pyelonephritic infections in infants under 6 months of age.", "Urinary tract infections are quite frequent in children. Urinary tract obstruction combined with recurrent urinary tract infections increase the risk for renal impairment. Therefore prophylaxis of reinfection is an important nephroprotective procedure. The aim of this open, controlled, randomised pilot study was to compare the efficacy and tolerance of a low dose prophylaxis with Cefixime versus Nitrofurantoin. 60 girls aged 1 to 11 years with at least 2 urinary tract infections within the preceding year were included in the study. The minimum duration of therapy was 6 months and was extended to 12 months for most of the children. The number of recurrent infections was the main criteria for efficacy evaluation, whereas adverse events were analysed to evaluate tolerance. Statistical significant differences between the two treatment groups, regarding recurrence rates could not be demonstrated. Tolerance was comparable in both groups. The influence on gut flora of cefixime given as a low dose regimen over a long period of time corresponds with already published results and was not correlated with a higher number of gastrointestinal side effects.\n Low-dose Cefixime (2 mg/kg bodyweight) is effective and well tolerated in the prophylaxis of recurrent urinary tract infections. Efficacy and tolerance of cefixime were comparable to the results obtained with nitrofurantoin. Due to the small number of patients this study was only a pilot study. Low-dose cefixime, however, could become an alternative to standard regimens in the prophylaxis of recurrent urinary tract infections. This should be investigated in further studies." ]	Compared with no treatment, use of long-term, low-dose antibiotics did not significantly reduce the number of repeat symptomatic and febrile UTIs in children with VUR. Considerable heterogeneity in the analyses and inclusion of only one adequately blinded study, made drawing firm conclusions challenging. Antibiotic prophylaxis significantly reduced the risk of developing new or progressive renal damage, but assuming an 8% baseline risk, 33 children would need long-term antibiotic prophylaxis to prevent one more child developing kidney damage over the course of two to three years. The added benefit of surgical or endoscopic correction of VUR over antibiotic treatment alone remains unclear. Eight children would require combined surgical and antibiotic treatment to prevent one additional child developing febrile UTI by five years, but it would not cause fewer children developing renal damage.
CD007952	[ "14974750", "11165450", "9585747", "10198656", "8546549", "12631309", "11996616", "9626609", "19858174", "10724056", "12971668" ]	[ "Can the poor adhere? Incentives for adherence to TB prevention in homeless adults.", "Incentives vs outreach workers for latent tuberculosis treatment in drug users.", "Tuberculosis screening and compliance with return for skin test reading among active drug users.", "Monetary versus nonmonetary incentives for TB skin test reading among drug users.", "Tuberculosis prophylaxis in the homeless. A trial to improve adherence to referral.", "Evaluation of efficacy of community-based vs. institutional-based direct observed short-course treatment for the control of tuberculosis in Kilombero district, Tanzania.", "Randomized controlled trial of interventions to improve follow-up for latent tuberculosis infection after release from jail.", "A clinical trial of a financial incentive to go to the tuberculosis clinic for isoniazid after release from jail.", "Food incentives to improve completion of tuberculosis treatment: randomised controlled trial in Dili, Timor-Leste.", "Adherence to isoniazid prophylaxis in the homeless: a randomized controlled trial.", "A randomised controlled clinical trial of the efficacy of family-based direct observation of anti-tuberculosis treatment in an urban, developed-country setting." ]	[ "Community-based population of homeless adults living in San Francisco, California.\n To compare the effect of cash and non-cash incentives on 1) adherence to treatment for latent tuberculosis infection, and 2) length of time needed to look for participants who missed their dose of medications.\n Prospective, randomized clinical trial comparing a 5 dollar cash or a 5 dollar non-cash incentive. All participants received directly observed preventive therapy and standardized follow-up per a predetermined protocol. Completion rates and amount of time needed to follow up participants was measured.\n Of the 119 participants, 102 (86%) completed therapy. There was no difference between the cash and non-cash arms. Completion was significantly higher among males (OR 5.65, 95%CI 1.36-23.40, P = 0.02) and persons in stable housing at study entry (OR 4.86, 95%CI 1.32-17.94, P = 0.02). No substance use or mental health measures were associated with completion. Participants in the cash arm needed significantly less follow-up to complete therapy compared to the non-cash arm (P = 0.03). In multivariate analysis, non-cash incentive, use of crack cocaine, and no prior preventive therapy were associated with more follow-up time.\n Simple, low cost incentives can be used to improve adherence to TB preventive therapy in indigent adults.", "Drug users are at increased risk for latent tuberculosis infection (LTBI) and also at increased risk for noncompletion of medication regimens for treatment of LTBI or tuberculosis disease. Directly observed therapy (DOT) provided by outreach workers, the use of incentives, or both have been suggested as a means to increase adherence.\n To compare the independent and combined effects of monetary incentives and outreach worker provision of DOT for LTBI treatment in a sample of active drug users.\n The research design was a randomized controlled trial in a community outreach program setting. Participants consisted of a volunteer sample of 163 active injection drug and crack cocaine users placed on twice weekly DOT. Condition 1 of the interventions consisted of provision of DOT by an outreach worker at a location chosen by the participant (active outreach) and a $5 per visit incentive. Condition 2 was comprised of active outreach with no monetary incentive, and Condition 3, provision of DOT at the study community site and a $5 per visit incentive. The main outcome measures were percentage of medication taken as prescribed and completion of medication regimen.\n The percentage of prescribed medication taken was higher for those who received incentives, either with (71%) or without (68%) active outreach, compared to those who received active outreach alone (13%). Only 4% of participants assigned to Condition 2 completed treatment, compared to 53% of Condition 1 participants, and 60% of Condition 3 participants.\n Monetary incentives were clearly superior to active outreach. Active outreach in combination with monetary incentives did not increase adherence over incentives alone.", "This study assessed the independent and combined effects of different levels of monetary incentives and a theory-based educational intervention on return for tuberculosis (TB) skin test reading in a sample of active injection drug and crack cocaine users. Prevalence of TB infection in this sample was also determined.\n Active or recent drug users (n = 1004), recruited via street outreach techniques, were skin tested for TB. They were randomly assigned to 1 of 2 levels of monetary incentive ($5 and $10) provided at return for skin test reading, alone or in combination with a brief motivational education session.\n More than 90% of those who received $10 returned for skin test reading, in comparison with 85% of those who received $5 and 33% of those who received no monetary incentive. The education session had no impact on return for skin test reading. The prevalence of a positive tuberculin test was 18.3%.\n Monetary incentives dramatically increase the return rate for TB skin test reading among drug users who are at high risk of TB infection.", "In a prior study, we reported that monetary incentives were effective in increasing return for tuberculosis (TB) skin test reading. The purpose of this study was to compare the effects of monetary versus nonmonetary incentives and a theory-based educational intervention on return for TB skin test reading in a sample of newly recruited active injection and crack cocaine users, and to determine the prevalence of TB infection in this sample.\n Active injection drug and/or crack cocaine users (n = 1,078), recruited using street outreach techniques, were skin tested for TB. They were randomly assigned to 1 of 5 experimental treatment conditions: $10 cash, grocery store coupons, bus tokens/fast-food coupons, motivational education, or usual encouragement to return. Nonmonetary incentives had a $10 value, and all incentives were provided at return for skin test reading.\n Ninety-five percent of those who received $10 returned for skin test reading compared to 86% of those who received grocery store coupons and 83% of those who received either bus tokens or fast-food coupons. In contrast, only 47% of those who received the educational session and only 49% of those who received usual encouragement returned for skin test reading. The prevalence of a positive tuberculin test was 21%, and was similar for crack cocaine and injection drug users.\n Nonmonetary and monetary incentives dramatically increased the return rate for TB skin test reading among drug users who are at high risk of TB infection. Nonmonetary incentives were somewhat less effective than monetary incentives.", "Adherence to tuberculosis evaluation is poor in a high-risk population such as the homeless.\n To test two interventions aimed at improving adherence to tuberculosis evaluation and to identify predictors of adherence.\n We conducted a randomized clinical trial in shelters and food lines in the inner city of San Francisco, Calif. We randomized 244 eligible subjects infected with tuberculosis to (1) peer health adviser (assistance by a peer [n = 83]), (2) monetary incentive ($5 payment [n = 82]), or (3) usual care (referral slips and bus tokens only [n = 79]). The primary outcome of the study was adherence to a first follow-up appointment at the tuberculosis clinic, where subjects were evaluated for active tuberculosis and the need for isoniazid prophylaxis.\n Of the subjects assigned to a monetary incentive, 69 (84%) completed their first follow-up appointment, compared with 62 subjects (75%) assigned to a peer health adviser and 42 subjects (53%) assigned to usual care. Adherence was higher in the monetary incentive and peer health adviser groups than in the usual care group (P < .001 and P = .004, respectively). Patients not using intravenous drugs and patients 50 years of age or older were more likely to adhere to a first follow-up appointment (odds ratios [95% confidence intervals], 2.5 [1.3 to 5.0] and 3.3 [1.2 to 8.8], respectively). Among the 173 tuberculosis-infected subjects who completed their appointment, isoniazid therapy was started for 72 individuals, and three cases of active tuberculosis were identified.\n A monetary incentive or a peer health adviser is effective in improving adherence to a first follow-up appointment in homeless individuals infected with tuberculosis. A monetary incentive appears to be superior. Intravenous drug users and young individuals are at high risk for poor adherence to referral.", "Tuberculosis (TB) has reappeared as a serious public health problem. Non-compliance to antituber-culous drug treatment is cited as one of the major obstacles to the containment of the epidemic. Compliance may be optimized by Directly Observed Treatment (DOT) and short-course treatment regimens. Since 1986, Tanzanian TB patients have received daily DOT at health facilities for the first 2 months of the treatment course. However, adherence and cure rates have been falling as the number of TB cases continues to increase and the burden on already stretched health facilities threatens to become unmanageable. We used an open cluster randomized controlled trial to compare community-based DOT (CBDOT) using a short-course drug regimen with institutional-based DOT (IBDOT). A total of 522 (301 IBDOT and 221 CBDOT) patients with sputum-positive TB were recruited. Overall, there was no significant difference in conversion and cure rates between the two strategies [M-H pooled odds ratio (OR) 0.62; 95% confidence interval (CI) 0.23, 1.71 and OR = 1.58; 95% CI 0.32, 7.88, respectively] suggesting that CBDOT may be a viable alternative to IBDOT. CBDOT may be particularly useful in parts of the country where people live far from health facilities.", "Adherence to treatment of persons with latent tuberculosis infection after release from jail has been poor.\n A randomized controlled trial was conducted at the San Francisco City and County Jail, San Francisco, Calif. Subjects undergoing therapy for latent tuberculosis infection who spoke either English or Spanish were randomly allocated to receive education every 2 weeks while in jail; an incentive if they went to the San Francisco County Tuberculosis Clinic within 1 month of release; or usual care. The main outcome measures were completion of a visit to the tuberculosis clinic within 1 month of release and completion of therapy.\n Of 558 inmates enrolled, 325 were released before completion of therapy. Subjects in either intervention group were significantly more likely to complete a first visit than were control subjects (education group, 37%; incentive group, 37%; and controls, 24%) (adjusted odds ratio based on pooled results for the education and incentive groups, 1.85; 95% confidence interval, 1.04-3.28; P =.02). Those in the education group were twice as likely to complete therapy compared with controls (adjusted odds ratio, 2.2; 95% confidence interval, 1.04-4.72; P =.04). Of those who went to the tuberculosis clinic after release, subjects in the education group were more likely to complete therapy (education group, 65% [24/37]; incentive group, 33% [14/42]; and control group, 48% [12/25]; P =.02).\n Education or the promise of an incentive improved initial follow-up. Education was superior to an incentive for the completion of therapy. Fairly modest strategies provided in jail can improve adherence. Further links between jail health services and community care should be explored.", "Screening for active tuberculosis (TB) and providing isoniazid (INH) preventive therapy in jails are important control measures. In San Francisco, however, historical data showed that 62% of inmates were released before completing preventive therapy, and of those only 3% attended the TB Clinic for follow-up.\n A randomized clinical trial to compare a $5 cash incentive plus standardized TB education with standardized TB education alone in encouraging released inmates to make a first visit to the clinic.\n Of 79 persons enrolled in the trial, 77.2% were released before INH completion. Rates of first visit were not significantly different for those receiving +5 plus standardized education (25.8%) versus standardized education alone (23.3%), but were higher than rates seen in historical data for inmates not receiving standardized education. Age was an important predictor of completion of a first visit (odds ratio 1.09, 95% confidence interval 1.02-1.16, P = 0.017). Other variables predicting adherence included intent to adhere, more previous time in jail, stable housing, and being partnered versus alone, although these were not statistically significant.\n Standardized education may be important in improving follow-up after release. Further work on the role of a financial incentive in this population is needed.", "To determine the effectiveness of the provision of whole food to enhance completion of treatment for tuberculosis.\n Parallel group randomised controlled trial.\n Three primary care clinics in Dili, Timor-Leste.\n 270 adults aged >or=18 with previously untreated newly diagnosed pulmonary tuberculosis.\n Completion of treatment (including cure). Secondary outcomes included adherence to treatment, weight gain, and clearance of sputum smears. Outcomes were assessed remotely, blinded to allocation status. Interventions Participants started standard tuberculosis treatment and were randomly assigned to intervention (nutritious, culturally appropriate daily meal (weeks 1-8) and food package (weeks 9-32) (n=137) or control (nutritional advice, n=133) groups. Randomisation sequence was computer generated with allocation concealment by sequentially numbered, opaque, sealed envelopes.\n Most patients with tuberculosis were poor, malnourished men living close to the clinics; 265/270 (98%) contributed to the analysis. The intervention had no significant beneficial or harmful impact on the outcome of treatment (76% v 78% completion, P=0.7) or adherence (93% for both groups, P=0.7) but did lead to improved weight gain at the end of treatment (10.1% v 7.5% improvement, P=0.04). Itch was more common in the intervention group (21% v 9%, P<0.01). In a subgroup analysis of patients with positive results on sputum smears, there were clinically important improvements in one month sputum clearance (85% v 67%, P=0.13) and completion of treatment (78% v 68%, P=0.3).\n Provision of food did not improve outcomes with tuberculosis treatment in these patients in Timor-Leste. Further studies in different settings and measuring different outcomes are required.\n Clinical Trials NCT0019256.", "To test 2 interventions to improve adherence to isoniazid preventive therapy for tuberculosis in homeless adults. We compared (1) biweekly directly observed preventive therapy using a $5 monetary incentive and (2) biweekly directly observed preventive therapy using a peer health adviser, with (3) usual care at the tuberculosis clinic.\n Randomized controlled trial in tuberculosis-infected homeless adults. Outcomes were completion of 6 months of isoniazid treatment and number of months of isoniazid dispensed.\n A total of 118 subjects were randomized to the 3 arms of the study. Completion in the monetary incentive arm was significantly better than in the peer health adviser arm (P = .01) and the usual care arm (P = .04), by log-rank test. Overall, 19 subjects (44%) in the monetary incentive arm completed preventive therapy compared with 7 (19%) in the peer health adviser arm (P = .02) and 10 (26%) in the usual care arm (P = .11). The median number of months of isoniazid dispensed was 5 in the monetary incentive arm vs 2 months in the peer health adviser arm (P = .005) and 2 months in the usual care arm (P = .04). In multivariate analysis, independent predictors of completion were being in the monetary incentive arm (odds ratio, 2.57; 95% CI, 1.11-5.94) and residence in a hotel or other stable housing at entry into the study vs residence on the street or in a shelter at entry (odds ratio, 2.33; 95% CI, 1.00-5.47).\n A $5 biweekly cash incentive improved adherence to tuberculosis preventive therapy compared with a peer intervention or usual care. Living in a hotel or apartment at the start of treatment also predicted the completion of therapy.", "A randomised, controlled clinical trial of the effectiveness of a family-based programme of directly observed treatment (DOT) for tuberculosis.\n TB patients seen in Victoria, Australia, were randomly allocated to DOT observed by a family member (FDOT), or to standard supervised but non-observed therapy (ST). The outcome measure was compliance, measured by blinded testing of isoniazid levels in urine. An intention-to-treat analysis was used.\n Of 173 patients, 87 were allocated to FDOT and 86 to ST. Only 58% in the FDOT group were able to receive FDOT, the major reason being living alone and not having a family member to observe treatment. The rate of non-compliance was 24% (41/173), with no significant difference between FDOT (22/87) and ST (19/86). No clinical or socio-demographic variable predicted compliance.\n We were unable to demonstrate a benefit of FDOT in an urban, industrialised country setting. FDOT may be more appropriate in developing countries, where extended family support is often available and the burden of TB is much higher. Poor compliance and the difficulty in predicting non-compliance shown in this study highlights the need for DOT for all TB patients." ]	There is limited evidence to support the use of material incentives to improve return rates for tuberculosis diagnostic test results and adherence to antituberculosis preventive therapy. The data are currently limited to trials among predominantly male drug users, homeless, and prisoner subpopulations in the USA, and therefore the results are not easily generalised to the wider adult population, or to low- and middle-income countries, where the tuberculosis burden is highest. Further high-quality studies are needed to assess both the costs and effectiveness of incentives to improve adherence to long-term treatment of tuberculosis.
CD004094	[ "11837755", "15127325", "15613431", "11887193", "12684359", "10678259", "11220522", "11874427", "9918478", "11191537", "14693982", "11407998", "15531005", "17098084", "11840224", "10693734", "10440592", "12941710", "15378354", "16291982", "9702435", "15863798", "10904462", "16847290", "9683204", "16524859", "11220553", "10230747", "15287931" ]	[ "Clinical evaluation of sibutramine in obese type 2 diabetic patients refractory to dietary management.", "Weight reduction by sibutramine in obese subjects in primary care medicine: the SAT Study.", "Treatment of obese adolescents with sibutramine: a randomized, double-blind, controlled study.", "Effects of sibutramine on the treatment of obesity in patients with arterial hypertension.", "Behavior therapy and sibutramine for the treatment of adolescent obesity: a randomized controlled trial.", "Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with orlistat for obesity. European Orlistat Obesity Study Group.", "Sibutramine is effective for weight loss and diabetic control in obesity with type 2 diabetes: a randomised, double-blind, placebo-controlled study.", "Role of sibutramine in the treatment of obese Type 2 diabetic patients receiving sulphonylurea therapy.", "Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial.", "Effect of sibutramine on weight maintenance after weight loss: a randomised trial. STORM Study Group. Sibutramine Trial of Obesity Reduction and Maintenance.", "XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients.", "Randomized placebo-controlled trial of long-term treatment with sibutramine in mild to moderate obesity.", "Use of sibutramine in overweight adult hispanic patients with type 2 diabetes mellitus: a 12-month, randomized, double-blind, placebo-controlled clinical trial.", "Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study.", "Sibutramine is safe and effective for weight loss in obese patients whose hypertension is well controlled with angiotensin-converting enzyme inhibitors.", "Orlistat in the long-term treatment of obesity in primary care settings.", "Absence of cardiac valve dysfunction in obese patients treated with sibutramine.", "One-year outcome of a combination of weight loss therapies for subjects with type 2 diabetes: a randomized trial.", "Addition of orlistat to conventional treatment in adolescents with severe obesity.", "Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia.", "Role of orlistat in the treatment of obese patients with type 2 diabetes. A 1-year randomized double-blind study.", "A double-blind, placebo-controlled trial of sibutramine for olanzapine-associated weight gain.", "Efficacy and safety of sibutramine in obese white and African American patients with hypertension: a 1-year, double-blind, placebo-controlled, multicenter trial.", "Effects of sibutramine treatment in obese adolescents: a randomized trial.", "Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group.", "Randomized, double-blind, placebo-controlled trial of orlistat for weight loss in adolescents.", "Weight loss with sibutramine improves glycaemic control and other metabolic parameters in obese patients with type 2 diabetes mellitus.", "Long-term maintenance of weight loss after a very-low-calorie diet: a randomized blinded trial of the efficacy and tolerability of sibutramine.", "Effects of orlistat on obesity-related diseases - a six-month randomized trial." ]	[ "An open, non-comparative study was carried out to assess the efficacy and toleration profile of sibutramine, a new antiobesity drug, in promoting weight loss in obese type 2 diabetes mellitus subject who failed to reduce weight after strict dietary control. Twenty seven patients completed the study. Sibutramine was started as a single morning dose of 10 mg and was subsequently increased to 15 mg daily if weight loss was not satisfactory. The total duration of the study was twelve weeks with followup at every four weeks. Effect of drug was monitored in terms of weight reduction, changes in body mass index, waist circumference, hip circumference, waist/hip ratio and other metabolic parameters. A fixed dietary prescription and concomitant therapy with drugs, if required and not likely to interfere with the trial therapy, was permitted but was not changed during the study period.\n At the end of 12 week, mean weight reduction in study subjects was 4.16 kg (p < 0.001), the corresponding BMI decreased by 1.6 (p < 0.0001) and hip circumference by 3.68 (p < 0.001). However, there was no significant change in fasting blood glucose and Hb(A1c) values.\n The study indicates sibutramine to be an effective and well tolerated agent leading to significant reduction in parameter of obesity in obese type 2 diabetic subjects.", "Sibutramine is a selective serotonin and noradrenaline reuptake inhibitor that is known to reduce body weight. The efficacy of this drug in primary care medicine is currently unknown.\n To study, in a primary healthcare setting, the effect of a standardized non-pharmacological treatment program and 15 mg sibutramine or placebo on long-term weight reduction in obese subjects with a body mass index >or= 30 and < 40 kg/m(2).\n A multicentre, double-blind, placebo-controlled, randomized, parallel group comparison over 54 weeks of continuous therapy.\n 33 general practitioners in Germany.\n 389 obese patients were recruited of whom 362 were randomized.\n Primary measure was weight reduction at week 54; others included reduction in BMI, waist circumference, waist-hip ratio, blood pressure and blood lipids.\n 348 obese subjects were analyzed using an intention-to-treat analysis. Mean weight loss in the sibutramine (S) group was 8.1 +/- 8.2 kg vs. 5.1 +/- 6.5 kg in the placebo (P) group (p < 0.001; Intent-to-treat analysis). More subjects lost more than 5 % and 10 % of initial weight with sibutramine than with placebo (5 %, S: 62.6 %, P: 41.4 %, p < 0.001; 10 %, S: 40.8, P: 19.0 %, p < 0.001). Weight loss was accompanied by an improvement in the lipid profile, in particular, an increase in HDL-cholesterol and a decrease in fasting triglycerides. In both groups, systolic and diastolic blood pressure decreased in those with moderate hypertension and remained unchanged in those with normal blood pressure at baseline. There was a modest increase in heart rate in S (1.9 beats/min) vs. P (- 0.9 beats/min) (p < 0.05).\n Under primary care conditions, sibutramine 15 mg daily proved to be a safe and effective drug for additional weight loss in obese subjects undergoing a comprehensive weight reduction program.", "Adolescent obesity is becoming a health problem in both developed and developing countries. Antiobesity drug therapy is not currently indicated for the treatment of adolescent obesity and remains investigational at this time. The aim of this study was to determine the efficacy and safety of sibutramine in obese adolescents. A randomized, double-blind, placebo-controlled trial, enrolling 60 adolescents, aged 14-17 yr, for 6 months was conducted. In the first month, all patients received placebo and a hypocaloric diet plus exercise orientation. For the next 6 months, participants received either sibutramine or placebo. Patients assigned to sibutramine group lost an average of 10.3 +/- 6.6 kg, and patients in placebo group lost 2.4 +/- 2.5 kg (P < 0.001). The mean body mass index reduction was significantly greater in the sibutramine group (3.6 +/- 2.5 kg/m(2)) than in the placebo group (0.9 +/- 0.9 kg/m(2); P < 0.001). No participant withdrew because of adverse events, and no difference in blood pressure or heart rate was noted between groups. There were no changes in echocardiographic parameters. In conclusion, sibutramine plus diet and exercise induced significantly more weight loss in obese adolescents.", "To assess the effects of weight reduction with 10mg of sibutramine or placebo on blood pressure during 24 hours (ambulatory blood pressure monitoring), on left ventricular mass, and on antihypertensive therapy in 86 obese and hypertensive patients for 6 months.\n The patients underwent echocardiography, ambulatory blood pressure monitoring, and measurement of the levels of hepatic enzymes prior to and after treatment with sibutramine or placebo.\n The group using sibutramine had a greater weight loss than that using placebo (6.7% versus 2.5%; p<0.001), an increase in heart rate (78.3 +/- 7.3 to 82 +/- 7.9 bpm; p=0.02), and a reduction in the left ventricular mass/height index (105 +/- 29.3 versus 96.6 +/- 28.58 g/m; p=0.002). Both groups showed similar increases in the levels of alkaline phosphatase and comparable adjustments in antihypertensive therapy; blood pressure, however, did not change.\n The use of sibutramine caused weight loss and a reduction in left ventricular mass in obese and hypertensive patients with no interference with blood pressure or with antihypertensive therapy.", "Adolescent obesity is becoming a national public health problem. Weight-loss medications including sibutramine facilitate weight control in adults and could be used with obese adolescents in combination with behavior therapy (BT).\n To examine whether increased weight loss in obese adolescents is induced when sibutramine is added to a family-based, behavioral weight control program.\n Randomized, double-blind, placebo-controlled trial consisting of 82 adolescents aged 13 to 17 years with a body mass index (BMI) of 32 to 44 conducted from March 1999 to August 2002 at a university-based clinic for 6 months, followed by open-label treatment during months 7 to 12.\n For the first 6 months, participants received either BT and sibutramine or BT and placebo. From months 7 to 12, all participants received sibutramine in open-label treatment.\n Percentage change in BMI; systolic and diastolic blood pressure and pulse; and hunger.\n In intention-to-treat analysis at month 6, participants in the BT and sibutramine group lost a mean (SD) of 7.8 kg (6.3 kg) and had an 8.5% (6.8%) reduction in BMI, which was significantly more than weight loss of 3.2 kg (6.1 kg) and reduction in BMI of 4.0% (5.4%) in the BT and placebo group. Significantly greater reductions in hunger (P =.002) also were reported by participants who received BT and sibutramine. From months 7 to 12, adolescents initially treated with sibutramine gained 0.8 kg (10.5 kg) with continued use of the medication, whereas those who switched from placebo to sibutramine lost an additional 1.3 kg (5.4 kg). Medication dose was reduced (n = 23) or discontinued (n = 10) to manage increases in blood pressure, pulse rate, or other symptoms.\n The addition of sibutramine to a comprehensive behavioral program induced significantly more weight loss than did BT and placebo. Until more extensive safety and efficacy data are available, medications for weight loss should be used only on an experimental basis in adolescents and children.", "To determine the effect of orlistat, a new lipase inhibitor, on long-term weight loss, to determine the extent to which orlistat treatment minimizes weight regain in a second year of treatment, and to assess the effects of orlistat on obesity-related risk factors.\n This was a 2-year, multicenter, randomized, double-blind, placebo-controlled study. Obese patients (body mass index 28 to 43 kg/m2) were randomized to placebo or orlistat (60 or 120 mg) three times a day, combined with a hypocaloric diet during the first year and a weight maintenance diet in the second year of treatment to prevent weight regain. Changes in body weight, lipid profile, glycemic control, blood pressure, quality of life, safety, and tolerability were measured.\n Orlistat-treated patients lost significantly more weight (p<0.001) than placebo-treated patients after Year 1 (6.6%, 8.6%, and 9.7% for the placebo, and orlistat 60 mg and 120 mg groups, respectively). During the second year, orlistat therapy produced less weight regain than placebo (p = 0.005 for orlistat 60 mg; p<0.001 for orlistat 120 mg). Several obesity-related risk factors improved significantly more with orlistat treatment than with placebo. Orlistat was generally well tolerated and only 6% of orlistat-treated patients withdrew because of adverse events. Orlistat leads to predictable gastrointestinal effects related to its mode of action, which were generally mild, transient, and self-limiting and usually occurred early during treatment.\n Orlistat administered for 2 years promotes weight loss and minimizes weight regain. Additionally, orlistat therapy improves lipid profile, blood pressure, and quality of life.", "To assess the efficacy and tolerability of sibutramine 15 mg once daily as a weight reduction agent in overweight and obese patients (body mass index (b.m.i.) > 26 kg/m2) with type 2 diabetes when given with a customised, reduced-calorie diet, and to evaluate the influence of weight loss on diabetic control.\n Randomised, placebo-controlled, double-blind, parallel-group, 12-week study conducted at two hospital-based obesity/diabetes clinics. Patients were men and women aged 30-65 years, with b.m.i. > 26 kg/m2 and < or = 35 kg/m2 and treated or untreated type 2 diabetes diagnosed > or = 6 months previously. Each patient was given sibutramine 15 mg or placebo once daily and advised to follow a customised diet of 500 kcal/day less than the individual's energy needs. The principal measure of efficacy was change in body weight (b.w.). Additional efficacy measurements were changes in b.m.i., body composition as measured by dual-energy X-ray absorptiometry, and change in waist and hip measurements. Changes in diabetic control were assessed by blood glucose levels fasting and after a standard test meal, fasting insulin level, and glycosylated haemoglobin level. Adverse events (AEs) were monitored at each visit, and routine laboratory safety tests were done at 4-week intervals.\n Ninety-one patients were randomised into the study, 44 to placebo and 47 to sibutramine 15 mg once daily. Eighty-three patients (91%) completed the study, 40 (91%) on placebo and 43 (91%) on sibutramine. Mean weight reduction from baseline was statistically significantly greater with sibutramine than with placebo at every measurement and at the end of the study (2.4 vs. 0.1 kg at week 12; p < 0.001; intent-to-treat). The proportion of patients who lost > 5% of their baseline b.w. was 19% in the sibutramine group and 0% in the placebo group (p < 0.001; 95% confidence interval: 9, 30). Patients receiving sibutramine lost significantly more fat mass compared with those receiving placebo, as a percentage (1.0% vs. 0.1%; p < 0.05) and in absolute terms (1.8 vs. 0.2 kg, p < 0.001). Loss of lean mass was not significantly different between the groups. Mean peak blood glucose concentration after a standard test meal decreased by 1.1 mmol/l in the sibutramine treatment group but increased by 0.5 mmol/l in the placebo group (p = 0.04; difference in means, 1.6, 95% confidence interval: -3.3, -0.1). Mean fasting blood glucose decreased by 0.3 mmol/l with sibutramine and increased by 1.4 mmol/l with placebo. Mean glycosylated haemoglobin levels decreased by 0.3% units with sibutramine treatment, and were unchanged with placebo. However, more sibutramine-treated patients (33%) than placebo-treated patients (5%) achieved decreases in glycosylated haemoglobin of 1% unit or more (p < 0.05). Sibutramine 15 mg was safe and well tolerated, and AEs were mostly mild or moderate in severity. No significant differences were found between treatment groups in blood pressure. No clinically significant conduction or rhythm abnormalities were observed on ECG.\n Sibutramine 15 mg once daily with a customised, reduced-calorie diet significantly reduced weight compared with placebo in overweight and obese patients (b.m.i. > 26 kg/m2) with type 2 diabetes. Sibutramine was well tolerated, and significant improvement in diabetic control was seen in conjunction with weight reduction on sibutramine treatment.", "To investigate whether the satiety-inducing agent sibutramine affected body weight and associated anthropometry in overweight and obese (body mass index (BMI) > 27) Type 2 diabetic patients on sulphonylurea therapy.\n A randomized, placebo-controlled trial was undertaken in 134 patients with stable metabolic control on chronic sulphonylurea therapy. Patients were placed on moderate caloric restriction and received treatment with either sibutramine (15 mg/day) or placebo for 6 months.\n Fifty-three of 69 sibutramine-treated and 57/65 placebo-treated patients completed the study. Both groups showed progressive weight loss. At the end of the trial weight loss was two times greater in the sibutramine group (mean +/- SEM; -4.5 +/- 0.5 kg) than placebo (-1.7 plus minus 0.5 kg, P < 0.001 vs. sibutramine). There was a trend for more patients to lose > 5% of initial body weight in the sibutramine group than placebo. BMI (P < 0.001) and waist circumference (P < 0.001) were also decreased to a greater extent by sibutramine. Mean reductions in HbA(1c) were commensurate with weight loss in both the sibutramine and placebo (- 0.78 +/- 0.17% and -0.73 +/- 0.23%; P = 0.84). Sibutramine was well tolerated with only two patients withdrawn due to potentially drug-related serious adverse events (palpitations).\n Sibutramine, in conjunction with moderate caloric restriction, enhances weight loss and reduces waist circumference in overweight and obese Type 2 diabetic patients receiving sulphonylurea therapy. This is associated with additional improvements in glycaemic control in a limited number of patients losing > or = 10% of their baseline body weight.", "Orlistat, a gastrointestinal lipase inhibitor that reduces dietary fat absorption by approximately 30%, may promote weight loss and reduce cardiovascular risk factors.\n To test the hypothesis that orlistat combined with dietary intervention is more effective than placebo plus diet for weight loss and maintenance over 2 years.\n Randomized, double-blind, placebo-controlled study conducted from October 1992 to October 1995.\n Obese adults (body mass index [weight in kilograms divided by the square of height in meters], 30-43 kg/m2) evaluated at 18 US research centers.\n Subjects received placebo plus a controlled-energy diet during a 4-week lead-in. On study day 1, the diet was continued and subjects were randomized to receive placebo 3 times a day or orlistat, 120 mg 3 times a day, for 52 weeks. After 52 weeks, subjects began a weight-maintenance diet, and the placebo group (n = 133) continued to receive placebo and orlistat-treated subjects were rerandomized to receive placebo 3 times a day (n = 138), orlistat, 60 mg (n = 152) or 120 mg (n = 153) 3 times a day, for an additional 52 weeks.\n Body weight change and changes in blood pressure and serum lipid, glucose, and insulin levels.\n A total of 1187 subjects entered the protocol, and 892 were randomly assigned on day 1 to double-blind treatment. For intent-to-treat analysis, 223 placebo-treated subjects and 657 orlistat-treated subjects were evaluated. During the first year orlistat-treated subjects lost more weight (mean +/- SEM, 8.76+/-0.37 kg) than placebo-treated subjects (5.81+/-0.67 kg) (P<.001). Subjects treated with orlistat, 120 mg 3 times a day, during year 1 and year 2 regained less weight during year 2 (3.2+/-0.45 kg; 35.2% regain) than those who received orlistat, 60 mg (4.26+/-0.57 kg; 51.3% regain), or placebo (5.63+/-0.42 kg; 63.4% regain) in year 2 (P<.001). Treatment with orlistat, 120 mg 3 times a day, was associated with improvements in fasting low-density lipoprotein cholesterol and insulin levels.\n Two-year treatment with orlistat plus diet significantly promotes weight loss, lessens weight regain, and improves some obesity-related disease risk factors.", "Sibutramine is a tertiary amine that has been shown to induce dose-dependent weight loss and to enhance the effects of a low-calorie diet for up to a year. We did a randomised, double-blind trial to assess the usefulness of sibutramine in maintaining substantial weight loss over 2 years.\n Eight European centres recruited 605 obese patients (body-mass index 30-45 kg/m2) for a 6-month period of weight loss with sibutramine (10 mg/day) and an individualised 600 kcal/day deficit programme based on measured resting metabolic rates. 467 (77%) patients with more than 5% weight loss were then randomly assigned 10 mg/day sibutramine (n=352) or placebo (n=115) for a further 18 months. Sibutramine was increased up to 20 mg/day if weight regain occurred. The primary outcome measure was the number of patients at year 2 maintaining at least 80% of the weight lost between baseline and month 6. Secondary outcomes included changes in uric acid concentrations and glycaemic and lipid variables. Analysis was by intention to treat.\n 148 (42%) individuals in the sibutramine group and 58 (50%) in the placebo group dropped out. Of the 204 sibutramine-treated individuals who completed the trial, 89 (43%) maintained 80% or more of their original weight loss, compared with nine (16%) of the 57 individuals in the placebo group (odds ratio 4.64, p<0.001). Patients had substantial decreases over the first 6 months with respect to triglycerides, VLDL cholesterol, insulin, C peptide, and uric acid; these changes were sustained in the sibutramine group but not the placebo group. HDL cholesterol concentrations rose substantially in the second year: overall increases were 20.7% (sibutramine) and 11.7% (placebo, p<0.001). 20 (3%) patients were withdrawn because of increases in blood pressure; in the sibutramine group, systolic blood pressure rose from baseline to 2 years by 0.1 mm Hg (SD 12.9), diastolic blood pressure by 2.3 mm Hg (9.4), and pulse rate by 4.1 beats/min (11.9).\n This individualised management programme achieved weight loss in 77% of obese patients and sustained weight loss in most patients continuing therapy for 2 years. Changes in concentrations of HDL cholesterol, VLDL cholesterol, and triglyceride, but not LDL cholesterol, exceed those expected either from weight loss alone or when induced by other selective therapies for low concentrations of HDL cholesterol relating to coronary heart disease.", "It is well established that the risk of developing type 2 diabetes is closely linked to the presence and duration of overweight and obesity. A reduction in the incidence of type 2 diabetes with lifestyle changes has previously been demonstrated. We hypothesized that adding a weight-reducing agent to lifestyle changes may lead to an even greater decrease in body weight, and thus the incidence of type 2 diabetes, in obese patients.\n In a 4-year, double-blind, prospective study, we randomized 3,305 patients to lifestyle changes plus either orlistat 120 mg or placebo, three times daily. Participants had a BMI >/=30 kg/m2 and normal (79%) or impaired (21%) glucose tolerance (IGT). Primary endpoints were time to onset of type 2 diabetes and change in body weight. Analyses were by intention to treat.\n Of orlistat-treated patients, 52% completed treatment compared with 34% of placebo recipients (P < 0.0001). After 4 years' treatment, the cumulative incidence of diabetes was 9.0% with placebo and 6.2% with orlistat, corresponding to a risk reduction of 37.3% (P = 0.0032). Exploratory analyses indicated that the preventive effect was explained by the difference in subjects with IGT. Mean weight loss after 4 years was significantly greater with orlistat (5.8 vs. 3.0 kg with placebo; P < 0.001) and similar between orlistat recipients with impaired (5.7 kg) or normal glucose tolerance (NGT) (5.8 kg) at baseline. A second analysis in which the baseline weights of subjects who dropped out of the study was carried forward also demonstrated greater weight loss in the orlistat group (3.6 vs. 1.4 kg; P < 0.001).\n Compared with lifestyle changes alone, orlistat plus lifestyle changes resulted in a greater reduction in the incidence of type 2 diabetes over 4 years and produced greater weight loss in a clinically representative obese population. Difference in diabetes incidence was detectable only in the IGT subgroup; weight loss was similar in subjects with IGT or NGT [correction].", "The researchers assessed the long-term weight reduction efficacy, tolerability, and safety of sibutramine used once daily in conjunction with behavior modification to treat mild to moderate obesity.\n This was a double-blind randomized placebo-controlled parallel-group comparative study of sibutramine 10 mg or 15 mg (or placebo) once daily for 1 year, given with dietary advice.\n A total of 485 obese men and women with uncomplicated obesity were included (mean age=42 years, mean body mass index=32.7 kg/m2).\n The outcomes were mean weight loss, percentage losing more than 5% or 10% of their body weight, and adverse drug effects.\n Among patients completing the study, those taking sibutramine 10 mg or 15 mg had greater mean weight loss compared with placebo at 12-month assessment (P < or = .001). Changes in body weight from baseline to end point were -1.6 kg for those taking placebo, -4.4 kg for those taking sibutramine 10 mg (P < or =.01, last observation carried forward [LOCF]), and -6.4 kg for those taking sibutramine 15 mg (P < or =.001, LOCF). For placebo patients, 20% lost 5% or more of their body weight compared with 39% of patients taking sibutramine 10 mg and 57% taking sibutramine 15 mg. Only 7% of the patients taking placebo lost 10% or more of their body weight, compared with 19% taking sibutramine 10 mg and 34% taking sibutramine 15 mg (P <.001 for both 10 mg and 15 mg vs placebo, and for both > or =5% and > or =10%).\n Sibutramine 10 mg or 15 mg once daily given with dietary advice produces and maintains statistically and clinically significantly greater weight loss than dietary advice alone (placebo) throughout a 12-month treatment period, and is safe and well tolerated.", "The management of type 2 diabetes mellitus is complicated by the presence of risk factors related to overweight and obesity, particularly visceral adiposity. However, weight loss and weight maintenance are difficult for patients with diabetes, and the benefits of dietary modifications are typically modest. Sibutramine is a serotonin- and norepinephrine-reuptake inhibitor that reduces food intake by inducing early satiety and attenuates the decrease in basal energy expenditure associated with weight loss. Previous trials of sibutramine in overweight and obese patients with type 2 diabetes have shown significant weight loss accompanied by better glycemic control.\n The goal of this study was to assess the effect on body weight and glycemic control of sibutramine in combination with glibenclamide in obese Hispanic patients with type 2 diabetes.\n This was a 12-month, randomized, double-blind, placebo-controlled clinical trial conducted at the Endocrinology Service, General Hospital of Mexico, Mexico City. Included were overweight or obese (body mass index [BMI] >27 kg/M2) patients with type 2 diabetes between the ages of 24 and 65 years who had been receiving glibenclamide monotherapy for at least 2 weeks and whose glucose concentrations were stable. Patients were randomized to receive sibutramine 10 mg or placebo once daily. The primary efficacy measures were change in body weight, waist circumference, and glycosylated hemoglobin (HbA1c). Anthropometrics and fasting glucose concentrations were measured monthly. HbA1c was determined at baseline and at 6 and 12 months. Laboratory parameters were measured at baseline and at the end of the study.\n Forty-four patients were randomized to receive sibutramine (28 women, 16 men; mean [SD] age, 47.6 [9.0] years), and 42 were randomized to receive placebo (31 women, 11 men; mean age, 45.8 [8.1] years). Twenty-four patients in the sibutramine group and 23 in the placebo group completed the trial. In the sibutramine group, body weight was reduced from a mean (SD) of 73.9 (10.3) kg at baseline to 69.8 (10.6) kg at month 12; BMI decreased from 29.9 (2.6) to 28.2 (2.9) kg/M2; waist circumference was reduced from 94.9 (8.4) to 90.8 (8.4) cm; the plasma fasting glucose concentration decreased from 140.4 (29.4) to 114.2 (32.0) mg/dL; and the HbA1c value was reduced from 8.9% (1.2) to 8.3% (1.2) (all, P < 0.001). In the placebo group, the corresponding changes were from 74.5 (10.3) kg at baseline to 73.1 (11.2) kg at month 12; from 30.1 (2.5) to 29.5 (2.9) kg/M2; from 94.4 (7.3) to 93.1 (8.3) cm (P < 0.05); from 140.7 (25.2) to 123.9 (38.3) mg/dL (P < 0.05); and from 9.0% (1.2) to 9.1% (1.3). In the sibutramine group, weight loss continued for up to 12 months.\n In this population of obese Hispanic patients with type 2 diabetes, sibutramine combined with glibenclamide therapy achieved weight loss for up to 12 months and was associated with better glycemic control than placebo.", "Rimonabant, a selective cannabinoid type 1 receptor blocker, reduces bodyweight and improves cardiovascular and metabolic risk factors in non-diabetic overweight or obese patients. The aim of the RIO-Diabetes trial was to assess the efficacy and safety of rimonabant in overweight or obese patients with type 2 diabetes that was inadequately controlled by metformin or sulphonylureas.\n 1047 overweight or obese type 2 diabetes patients (body-mass index 27-40 kg/m2) with a haemoglobin A1c (HbA1c) concentration of 6.5-10.0% (mean 7.3% [SD 0.9] at baseline) already on metformin or sulphonylurea monotherapy were given a mild hypocaloric diet and advice for increased physical activity, and randomly assigned placebo (n=348), 5 mg/day rimonabant (360) or 20 mg/day rimonabant (339) for 1 year. Two individuals in the 5 mg/day group did not receive double-blind treatment and were thus not included in the final analysis. The primary endpoint was weight change from baseline after 1 year of treatment. Analyses were done on an intention-to-treat basis. This trial is registered at ClinicalTrials.gov, number NCT00029848.\n 692 patients completed the 1 year follow-up; numbers in each group after 1 year were much the same. Weight loss was significantly greater after 1 year in both rimonabant groups than in the placebo group (placebo: -1.4 kg [SD 3.6]; 5 mg/day: -2.3 kg [4.2], p=0.01 vs placebo; 20 mg/day: -5.3 kg [5.2], p<0.0001 vs placebo). Rimonabant was generally well tolerated. The incidence of adverse events that led to discontinuation was slightly greater in the 20 mg/day rimonabant group, mainly due to depressed mood disorders, nausea, and dizziness.\n These data indicate that 20 mg/day rimonabant, in combination with diet and exercise, can produce a clinically meaningful reduction in bodyweight and improve HbA1c and a number of cardiovascular and metabolic risk factors in overweight or obese patients with type 2 diabetes inadequately controlled by metformin or sulphonylureas.", "Sibutramine treatment in obesity results in significantly greater weight reduction compared with placebo, although weight loss with sibutramine may be accompanied by small but statistically significant mean increases in blood pressure (BP). This 52-week, placebo-controlled, double-blind, randomised study investigated the effects of sibutramine 20 mg once daily or placebo on body weight in 220 obese (body mass index (BMI) 27-40 kg/m2), hypertensive patients. At randomisation, hypertension was well controlled (< or = 95 mm Hg diastolic blood pressure (DBP)) with an angiotensin-converting enzyme (ACE) inhibitor, with or without concomitant thiazide diuretic therapy. Therapy for hypertension continued for the 52 weeks of the study. Sibutramine 20 mg produced significantly greater weight loss compared with placebo: 4.5 kg with sibutramine compared with 0.4 kg with placebo (last observation carried forward (LOCF); P < or = 0.05). A total of 62 patients (42.8%) treated with sibutramine lost < or = 5% of their body weight compared with six patients (8.3%) treated with placebo; 19 patients (13.1%) treated with sibutramine lost > or = 10% of their body weight compared with two patients (2.8%) treated with placebo (LOCF; P < or = 0.05 for both comparisons). Hypertension remained well controlled for the 52 weeks of the study with both sibutramine and placebo treatment. After 52 weeks, the differences between placebo treatment and sibutramine treatment for both mean supine systolic blood pressure (SBP) and DBP were approximately 3 mm Hg: mean DBP was 82.8 mm Hg with placebo treatment compared with 85.5 mm Hg with sibutramine treatment (LOCF; P = 0.004) and mean SBP was 130.4 mm Hg with placebo compared with 133.1 mm Hg with sibutramine (LOCF; P = 0.0497; both comparisons, sibutramine vs placebo). The mean increases in SBP and DBP did not appear to change the overall risk category for coronary heart disease end points. Changes in pulse rate at week 52 were a decrease of 0.3 beats per minute (bpm) for placebo treatment compared with an increase of 5.7 bpm for sibutramine treatment (P < 0.001). Mandated withdrawals from the study due to protocol-defined changes in BP were not statistically different between the two treatment groups. Greater favourable changes in lipid profile, serum glucose, and uric acid could be accounted for by greater weight losses occurring in the sibutramine treatment group. Sibutramine was well tolerated. This study indicates that in obese patients whose hypertension is well controlled at the outset with an ACE inhibitor, with or without concomitant thiazide diuretic therapy, sibutramine safely and effectively achieves weight loss without compromising good BP control.", "To evaluate the long-term efficacy and tolerability within primary care settings of orlistat, a gastrointestinal lipase inhibitor, for the treatment of obesity.\n Randomized, double-blind, placebo-controlled, multicenter study.\n A group of 796 obese patients (body mass index, 30-44 kg/m2), treated with placebo 3 times a day (TID), 60 mg of orlistat TID, or 120 mg of orlistat TID, in conjunction with a reduced-energy diet for the first year and a weight-maintenance diet during the second year.\n Seventeen primary care centers in the United States.\n Changes in body weight and obesity-related disease risk factors.\n Patients treated with orlistat lost significantly more weight (7.08 +/- 0.54 and 7.94 +/- 0.57 kg for the 60-mg and 120-mg orlistat groups, respectively) than those treated with placebo (4.14 +/- 0.56 kg) in year 1 (P<.001) and sustained more of this weight loss during year 2 (P<.001). More patients treated with orlistat lost 5% or more of their initial weight in year 1 (48.8% and 50.5% of patients in the 60-mg and 120-mg groups, respectively) compared with placebo (30.7%; P<.001), and approximately 34% of patients in the orlistat groups sustained weight loss of 5% or greater over 2 years compared with 24% in the placebo group (P<.001). Orlistat produced greater improvements than placebo in serum lipid levels and blood pressure and was well tolerated, although treatment resulted in a higher incidence of gastrointestinal events.\n This long-term study indicates that orlistat is an effective adjunct to dietary intervention in the treatment of obesity in primary care settings.", "Serotonin-releasing agents prescribed as weight-loss medications have been implicated as a cause of acquired aortic and mitral valve abnormalities. Sibutramine hydrochloride (MERIDIA) is a serotonin and norepinephrine reuptake inhibitor with proven efficacy of weight reduction. The purpose of this study was to determine the incidence of cardiac valve disease in sibutraminetreated patients.\n Obese patients with type 2 diabetes mellitus enrolled in an ongoing double-blind, placebo-controlled, parallel-arm, 12-month study of sibutramine (followed by a 12-month open label extension) underwent transthoracic echocardiographic imaging and color Doppler interrogation for assessment of cardiac valve anatomy and function.\n A total of 210 patients were evaluated. Of these, 133 were receiving sibutramine (72 in the double-blind period), and 77 were receiving placebo. The mean+/-Standard Deviation age was 54+/-9 years, and the mean duration of treatment was 229+/-117 days (approximately 7.6 months). The prevalence of left-sided cardiac valve dysfunction was low and similar for the two treatment groups (sibutramine 3/133, or 2.3%; placebo 2/77, or 2.6%). All five cases were cases of aortic insufficiency; four were mild, one was severe (in a placebo patient). All three sibutramine cases were patients over age 50; two had a history of systemic hypertension.\n The prevalence of left-sided cardiac valve dysfunction was not higher than background in obese patients treated with sibutramine for an average of 7.6 months.", "The purpose of this study was to evaluate the effects of a combination weight loss program using intermittent low-calorie diets, energy-controlled meal replacement products, and sibutramine on weight loss, diabetes control, and cardiovascular risk factors in overweight or obese subjects with type 2 diabetes.\n Overweight or obese individuals with type 2 diabetes treated with diet or oral medication were randomly assigned to either a standard therapy or combination therapy group. Both groups received a standardized program to facilitate weight loss. The combination therapy group also received 10-15 mg sibutramine daily, low-calorie diets using meal replacement products for 1 week every 2 months, and between low-calorie diet weeks, once daily use of meal replacement product and snack bars to replace one usual meal and snack. Primary outcome measures were changes in body weight, glycemic control, plasma lipids, blood pressure, pulse, and body composition at 1 year.\n At 1 year, combination therapy, compared with standard therapy, resulted in significantly more weight loss (-7.3 +/- 1.3 kg vs. -0.8 +/- 0.9 kg, P < 0.001) and reduction in HbA(1c) (-0.6 +/- 0.3 vs. 0.0 +/- 0.2%, P = 0.05). Combination therapy resulted in reduced requirement for diabetes medications and decreased fat mass and lean body mass. A 5-kg decrease in weight at 1 year was associated with a decrease of 0.4% in HbA(1c) (P = 0.006). Changes in fasting glucose, lipids, pulse, and blood pressure did not differ between groups.\n This combination weight loss program resulted in greater weight loss and improved diabetes control compared with a standard weight loss program in overweight or obese subjects with type 2 diabetes.", "To investigate the efficacy and tolerability of orlistat in obese adolescents, a prospective, open-label, randomised, controlled pilot trial was performed. A total of 22 adolescents with exogeneous obesity were started on orlistat (120 mg tid) and a daily multivitamin preparation in addition to conventional treatment which included nutritional and lifestyle modification programmes. The control group consisted of 20 obese adolescents who had similar duration of follow-up under conventional treatment alone. Of the 22 patients, 7 dropped out within the 1st month of the trial due to side-effects attributable to orlistat. The remaining 15 patients on orlistat were followed for 5-15 months (average duration of treatment 11.7 +/- 3.7 months). The control group was similar in age, sex, and duration of follow-up (10.2 +/- 3.7 months, range 6-17 months) to the orlistat group. Compared to initial body weight, patients in the orlistat group lost -6.27 +/- 5.4 kg, whereas those in the control group gained 4.16 +/- 6.45 kg (P < 0.001) during the study period. Patients in the orlistat group lost -7.65% +/- 6.5% of their initial body weight, whereas, those of the control group gained 5.7% +/- 8.3% (P < 0.001). The body mass index decreased in the orlistat group by -4.09 +/- 2.9 kg/m2 while it increased by + 0.11 +/- 2.49 kg/m2 in the control group (P < 0.001). Mild gastrointestinal complaints (frequent stools) were experienced by all patients in the orlistat group. Conclusion: Orlistat could be a useful adjunct in the treatment of severe obesity in adolescents; however, gastrointestinal side-effects limit its usefulness in almost one in three adolescents.", "Rimonabant, a selective cannabinoid-1 receptor (CB1) blocker, has been shown to reduce body weight and improve cardiovascular risk factors in obese patients. The Rimonabant in Obesity-Lipids (RIO-Lipids) study examined the effects of rimonabant on metabolic risk factors, including adiponectin levels, in high-risk patients who are overweight or obese and have dyslipidemia.\n We randomly assigned 1036 overweight or obese patients (body-mass index [the weight in kilograms divided by the square of the height in meters], 27 to 40) with untreated dyslipidemia (triglyceride levels >1.69 to 7.90 mmol per liter, or a ratio of cholesterol to high-density lipoprotein [HDL] cholesterol of >4.5 among women and >5 among men) to double-blinded therapy with either placebo or rimonabant at a dose of 5 mg or 20 mg daily for 12 months in addition to a hypocaloric diet.\n The rates of completion of the study were 62.6 percent, 60.3 percent, and 63.9 percent in the placebo group, the group receiving 5 mg of rimonabant, and the group receiving 20 mg of rimonabant, respectively. The most frequent adverse events resulting in discontinuation of the drug were depression, anxiety, and nausea. As compared with placebo, rimonabant at a dose of 20 mg was associated with a significant (P<0.001) mean weight loss (repeated-measures method, -6.7+/-0.5 kg, and last-observation-carried-forward analyses, -5.4+/-0.4 kg), reduction in waist circumference (repeated-measures method, -5.8+/-0.5 cm, and last-observation-carried-forward analyses, -4.7+/-0.5 cm), increase in HDL cholesterol (repeated-measures method, +10.0+/-1.6 percent, and last-observation-carried-forward analyses, +8.1+/-1.5 percent), and reduction in triglycerides (repeated-measures method, -13.0+/-3.5 percent, and last-observation-carried-forward analyses, -12.4+/-3.2 percent). Rimonabant at a dose of 20 mg also resulted in an increase in plasma adiponectin levels (repeated-measures method, 57.7 percent, and last-observation-carried-forward analyses, 46.2 percent; P<0.001), for a change that was partly independent of weight loss alone.\n Selective CB1-receptor blockade with rimonabant significantly reduces body weight and waist circumference and improves the profile of several metabolic risk factors in high-risk patients who are overweight or obese and have an atherogenic dyslipidemia.\n Copyright 2005 Massachusetts Medical Society.", "Obesity is an important risk factor for type 2 diabetes. Weight loss in patients with type 2 diabetes is associated with improved glycemic control and reduced cardiovascular disease risk factors, but weight loss is notably difficult to achieve and sustain with caloric restriction and exercise. The purpose of this study was to assess the impact of treatment with orlistat, a pancreatic lipase inhibitor, on weight loss, glycemic control, and serum lipid levels in obese patients with type 2 diabetes on sulfonylurea medications.\n In a multicenter 57-week randomized double-blind placebo-controlled study, 120 mg orlistat or placebo was administered orally three times a day with a mildly hypocaloric diet to 391 obese men and women with type 2 diabetes who were aged > 18 years, had a BMI of 28-40 kg/m2, and were clinically stable on oral sulfonylureas. Changes in body weight, glycemic control, lipid levels, and drug tolerability were measured.\n After 1 year of treatment, the orlistat group lost 6.2 +/- 0.45% (mean +/- SEM) of initial body weight vs. 4.3 +/- 0.49% in the placebo group (P < 0.001). Twice as many patients receiving orlistat (49 vs. 23%) lost > or = 5% of initial body weight (P < 0.001). Orlistat treatment plus diet compared with placebo plus diet was associated with significant improvement in glycemic control, as reflected in decreases in HbA1c (P < 0.001) and fasting plasma glucose (P < 0.001) and in dosage reductions of oral sulfonylurea medication (P < 0.01). Orlistat therapy also resulted in significantly greater improvements than placebo in several lipid parameters, namely, greater reductions in total cholesterol, (P < 0.001), LDL cholesterol (P < 0.001), triglycerides (P < 0.05), apolipoprotein B (P < 0.001), and the LDL-to-HDL cholesterol ratio (P < 0.001). Mild to moderate and transient gastrointestinal events were reported with orlistat therapy, although their association with study withdrawal was low. Fat-soluble vitamin levels generally remained within the reference range, and vitamin supplementation was required in only a few patients.\n Orlistat is an effective treatment modality in obese patients with type 2 diabetes with respect to clinically meaningful weight loss and maintenance of weight loss, improved glycemic control, and improved lipid profile.", "Weight gain is commonly observed with olanzapine treatment and can increase the risk for obesity, cardiovascular disease, hypertension, and diabetes mellitus. This study examined the effectiveness of sibutramine, an approved weight loss agent, in overweight and obese subjects taking olanzapine for schizophrenia or schizoaffective disorder.\n Each subject had a DSM-IV diagnosis of schizophrenia or schizoaffective disorder, had been taking a stable dose of olanzapine for at least 4 months, and had a body mass index of >/=30 kg/m(2) or >/=27 kg/m(2) plus at least one cardiovascular risk factor. In a 12-week double-blind, randomized, placebo-controlled study, 37 subjects received placebo or sibutramine (up to 15 mg/day). For the first 8 weeks all subjects participated in weekly group sessions focused on nutrition and behavioral modification.\n The sibutramine and placebo groups had no significant baseline differences on age, gender, education, ethnicity, diagnosis, weight, body mass index, and blood pressure. At week 12 the sibutramine group had significantly greater losses than the placebo group in weight (mean=8.3 lb, SD=2.4, versus mean=1.8 lb, SD=1.6), waist circumference, body mass index, and hemoglobin A(1c). There were no significant differences on most side effects, although the sibutramine group exhibited a mean increase in systolic blood pressure of 2.1 mm Hg (SD=8.5), and anticholinergic side effects and sleep disturbances were at least twice as common in the sibutramine group.\n Sibutramine was an effective and well-tolerated adjunct to behavior modification for weight loss in patients with schizophrenia and schizoaffective disorder being treated with olanzapine.", "Obesity is a highly prevalent medical condition and is commonly accompanied by hypertension. This study assessed the efficacy and safety of treatment with sibutramine hydrochloride for promoting and maintaining weight loss in obese patients with controlled hypertension, including a subset analysis of African American patients.\n Obese patients with a body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) between 27 and 40 and a history of hypertension controlled with a calcium channel blocker (with or without concomitant thiazide diuretic treatment) were randomized to receive sibutramine (n = 150) or placebo (n = 74) with minimal behavioral intervention for 52 weeks. African Americans constituted 36% of enrolled patients. Efficacy assessments were body weight and related parameters (BMI and waist and hip circumferences), metabolic parameters (serum levels of triglycerides, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], total cholesterol, glucose, and uric acid), and quality-of-life measures. Safety assessments included recording of blood pressure, pulse rate, adverse events, and reasons for discontinuation.\n For patients receiving sibutramine, weight loss occurred during the first 6 months of the trial and was maintained to the end of the 12-month treatment period. Among patients receiving sibutramine, 40.1% lost 5% or more of body weight (5% responders) and 13.4% lost 10% or more of body weight (10% responders) compared with 8.7% and 4.3% of patients in the placebo group, respectively (P<.05). Changes in body weight were similar among African Americans and whites. Sibutramine-induced weight loss was associated with significant improvements in serum levels of triglycerides, HDL-C, glucose, and uric acid. Waist circumference and quality-of-life measures also improved significantly in patients receiving sibutramine. Sibutramine-treated patients had small but statistically significant mean increases in diastolic blood pressure (2.0 mm Hg) and pulse rate (4.9 beats/min) compared with placebo-treated patients (-1.3 mm Hg and 0.0 beats/min; P<.05); these changes were similar among African Americans and whites. Most adverse events were mild to moderate in severity and transient. The most common adverse event resulting in discontinuation among patients receiving sibutramine was hypertension (5.3% of patients receiving sibutramine vs 1.4% of patients receiving placebo).\n In obese patients with controlled hypertension, sibutramine was an effective and well-tolerated treatment for weight loss and maintenance. Sibutramine-induced weight loss resulted in improvements in serum levels of triglycerides, HDL-C, uric acid, and glucose, and in waist circumference and quality-of-life measures. Blood pressure and heart rate increased by a small amount. Efficacy and safety profiles for sibutramine among African American and white obese patients with controlled hypertension were similar.", "Increased prevalence of adolescent obesity requires effective treatment options beyond behavior therapy.\n To see whether sibutramine reduced weight more than placebo in obese adolescents who were receiving a behavior therapy program.\n 12-month, 3:1 randomized, double-blind trial conducted from July 2000 to February 2002.\n 33 U.S. outpatient clinics.\n 498 participants 12 to 16 years of age with a body mass index (BMI) that was at least 2 units more than the U.S. weighted mean of the 95th percentile based on age and sex, to the upper limit of 44 kg/m2. Interventions: Site-specific behavior therapy plus 10 mg of sibutramine or placebo. Blinded study medication dose was uptitrated to 15 mg or placebo at month 6 if initial BMI was not reduced by 10%.\n Body mass index, waist circumference, body weight, fasting lipid and glycemic variables, safety, and tolerability.\n Seventy-six percent of patients in the sibutramine group and 62% of patients in the placebo group completed the study. The estimated mean treatment group difference at month 12 (linear mixed-effects model) favored sibutramine for change from baseline in BMI (-2.9 kg/m2 [95% CI, -3.5 to -2.2 kg/m2]) and body weight (-8.4 kg [CI, -9.7 to -7.2 kg]) (P < 0.001 for both). The sibutramine group had greater improvements in triglyceride levels, high-density lipoprotein cholesterol levels, insulin levels, and insulin sensitivity (P < or = 0.001 for all). The rate of tachycardia was greater with sibutramine vs. placebo (12.5% vs. 6.2%; difference, 6.3 percentage points [CI, 1.0 to 11.7 percentage points]) but did not lead to increased withdrawal (2.4% vs. 1.5%; difference, 0.9 percentage point [CI, -1.7 to 3.5 percentage points]).\n The 1-year study duration precluded assessment of long-term weight maintenance and putative health benefits and harms, and 24% and 38% of the sibutramine and placebo groups, respectively, did not complete follow-up.\n Sibutramine added to a behavior therapy program reduced BMI and body weight more than placebo and improved the profile of several metabolic risk factors in obese adolescents.", "We undertook a randomised controlled trial to assess the efficacy and tolerability of orlistat, a gastrointestinal lipase inhibitor, in promoting weight loss and preventing weight regain in obese patients over a 2-year period.\n 743 patients (body-mass index 28-47 kg/m2), recruited at 15 European centres, entered a 4-week, single-blind, placebo lead-in period on a slightly hypocaloric diet (600 kcal/day deficit). 688 patients who completed the lead-in were assigned double-blind treatment with orlistat 120 mg (three times a day) or placebo for 1 year in conjunction with the hypocaloric diet. In a second 52-week double-blind period patients were reassigned orlistat or placebo with a weight maintenance (eucaloric) diet.\n From the start of lead-in to the end of year 1, the orlistat group lost, on average, more bodyweight than the placebo group (10.2% [10.3 kg] vs 6.1% [6.1 kg]; LSM difference 3.9 kg [p<0.001] from randomisation to the end of year 1). During year 2, patients who continued with orlistat regained, on average, half as much weight as those patients switched to placebo (p<0.001). Patients switched from placebo to orlistat lost an additional 0.9 kg during year 2, compared with a mean regain of 2.5 kg in patients who continued on placebo (p<0.001). Total cholesterol, low-density lipoprotein (LDL) cholesterol, LDL/high-density lipoprotein ratio, and concentrations of glucose and insulin decreased more in the orlistat group than in the placebo group. Gastrointestinal adverse events were more common in the orlistat group. Other adverse symptoms occurred at a similar frequency during both treatments.\n Orlistat taken with an appropriate diet promotes clinically significant weight loss and reduces weight regain in obese patients over a 2-year period. The use of orlistat beyond 2 years needs careful monitoring with respect to efficacy and adverse events.", "To evaluate the efficacy of orlistat to enhance weight loss in obese adolescents.\n The study was a 6-month randomized, double-blind, placebo-controlled trial to compare the effects of orlistat (120 mg orally 3 times a day) and placebo on reduction of body mass index (BMI). Forty adolescents between 14 and 18 years of age with a mean BMI of 40 kg/m2 entered the protocol between December 2002 and February 2003. Study subjects stayed overnight in the General Clinical Research Center, during which dietary records were reviewed and lifestyle recommendations were given. The study participants received either orlistat (120 mg orally 3 times a day) or placebo and were assessed monthly for 6 months. At 0, 3, and 6 months, fasting laboratory tests were performed. The primary end point was the change in BMI from baseline to 6 months. Secondary outcomes included changes in weight, lean body mass, and results of blood chemistry studies.\n No statistically significant difference was noted between the 2 study groups for decrease in BMI from baseline to 6 months (P = 0.39). The decrease in BMI within the orlistat group (-1.3 +/- 1.6 kg/m2; P = 0.04) and within the placebo group (-0.8 +/- 3.0 kg/m2; P = 0.02), however, was statistically significant. Laboratory measurements did not differ between the 2 groups. In comparison with the placebo group, the orlistat group had increased adverse events, primarily gastrointestinal symptoms and findings.\n In this study of obese adolescents, orlistat did not significantly reduce BMI in comparison with placebo at 6 months.", "To determine the efficacy and tolerability of sibutramine hydrochloride in obese patients whose type 2 diabetes was poorly controlled on diet alone or with an oral antidiabetic agent.\n This study was a 24-week, double-blind, multicentre trial following a 5-week placebo run-in period. One hundred and seventy-five obese (body mass index (b.m.i.) > or =27 kg/m2) patients with poorly controlled type 2 diabetes mellitus were randomized either to sibutramine (n = 89; mean age 53.5 years; mean weight 99.3 kg) or placebo (n = 86; mean age 55 years; mean weight 98.2 kg) at 16 participating centres. To achieve moderate calorie restriction (deficit > or = 250-500 kcal/day), individual dietary counselling was accompanied by either placebo or sibutramine (initial dosage of 5 mg/day titrated up by 5 mg biweekly through week 6, and maintained at 20 mg through week 24). The main outcome measures included changes in weight, b.m.i., waist and hip circumference, glycaemic control, lipid profile, and quality of life, and evaluation of reported adverse events.\n Sixty-seven per cent of sibutramine patients and 71% of placebo patients completed the study. At week 24 when comparing those who completed the course, sibutramine compared with placebo patients showed significantly greater (p < 0.001) absolute (-4.3 vs. -0.4 kg) and percentage (-4.5% vs. -0.5%) weight loss. Weight loss > or =5% or 10% was achieved by 33% and 8% of sibutramine patients, respectively, but no placebo patients (p < 0.03 or better). Improvement in glycaemic control was correlated with weight loss (p < 0.001). In 5% and 10% weight-loss responders, mean treatment differences were -0.53% and -1.65% (p < or = 0.05), respectively, for HbA1c, and -1.4 mmol/l (p < or =0.05) and -3.8 (p < or =0.05) mmol/l for fasting plasma glucose. Sibutramine patients also showed improvements in fasting insulin, triglycerides, HDL cholesterol, and quality-of-life assessments. Overall, sibutramine was well tolerated compared with the placebo. Sibutramine treatment was associated with small mean increases in blood pressure (BP) and pulse, although an increase in BP was not seen in sibutramine-treated patients who lost > or = 5% of their weight.\n Sibutramine produced statistically and clinically significant weight loss when used in combination with recommendations for moderate caloric restriction. This weight loss was associated with improvements in metabolic control and quality of life, and sibutramine was generally well tolerated in obese patients with type 2 diabetes.", "Very-low-calorie diets are a well established method to achieve substantial short-term weight loss in obese patients, but long-term maintenance of the weight loss is very disappointing. A combined very-low-calorie diet and pharmacologic approach could be an effective means of prolonging its benefits.\n Eligible patients had a body-mass index greater than 30 kg/m2; those who lost 6 kg or more during a 4-week treatment with a very-low-calorie diet were randomly assigned to 1 year of treatment with sibutramine (10 mg) or identical placebo.\n In an intention-to-treat analysis, mean (+/-SD) absolute weight change at 1 year (or study endpoint) was -5.2 (+/-7.5) kg in the 81 patients in the sibutramine group and +0.5 (+/-5.7) kg in the 78 patients in the placebo group (P = 0.004). When compared with their weight at study entry (before the very-low-calorie diet), 86% of patients in the sibutramine group had lost at least 5% of their weight, compared with only 55% of those in the placebo group (P <0.001) at the study endpoint. Similarly, at month 12, 75% of subjects in the sibutramine group maintained at least 100% of the weight loss achieved with a very-low-calorie diet, compared with 42% in the placebo group (P <0.01).\n Following a very-low-calorie diet, sibutramine is effective in maintaining and improving weight loss for up to 1 year.", "To assess the effect of orlistat on body weight and concomitant diseases in patients with body mass index (BMI) of > 28 kg/m2 and poorly controlled type 2 diabetes, hypertension or hypercholesterolaemia.\n This trial was a six-month, randomized, double-blind, placebo-controlled study of orlistat 120 mg three times daily plus a mildly reduced-calorie diet. 1004 obese patients (BMI 28-40 kg/m2) were included by 253 private endocrinologists and received orlistat (n = 499) or placebo (n = 505). Patients were stratified by concomitant disorder (type 2 diabetes, n = 193; hypertension, n = 614; hypercholesterolaemia, n = 197). Body weight, anthropometry, lipid and glycaemic control parameters and blood pressure.\n After six months, orlistat produced a significantly greater weight loss than placebo in type 2 diabetes (-4.2% vs. -1.4%), hypertension (-6.2% vs. -1.9%) and hypercholesterolaemia (-5.5% vs. -2.3%) groups (p < 0.0001 for all). There was a greater decrease in HbA(1c) in the type 2 diabetes group (-0.54 vs. -0.18%; p = 0.002) and low-density lipoprotein (LDL)-cholesterol in the hypercholesterolaemia group (-11.7% vs. -4.5%; p = 0.004) with orlistat vs. placebo. Early weight loss (> or = 5% at 12 weeks) was associated with the highest weight loss in each group, and the highest decreases in HbA1c, LDL-cholesterol and diastolic blood pressure in patients with type 2 diabetes, hypercholesterolaemia and hypertension, respectively, at six months. The incidence of adverse events was similar for orlistat and placebo, except for certain generally well-tolerated gastrointestinal events that were more common with orlistat.\n Orlistat plus a mildly reduced-calorie diet produced clinically meaningful weight loss and improvements in risk factors in overweight and obese patients with poorly controlled type 2 diabetes, hypertension or hypercholesterolaemia.\n Copyright 2004 Blackwell Publishing Ltd" ]	Orlistat, sibutramine and rimonabant have been studied in trials of one year or longer. Internal validity of studies was limited by high attrition rates. All three antiobesity agents are modestly effective in reducing weight and have differing effects on cardiovascular risk and adverse effects profiles. Longer and more methodologically rigorous studies of anti-obesity drugs that are powered to examine endpoints such as mortality and cardiovascular morbidity are required.
CD002127	[ "17623736", "19949030", "11591843" ]	[ "Intravenous immunoglobulin in primary and secondary chronic progressive multiple sclerosis: a randomized placebo controlled multicentre study.", "A short-term randomized MRI study of high-dose oral vs intravenous methylprednisolone in MS.", "Effects of IV methylprednisolone on brain atrophy in relapsing-remitting MS." ]	[ "In patients with relapsing-remitting multiple sclerosis (MS), IVIG was shown to reduce the relapse rate and progression of disability. In patients with chronic progressive MS, a beneficial effect of IVIG was not documented in placebo controlled studies. This trial investigated the influence of IVIG in primary (PPMS) and secondary (SPMS) chronic progressive MS. Two-hundred and thirty-one patients stratified for PPMS (n=34) and SPMS (n=197) were randomly assigned to IVIG 0.4 g/kg per month or to placebo for 24 months. Primary endpoints were 1) the time to sustained progression of disease identified as worsening of the expanded disability status scale (EDSS) sustained for 3 months, and 2) the improvement of neurological functions defined by a patient's best EDSS score. Secondary endpoints were the proportion of patients with sustained progression, the relapse rate, the assessment of fine motor skills, visual evoked potentials, contrast sensitivity, depression and quality of life. Analysis of the intention-to-treat (ITT) population of combined PPMS and SPMS patients showed that the mean time to sustained progression was 74 weeks in the IVIG compared with 62 weeks in the placebo group (P=0.0406). When PPMS and SPMS patients were analysed separately, the time to sustained progression was also longer in the IVIG group, but the difference was not significant. There was no IVIG-mediated improvement in neurological functions. In the combined per protocol (PP) treated patients, IVIG treatment prolonged time to sustained progression by 13 weeks (P=0.0396). PPMS patients, but not SPMS patients showed a slight favourable IVIG effect on the best EDSS score. In the combined ITT population there were less patients with sustained progression in the IVIG than in the placebo group (P=0.028). The difference was significant in PPMS (P=0.016), but not in SPMS patients. In the combined PP population, there was a trend for a favorable IVIG effect on the rates of patients with sustained progression. In patients with PPMS, this IVIG effect reached significance (P=0.036). Other secondary endpoints did not show significant differences between treatment groups. Eighteen patients with PPMS and 102 patients with SPMS withdrew from the study for various reasons. Treatment was generally well tolerated. It was concluded that monthly IVIG infusion could delay progression of disease in patients with PPMS, and that there was a trend in favour of IVIG treatment in patients with SPMS.", "To compare the efficacy, tolerability, and safety of IV methylprednisolone (IV MP) vs oral methylprednisolone (oMP) at equivalent high doses in patients with multiple sclerosis (MS) experiencing a recent relapse.\n Patients with a clinical relapse within the previous 2 weeks and at least 1 gadolinium (Gd)-enhancing lesion on a screening brain MRI scan were included. Forty patients with MS were randomized to receive either 1 g/day for 5 days of oMP (20 patients) or 1 g/day for 5 days of IV MP (20 patients). Expanded Disability Status Scale (EDSS) and brain MRI (dual-echo and postcontrast T1-weighted scans) were assessed at baseline and at weeks 1 and 4. The study primary research question (endpoint) was to compare the efficacy of the 2 treatment routes in reducing the number of Gd-enhancing lesions after 1 week from treatment initiation. Secondary outcomes were safety, tolerability, and clinical efficacy profiles of the 2 routes of administration.\n The 2 groups showed a reduction of Gd-enhancing lesions over time (p = 0.002 for oMP and p = 0.001 for IV MP) with a \"non-inferiority effect\" between the 2 routes of administration at week 1. Both groups showed an improvement of EDSS over time (p < 0.001) without between-group difference at week 4. Both treatments were well-tolerated and adverse events were minimal and occurred similarly in the 2 treatment arms.\n Oral methylprednisolone (oMP) is as effective as IV methylprednisolone in reducing gadolinium-enhancing lesions in patients with MS soon after an acute relapse with similar clinical, safety, and tolerability profiles. This study provides class III evidence that 1 g oMP x 5 days is not inferior to 1 g IV MP x 5 days in reducing the number of gadolinium-enhancing lesions over a period of 1 week (mean difference in lesion reduction comparing IV MP to oMP is -20%, 95% confidence interval -48% to + 5%).", "IV methylprednisolone (IVMP) has been used to treat relapses in patients with relapsing-remitting (RR) MS, but its effect on disease progression is not known. Furthermore, there are no data on the impact of IVMP on T1 black holes or whole-brain atrophy.\n To determine the effect of IVMP on MRI measures of the destructive pathology in patients with RR-MS and secondarily to determine the effect of IVMP on disability progression in patients with RR-MS.\n The authors conducted a randomized, controlled, single-blind, phase II clinical trial of IVMP in patients with RR-MS. Eighty-eight patients with RR-MS with baseline Expanded Disability Status Scale (EDSS) scores of < or =5.5 were randomly assigned to regular pulses of IVMP (1 g/day for 5 days with an oral prednisone taper) or IVMP at the same dose schedule only for relapses (IVMP for relapses) and followed without other disease-modifying drug therapy for 5 years. Pulsed IVMP was given every 4 months for 3 years and then every 6 months for the subsequent 2 years. Patients had quantitative cranial MRI scans at study entry and after 5 years and standardized clinical assessments every 4 to 6 months.\n Eighty-one of 88 patients completed the trial as planned, and treatment was well tolerated. Baseline demographic, clinical, and MRI measures were well matched in the two study arms. Patients on the pulsed IVMP arm received more MP than patients on the control arm of the study (p < 0.0001). Mean change in T1 black hole volume favored pulsed IVMP therapy (+1.3 vs +5.2 mL; p < 0.0001), as did mean change in brain parenchymal volume (+2.6 vs -74.5 mL; p = 0.003). There was no significant difference between treatment arms in the change in T2 volume or annual relapse rate during the study. However, there was significantly more EDSS score worsening in the control group, receiving IVMP only for relapses. There was a 32.2% reduction (p </= 0.0001) in the probability of sustained EDSS score worsening in the pulsed MP arm compared with the relapse treatment arm. At the end of the study, EDSS was better in the pulsed MP group (1.7 vs 3.4; p < 0.0001). Prolonged treatment with pulsed IVMP was safe and well tolerated; only two patients dropped out for toxic side effects over 5 years.\n In patients with RR-MS, treatment with pulses of IVMP slows development of T1 black holes, prevents or delays whole-brain atrophy, and prevents or delays disability progression. A phase III study of IVMP pulses is warranted." ]	MX shows a significant but partial efficacy in reducing the risk of MS progression and the frequency of relapses in patients affected by worsening RRMS, PRMS and SPMS in the short-term follow-up (two years). No major neoplastic events or symptomatic cardiotoxicity related to MX have been reported; however studies with longer follow-up (not included in this review) have raised concerns about the risk of systolic disfunction (~12%) and therapy-related acute leukaemias (0.8%), which are increasingly reported in the literature. MX should be limited to treating patients with worsening RRMS and SPMS and with evidence of persistent inflammatory activity after a careful assessment of the individual patients’ risk and benefit profiles. Assessment should also consider the present availability of alternative therapies with less severe adverse events.
CD000364	[ "11794219", "14656755", "18097856", "3709244", "10227267", "9652613", "11791098", "17006278", "2194380", "1437427", "19084453", "8648202", "8356846", "2968738", "8653819", "20629771" ]	[ "The safety of inactivated influenza vaccine in adults and children with asthma.", "Influenza vaccination in children with asthma: randomized double-blind placebo-controlled trial.", "Influenza vaccination in adults with asthma: safety of an inactivated trivalent influenza vaccine.", "Lack of clinical exacerbations in adults with chronic asthma after immunization with killed influenza virus.", "Effects of inactivated influenza virus vaccination on bronchial reactivity symptom scores and peak expiratory flow variability in patients with asthma.", "Randomised placebo-controlled crossover trial on effect of inactivated influenza vaccine on pulmonary function in asthma.", "Safety and tolerability of cold-adapted influenza virus vaccine in children and adolescents with asthma.", "Comparison of the efficacy and safety of live attenuated cold-adapted influenza vaccine, trivalent, with trivalent inactivated influenza virus vaccine in children and adolescents with asthma.", "Effect of live attenuated, cold recombinant (CR) influenza virus vaccines on pulmonary function in healthy and asthmatic adults.", "Improving influenza vaccination rates in children with asthma: a test of a computerized reminder system and an analysis of factors predicting vaccination compliance.", "The safety and immunogenicity of influenza vaccine in children with asthma in Mexico.", "Evaluation of live attenuated influenza vaccines in children 6-18 months of age: safety, immunogenicity, and efficacy. National Institute of Allergy and Infectious Diseases, Vaccine and Treatment Evaluation Program and the Wyeth-Ayerst ca Influenza Vaccine Investigators Group.", "Immunization of institutionalized asthmatic children and patients with psychomotor retardation using live attenuated cold-adapted reassortment influenza A H1N1, H3N2 and B vaccines.", "[The results of state trials of inactivated influenza vaccines for children].", "Clinical and epidemiological evaluation of a live, cold-adapted influenza vaccine for 3-14-year-olds.", "Protective effect of single-dose adjuvanted pandemic influenza vaccine in children." ]	[ "Influenza causes substantial morbidity in adults and children with asthma, and vaccination can prevent influenza and its complications. However, there is concern that vaccination may cause exacerbations of asthma.\n To investigate the safety of the inactivated trivalent split-virus influenza vaccine in adults and children with asthma, we conducted a multicenter, randomized, double-blind, placebo-controlled, cross-over trial in 2032 patients with asthma (age range, 3 to 64 years). The order of injection of vaccine and placebo was assigned randomly, with a mean of 22 days between the injections. Each day during the two weeks after each injection, the patients recorded peak expiratory flow rates, symptoms thought to be related to the injection, use of asthma medications, unscheduled health care visits for asthma, and asthma-related absences from school or work. The primary outcome measure was an exacerbation of asthma in the two weeks after the injections.\n The frequency of exacerbations of asthma was similar in the two weeks after the influenza vaccination and after placebo injection (28.8 percent and 27.7 percent, respectively; absolute difference, 1.1 percent; 95 percent confidence interval, -1.4 percent to 3.6 percent). The exacerbation rates were similar in subgroups defined according to age, severity of asthma, and other factors. Among symptoms thought to be associated with the injection, only body aches were more frequent after the vaccine injection than after placebo injection (25.1 percent vs. 20.8 percent, P<0.001).\n The inactivated influenza vaccine is safe to administer to adults and children with asthma, including those with severe asthma. Given the morbidity of influenza, all those with asthma should receive the vaccine annually.", "There is little evidence that influenza vaccination reduces asthma exacerbations. We determined whether influenza vaccination is more effective than placebo in 6-18-year-old children with asthma. We performed a randomized, double-blind, placebo-controlled trial. Parenteral vaccination with inactivated influenza vaccine or placebo took place approximately November 1, and children were followed until April 1 of the next year. Airway symptoms were reported in a diary. When symptom scores reached a predefined level, a pharyngeal swab was taken. Primary outcome was the number of asthma exacerbations associated with virologically proven influenza infection. Three hundred forty-nine children were assigned placebo, and 347 were assigned vaccine. Pharyngeal swabs positive for influenza were related to 42 asthma exacerbations, 24 in the vaccine group and 18 in the placebo group, a difference of 33% favoring placebo (31% after adjustment for confounders; 95% confidence interval, -34% to 161%). Influenza-related asthma exacerbations were of similar severity in both groups; they lasted 3.1 days shorter in the vaccine group (95% confidence interval, -6.2 to 0.002 days, p = 0.06). We conclude that influenza vaccination did not result in a significant reduction of the number, severity, or duration of asthma exacerbations caused by influenza. Additional studies are warranted to justify routine influenza vaccination of children with asthma.", "Despite recommendations in most countries for giving inactivated influenza vaccine to people with asthma, only a minority currently receive it. One reason for low vaccine coverage has been concern that vaccination may induce exacerbations of asthma. In this randomized trial, 291 patients between 18 and 65 years of age received either an inactivated influenza vaccine followed 14 days later by a saline placebo or placebo followed by the vaccine. Each patient received 1 dose of vaccine and 1 dose of placebo. The percentage of patients reporting at least one asthma exacerbation within 14 days after injection was similar following vaccine or placebo (28.3% and 25.5%, respectively). The combined exacerbation rate during the first 14-day interval was higher (31.5%) than that during the second 14-day interval (22.4%, P = 0.0135), indicating that the occurrence of exacerbations was not likely to be related to the sequence of injections. The percentages of individuals with solicited systemic symptoms were 56.6% and 44.8% after vaccine or placebo injection, respectively. We conclude that influenza vaccination did not increase the incidence of asthma exacerbations compared to placebo in this study and the vaccine was well tolerated. The results thus support annual influenza vaccination in patients with asthma.", "The effects of immunization with killed influenza virus vaccine were assessed by comparison with placebo in a double-blind study of 318 adult patients with chronic asthma. The patients were randomly allocated to active vaccine and placebo. No difference was observed in peak expiratory flow rate or in clinical symptoms of bronchial obstruction between the groups receiving active vaccine and placebo during the first week after immunization. The data were analyzed separately for age, sex, duration of the disease, hypersensitivity to aspirin (acetylsalicylic acid), atopic status, patients with a history of attacks of asthma induced by viral infections, patients with a diurnal variation of baseline peak expiratory flow of 20 percent or more, and patients receiving continuous oral steroid medication, but none of these factors seemed to predict any short-term adverse effects of vaccination. Follow-up for eight months after the vaccination revealed no differences in asthmatic symptoms between the patients treated with active vaccine and those receiving placebo. The antiviral antibody response to vaccination was normal. The possible protection provided by the vaccination against exacerbation of asthma induced by influenza could not be evaluated, since the influenza epidemic expected during the season failed to occur in Finland. It is concluded that immunization with killed influenza vaccine is safe and is not associated with any significant side effects in adult patients with chronic asthma.", "Even though annual influenza vaccinations are recommended by many authorities, some doctors may be reluctant to vaccinate asthmatic patients because of the risk of inducing bronchial reactivity and exacerbating the asthma. In this study we investigated the effect of inactivated trivalent influenza vaccine on airway reactivity symptom scores and peak expiratory flow (PEF) variability in 24 patients with mild stable asthma. Baseline spirometry and methacholine challenge tests were performed on all patients. Patients were then asked to record their peak expiratory flow every morning and evening, complete daily symptom score charts (morning tightness, daytime asthma, cough, and night asthma), and note bronchodilator usage for 1 week. After baseline measurements, the patients were allocated to inactivated vaccine and placebo in a random and single-blind manner. The lung function measurements and methacholine challenge tests were repeated 1 week after vaccination and placebo administration at the same time of day. PD20 (mg/mL) methacholine doses were 3.06+/-3.0 mg/mL before vaccination, 2.96+/-3.2 mg/mL after vaccination, and 2.76+/-2.91 mg/mL after placebo administration. There were no significant changes in PD20 methacholine after influenza vaccination (p>0.05). There were also no significant changes in symptom scores, bronchodilator usage, and PEFR after vaccination (p>0.05). None of the patients experienced significant local or systemic side effects after vaccination. Immunization with inactivated influenza vaccine does not induce clinical exacerbations of asthma or airway hyperreactivity in patients with mild asthma.", "Despite current recommendations, many people with asthma do not receive annual vaccination against influenza, partly because of concern that vaccine may trigger exacerbations. Colds can trigger exacerbations, which may be mistaken for vaccine-related adverse events. We undertook a double-blind placebo-controlled multicentre crossover study to assess the safety of influenza vaccine in patients with asthma, with allowance for the occurrence of colds.\n We studied 262 patients, aged 18-75 years, who recorded daily peak expiratory flow (PEF), respiratory symptoms, medication, medical consultations, and hospital admissions for 2 weeks before the first injection and until 2 weeks after the second injection. Order of injection (vaccine and placebo) was assigned randomly. There was an interval of 2 weeks between injections. The main outcome measure was an exacerbation of asthma within 72 h of injection (defined as a fall in PEF of >20%).\n Among 255 participants with paired data, 11 recorded a fall in PEF of more than 20% after vaccine compared with three after placebo (McNemar's test p=0.06); a fall of more than 30% was recorded by eight after vaccine compared with none after placebo (binomial test p=0.008). However, when participants with colds were excluded, there was no significant difference in the numbers with falls of more than 20% between vaccine and placebo (six vs three; binomial test p=0.51), although the difference for PEF decreases of more than 30% approached significance (five vs none; binomial test, p=0.06). This association was confined to first-time vaccinees.\n Our findings indicate that pulmonary-function abnormalities may occur as a complication of influenza vaccination. However, the risk of pulmonary complications is very small and outweighed by the benefits of vaccination.", "Influenza infections can cause severe respiratory disease in high risk persons such as those with asthma, but immunization rates for high risk groups remain suboptimal. An investigational influenza virus vaccine, trivalent, types A and B, live, cold-adapted (CAIV-T) administered by intranasal spray was shown previously to be effective in healthy adults and healthy children.\n To assess the safety and tolerability of CAIV-T in subjects 9 years of age and older with moderate to severe asthma.\n In this randomized, double blind, placebo-controlled study, spirometry was performed twice before vaccination to establish a baseline forced expiratory volume at 1 s (FEV1) and once 2 to 5 days thereafter. The primary outcome index was the percent change in percent predicted FEV1 before and after vaccination. Peak flows, clinical asthma symptom scores and nighttime awakening scores were measured daily from 7 days pre- to 28 days postvaccination.\n The primary outcome index (percentage change in percent predicted FEV1) was not different between the two groups (0.2% vs. 0.4% for the treatment and placebo groups, respectively; P = 0.78). Secondary outcomes did not differ between the two groups; these included the number of subjects with a decrease in FEV1 > or =15% from baseline, reductions in peak flows > or =15%, > or =30% or > or =2 sd below baseline, use of beta-adrenergic rescue medications, asthma exacerbations and clinical asthma symptom scores before and after vaccination. The same proportion of subjects in each group experienced postvaccination symptoms within 10 days (92% and 91%, respectively; P = 1.0). No serious adverse event occurred.\n CAIV-T was generally safe and well-tolerated in children and adolescents with moderate to severe asthma.", "Despite their potential for increased morbidity, 75% to 90% of asthmatic children do not receive influenza vaccination. Live attenuated influenza vaccine (LAIV), a cold-adapted, temperature-sensitive, trivalent influenza vaccine, is approved for prevention of influenza in healthy children 5 to 19 years of age. LAIV has been studied in only a small number of children with asthma.\n Children 6 to 17 years of age, with a clinical diagnosis of asthma, received a single dose of either intranasal CAIV-T (an investigational refrigerator-stable formulation of LAIV; n = 1114) or injectable trivalent inactivated influenza vaccine (TIV; n = 1115) in this randomized, open-label study during the 2002-2003 influenza season. Participants were followed up for culture-confirmed influenza illness, respiratory outcome, and safety.\n The incidence of community-acquired culture-confirmed influenza illness was 4.1% (CAIV-T) versus 6.2% (TIV), demonstrating a significantly greater relative efficacy of CAIV-T versus TIV of 34.7% (90% confidence interval [CI] 9.4%-53.2%; 95% CI = 3.9%-56.0%). There were no significant differences between treatment groups in the incidence of asthma exacerbations, mean peak expiratory flow rate findings, asthma symptom scores, or nighttime awakening scores. The incidence of runny nose/nasal congestion was higher for CAIV-T (66.2%) than TIV (52.5%) recipients. Approximately 70% of TIV recipients reported injection site reactions.\n CAIV-T was well tolerated in children and adolescents with asthma. There was no evidence of a significant increase in adverse pulmonary outcomes for CAIV-T compared with TIV. CAIV-T had a significantly greater relative efficacy of 35% compared with TIV in this high-risk population.", "The effects of intranasal inoculation with live attenuated, CR influenza virus vaccines on pulmonary function in healthy and asthmatic adults were evaluated in placebo-controlled, double-blind studies. In 46 healthy adult volunteers, there were no statistically significant alterations in pulmonary function as measured by spirometry and histamine bronchoprovocation tests in the first week following monovalent CR influenza virus vaccine [type A (H3N2, H1N1) and type B]. Among healthy adults with pre-inoculation PC20s less than 10 mg ml-1, 8/12 were infected following vaccination but no significant alterations occurred in histamine bronchoprovocation. In 11 asthmatic adults, no statistically significant alterations in pulmonary function, as measured by spirometry, were noted during the first 7 days postinoculation with bivalent CR influenza virus vaccine type A (H3N2 and H1N1). Postinoculation respiratory illnesses were more common in CR influenza virus vaccine recipients than placebo recipients, but they were mild, consisting of afebrile pharyngitis and transient rhinorrhea. Attenuated CR influenza virus vaccines do not appear to impair pulmonary function during the first week following immunization of healthy and asthmatic adults.", "Fewer than 10% of children with moderate or severe asthma receive an annual influenza vaccination despite their heightened susceptibility to severe infections and recommendations by the American Academy of Pediatrics and the Immunization Practices Advisory Committee that all such children be vaccinated annually. Patient, provider, and system factors leading to this poor vaccination rate are not well understood. This study tested the effectiveness of a computerized reminder system in improving influenza vaccination rates in children with asthma and examined patient barriers to vaccination at one pediatric clinic in an urban teaching hospital. A computer database identified 124 children with moderate or severe asthma. Patients were randomly assigned either to study group (n = 63), who were sent a personalized letter reminder about the need for an influenza vaccination, or to a control group (n = 61), who received no reminder. Study group mothers were interviewed 2 months after the letter was sent to assess factors associated with receipt of vaccination, including demographic features, parental worry about asthma and vaccine side effects, the four dimensions of the Health Belief Model, and health locus of control beliefs. Nineteen study group patients (30%) received an influenza vaccination, compared with only 4 control patients (7%) (P < .01). Forty-three mothers of children in the study group were interviewed; 14 (33%) of these children had received the vaccination. Of the characteristics investigated, two significantly correlated with vaccination compliance: high levels of parental worry about asthma (positively correlated: odds ratio = 23.3, P < .01) and high levels of parental worry about vaccine side effects (negatively correlated: odds ratio = 0.087, P = .025).(ABSTRACT TRUNCATED AT 250 WORDS)", "The morbidity and mortality associated with influenza is substantial in children with asthma. There are no available data on the safety and immunogenicity of influenza vaccine in children with asthma in Latin America. Furthermore, it is unclear if influenza vaccination may cause asthma exacerbations.\n We conducted a placebo-controlled trial to investigate the safety and immunogenicity of an inactivated trivalent split virus influenza vaccine in children with asthma in Mexico. We also measured the impact of influenza vaccination on pulmonary function tests in this population.\n The inactivated influenza vaccine was immunogenic and safe in terms of local and systemic side effects compared to placebo. We observed no significant impact on pulmonary function tests among vaccine recipients.\n Given the significant morbidity associated with influenza in children, strategies to promote increased influenza vaccination coverage in this high-risk group in Latin America and elsewhere are urgently needed.", "Live attenuated, cold-adapted (ca) monovalent and bivalent influenza A vaccines were evaluated in seronegative infants (ages 6-18 months) in a double-blind placebo-controlled trial to assess safety and immunogenicity. A total of 182 seronegative subjects received a single intranasal dose (10(6.2) TCID50) of ca A/Kawasaki/9/86 (H1N1) or ca A/Los Angeles/2/87 (H3N2), both as a bivalent vaccine, or placebo. Respiratory and systemic symptoms did not differ between groups after vaccination. Hemagglutination antibody seroconversions (> or = 1:8) to H3N2 exceeded 90%. In contrast, seroconversions to A/Kawasaki/9/86 (H1N1) were significantly less frequent in bivalent ca vaccine recipients (31%) than in monovalent ca H1N1 recipients (83%) (P < .002). During a subsequent H3N2 epidemic, nasal washes were cultured for viruses from any subject with respiratory illness. H3N2 infections documented by virus isolation were reduced by 65% in ca H3N2 recipients compared with placebo or ca HIM recipients (P = .01).", "Live attenuated cold-adapted reassortant (CR) influenza virus vaccines were evaluated in institutionalized asthmatic children and severe psychomotor-retarded (SPR) patients. Almost all the vaccinees were seropositive to the vaccine strains before immunization. Trivalent CR vaccine (containing A H1N1 (CR-125), A H3N2 (CR-149) and B (CRB-117)), bivalent CR vaccine (CR-125 and CR-149) and monovalent CRB-117 were inoculated to 19 asthmatic children and 36 and 16 SPR patients, respectively. Overall 49, 22, and 11% of vaccinees were infected by A H1N1, A H3N2 or B vaccine viruses, respectively, as indicated by significant haemagglutination-inhibition (HI) antibody titre rises 4 weeks after inoculation. No severe adverse reactions associated with CR vaccination were observed in the handicapped patients. A nosocomial outbreak of influenza A H1N1 occurred in the ward with asthmatic children, but none of the 19 CR-trivalent vaccinees became infected. However, five of 20 non-vaccinees in the same ward, and ten of 30 vaccinees in another ward that received inactivated split vaccine became infected. The CR vaccines demonstrated significant protective effects against natural exposure to the A H1N1 virus, and were well tolerated and safe when given to patients with bronchial asthma and severe psychomotor retardation.", "Controlled epidemiological surveillance covering the total number of 13,355 schoolchildren aged 11-14 years and adolescents was carried out with a view to compare the efficacies of inactivated influenza vaccines. The children were immunized intradermally in a single injection with inactivated influenza vaccines containing A (H3N2) and A (H1N1) hemagglutinins, 3.5 micrograms per 0.2 ml of the preparation each. The studies demonstrated the safety and low reactogenicity of these vaccines, as well as their high antigenic potency. In 1984 during mixed influenza B + A (H1N1) epidemic the preparations produced a pronounced prophylactic effect: the efficacy indices were 1.6-1.9 (p less than 0.001). The results obtained in these studies made it possible to recommend two inactivated influenza vaccines (chromatographic and centrifugal) for practical medicine with the aim of protecting children aged 11 years and over from influenza.", "Reported is a study of live, cold-adapted (CA) reassortant mono-, di-, and trivalent influenza type A and B vaccines in a series of controlled clinical and epidemiological investigations involving nearly 130 000 children aged 3-15 years. The results of clinical, immunological, and morbidity investigations of the vaccinees and a control group over 6-months' follow-up indicated that the vaccines were completely attenuated by the children. Transient febrile reactions occurred in < 1% of the children after vaccination, including double seronegative individuals with low antibody titres. The type A reisolates examined were genetically stable. The reassortants did not suppress each other after simultaneous inoculation of children and stimulated antibody response to influenza virus strains A1, A3, and B. The incidence of influenza-like diseases was approximately 30-40% lower among the vaccinated group than among the control group. The study demonstrates, for the first time, the efficacy of CA vaccine against infections caused by influenza B virus.", "During the first wave of A/California/7/2009(H1N1) influenza, high rates of hospitalization in children under 5 years were seen in many countries. Subsequent policies for vaccinating children varied in both type of vaccine and number of doses. In Canada, children 36 months to <10 years received a single dose of 0.25 ml of the GSK adjuvanted vaccine (Arepanrix) equivalent to 1.9 microg HA. Children 6 months to 35 months received two doses as did those 36-119 months with chronic medical conditions.\n We conducted a community-based case-control vaccine effectiveness (VE) review of children under 10 years with influenza like illness who were tested for H1N1 infection at the central provincial laboratory. Laboratory-confirmed influenza was the primary outcome, and vaccination status the primary exposure to assess VE after a single 0.25-ml dose.\n If vaccination was designated to be effective after 14 days, no vaccinated child had laboratory-confirmed influenza compared to 38% of controls. The VE of 100% was statistically significant for children <10 years of age and <5 years considered separately. If vaccination was considered effective after 10 days, VE dropped to 96% overall but was statistically significant and over 90% in all age subgroups, including those under 36 months.\n A single 0.25-ml dose of the GSK adjuvanted vaccine (Arepanrix) protects children against laboratory-confirmed pandemic influenza potentially avoiding any increased reactogenicity associated with second doses. Adjuvanted vaccines offer hope for improved seasonal vaccines in the future." ]	Uncertainty remains about the degree of protection that vaccination affords against asthma exacerbations that are related to influenza infection. Evidence from more recently published randomised trials of inactivated split-virus influenza vaccination indicates that there is no significant increase in asthma exacerbations immediately after vaccination in adults or children over three years of age. We were unable to address concerns regarding possible increased wheezing and hospital admissions in infants given live intranasal vaccination.
CD004153	[ "16393498" ]	[ "The use of ozone in dentistry and medicine. Part 2. Ozone and root caries." ]	[ "A previous paper, recently published in Primary Dental Care, gave an overview of the medical uses of ozone and outlined some of its uses in dentistry. The current paper focuses on a description of use of ozone in the management of root caries and considers recent studies in this area. There has been relatively limited research into the non-invasive (pharmaceutical) management of root caries. The best management strategy still remains to be developed. Initial studies have indicated that an application of ozone for a period of either 10 or 20 seconds is capable of clinically reversing leathery root carious lesions. It is suggested that, subject to confirmation from extensive trials, this simple and non-invasive technique may benefit many patients with root caries throughout the world since this approach to treat root caries can easily be employed in primary care clinics and in the domiciliary treatment of home-bound elderly people and immobile patients in hospices and hospitals." ]	Given the high risk of bias in the available studies and lack of consistency between different outcome measures, there is no reliable evidence that application of ozone gas to the surface of decayed teeth stops or reverses the decay process. There is a fundamental need for more evidence of appropriate rigour and quality before the use of ozone can be accepted into mainstream primary dental care or can be considered a viable alternative to current methods for the management and treatment of dental caries.
CD003410	[ "16389204", "6996635", "17602126", "11391170", "17628351", "14563543" ]	[ "A randomized controlled trial of interim methadone maintenance.", "Evaluation of heroin maintenance in controlled trial.", "Heroin-assisted treatment for opioid dependence: randomised controlled trial.", "Methadone maintenance as HIV risk reduction with street-recruited injecting drug users.", "A randomized clinical trial of methadone maintenance for prisoners: results at 1-month post-release.", "A randomised controlled trial of methadone maintenance treatment versus wait list control in an Australian prison system." ]	[ "Effective alternatives to long waiting lists for entry into methadone hydrochloride maintenance treatment are needed to reduce the complications of continuing heroin dependence and to increase methadone treatment entry.\n To compare the effectiveness of interim methadone maintenance with that of the usual waiting list condition in facilitating methadone treatment entry and reducing heroin and cocaine use and criminal behavior.\n Randomized, controlled, clinical trial using 2 conditions, with treatment assignment on a 3:2 basis to interim maintenance-waiting list control.\n A methadone treatment program in Baltimore.\n A total of 319 individuals meeting the criteria for current heroin dependence and methadone maintenance treatment.\n Participants were randomly assigned to either interim methadone maintenance, consisting of an individually determined methadone dose and emergency counseling only for up to 120 days, or referral to community-based methadone treatment programs.\n Entry into comprehensive methadone maintenance therapy at 4 months from baseline; self-reported days of heroin use, cocaine use, and criminal behavior; and number of urine drug test results positive for heroin and cocaine at the follow-up interview conducted at time of entry into comprehensive methadone treatment (or at 4 months from baseline for participants who did not enter regular treatment).\n Significantly more participants assigned to the interim methadone maintenance condition entered comprehensive methadone maintenance treatment by the 120th day from baseline (75.9%) than those assigned to the waiting list control condition (20.8%) (P<.001). Overall, in the past 30 days at follow-up, interim participants reported significantly fewer days of heroin use (P<.001), had a significant reduction in heroin-positive drug test results (P<.001), reported spending less money on drugs (P<.001), and received less illegal income (P<.02) than the waiting list participants.\n Interim methadone maintenance results in a substantial increase in the likelihood of entry into comprehensive treatment, and is an effective means of reducing heroin use and criminal behavior among opioid-dependent individuals awaiting entry into a comprehensive methadone treatment program.", "Ninety-six confirmed heroin addicts requesting a heroin maintenance prescription were randomly allocated to treatment with injectable heroin or oral methadone. Progress was monitored throughout the next 12 months by research workers operating independently of the clinic. Heroin can be seen as maintaining the status quo, with the majority continuing to inject heroin regularly and to supplement their maintenance prescription from other sources; it was associated with a continuing intermediate level of involvement with the drug subculture and criminal activity. Refusal to prescribe heroin while offering oral methadone constituted a more confrontational response and resulted in a higher abstinence rate, but also a greater dependence on illegal sources of drugs for these who continued to inject. Those offered oral methadone tended to polarize toward high or low categories of illegal drug use and involvement with the drug subculture, and were more likely to be arrested during the 12-month follow-up. There was no difference between the two groups in terms of employment, health, or consumption of nonopiate drugs. Refusal to prescribe heroin resulted in a significantly greater drop out from regular treatment.", "Heroin-assisted treatment has been found to be effective for people with severe opioid dependence who are not interested in or do poorly on methadone maintenance.\n To study heroin-assisted treatment in people on methadone who continue intravenous heroin and in those who are heroin dependent but currently not in treatment.\n In an open-label multicentre randomised controlled trial, 1015 people with heroin dependence received a variable dose of injectable heroin (n=515) or oral methadone (n=500) for 12 months. Two response criteria, improvement of physical and/or mental health and decrease in illicit drug use, were evaluated in an intent-to-treat analysis.\n Retention was higher in the heroin (67.2%) than in the methadone group (40.0%) and the heroin group showed a significantly greater response on both primary outcome measures. More serious adverse events were found in the heroin group, and were mainly associated with intravenous use.\n Heroin-assisted treatment is more effective for people with opioid dependence who continue intravenous heroin while on methadone maintenance or who are not enrolled in treatment. Despite a higher risk, it should be considered for treatment resistance under medical supervision.", "To compare changes in HIV risk behaviors between street-recruited opiate injectors who entered and remained in methadone maintenance treatment and those who did not.\n Three hundred sixteen participants were interviewed at baseline, received outreach interventions, and were interviewed again 6 months later.\n Significant (p <.001) reductions in HIV-related risk behaviors, including frequency of injecting, injecting with used (dirty) needles, and sharing injection paraphernalia, were demonstrated. Participants (31%) who entered and remained in methadone maintenance treatment for at least 90 days before follow-up showed a significantly greater reduction in heroin injections than those who did not. They did not show a greater reduction in using dirty needles or sharing other injection paraphernalia.\n These findings suggest that although methadone maintenance may reduce injection frequency, it does not reduce other HIV-related risk behaviors above and beyond what can be accomplished through outreach interventions. Treatment facilities and outreach intervention programs should collaborate to provide a comprehensive approach to reducing HIV risk behaviors among drug injectors both in and out of drug treatment.", "Despite its effectiveness, methadone maintenance is rarely provided in American correctional facilities. This study is the first randomized clinical trial in the US to examine the effectiveness of methadone maintenance treatment provided to prisoners with pre-incarceration heroin addiction.\n A three-group randomized controlled trial was conducted between September 2003 and June 2005. Two hundred eleven Baltimore pre-release inmates who were heroin dependent during the year prior to incarceration were enrolled in this study. Participants were randomly assigned to the following: counseling only: counseling in prison, with passive referral to treatment upon release (n=70); counseling+transfer: counseling in prison with transfer to methadone maintenance treatment upon release (n=70); and counseling+methadone: methadone maintenance and counseling in prison, continued in a community-based methadone maintenance program upon release (n=71).\n Two hundred participants were located for follow-up interviews and included in the current analysis. The percentages of participants in each condition that entered community-based treatment were, respectively, counseling only 7.8%, counseling+transfer 50.0%, and counseling+methadone 68.6%, p<.05. All pairwise comparisons were statistically significant (all ps<.05). The percentage of participants in each condition that tested positive for opioids at 1-month post-release were, respectively, counseling only 62.9%, counseling+transfer 41.0%, and counseling+methadone 27.6%, p<.05, with the counseling only group significantly more likely to test positive than the counseling+methadone group.\n Methadone maintenance initiated prior to or immediately after release from prison appears to have beneficial short-term impact on community treatment entry and heroin use. This intervention may be able to fill an urgent treatment need for prisoners with heroin addiction histories.", "The aim was to determine whether methadone maintenance treatment reduced heroin use, syringe sharing and HIV or hepatitis C incidence among prisoners.\n All eligible prisoners seeking drug treatment were randomised to methadone or a waitlist control group from 1997 to 1998 and followed up after 4 months. Heroin use was measured by hair analysis and self report; drugs used and injected and syringe sharing were measured by self report. Hepatitis C and HIV incidence was measured by serology.\n Of 593 eligible prisoners, 382 (64%) were randomised to MMT (n=191) or control (n=191). 129 treated and 124 control subjects were followed up at 5 months. Heroin use was significantly lower among treated than control subjects at follow up. Treated subjects reported lower levels of drug injection and syringe sharing at follow up. There was no difference in HIV or hepatitis C incidence.\n Consideration should be given to the introduction of prison methadone programs particular where community based programs exist." ]	The available evidence suggests an added value of heroin prescribed alongside flexible doses of methadone for long-term, treatment refractory, opioid users, to reach a decrease in the use of illicit substances, involvement in criminal activity and incarceration, a possible reduction in mortaliity; and an increase in retention in treatment. Due to the higher rate of serious adverse events, heroin prescription should remain a treatment for people who are currently or have in the past failed maintenance treatment, and it should be provided in clinical settings where proper follow-up is ensured.
CD001442	[ "14526208", "12671780", "16770291", "15659884", "17891043", "15040540", "15867495", "16283835", "14617500", "12698766", "18077833", "12781934", "21457056", "15751766", "12469544", "21252632", "15294086" ]	[ "Impact of a patient education program on adherence to HIV medication: a randomized clinical trial.", "Efficacy of an educational and counseling intervention on adherence to highly active antiretroviral therapy: French prospective controlled study.", "Home visits to improve adherence to highly active antiretroviral therapy: a randomized controlled trial.", "Multidisciplinary HIV adherence intervention: a randomized study.", "Telephone support to improve antiretroviral medication adherence: a multisite, randomized controlled trial.", "Effect of individual cognitive behaviour intervention on adherence to antiretroviral therapy: prospective randomized trial.", "Couple-focused support to improve HIV medication adherence: a randomized controlled trial.", "Effects of a treatment adherence enhancement program on health literacy, patient-provider relationships, and adherence to HAART among low-income HIV-positive Spanish-speaking Latinos.", "Use of an on-line pager system to increase adherence to antiretroviral medications.", "Using motivational interviewing to promote adherence to antiretroviral medications: a pilot study.", "Motivational interviewing and cognitive-behavioral intervention to improve HIV medication adherence among hazardous drinkers: a randomized controlled trial.", "A medication self-management program to improve adherence to HIV therapy regimens.", "Brief behavioral self-regulation counseling for HIV treatment adherence delivered by cell phone: an initial test of concept trial.", "A randomized controlled trial to enhance antiretroviral therapy adherence in patients with a history of alcohol problems.", "Results of a pilot intervention trial to improve antiretroviral adherence among HIV-positive patients.", "Mobile phone technologies improve adherence to antiretroviral treatment in a resource-limited setting: a randomized controlled trial of text message reminders.", "Adherence to antiretroviral therapy in HIV-infected pediatric patients improves with home-based intensive nursing intervention." ]	[ "Patients' knowledge of their HIV condition and its treatment, which has been recognized as a factor that influences adherence to antiretroviral therapy, can be improved through educational programs. This prospective, randomized, controlled trial compared an experimental group that participated in an educational program and a control group with standard care. The study evaluated the impact of an educational intervention on adherence to antiretroviral therapy, patients' knowledge, quality of life, and therapeutic response in patients treated with highly active antiretroviral therapy. Three hundred twenty-six patients were analyzed at inclusion. A higher level of adherence was associated with patients who were older, had higher incomes, and did not smoke. CD4 cell count and plasma viral load were correlated with adherence at entry. The educational intervention had an impact on adherence and knowledge in the experimental group at 6 months, which was maintained at 12 and 18 months. A delayed increase in adherence was observed in the control group at 12 months. No significant impact on quality of life was observed over time. The patients' health status improved in 56% of the experimental group subjects and 50% of the control subjects. However, no significant impact was shown on CD4 cell count and plasma viral load. This study shows that an educational intervention improves adherence to antiretroviral regimens and health status and suggests that it should be initiated early in therapy.", "The objective was to evaluate the impact of an intervention for improving adherence to antiretroviral therapies (HAART) in HIV-infected patients.\n We designed a prospective, controlled, randomized trial to assess the impact of an educational and counseling intervention in addition to standard of care. At M0, the study enrolled 244 HAART-treated patients who attended a medical consultation between September and December 1999 who were not included in another protocol. Patients in the intervention group (IG) were offered three individual sessions by trained nurses. The proportions of adherent patients at 6 months followup (M6) and the change in HIV RNA between M0 and M6 were measured.\n Between M0 and M6, HIV RNA significantly decreased in the 123 patients of the IG (mean difference = -0.22 log [+/-0.86], p =.013), while it increased (+0.12 log [+/-0.90], p =.14) in the 121 patients of the control group. However, the proportion of patients with HIV RNA <40 copies/mL remained similar in both groups. In an intent-to-treat analysis, the only significant predictor of 100% adherence at M6 was the intervention group (p =.05) after adjustment for baseline adherence (p =.001). Among the 202 patients with available data on adherence, the proportion of adherent patients was similar in both groups at M0 (58% vs. 63%, p =.59) but became higher in the IG at M6 (75% vs. 61%, p =.04).\n The educational and counseling intervention was efficient for increasing adherence to HAART and could be implemented in most clinical settings.", "Few rigorously designed studies have documented the efficacy of interventions to improve medication adherence among patients prescribed highly active antiretroviral. Data are needed to justify the use of limited resources for these programs.\n A 2-arm, randomized, controlled trial evaluated the efficacy of a community-based, home-visit intervention to improve medication adherence. Participants were 171 HIV-infected adults prescribed a minimum of 3 antiretroviral agents. The majority had a past or current history of substance abuse. Subjects were randomly assigned to receive home visits for 1 year or usual care. Medication adherence was assessed with Medication Event Monitoring stem caps at 3-month intervals from randomization through 3 months after the conclusion of the intervention.\n A larger proportion of subjects in the intervention group demonstrated adherence greater than 90% compared with the control group at each time point after baseline. The difference over time was statistically significant (Extended Mantel-Haenszel test: 5.80, P = 0.02). A statistically significant intervention effect on HIV-RNA level or CD4 cell count was not seen, but there was a statistically significant association between greater than 90% adherence and an undetectable HIV-RNA over time (P < 0.03).\n Home visits from a nurse and a community worker were associated with medication adherence greater than 90% among a cohort of socially vulnerable people living with HIV/AIDS in northeastern United States.", "Maintaining greater than 95% adherence to antiretroviral medication is necessary in order to have the greatest therapeutic impact on HIV infection. Furthermore, evidence suggests that adherence rates of between 70% and 89% are significantly associated with viral rebound and the development of drug resistance. Adherence rates at and above the 95% level are difficult for patients to achieve and maintain. Our aim was to determine if an adherence intervention could improve adherence among patients attending an ambulatory care clinic at a large public hospital. The intervention was delivered by a multidisciplinary team of health care professionals and consisted of education coupled with the provision of devices designed to assist patient memory and adherence. A crucial component of the intervention consisted of the identification of patient specific barriers to adherence and the development of strategies to circumvent these problems. Adherence was assessed using patient self-report over the past 4, 7, and 28 days and by calculation of the Morisky score. The study was conducted as a randomised controlled trial using the stepped wedge design with a total of 68 subjects randomised to receive the intervention over a 20-week period. Adherence before and after the intervention formed the analysis. There was a significant decrease in the number of missed doses over the past 4 (1.9 to 1.0, p < 0.001), 7 (3.0 to 1.8, p < 0.001) and 28 (7.4 to 4.2, p < 0.001) days and a decrease in the Morisky score, indicating an improvement in medication taking behaviour (1.3 to 0.5 p < 0.001).", "To determine whether proactive telephone support improves adherence to antiretroviral therapy (ART) and clinical outcomes when compared to standard care.\n A multisite, randomized controlled trial (RCT) was conducted with 109 ART-naive subjects coenrolled in AIDS Clinical Trials Group (ACTG) 384. Subjects received standard clinic-based patient education (SC) or SC plus structured proactive telephone calls. The customized calls were conducted from a central site over 16 weeks by trained registered nurses. Outcome measures (collected over 64 weeks) included an ACTG adherence questionnaire and 384 study endpoints.\n For the primary endpoint, self-reported adherence, a significantly better overall treatment effect was observed in the telephone group (P = 0.023). In a post hoc analysis, composite adherence scores, taken as the first 2 factor scores from a principal components analysis, also found significant intervention benefit (P = 0.023 and 0.019 respectively). For the 384 primary study endpoint, time to regimen failure, the Kaplan-Meier survival curve for the telephone group remained above the SC group at weeks 20 to 64; a Cox proportional hazard model that controlled for baseline RNA stratification, CD4, gender, age, race/ethnicity, and randomized ART treatment arm suggested the telephone group tended to have a lower risk for failure (hazard ratio = 0.68; 95% confidence interval: 0.38 to 1.23).\n Findings indicate that customized, proactive telephone calls have good potential to improve long-term adherence behavior and clinical outcomes.", "A high level of adherence to antiretroviral therapy is required for complete suppression of HIV replication, immunological and clinical effectiveness. We investigated whether cognitive behaviour therapy can improve medication adherence.\n Prospective randomized 1-year trial.\n Collaboration of HIV university outpatient clinic and psychotherapists in private practice.\n 60 HIV-infected persons on stable antiretroviral combination therapy and viral load below 50 copies/ml.\n Cognitive behaviour intervention in individual patients, in addition to standard of care.\n Feasibility and acceptance of intervention; adherence to therapy assessed using medication event monitoring system (MEMS) and self-report questionnaire; virological failure; psychosocial measures.\n The median number of sessions for cognitive behaviour intervention per patient during the 1-year trial was 11 (range 2-25). At months 10-12, mean adherence to therapy as assessed using MEMS was 92.8% in the intervention and 88.9% in the control group (P=0.2); the proportion of patients with adherence > or = 95% was 70 and 50.0% (P=0.014), respectively. While there was no significant deterioration of adherence during the study in the intervention arm, adherence decreased by 8.7% per year (P=0.006) in the control arm. No differences between the intervention group and standard of care group were found regarding virological outcome. Compared with the control group, participants in the intervention group perceived a significant improvement of their mental health during the study period.\n Cognitive behavioural support in addition to standard of care of HIV-infected persons is feasible in routine practice, and can improve medication adherence and mental health.", "To assess the efficacy of a couple-based intervention to improve medication-taking behavior in a clinic population with demonstrated adherence problems.\n A randomized controlled trial (SMART Couples Study) conducted between August 2000 and January 2004.\n Two HIV/AIDS outpatient clinics in New York City.\n Heterosexual and homosexual HIV-serodiscordant couples (n = 215) in which the HIV-seropositive partner had < 80% adherence at baseline. The sample was predominantly lower-income racial/ethnic minorities.\n Participants were randomly assigned to a four-session couple-focused adherence intervention or usual care. The intervention consisted of education about treatment and adherence, identifying adherence barriers, developing communication and problem-solving strategies, optimizing partner support, and building confidence for optimal adherence.\n Medication adherence at week 8 (2 weeks after the intervention) compared with baseline, assessed with a Medication Event Monitoring System cap.\n Intervention participants showed higher mean medication adherence at post-intervention when compared with controls whether adherence was defined as proportion of prescribed doses taken (76% versus 60%) or doses taken within specified time parameters (58% versus 35%). Also, participants in the intervention arm were significantly more likely to achieve high levels of adherence (> 80%, > 90%, or > 95%) when compared with controls. However, in most cases, effects diminished with time, as seen at follow-up at 3 and 6 months.\n The SMART Couples program significantly improved medication adherence over usual care, although the level of improved adherence, for many participants, was still suboptimal and the effect was attenuated over time.", "The impact of an adherence enhancement program for low income HIV-infected Spanish-speaking Latinos on health literacy, patient-provider relationships, and adherence to HAART was examined. Evaluations were conducted at baseline, 6 weeks, and 6 months for participants (n = 85) randomly assigned to either the intervention group or a comparison group; 69 (81%) remained in the study for the entire 6-month duration. The intervention group scored significantly better than the comparison group on 3 of 5 measures of HIV health literacy at 6 weeks and on 2 of 5 measures, at 6 months. While there was a weak trend for the intervention group to report an increase in self-efficacy of medication adherence management, baseline to 6 weeks, no other changes were significant. Perceptions of the quality of relationship and communications with their HIV-treating physicians improved both at 6 weeks (p = 0.04) and at 6 months (p < 0.001). The comparison group showed little change baseline to 6 weeks and baseline to 6 months. While there was a trend for the pilot group to report better medication adherence, these differences were not statistically significant. Further evaluation of the impact of this adherence enhancement program is needed.", "Adherence to antiretroviral therapy is critical for treatment success. Antiretroviral therapy typically requires multiple pills at multiple dosing times. To address this, we tested the feasibility, utility, and efficacy of a customizable reminder system using pagers, which were programmed using web-based technology, to increase and maintain proper adherence in patients with pre-existing adherence problems. After a two-week monitoring period with an electronic pill-cap, participants with less than 90% adherence were randomized to continue monitoring or to receive a pager. The group who received the pagers had greater improvements in adherence from baseline to Week 2 and Week 12 than those who monitored their medications only. However, adherence in both groups at the outcome assessments points was still poor. While the provision of a reminder system helped improve adherence, it is likely that more intensive interventions are required for patients with pre-existing problems.", "This report describes a pilot study of a nursing intervention to increase adherence to combination therapy. The intervention was based on motivational interviewing (MI). Participants completed a baseline assessment using the computer-administered self-interview with audio (ACASI) data collection method and then were randomly assigned to the MI intervention or control condition. Nurse counselors met with participants in the MI intervention group for three adherence sessions. Two months following baseline, participants completed a follow-up assessment. Mean scores on ratings of missed medications were lower for participants in the intervention group than those in the control group. Although there were no significant differences in the number of medications missed during the past 4 days, participants in the MI group reported being more likely to follow the medication regimen as prescribed by their health care provider. The pilot study provided useful information about the acceptability of ACASI and the adequacy of intervention procedures. The results of this pilot study show promise for the use of MI as an intervention to promote adherence to antiretroviral medications.", "To assess the efficacy of a behavioral intervention designed to improve HIV medication adherence and reduce alcohol consumption among HIV-positive men and women.\n A randomized controlled trial conducted between July 2002 and August 2005.\n A behavioral research center in New York City.\n HIV-positive men and women (n = 143) who were on HIV antiretroviral medication and met criteria for hazardous drinking.\n Participants were randomly assigned to an 8-session intervention based on motivational interviewing and cognitive-behavioral skills building or a time- and content-equivalent educational condition.\n Viral load, CD4 cell count, and self-reported adherence and drinking behavior were assessed at baseline and at 3- and 6-month follow-ups.\n Relative to the education condition, participants in the intervention demonstrated significant decreases in viral load and increases in CD4 cell count at the 3-month follow-up and significantly greater improvement in percent dose adherence and percent day adherence. There were no significant intervention effects for alcohol use, however, and effects on viral load, CD4 cell count, and adherence were not sustained at 6 months.\n An 8-session behavioral intervention can result in improvement in self-report and biologic markers of treatment adherence and disease progression. This type of intervention should be considered for dissemination and integration into HIV clinics providing comprehensive care for HIV-positive persons with alcohol problems. Although the effect was attenuated over time, future studies might test the added effectiveness of booster sessions or ongoing adherence counseling.", "This study examined whether a self-management intervention based on feedback of adherence performance and principles of social cognitive theory improves adherence to antiretroviral dosing schedules. Forty-three individuals with HIV/AIDS who were starting or switching to a new protease inhibitor regimen were randomly assigned to be in a medication self-management program or usual care control group. The self-management program included skills development exercises, three monthly visits for medication consultations, and monthly feedback of adherence performance using electronic monitors on medication bottles. Participants also completed a 40-item questionnaire that measured self-efficacy to take medications, on schedule, in a variety of situations. Logistic regression analysis indicated that individuals in the self-management group were significantly more likely to take 80% or more of their doses each week than individuals in the control group (n=29, OR=7.8, 95% CI=2.2-28.1). Self-management training with feedback of adherence performance is a potentially useful model for improving adherence to complex regimens in HIV/AIDS care.", "Affordable and effective antiretroviral therapy (ART) adherence interventions are needed for many patients to promote positive treatment outcomes and prevent viral resistance. We conducted a two-arm randomized trial (n = 40 men and women receiving and less than 95% adherent to ART) to test a single office session followed by four biweekly cell phone counseling sessions that were grounded in behavioral self-management model of medication adherence using data from phone-based unannounced pill counts to provide feedback-guided adherence strategies. The control condition received usual care and matched office and cell phone/pill count contacts. Participants were baseline assessed and followed with biweekly unannounced pill counts and 4-month from baseline computerized interviews (39/40 retained). Results showed that the self-regulation counseling delivered by cell phone demonstrated significant improvements in adherence compared to the control condition; adherence improved from 87% of pills taken at baseline to 94% adherence 4 months after baseline, p < 0.01. The observed effect sizes ranged from moderate (d = 0.45) to large (d = 0.80). Gains in adherence were paralleled with increased self-efficacy (p < 0.05) and use of behavioral strategies for ART adherence (p < 0.05). We conclude that the outcomes from this test of concept trial warrant further research on cell phone-delivered self-regulation counseling in a larger and more rigorous trial.", "To assess the effectiveness of an individualized multicomponent intervention to promote adherence to antiretroviral therapy (ART) in a cohort of HIV-infected individuals with a history of alcohol problems.\n We conducted a randomized controlled trial to compare the usual medical follow-up with an adherence intervention.\n The principal enrolment site was Boston Medical Center, a private, not-for-profit, academic medical institution.\n HIV-infected patients with a history of alcohol problems on ART. A total of 151 were enrolled and 141 (93%) were assessed at follow-up. Intervention: A nurse, trained in motivational interviewing, completed the following over 3 months in four encounters: addressed alcohol problems; provided a watch with a programmable timer to facilitate pill taking; enhanced perception of treatment efficacy; and delivered individually tailored assistance to facilitate medication use.\n Prior 30-day adherence > or =95%, prior 3-day adherence of 100%, CD4 cell count, HIV RNA and alcohol consumption, each at both short- and long-term follow-up.\n At follow-up, no significant differences in medication adherence, CD4 cell count, HIV RNA or alcohol consumption were found (all P values >0.25).\n A multicomponent intervention to enhance adherence among HIV-infected individuals with a history of alcohol problems was not associated with changes in medication adherence, alcohol consumption or markers of HIV disease progression. The failure to change adherence in a group at high risk for poor adherence, despite utilizing an intensive individual-focused patient intervention, supports the idea of addressing medication adherence with supervised medication delivery or markedly simplified dosing regimens.", "A small pilot trial of a multicomponent (behavioral strategies, simplified patient information, and social support) and multidisciplinary (cognitive-behavioral therapy and nursing) medication adherence intervention was conducted for HIV-infected adults prescribed antiretrovirals. Patients (N = 33) were randomly assigned to the intervention condition or standard care. Compared to the control group, patients in the intervention condition had significantly higher self-efficacy to communicate with clinic staff (p = .04) and to continue treatment (p = .04), were significantly more likely to be using behavioral and cognitive strategies (p = .01 and p = .04), reported significantly higher life satisfaction (p = .03), reported significantly increased feelings of social support (p = .04), and showed a trend toward an increase in taking their medications on schedule (p = .06). The intervention, however, did not appear to affect health-related anxiety or to significantly improve adherence to dose. Implications for future intervention planning are discussed.", "There is limited evidence on whether growing mobile phone availability in sub-Saharan Africa can be used to promote high adherence to antiretroviral therapy (ART). This study tested the efficacy of short message service (SMS) reminders on adherence to ART among patients attending a rural clinic in Kenya.\n A randomized controlled trial of four SMS reminder interventions with 48 weeks of follow-up.\n Four hundred and thirty-one adult patients who had initiated ART within 3 months were enrolled and randomly assigned to a control group or one of the four intervention groups. Participants in the intervention groups received SMS reminders that were either short or long and sent at a daily or weekly frequency. Adherence was measured using the medication event monitoring system. The primary outcome was whether adherence exceeded 90% during each 12-week period of analysis and the 48-week study period. The secondary outcome was whether there were treatment interruptions lasting at least 48 h.\n In intention-to-treat analysis, 53% of participants receiving weekly SMS reminders achieved adherence of at least 90% during the 48 weeks of the study, compared with 40% of participants in the control group (P = 0.03). Participants in groups receiving weekly reminders were also significantly less likely to experience treatment interruptions exceeding 48 h during the 48-week follow-up period than participants in the control group (81 vs. 90%, P = 0.03).\n These results suggest that SMS reminders may be an important tool to achieve optimal treatment response in resource-limited settings.", "Adherence to combination antiretroviral therapy (ART) has been shown to be a determining factor in controlling viral replication, maintaining immunologic function and long-term survival in HIV-positive individuals. Little information is available on strategies to improve adherence in pediatric HIV-infected patients. We conducted a randomized, nonblinded, pilot study to determine if a home-based nursing intervention would improve medication adherence. The study was offered to all eligible HIV-positive patients receiving care at Connecticut Children's Medical Center's (CCMC) Pediatric and Youth HIV Program. Sixty-seven percent (37/55) of the patients and their caretakers participated. We randomized participants to either standard of care or the intervention trial. The intervention was designed to improve knowledge and understanding of HIV infection and HIV medications and to resolve or modify barriers to adherence. Both groups completed pre- and post-intervention questionnaires, assessing their knowledge and understanding of HIV, ART, and adherence. Adherence was estimated objectively from medication refill history and subjectively from a self-report score. We also inferred adherence from pre- to post-test plasma viral load and CD4+ T-cell percentages. The knowledge score (p = 0.02) and medication refill history (p = 0.002) improved significantly in the intervention group. The adherence self-report score improved, although not significantly (p = 0.07). We did not observe statistical differences in CD4+ T-cell counts or viral load between groups. We conclude that our home-based nursing intervention helped HIV-positive children and their families in better adhering to prescribed medication regimens." ]	We found evidence to support the effectiveness of patient support and education interventions intended to improve adherence to antiretroviral therapy. Interventions targeting practical medication management skills, those interventions administered to individuals vs groups, and those interventions delivered over 12 weeks or more were associated with improved adherence outcomes. There is a need for standardization and increased methodological rigour in the conduct of adherence trials.
CD003431	[ "11535842", "11668104", "17522765", "12524411", "10626860", "14523338", "19137320", "16988850", "12780888", "10395629", "9369106", "11008725", "17256809", "15200038", "9221864", "10205213", "10458121", "9435326", "18783071", "11856083", "19918682", "19367435", "17190281", "8988115", "23577680", "20703472", "12619423", "15250565", "16612915", "6338993", "18365505", "12950424", "15521346", "11854696", "12432293", "12463433", "18470565", "12352236", "17869598", "16398803", "10737578", "15820455", "15739214", "16614779", "11419556", "12790983", "3039130", "15972045", "1298616", "6337670", "15309644", "17573751", "10950002", "16091912", "16204903", "19361582", "14994114", "19415396" ]	[ "A randomized trial of oral vs. topical diltiazem for chronic anal fissures.", "Double blind randomised controlled trial of topical glyceryl trinitrate in anal fissure.", "A comparison of the effects of diltiazem and glyceryl trinitrate ointment in the treatment of chronic anal fissure: a randomized clinical trial.", "A dose finding study with 0.1%, 0.2%, and 0.4% glyceryl trinitrate ointment in patients with chronic anal fissures.", "A prospective, randomized, double-blind, placebo-controlled trial of glyceryl-trinitrate ointment in the treatment of children with anal fissure.", "The use of glyceryl trinitrate (GTN) in the treatment of chronic anal fissure in children.", "Topical anal fissure treatment: placebo-controlled study of mononitrate and trinitrate therapies.", "Randomized clinical trial of botulinum toxin plus glyceryl trinitrate vs. botulinum toxin alone for medically resistant chronic anal fissure: overall poor healing rates.", "A prospective randomized trial of diltiazem and glyceryltrinitrate ointment in the treatment of chronic anal fissure.", "A comparison of injections of botulinum toxin and topical nitroglycerin ointment for the treatment of chronic anal fissure.", "Glyceryl trinitrate vs. sphincterotomy for treatment of chronic fissure-in-ano: a randomized, controlled trial.", "A randomized trial of glyceryl trinitrate ointment and nitroglycerin patch in healing of anal fissures.", "Randomized clinical trial comparing botulinum toxin injections with 0.2 per cent nitroglycerin ointment for chronic anal fissure.", "A randomised study comparing systemic transdermal treatment and local application of glyceryl trinitrate ointment in the management of chronic anal fissure.", "Local nitroglycerin for treatment of anal fissures: an alternative to lateral sphincterotomy?", "Randomised controlled trial shows that glyceryl trinitrate heals anal fissures, higher doses are not more effective, and there is a high recurrence rate.", "Glyceryl trinitrate ointment for the treatment of chronic anal fissure: results of a placebo-controlled trial and long-term follow-up.", "A comparison of botulinum toxin and saline for the treatment of chronic anal fissure.", "Comparative study of lateral internal sphincterotomy versus local 0.2% glyceryl trinitrate ointment for the treatment of chronic anal fissure.", "Topical mononitrate treatment in patients with anal fissure.", "Study of efficacy and safety of a new local cream ('healer') in the treatment of chronic anal fissure: a prospective, randomized, single-blind, comparative study.", "Glyceryl trinitrate ointment (0.25%) and anal cryothermal dilators in the treatment of chronic anal fissures.", "[Efficacy of anal dilators in the treatment of acute anal fissure. A controlled clinical trial].", "A randomised, prospective, double-blind, placebo-controlled trial of glyceryl trinitrate ointment in treatment of anal fissure.", "Chronic anal fissures treated with botulinum toxin injections: a dose-finding study with Dysport(®).", "Botulinum toxin injection versus lateral internal sphincterotomy in the treatment of chronic anal fissure: a randomized controlled trial.", "A randomized trial of botulinum toxin vs lidocain pomade for chronic anal fissure.", "Randomized, double-blind trial comparing topical nitroglycerine with xylocaine and Proctosedyl in idiopathic chronic anal fissure.", "Comparison of topical glyceryl trinitrate ointment and oral nifedipine in the treatment of chronic anal fissure.", "The conservative treatment of fissure-in-ano.", "[Surgical or biologic sphincterotomy in the treatment of chronic anal fissure].", "Lack of effficacy of botulinum toxin in chronic anal fissure.", "[A prospective, randomized double-blind study on the treatment of anal fissures with Nitroglycerin ointment].", "Effectiveness of higher doses of botulinum toxin to induce healing in patients with chronic anal fissures.", "Topical nifedipine with lidocaine ointment vs. active control for treatment of chronic anal fissure: results of a prospective, randomized, double-blind study.", "Randomised trial of topical 0.2% glyceryl trinitrate and lateral internal sphincterotomy for the treatment of patients with chronic anal fissure: long-term follow-up.", "Safety and efficacy of new glyceryl trinitrate suppository formula: first double blind placebo-controlled clinical trial.", "A study to determine the nitroglycerin ointment dose and dosing interval that best promote the healing of chronic anal fissures.", "Comparison of topical glyceryl trinitrate with lignocaine ointment for treatment of anal fissure: a randomised controlled trial.", "Topical nitroglycerin versus lateral internal sphincterotomy for chronic anal fissure: prospective, randomized trial.", "Influence of botulinum toxin site of injections on healing rate in patients with chronic anal fissure.", "Surgical versus chemical (botulinum toxin) sphincterotomy for chronic anal fissure: long-term results of a prospective randomized clinical and manometric study.", "Randomized clinical trial comparing oral nifedipine with lateral anal sphincterotomy and tailored sphincterotomy in the treatment of chronic anal fissure.", "Controlled dose delivery in topical treatment of anal fissure: pilot study of a new paradigm.", "Isosorbide dinitrate in the treatment of anal fissure: a randomised, prospective, double blind, placebo-controlled trial.", "A double-blind randomized placebo-controlled trial of oral indoramin to treat chronic anal fissure.", "Maintenance therapy with unprocessed bran in the prevention of acute anal fissure recurrence.", "Randomized prospective controlled trial of lateral internal sphincterotomy versus injection of botulinum toxin for the treatment of idiopathic fissure in ano.", "Surgical treatment of chronic fissure-in-ano: a prospective randomised study.", "The anal dilator in the conservative management of acute anal fissures.", "Hydropneumatic anal dilation in conservative treatment of chronic anal fissure: clinical outcomes and randomized comparison with topical nitroglycerin.", "Clove oil cream: a new effective treatment for chronic anal fissure.", "Internal sphincterotomy is superior to topical nitroglycerin in the treatment of chronic anal fissure: results of a randomized, controlled trial by the Canadian Colorectal Surgical Trials Group.", "Topical 0.5% nifedipine vs. lateral internal sphincterotomy for the treatment of chronic anal fissure: long-term follow-up.", "Treatment of anal fissures using a combination of minoxidil and lignocaine: a randomized, double-blind trial.", "Comparison of controlled-intermittent anal dilatation and lateral internal sphincterotomy in the treatment of chronic anal fissures: a prospective, randomized study.", "Randomized, prospective trial comparing 0.2 percent isosorbide dinitrate ointment with sphincterotomy in treatment of chronic anal fissure: a two-year follow-up.", "A comparison between the results of fissurectomy and lateral internal sphincterotomy in the surgical management of chronic anal fissure." ]	[ "Chemical sphincterotomy has proved effective in treating chronic anal fissure. Glyceryl trinitrate is the most widely used agent, and topical 0.2 percent glyceryl trinitrate ointment heals up to two thirds of chronic anal fissures. Unfortunately, however, many patients experience troublesome headaches as a side effect of this treatment. This study assessed the effectiveness of oral and topical diltiazem in healing chronic fissures.\n Fifty consecutive patients with chronic anal fissures were randomly assigned to receive oral (60 mg) or topical (2 percent gel) diltiazem twice daily for up to eight weeks. Anal manometry was performed before and after the first dose, and blood pressure was recorded at 15-minute intervals. Patients were reviewed fortnightly, pain was expressed with a visual linear analog scale, blood pressure was recorded, fissure healing was assessed, and side effects were noted.\n Twenty-four patients received oral diltiazem, and 26 received topical diltiazem. Mean (+/- standard error of the mean) maximum resting anal pressures fell by 15 and 23 percent from 95 +/- 4 to 81 +/- 4 and from 102 +/- 5 to 79 +/- 5 cm H2O in the two groups, respectively. There was no significant reduction in blood pressure during the study or at follow-up in either group. Fissure healing was complete in 9 patients (38 percent) receiving oral diltiazem and 15 (65 percent) on topical treatment by eight weeks. Oral diltiazem caused side effects in eight patients (rash, two; headaches, two; nausea or vomiting, three; reduced smell and taste, one), whereas no side effects were seen in those receiving topical therapy (P = 0.001).\n Oral and topical diltiazem heal chronic anal fissures. Topical diltiazem is more effective, achieving healing rates comparable to those reported with topical nitrates, with significantly fewer side effects.", "To determine the effectiveness and safety of topical glyceryl trinitrate (GTN) in the management of acute anal fissure in children.\n Individual children were randomised to receive GTN paste or placebo for six weeks in addition to oral senna and lactulose. Patients took laxatives alone for a further 10 weeks. Each week a research nurse telephoned families to assess pain scores and give advice. Main outcome measures were validated standardised pain scores and time to painless defaecation.\n Forty subjects were recruited from 46 eligible children; 31 children completed the trial (13 in the GTN group and 18 in the placebo group). No differences in the proportion of those achieving pain free defaecation with relation to time were seen between the two groups. Similarly, there were no significant differences in pain scores between the two groups over the 16 week study period. However, in both groups pain scores had decreased significantly. There were no differences in the incidence of rectal bleeding, faecal soiling, presence of visible fissure, skin tag, or faecal loading at outpatient review at the time of recruitment, or at 6 weeks and 16 weeks. No serious adverse effects were observed.\n This study suggests that 0.2% GTN paste is ineffective in the treatment of acute anal fissures in childhood. However the overall fissure healing rate is high (84%) with associated reduction in pain scores, suggesting that a nurse based treatment programme can achieve a high rate of fissure healing.", "Anal fissure is a common problem affecting all age groups with an equal incidence in both sexes. Traditional surgical treatments, like manual anal dilatation or a sphincterotomy, effectively heal most fissures within a few weeks but such procedures may result in anal incontinence. In recent years, various medical therapies have been used for the treatment of chronic anal fissure without fear of incontinence.\n Ninety patients with a symptomatic anal fissure were randomly divided into three groups. Group I was treated with 2% diltiazem ointment, Group II was treated with 0.2% glyceryl trinitrate (GTN) ointment, and Group III was kept as the control group. The improvement in the signs and symptoms, the time taken for healing, and side effects were recorded in each group. The patients were followed up monthly and then every 3 months for any recurrence of fissure. Comparative evaluations of the three groups regarding an improvement in symptoms, progress in healing, appearance of side effects, and recurrence were made using the Tukey HSD test.\n Diltiazem ointment was found to be superior regarding pain relief, fewer side effects, and late recurrence as compared with GTN ointment.\n Diltiazem ointment (2%) and GTN ointment (0.2%) are both effective treatment modalities for chronic anal fissure, with diltiazem giving better patient outcome.", "Anal fissure is a common painful condition affecting the anal canal. The majority of acute fissures heal spontaneously. However, some of these acute fissures do not resolve but become chronic. Chronic anal fissures were traditionally treated by anal dilation or by lateral sphincterotomy. However, both of these surgical treatments may cause a degree of incontinence in up to 30% of patients. Several recent trials have shown that nitric oxide donors such as glyceryl trinitrate (GTN) can reduce sphincter pressure and heal up to 70% of chronic fissures.\n This study addressed the dose-response to three different concentrations of GTN ointment compared with placebo in a double blind randomised controlled trial.\n A double blind, multicentre, randomised controlled trial was set up to compare placebo ointment against three active treatment arms (0.1%, 0.2%, and 0.4% GTN ointment applied at a dose of 220 mg twice daily) in chronic anal fissures. The primary end point was complete healing of the fissure.\n Two hundred patients were recruited over an eight month period from 18 centres. After eight weeks of treatment the healing rate in the placebo group was 37.5% compared with 46.9% for 0.1%, 40.4% for 0.2%, and 54.1% for 0.4% GTN. None was significantly better than the placebo response. A secondary analysis excluded fissures without secondary criteria for chronicity. Healing rates were then found to be 24% in the placebo group compared with 50% in the 0.1% GTN group, 36% in the 0.2% group, and 57% in the 0.4% GTN group. These values were statistically significantly different for the placebo group compared with 0.1% GTN, 0.4% GTN, and for the GTN treated group as a whole.\n The results of this study have demonstrated the significant benefit of topical GTN when applied to patients suffering from chronic anal fissures but acute fissures showed a tendency to resolve spontaneously. The high proportion of fissures which healed in the placebo group suggests that the definition of \"chronicity\" needs to be reassessed. Further studies are required to confirm the optimal therapeutic strategy.", "Anal fissure in children usually is treated by sitz baths, stool softeners, and analgesic ointments. However, some cases are intractable to the treatment. In recent years, it has been reported that nitric oxide donors such as local glyceryl-trinitrate (GTN) ointment causes a reversible chemical sphincterotomy. Although the GTN ointment can be an alternative therapy for adult cases, it has not yet been studied in the children who suffer from anal fissure.\n Sixty-five children with anal fissure were divided randomly into 3 groups. Each group received double-blinded a topical ointment that contained either 0.2% GTN, 10% lidocaine, or placebo. These ointments were applied to the lowest part of the anal canal twice daily. Patients were periodically reviewed, and the study was ended after 8 weeks.\n Complete healing of the fissure occurred in 26 of 31 (83.9%) patients treated with GTN, 7 of 14 (50%) patients treated with lidocaine, and 6 of 17 (35.2%) treated with placebo. In 29 of 31 (93.5%) GTN-treated patients, a total relief of symptoms was observed, whereas this occurred in 7 of 14 (50%) treated with lidocaine and 6 of 11 (35.3%) in the placebo group. The differences between the study group and control groups were highly statistically significant (P < .001).\n The majority of children suffering from anal fissure will be cured and have relief of symptoms after topical application of GTN ointment to the anal canal.", "0.2 per cent topical glyceryl trinitrate (GTN) ointment heals up to two-thirds of chronic anal fissures in adults although many patients experience troublesome headaches. This double blind randomised pilot study assessed the efficacy and side effects of 0.1 and 0.05 per cent GTN ointment in treatment of chronic anal fissures in children.\n 15 consecutive children with chronic anal fissures were randomised to receive either 0.05 or 0.1 per cent GTN ointment applied topically twice daily for eight weeks. Clinical review was undertaken at weeks 4 and 8 and questions relating to symptoms and the incidence of headache were asked.\n The median age of the 15 (8 male) patients was 6 years (range 3-13). There were 5 anterior and 10 posterior fissures. The median duration of symptoms was 9 (3-30) months. 13/15 (86.7%) patients were taking laxatives at the time of referral. Fissure healing was complete at 8 weeks in all seven patients who received 0.05% and in 5/8 (62.5%) patients using the 0.1% ointment (Fisher's exact test, not significant). One patient from each arm experienced headaches during the first week of the trial which resolved without treatment and did not affect compliance. There were no other side effects.\n Topical glyceryl trinitrate ointment is effective in healing chronic anal fissures in children. Healing rates and side effect profile are comparable when either 0.05 or 0.1 per cent ointment is used.", "The present study aims to evaluate and compare the efficacy of two nitrate gels, containing isosorbide-5-mononitrate (ISMN) or glyceryl trinitrate (GTN), in the therapy of chronic anal fissure.\n The patients were randomly assigned to three groups: 0.1% ISMN gel (21 patients), 0.1% GTN gel (21 patients) and a placebo group (ten patients). The ethic committee of our hospital approved the protocol and informed consent was obtained from all participants. All patients underwent clinical examination, visual inspection of the fissure and anal manometry prior to and after therapy.\n The chronic anal fissure was completely healed in 71% of the patients treated with ISMN, 67% with GTN and in 30% from the placebo group. One patient in the ISMN group reported mild headache. Three patients in the GTN group had anal burning.\n Both topical nitrate treatments (ISMN and GTN) were effective for chronic anal fissures. The reduction of the anal pressure was slightly higher after ISMN treatment (28%) than the treatment with GTN (23%). However, the statistical difference was not significant (p>0.05).", "This study was designed to assess whether addition of glyceryl trinitrate to botulinum toxin improves the healing rate of glyceryl trinitrate-resistant fissures over that achieved with botulinum toxin alone.\n Patients were randomized between botulinum toxin plus glyceryl trinitrate (Group A) and botulinum toxin plus placebo paste (Group B). Patients were seen at baseline, four and eight weeks, and six months. The primary end point was fissure healing at eight weeks. Secondary end points were symptomatic relief, need for surgery, side effects, and reduction in maximum resting and squeeze pressures.\n Thirty patients were randomized. Two-thirds of patients had maximum anal resting pressures below or within the normal range at entry to the study. Healing rates in both treatment groups were disappointing. There was a nonsignificant trend to better outcomes in Group A compared with Group B in terms of fissure healing (47 vs. 27 percent), symptomatic improvement (87 vs. 67 percent), and resort to surgery (27 vs. 47 percent).\n There is some evidence to suggest that combining glyceryl trinitrate with botulinum toxin is superior to the use of botulinum toxin alone for glyceryl trinitrate-resistant anal fissure. The poor healing rate may reflect the fact that many of the patients did not have significant anal spasm at trial entry.", "The aim of this study was to compare prospectively diltiazem with GTN ointment in the treatment of anal fissure.\n Of 43 outpatients with chronic anal fissure, 22 patients were randomized to topical diltiazem (2%) ointment and 21 patients to glyceryltrinitrate (GTN) (0.5%) ointment twice daily for 8 weeks. During the course of treatment each patient was seen three times. Side-effects and healing were recorded.\n Healing occurred in 19 of 22 patients treated with diltiazem and 18 of 21 patients were cured with GTN (P = 0.95). Those who were treated with nitroglycerin ointment developed headache and dizziness developed after GTN in 33.3% of cases while no patient had any side-effects after diltiazem.\n Diltiazem and glyceryltrinitrate (GTN) were equally effective in healing anal fissure but the former resulted in fewer side-effects.", "Lateral internal sphincterotomy, the most common treatment for chronic anal fissure, may cause permanent injury to the anal sphincter, which can lead to fecal incontinence. We compared two nonsurgical treatments that avert the risk of fecal incontinence. We randomly assigned 50 adults with symptomatic chronic posterior anal fissures to receive treatment with either a total of 20 U of botulinum toxin injected into the internal anal sphincter on each side of the anterior midline or 0.2 percent nitroglycerin ointment applied twice daily for six weeks.\n After two months, the fissures were healed in 24 of the 25 patients (96 percent) in the botulinum-toxin group and in 15 of the 25 (60 percent) in the nitroglycerin group (P=0.005). No patient in either group had fecal incontinence. At some time during treatment, five patients in the nitroglycerin group had transient, moderate-to-severe headaches that were related to treatment. None of the patients in the botulinum-toxin group reported adverse effects. Ten patients who did not have a response to the assigned treatment - 1 in the botulinum-toxin group and 9 in the nitroglycerin group - crossed over to the other treatment; the fissures subsequently healed in all 10 patients. There were no relapses during an average of about 15 months of follow-up.\n Although treatment with either topical nitroglycerin or botulinum toxin is effective as an alternative to surgery for patients with chronic anal fissure, botulinum toxin is the more effective nonsurgical treatment.", "This study was undertaken to compare local application of a glyceryl trinitrate ointment with lateral internal sphincterotomy for the treatment of chronic fissure-in-ano.\n A sample of 24 consecutive patients with chronic anal fissure was randomly allocated to treatment with sphincterotomy or local glyceryl trinitrate. Patients were followed-up for a median of 22 months.\n All 12 patients healed following sphincterotomy; 10 of 12 healed with local glyceryl trinitrate (P = 0.239). There were no recurrences or side-effects in either group.\n Local application of glyceryl trinitrate can avoid surgery in more than 80 percent of patients with chronic anal fissure.", "Mean maximum anal resting pressure is directly related to the activity of the smooth muscles of the internal and external sphincters and has been found to be increased in the patients of anal fissure. It has been shown that blood flow at the posterior midline of anoderm is inversely related to the mean maximum anal resting pressure, and topical application of glyceryl trinitrate (GTN) ointments is a very successful treatment. This randomized study was designed to evaluate the relative value of a nitroglycerin patch applied at a distance from the fissure site in healing anal fissure compared to GTN ointment and compared to surgical treatment. Forty-two consecutive patients with chronic anal fissure of more than 4 months' duration were randomized into two equally sized groups: those in group A received 0.2% GTN ointment while those in group B received a 10-mg nitroglycerin patch for 8 weeks. Patients were also asked to rate their pain intensity on a scale of 0-10. Five patients were excluded for various reasons; results were analyzed for the remaining 37 patients (group A, n=18; group B, n=19). A control group C consisted of 12 patients who underwent surgical treatment. Fissures healed completely in 12 of 18 (66.7%) patients in group A, 12 of 19 (63.2%) in group B and 11/12 (91.7%) in group C. The healing rates in groups A and B did not differ significantly (P=0.7), nor was there a difference between these and surgical group C (P=0.13). The local application of GTN ointment and the nitroglycerin patch are both effective, economical, and alternative treatment options for most patients with anal fissures.", "In recent years treatment of chronic anal fissure has shifted from surgical to medical. This study compared the ability of two non-surgical treatments-botulinum toxin injections and nitroglycerin ointment-to induce healing in patients with idiopathic anal fissure.\n One hundred adults were assigned randomly to receive treatment with either type A botulinum toxin (30 units Botox or 90 units Dysport) injected into the internal anal sphincter or 0.2 per cent nitroglycerin ointment applied three times daily for 8 weeks.\n After 2 months, the fissures were healed in 46 (92 per cent) of 50 patients in the botulinum toxin group and in 35 (70 per cent) of 50 in the nitroglycerin group (P=0.009). Three patients in the botulinum toxin group and 17 in the nitroglycerin group reported adverse effects (P<0.001). Those treated with botulinum toxin had mild incontinence to flatus that lasted 3 weeks after treatment but disappeared spontaneously, whereas nitroglycerin treatment was associated with transient, moderate-to-severe headaches. Nineteen patients who did not have a response to the assigned treatment crossed over to the other therapy.\n Although treatment with either topical nitroglycerin or botulinum toxin is effective as an alternative to surgery for patients with chronic anal fissure, botulinum toxin is the more effective option.\n Copyright (c) 2007 British Journal of Surgery Society Ltd.", "To compare a systemic transdermal therapeutic system with local application of glyceryl trinitrate ointment in the treatment of anal fissure.\n Prospective, multicentre, randomised trial.\n Three teaching hospitals, Turkey.\n 89 outpatients with chronic anal fissure were randomly assigned to be treated with either transdermal (n = 52) or 0.2% glyceryl trinitrate ointment (n = 37).\n The patients were assessed at the sixth and the twelfth week after initial evaluation by physical examination, anoscopy, and anal manometry.\n Changes in the maximal anal resting pressure, healing rate.\n Anal fissure was completely healed in 38 (73%) and 24 (64%) of the patients after 6 weeks and 48 (81%) and 27 (79%) of the patients in transdermal group and ointment group, respectively. Maximal anal resting pressure was reduced by 24% and 21% in transdermal and ointment groups, respectively.\n Systemic transdermal application of glyceryl trinitrate gave a satisfactory healing rate, which was comparable to that of local application of ointment.", "Nitric oxide is an important neurotransmitter mediating internal anal sphincter relaxation. Patients suffering from fissure-in-ano were treated with topical nitroglycerine. The clinical evidence for therapeutic adequacy was examined in a prospective, randomized study.\n The study included 35 patients with acute and chronic anal fissures. In Group A, including 20 patients with the clinical diagnosis of acute (12 patients) and chronic (8 patients) anal fissures, treatment consisted of topical nitroglycerine. Group B, consisting of 15 patients (10 acute and 5 chronic fissures), received topical anesthetic gel during therapy. Manometry was performed before and on days 14 and 28 in the course of topical application of either 0.2 percent glyceryl trinitrate ointment or anesthetic gel (lignocaine). Anal pressures were documented by recording the maximum resting and squeeze pressures.\n In 60 percent of cases treated with topical nitroglycerine (Group A, 11 acute (91.6 percent) and 1 chronic (12.5 percent)), anal fissure healed within 14 days, in contrast to Group B in which no healing was observed. The healing rate after one month was 80 percent (11 acute (91.6 percent); 5 chronic (62.5 percent)) in Group A and was significantly superior to Group B (healing rate, 40 percent: 5 acute (50 percent); 1 chronic (20 percent)).\n Previously increased maximum resting pressures decreased from a mean value of 110 to 87 cm H2O. This represents a mean reduction of 20 percent (P = 0.0022). We also noted a significant decrease in squeeze pressures (from 177.8 to 157.9 cm H2O (11 percent)). However, anal pressures did not decrease significantly in the four chronic fissure patients from Group A, whose fissures only healed after 28 days. Similarly to these Group A chronic fissure patients, no significant anal pressure reduction was observed in any Group B patients. Except for mild headache (20 percent), no side effects of treatment were reported.\n Topical application of nitroglycerine represents a new, easily handled, and effective alternative in the treatment of anal fissures. All of our patients reported a dramatic reduction in acute anal pain. However, it should be noted that a lack of sphincter tone reduction is a likely reason for the great tendency of chronic anal fissures to recur.", "Topical application of glyceryl trinitrate (GTN) ointment heals chronic anal fissures, providing an alternative to the traditional first line treatment of surgical sphincterotomy.\n To determine the most effective dose of topical GTN for treatment of chronic anal fissures and to assess long term results.\n Seventy consecutive patients with chronic anal fissure, were randomly allocated to eight weeks treatment with placebo, 0.2% GTN three times daily, or GTN starting at 0.2% with weekly 0.1% increments to a maximum of 0.6%, in a double blind study.\n After eight weeks fissure had healed in 67% of patients treated with GTN compared with 32% with placebo (p=0.008). No significant difference was seen between the two active treatments. Headaches were reported by 72% of patients on GTN compared with 27% on placebo (p<0.001). Maximum anal sphincter pressure reduced significantly from baseline by GTN treatment (p=0.02), but not placebo (p=0.8). Mean pain scores were lower after treatment with GTN compared with placebo (NS). Of fissures healed with placebo 43% recurred, compared with 33% of those healed with 0.2% GTN and 25% healed with escalating dose GTN (p=0.7).\n GTN is a good first line treatment for two thirds of patients with anal fissure. An escalating dose of GTN does not result in earlier healing. Significant recurrence of symptomatic fissures and a high incidence of headaches are limitations of the treatment.", "A randomized, double-blind, placebo-controlled trial was performed to test the effect of intra-anal glyceryl trinitrate ointment in patients with chronic anal fissures that would normally have been treated by sphincterotomy. Long-term follow-up was then performed to assess fissure healing.\n Patients with chronic anal fissures were randomly assigned to 0.2 percent topical glyceryl trinitrate ointment or placebo. Anal manometry was performed before treatment, one week later, and 48 hours after treatment ceased at four weeks. Fissure healing was assessed by an observer blinded to the treatment arm. Pain was recorded on a linear analog scale. At the completion of the trial, treatment was continued with glyceryl trinitrate until fissure healing was obtained or lateral sphincterotomy was performed if required for ongoing pain. A long-term follow-up assessment was made at a mean of 29 (range, 25-33) months.\n There was a significant reduction in anal resting pressure at Week 1 with glyceryl trinitrate (P = 0.001) but not placebo, and at Week 4 there was a significant reduction in pain score with glyceryl trinitrate (P = 0.001) and placebo (P = 0.01) and a significant reduction in fissure grade with glyceryl trinitrate (P = 0.0001) and placebo (P = 0.02). Forty-six percent of fissures healed with glyceryl trinitrate and 16 percent healed with placebo (P = 0.001). At long-term follow-up in 40 of 43 patients, 14 patients (35 percent) had undergone lateral sphincterotomy, and in the remainder who were treated with glyceryl trinitrate there was a significant reduction in pain score (P = 0.0002). Seventeen patients attended for repeat manometry and fissures were healed with glyceryl trinitrate in ten (59 percent) cases. High internal sphincter pressures persisted at long-term follow-up in patients successfully treated with glyceryl trinitrate, indicating that the sphincter is the cause rather than effect of anal fissure.\n Topical glyceryl trinitrate produces a successful internal sphincterotomy, which resulted in long-term healing of 59 percent of chronic anal fissures and significant improvement in pain. Internal sphincter spasm is the cause of chronic anal fissure.", "Chronic anal fissure is a tear in the lower half of the anal canal that is maintained by contraction of the internal anal sphincter. Sphincterotomy, the most widely used treatment, is a surgical procedure that permanently weakens the internal sphincter and may lead to anal deformity and incontinence.\n We conducted a double-blind, placebo-controlled study of botulinum toxin for the treatment of chronic anal fissure in 30 consecutive symptomatic adults. All the patients received two injections (total volume, 0.4 ml) into the internal anal sphincter; the treated group (15 patients) received 20 U of botulinum toxin A, and the control group (15 patients) received saline. Success was defined as healing of the fissure (formation of a scar), and symptomatic improvement was defined as the presence of a persistent fissure without symptoms.\n After two months, 11 patients in the treated group and 2 in the control group had healed fissures (P=0.003); 13 in the treated group and 4 in the control group had symptomatic relief (P=0.003). The maximal voluntary pressures were similar to those at base line in both groups, and the resting anal pressure was reduced by 25 percent in the treated group but not in the control group. Three patients in the control group later underwent sphincterotomy, and 10 received botulinum-toxin injections (20 U). Of the latter, seven had healed fissures after two months; the other three left the study and underwent surgery. Four patients in the treated group were later re-treated (with 25 U of botulinum toxin); all had healed fissures after two months. One patient in the control group had temporary flatus incontinence after treatment with botulinum toxin. No relapses occurred during an average of 16 months of follow-up.\n Local infiltration of botulinum toxin into the internal anal sphincter is an effective treatment of chronic anal fissure.", "The gold standard surgical treatment of chronic anal fissure is lateral internal sphincterotomy which lowers the resting anal pressure and effectively heals the majority of fissures. Local application of 0.2% glyceryl trinitrate ointment has been used as an agent for chemical sphincterotomy, causing temporary alleviation of sphincter spasm and allowing the fissure to heal without compromising the anal continence. The aim of the present study was to compare the results of surgical sphincterotomy with that of local 0.2% glyceryl trinitrate ointment in the treatment of chronic anal fissure. Seventy adult patients between the age of 18 and 50 years with chronic anal fissure were randomized in a prospective trial to receive either surgical sphincterotomy or 0.2% glyceryl trinitrate ointment locally. Patients were followed up at 2 weeks' interval for 10 weeks. Symptom relief, fissure healing and continence scores were the outcomes assessed. Six patients were excluded for protocol violations. Surgical sphincterotomy was significantly more effective in providing pain relief and was associated with significantly better fissure healing rates at 6 weeks and 10 weeks (both p < 0.001). There were substantial problems with compliance in ointment group related to slow healing and longer time needed for symptomatic relief. Minor incontinence was 6% in sphincterotomy group and none in ointment group (p > 0.05). Considering early symptomatic relief, rapid fissure healing and better patient compliance surgical sphincterotomy is the treatment of choice for chronic anal fissure.", "To assess the efficacy and patient compliance of topical mononitrate hydrogel for the treatment of anal fissure.\n Nineteen patients with symptomatic chronic anal fissures were randomly allocated to receive either active (10 patients) or placebo (nine patients) gel treatment. Rectal administration of hydrogel containing 0.2% isosorbide-5-mononitrate was prescribed. Patients were instructed on its application to the anal canal twice daily for 3 weeks. A questionnaire was used to determine patient compliance with therapy. Anal manometry was performed before and after therapy.\n At the end of therapy, the fissures were healed in 80% of actively treated patients compared with 22% of the control group. There was a mean reduction of 28% in mean resting anal pressure. Two actively treated patients (20%) suffered from mild headache relieved with oral analgesics and menthol lozenges. Faecal incontinence was not observed. There were no recurrences during at least 3 months of follow-up.\n Topical mononitrate gel therapy of anal fissures is an effective and safe approach. In this study, the few cases of headache were rapidly relieved with oral analgesia and menthol lozenges.", "To determine the efficacy and safety of 'healer' cream as monotherapy in the treatment of acute and chronic anal fissure.\n A prospective, randomized, single blinded, comparative trial.\n Sixty patients suffering from anal fissure were included in the study. Patients were randomly divided into three groups: group A: treated with 'healer' local cream application 3 times daily; group B: treated with nitroglycerine 0.25% local cream 3 times daily; group C: treated with a lidocaine 2% cream applied locally 3 times daily. All the followings were followed up and compared between groups. (1) Visual pain analogue score after defecation; (2) severity of straining and discomfort during defecation; (3) frequency of ulcer healed at 30 days; (4) any side effects or complications.\n The pain scoring after defecation was significantly reduced in the three treatment groups. The group treated with 'healer' isosorbide-di-nitrate showed the greatest reduction of the visual pain analogue score median from 9 before treatment to 3 & 1 after 10 and 20 days respectively, while the median visual pain analogue score in group B treated with nitroglycerine cream was 9 reduced to 4 & 2 after 10 and 20 days respectively, and the median visual pain analogue score in lidocaine group only dropped from 9 to 6 and 4, respectively. The reduction of both pain scoring and defecation scoring with 'healer' was statistically significantly greater than the other two treatments by Kruskal-Wallis test, P<0.001. The number of patients experiencing complete relief and passing stools easily after 10 days was significantly higher in 'healer' group, by Pearson Chi square = 22.94, P<0.001. After 30 days, the fissures were healed in 18 (90%) of 20 patients in the 'healer' group and in 12 (60%) of 20 in the nitroglycerin group, while only 6 (30%) of patients treated with lidocaine cream had their fissures healed by the 30 days treatment. Chi square = 15 (P = 0.001).\n 'Healer' is a promising effective and safe line of treatment in acute and chronic anal fissure. The characteristic pharmacokinetics of isosorbide-di-nitrate leads to a better effect than nitroglycerin in healing (more prolonged action). Also the less fast absorption than nitroglycerin leading to a smoother dose concentration curve, may be the cause that headache is less frequent and less severe in 'healer' treatment versus nitroglycerin.", "Chronic anal fissure is a common benign disorder; for this condition, lateral internal sphincterotomy is the \"gold standard\" of treatment. Alternative medical treatments have not proven to be as effective as left lateral internal sphincterotomy.\n This randomized trial was designed to compare the use of 0.25% glyceryl trinitrate ointment and anal cryothermal dilators with the use of 0.4% glyceryl trinitrate ointment alone in the treatment of chronic anal fissures.\n Between 1 June 2006 and 31 December 2007, 60 consecutive patients who were suffering from chronic anal fissures were randomized into two groups. The patients in group A (n = 30) were treated with 0.25% glyceryl trinitrate ointment and anal cryothermal dilators twice daily, and those in group B (n = 30) were treated with 0.4% glyceryl trinitrate ointment alone twice daily. The treatment was administered to the patients in each group for 6 weeks, and all patients were examined 7 weeks after the start of the trial.\n Prior to treatment, the symptoms and the measurements of anal pressure were similar in both groups. At 7 weeks, the maximum resting pressure was significantly lower in group A (P < 0.05), in which 86.6% of the patients were asymptomatic in comparison with 73.3% of the patients in group B. After 1 year of follow-up, 25 patients (83.3%) in group A and 18 patients (60%) in group B presented no recurrence of symptoms (P < 0.05)\n Treatment of chronic anal fissures with 0.25% glyceryl trinitrate ointment and anal cryothermal dilators was more effective than the administration of 0.4% glyceryl trinitrate ointment alone.", "Procedures involving the use of anal dilators or topical nitroderivatives for the treatment of anal fissure are efficacious, economic and safe. The aim of our study was to compare the efficacy of two conservative treatments - passive dilation with anal dilators or topical nitroderivatives - in reducing anal pressure and resolving anal fissures. A total of 40 patients with a clinical diagnosis of acute anal fissure in the absence of hypotonic anal sphincter, abscess or perianal fistula, haemorrhoidal thrombosis, chronic inflammatory bowel disease or lower gastrointestinal neoplasia were randomly assigned to treatment with dilators (20 patients) or topical nitroderivatives (20 patients). After 4 weeks of treatment, 90% of patients treated with dilators and only 45% treated with topical nitroderivatives showed complete resolution of their anal fissures and a reduction of sphincter hypertone. After 12 weeks, 2/18 patients successfully treated with dilators and 1/9 patients successfully treated with topical derivatives presented recurrence of the anal fissure. The use of anal dilators would appear to induce better resolution of acute anal fissures than topical nitroderivates, as confirmed by the low relapse rate at 12 weeks.", "Anal fissure is most commonly treated surgically by internal anal sphincterotomy. However, there is some concern over the effects of this procedure on continence. Nitric oxide donors such as glyceryl trinitrate (GTN) have been shown to cause a reversible chemical sphincterotomy capable of healing fissures in a small series of cases. This study reports a prospective, randomised, double-blind, placebo-controlled trial to test the hypothesis that topical GTN is the best first-line treatment for chronic anal fissure.\n 80 consecutive patients were randomised to receive treatments with topical 0.2% GTN ointment or placebo. Maximum anal resting pressure (MARP) was measured with a constantly perfused side-hole catheter before and after the first application of trial ointment. Anodermal blood flow was measured during manometry by laser Doppler flowmetry. After initial treatments, patients were given a supply of ointment (either GTN or placebo) to be applied to the lower anal canal twice daily. Patients were reviewed 2-weekly. At the initial and follow up visits patients were asked to record pain experienced on defaecation on a linear analogue pain score. Endpoints were healing of the fissure or condition after 8 weeks of treatment.\n After 8 weeks, healing was observed in 26/38 (68%) patients treated with GTN and in 3/39 (8%) patients treated with placebo (p < 0.0001, chi 2 test). Linear analogue pain score fell significantly in both groups after 2 weeks of treatment. This fall was maintained in those treated with GTN but pain scores returned to pre-treatment values by 4 weeks on treatment with placebo. MARP fell significantly from a mean of 115.9 (SD 31.6) to 75.9 (30.1) cm H2O (p < 0.001, Student's paired t-test) in patients treated with GTN but no change was seen in MARP after placebo. Anodermal blood flow measured by laser Doppler flowmetry significantly increased after application of GTN ointment but was unaffected by placebo.\n Topical GTN provides rapid, sustained relief of pain in patients with anal fissure. Over two-thirds of patients treated in this way avoided surgery which would otherwise have been required for healing. Long-term follow up is needed to assess the risk of recurrent fissure in patients with GTN.", "Botox(®) injection of the anal sphincter muscle cures chronic uncomplicated anal fissures in up to 80% of patients. This study examines the therapeutic efficacy and side effect profile of the British botulinum product Dysport(®) . Fifty patients (29 women) were recruited to participate in this randomized dose-finding study, their mean age being 32.9 years. The low dose group A was treated with a total dose of 20 U injected in two sites each lateral to the fissure, the high dose group B was treated with 40 U. Eighty-two percent of patients were pain-free within a week following the injections. The fissure was healed in 78% of treated patients after 3 months. Three patients relapsed within 6 months. The most common adverse side effect was transient incontinence (n = 4). Clinical outcome was not significantly different between the two treatment groups. The low dose can therefore be regarded sufficient for the treatment of anal fissure. Therapeutic efficacy was equivalent to published data on Botox treatment. Both Dysport(®) and Botox(®) can therefore be used to treat chronic uncomplicated anal fissures. Both Dysport(®) and Botox(®) therapy are well tolerated, can be performed on an out-patient basis and avoid the risk of permanent faecal incontinence which complicates surgical treatment of anal fissures.", "Although lateral internal sphincterotomy has been the gold standard of treatment for chronic anal fissure, the main concern remains its effects on anal continence. Intrasphincteric injection of botulinum toxin seems to be a reliable option providing temporary alleviation of sphincter spasm and allowing the fissure to heal. The aim of the present prospective controlled randomized study was to compare the outcome of lateral internal sphincterotomy and botulinum toxin injection treatments in patients with uncomplicated chronic anal fissure.\n Eighty consecutive patients with uncomplicated chronic anal fissure who had failed conservative treatment were randomized to receive either intrasphincteric injection of botulinum toxin (BT) or lateral internal sphincterotomy (LIS). Postoperative pain relief, healing of fissure, continence scores, and fissure relapse during 18 weeks of follow-up were the outcomes assessed.\n There was a statistically significantly higher healing in the LIS group than the BT group (p = 0.0086 and 95% CI = 7.38-45.69%). In addition, LIS was associated with a high rate of anal incontinence as compared to BT (p = 0.0338 and 95% CI = -1.64-27.53%). The recurrence rate in the BT group was significantly higher statistically than that in the LIS group (p = 0.0111 and 95% CI = 6.68-46.13%).\n Surgical internal sphincterotomy has a higher healing rate and a lower recurrence rate than intrasphincteric injection of botulinum toxin in the treatment of uncomplicated chronic anal fissure. Injection of botulinum toxin, however, is a simple noninvasive technique that avoids the greater risk of incontinence. It could be used as the first therapeutic approach in patients without clinical risk factors of recurrence.", "As lateral sphincterotomy and anal dilatation causes complications, a reversible chemical sphincterotomy method has been recently proposed as an alternative treatment in patients with anal fissure. In this study, the effect of botulinum toxin causing temporary paralysis in internal anal sphincter was compared with that of lidocaine in patients with chronic anal fissure.\n A total of 62 outpatients were randomly assigned to receive botulinum toxin or lidocaine pomade. The patients were evaluated before and after two months of treatment with physical examination and anal manometry. Pain and nocturnal pain were scored.\n In an evaluation period of two months, in 24 of 34 patients of botulinum group (70.58%), and in six of 28 patients of lidocaine group (21.42%) showed complete epithelization (p = 0.006). All patients who had previously reported nocturnal pain became symptom free in botulinum group and in four patients of lidocaine group. Pain following defecation disappeared in 24 patients of botulinum group and in 20 patients of control group (p = 0.959). There was no adverse effect in both groups. While resting anal pressure and maximum voluntary pressure were significantly low in botulinum toxin group, both parameters did not change in lidocaine group.\n Botulinum toxin is a reliable and effective method for patients with chronic anal fissure. It can be applied easily without any anesthesia and instrumentation. It is cheaper in comparison with surgical methods and it can be a good alternative treatment in patients with risk of incontinence.", "To compare symptomatic relief, healing, and changes in maximal anal resting pressure with the use of topical formulations in patients with chronic anal fissure.\n Sixty-four consecutive patients with chronic anal fissure were randomized into 4 groups that received, in a double-blind manner, a topical ointment that contained 0.2% nitroglycerine (GTN), 5% xylocaine, Proctosedyl (hydrocortisone acetate, heparin, framycetin sulfate, esculoside, ethoform, butoform) or petroleum jelly (Vaseline), to be applied twice daily. Patients were reviewed at 2-week intervals for 6 weeks. Anal manometry was done before, and 20 minutes after, the first application of the ointment.\n There was significant (p < 0.0001) reduction in mean anal resting pressure after application of GTN, but not any other ointment. Of 16 patients receiving GTN, complete pain relief occurred in 6 and 15 patients after 2 and 4 weeks of treatment, respectively; this was more frequent than in the other 3 groups. At 6 weeks also, complete pain relief occurred more often with GTN than with Vaseline or xylocaine. After 4 weeks of treatment, 3 patients on GTN had complete healing of fissure as compared to one each in the xylocaine and Proctosedyl groups and none in the Vaseline group. At 6 weeks, healing of fissure had occurred in 15 of 16 patients receiving GTN as compared to 4 receiving Vaseline, 11 receiving xylocaine, and 12 on Proctosedyl.\n Topical nitroglycerine produces 'chemical sphincterotomy' with reduction in mean anal resting pressure. Pain relief and healing of fissure occurred earlier with GTN than with other treatments. GTN should be considered as the treatment of choice for the non-surgical management of patients with chronic anal fissure.", "This study was designed to compare the effect of topical glyceryl trinitrate (GTN) and oral nifedipine treatments on maximal anal resting pressure (MARP) and subsequently to assess their effectiveness in healing of chronic anal fissure (CAF). Patients were allocated randomly to receive either oral nifedipine retard (10 patients) 20 mg twice daily or instructed to apply glyceryl trinitrate (0.2 percent) ointment (10 patients) into the lower half of the anal canal twice daily. They were reviewed and assessed at the first visit and every fortnight for measurement of MARP, pain scores, blood pressure, pulse rate, healing of the fissure and adverse effects. Treatment were continued until healing had occurred or for up to 8 weeks. MARP values before and after application of the GTN ointment was 113.2 cm H2O and 72.5 cm H2O respectively (P < 0.001). Nifedipine caused a reduction in mean MARP from 105.2 to 74.0 cm H2O (P < 0.001). Linear analogue pain scores were significantly reduced after 2 weeks treatment with GTN and nifedipine (P < 0.001) and continued throughout the treatment period. At the end of the study; 7 of the 10 patients in the GTN group were deemed to be healed (5) or improved (2), compared with 6 of the 10 patients in the nifedipine group (5 healed, 1 improved). Headaches occurred in 3 patients in the GTN group, compared with one patient in the nifedipine group. There was no significant difference between GTN and nifedipine in terms of reduction in MARP and pain score, healing of the fissure and incidence of early recurrence and side effects of treatments. We conclude that GTN ointment and oral nifedipine are equally effective in the treatment of chronic anal fissure.", "A randomized clinical trial assessed the value of regular anal dilatation in combination with a topical local anaesthetic in the treatment of 82 patients with a posterior fissure-in-ano. One month after treatment the fissure had healed in 43.6 per cent of patients using 2 per cent lignocaine gel alone and in 41.9 per cent of patients who also used a St Mark's Hospital anal dilator. Thus the regular use of such a dilator did not contribute to the success of conservative therapy in patients with a posterior anal fissure. A review of patients who presented with anterior or lateral anal fissures during the trial period revealed that healing was achieved in 73.3 per cent of patients without operation within 1 month of diagnosis.", "Chronic anal fissure is a lineal ulcer of the lower part of the anal canal. It is a painful condition characterized by postdefecational pain and bleeding. It is associated with internal anal sphincter spasm. The relief of internal anal sphincter spasm is the key for providing fissure healing. Gold standard in the treatment of chronic anal fissure is partial lateral internal anal sphincterotomy.\n Sixty patients with chronic anal fissure were randomly assigned into two groups treated either by surgical sphincterotomy or injections of botulinum toxin into internal anal sphincter. Manometric measurements were performed before and three months after treatment. Follow up period was six months. The aim of the study was to compare results between these two groups.\n Both methods efficiently reduced resting anal pressure and successfully healed chronic anal fissure.\n Surgical and biologic sphincterotomy are almost equally effective in the treatment of chronic anal fissure. Injecting botulinum toxin into internal anal sphincter is a safe, easy to apply and effective method in the management of anal fissure.", "Hypertonicity of internal anal sphincter plays a major role in the persistence of chronic anal fissure. Botulinum toxin could induce internal anal sphincter relaxation without the adverse effects of surgery (long-term faecal incontinence) or topical nitrates (anal burning, headaches, hypotension).\n We conducted a placebo-controlled, randomised, double-blind study to assess the efficacy of a single injection of botulinum toxin in the internal anal sphincter of patients with chronic anal fissure in six ambulatory care clinics. Eligibility criteria included a mean value of post-defecation anal pain >or= 30 mm on a 100 mm visual analogue scale over the week preceding inclusion. Main endpoint was the proportion of patients with symptomatic improvement during the fourth week after inclusion (post-defecation anal pain below 10 mm).\n Forty-four patients (22 in each group) were included. At inclusion, there was no significant difference between groups on age, sex ratio, pain duration, post-defecation anal pain, analgesic consumption and stool frequency. Ten (45%) and 11 (50%) patients reported symptomatic improvement on the main endpoint (P=0.76) in placebo and botulinum toxin groups, respectively. Ten patients (five in each group) had healed fissure at week 4 and ten patients (five in each group) required surgical treatment between weeks 4 and 12. Similarly, there was no significant difference between groups on other variables between weeks 4 and 12.\n The efficacy of a single injection of botulinum toxin in the internal anal sphincter does not differ from that of a placebo in patients with chronic anal fissure.", "Anal fissure is a common disease. Treatment includes conservative measures or surgery. One of the treatment options is topical Nitroglycerin ointment.\n We present a prospective, randomized, double-blind study, encompassing 48 patients suffering from chronic anal fissure. The subjects were divided into three groups according to the dose of Nitroglycerin ointment received--group I--0% (placebo), group II--0.2% (0.75 mg) and group III--0.4% (1.5 mg). Demographic data, medical history and physical findings were recorded. Healing, pain relief and adverse events were evaluated during and after the treatment period.\n No significant difference (p<0.05) was found between the groups with respect to patient age, gender, past history, physical examination, amount of ointment used and adverse events. Thirty three of the 48 (69%) patients completed the study. No significant differences were found between the groups with respect to the reasons and rates of leaving the study (p=0.494). Fifteen patients failed to complete the study; eight patients (17%) due to headaches, one patient was operated upon and six patients left the study because of cooperation problems. No significant difference was found between the groups regarding healing (p=0.952) or pain relief (p=0.458-0.8 according to the type of pain checked).\n According to our study, there was no benefit regarding healing or pain relief, in treating patients suffering from an anal fissure with Nitroglycerin ointment in combination with stool softeners and sitz baths, compared to the same treatment without Nitroglycerin ointment.", "Botulinum toxin induces healing in patients with idiopathic anal fissures.\n One hundred-fifty patients with posterior anal fissures were treated with botulinum toxin injected in the internal anal sphincter on each side of the anterior midline. Subjects were randomized into 2 treatment groups based on the number of units of botulinum toxin injected. Patients in group I were treated with 20 units of botulinum toxin and, if the fissure persisted, were retreated with 30 units. Patients in group II were treated with 30 units and retreated with 50 units, if the fissure persisted.\n The 2 groups were comparable in age, gender distribution, duration of symptoms, resting pressure, and maximum voluntary pressure at anorectal manometry. One month after the injection, examinations revealed complete healing in 55 patients (73%) from group I and 65 patients (87%) from group II (P =.04). Five patients from group II reported a mild incontinence of flatus that lasted 2 weeks after the treatment and disappeared spontaneously. The values of the resting anal pressure (P=.3) and the maximum voluntary pressure (P =.2) did not differ between the 2 groups. At 2 months' evaluation, a healing scar was found in 67 patients (89%) from group I and 72 patients (96%) from group II. A relapse of the fissure was observed in 6 patients (8%) from group I who had a healing scar at 1 month, and 2 other patients never healed. A persistent fissure was present in 3 patients from group II who had no other symptoms.\n Botulinum toxin injected into the internal anal sphincter is effective in managing anal fissures and avoiding permanent complications. All patients were treated with the active drug and healed after 1 or 2 successive treatments. The results also confirm that higher doses account for a higher success rate, with little increase in complications or side effects, which is probably related to the diffusion of the toxin to the external sphincter.", "Chronic anal fissure may be treated by chemical or surgical sphincterotomy. The aim of this study was to test the efficacy of local application of nifedipine and lidocaine ointment in healing chronic anal fissure.\n The study was performed according to a prospective, randomized, double-blind design. One hundred ten patients who gave informed consent were recruited. They received a clinical examination, a questionnaire to evaluate symptoms and pain, anorectal manometry, and anoscopy. Healing of anal fissure at Day 42 of therapy was defined as the primary efficacy variable of the study. Patients treated with nifedipine (n = 55) used topical 0.3 percent nifedipine and 1.5 percent lidocaine ointment every 12 hours for 6 weeks. The control group (n = 55) received topical 1.5 percent lidocaine and 1 percent hydrocortisone acetate ointment during therapy. Anal pressures were measured by recording resting and maximal voluntary contraction pressures at baseline and at Day 21. Long-term outcomes were determined after a median follow-up of 18 months.\n Healing of chronic anal fissure was achieved after 6 weeks of therapy in 94.5 percent of the nifedipine-treated patients (P < 0.001) as opposed to 16.4 percent of the controls. Mean anal resting pressure decreased from a mean value +/- standard deviation of 47.2 +/- 14.6 to 42 +/- 12.4 mmHg in the nifedipine group. This represents a mean reduction of 11 percent (P = 0.002). Changes of maximal voluntary contraction in nifedipine-treated patients were not significant. No changes in mean anal resting pressure and maximal voluntary contraction were observed in the control group. We did not observe any systemic side effect in patients treated with nifedipine. After the blinding was removed, recurrence of the fissure was observed in 3 of 52 patients in the nifedipine group within 1 year of treatment, and 2 of these patients healed with an additional course of topical nifedipine and lidocaine ointment.\n Our study clearly demonstrates that the therapeutic use of topical nifedipine and lidocaine ointment should be extended to the conservative treatment of chronic anal fissure.", "To compare outcomes 24 months after treatment of chronic anal fissure with 0.2% glyceryl trinitrate ointment (GTN) or lateral internal sphincterotomy.\n Prospective, randomised trial.\n One teaching, one private, and 3 district hospitals, U.K.\n Seventy patients were randomised into two groups of 35 each to use 0.2% GTN ointment or have a lateral internal sphincterotomy.\n Resolution of symptoms and healing of fissures assessed after 24 months.\n All those operated on were initially cured but one fissure recurred after 8 months. Nineteen of 35 fissures treated with GTN healed. The remaining 16 patients randomised to use GTN ointment whose fissures did not heal were then treated by sphincterotomy. Three patients whose fissures healed successfully with GTN developed recurrences within 6 months of completing treatment. The remaining 16 of 19 patients treated with GTN whose fissures healed were free of symptoms with no clinical evidence of recurrence after 24 months follow-up.\n Many anal fissures heal with topical treatment with GTN. Lateral internal sphincterotomy remains effective but should be reserved for patients who fail to respond to initial chemical sphincterotomy.", "This study was designed to assess the safety and efficacy of 0.2 percent glyceryl trinitrate suppository form in the healing of chronic anal fissure.\n Thirty-four patients with symptomatic chronic anal fissures were assigned to 0.2 percent glyceryl trinitrate suppository (n = 21) or placebo (n = 13) in a double blind design. Patient's symptom scores were registered at first visit. A validated daily chart was given to assess their symptoms on a daily basis. Both groups received psyllium from the beginning of the study. They were assessed at two-week intervals for six weeks. Then, they started a washout period of one month and after that were crossed over for another six weeks. Chi-squared, t-tests, and analysis of variance were used for statistical analysis.\n Complete healing at six weeks was achieved in 12 of 21 patients (57 percent) in the glyceryl trinitrate group and 5 of 13 patients (38 percent) in the placebo (P < 0.05). The overall healing rates at the end of study were 15 of 21 (71 percent) vs. 11 of 13 (84 percent) in the glyceryl trinitrate and placebo groups, respectively (P > 0.05).\n Application of 0.2 percent glyceryl trinitrate suppository form represents a new, promising, and effective treatment for chronic anal fissure.", "The aim of this study was to determine the optimal dose and dosing interval of nitroglycerin ointment to heal chronic anal fissures.\n A randomized, double-blind study of intra-anally applied nitroglycerin ointment (Anogesic) was conducted in 17 centers in 304 patients with chronic anal fissures. The patients were randomly assigned to one of eight treatment regimens (0.0, 0.1, 0.2, 0.4 percent nitroglycerin ointment applied twice or three times per day), for up to eight weeks. A dose-measuring device standardized the delivery of 374 mg ointment. Healing of fissures (complete reepithelialization) was assessed by physical examination using an observer unaware of treatment allocation. The subjects assessed pain intensity daily by completing a diary containing a visual analog scale for average pain intensity for the day, the worst pain intensity for the day, and pain intensity at the last defecation.\n There were no significant differences in fissure healing among any of the treatment groups; all groups, including placebo had a healing rate of approximately 50 percent. This rate of placebo response was inexplicably higher than previously reported in the literature. Treatment with 0.4 percent (1.5 mg) nitroglycerin ointment was associated with a significant (P < 0.0002) decrease in average pain intensity compared with vehicle as assessed by patients with a visual analog scale. The decreases were observed by Day 4 of treatment. At 8 weeks the magnitude of the difference between 0.4 percent nitroglycerin and control was a 21 percent reduction in average pain. Treatment was well tolerated, with only 3.29 percent of patients discontinuing treatment because of headache. Headaches were the primary adverse event and were dose related.\n Nitroglycerin ointment did not alter healing but significantly and rapidly reduced the pain associated with chronic anal fissures.", "Topical glyceryl trinitrate (GTN) has gained popularity as a treatment for anal fissure in the West. In our country, lignocaine is still the current treatment for the entity. This study was done to compare the effect of GTN with lignocaine in terms of healing rate and recurrence in South Asian population.\n A prospective, double blinded, randomised controlled trial was conducted on 50 patients (both treatment arms included) of all ages and either gender with a clinical diagnosis of anal fissure. Group A was given 0.2% GTN ointment and Group B was given lignocaine ointment. Both subjective and objective signs of healing were assessed and adverse effects of the treatment were sought.\n Symptomatic relief was earlier with GTN as compared with lignocaine. Pain relief was steady and sustained in those treated with GTN but returned to pre-treatment status within 5 weeks in patients with lignocaine. After 8 weeks of treatment, 80% of patients in Group A showed clinical signs of healing compared to 32% in Group B (p=0.001). Headache was the main side effect of GTN. At 6-month follow-up, recurrence was seen in 3/8 patients in Group B compared to 8/20 in the GTN Group (p=1).\n Topical GTN has earlier and a higher rate of clinical healing of anal fissure with acceptable side effects. The recurrence rate is high and comparable to lignocaine ointment. It is a safe and an effective treatment of anal fissure in a South Asian population.", "Topical nitroglycerin (GTN) is one of the medical treatments of choice in chronic anal fissure. The present prospective, randomized, clinical trial was conducted to study the symptomatic relief, healing, and changes in the maximum anal resting pressure (MARP) in patients with chronic anal fissure comparing topical GTN and lateral sphincterotomy.\n Forty consecutive patients with chronic anal fissure were randomized for treatment with either topical GTN or internal sphincterotomy (20 patients in each group). Anal manometry was done before treatment in all patients, and 1 h after application of GTN or sphincterotomy. Patients were followed at 2-weekly intervals for 6 weeks for symptomatic relief and healing.\n Both GTN and sphincterotomy brought about a highly significant, but comparable drop in the MARP after treatment (P < 0.0001 in both groups). Sphincterotomy relieved pain much earlier compared to GTN (70% vs 40% at 2 weeks, P = 0.0032); but after 4 weeks of treatment, pain relief in both groups was comparable. Healing in the sphincterotomy group was also earlier than with GTN (55% vs 0% at 2 weeks, P < 0.0001; and 85% vs 30% at 4 weeks, P < 0.0001); but after 6 weeks, healing in both groups was comparable. Sphincterotomy had a significant incidence of minor, short-term complications; it also required surgical expertise, theatre time, and day-care beds. Nitroglycerin is safe, with mild and tolerable side-effects of headache and local burning sensation.\n Topical GTN should be the initial treatment in chronic anal fissure. Lateral sphincterotomy should be reserved for patients with severe disabling pain (because pain relief is much faster), and for patients not responding to at least 4 weeks of GTN therapy.", "Botulinum toxin induces healing in patients with idiopathic anal fissure.\n Fifty patients affected by posterior anal fissure were treated with 20 units of botulinum toxin, injection in the internal anal sphincter on each side of the posterior midline (group I) or on each side of the anterior midline (group II).\n At 2 months evaluation, a healing scar was observed in 15 patients of group I and in 22 patients of group II(P = 0.025). Resting anal pressure was significantly different from the baseline values at 1-month as well as at 2-month check-ups in both groups, but the values were significantly lower in patients of group II.\n The intersite comparison revealed that anterior injection of the internal anal sphincter resulted in improved lowering of resting anal pressure and produced an earlier healing scar.", "The aim of this prospective randomized trial was to compare the effectiveness and morbidity of surgical versus chemical sphincterotomy in the treatment of chronic anal fissure after a 3-year follow-up.\n Eighty patients with chronic anal fissure were treated by whether open lateral internal sphincterotomy (group 1) or chemical sphincterotomy with 25 U botulinum toxin injected into the internal sphincter (group 2). Clinical and manometric results were analyzed.\n Overall healing was 92.5% in the open sphincterotomy group and 45% in the toxin botulinum group (P<.001). There is a group of patients with clinical (duration of disease >12 months and presence of a sentinel pile before treatment) and manometric factors (persistently elevated mean resting pressure, % of time presence of slow waves, and number of patients or the time presence ultra slow waves after treatment) associated with a higher recurrence of anal fissure. The final percentage of incontinence was 5% in the open sphincterotomy group and 0% in the botulinum toxin group (P>.05).\n We recommend surgical sphincterotomy as the first therapeutic approach in patients with clinical and manometric factors of recurrence. We prefer the use of botulinum toxin in patients older than 50 years or with risk factors for incontinence, despite the higher rate of recurrence, since it avoids the greater risk of incontinence in the surgical group.", "The conventional treatment of chronic anal fissure is lateral sphincterotomy (LAS). The alternative options of tailored sphincterotomy (TS) and 'chemical sphincterotomy' using medication such as nifedipine have recently become available.\n A prospective randomized trial was conducted to compare LAS with TS and oral nifedipine. The main endpoints were fissure healing, symptom relief, recurrence and continence.\n One hundred and thirty-two patients were treated and followed up for 4 months. LAS was significantly more effective than TS in providing pain relief (P = 0.004) and better patient satisfaction (P = 0.020) at 4 weeks. Surgery (LAS and TS) was associated with significantly better fissure healing rates (both P < 0.001 at 16 weeks) and less recurrence (both P = 0.003) than nifedipine. There were substantial problems with compliance in the nifedipine group (17 of 41 patients), related to side-effects and slow healing. There were no differences in continence between the three treatment groups.\n LAS was most effective in providing pain relief and allowing rapid fissure healing, with minimal recurrence and no increased risk of incontinence, in patients with good anal sphincter function.", "Topical nitroglycerin has been widely used as a means for avoiding surgery in patients with anal fissure. However, nitroglycerin has not been universally accepted for this application because of inconsistency of efficacy and side effects. This study compares conventional digital application with precise intra-anal dosing of nitroglycerin using a specialized dose-delivery device and anal cannula.\n Twenty-six consecutive patients (13 males) with chronic anal fissure and no previous treatment were randomly allocated to receive 0.75 ml of 0.3 percent nitroglycerin ointment (2.25 mg nitroglycerin) t.i.d. intra-anal using the cannula (Group A) or perianally with the gloved finger (Group B). Nitroglycerin dosage was controlled in Group A by the dose-delivery device connected to the cannula and by single-dose preloaded syringes in Group B.\n Anal manometry: pressure reduction after application of nitroglycerin was 47 +/- 18.6 in Group A and 20.7 +/- 13.4 percent in Group B (P < 0.01). Headaches were reported by 1 of 10 patients in Group A and 10 of 12 patients in Group B (P = 0.0027). Seven patients of Group B had to be crossed to intra-anal treatment as a result of intensity of headaches. Pain relief was noted by 8 of 10 and 9 of 12 patients in Groups A and B, respectively (P = 0.6). Sphincterotomy was required in only 13.6 percent of all patients.\n Controlled intra-anal dosing of topical nitroglycerin produces a significantly greater reduction in sphincteric pressure and lower incidence of headaches than with perianal administration of the same dose of ointment. These results suggest a new paradigm for increasing safety and efficacy of dose-dependent prescription anal topical medications.", "To assess the efficacy of isosorbide dinitrate in healing anal fissures.\n Randomised, prospective, double blind, placebo controlled trial.\n Teaching hospital, The Netherlands.\n 37 consecutive subjects with anal fissure diagnosed in the surgical outpatient department.\n After randomisation, 20 patients were given isosorbide dinitrate, and 17 patients placebo.\n Healing of anal fissure, recurrence, and tolerance.\n Both groups were treated for a median (range) of 5 weeks (range 1-10). After this period, 17 in the isosorbide group had healed compared with 6 controls (p < 0.003). The fissure recurred in 2 patients who had had an initial good response to isosorbide, and in 2 in the control group. Side effects (particularly headache) were more common after isosorbide dinitrate, but not significantly so (9/20 compared with 3/17).\n Isosorbide dinitrate is an effective treatment for anal fissure, and is significantly better than placebo.", "Indoramin is an alpha1-adrenoceptor antagonist and has been shown to reduce anal resting pressure. Its therapeutic potential has not been explored. The aim of this study was to determine the outcome of treatment with oral indoramin on patients with chronic anal fissure in the setting of a double-blind randomized placebo-controlled trial.\n Twenty-three patients with chronic anal fissure were computer randomized to receive a 6-week course of oral indoramin (20 mg) or placebo in identical capsules, twice daily and with bulk-forming laxatives. Pain was assessed by a visual analogue scale from 0 to 10. Anal resting pressure, heart rate and blood pressure were recorded. Patients were reviewed 1 h after taking the capsule and at 2, 6 and 12 weeks thereafter.\n Fourteen patients were randomized to indoramin and 9 to placebo. Maximum anal resting pressure was reduced from a mean of 96.4 cm H2O (+/- 32) to 67.6 cm H2O (+/- 26), 1 h after indoramin (P=0.02) and there was no significant change after placebo. There were no significant changes in heart rate or blood pressure. Pain was reduced in the placebo group from a score of 4.9 to 2.0 after 6 weeks (P < 0.01) but not in the indoramin group. After 6 weeks, healing had occurred in one (7%) patient in the indoramin group and in 2 (22%) in the placebo group (P > 0.1). After 3 months, the chronic anal fissure in the indoramin group had recurred. The trial was terminated early because of poor healing rates.\n An oral dose of indoramin (20 mg) administered twice daily reduced anal resting pressure by 30% compared with pretreatment levels but was ineffective in healing chronic anal fissures.", "The effect of unprocessed bran in a dose of 5 g three times daily and a dose of 2.5 g three times daily for one year on the recurrence rate of anal fissures was studied in a double-blind, placebo-controlled trial in 90 patients with recently healed acute posterior anal fissures. Fifteen patients (16.6%) were withdrawn before the code was broken due to failure to follow the trial protocol for various reasons. Significantly fewer recurrences occurred in patients receiving bran 5 g three times daily (recurrence rate 16%, 95% confidence limits, 4.54 to 36.08) when compared with patients receiving bran 2.5 g three times daily (60%; 38.67 to 78.87) (P less than 0.01) and with patients receiving placebo three times daily (68%; 46.50 to 85.05) (P less than 0.01). No significant difference in recurrences was found between patients on bran 2.5 g and those on placebo.", "Chronic anal fissure is a significant cause of morbidity. Internal sphincterotomy has long been the operative treatment of choice. Concerns remain, however, on its effects on continence. Botulinum toxin has been used as an agent for chemical sphincterotomy, causing temporary alleviation of sphincter spasm and allowing the fissure to heal. The aim of the present study was to compare the results of sphincterotomy to botulinum toxin.\n The study was designed as a randomized controlled trial. All adult patients over the age of 18 with chronic idiopathic fissure in ano who had failed conservative treatment were included in the trial. Patients were randomized to receive either Botox or sphincterotomy. Pain, healing of fissure and continence scores were the outcomes assessed.\n A total of 38 patients were studied. Seventeen patients were randomized to receive Botox and 21, sphincterotomy. Patients in the Botox group were found to have significantly higher 2-week pain scores and reoperation rates, and poor healing. Continence scores were not significantly different in the two groups.\n Sphincterotomy gives better results than Botox in the treatment of fissure. Botox, however, is safe with no complications and no detriment to continence and could be used in certain situations.", "A prospective randomised study compared anal dilatation (n = 37), posterior internal sphincterotomy (n = 21) and lateral sphincterotomy (n = 20) in the surgical treatment of chronic anal fissures in 78 consecutive patients. All the operations were performed under general anaesthesia using standard techniques. Anal dilatation relieved anal pain early (immediate relief in 57% of patients; the mean pain-days +/- SD of 3.2 +/- 5.4 days). Anal fissures after this operation healed in a mean time +/- SD of 20.3 +/- 12.5 days, coming in second place to lateral sphincterotomy. Anal dilatation was followed by insignificant wound infection but its main disadvantage was a high rate of post operative anal incontinence (in 24.3% of patients). Fissurectomy and posterior internal sphincterotomy was followed by the longest period of post operative anal pain (mean +/- SD of 32.4 +/- 10 days) as compared to the other two operations. It was the least favourable operation. Lateral sphincterotomy was followed by early relief of pain (immediate relief in 95% of patients). It was not followed by wound infection. It had the quickest healing time for the fissures (a mean +/- SD of 14.7 +/- 8.7 days). It was followed by anal incontinence in only one patient. In conclusion lateral sphincterotomy was the most favourable operation and it is perhaps the operation of choice to perform in patients with chronic anal fissures needing surgical treatment.", "Patients presenting with acute anal fissure were randomized into two treatment groups in a prospective clinical trial. Both groups received treatment for 3 weeks with a stool softener and lignocaine jelly. Those entered in group 1 (35 patients) were asked in addition to insert an anal dilator (no. 2) twice daily while those in group 2 (31 patients) applied the anaesthetic jelly without a dilator. At 6 weeks 11 (31.4 per cent) patients in group 1 and 12 (38.7 per cent) patients in group 2 had been referred for sphincterotomy owing to failure of the treatment. At 6 months this figure had risen to 14 (40 per cent) in group 1 and 15 (48.4 per cent) in group 2. This difference was not statistically significant, suggesting that the addition of a dilator to the conservative treatment regimen did not diminish the likelihood of surgery.", "The surgical approach in chronic anal fissures (CAF) may, occasionally result in anal incontinence. The aim of this investigation was to study feasibility, effectiveness, and safety of hydropneumatic anal dilation (HAD) in conservative treatment of CAF and to compare it with local nitroglycerin (GTN) treatment.\n Efficacy of HAD was evaluated in 109 patients (65 male, 44 female; mean age, 53.3 years), following anal dilation using Microvasive Rigiflex instrument (Otw 40 mm). Thereafter, 36 patients were randomly divided into two groups to undergo treatment with 0.25% GTN or HAD.\n Recovery rate with HAD was 79.8% after 10 days and 94.5% after 30 days. An immediate (within 24 hours) drop was observed in the level of pain; no significant complications or recurrence were reported within 2 years. Healing rate was 94.5% following HAD vs. 38.9% after GTN.\n HAD should be considered a new safe option in CAF treatment.", "Anal fissure is a common painful condition affecting the anal canal and causes considerable morbidity and reduction in quality of life. Surgical treatment has been associated with a degree of incontinence in up to 30% of patients. This study discussed the results of clove oil 1% cream in healing of chronic anal fissure.\n A single-blind randomized comparative trial was setup to compare traditional treatment with stool softeners and lignocaine cream 5% against clove oil 1% cream for 6 weeks.\n 55 patients were included in this study, 30 patients in clove oil group and 25 patients in control group. Healing had occurred in 60% of patients in clove oil group and in 12% of patients in the control group after 3-month follow up (P < 0.001). Patients in clove oil group showed significant reduction in resting anal pressure and almost all other anorectal manometric pressures compared with patients in control group.\n Topical application of clove oil cream demonstrated a significant beneficial effect when applied to patients suffering from chronic anal fissure.", "This was a multicenter, randomized, controlled trial to compare the effectiveness of topical nitroglycerin with internal sphincterotomy in the treatment of chronic anal fissure.\n Patients with symptomatic chronic anal fissures were randomly assigned to 0.25 percent nitroglycerin tid or internal sphincterotomy. Both groups received stool softeners and fiber supplements and were assessed at six weeks and six months.\n Ninety patients were accrued, but 8 were excluded from the analysis because they refused internal sphincterotomy after randomization (6), the fissure healed before surgery (1), or a fissure was not observed at surgery (1). There were 38 patients in the internal sphincterotomy group (22 males; mean age, 40.3 years) and 44 patients in the nitroglycerin group (15 males; mean age, 38.7 years). At six weeks 34 patients (89.5 percent) in the internal sphincterotomy group compared with 13 patients (29.5 percent) in the nitroglycerin group had complete healing of the fissure (P = 5x10(-8)). Five of the 13 patients in the nitroglycerin group relapsed, whereas none in the internal sphincterotomy group did. At six months fissures in 35 (92.1 percent) patients in the internal sphincterotomy group compared with 12 (27.2 percent) patients in the nitroglycerin group had healed (P = 3x10(-9)). One (2.6 percent) patient in the internal sphincterotomy group required further surgery for a superficial fistula compared with 20 (45.4 percent) patients in the nitroglycerin group who required an internal sphincterotomy (P = 9x10(-6)). Eleven (28.9 percent) patients in the internal sphincterotomy group developed side effects compared with 37 (84 percent) patients in the nitroglycerin group (P<0.0001). Nine (20.5 percent) patients discontinued the nitroglycerin because of headaches (8) or a severe syncopal attack (1).\n Internal sphincterotomy is superior to topical nitroglycerin 0.25 percent in the treatment of chronic anal fissure, with a high rate of healing, few side effects, and low risk of early incontinence. Thus, internal sphincterotomy remains the treatment of choice for chronic anal fissure.", "The aim of this study was to compare the efficacy of the local application of 0.5% nifedipine ointment vs. lateral internal sphincterotomy in the healing of chronic anal fissure.\n Sixty-four patients with symptomatic chronic anal fissures were randomly assigned to 0.5% nifedipine ointment (n=32) every 8 h for 8 weeks or lateral internal sphincterotomy (n=32). Both groups received stool softeners and fiber supplements and were assessed at 2, 4, 6, and 8 weeks. Long-term outcomes were determined after a median follow-up of 19 months (nifedipine group) and 20.5 months (lateral internal sphincterotomy group).\n Complete healing at 8 weeks was achieved in 30 out of 31 patients (96.7%) in the nifedipine group and 32 out of 32 patients (100%) in the lateral internal sphincterotomy group (p=0.49). The overall healing rates at the end of follow-up were 28 out of 30 (93%) vs. 32 out of 32 (100%) in the nifedipine and sphincterotomy groups respectively (p=0.48). Two of the 30 patients in the nifedipine group relapsed whereas none in the sphincterotomy group did. Sixteen patients (50%) developed side effects in the nifedipine group, compared with six patients (18.7%) in the sphincterotomy group.\n Topical application of 0.5% nifedipine ointment represents a new, promising, easily handled, effective alternative to lateral internal sphincterotomy.", "Anal fissures are associated with hypertonia of the internal anal sphincter and pain. We evaluated the efficacy of local application of a combination of minoxidil and lignocaine in healing anal fissures.\n In this prospective, randomized, double-blind study, 90 patients with anal fissure were recruited. Patients received local applications of ointments containing 5% lignocaine (n=28), 0.5% minoxidil (n=36), or both (n=26). Healing of anal fissure at 6 weeks was used as the primary end-point.\n Rates of complete healing of fissure were similar in the three groups (lignocaine alone 8/27, minoxidil alone 10/34, combination 7/22; p=ns). Mean (SD) time taken for complete healing with combination treatment [1.9 (0.6) weeks] was significantly shorter than that with minoxidil alone (3.1 [1.7] weeks; p=0.001) or with lignocaine alone (3.3 [0.8] weeks; p=0.002). Rates of pain relief were similar in the three groups. Stoppage of bleeding occurred more often with combination treatment than with lignocaine alone. No patient had systemic or local side effects.\n Combination treatment with minoxidil and lignocaine helps in faster healing of anal fissures and provides better symptomatic relief than either drug alone.", "The results of controlled-intermittent anal dilatation (CIAD) or lateral internal sphincterotomy (LIS) in the treatment of chronic anal fissures are presented.\n Forty patients who were randomized to two groups underwent CIAD or a LIS. The pre- and post-operative mean anal canal resting pressures (MACRPs) and symptoms were recorded and the results were compared.\n Two months post-operatively, 18 patients in the CIAD group and 17 patients in the LIS group had healed completely, and had no anal incontinence or other complications. The post-operative improvement in pain, bleeding, and constipation did not differ significantly between the two groups. In the CIAD and LIS groups, the pre-operative MACRPs were 89.7+/-16.5 and 87.6+/-12.3 mmHg, respectively; 2 months post-operatively, the MACRPs had significantly decreased to 76.9+/-13.7 and 78.1+/-11.3 mmHg in the CIAD and LIS groups, respectively. No statistical difference existed in the pre- or post-treatment MACRPs between the groups.\n CIAD applied with a standardized technique reduced anal canal resting pressure and provided symptomatic healing that was equivalent to a LIS. Since there were no findings of incontinence, or situations which resulted in sphincter damage, we conclude that CIAD is suitable for patients with chronic anal fissures because it is less invasive than LIS, with equivalent efficacy and safety. In addition, the CIAD method may be an alternative procedure in older and multiparous women who has a higher risk of incontinence.", "The aim of this trial was to compare lateral internal sphincterotomy with local 0.2 percent isosorbide dinitrate in the treatment of chronic anal fissure to minimize surgical complications such as minor fecal incontinence.\n Fifty-four patients with chronic anal fissure were randomized in a prospective trial to either sphincterotomy or local 0.2 percent isosorbide dinitrate. All patients had anal function tests before and 5 weeks after treatment.\n In the ointment group, 18 patients (67 percent) healed at 5 weeks and 24 (89 percent) healed at 10 weeks of treatment. Maximum resting anal pressure was reduced 30 percent. Eight patients (30 percent) had minor side effects. In the surgical group, 26 patients (96 percent) healed at 5 weeks and 100 percent healed at 10 weeks after treatment, with 33 percent reduction in maximum resting anal pressure. Forty-four percent of patients had minor fecal incontinence, which remained in 15 percent after 24 months follow-up. No statistical difference in maximum resting anal pressure was found between groups ( P = 0.16), but the percentage of healing at 5 weeks was greater in the surgical group ( P < 0.001).\n Isosorbide dinitrate ointment must be considered as the first choice of treatment in patients with chronic anal fissure. Surgery should be indicated if chemical sphincterotomy fails.", "We compare lateral internal sphincterotomy as an effective treatment of chronic fissure in ano to fissurectomy, which is as an alternative surgical treatment.\n Sixty two consecutive patients were divided into two groups through sequential sampling. Thirty patients underwent fissurectomy and 32 underwent lateral internal sphincterotomy. After a median follow-up of 22 months, we compared the results of the two procedures. In addition to frequent visits on a predetermined basis, a telephone inquiry into fissure recurrence and continence status was made.\n All patients in both groups were pain-free and without bleeding within 1 week. In both groups, urinary retention was noted in one patient. Incontinence to flatus was noted in the fissurectomy (F) group in two (6.2%) patients, but no incontinence was noted in the lateral internal sphincterotomy (LIS) group. There was one patient (3.1%) with fissure recurrence in the F group but none in the LIS group. No patient in either group was afflicted with anal stenosis or perianal infections. All wounds healed within 8 weeks. Twenty nine patients (96.6%) in the LIS group and 28 (87.5%) in the F group reported satisfactory results with their procedure.\n In the surgical treatment of chronic anal fissure not responding to conservative management, LIS may be the better treatment and, perhaps, the preferable surgical technique with fewer total complications (P < 0.005)." ]	Medical therapy for chronic anal fissure, currently consisting of topical glyceryl trinitrate, botulinum toxin injection or the topical calcium channel blockers nifedipine or diltiazem in acute and chronic fissure and fissure in children may be applied with a chance of cure that is marginally better than placebo. For chronic fissure in adults all medical therapies are far less effective than surgery. A few of the newer agents investigated show promise based only upon single studies (clove oil, sildenifil and a "healer cream") but lack comparison to more established medications.
CD000495	[ "2665802" ]	[ "Ultrasound and pulsed electromagnetic energy treatment for perineal trauma. A randomized placebo-controlled trial." ]	[ "Ultrasound and pulsed electromagnetic energy therapies are increasingly used for perineal trauma sustained during childbirth. The study included 414 women with moderate or severe perineal trauma randomly allocated to receive active ultrasound, or active pulsed electromagnetic energy, or corresponding placebo therapies; the allocation was double-blind for each machine. Overall, more than 90% thought that treatment made their problem better. There were no clear differences between the groups in outcome either immediately after treatment, or 10 days or 3 months postpartum, other than more pain associated with pulsed electromagnetic energy treatment at 10 days. Bruising looked more extensive after ultrasound therapy but then seemed to resolve more quickly. Neither therapy had an effect on perineal oedema or haemorrhoids. The place of these new therapies in postnatal care should be clarified by further controlled trials before they become part of routine care." ]	There is not enough evidence to evaluate the use of ultrasound in treating perineal pain or dyspareunia, or both, following childbirth.
CD000398	[ "11306778" ]	[ "The effect of transdermal glyceryl trinitrate, a nitric oxide donor, on blood pressure and platelet function in acute stroke." ]	[ "Hypertension is a common medical complication in acute stroke and is associated with a poor outcome. However, no large trials have assessed the effect of lowering blood pressure (BP) on outcome, and it remains unclear how BP should be managed in acute stroke. We assessed, in a double-blind randomised controlled trial, whether the nitric oxide (NO) donor glyceryl trinitrate (GTN, a known systemic and cerebral vasodilator), would lower BP and alter platelet function.\n Thirty-seven patients with recent (< 5 days) ischaemic or haemorrhagic stroke were randomised by minimisation to 12 days of daily treatment with transdermal GTN or matching placebo patches. Twenty-four-hour ambulatory BP was measured before and during GTN treatment at days 0, 1 and 8. Platelet aggregation and expression of adhesion molecules were assessed at the same time points. Functional outcome (Rankin scale) and case fatality were assessed at 3 months. Analysis was by intention-to-treat.\n GTN significantly lowered BP by 13.0/5.2 mm Hg at day 1 and 9.3/5.0 mm Hg at day 8. The lesser reduction at day 8 than day 1 suggests that tolerance to GTN was developing. Non-significant falls of 0.9/0.6 and 3.8/0.0 mm Hg occurred at days 1 and 8, respectively, in the placebo group. GTN had no effect on heart rate, or platelet aggregation or expression of platelet adhesion molecules, including glycoproteins Ia, Ib, IIIa and P-selectin. Additionally, GTN did not alter case fatality or dependency, although the study was not powered for these outcomes.\n Transdermal GTN, an NO donor, lowered BP by 5-8%, a clinically significant and relevant, but not excessive, degree in patients with acute stroke. However, GTN had no effect on platelet aggregation or expression of adhesion molecules. Since NO donors increase cerebral blood flow in patients with acute ischaemic stroke, GTN may be an appropriate drug for testing the effect of lowering BP on functional outcome.\n Copyright 2001 S. Karger AG, Basel" ]	There is currently insufficient evidence from randomised trials on the effects of nitric oxide donors, L-arginine, or nitric oxide synthase-inhibitors in patients with acute stroke to recommend their use. A large controlled trial of glyceryl trinitrate patches is underway.
CD006481	[ "2961818", "6233921", "6755247", "1335647", "6235453", "7975854", "7798683", "9651632", "2141247", "6138642", "12972790" ]	[ "Hepatitis B vaccines in patients with chronic renal failure before dialysis.", "Hepatitis B vaccine in health care personnel: safety, immunogenicity, and indicators of efficacy.", "Hepatitis B vaccine in medical staff of hemodialysis units: efficacy and subtype cross-protection.", "Simultaneous vaccination against hepatitis A and B: results of a controlled study.", "Hepatitis B vaccine in patients receiving hemodialysis. Immunogenicity and efficacy.", "Influence of smoking on immunological responses to hepatitis B vaccine.", "Long-term efficacy of active postexposure immunization of infants for prevention of hepatitis B virus infection. United States-People's Republic of China Study Group on Hepatitis B.", "Immunogenicity of hepatitis B Vaccines. Implications for persons at occupational risk of hepatitis B virus infection.", "A randomized double-blind clinical trial of a mammalian cell-derived recombinant DNA hepatitis B vaccine compared with a plasma-derived vaccine.", "Prevention of perinatally transmitted hepatitis B virus infections with hepatitis B immune globulin and hepatitis B vaccine.", "Hepatitis A and B vaccination in a sexually transmitted disease clinic for men who have sex with men." ]	[ "Hepatitis B remains a significant risk to patients receiving chronic hemodialysis, but no certain method of prevention has been identified. We tested two vaccines, plasma-derived vaccine (40-micrograms dose) and recombinant-derived vaccine (40-micrograms and 20-micrograms doses), in 61 patients with chronic renal failure who were not yet dependent on dialysis. Patients were followed up clinically and with laboratory tests of kidney function and hepatitis B virus serology for one year. Significantly more recipients of plasma-derived vaccine responded to vaccination; they also achieved a higher titer of antibody to hepatitis B virus than did recipients of recombinant-derived vaccine when evaluated at 6, 7, 9, and 12 mo after vaccination. No serious side effects were observed with any vaccine preparation, nor were excessive adverse effects observed in any group. Compared with the dialysis patients previously studied, patients with renal failure who were not yet dependent on dialysis responded more favorably to the hepatitis B virus vaccine.", "In a double-blind trial, we randomly assigned 1330 high-risk health care personnel to receive three 20-micrograms doses of hepatitis B vaccine or placebo. Among vaccine recipients 58% responded within 1 month and 97% within 9 months; there was no difference in immune response to the vaccine between men and women. Efficacy was evaluated after a mean follow-up of only 13.2 months, just before the vaccine was released commercially. Five hepatitis B infections were identified in placebo recipients and one in a vaccine recipient. Although the number of infections was too small to allow confident conclusions about protective efficacy of the vaccine, we saw a 67% reduction in the need for hepatitis B immune globulin after accidental hepatitis B inoculation in the vaccine group (relative risk, 5.08; 95% confidence intervals, 1.3 to 19.9). Minor side effects occurred with equal frequency after vaccine (28.7%) and placebo (27.2%) injections; no participant had a severe adverse reaction. Vaccination with the 20-micrograms hepatitis B vaccine was highly immunogenic and safe in health care workers.", "We evaluated the efficacy of hepatitis B vaccine (Heptavax-B) containing only the ad subtype in a randomized, placebo-controlled, double-blind trial among 865 staff members of 43 hemodialysis units in the United States. Surface antibody developed in 92.6 per cent of the subjects after two doses of vaccine and in 96 per cent after the six-month booster. The incidence of infections with hepatitis B virus (with or without hepatitis) was 9.9 per cent in placebo recipients and 2.2 per cent in vaccine recipients (P less than 0.01). The two cases of hepatitis B among vaccine recipients did not occur in subjects in whom antibody had developed. In 81 per cent of the hepatitis events, the virus was of the ay subtype. The indicence of ay virus was 8.2 per cent among placebo recipients and 1.2 per cent among vaccine recipients (P less than 0.005). We conclude that these data confirm the efficacy of the vaccine and demonstrate subtype cross-protection.", "Hepatitis A and hepatitis B are endemic in many countries and must be considered as serious health risks for large parts of the world population. Simultaneous or combined vaccination against these two diseases would therefore be most advantageous. In order to investigate possible interactions between these vaccines with respect to their tolerability and immunogenicity, we conducted a randomized prospective study comparing single and simultaneous administration of the two vaccines. Three groups of healthy volunteers, each with 55 persons, were included in the study. All were negative for hepatitis A and hepatitis B markers and had normal serum liver enzyme values. Group I received hepatitis A vaccine (720 ELISA units) into the left deltoid muscle, group II received hepatitis B vaccine (20 micrograms) into the right deltoid muscle and group III received hepatitis A vaccine into the left, and hepatitis B vaccine into the right deltoid muscle. Three doses of the vaccines were administered at 0, 1 and 6 months. Local and systemic reactions were monitored by means of questionnaires. Blood samples for determination of antibody to hepatitis A virus (anti-HAV) and antibody to hepatitis B surface antigen (anti-HBs) and of serum SGOT and SGPT levels were drawn at months 0, 1, 2, 6 and 7. There were no serious general and only mild local reactions. The mean serum SGOT and SGPT values remained in the normal range in all groups. The seroconversion rates and mean geometric titres of the anti-HAV and anti-HBs antibodies were similar when the vaccines were administered separately or simultaneously. There were no significant differences between the compared groups.(ABSTRACT TRUNCATED AT 250 WORDS)", "We evaluated the immunogenicity and efficacy of hepatitis B vaccine (Heptavax-B) in a randomized, double-blind, placebo-controlled trial involving 1311 patients receiving hemodialysis in the United States. After three doses of vaccine (40 micrograms each) had been administered, 63 per cent of the patients were antibody-positive. After correction for possible passive transfer of antibodies by blood transfusion, only 50 per cent of vaccine recipients were considered vaccine responders. The incidence of hepatitis B viral infection during the 25 months of the trial was much lower than had been anticipated and was virtually the same in the vaccine and placebo recipients (6.4 and 5.4 per cent, respectively). Four cases of hepatitis B occurred in patients who had an apparent antibody response to the vaccine, but in each case either antibody had reached low or undetectable levels before hepatitis B surface antigen was detected or the patient had been receiving immunosuppressive therapy. This study did not demonstrate the efficacy of the vaccine in a population of patients receiving dialysis in whom both the rate of antibody response to hepatitis B vaccine and the viral attack rate were low. Other measures to control transmission of hepatitis B virus in dialysis units, including surveillance for hepatitis B surface antigen and isolation of patients who are positive for the antigen, must be continued.", "When 115 health-care workers participated in a study that monitored their serological responses to hepatitis B vaccine at regular intervals, it was found that smoking significantly affected their antibody titre responses adversely. The study group was randomly allocated into two comparable groups that received hepatitis B vaccine either in a rapid schedule (vaccination at 0, 1, 2 and 12 months) or a standard schedule-most commonly used worldwide-(vaccination at 0, 1, and 6 months). A significantly higher proportion of smokers, in both schedules, failed to seroconvert and to achieve higher antibody levels at month 3 (p = 0.01) and at month 13 (p = 0.0003). At month 7 a similar pattern was noted in smokers following the standard vaccination schedule (p < or = 0.05), but not in those following the rapid schedule.", "Perinatal transmission of hepatitis B virus (HBV) contributes to the high prevalence of chronic infection in China and many other countries. In a placebo-controlled trial among 166 infants, the 12-month efficacy of active postexposure prophylaxis to prevent chronic perinatal HBV infection varied by vaccine (range, 45%-89%). In a 5-year follow-up study, 2 additional infants became chronically infected with HBV, and the efficacy of active prophylaxis was estimated to be 38% and 72% for the two vaccines at 5 years. In addition, 80% of immunized infants continued to have protective levels of antibody at the end of 5 years. However, among 27 infants who received passive-active immunoprophylaxis with high-dose hepatitis B immune globulin, only 60% (11/19) had protective antibody levels. These data indicate that active postexposure immunization initiated soon after birth continues to provide protection during early childhood when there is a high risk of chronic HBV infection.", "To assess risk factors for decreased immunogenicity among adults vaccinated with hepatitis B vaccine and to determine the importance of differences in immunogenicity between vaccines among health care workers (HCWs).\n Randomized clinical trial and decision analysis.\n HCSw.\n Development of seroprotective levels of antibody to hepatitis B surface antigen (anti-HBs) and the number of expected chronic hepatitis B virus (HBV) infections associated with lack of protection.\n Overall, 88% of HCWs developed seroprotection. Risk factors associated with failure to develop seroprotection included increasing age, obesity, smoking and male gender (P < .05). Presence of a chronic disease was associated with lack of seroprotection only among persons > or = 40 years of age (P < .05). The two vaccines studied differed in their overall seroprotection rates (90% vs. 86%; P < .05), however, this difference was restricted to persons > or = 40 years of age (87% vs. 81%; P < .01). Among HCWs > or = 40 years of age, the decision analysis found 44 (0.34/100,000 person-years) excess chronic HBV infections over the working life of the cohort associated with use of the less immunogenic vaccine compared to the other.\n He patitis B vaccines are highly immunogenic, but have decreased immunogenicity associated with increasing age, obesity, smoking, and male gender; and among older adults, the presence of a chronic disease. One of the two available vaccines is more immunogenic among older adults; however, this finding has little clinical or public health importance. Hepatitis B vaccines should be administered to persons at occupational risk for HBV infection early in their career, preferably while they are still in their training.", "Eight hundred volunteers from heath care and emergency fields participated in a randomized double-blind clinical trial of a new experimental mammalian cell-derived recombinant DNA hepatitis B vaccine (Betagen) compared with a licensed plasma-derived vaccine (Heptavax-B). Vaccine injections (20 micrograms) were administered intramuscularly at 0, 1, and 6 months, and sera were tested at 0, 1, 2, 3, 6, 7, and 12 months for hepatitis B surface antigen, antibody to hepatitis B surface antigen, and antibody to hepatitis B core antigen. Data from 745 vaccinees (93.1%), analyzed at the 7th month of follow-up, showed no significant difference in the seroconversion rates for Betagen (94.4%) vs Heptavax-B (97.3%), but the geometric mean titer of antibody was significantly higher for Heptavax-B (11 833 mIU/L) than for Betagen (4628 mIU/mL). The antibody response of Betagen was significantly and independently related to age and sex, while that of Heptavax-B was related to age only. Reported side effects from both vaccines were minor and mild, with approximately one fourth of all vaccinees reporting at least one side effect. Vaccinees, who had a protective level of antibody at the 7th month, were tested for antibodies at the 12th month. Of those in the Betagen-vaccinated group and those in the Heptavax-B-vaccinated group, 99.0% and 100%, respectively, were still protected. There was a proportionately larger decline in the geometric mean titers of antibody to hepatitis B surface antigen for Heptavax-B than for Betagen.", "A randomised blind controlled trial of hepatitis B immune globulin (HBIG) plus hepatitis B vaccine for the prevention of the perinatally transmitted HBsAg carrier state was conducted in Taipei. Infants of e-antigen-positive HBsAg carrier mothers were given HBIG immediately after birth, and then one of three schedules of vaccination. There was no difference in efficacy between the three schedules; the combined efficacy was 94%, compared with that of HBIG alone (71%) or of vaccination alone (75%). Persistent HBs antigenaemia developed in only 9 (6%) of the 159 infants receiving prophylaxis, but in 88% of the controls. Antibodies developed in all those who did not become antigenaemic and presumably will provide long-term protection from hepatitis B virus infection. HBIG should be given as soon as possible after birth and need not be given again if the infant is subsequently vaccinated. With HBIG coverage from birth, the timing of the start of vaccination does not seem to be of importance within the first month of life, but to maximise compliance and minimise costs hepatitis B vaccination should be initiated during the confinement.", "Sexually transmitted disease clinics can deliver hepatitis vaccines to men who have sex with men, but have been reluctant to do so because of perceived low vaccination completion rates.\n The goal was to evaluate hepatitis A and B vaccination eligibility, acceptance, and completion and the effectiveness of reminder/recall in a sexually transmitted disease clinic serving men who have sex with men.\n Clients self-reported their eligibility for free vaccine. Consenting clients who accepted a first dose of vaccine were systematically assigned to receive telephone reminder/recall or standard follow-up.\n Of 1203 clients, 71.8% were eligible for both vaccines; 62.6% of those eligible accepted both. Reminder/recall was associated with increased receipt of the second dose of hepatitis B vaccine (86.7% versus 80.4% among intervention and control groups, respectively), but not with completion of both vaccine series (55.9% versus 58.8%).\n The majority of clients were eligible for both hepatitis vaccines, and most eligible clients accepted a first dose of both vaccines. Reminder/recall, as delivered at this clinic, failed to increase the proportion of clients who received all vaccine doses. New delivery mechanisms should be explored." ]	In people not previously exposed to hepatitis B, vaccination has unclear effect on the risk of developing infection, as compared to no vaccination. The risk of lacking protective antibody levels as well as serious and non-serious adverse events appear comparable among recipients and non-recipients of hepatitis B vaccine.
CD003855	[ "20159179", "16487195", "15039412", "11214131", "11476777", "19897857", "21092958", "12563136", "8982752" ]	[ "A randomized prospective trial comparing the levonorgestrel-releasing intrauterine system with thermal balloon ablation for the treatment of heavy menstrual bleeding.", "A randomised trial comparing the levonorgestrel intrauterine system and thermal balloon ablation for heavy menstrual bleeding.", "Clinical outcomes and costs with the levonorgestrel-releasing intrauterine system or hysterectomy for treatment of menorrhagia: randomized trial 5-year follow-up.", "Quality of life and cost-effectiveness of levonorgestrel-releasing intrauterine system versus hysterectomy for treatment of menorrhagia: a randomised trial.", "Treatment of menorrhagia with the levonorgestrel intrauterine system versus endometrial resection.", "Randomized placebo-controlled trial of CDB-2914 in new users of a levonorgestrel-releasing intrauterine system shows only short-lived amelioration of unscheduled bleeding.", "A randomized clinical trial of a levonorgestrel-releasing intrauterine system and a low-dose combined oral contraceptive for fibroid-related menorrhagia.", "Uterine fibroids: uterine artery embolization versus abdominal hysterectomy for treatment--a prospective, randomized, and controlled clinical trial.", "Oestrogen treatment for increased bleeding in Norplant users: preliminary results." ]	[ "Use of the levonorgestrel-releasing intrauterine system (LNG-IUS) was compared with thermal balloon ablation (TBA) for the treatment of heavy menstrual bleeding (HMB).\n A prospective randomized trial comparing the LNG-IUS (n=30 women) and TBA (n=28 women).\n Hemoglobin levels increased (p<.001) and blood loss was reduced (p<.001) in both groups after 1 year of treatment. Menstrual bleeding was less in the LNG-IUS group compared to the TBA group at 6 and 12 months of treatment (p=.035 and p=.048, respectively). Intermenstrual bleeding was significantly less in the TBA group at 6 months compared to the LNG-IUS group (p=.044); however, there was no significant difference at 12 months (p=.129). No difference was found in psychological aspects between pre- and posttreatment variables in either of the groups (p=.537).\n Both the LNG-IUS and TBA appear to be effective in controlling HMB; however, posttreatment uterine bleeding patterns are different.\n Copyright (c) 2010 Elsevier Inc. All rights reserved.", "To compare the levonorgestrel intrauterine system (LNG-IUS) (Mirena); Schering Co., Turku, Finland) and thermal balloon ablation (Thermachoice; Gynecare Inc., Menlo Park, CA, USA) for the treatment of heavy menstrual bleeding.\n An open, pragmatic, prospective randomised trial.\n A menstrual disorders clinic at National Women's Hospital, Auckland, New Zealand.\n Seventy-nine women with heavy menstrual bleeding randomised to the LNG-IUS (40 women) or the thermal balloon ablation (39 women).\n Women were randomised to treatment with the LNG-IUS or thermal balloon ablation and followed up by a postal and telephone questionnaire.\n Menstrual loss measured by a pictorial bleeding assessment chart (PBAC) at 3, 6, 12 and 24 months. Patient satisfaction, quality of life and menstrual symptoms were assessed by questionnaire administered at 3, 6, 12 and 24 months. Treatment side effects and treatment failures were also recorded.\n Both the treatments resulted in a significant reduction in PBAC scores. At 12 and 24 months, median PBAC scores were significantly lower in women treated with the LNG-IUS compared with women treated by thermal balloon ablation (11.5 versus 60.0 at 12 months [P= 0.002]; 12.0 versus 56.5 [P= 0.002] at 24 months). At 24 months, nine (35%) women still using the LNG-IUS had amenorrhoea compared with one (5%) woman successfully treated by thermal balloon ablation (P = 0.025). There were no significant differences in patient satisfaction between two treatments during follow up. Treatment failed in 11 (28%) women using the LNG-IUS and in 10 (26%) women treated with thermal balloon ablation. Overall, women in both groups showed an increased quality of life as a result of the treatment, with Short Form-36 scores increasing from 63.7 at randomisation to 76.1 at 24 months.\n At 12 and 24 months of follow up, women with heavy menstrual bleeding treated with the LNG-IUS have significantly lower PBAC scores than women treated with thermal balloon ablation. Both the treatments resulted in a significant increase in overall quality of life, but there were no significant differences between either treatment in quality of life, patient satisfaction or the number of women requesting an alternative treatment during 24 months of follow up.", "Because menorrhagia is often a reason for seeking medical attention, it is important to consider outcomes and costs associated with alternative treatment modalities. Both the levonorgestrel-releasing intrauterine system (LNG-IUS) and hysterectomy have proven effective for treatment of menorrhagia but there are no long-term comparative studies measuring cost and quality of life.\n To compare outcomes, quality-of-life issues, and costs of the LNG-IUS vs hysterectomy in the treatment of menorrhagia.\n Randomized controlled trial conducted between October 1, 1994, and October 6, 2002, and enrolling 236 women (mean [SD] age, 43 [3.4] years) referred to 5 university hospitals in Finland for complaints of menorrhagia.\n Participants were randomly assigned to treatment with the LNG-IUS (n = 119) or hysterectomy (n = 117) and were monitored for 5 years.\n Health-related quality of life (HRQL) as measured by the 5-Dimensional EuroQol and the RAND 36-Item Short-Form Health Survey, other measures of psychosocial well-being (anxiety, depression, and sexual function), and costs.\n After 5 years of follow-up, 232 women (99%) were analyzed for the primary outcomes. The 2 groups did not differ substantially in terms of HRQL or psychosocial well-being. Although 50 (42%) of the women assigned to the LNG-IUS group eventually underwent hysterectomy, the discounted direct and indirect costs in the LNG-IUS group (2817 dollars [95% confidence interval, 2222 dollars-3530 dollars] per participant) remained substantially lower than in the hysterectomy group (4660 dollars [95% confidence interval, 4014 dollars-5180 dollars]). Satisfaction with treatment was similar in both groups.\n By providing improvement in HRQL at relatively low cost, the LNG-IUS may offer a wider availability of choices for the patient and may decrease costs due to interventions involving surgery.", "Heavy menstrual blood loss is a common reason for women to seek medical care. The levonorgestrel-releasing intrauterine system (IUS) is an effective medical treatment for menorrhagia. We report a randomised comparison of this approach with hysterectomy in terms of the quality of life of women with menorrhagia and cost-effectiveness.\n Of 598 women referred with menorrhagia to five university hospitals in Finland, 236 were eligible and agreed to take part. They were randomly assigned treatment with the levonorgestrel-releasing IUS (n=119) or hysterectomy (n=117). The amount of menstrual blood loss was objectively measured. The primary outcome measure was health-related quality of life at 12-month follow-up. Analyses were by intention to treat.\n In the group assigned the levonorgestrel-releasing IUS, 24 (20%) women had had hysterectomy and 81 (68%) continued to use the system at 12 months. Of the women assigned to the hysterectomy group, 107 underwent the operation. Health-related quality of life improved significantly in both the IUS and hysterectomy groups (change 0.10 [95% CI 0.06-0.14] in both groups) as did other indices of psychological wellbeing. There were no significant differences between the treatment groups except that women with hysterectomy suffered less pain. Overall costs were about three times higher for the hysterectomy group than for the IUS group.\n The significant improvement in health-related quality of life highlights the importance of treating menorrhagia. During the first year the levonorgestrel-releasing IUS was a cost-effective alternative to hysterectomy in treatment of this disorder.", "Treatment of menorrhagia with levonorgestrel intrauterine system (LNG IUS) and transcervical resection.\n An open, therapeutic, randomized study.\n Central county hospital specializing in hysteroscopy.\n Two parallel groups of 30 subjects each.\n Thirty patients had a LNG IUS inserted within the first 7 days of menses; 29 patients underwent endometrial resection.\n A 12-month follow-up of menstrual blood loss and adverse events were evaluated.\n LNG IUS group: 13 patients reported one or more pelvic adverse events, bleeding disorders (n = 6), abdominal pain (n = 4), breast tenderness (n = 3), headache, acne (n = 2), and mood changes (n = 1). Six patients discontinued treatment because of irregular bleeding (n = 3), pain (n = 2), and acne (n = 1). In both groups, general feeling of genital health increased with Visual Analogue Scale score. Nine patients reported adverse events. This included pelvic pain indicating inflammation (n = 4), bleeding (n = 3), vaginitis (n = 1), and ulceration (n = 1). Treatment success at 12 months was achieved in 20 (67%) of the 30 patients in the LNG IUS group and in 26 (90%) of the 29 patients in the transcervical resection group. Adverse events were more often reported in the LNG IUS group.\n Both treatments effectively reduced the menstrual blood loss. Furthermore, the LNG IUS treatment is reversible and has no operative hazards.", "The levonorgestrel-releasing intrauterine system (LNG-IUS) is a highly effective contraceptive. However, during early months of use unscheduled vaginal bleeding is common, sometimes leading to discontinuation. This study aimed to determine whether intermittent administration of progesterone receptor modulator CDB-2914 would suppress unscheduled bleeding during the first 4 months after insertion of the LNG-IUS.\n CDB-2914 150 mg, in divided doses, or placebo tablets, were administered over three consecutive days starting on Days 21, 49 and 77 after LNG-IUS insertion, in a double-blind randomized controlled trial of women aged 19-49 years, newly starting use of LNG-IUS. Daily bleeding diaries were completed for 6 months, and summarized across blocks as percentage days bleeding/spotting (BS%).\n Of 69 women randomized to receive CDB-2914, and 67 placebo, 61 and 55, respectively, completed the trial. BS% decreased with time in both arms, but showed a much steeper treatment-phase gradient in the placebo arm (P < 0.0001), so that a benefit of CDB-2914 in the 28 days after first treatment (-11% points, 95% CI -19 to -2), converted to a disadvantage by 64 days after the third treatment (+10% points, 95% CI 1-18).\n The effect of CDB-2914 on BS% was initially beneficial but then by third treatment was disadvantageous. Nevertheless, only 3% (4/136) of all women discontinued LNG-IUS. These findings give insight into possible mechanisms and suggest future research directions. ISRCTN Trial no. ISRCTN58283041; EudraCT no. 2006-006511-72.", "To compare the efficacy of a levonorgestrel-releasing intrauterine system (LNG-IUS) with that of a low-dose combined oral contraceptive (COC) in reducing fibroid-related menorrhagia.\n In this single-center, open, randomized clinical trial, 58 women with menorrhagia who desired contraception were randomized to receive a LNG-IUS or COC. The outcomes included treatment failure, defined as the need for another treatment; menstrual blood loss (MBL) by the alkaline hematin method and a pictorial assessment chart (PBAC); hemoglobin levels; and \"lost days.\"\n Treatment failed in 6 women (23.1%) in the LNG-IUS group and 11 (37.9%) in the COC group, for a hazard ratio of 0.46 (95% CI, 0.17-1.17, P=0.101). Using the alkaline hematin test, the reduction of MBL was significantly greater in the LNG-IUS group (90.9% ± 12.8% vs 13.4% ± 11.1%; P<0.001). Using PBAC scores, the reduction was also significantly greater in the LNG-IUS group (88.0% ± 16.5% vs 53.5% ± 5 1.2%; P=0.02). Moreover, hemoglobin levels increased from 9.7 ± 1.9g/dL to 11.7 ± 1.2g/dL (P<0.001) and lost days decreased from 8.2 ± 3.3 days to 1.3 ± 1.5 days (P=0.003) in the LNG-IUS group.\n Although the rate of treatment failure was similar in both groups, the LNG-IUS was more effective in reducing MBL than the COC in women with fibroid-related menorrhagia.\n Copyright Â© 2010 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.", "To evaluate the effectiveness of uterine artery embolization (UAE) in the management of bleeding in patients with uterine fibroids and to compare UAE with hysterectomy, particularly with regard to length of hospital stay and associated complications (ie, safety).\n A prospective clinical trial was performed with patients who were randomly assigned to one of two groups: patients who were offered the option of undergoing either UAE or hysterectomy (group 1) and patients who were not informed of the alternative treatment-that is, UAE (group 2). The primary variables that were considered for evaluation of the effectiveness, efficiency, and safety of the two procedures were, respectively, bleeding cessation, total length of hospital stay, and resulting complications. The lengths of hospital stay in the two study arms were compared on an intent-to-treat basis. Owing to crossover between the treatment arms, however, effectiveness and safety were evaluated on the basis of the actual treatment received.\n The clinical success rate for the patients who underwent UAE, which was based on the cessation of bleeding, was 86% (31 of 36 patients). The mean hospital stay for group 1 was 4.14 days shorter than that for group 2 (P <.001). Ten (25%) of the 40 patients who underwent UAE experienced minor complications, in contrast to four (20%) of the 20 who underwent hysterectomy and experienced major complications.\n Compared with hysterectomy, UAE is safe and effective for treatment of bleeding fibroids, necessitates a shorter hospital stay, and results in fewer major complications.", "A clinical study was conducted to assess the effects of oestrogen in controlling increased endometrial bleeding problems in the first year of Norplant use. Three treatment groups were studied: (i) 50 micrograms ethinyl oestradiol (EE); (ii) a combined pill containing 30 micrograms EE and 150 micrograms levonorgestrel (LNG); and (iii) placebo. Based on menstrual diary records, women with prolonged, frequent or irregular bleeding, as defined by World Health Organization criteria, were randomly allocated to one treatment for 21 days. A first endometrial biopsy was taken before commencing treatment and a second biopsy at either day 14 or 21 of treatment. Following treatment, all subjects kept a menstrual diary card for 90 days. In this preliminary study, 48 subjects had completed the full 90 day post-treatment record. Within 21 days of EE treatment, the number of bleeding/spotting days was reduced significantly (P < 0.02). In the 90 days following treatment, the administration of EE and EE + LNG significantly decreased the number of bleeding/spotting days (P < 0.05). There was no reduction in the number of bleeding/spotting episodes in the EE and EE + LNG groups, but the length of each bleeding/spotting episode was significantly shorter (P < 0.05). Histopathological findings of endometrium on day 0 revealed consistent progestogenic effects, and there was no apparent change in response by day 14 or 21 of EE or EE + LNG treatment. The results of this study confirm the clinical effectiveness of EE and EE + LNG for the treatment of irregular, frequent and prolonged bleeding in Norplant users." ]	Surgery, especially hysterectomy, reduces menstrual bleeding more than medical treatments at one year but LNG-IUS may be comparable in improving quality of life. The evidence for longer-term comparisons is weak and inconsistent. Oral medication suits a minority of women long term.
CD000977	[ "12922085", "10876850", "1557929", "14615149", "16624457", "2316281", "8994317", "2842677", "11144370" ]	[ "Antigen dependent adverse reactions and seroconversion of a tick-borne encephalitis vaccine in children.", "[A cultured concentrated inactivated vaccine against tick-borne encephalitis studied during the immunization of children and adolescents].", "A randomized phase II study of a new tick-borne encephalitis vaccine using three different doses and two immunization regimens.", "Randomized, phase II dose-finding studies of a modified tick-borne encephalitis vaccine: evaluation of safety and immunogenicity.", "Safety and immunogenicity of the modified adult tick-borne encephalitis vaccine FSME-IMMUN: results of two large phase 3 clinical studies.", "A new vaccine against tick-borne encephalitis: initial trial in man including a dose-response study.", "Tick-borne encephalitis: development of a paediatric vaccine. A controlled, randomized, double-blind and multicentre study.", "Protection against Japanese encephalitis by inactivated vaccines.", "Immunogenicity and safety of a new liquid hexavalent combined vaccine compared with separate administration of reference licensed vaccines in infants." ]	[ "Two randomized, double blind dose comparison studies were conducted in 595 children in Austria and Germany with an albumin-free and thiomersal-free tick-borne encephalitis (TBE) vaccine. Vaccinated subjects of an age between 6 months and 12 years randomly assigned received either the full adult dose or half the adult dose. Results from vaccinated children under 1 year of age at the time of the first vaccination (159 subjects) showed an age dependent immune response. There were significantly fewer adverse systemic events (e.g. fever reactions). In children who received only half the adult dose, while seroconversion was not significantly different (93% versus 98%) after the second vaccination, and 100% for both groups after the third vaccination. Based on these results, it is recommended to vaccinate children between the ages of 1 and 12 years with half the adult dose.", "The word deals with the results obtained in the study of the reactogenicity and immunological activity of concentrated and inactivated tissue-culture tick-borne encephalitis vaccine, manufactured by the Chumakov Institute of Poliomyelitis and Viral Encephalitides, in the immunization of children and adolescents. The vaccine proved to be moderately reactogenic and exhibited pronounced immunological activity. In 91.5% of the immunized children the fourfold increase of the antibody level was observed. On the basis of the data obtained in this study the tick-borne encephalitis vaccine was recommended for use in medical practice for the prophylaxis of tick-borne encephalitis among children and adolescents.", "A new, highly purified inactivated tick-borne encephalitis (TBE) vaccine (FSME-Vaccine Behring, BI 71.061) was recently registered in Germany. A multinational phase II study was performed in seven centres located in areas endemic for TBE. A total of 379 healthy adults were randomly allocated into three dosage groups (1.0, 1.5 and 2.0 micrograms antigen per dose, respectively) and into two immunization schedules [vaccination with one dose of 0.5 ml intramuscularly on days 0, 7 and 21 (abbreviated schedule), or on days 0, 28 and 300 (conventional schedule)]. Antibody response to vaccination was assayed by enzyme-linked immunosorbent assay (ELISA), haemagglutination inhibition test (HIT) and neutralization test (NT). Seroconversion rates in the different groups 28 days after one single dose were 75.3-83.5% in ELISA, 35.8-50.6% in HIT, and 100% in NT. All vaccinees showed seroconversion in all tests on day 42 in the conventional schedule and on day 35 in the abbreviated schedule, with the exception of one subject, who remained seronegative in HIT only. Geometric mean titres (GMT) of about 3000 in ELISA were achieved by two vaccinations in the conventional schedule and showed a booster increase to 5500-8000 GMT after revaccination on day 300. Overall frequency of adverse events (related and unrelated) was 37% (conventional schedule) and 46% (abbreviated schedule) after the first, 9% and 21% after the second, and 5% and 15% after the third vaccination, respectively. Generally, side effects were mild and transient, including mainly headache, fever, malaise and local irritation. Serious, vaccine-related side effects did not occur.(ABSTRACT TRUNCATED AT 250 WORDS)", "Two clinical studies were conducted to identify the optimal dose of a modified tick-borne encephalitis (TBE) vaccine (FSME-IMMUN \"new\") in adults. A prospective, randomised, phase II, double-blind dose-finding study with the FSME-IMMUN \"new\" vaccine was performed in volunteers aged 16-65 years (n=405) to evaluate the immunogenicity and safety of two vaccinations with three vaccine doses (0.6, 1.2 and 2.4microg antigen). The safety and immunogenicity of the third vaccination were investigated in a follow-up study on the same study population. Antibody response to vaccination was assessed by enzyme-linked immunosorbent assay (ELISA) and, after the third vaccination, by neutralisation test (NT). Seroconversion rates (ELISA) in the different dose groups (0.6, 1.2 and 2.4 microg) were 85.1, 96.2 and 97.0%, respectively, after the second vaccination, which 73% of the volunteers received only 21 days after the first vaccination. Seroconversion rates after the third vaccination were 96, 99.2 and 100% (ELISA) as well as 77, 93 and 96.6% (NT) with the 0.6, 1.2 and 2.4 microg doses, respectively. No unexpected AEs or vaccine-related serious adverse events (SAE) were observed during either study. Local and systemic reactions were mainly mild and not dose-dependent, with an overall fever rate of <1% after the first vaccination. The 2.4 microg dose is the optimal dose for the FSME-IMMUN \"new\" preparation in adults, as it was found to: (1) be non-inferior to the 1.2 microg dose with respect to fever rate after the first vaccination; (2) induce the highest seroconversion rate; and (3) be well-tolerated with respect to local and systemic reactions. The results of both studies demonstrate that the FSME-IMMUN \"new\" vaccine is safe and highly immunogenic in adults.", "A prospective, randomised, multicentre, single-blind phase 3 study was performed to assess the safety of a vaccination schedule consisting of two vaccinations (21-35 days apart) with the tick-borne encephalitis (TBE) vaccine FSME-IMMUN \"adults\" (five consecutive lots) in comparison to another licensed TBE vaccine (Encepur), with polygeline) (two lots) in healthy volunteers (n=3966) aged 16-65 years. The safety of the third vaccination with FSME-IMMUN \"adults\" (6 months after the first vaccination) was investigated in a follow-up study on the same population (n=3705) and TBE antibody titres were analysed pre- and post-vaccination in a subgroup of volunteers (n=564). Following the first vaccination, the overall incidence of fever (> or =38.0 degrees C) was 0.8% in the FSME-IMMUN \"adults\" study group and 5.6% in the comparator study group; fever was mainly mild. The fever rate after the second vaccination was 0.6% and 0.5% in the two study groups, respectively. Local and systemic reactions after the first vaccination occurred with a lower frequency in the FSME-IMMUN \"adults\" study group than in the comparator group. Upon analysing the tolerability of the third vaccination with FSME-IMMUN \"adults\", similar results were determined in both study groups of volunteers previously vaccinated with FSME-IMMUN \"adults\" or with the comparator vaccine. The immunogenicity results demonstrated similar seroconversion rates (as determined by ELISA or neutralization test) before and after the third vaccination in the FSME-IMMUN \"adults\" group and in the comparator group respectively. The results of both studies demonstrate that: (1) FSME-IMMUN \"adults\" is safe and highly immunogenic, (2) all five production lots of FSME-IMMUN \"adults\" were consistent with respect to a low rate of adverse events, (3) FSME-IMMUN \"adults\" induces considerably lower adverse reaction rates than the comparator vaccine after the first vaccination, and (4) two vaccinations with the comparator vaccine can be successfully followed by a third vaccination with FSME-IMMUN \"adults\".", "A new vaccine against tick-borne encephalitis was investigated in 56 healthy volunteers randomized for five different doses of antigen in a comparative group trial. Good tolerability and high immunogenicity were found using three different antibody test systems. The dose response study revealed that there was a strong relationship between the amount of antigen administered and the antibody response over the range of 0.03-3.0 micrograms antigen per dose.", "A total of 522 children between 18 months and 14 years and 191 adults between 18 and 60 years were vaccinated with TBE-vaccine according to an abbreviated schedule (0, 7, 21). The aim of the study was to investigate whether reducing the amount of antigen in the vaccination for children would preserve an adequate immune response and decrease the rate of side-effects. Efficacy was determined on the extent to which children, vaccinated with the low doses (0.4 microgram or 0.75 microgram), reacted by developing antibodies in the same way as adults treated with the approved dose of 1.5 micrograms (equivalence of titres). The titres obtained in the children with the two lower doses were equivalent to those in the adults obtained with the standard dose. Titres decreased in the children with increasing age. Children older than 12 years in the approved dosage group had the same median titres as adults. The frequency of side-effects in the two lower dose groups, especially raised temperature, was markedly reduced. Whereas 30.1% of the children vaccinated with the approved dose had raised temperature higher than 38 degrees C only 18.8% and 18.4%, respectively, of the children vaccinated with the lower doses developed such temperatures. This improved tolerance in terms of raised temperature was also reflected in the other general reactions such as tiredness, joint pain or headache.", "Encephalitis caused by Japanese encephalitis virus occurs in annual epidemics throughout Asia, making it the principal cause of epidemic viral encephalitis in the world. No currently available vaccine has demonstrated efficacy in preventing this disease in a controlled trial. We performed a placebo-controlled, blinded, randomized trial in a northern Thai province, with two doses of monovalent (Nakayama strain) or bivalent (Nakayama plus Beijing strains) inactivated, purified Japanese encephalitis vaccine made from whole virus derived from mouse brain. We examined the effect of these vaccines on the incidence and severity of Japanese encephalitis and dengue hemorrhagic fever, a disease caused by a closely related flavivirus. Between November 1984 and March 1985, 65,224 children received two doses of monovalent Japanese encephalitis vaccine (n = 21,628), bivalent Japanese encephalitis vaccine (n = 22,080), or tetanus toxoid placebo (n = 21,516), with only minor side effects. The cumulative attack rate for encephalitis due to Japanese encephalitis virus was 51 per 100,000 in the placebo group and 5 per 100,000 in each vaccine group. The efficacy in both vaccine groups combined was 91 percent (95 percent confidence interval, 70 to 97 percent). Attack rates for dengue hemorrhagic fever declined, but not significantly. The severity of cases of dengue was also reduced. We conclude that two doses of inactivated Japanese encephalitis vaccine, either monovalent or bivalent, protect against encephalitis due to Japanese encephalitis virus and may have a limited beneficial effect on the severity of dengue hemorrhagic fever.", "The immunogenicity and safety of a new liquid hexavalent vaccine (diphtheria-tetanus-acellular pertussis-inactivated polio vaccine-hepatitis B-polyribosyl ribitol phosphate conjugated to tetanus protein; Hexavac; Aventis Pasteur MSD, Lyon, France) are compared with those of reference vaccines [diphtheria-tetanus-acellular pertussis-inactivated polio vaccine reconstituting lyophilized purified Haemophilus influenzae polysaccharide conjugated to tetanus protein vaccine (Pentavac; Aventis Pasteur MSD) and hepatitis B vaccine (H-B-Vax II; Aventis Pasteur MSD)] injected separately at the same visit in a prospective multicenter, comparative, open label trial.\n Infants were randomized to receive Hexavac (n = 423) or Pentavac and H-B-Vax II (n = 425) as a primary immunization series at 2, 4 and 6 months of age. Seroprotection and seroconversion rates against all antigens at 1 month after the primary series were compared between the two vaccine groups with 95% confidence intervals (CI0.95) and were considered clinically equivalent (not inferior) when the upper limit of the 95% confidence interval on the difference (reference, hexavalent) was below predefined differences.\n Hexavac met and surpassed the pre-defined criteria for clinical equivalence to Pentavac and H-B-Vax II given concomitantly. It elicited similar seroprotection and seroconversion rates against all antigens. Seroprotection and seroconversion rates obtained 1 month after the third dose of Hexavac were >90% for all antigens. The postimmunization antibody geometric mean titers (GMT) for hepatitis B and purified Haemophilus influenzae polysaccharide were about 2-fold higher in infants who received the reference vaccines than in infants who had received Hexavac. GMTs for poliovirus antibodies tended to be enhanced in infants vaccinated with Hexavac. GMTs for all other antigens were very similar among both groups. Hexavac was generally well-tolerated. At least one local reaction was reported in 20.3% of Hexavac injections compared with 15.8% at the Pentavac injections site and 3.8% at the H-B-Vax II injections site. These reactions were generally mild and transient. At least one systemic adverse event was reported in 45.7% of Hexavac injections compared with 42.2% of Pentavac and H-B-Vax II injections (mild fever, irritability and drowsiness were most frequently reported). The frequency of adverse events was not significantly different between groups. No vaccine-related serious adverse event occurred during the study.\n This liquid hexavalent vaccine was generally well-tolerated and provided immune responses adequate to be protective against six infectious diseases with a single injection, given at 2, 4 and 6 months of age." ]	Tick-borne encephalitis vaccines appear to be highly immunogenic, but the relationship between seroconversion and clinical protection has not been established. Although adverse effects were commonly reported, none were serious or life threatening.
CD003057	[ "3897808", "3520382", "6336824", "3320274", "2950392", "3080173", "2879344", "3891920" ]	[ "A double-blind trial of hyperbaric oxygen in the treatment of multiple sclerosis.", "Hyperbaric oxygen therapy in chronic stable multiple sclerosis: double-blind study.", "Hyperbaric-oxygen treatment of multiple sclerosis. A randomized, placebo-controlled, double-blind study.", "Hyperbaric oxygen and multiple sclerosis: final results of a placebo-controlled, double-blind trial.", "[Ineffectiveness of hyperbaric oxygen therapy in multiple sclerosis. A randomized placebo-controlled double-blind study].", "Hyperbaric oxygen in multiple sclerosis: a double blind trial.", "[Double-blind treatment of 49 cases of chronic multiple sclerosis using hyperbaric oxygen].", "Hyperbaric oxygen in chronic progressive multiple sclerosis: visual evoked potentials and clinical effects." ]	[ "A randomized double-blind trial of hyperbaric oxygen (2 atmospheres absolute for 20 sessions of 90 minutes, over a period of one month) demonstrated no advantage over a placebo gas mixture in the treatment of multiple sclerosis. Of 41 patients completing the trial, 21 had been treated with oxygen, eight of whom reported improvement (two confirmed objectively). Of 20 patients in the placebo group, seven claimed improvement (four confirmed objectively). Even when patients with mild disease were considered separately, or when functional systems were assessed individually, no benefit could be shown to result from hyperbaric oxygen therapy.", "We carried out a randomized, double-blind, placebo-controlled trial of hyperbaric oxygen therapy (HBO) in patients with chronic stable MS. Eighty-two patients were treated in a multiplace hyperbaric chamber with gas supplied by mask. Forty-one patients received 20 consecutive daily treatments of 100% O2 followed by 7 \"booster\" treatments in the next 6 months; 41 control patients received \"air\" (12.5% O2 at 1.75 atmospheres absolute). There was no significant difference in treatment and control groups in the Extended Kurtzke Disability scores, Kurtzke Functional scores, magnetic resonance imaging, or evoked potentials after the initial 20 treatments or after the boosters. HBO is not effective in treating chronic stable MS.", "Several uncontrolled studies have suggested a beneficial effect of hyperbaric oxygen on multiple sclerosis. We studied 40 patients with advanced chronic multiple sclerosis who were randomly divided into two matching groups. The experimental group received pure oxygen, and the placebo group received a mixture of 10 per cent oxygen and 90 per cent nitrogen; both groups were treated at a pressure of 2 atmospheres absolute for 90 minutes once daily, for a total of 20 exposures. Objective improvement occurred in 12 of 17 patients treated with hyperbaric oxygen and in 1 of 20 patients treated with placebo (P less than 0.0001). Improvement was transient in seven of the patients treated with oxygen and long-lasting in five. Those with less severe forms of the disease had a more favorable and lasting response. At one year of follow-up, deterioration was noticed in 2 patients (12 per cent) in the oxygen group, neither of whom had had an initial response, and in 11 patients (55 per cent) in the placebo group, one of whom had had a positive initial response (P less than 0.0008). Minor ear problems and reversible myopia were the only side effects observed. These preliminary results suggest a positive, though transient, effect of hyperbaric oxygen on advanced multiple sclerosis, warranting further study. This therapy cannot be generally recommended without longer follow-up periods and additional confirmatory experience.", "The long term results are reported of a trial involving 120 patients with chronic multiple sclerosis who were randomised to receive either 100% oxygen at 2 atmospheres absolute (ATA) for 90 minutes daily for 20 sessions or placebo therapy with air using a simulated compression procedure. The previous finding of subjective improvement in bowel/bladder function at the end of treatment was not confirmed by objective urodynamic assessment. The treatment did not alter disease progression as measured by the Kurtzke disability status scale nor did it alter the rate of acute relapse. There was less deterioration in cerebellar function at one year in the treated patients as measured by the Kurtzke functional systems scale. No other differences were found between the two groups. Psychometric tests and measurements of lymphocyte sub-populations showed no treatment related effects. Evoked potential studies showed no improvements but there was a significant reduction in amplitude of the visual evoked potential in the treated patients at the end of therapy. This might indicate a reversible degree of retinal damage induced by oxygen toxicity.", "Seventeen patients with definite and progressive multiple sclerosis entered a double-blind randomized placebo-controlled therapeutic trial of hyperbaric oxygen (HBO). Exposure in monoplace chamber was 90 minutes long each time, 5 days a week, for 4 weeks. The treatment and placebo groups received 100% oxygen at 1.5 bar constant pressure or normal air at 0.1-0.2 bar, respectively. The clinical status of the patients in both groups were compared until one year after treatment. There was no benefit of HBO versus placebo according to the Kurtzke disability status scale. A lesser proportion of patients with deterioration of bowel/bladder function 12 months after therapy was the only benefit of HBO versus placebo according to Kurtzke functional systems scales. On the whole however, HBO is useless in the management of progressive forms of multiple sclerosis.", "Eighty four patients with multiple sclerosis were treated in monoplace chambers with either hyperbaric oxygen at 2 atmospheres absolute or placebo. Comprehensive double blind assessment was carried out before, immediately after, and one month after treatment. There was no clinically important or significant benefit in any of the four major criteria of outcome--namely, the patient's subjective opinion, the examiner's opinion, the score on the Kurtzke disability status scale, or the time taken to walk 50 m. Out of 40 other clinical variables assessed, two (the sensory scale and timed writing with the left hand) showed a significant improvement without any subjective clinical correlate or change in any of seven other tests of left hand function. No group of symptoms was perceived by the patients as having improved more after treatment with hyperbaric oxygen than placebo. It is concluded that there is no basis for recommending hyperbaric oxygen in the treatment of multiple sclerosis.", "Forty nine patients with a chronic form of multiple sclerosis (MS) [progressive or stable] were treated with hyperbaric oxygen (HO) in a double blind trial. Patients were divided in three groups: the first group (group I) received a course of 2.3 ATA HO with diazepam (5 mg); the second group (group II) received a course of 2 ATA HO; the third group (group III) was the control group. Each patient breathed an adapted gaseous mixture in high pressure. Each patient received 20 sessions of this procedure during 4 weeks. Patients were evaluated with clinical, neurophysiological and immunological parameters. Clinical examination consisted in the evaluation of the Kurtzke's Disability Status Scale (DSS) and Functional Status Scale (FSS). This evaluation was done in the week before the procedure, the week following the treatment, then in the third and sixth month. The neurophysiological study was a comparative analysis from the variations of visual, somesthesic and brain stem auditory potentials. The immunological study was the analysis of the lymphocyte populations (OKT4/OKT8 ratio). Each examination was carried out the week before, then the week following the procedure. We found no amelioration into three groups. Subjectively, some patients thought to be better, but this was true in the two treated groups (I, II) and in the control group (III). There was not an FSS significant variation. We also found no significant variation of evoked potentials and OKT4/OKT8 ratio. We observed some incidental effects of the treatment, particularly in group I, in which patients were treated with a higher pressure.(ABSTRACT TRUNCATED AT 250 WORDS)", "The effects of hyperbaric oxygen at a pressure of two atmospheres absolute were studied in a group of patients with chronic progressive multiple sclerosis. A slight but statistically insignificant shortening of the visual evoked potential latencies was seen after treatment with hyperbaric oxygen as compared with placebo treatment. The treatment did not appreciably halt the progression of the disease and deferioration occurred more often among the patients in the treatment group than in the control group." ]	We found no consistent evidence to confirm a beneficial effect of hyperbaric oxygen therapy for the treatment of multiple sclerosis and do not believe routine use is justified. The small number of analyses suggestive of benefit are isolated, difficult to ascribe with biological plausibility and would need to be confirmed in future well-designed trials. Such trials are not, in our view, justified by this review.
CD004525	[ "20574649", "15001324", "11096165", "9920948", "10075615", "19644849", "15146409", "16935912", "17029087" ]	[ "Etanercept (ETN) with methotrexate (MTX) is better than ETN monotherapy in patients with active rheumatoid arthritis despite MTX therapy: a randomized trial.", "Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial.", "A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.", "A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate.", "Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial.", "Golimumab, a human anti-tumor necrosis factor alpha monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: twenty-four-week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumab before methotrexate as first-line therapy for early-onset rheumatoid arthritis.", "Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial.", "Selective costimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept: a randomised clinical trial.", "Therapeutic effects of the combination of methotrexate and bucillamine in early rheumatoid arthritis: a multicenter, double-blind, randomized controlled study." ]	[ "The superiority of the combination therapy of methotrexate (MTX) and anti-tumor necrosis factor (TNF) biological agents over anti-TNF monotherapy in MTX-naïve patients with rheumatoid arthritis (RA) has been demonstrated. We investigated the efficacy and safety of continuation versus discontinuation of MTX at the commencement of etanercept (ETN) in patients with active RA despite MTX therapy. In total, 151 patients with active RA despite treatment with MTX were randomized to either ETN 25 mg twice a week and MTX 6-8 mg/week (the E + M group) or ETN alone (the E group). Co-primary endpoints included the European League Against Rheumatism (EULAR) good response rate and the American College of Rheumatology (ACR) 50 response rate at week 24. Demographic and clinical features between groups at baseline were similar. The EULAR good response rates were significantly higher in the E + M group (52%) than in the E group (33%) at week 24 (p = 0.0001). Although the ACR50 response rate, one of the co-primary endpoints, and the ACR70 response rate at week 24 were not significantly greater in the E + M group (64 and 38%, respectively) than in the E group (48 and 26%, respectively), the ACR20 response rate was significantly greater in the E + M group (90%) than in the E group (64%; p = 0.0002). Safety profiles were similar for the groups. Thus, MTX should be continued at the commencement of ETN therapy, even in RA patients who show an inappropriate response to MTX.", "Etanercept and methotrexate are effective in the treatment of rheumatoid arthritis but no data exist on concurrent initiation or use of the combination compared with either drug alone. We aimed to assess combination treatment with etanercept and methotrexate versus the monotherapies in patients with rheumatoid arthritis.\n In a double-blind, randomised, clinical efficacy, safety, and radiographic study, 686 patients with active rheumatoid arthritis were randomly allocated to treatment with etanercept 25 mg (subcutaneously twice a week), oral methotrexate (up to 20 mg every week), or the combination. Clinical response was assessed by criteria of the American College of Rheumatology (ACR). The primary efficacy endpoint was the numeric index of the ACR response (ACR-N) area under the curve (AUC) over the first 24 weeks. The primary radiographic endpoint was change from baseline to week 52 in total joint damage and was assessed with the modified Sharp score. Analysis was by intention to treat.\n Four patients did not receive any drug; thus 682 were studied. ACR-N AUC at 24 weeks was greater for the combination group compared with etanercept alone and methotrexate alone (18.3%-years [95% CI 17.1-19.6] vs 14.7%-years [13.5-16.0], p<0.0001, and 12.2%-years [11.0-13.4], p<0.0001; respectively). The mean difference in ACR-N AUC between combination and methotrexate alone was 6.1 (95% CI 4.5-7.8, p<0.0001) and between etanercept and methotrexate was 2.5 (0.8-4.2, p=0.0034). The combination was more efficacious than methotrexate or etanercept alone in retardation of joint damage (mean total Sharp score -0.54 [95% CI -1.00 to -0.07] vs 2.80 [1.08 to 4.51], p<0.0001, and 0.52 [-0.10 to 1.15], p=0.0006; respectively). The mean difference in total Sharp score between combination and methotrexate alone was -3.34 (95% CI -4.86 to -1.81, p<0.0001) and between etanercept and methotrexate was -27 (-3.81 to -0.74, p=0.0469). The number of patients reporting infections or adverse events was similar in all groups.\n The combination of etanercept and methotrexate was significantly better in reduction of disease activity, improvement of functional disability, and retardation of radiographic progression compared with methotrexate or etanercept alone. These findings bring us closer to achievement of remission and repair of structural damage in rheumatoid arthritis.", "Etanercept, which blocks the action of tumor necrosis factor, reduces disease activity in patients with long-standing rheumatoid arthritis. Its efficacy in reducing disease activity and preventing joint damage in patients with active early rheumatoid arthritis is unknown.\n We treated 632 patients with early rheumatoid arthritis with either twice-weekly subcutaneous etanercept (10 or 25 mg) or weekly oral methotrexate (mean, 19 mg per week) for 12 months. Clinical response was defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology. Bone erosion and joint-space narrowing were measured radiographically and scored with use of the Sharp scale. On this scale, an increase of 1 point represents one new erosion or minimal narrowing.\n As compared with patients who received methotrexate, patients who received the 25-mg dose of etanercept had a more rapid rate of improvement, with significantly more patients having 20 percent, 50 percent, and 70 percent improvement in disease activity during the first six months (P<0.05). The mean increase in the erosion score during the first 6 months was 0.30 in the group assigned to receive 25 mg of etanercept and 0.68 in the methotrexate group (P= 0.001), and the respective increases during the first 12 months were 0.47 and 1.03 (P=0.002). Among patients who received the 25-mg dose of etanercept, 72 percent had no increase in the erosion score, as compared with 60 percent of patients in the methotrexate group (P=0.007). This group of patients also had fewer adverse events (P=0.02) and fewer infections (P= 0.006) than the group that was treated with methotrexate.\n As compared with oral methotrexate, subcutaneous [corrected] etanercept acted more rapidly to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis.", "Patients treated with methotrexate for rheumatoid arthritis often improve but continue to have active disease. This study was undertaken to determine whether the addition of etanercept, a soluble tumor necrosis factor receptor (p75):Fc fusion protein (TNFR:Fc), to methotrexate therapy would provide additional benefit to patients who had persistent rheumatoid arthritis despite receiving methotrexate.\n In a 24-week, double-blind trial, we randomly assigned 89 patients with persistently active rheumatoid arthritis despite at least 6 months of methotrexate therapy at a stable dose of 15 to 25 mg per week (or as low as 10 mg per week for patients unable to tolerate higher doses) to receive either etanercept (25 mg) or placebo subcutaneously twice weekly while continuing to receive methotrexate. The primary measure of clinical response was the American College of Rheumatology criteria for a 20 percent improvement in measures of disease activity (ACR 20) at 24 weeks.\n The addition of etanercept to methotrexate therapy resulted in rapid and sustained improvement. At 24 weeks, 71 percent of the patients receiving etanercept plus methotrexate and 27 percent of those receiving placebo plus methotrexate met the ACR 20 criteria (P<0.001); 39 percent of the patients receiving etanercept plus methotrexate and 3 percent of those receiving placebo plus methotrexate met the ACR 50 criteria (for a 50 percent improvement) (P<0.001). Patients receiving etanercept plus methotrexate had significantly better outcomes according to all measures of disease activity. The only adverse events associated with etanercept were mild injection-site reactions, and no patient withdrew from the study because of adverse events associated with etanercept.\n In patients with persistently active rheumatoid arthritis, the combination of etanercept and methotrexate was safe and well tolerated and provided significantly greater clinical benefit than methotrexate alone.", "In a phase II study, etanercept (recombinant human tumor necrosis factor receptor [p75]:Fc fusion protein) safely produced rapid, dose-dependent improvement in rheumatoid arthritis over 3 months.\n To confirm the benefit of etanercept therapy of longer duration and simplified dosing in patients with rheumatoid arthritis.\n Randomized, double-blind, placebo-controlled trial with blinded joint assessors.\n 13 North American centers.\n 234 patients with active rheumatoid arthritis who had an inadequate response to disease-modifying antirheumatic drugs.\n Twice-weekly subcutaneous injections of etanercept, 10 or 25 mg, or placebo for 6 months.\n The primary end points were 20% and 50% improvement in disease activity according to American College of Rheumatology (ACR) responses at 3 and 6 months. Other end points were 70% ACR responses at 3 and 6 months and other measures of disease activity at 3 and 6 months.\n Etanercept significantly reduced disease activity in a dose-related fashion. At 3 months, 62% of the patients receiving 25 mg of etanercept and 23% of the placebo recipients achieved 20% ACR response (P < 0.001). At 6 months, 59% of the 25-mg group and 11% of the placebo group achieved a 20% ACR response (P < 0.001); 40% and 5%, respectively, achieved a 50% ACR response (P < 0.01). The respective mean percentage reduction in the number of tender and swollen joints at 6 months was 56% and 47% in the 25-mg group and 6% and -7% in the placebo group (P < 0.05). Significantly more etanercept recipients achieved a 70% ACR response, minimal disease status (0 to 5 affected joints), and improved quality of life. Etanercept was well tolerated, with no dose-limiting toxic effects.\n Etanercept can safely provide rapid, significant, and sustained benefit in patients with active rheumatoid arthritis.", "To assess the safety and efficacy of golimumab in methotrexate (MTX)-naive patients with active rheumatoid arthritis (RA).\n MTX-naive patients with RA (n = 637) were randomized to receive placebo plus MTX (group 1), golimumab 100 mg plus placebo (group 2), golimumab 50 mg plus MTX (group 3), or golimumab 100 mg plus MTX (group 4). Subcutaneous injections of golimumab or placebo were administered every 4 weeks. The dosage of MTX/placebo capsules started at 10 mg/week and escalated to 20 mg/week. The primary end point, the proportion of patients meeting the American College of Rheumatology 50% improvement criteria (achieving an ACR50 response) at week 24, required significant differences between groups 3 and 4 combined (combined group) versus group 1 and significant differences in a pairwise comparison (group 3 or group 4 versus group 1).\n An intent-to-treat (ITT) analysis of the ACR50 response at week 24 did not show a significant difference between the combined group and group 1 (38.4% and 29.4%, respectively; P=0.053), while a post hoc modified ITT analysis (excluding 3 untreated patients) of the ACR50 response showed statistically significant differences between the combined group and group 1 (38.5% versus 29.4%; P=0.049) and between group 3 (40.5%; P=0.038) but not group 4 (36.5%; P=0.177) and group 1. Group 2 was noninferior to group 1 for the ACR50 response at week 24 (33.1%; 95% confidence interval lower bound -5.2%; predefined delta value for noninferiority -10%). The combination of golimumab plus MTX demonstrated a significantly better response compared with placebo plus MTX in most other efficacy parameters, including response/remission according to the Disease Activity Score in 28 joints. Serious adverse events occurred in 7%, 3%, 6%, and 6% of patients in groups 1, 2, 3, and 4, respectively.\n Although the primary end point was not met, the modified ITT analysis of the primary end point and other prespecified efficacy measures demonstrated that the efficacy of golimumab plus MTX is better than, and the efficacy of golimumab alone is similar to, the efficacy of MTX alone in reducing RA signs and symptoms in MTX-naive patients, with no unexpected safety concerns.", "Tumor necrosis factor (TNF) is an important proinflammatory cytokine that mediates inflammatory synovitis and articular matrix degradation in rheumatoid arthritis (RA). We investigated the ability of adalimumab, a human anti-TNF monoclonal antibody, to inhibit the progression of structural joint damage, reduce the signs and symptoms, and improve physical function in patients with active RA receiving concomitant treatment with methotrexate (MTX).\n In this multicenter, 52-week, double-blind, placebo-controlled study, 619 patients with active RA who had an inadequate response to MTX were randomized to receive adalimumab 40 mg subcutaneously every other week (n = 207), adalimumab 20 mg subcutaneously every week (n = 212), or placebo (n = 200) plus concomitant MTX. The primary efficacy end points were radiographic progression at week 52 (total Sharp score by a modified method [TSS]), clinical response at week 24 (improvements of at least 20% in the American College of Rheumatology core criteria [ACR20]), and physical function at week 52 (disability index of the Health Assessment Questionnaire [HAQ]).\n At week 52, there was statistically significantly less radiographic progression, as measured by the change in TSS, in the patients receiving adalimumab either 40 mg every other week (mean +/- SD change 0.1 +/- 4.8) or 20 mg weekly (0.8 +/- 4.9) as compared with that in the placebo group (2.7 +/- 6.8) (P < or = 0.001 for each comparison). In addition, there were statistically significant changes in the components of the TSS. At week 24, ACR20 responses were achieved by 63% and 61% of patients in the adalimumab 40 mg every other week and 20 mg weekly groups, respectively, versus 30% of patients in the placebo group (P < or = 0.001 for each comparison). At week 52, ACR20 responses were achieved by 59% and 55% of patients taking adalimumab 40 mg every other week and 20 mg weekly, respectively, versus 24% of patients taking placebo (P < or = 0.001 for each comparison). At week 52, physical function as measured by the HAQ demonstrated statistically significant improvement with adalimumab 40 mg every other week and 20 mg weekly compared with placebo (mean change in HAQ score -0.59 and -0.61, respectively, versus -0.25; P < or = 0.001 for each comparison). A total of 467 patients (75.4%) completed 52 weeks of treatment. Adalimumab was generally well tolerated. Discontinuations occurred in 22.0% of adalimumab-treated patients and in 30.0% of placebo-treated patients. The rate of adverse events (both serious and nonserious) was comparable in the adalimumab and placebo groups, although the proportion of patients reporting serious infections was higher in patients receiving adalimumab (3.8%) than in those receiving placebo (0.5%) (P < or = 0.02), and was highest in the patients receiving 40 mg every other week.\n In this 52-week trial, adalimumab was more effective than placebo at inhibiting the progression of structural joint damage, reducing the signs and symptoms, and improving physical function in patients with active RA who had demonstrated an incomplete response to MTX.", "To investigate the efficacy and safety of abatacept in combination with etanercept in patients with active rheumatoid arthritis during a 1-year, randomised, placebo-controlled, double-blind phase, followed by an open-label, long-term extension (LTE).\n Patients continued etanercept (25 mg twice weekly) and were randomised to receive abatacept 2 mg/kg (n = 85) or placebo (n = 36). As the effective dose of abatacept was established as 10 mg/kg in a separate trial, all patients received abatacept 10 mg/kg and etanercept during the LTE.\n A total of 121 patients were randomised; 80 completed double-blind treatment and entered the LTE. During double-blind treatment, the difference in the percentage of patients achieving the primary end point (modified American College of Rheumatology (ACR) 20 response at 6 months) was not significant between groups (48.2% v 30.6%; p = 0.072). At 1 year, no notable changes in modified ACR responses were observed. Subsequent to the dosing change, similar modified ACR responses were seen during the LTE. Significant improvements in quality of life were observed with abatacept and etanercept versus placebo and etanercept in five of the eight short-form 36 subscales at 1 year. More abatacept and etanercept-treated patients experienced serious adverse events (SAEs) at 1 year than patients receiving placebo and etanercept (16.5% v 2.8%), with 3.5% v 0% experiencing serious infections.\n The combination of abatacept (at a dose of 2 mg/kg during the double-blind phase and 10 mg/kg during the LTE) and etanercept was associated with an increase in SAEs, including serious infections, with limited clinical effect. On the basis of the limited efficacy findings and safety concerns, abatacept in combination with etanercept should not be used for rheumatoid arthritis treatment.", "Disease-modifying antirheumatic drug (DMARD) combination therapies are used widely, but there have been few reports clearly demonstrating that combination therapy is more effective than DMARD monotherapy. We conducted a multicenter, double-blind controlled trial in order to clarify that the combination of methotrexate and bucillamine is more effective than either alone. The subjects of this study were 71 patients with active rheumatoid arthritis within 2 years of onset. Dosages were 8 mg methotrexate with 5 mg folic acid per week (MTX group), 200 mg bucillamine per day (BUC group), or both MTX and BUC (combination group). Clinical effects and adverse reactions were observed for 96 weeks. The ACR 20 response rate was 79.2% in the combination group, significantly higher than the rates of 43.5% for the MTX group (P = 0.008) and 45.8% for the BUC group (P = 0.0178). The cumulative survival curve of maintaining the ACR 20 response was significantly higher in the combination group than in the MTX and BUC groups (P = 0.0123 and P = 0.0088, respectively). The mean increase in the total Sharp score over 96 weeks was 12.6 +/- 9.0 in the combination group, significantly lower (P = 0.0468) than the value of 28.0 +/- 28.3 for the single DMARD (combined MTX and BUC) group. The incidence of adverse reactions did not differ significantly between the three groups. It was concluded that the combination therapy with MTX and BUC showed significantly higher clinical efficacy than either of the single DMARD therapies." ]	Etanercept 25 mg administered subcutaneously twice weekly together with MTX was more efficacious than either etanercept or MTX monotherapy for ACR50 and it slowed joint radiographic progression after up to three years of treatment for all participants (responders or not). There was no evidence of a difference in the rates of infections between groups.
CD005004	[ "16141630", "17606381", "12177800", "11519758", "17548688", "17183063", "9578298", "11228277", "18766189", "17724377", "15286468", "9033623", "18580440", "15054454", "8580302", "11679799", "17906295", "11237198", "8182766", "12845655", "16804523", "18669903", "16951537", "20807303", "15781210", "12163323", "18090127", "11304697", "12816709", "14678179", "16968850", "17557985", "19680234", "18349292", "19074207", "15005829", "18006026", "8640692", "16351782", "17392149", "10682542", "12824094", "19176733", "18444146", "9602395", "16076989", "12750246", "16424063", "3930448", "17416758", "18468736" ]	[ "Green tea and the risk of colorectal cancer: pooled analysis of two prospective studies in Japan.", "A prospective study of green tea consumption and oral cancer incidence in Japan.", "A prospective study of stomach cancer death in relation to green tea consumption in Japan.", "A prospective study of green tea consumption and cancer incidence, Hiroshima and Nagasaki (Japan).", "Prospective cohort study of green tea consumption and colorectal cancer risk in women.", "Green tea and the prevention of breast cancer: a case-control study in Southeast China.", "Tea and coffee consumption and the risk of digestive tract cancers: data from a comparative case-referent study in Japan.", "Green tea and the risk of gastric cancer in Japan.", "Green tea consumption and lung cancer risk: the Ohsaki study.", "Green tea and black tea consumption in relation to colorectal cancer risk: the Singapore Chinese Health Study.", "Green tea consumption and subsequent risk of gastric cancer by subsite: the JPHC Study.", "Green tea consumption and the risk of pancreatic and colorectal cancers.", "Green tea consumption and the risk of pancreatic cancer in Japanese adults.", "Green tea and the risk of breast cancer: pooled analysis of two prospective studies in Japan.", "Green-tea consumption and risk of stomach cancer: a population-based case-control study in Shanghai, China.", "A population-based case-control study of lung cancer and green tea consumption among women living in Shanghai, China.", "Green tea consumption and prostate cancer risk in Japanese men: a prospective study.", "Preventive effects of drinking green tea on cancer and cardiovascular disease: epidemiological evidence for multiple targeting prevention.", "Reduced risk of esophageal cancer associated with green tea consumption.", "Green tea and risk of breast cancer in Asian Americans.", "No association between green tea and prostate cancer risk in Japanese men: the Ohsaki Cohort Study.", "Green tea intake, MTHFR/TYMS genotype and breast cancer risk: the Singapore Chinese Health Study.", "Smoking, alcohol drinking, green tea consumption and the risk of esophageal cancer in Japanese men.", "Green tea improves metabolic biomarkers, not weight or body composition: a pilot study in overweight breast cancer survivors.", "Green tea consumption, genetic susceptibility, PAH-rich smoky coal, and the risk of lung cancer.", "Tea consumption and ovarian cancer risk: a case-control study in China.", "Green tea and coffee intake and risk of pancreatic cancer in a large-scale, population-based cohort study in Japan (JPHC study).", "Protective effect of green tea on the risks of chronic gastritis and stomach cancer.", "[A case-control study on drinking green tea and decreasing risk of cancers in the alimentary canal among cigarette smokers and alcohol drinkers].", "Foods and beverages in relation to urothelial cancer: case-control study in Japan.", "Green tea consumption and mortality due to cardiovascular disease, cancer, and all causes in Japan: the Ohsaki study.", "A green tea extract high in catechins reduces body fat and cardiovascular risks in humans.", "Effects of catechin enriched green tea on body composition.", "Coffee, tea, colas, and risk of epithelial ovarian cancer.", "Green tea catechin consumption enhances exercise-induced abdominal fat loss in overweight and obese adults.", "Effects of green tea on weight maintenance after body-weight loss.", "Effectiveness of green tea on weight reduction in obese Thais: A randomized, controlled trial.", "The influence of cigarette smoking, alcohol, and green tea consumption on the risk of carcinoma of the cardia and distal stomach in Shanghai, China.", "Effect of green tea on resting energy expenditure and substrate oxidation during weight loss in overweight females.", "Tea and lycopene protect against prostate cancer.", "[A case-control study on the dietary risk factors of upper digestive tract cancer].", "Cholesterol-lowering effect of a theaflavin-enriched green tea extract: a randomized controlled trial.", "Green tea catechin plus caffeine supplementation to a high-protein diet has no additional effect on body weight maintenance after weight loss.", "The nutritional prevention of cancer: 400 mcg per day selenium treatment.", "Intakes of selected foods and beverages and the incidence of gastric cancer among the Japanese residents of Hawaii: a prospective study.", "Body weight loss and weight maintenance in relation to habitual caffeine intake and green tea supplementation.", "No association between green tea and the risk of gastric cancer: pooled analysis of two prospective studies in Japan.", "Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study.", "Dietary habits and gastro-intestinal cancers: a comparative case-control study of stomach and large intestinal cancers in Nagoya, Japan.", "Dietary flavonoids and the risk of colorectal cancer.", "Effect of green tea extract on obese women: a randomized, double-blind, placebo-controlled clinical trial." ]	[ "Although laboratory experiments suggest protective effects of green tea against colorectal cancer, few prospective cohort studies have been conducted.\n We conducted a pooled analysis of two prospective cohort studies among residents in Miyagi Prefecture in rural northern Japan. The first study started in 1984 and included 26,311 subjects. The second study started in 1990 and included 39,604 subjects. The subjects responded to a self-administered questionnaire including an item on green tea consumption. With 7 to 9 years of follow-up, 305 colon and 211 rectal cancers were identified in the two cohorts through record linkage to a regional cancer registry. We used Cox regression to estimate the hazard ratio (HR) of colorectal cancer according to the consumption of green tea with adjustment for potential confounders, and pooled the estimates obtained from each cohort by general variance-based method.\n Multivariate pooled HRs for colon cancer associated with drinking 1-2, 3-4, and 5 or more cups of green tea per day, as compared with less than 1 cup per day, were 1.06 (95% confidence interval [CI]=0.74-1.52), 1.10 (0.78-1.55), 0.97 (0.70-1.35), respectively (trend p=0.81). Corresponding HRs for rectal cancer were 0.85 (95% CI=0.56-1.29), 0.70 (0.45-1.08), 0.85 (0.58-1.23), respectively (trend p=0.31).\n Consumption of green tea was not associated with lower risk of colorectal cancer.", "To examine the relation of green tea consumption with oral carcinogenesis, we prospectively analyzed data from a nationwide large-scale cohort study in Japan.\n A total of 20,550 men and 29,671 women aged 40-79 years, without any history of oral and pharyngeal cancer at baseline survey, were included in the present study. During a mean follow-up period of 10.3 years, 37 oral cancer cases were identified. The Cox proportional hazard model was used to estimate the hazard ratio (HR) and 95% confidence interval (95% CI) for oral cancer according to green tea consumption by sex, while adjusting for age, smoking, alcohol drinking, and other dietary factors.\n For women, the HRs of oral cancer for green tea consumption of 1-2, 3-4, and 5 or more cups per day were 0.51 (95% CI: 0.10-2.68), 0.60 (95% CI: 0.17-2.10), and 0.31 (95% CI: 0.09-1.07), respectively, compared with those who drank less than one cup per day (p for trend, 0.08). For men, no such trends were observed.\n Our findings did not suggest a prominent inverse association of green tea consumption with oral cancer, although there was a tendency for a reduced risk in women.", "To evaluate whether green tea consumption provides protection against stomach cancer death, relative risks were calculated using Cox proportional hazards regression analysis in the Japan Collaborative Study for Evaluation of Cancer Risk, sponsored by the Ministry of Health and Welfare (JACC Study). The study was based on 30 370 men and 42 481 women aged 40-79. After adjustment for age, smoking status, history of peptic ulcer, family history of stomach cancer along with certain dietary items, the risks associated with drinking one or two, three or four, five to nine, and 10 or more cups of green tea per day, relative to those of drinking less than one cup per day, were 1.6 (95% CI: 0.9-2.9), 1.1 (95% CI: 0.6-1.9), 1.0 (95% CI: 0.5-2.0), and 1.0 (95% CI: 0.5-2.0), respectively, in men (P for trend=0.669), and 1.1 (95% CI: 0.5-2.5), 1.0 (95% CI: 0.5-2.5), 0.8 (95% CI: 0.4-1.6), and 0.8 (95% CI: 0.3-2.1), respectively, in women (P for trend=0.488). We found no inverse association between green tea consumption and the risk of stomach cancer death.\n Copyright 2002 Cancer Research UK", "Laboratory and animal studies have shown a protective effect of green tea on cancer of different sites, but epidemiological evidence is limited and inconclusive. This prospective study in Japan examined the association between green tea consumption and cancer incidence.\n Subjects were 38,540 people (14,873 men, mean age 52.8 years; 23,667 women, mean age 56.8 years) who responded to a mail survey carried out between 1979 and 1981. A self-administered questionnaire ascertained consumption frequency of green tea using precoded answers (never, once per day, twice to four times per day, and five or more times per day). Follow-up continued until 31 December 1994. The study analyzed solid cancers (n = 3881); hematopoietic cancers (188); cancers of all sites combined (4069); and cancer of specific sites with more than 100 cases, i.e. stomach (901), colon (432), rectum (193), liver (418), gallbladder (122), pancreas (122), lung (436), breast (281), and bladder (122). Poisson regression was used to allow for city, gender, age, radiation exposure, smoking status, alcohol drinking, body-mass index, education level, and calendar time.\n Green tea consumption was virtually unrelated to incidence of cancers under study. The relative risks of all cancers for those consuming green tea twice to four times per day and five or more times per day were 1.0 (95% confidence interval 0.91-1.1) and 0.98 (0.88-1.1), respectively, as compared with those consuming green tea once per day or less.\n Our findings do not provide evidence that regular green tea consumption is related to reduced cancer risks.", "Tea and its constituents have shown anticarcinogenic activities in in vitro and animal studies. Epidemiologic studies, however, have been inconsistent. We prospectively evaluated the association between green tea consumption and colorectal cancer (CRC) risk in a cohort of 69,710 Chinese women aged 40 to 70 years. Information on tea consumption was assessed through in-person interviews at baseline and reassessed 2 to 3 years later in a follow-up survey. During 6 years of follow-up, 256 incident cases of CRC were identified. The multivariate relative risk of CRC was 0.63 (95% confidence interval, 0.45-0.88) for women who reported drinking green tea regularly at baseline compared with nonregular tea drinkers. A significant dose-response relationship was found for both the amount of tea consumed (Ptrend = 0.01) and duration in years of lifetime tea consumption (Ptrend = 0.006). The reduction in risk was most evident among those who consistently reported to drink tea regularly at both the baseline and follow-up surveys (relative risk, 0.43; 95% confidence interval, 0.24-0.77). The inverse association with regular tea drinking was observed for both colon and rectal cancers. This study suggests that regular consumption of green tea may reduce CRC risk in women.", "Breast cancer is the most common malignancy in women worldwide. Tea has anticarcinogenic effects against breast cancer in experimental studies. However, epidemiologic evidence that tea protects against breast cancer has been inconsistent. A case-control study was conducted in Southeast China between 2004 and 2005. The incidence cases were 1009 female patients aged 20-87 years with histologically confirmed breast cancer. The 1009 age-matched controls were healthy women randomly recruited from breast disease clinics. Information on duration, frequency, quantity, preparation, type of tea consumption, diet and lifestyle were collected by face-to-face interview using a validated and reliable questionnaire. Conditional logistic regression analyses were used to estimate odds ratios (ORs) and associated 95% confidence intervals. Compared with non-tea drinkers, green tea drinkers tended to reside in urban, have better education and have higher consumption of coffee, alcohol, soy, vegetables and fruits. After adjusting established and potential confounders, green tea consumption was associated with a reduced risk of breast cancer. The ORs were 0.87 (0.73-1.04) in women consuming 1-249 g of dried green tea leaves per annum, 0.68 (0.54-0.86) for 250-499 g per annum, 0.59 (0.45-0.77) for 500-749 g per annum and 0.61 (0.48-0.78) for >or=750 g per annum, with a statistically significant test for trend (P < 0.001). Similar dose-response relationships were observed for duration of drinking green tea, number of cups consumed and new batches prepared per day. We conclude that regular consumption of green tea can protect against breast cancer. More research to closely examine the relationship between tea consumption and breast cancer risk is warranted.", "The purpose of this study was to examine the hypothesis that tea and coffee consumption have a protective effect against development of digestive tract cancers.\n A comparative case-referent study was conducted using Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC) data from 1990 to 1995 in Nagoya, Japan. This study comprised 1,706 histologically diagnosed cases of digestive tract cancers (185 esophagus, 893 stomach, 362 colon, 266 rectum) and a total of 21,128 non-cancer outpatients aged 40 years and over. Logistic regression was used to analyze the data, adjusting for gender; age; year and season at hospital-visit; habitual smoking and alcohol drinking; regular physical exercise; fruit, rice, and beef intake; and beverage intake.\n The odds ratio (OR) of stomach cancer decreased to 0.69 (95 percent confidence interval [CI] = 0.48-1.00) with high intake of green tea (seven cups or more per day). A decreased risk was also observed for rectal cancer with three cups or more daily intake of coffee (OR = 0.46, CI = 0.26-0.81).\n The results suggest the potential for protective effect against site-specific digestive tract cancer by consumption of green tea and coffee, although most associations are limited only to the upper category of intake and have no clear explanation for site-specificity.", "Although laboratory experiments and case-control studies have suggested that the consumption of green tea provides protection against gastric cancer, few prospective studies have been performed.\n In January 1984, a total of 26,311 residents in three municipalities of Miyagi Prefecture, in northern Japan (11,902 men and 14,409 women 40 years of age or older), completed a self-administered questionnaire that included questions about the frequency of consumption of green tea. During 199,748 person-years of follow-up, through December 1992, we identified 419 cases of gastric cancer (in 296 men and 123 women). We used Cox regression to estimate the relative risk of gastric cancer according to the consumption of green tea.\n Green-tea consumption was not associated with the risk of gastric cancer. After adjustment for sex, age, presence or absence of a history of peptic ulcer smoking status, alcohol consumption, other dietary elements, and type of health insurance, the relative risks associated with drinking one or two, three or four, and five or more cups of green tea per day, as compared with less than one cup per day, were 1.1 (95 percent confidence interval, 0.8 to 1.6), 1.0 (95 percent confidence interval, 0.7 to 1.4), and 1.2 (95 percent confidence interval, 0.9 to 1.6), respectively (P for trend=0.13). The results were similar after the 117 cases of gastric cancer that were diagnosed in the first three years of follow-up had been excluded, with respective relative risks of 1.2 (95 percent confidence interval, 0.8 to 1.8) 1.0 (95 percent confidence interval, 0.7 to 1.5), and 1.4 (95 percent confidence interval, 1.0 to 1.9) (P for trend=0.07).\n In a population-based, prospective cohort study in Japan, we found no association between green-tea consumption and the risk of gastric cancer.", "We examined the risk of lung cancer in relation to green tea consumption in a population-based cohort study in Japan among 41,440 men and women, aged 40-79 years, who completed a questionnaire in 1994 regarding green tea consumption and other health-related lifestyle factors. During the follow-up period of 7 years (from 1995 to 2001), 302 cases of lung cancer were identified, and the Cox proportional hazards regression model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). The multivariable-adjusted HRs of lung cancer incidence for green tea consumption of 1 or 2, 3 or 4, and 5 or more cups/day as compared to less than 1 cup/day were 1.14 (95% CI: 0.80-1.62), 1.18 (95% CI: 0.83-1.66), and 1.17 (95% CI: 0.85-1.61), respectively (P for trend=0.48). This cohort study has found no evidence that green tea consumption is associated with lung cancer.", "The relationships between green tea and black tea consumption and colorectal cancer risk were examined within the Singapore Chinese Health Study, a prospective cohort study of diet and cancer involving >60,000 men and women. Intake of green tea and black tea was assessed through in-person interviews. Incident cancer cases and deaths among cohort members were identified through record linkage of the cohort database with respective databases from the nationwide Singapore Cancer Registry and the Singapore Registry of Births and Deaths. The proportional hazard regression method was used to examine the associations between intake of green and black tea separately and colorectal cancer risk with adjustment for potential confounders. After an average of 8.9 years of follow-up, 845 colorectal cancer cases were identified. Subjects who drank green tea exhibited a statistically non-significant increase in risk [relative risk (RR) = 1.12, 95% confidence interval (CI) = 0.97-1.29] relative to non-drinkers of green tea. This risk increase was mainly confined to men (RR = 1.31, 95% CI = 1.08-1.58); the comparable RR in women was 0.89 (95% CI = 0.71-1.12). In men, the green tea-colorectal cancer association was noted mainly in those with advanced disease (Duke C or D) (RR = 1.53, 95% CI = 1.19-1.97), and the association was dose dependent (P for trend = 0.0002). This latter association was especially strong within the colon subsite (RR = 1.75, 95% CI = 1.24-2.46; P for trend < 0.0001). Irrespective of gender, intake of black tea was not associated with risk of colorectal cancer (RR = 0.92, 95% CI = 0.79-1.07) in this Asian population.", "To investigate the relationship between green tea consumption and subsequent risk of gastric cancer at different anatomical subsites in a population-based prospective study.\n The Japan Public Health Center-based prospective study (JPHC Study) was established in 1990 for Cohort I and in 1993 for Cohort II. Among 72,943 subjects (34,832 men and 38,111 women), 892 gastric cancer cases (665 men and 227 women) were identified from 1990 to 2001.\n While no association between green tea consumption and gastric cancer was observed among men, a decreased risk of gastric cancer was observed among women after adjustment for potential confounding factors. This result was more remarkable when only the tumors in the distal portion were analyzed; for that subsite, the relative risk was 0.51 (95% confidence interval 0.30-0.86) in the highest category of green tea consumption (5 or more cups per day versus less than 1 cup per day) (p for trend = 0.01). The null association for upper-third gastric cancer was consistent for both sexes.\n An inverse association between green tea consumption and distal gastric cancer was observed among women. More prospective studies with detailed information are needed to confirm the role of green tea in the occurrence of gastric cancer.\n Copyright 2004 Kluwer Academic Publishers", "The effect of green tea drinking in reducing human cancer risk is unclear, though a protective effect has been reported in numerous animal studies and several epidemiologic investigations. Herein the hypothesis that green tea consumption may reduce the risk of cancers of the colon, rectum and pancreas is examined in a large population-based case-control study conducted in Shanghai, China. Newly diagnosed cancer cases (931 colon, 884 rectum and 451 pancreas) during 1990-1993 among residents 30-74 years of age were included. Controls (n = 1,552) were selected among Shanghai residents and frequency-matched to cases by gender and age. Multivariate odds ratios (ORs) and 95% confidence intervals (CIs) of each cancer associated with green tea consumption were derived after adjustment for age, income, education and cigarette smoking. Additional adjustment for dietary items and body size was found to have minimal impact. An inverse association with each cancer was observed with increasing amount of green tea consumption, with the strongest trends for rectal and pancreatic cancers. For men, compared with non-regular tea drinkers, ORs among those in the highest tea consumption category (> or = 300 g/month) were 0.82 for colon cancer, 0.72 for rectal cancer and 0.63 for pancreatic cancer, with p values for trend being 0.38, 0.04 and 0.04, respectively. For women, the respective ORs for the highest consumption category (> or = 200 g/month) were 0.67, 0.57 and 0.53, with the respective p values for trend being 0.07, 0.001 and 0.008. Our findings provide further evidence that green tea drinking may lower the risk of colorectal and pancreatic cancers.", "Green tea polyphenols have been shown to inhibit tumor growth in animal and in vitro studies. We examined the relationship between green tea consumption and the risk of death from pancreatic cancer in a large Japanese cohort.\n At baseline (1988-1990), study participants reported the frequency and amount of green tea consumption during the past year. They were followed-up for mortality until December 31, 2003. Relative risk and 95% confidence intervals were calculated from Cox proportional hazard models.\n During an average follow-up of 13 years, we observed 292 pancreatic cancer deaths. In men and women combined, the relative risk was 1.23 (95% confidence interval, 0.84-1.80) for participants who consumed 7 or more cups of green tea per day as compared with those who consumed less than 1 cup per day, after adjustment for potential confounding factors. No significant trend in risk reduction was noted, with increasing consumption of green tea. We found no inverse association between cups of green tea consumed per day and the risk of pancreatic cancer in either men or women.\n Our findings do not support the hypothesis that green tea consumption is associated with decreased risk of pancreatic cancer in humans.", "In a pooled analysis of two prospective studies with 35004 Japanese women, green-tea intake was not associated with a lower risk of breast cancer (222 cases), the multivariate relative risk for women drinking >or=5 cups compared with <1 cup per day being 0.84 (95% confidence interval 0.57-1.24, Trend P=0.69).", "The effect of drinking Chinese green tea on the risk of stomach cancer was evaluated in a population-based case-control study conducted in Shanghai, China, from October 1991 to December 1993. Eligible cases were incident cases of primary stomach cancer diagnosed during the study period among residents of Hongkou district and Nanhui county aged under 80 years. Controls were selected from the same street or commune where the case resided and were matched to the cases on age (within three years) and gender. A total of 711 cases and 711 matched controls, more than 90 percent of the eligible subjects, completed the interview. Information was obtained on the types of tea used, age when habitual tea drinking started, frequency of new batches of tea leaves used per day, number of cups brewed from each batch, total duration of drinking for each batch, strength and temperature of the tea consumed. Statistical analysis was based on modelling through conditional logistic regression. After adjusting for age, gender, place of residence, education, birthplace, alcohol consumption, and cigarette smoking, the odds ratio (OR) comparing drinkers of green tea with nondrinkers was 0.71 (95 percent confidence interval = 0.54-0.93). The adjusted OR decreased with increasing number of new batches of the green tea consumed each day (P value trend = 0.006). With the largest series of stomach cancer cases to date, this study found green-tea consumption associated with lower risk of stomach cancer. Among drinkers of green tea, the risk of stomach cancer did not depend on the age when habitual green-tea drinking started. Green tea may disrupt gastric carcinogenesis at both the intermediate and the late stages.", "Epidemiologic evidence regarding the association between the consumption of green tea and lung cancer is limited and inconclusive, although experimental studies have shown consistently that tea preparations and tea polyphenols may inhibit the induction of a variety of cancers, including lung cancer. In this population-based case-control study, we examined the association between past consumption of green tea and the risk of lung cancer. We identified 649 incident cases of primary lung cancer among women diagnosed from February 1992 through January 1994 using the population-based Shanghai Cancer Registry. We randomly selected a control group of 675 women from the Shanghai Residential Registry, frequency-matched to the expected age distribution of the cases. Green tea consumption was ascertained through face-to-face interviews. We estimated adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) using unconditional logistic regression. Among nonsmoking women, consumption of green tea was associated with a reduced risk of lung cancer (OR = 0.65; 95% CI = 0.45-0.93), and the risks decreased with increasing consumption. We found little association, however, among women who smoked (OR = 0.94; 95% CI = 0.40-2.22). The inconsistency in the association between drinking tea and the risk of lung cancer reported in previous studies may in part be due to inadequate control of confounding of active smoking.", "The incidence of prostate cancer is much lower in Asian than Western populations. Given that environmental factors such as dietary habits may play a major role in the causation of prostate cancer and the high consumption of green tea in Asian populations, this low incidence may be partly due to the effects of green tea. The JPHC Study (Japan Public Health Center-based Prospective Study) was established in 1990 for cohort I and in 1993 for cohort II. The subjects were 49,920 men aged 40-69 years who completed a questionnaire that included their green tea consumption habit at baseline and were followed until the end of 2004. During this time, 404 men were newly diagnosed with prostate cancer, of whom 114 had advanced cases, 271 were localized, and 19 were of an undetermined stage. Green tea was not associated with localized prostate cancer. However, consumption was associated with a dose-dependent decrease in the risk of advanced prostate cancer. The multivariate relative risk was 0.52 (95% confidence interval: 0.28, 0.96) for men drinking 5 or more cups/day compared with less than 1 cup/day (p(trend) = 0.01). Green tea may be associated with a decreased risk of advanced prostate cancer.", "The significance of drinking green tea in prevention of two of the main lifestyle-related diseases, cancer and cardiovascular disease, was demonstrated in terms of a prospective cohort study on a total of 8,552 general residents in Saitama Prefecture, Japan. On the basis of the follow-up study, we revealed decreased relative risk of cancer incidence for those consuming over 10 cups a day, compared with those consuming below 3 cups: 0.54 (95% confidence interval, 0.22-1.34) for men, 0.57 (0.34-0.98) for women, and 0.59 (0.35-0.98) for both sexes. Furthermore, a significant delay in cancer onset was associated with increased consumption of green tea. Next, decreased relative risk of death from cardiovascular disease was 0.58 (0.34-0.99) for men, 0.82 (0.49-1.38) for women, and 0.72 (0.60-1.04) for members of both sexes consuming over 10 cups a day. Finally, we evaluated the life-prolonging effects of drinking green tea on cumulative survival, using the life table.", "Studies in laboratory animals have suggested inhibitory effects of green tea on the induction of some cancers, notably, esophageal cancer. However, only a few epidemiologic studies have evaluated green tea as a potential inhibitor of human esophageal cancer.\n Our purpose was to evaluate the relationship between green tea consumption and the risk of esophageal cancer.\n This esophageal cancer study was part of a larger multicenter, case-control study that included three other gastrointestinal sites (pancreas, colon, and rectum). Medical records of patients aged 30-74 years old who were diagnosed with esophageal cancer from October 1, 1990, through January 31, 1993, were identified from the Shanghai Cancer Registry, which covers 6.8 million people in the urban area of Shanghai, People's Republic of China. During the ascertainment period, records of 1016 eligible cases of esophageal cancer were identified. Control subject records were selected by frequency matching in accordance with the age-sex distribution of the four gastrointestinal cancers ascertained by the cancer registry during 1986-1987. Patient interviews were then conducted using a structured, standardized questionnaire to obtain information on demographic characteristics, residential history, height and weight, diet, smoking, alcohol and tea drinking, medical history, family history of cancer, occupation, physical activity, and reproductive history.\n Of the 902 patients interviewed, 734 (81.4%) had their disease pathologically confirmed. There were 1552 control subjects interviewed, including 240 alternates. All analyses of tea effects were conducted separately among men and women and all were adjusted for age. After further adjustment for other known confounders, a protective effect of green tea drinking on esophageal cancer was observed among women (odds ratio [OR] = 0.50; 95% confidence interval [CI] = 0.30-0.83), and this risk decreased (P for trend < or = .01) as tea consumption increased. Among men, the ORs were also below 1.00, although not statistically significant. ORs for green tea intake were estimated among those persons who neither smoked nor drank alcohol. In this subset, statistically significant decreases in risk among tea drinkers were observed for both men (OR = 0.43; 95% CI = 0.22-0.86; P for trend = .05) and women (OR = 0.40; 95% CI = 0.20-0.77; P for trend < .001).\n This population-based, case-control study of esophageal cancer in urban Shanghai suggests a protective effect of green tea consumption. Although these findings are consistent with studies in laboratory animals, indicating that green tea can inhibit esophageal carcinogenesis, further investigations are definitely needed.", "There is substantial in vitro and in vivo evidence implicating tea polyphenols as chemopreventive agents against various cancers. However, epidemiologic data obtained from mainly Western populations are not supportive of a protective role of tea, mainly black tea, in the etiology of breast cancer. Much less is known about the relationship between green tea and breast cancer risk. During 1995-1998, we conducted a population-based, case-control study of breast cancer among Chinese, Japanese and Filipino women in Los Angeles County and successfully interviewed 501 breast cancer patients and 594 control subjects. Detailed information on menstrual and reproductive factors; dietary habits, including intake of black and green tea; and other lifestyle factors was collected. Risk of breast cancer was not related to black tea consumption. In contrast, green tea drinkers showed a significantly reduced risk of breast cancer, and this was maintained after adjusting for age, specific Asian ethnicity, birthplace, age at menarche, parity, menopausal status, use of menopausal hormones, body size and intake of total calories and black tea. Compared to women who did not drink green tea regularly (i.e., less than once a month), there was a significant trend of decreasing risk with increasing amount of green tea intake, adjusted odds ratios being 1.00, 0.71 (95% confidence interval [CI] 0.51-0.99) and 0.53 (95% CI 0.35-0.78), respectively, in association with no, 0-85.7 and >85.7 ml of green tea per day. The significant inverse association between risk of breast cancer and green tea intake remained after further adjustment for other potential confounders, including smoking; alcohol, coffee and black tea intake; family history of breast cancer; physical activity; and intake of soy and dark green vegetables. While both green tea and soy intake had significant, independent protective effects on breast cancer risk, the benefit of green tea was primarily observed among subjects who were low soy consumers. Similarly, the protective effect of soy was primarily observed among subjects who were nondrinkers of green tea. In summary, our results point to an important role of both green tea and soy intake in relation to breast cancer risk in Asian-American women.\n Copyright 2003 Wiley-Liss, Inc.", "In a prospective study of 19,561 Japanese men, green-tea intake was not associated with a lower risk of prostate cancer (110 cases), the multivariate hazard ratio for men drinking > or =5 cups compared with <1 cup per day being 0.85 (95% confidence interval 0.50-1.43, trend P = 0.81).", "The tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) has been reported to act as a cancer preventive agent through folate pathway inhibition in experimental studies. We hypothesized that if folate pathway inhibition is the mechanism of cancer preventive activities of EGCG, then the protective effect against breast cancer would be stronger among women with low dietary folate intake and the high-activity methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TYMS) genotypes. In a nested case-control study of 380 women with incident breast cancer and 662 controls within the Singapore Chinese Health Study, we found no association between either green tea intake or gene polymorphisms of MTHFR (C677T and A1298C) and TYMS (1494 ins/del) and breast cancer risk. However, among women with low folate intake (<133.4 microg/day), weekly/daily green tea intake was inversely associated with breast cancer risk compared with less green tea intake [odds ratio (OR) = 0.45, 95% confidence interval (CI) = 0.26-0.79, P for interaction = 0.02]. Among women with high folate intake (>or=133.4 microg/day), green tea intake was not associated with breast cancer. Similarly, among women possessing the high-activity MTHFR/TYMS genotypes (0-1 variant allele), weekly/daily versus less frequent green tea intake was associated with lower breast cancer risk (OR = 0.66, 95% CI = 0.45-0.98), which was observed even more strongly among those who also had low folate intake (OR = 0.44, 95% CI = 0.22-0.89) than high folate intake (OR = 0.92, 95% CI = 0.55-1.54). This association was not observed among women possessing the low-activity genotypes (2-4 variant alleles). Our findings suggest that folate pathway inhibition may be one mechanism through which green tea protects against breast cancer in humans.", "Although smoking and alcohol drinking are established risk factors of esophageal cancer, their public health impact is unclear. Furthermore, the effect of green tea is controversial.\n The present study was based on a pooled analysis of two prospective cohort studies. A self-administered questionnaire about health habits was distributed to 9,008 men in Cohort 1 and 17,715 men in Cohort 2, aged 40 years or older, with no previous history of cancer. We identified 38 and 40 patient cases with esophageal cancer among the subjects in Cohort 1 (9.0 years of follow-up) and Cohort 2 (7.6 years of follow-up), respectively. Cox proportional hazards regression was used to estimate hazard ratios (HRs) of the risk of esophageal cancer incidence.\n Cigarette smoking, alcohol drinking and green tea consumption were significantly associated with an increased risk of esophageal cancer. Compared with men who had never smoked, never drunk alcohol or green tea, the pooled multivariate HRs (95% confidence intervals) were 5.09 (1.80-14.40) (p for trend <0.0001), 2.73 (1.55-4.81) (p for trend=0.0002), or 1.67 (0.89-3.16) (P for trend=0.04) for men who were currently smoking > or =20 cigarettes/day, drinking alcohol daily, or drinking > or =5 cups green tea/day, respectively. The population attributable fractions of esophageal cancer incidence that was attributable to smoking, alcohol drinking and green tea consumption were 72.0%, 48.6%, and 22.1%, respectively.\n Among the variables studied, smoking has the largest public health impact on esophageal cancer incidence in Japanese men, followed by alcohol drinking and green tea drinking.", "Overweight status after breast cancer treatment may increase a woman's risk for recurrent disease and/or early onset cardiovascular disease. Green tea has been proposed to promote weight loss and favourably modify glucose, insulin and blood lipids. This pilot study tested the effect of daily decaffeinated green tea consumption for 6 months on weight and body composition, select metabolic parameters and lipid profiles in overweight breast cancer survivors.\n The effect of daily decaffeinated green tea intake on weight, body composition and changes in resting metabolic rate, energy intake, glucose, insulin, homeostasis model assessment--insulin resistance (HOMA-IR) and lipids was evaluated in overweight breast cancer survivors. Participants had a mean weight of 80.2 kg; body mass index (BMI) 30.1 kg m⁻²; and body fat 46.4%. Participants (n = 54) were randomised to 960 mL of decaffeinated green or placebo tea daily for 6 months.\n Mean (SD) tea intake among study completers (n = 39) was 5952 (1176) mL week⁻¹ and was associated with a significant reduction in energy intake (P = 0.02). Change in body weight of -1.2 kg (green tea) versus +0.2 kg (placebo) suggests a weight change effect, although this was not statistically significant. Decaffeinated green tea intake was associated with elevated high-density lipoprotein (HDL) levels (P = 0.003) and nonsignificant improvements in the HDL/LDL ratio and HOMA-IR (-1.1 ± 5.9: green tea; +3.2 ± 7.2: herbal).\n Intake of decaffeinated green tea for 6 months was associated with a slight reduction in body weight and improved HDL and glucose homeostasis in overweight breast cancer survivors.\n © 2010 The Authors. Journal compilation © 2010 The British Dietetic Association Ltd.", "Experimental evidence suggests that green tea (Camellia sinesis) may reduce the risk of lung cancer through several hypothesized mechanisms including scavenging oxidative radicals, inhibition of tumor initiation, and modulation of detoxification enzymes. However, epidemiologic results have not been consistent as to the relationship between green tea consumption and lung caner prevention. We employed a population-based case-control study of 122 cases and 122 controls to investigate the effect that green tea consumption may have on the risk of lung cancer and whether polymorphisms in 8-oxoguanine-DNA glycosylase (OGG1), glutathione-S-transferase M1 (GSTM1), and aldo-keto reductase 1C3 (AKR1C3) modify such an association. Daily green tea consumption was associated with a non-significant reduction in lung cancer risk. However, the effect of smoky coal exposure was higher for non-drinkers (odds ratio (OR)=4.93; 95% confidence interval (95% CI)=1.27-19.13) than for drinkers (OR=1.88; 95% CI=1.01-3.48). Further, among individuals with the OGG1 Cys(326) allele, daily consumption was associated with a 72% reduction (95% CI=0.09-0.94). Among GSTM1 null homozygotes, those who consumed green tea daily had a non-significant reduction in risk compared with non-consumers. Green tea consumption had no effect among OGG1 Ser(326) homozygotes or GSTM1 carriers. In addition, AKR1C3 genotype did not modulate the effect of green tea consumption. The chemopreventive effects of green tea in this population may be restricted to individuals who are particularly susceptible to oxidative stress and oxidative DNA damage.", "To investigate whether tea consumption has an etiological association with ovarian cancer, a case-control study was conducted in China during 1999-2000. The cases were 254 patients with histologically confirmed epithelial ovarian cancer. The 652 controls comprised 340 hospital visitors, 261 non-neoplasm hospital outpatients, and 51 women recruited from the community. Information on the frequency, type, and duration of tea consumption was collected by personal interview using a validated questionnaire. The risk of ovarian cancer for tea consumption was assessed using adjusted odds ratios based on multivariate logistic regression analysis, accounting for confounding demographic, lifestyle, and familial factors including hormonal status and family ovarian cancer. The ovarian cancer risk declined with increasing frequency and duration of overall tea consumption. The adjusted odds ratio was 0.39 for those drinking tea daily and 0.23 for those drinking tea for >30 years, compared with nontea drinkers. The dose response relationships were significant, and the inverse association with ovarian cancer was observed for green tea consumption. We concluded that increasing frequency and duration of tea drinking, especially green tea, can reduce the risk of ovarian cancer. However, the protective effects of black tea and Oolong tea need to be additionally investigated.", "Pancreatic cancer is one of the most aggressive and treatment-refractory malignancies in humans. The most effective means of reducing pancreatic cancer mortality may be primary prevention. Although laboratory studies have demonstrated that green tea possesses anticancer activities, results from epidemiological studies have failed to show a consistent cancer-preventive effect. In addition, there is a lingering concern that coffee mighty increase the risk of pancreatic cancer although the most recent epidemiological studies showed no overall association between coffee and risk. Here, we examined the association between the drinking of green tea or coffee and the risk of pancreatic cancer in a large population-based cohort study in Japan (JPHC study). In total, 102 137 participants were followed for an average of 11 years through to the end of 2003. A total of 233 incident cases of pancreatic cancer were identified among 1 116 945 person-years of follow-up. Overall, the risk of pancreatic cancer was not associated with either green tea or coffee intake in our population, although a reduced risk was apparent among men who drank at least three cups of coffee per day compared with those who did not drink any or only rarely drank coffee. In conclusion, our findings support the idea that green tea or coffee consumption does not have a substantial impact on pancreatic cancer risk in general.", "Despite the declining trend, stomach cancer remains the second most common cancer worldwide. We examined the role of green tea consumption on chronic gastritis and stomach cancer risks. A population-based case-control study was conducted in Yangzhong, China, with 133 stomach cancer cases, 166 chronic gastritis cases, and 433 healthy controls. Epidemiologic data were collected by standard questionnaire and odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression models in SAS. Inverse association was observed between green tea drinking and chronic gastritis and stomach cancer risks. After adjusting for age, gender, education, body mass index, pack-years of smoking and alcohol drinking, ORs of green tea drinking were 0.52 (95% CI: 0.29-0.94) and 0.49 (95% CI: 0.31-0.77) for stomach cancer and chronic gastritis, respectively. In addition, dose-response relationships were observed with years of green tea drinking in both diseases. The results provide further support on the protective effect of green tea against stomach cancer. This is the first time that green tea drinking was found to be protective against chronic gastritis, which may be of importance when designing intervention strategies for stomach cancer and its pre-malignant lesions in the high-risk population.", "To explore the role of green tea in decreasing the risks of gastric cancer, liver cancer, esophageal cancer among alcohol drinkers or cigarette smokers.\n A population based case-control study was conducted in Taixing, Jiangsu province.\n In Taixing city, identified cases of stomach, liver and esophageal cancers were chosen with informed consent. The numbers were 206, 204, 218 respectively. Controls were chosen from normal population having lived in the area for longer than 10 years, also with informed consent. Green tea drinking seemed to have decreased 81%, 78%, 39% risk for the development of gastric cancer, liver cancer and esophageal cancer among alcohol drinkers. It might also have decreased 16%, 43%, 31% on the risks of developing the three kinds of cancers among cigarette smokers. Interaction assessment showed that drinking green tea could significantly decrease the risk of gastric cancer and liver cancer among alcohol drinkers, with ORs of interaction item 0.23 (95% CI: 0.10 - 0.55) and 0.25 (95% CI: 0.11 - 0.57) respectively.\n Habit of drinking green tea seemed to have significant protective effects on the development of both gastric and liver cancer among alcohol drinkers while, green tea also having some protective effect on esophageal cancer among alcohol drinkers and on three kinds of cancers among cigarette smokers.", "The roles of several foods and beverages in the development of bladder cancer remain unclear.\n We undertook a hospital-based case-control study at Aichi Cancer Center Hospital, Japan. Subjects included 124 men and women (bladder cancer cases) with newly diagnosed cancers of the renal pelvis (n = 5), ureter (n = 6) or bladder (n = 113) and 620 age- and sex-matched, cancer-free outpatients (controls) presenting at the hospital in the period from 1994 to 2000. Smoking-adjusted odds ratios (OR) were estimated to assess the strength of associations between self-reported intake of foods or drinks and bladder cancer risk, using conditional logistic models.\n We found a decreased risk in relation to frequent intake of green-yellow vegetables; the OR for the highest intake score compared with the lowest was 0.54 (95% confidence interval [CI] 0.29-0.99). The OR for carrot intake of >/=5 times/week compared with </=1-3 times/month was 0.41 (95% CI 0.16-1.01) and a decreasing risk with increasing consumption of green vegetables was also detected (P for trend = 0.063). Inverse associations between black tea, eggs and meat and risk were also suggested, whereas moderate drinkers of green tea (5-9 cups/day) showed an elevated risk. Coffee and milk consumption did not appear to exert any influence.\n Those with an increased risk of bladder cancer, such as smokers, may benefit from increasing their consumption of green-yellow vegetables.", "Green tea polyphenols have been extensively studied as cardiovascular disease and cancer chemopreventive agents in vitro and in animal studies. However, the effects of green tea consumption in humans remain unclear.\n To investigate the associations between green tea consumption and all-cause and cause-specific mortality.\n The Ohsaki National Health Insurance Cohort Study, a population-based, prospective cohort study initiated in 1994 among 40,530 Japanese adults aged 40 to 79 years without history of stroke, coronary heart disease, or cancer at baseline. Participants were followed up for up to 11 years (1995-2005) for all-cause mortality and for up to 7 years (1995-2001) for cause-specific mortality.\n Mortality due to cardiovascular disease, cancer, and all causes.\n Over 11 years of follow-up (follow-up rate, 86.1%), 4209 participants died, and over 7 years of follow-up (follow-up rate, 89.6%), 892 participants died of cardiovascular disease and 1134 participants died of cancer. Green tea consumption was inversely associated with mortality due to all causes and due to cardiovascular disease. The inverse association with all-cause mortality was stronger in women (P = .03 for interaction with sex). In men, the multivariate hazard ratios of mortality due to all causes associated with different green tea consumption frequencies were 1.00 (reference) for less than 1 cup/d, 0.93 (95% confidence interval [CI], 0.83-1.05) for 1 to 2 cups/d, 0.95 (95% CI, 0.85-1.06) for 3 to 4 cups/d, and 0.88 (95% CI, 0.79-0.98) for 5 or more cups/d, respectively (P = .03 for trend). The corresponding data for women were 1.00, 0.98 (95% CI, 0.84-1.15), 0.82 (95% CI, 0.70-0.95), and 0.77 (95% CI, 0.67-0.89), respectively (P<.001 for trend). The inverse association with cardiovascular disease mortality was stronger than that with all-cause mortality. This inverse association was also stronger in women (P = .08 for interaction with sex). In women, the multivariate hazard ratios of cardiovascular disease mortality across increasing green tea consumption categories were 1.00, 0.84 (95% CI, 0.63-1.12), 0.69 (95% CI, 0.52-0.93), and 0.69 (95% CI, 0.53-0.90), respectively (P = .004 for trend). Among the types of cardiovascular disease mortality, the strongest inverse association was observed for stroke mortality. In contrast, the hazard ratios of cancer mortality were not significantly different from 1.00 in all green tea categories compared with the lowest-consumption category.\n Green tea consumption is associated with reduced mortality due to all causes and due to cardiovascular disease but not with reduced mortality due to cancer.", "The body fat reducing effect and reduction of risks for cardiovascular disease by a green tea extract (GTE) high in catechins was investigated in humans with typical lifestyles.\n Japanese women and men with visceral fat-type obesity were recruited for the trial. After a 2-week diet run-in period, a 12-week double-blind parallel multicenter trial was performed, in which the subjects ingested green tea containing 583 mg of catechins (catechin group) or 96 mg of catechins (control group) per day. Randomization was stratified by gender and body mass index at each medical institution. The subjects were instructed to maintain their usual dietary intake and normal physical activity.\n Data were analyzed using per-protocol samples of 240 subjects (catechin group; n = 123, control group; n = 117). Decreases in body weight, body mass index, body fat ratio, body fat mass, waist circumference, hip circumference, visceral fat area, and subcutaneous fat area were found to be greater in the catechin group than in the control group. A greater decrease in systolic blood pressure (SBP) was found in the catechin group compared with the control group for subjects whose initial SBP was 130 mm Hg or higher. Low-density lipoprotein (LDL) cholesterol was also decreased to a greater extent in the catechin group. No adverse effect was found.\n The continuous ingestion of a GTE high in catechins led to a reduction in body fat, SBP, and LDL cholesterol, suggesting that the ingestion of such an extract contributes to a decrease in obesity and cardiovascular disease risks.", "Obesity is a major health problem in the developed and developing world. Many \"functional\" foods and ingredients are advocated for their effects on body composition but few have consistent scientific support for their efficacy. However, an increasing amount of mechanistic and clinical evidence is building for green tea (GT). This experiment was therefore undertaken to study the effects of a high-catechin GT on body composition in a moderately overweight Chinese population. In a randomized placebo-controlled trial, 182 moderately overweight Chinese subjects, consumed either two servings of a control drink (C; 30 mg catechins, 10 mg caffeine/day), one serving of the control drink and one serving of an extra high-catechin GT1 (458 mg catechins, 104 mg caffeine/day), two servings of a high-catechin GT2 (468 mg catechins, 126 mg caffeine/day) or two servings of the extra high-catechin GT3 (886 mg catechins, 198 mg caffeine/day) for 90 days. Data were collected at 0, 30, 60, and 90 days. We observed a decrease in estimated intra-abdominal fat (IAF) area of 5.6 cm(2) in the GT3 group. In addition, we found decreases of 1.9 cm in waist circumference and 1.2 kg body weight in the GT3 group vs. C (P < 0.05). We also observed reductions in total body fat (GT2, 0.7 kg, P < 0.05) and body fat % (GT1, 0.6%, P < 0.05). We conclude that consumption of two servings of an extra high-catechin GT leads to improvements in body composition and reduces abdominal fatness in moderately overweight Chinese subjects.", "Associations of coffee, tea, and other caffeinated beverages with ovarian cancer risk remain uncertain. In a population-based study in Washington State, 781 women with epithelial ovarian cancer diagnosed in 2002 to 2005 and 1,263 controls completed self-administered questionnaires detailing consumption of caffeinated and noncaffeinated coffee, teas, and colas and in-person interviews regarding reproductive and hormonal exposures. We assessed risk associated with coffee, tea, and cola drinking and with total caffeine consumption using logistic regression to calculate odds ratios and 95% confidence intervals. Neither caffeinated nor decaffeinated coffees were associated with ovarian cancer risk; also, we observed no association of total caffeine with risk using a combined index that summed intake from coffee, tea, and carbonated soft drinks. Among teas, neither herbal/decaffeinated nor black teas were associated with risk; however, women who reported drinking >or=1 cup/d of green tea had a 54% reduction in risk (P trend = 0.01). Associations of green tea with risk were similar when invasive and borderline cases were considered separately and when Asian women were excluded from analysis. Green tea, which is commonly consumed in countries with low ovarian cancer incidence, should be further investigated for its cancer prevention properties.", "This study evaluated the influence of a green tea catechin beverage on body composition and fat distribution in overweight and obese adults during exercise-induced weight loss. Participants (n = 132 with 107 completers) were randomly assigned to receive a beverage containing approximately 625 mg of catechins with 39 mg caffeine or a control beverage (39 mg caffeine, no catechins) for 12 wk. Participants were asked to maintain constant energy intake and engage in >or=180 min/wk moderate intensity exercise, including >or=3 supervised sessions per week. Body composition (dual X-ray absorptiometry), abdominal fat areas (computed tomography), and clinical laboratory tests were measured at baseline and wk 12. There was a trend (P = 0.079) toward greater loss of body weight in the catechin group compared with the control group; least squares mean (95% CI) changes, adjusted for baseline value, age, and sex, were -2.2 (-3.1, -1.3) and -1.0 (-1.9, -0.1) kg, respectively. Percentage changes in fat mass did not differ between the catechin [5.2 (-7.0, -3.4)] and control groups [-3.5 (-5.4, 1.6)] (P = 0.208). However, percentage changes in total abdominal fat area [-7.7 (-11.7, -3.8) vs. -0.3 (-4.4, 3.9); P = 0.013], subcutaneous abdominal fat area [-6.2 (-10.2, -2.2) vs. 0.8 (-3.3, 4.9); P = 0.019], and fasting serum triglycerides (TG) [-11.2 (-18.8, -3.6) vs. 1.9 (-5.9, 9.7); P = 0.023] were greater in the catechin group. These findings suggest that green tea catechin consumption enhances exercise-induced changes in abdominal fat and serum TG.", "The present study was conducted to investigate whether green tea may improve weight maintenance by preventing or limiting weight regain after weight loss of 5 to 10 % in overweight and moderately obese subjects. The study had a randomised, parallel, placebo-controlled design. A total of 104 overweight and moderately obese male and female subjects (age 18-60 years; BMI 25-35 kg/m(2)) participated. The study consisted of a very-low-energy diet intervention (VLED; 2.1 MJ/d) of 4 weeks followed by a weight-maintenance period of 13 weeks in which the subjects received green tea or placebo. The green tea contained caffeine (104 mg/d) and catechins (573 mg/d, of which 323 mg was epigallocatechin gallate). Subjects lost 6.4 (sd 1.9) kg or 7.5 (sd 2.2) % of their original body weight during the VLED (P<0.001). Body-weight regain was not significantly different between the green tea and the placebo group (30.5 (sd 61.8) % and 19.7 (sd 56.9) %, respectively). In the green tea treatment, habitual high caffeine consumption was associated with a higher weight regain compared with habitual low caffeine consumption (39 (sd 17) and 16 (sd 11) %, respectively; P<0.05). We conclude that weight maintenance after 7.5 % body-weight loss was not affected by green tea treatment and that habitual caffeine consumption affected weight maintenance in the green tea treatment.", "This study was undertaken to investigate the effects of green tea on weight reduction in obese Thais. A randomized, controlled trial involving 60 obese subjects (body mass index, BMI > 25 kg/m2) was conducted. All subjects consumed a Thai diet containing 3 meals (8373.6 kJ/day) for 12 weeks, prepared by the Nutritional Unit at Srinagarind Hospital. The diet contained 65% carbohydrates, 15% protein, and 20% fat. Body weight, BMI, body composition, resting energy expenditure, and substrate oxidation were measured at baseline, and during weeks 4, 8, and 12 of the study. Serum levels of leptin and urine VMA were measured at baseline and during the 12th week. Differences over time and between the treatments (green tea or placebo) over time were determined using two-factor ANOVA with repeated measures. In comparing the two groups, differences in weight loss were 2.70, 5.10, and 3.3 kg during the 4th, 8th, and 12th weeks of the study, respectively. At the 8th and 12th weeks of the study, body weight loss was significantly different (P < 0.05). At the 8th week, the difference in resting energy expenditure was 183.38 kJ/day (P < 0.001), the difference in the respiratory quotient was 0.02 (P < 0.05), and no significant differences existed in satiety score, food intake, or physical activity. Urine VMA was significantly different in the 12th week of the study (P < 0.05). We conclude that green tea can reduce body weight in obese Thai subjects by increasing energy expenditure and fat oxidation.", "The divergent incidence patterns of gastric cardia and distal stomach cancer may suggest different etiologies. This study examined the role of cigarette smoking, alcohol drinking, and green tea consumption as risk factors for carcinoma by anatomic subsite of stomach.\n Newly-diagnosed stomach carcinoma patients (n = 1124) and frequency-matched population controls (n = 1451) were interviewed in person. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression models.\n Excess risks associated with cigarette smoking and alcohol consumption were observed largely among men. The adjusted ORs for all stomach cancer combined were 1.35 (CI: 1.06-1.71) for current smokers, and 1.26 (CI: 0.86-1.84) for ex-smokers. For tumors of the distal stomach, statistically significant positive dose-response trends were found for the number of cigarettes smoked per day, the duration and pack-years of smoking, and inverse trends for years of stopped smoking. For tumors of the gastric cardia, however, a monotonic association was found only for the number of cigarettes smoked per day (P=0.06). Alcohol consumption was not related to the risk of cardia cancer, while a moderate excess risk of distal stomach cancer (OR: 1.55; CI: 1.07-2.26) was observed among heavy alcohol drinkers. Green tea drinking was inversely associated with risk of stomach cancer arising from either subsite, with ORs of 0.77 (CI: 0.52-1.13) among female heavy drinkers, and 0.76 (CI: 0.55-1.27) among male heavy drinkers.\n Our findings provide further evidence that cigarette smoking and, possibly, alcohol consumption increase the risk of stomach carcinoma, notably of the distal segment. An inverse association with green tea drinking was also observed.", "We assessed the effect of ingestion of green tea (GT) extract along with a low-energy diet (LED) on resting energy expenditure (REE), substrate oxidation and body weight as GT has been shown to increase energy expenditure and fat oxidation in the short term in both animals and people. Forty-six overweight women (BMI 27.6 (sd 1.8) kg/m2) were fed in energy balance from day 1 to day 3, followed by a LED with GT (1125 mg tea catechins +225 mg caffeine/d) or placebo (PLAC) from day 4 to day 87. Caffeine intake was standardised to 300 mg/d. Energy expenditure was measured on days 4 and 32. Reductions in weight (4.19 (sd 2.0) kg PLAC, 4.21 (sd 2.7) kg GT), BMI, waist:hip ratio, fat mass and fat-free mass were not statistically different between treatments. REE as a function of fat-free mass and fat mass was significantly reduced over 32 d in the PLAC group (P<0.05) but not in the GT group. Dietary restraint increased over time (P<0.001) in both groups, whereas disinhibition and general hunger decreased (P<0.05). The GT group became more hungry over time and less thirsty, and showed increased prospective food consumption compared with PLAC (P<0.05). Taken together, the ingestion of GT along with a LED had no additional benefit for any measures of body weight or body composition. Although the decrease in REE as a function of fat-free mass and fat mass was not significant with GT treatment, whereas it was with PLAC treatment, no significant effect of treatment over time was seen, suggesting that a robust limitation of REE reduction during a LED was not achieved by GT.", "Prostate cancer is the most common male cancer in developed countries and is increasing in the developing world. Its long latency and geographical variation suggest the possibility of prevention or postponement of onset by dietary modification. To investigate the possible joint effect of lycopene and green tea on prostate cancer risk, a case-control study was conducted in Hangzhou, China, with 130 prostate cancer patients and 274 hospital controls. Information on tea and dietary intakes, and possible confounders was collected using a structured questionnaire. The risk of prostate cancer for the intake of tea and lycopene and their joint effect were assessed using multivariate logistic regression models. Prostate cancer risk was reduced with increased consumption of green tea. The protective effect of green tea was significant (odds ratio 0.14, 95% CI: 0.06-0.35) for the highest quartile relative to the lowest after adjusting for total vegetables and fruits intakes and other potential confounding factors. Intakes of vegetables and fruits rich in lycopene were also inversely associated with prostate cancer risk (odds ratio 0.18, 95% CI 0.08-0.39). Interaction analysis showed that the protective effect from tea and lycopene consumption was synergistic (p<0.01). This study suggests that habitual drinking tea and intakes of vegetables and fruits rich in lycopene could lead to a reduced risk of prostate cancer in Chinese men. Together they have a stronger preventive effect than either component taken separately. This is the first epidemiological study to investigate the joint effect between tea drinking and lycopene intake.", "To understand the effect of dietary factors in Yangzhong, Jiangsu Province-a high prevalence area in China.\n A case-control study on 209 cases of upper digestive tract cancer was conducted. There were 68 cases of esophageal cancer, 69 cases of cardiac cancer and 72 cases of other gastric cancers including 129 males and 80 females aged 35-79 under the study.\n It is revealed that intake of pickled vegetables increases the ORs of esophageal, cardiac and other gastric cancers (OR = 2.82, OR = 5.17, OR = 2.92, respectively). It is also concluded that the intake of leftovers can elevate the ORs of esophageal and cardiac gastric cancer (OR = 1.88 and OR = 1.90) and over consumption of salt also elevates the OR of cardiac cancer (OR = 1.87). However, drinking green tea may decrease the ORs of esophageal and other gastric cancers (OR = 0.20 and OR = 0.28) while fruits consumption may reduce the OR of esophageal cancers (OR = 0.51).\n Tumors from upper digestive tract have some relations with diet factors but the effects vary with the differences of tumor sites, dose of exposure and area, etc.", "Tea consumption has been associated with decreased cardiovascular risk, but potential mechanisms of benefit are ill-defined. While epidemiologic studies suggest that drinking multiple cups of tea per day lowers low-density lipoprotein cholesterol (LDL-C), previous trials of tea drinking and administration of green tea extract have failed to show any impact on lipids and lipoproteins in humans. Our objective was to study the impact of a theaflavin-enriched green tea extract on the lipids and lipoproteins of subjects with mild to moderate hypercholesterolemia.\n Double-blind, randomized, placebo-controlled, parallel-group trial set in outpatient clinics in 6 urban hospitals in China. A total of 240 men and women 18 years or older on a low-fat diet with mild to moderate hypercholesterolemia were randomly assigned to receive a daily capsule containing theaflavin-enriched green tea extract (375 mg) or placebo for 12 weeks. Main outcome measures were mean percentage changes in total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglyceride levels compared with baseline.\n After 12 weeks, the mean +/- SEM changes from baseline in total cholesterol, LDL-C, HDL-C, and triglyceride levels were -11.3% +/- 0.9% (P =.01), -16.4% +/- 1.1% (P =.01), 2.3% +/- 2.1% (P =.27), and 2.6% +/- 3.5% (P =.47), respectively, in the tea extract group. The mean levels of total cholesterol, LDL-C, HDL-C, and triglycerides did not change significantly in the placebo group. No significant adverse events were observed.\n The theaflavin-enriched green tea extract we studied is an effective adjunct to a low-saturated-fat diet to reduce LDL-C in hypercholesterolemic adults and is well tolerated.", "Green tea (epigallocatechin gallate + caffeine) and protein each were shown to improve body weight maintenance after weight loss.\n We investigated the effect of a green tea-caffeine mixture added to a high-protein (HP) diet on weight maintenance (WM) after body weight loss in moderately obese subjects.\n A randomized, placebo-controlled, double-blind parallel trial was conducted in 80 overweight and moderately obese subjects [age (mean +/- SD): 44 +/- 2 y; body mass index (BMI; in kg/m(2)): 29.6 +/- 2.0] matched for sex, age, BMI, height, body mass, and with a habitually low caffeine intake. A very-low-energy diet intervention during 4 wk was followed by 3 mo of WM; during the WM period, the subjects received a green tea-caffeine mixture (270 mg epigallocatechin gallate + 150 mg caffeine/d) or placebo, both in addition to an adequate protein (AP) diet (50-60 g protein/d) or an HP diet (100-120 g protein/d).\n Subjects lost 7.0 +/- 1.6 kg, or 8.2 +/- 2.0%, body weight (P < 0.001). During the WM phase, WM, resting energy expenditure, and fat-free mass (FFM) increased relatively in both the HP groups and in the AP + green tea-caffeine mixture group (P < 0.05), whereas respiratory quotient and body fat mass decreased, all compared with the AP + placebo group. Satiety increased only in both HP groups (P < 0.05). The green tea-caffeine mixture was only effective with the AP diet.\n The green tea-caffeine mixture, as well as the HP diet, improved WM independently through thermogenesis, fat oxidation, sparing FFM, and, for the HP diet, satiety; a possible synergistic effect failed to appear.", "Nonexperimental studies suggest that individuals with higher selenium (Se) status are at decreased risk of cancer. The Nutritional Prevention of Cancer (NPC) study randomized 1,312 high-risk dermatology patients to 200-mcg/day of Se in selenized yeast or a matched placebo; selenium supplementation decreased the risk of lung, colon, prostate, and total cancers but increased the risk of nonmelanoma skin cancer. In this article, we report on a small substudy in Macon, GA, which began in 1989 and randomized 424 patients to 400-mcg/day of Se or to matched placebo. The subjects from both arms had similar baseline Se levels to those treated by 200 mcg, and those treated with 400-mcg attained plasma Se levels much higher than subjects treated with 200 mcg. The 200-mcg/day Se treatment decreased total cancer incidence by a statistically significant 25%; however, 400-mcg/day of Se had no effect on total cancer incidence.", "We report on the associations between the intake of certain foods and beverages and the incidence of gastric cancer in a cohort of 11,907 randomly selected Japanese residents of Hawaii (6297 women and 5610 men).\n The daily intake of six beverages, cigarettes and alcohol and the weekly frequency of intake of 13 foods and food groups was estimated with a short food frequency questionnaire. Over an average follow-up period of 14.8 years, 108 cases of gastric cancer (44 women, 64 men) were identified via linkage to the Hawaii Tumor Registry.\n In gender-combined proportional hazards analyses, the consumption of fresh fruit seven or more times per week was associated with a significantly reduced risk of gastric cancer, compared to lower levels of consumption (relative hazard (RH): 0.6, 95% confidence interval (CI): 0.4-1.0, P = 0.03). The combined intake of fresh fruit and raw vegetables was inversely associated with the risk of gastric cancer in the total cohort, and among the men (P < 0.05). No significant relationships were found between gastric cancer incidence and the intake of pickled vegetables, miso soup, dried or salted fish, or processed meats among either gender. Compared to non-drinkers, men who drank one cup of coffee per day had a significantly elevated risk of gastric cancer (RH: 2.5, 95% CI: 1.0-6.1, P = 0.05), but there was no evidence of a dose-response relationship. Cigarette smoking and consumption of alcohol were not related to gastric cancer, in analyses restricted to the men.\n The results related to fruit and vegetable intake are consistent with an anti-nitrosating effect of these foods, while the unexpected association between coffee consumption and gastric cancer is difficult to explain and may represent a chance finding.", "Investigation of the effect of a green tea-caffeine mixture on weight maintenance after body weight loss in moderately obese subjects in relation to habitual caffeine intake.\n A randomized placebo-controlled double blind parallel trial in 76 overweight and moderately obese subjects, (BMI, 27.5 +/- 2.7 kg/m2) matched for sex, age, BMI, height, body mass, and habitual caffeine intake was conducted. A very low energy diet intervention during 4 weeks was followed by 3 months of weight maintenance (WM); during the WM period, the subjects received a green tea-caffeine mixture (270 mg epigallocatechin gallate + 150 mg caffeine per day) or placebo.\n Subjects lost 5.9 +/-1.8 (SD) kg (7.0 +/- 2.1%) of body weight (p < 0.001). At baseline, satiety was positively, and in women, leptin was inversely, related to subjects' habitual caffeine consumption (p < 0.01). High caffeine consumers reduced weight, fat mass, and waist circumference more than low caffeine consumers; resting energy expenditure was reduced less and respiratory quotient was reduced more during weight loss (p < 0.01). In the low caffeine consumers, during WM, green tea still reduced body weight, waist, respiratory quotient and body fat, whereas resting energy expenditure was increased compared with a restoration of these variables with placebo (p < 0.01). In the high caffeine consumers, no effects of the green tea-caffeine mixture were observed during WM.\n High caffeine intake was associated with weight loss through thermogenesis and fat oxidation and with suppressed leptin in women. In habitual low caffeine consumers, the green tea-caffeine mixture improved WM, partly through thermogenesis and fat oxidation.", "nan", "Green tea catechins (GTCs) proved to be effective in inhibiting cancer growth in several experimental models. Recent studies showed that 30% of men with high-grade prostate intraepithelial neoplasia (HG-PIN) would develop prostate cancer (CaP) within 1 year after repeated biopsy. This prompted us to do a proof-of-principle clinical trial to assess the safety and efficacy of GTCs for the chemoprevention of CaP in HG-PIN volunteers. The purity and content of GTCs preparations were assessed by high-performance liquid chromatography [(-)-epigallocathechin, 5.5%; (-)-epicatechin, 12.24%; (-)-epigallocatechin-3-gallate, 51.88%; (-)-epicatechin-3-gallate, 6.12%; total GTCs, 75.7%; caffeine, <1%]. Sixty volunteers with HG-PIN, who were made aware of the study details, agreed to sign an informed consent form and were enrolled in this double-blind, placebo-controlled study. Daily treatment consisted of three GTCs capsules, 200 mg each (total 600 mg/d). After 1 year, only one tumor was diagnosed among the 30 GTCs-treated men (incidence, approximately 3%), whereas nine cancers were found among the 30 placebo-treated men (incidence, 30%). Total prostate-specific antigen did not change significantly between the two arms, but GTCs-treated men showed values constantly lower with respect to placebo-treated ones. International Prostate Symptom Score and quality of life scores of GTCs-treated men with coexistent benign prostate hyperplasia improved, reaching statistical significance in the case of International Prostate Symptom Scores. No significant side effects or adverse effects were documented. To our knowledge, this is the first study showing that GTCs are safe and very effective for treating premalignant lesions before CaP develops. As a secondary observation, administration of GTCs also reduced lower urinary tract symptoms, suggesting that these compounds might also be of help for treating the symptoms of benign prostate hyperplasia.", "A simultaneous case-control study on stomach cancer and colo-rectal cancer involving 93 cases with stomach cancer, 93 cases with colo-rectal cancer and 186 controls was conducted using a common questionnaire at the Aichi Cancer Center Hospital in 1981-83. A fondness for salty tastes, especially salted foods such as pickled hakusai (vegetable) and dried & salted fishes, which are typical traditional Japanese foods showed a significantly positive association with stomach cancer (relative risk(RR) = 2.60, P less than 0.01). On the other hand, the habit of eating a western-style breakfast, particularly for 10 years or more made a significant contribution to the risk of colon cancer (RR = 2.24, P less than 0.05) but conversely decreased the risk of stomach cancer (RR = 0.50, not significant (NS)) and rectal cancer (RR = 0.40, NS). In this study, relatively frequent intakes (4 times/week) of some vegetables, i.e. pumpkin, green pepper, onion and cabbage, showed high relative risks for both stomach and colon cancers, contrary to the findings of previous epidemiological studies. Cigarette smoking increased the risk of stomach cancer (RR = 1.99, NS) but decreased that of colon cancer (RR = 0.61, NS). There was no positive relation between drinking and cancer at any site. Some other factors with opposite effects on the two contrasting cancers and some independent factors were identified in this comparative case-control study.", "In vitro and in vivo laboratory data point to chemoprotective effects of flavonoids on colorectal cancer. However, there has been limited epidemiologic research on the dietary intake of flavonoids and risk of colorectal cancer. Recent expansions of dietary databases to include flavonoid data now make such studies feasible. Association between the six main classes of flavonoids and the risk of colorectal cancer was examined using data from a national prospective case-control study in Scotland, including 1,456 incident cases and 1,456 population-based controls matched on age, sex, and residence area. Dietary, including flavonoid data, were obtained from a validated, self-administered food frequency questionnaire. Risk of colorectal cancer was estimated using conditional logistic regression models in the whole sample and stratified by sex, smoking status, and cancer site and adjusted for established and putative risk factors. After energy adjustment, reductions in colorectal cancer risk associated with the highest quartiles of intake (versus the lowest quartile) were 27% for flavonols [odds ratio (OR), 0.73; P(trend) = 0.012], 32% for quercetin (OR, 0.68; P(trend) = 0.001), 32% for catechin (OR, 0.68; P(trend) < 0.0005); 26% for epicatechin (OR, 0.74; P(trend) = 0.019), and 22% for procyanidins (OR, 0.78; P(trend) = 0.031). The significant dose-dependent reductions in colorectal cancer risk that were associated with increased consumption of flavonols, quercetin, catechin, and epicatechin remained robust after controlling for overall fruit and vegetable consumption or for other flavonoid intake. The risk reductions were greater among nonsmokers, but no interaction beyond a multiplicative effect was present. Sex-specific or cancer-type differences were not observed. No risk reductions were associated with intake of flavones (P(trend) = 0.64), flavonones (P(trend) = 0.22), and phytoestrogens (P(trend) = 0.26). This was the first of several a priori hypotheses to be tested in this large study and showed strong and linear inverse associations of flavonoids with colorectal cancer risk.", "To examine the effect of green tea extract (GTE) on obese women and to explore the relationship between GTE and obesity-related hormone peptides.\n A randomized, double-blind, placebo-controlled clinical trial was conducted from July 2006 to June 2007 in Taipei Hospital, Taiwan. Seventy-eight of 100 obese women aged between 16 and 60 years with BMI>27 kg/m(2) and who had not received any other weight control maneuvers within the last 3 months completed this study. The subjects were randomly divided into Groups A and B. Group A (n=41) received GTE while Group B (n=37) took cellulose as a placebo, one capsule (400mg) three times each day for 12 weeks. The body weight (BW), body mass index (BMI) and waist circumflex (WC) were measured at the beginning of the study and after 12 weeks of treatment with GTE. The data were compared and expressed as % reduction.\n There was only a 0.3% reduction in BW (0.15 kg) after 12 weeks of treatment with GTE. There was no statistical difference in % reduction in BW, BMI and WC between the GTE and placebo groups. Within group comparison revealed that the GTE group had significant reduction in LDL-cholesterol and triglyceride, and marked increase in the level of HDL-cholesterol, adiponectin and ghrelin. On the other hand, the placebo group showed significant reduction in triglyceride only, and a marked increase in the level of ghrelin alone.\n This study showed no statistical difference in % reduction in BW, BMI and WC between the GTE and placebo groups after 12 weeks of treatment. The intake of GTE (491 mg catechins containing 302 mg EGCG) for 12 weeks is considered safe as shown by the results." ]	There is insufficient and conflicting evidence to give any firm recommendations regarding green tea consumption for cancer prevention. The results of this review, including its trends of associations, need to be interpreted with caution and their generalisability is questionable, as the majority of included studies were carried out in Asia (n = 47) where the tea drinking culture is pronounced. Desirable green tea intake is 3 to 5 cups per day (up to 1200 ml/day), providing a minimum of 250 mg/day catechins. If not exceeding the daily recommended allowance, those who enjoy a cup of green tea should continue its consumption. Drinking green tea appears to be safe at moderate, regular and habitual use.
CD005308	[ "14592306", "12684301", "9741373", "8681614" ]	[ "A prospective 8 week trial of nasal interfaces vs. a novel oral interface (Oracle) for treatment of obstructive sleep apnea hypopnea syndrome.", "Clinical outcomes related to interface type in patients with obstructive sleep apnea/hypopnea syndrome who are using continuous positive airway pressure.", "Comparison of nose and face mask CPAP therapy for sleep apnoea.", "Nasal-CPAP, surgery, and conservative management for treatment of obstructive sleep apnea syndrome. A randomized study." ]	[ "To compare efficacy, compliance rates, and side effects of a new strapless oral interface, the Oracle, with available nasal masks over 8 weeks of use for the treatment of obstructive sleep apnea hypopnea syndrome (OSAHS).\n A total of 38 patients with OSAHS (respiratory disturbance index (RDI) >/=15/h) were enrolled after the diagnostic polysomnogram for subsequent continuous positive airway pressure (CPAP) therapy. After randomization, therapeutic pressures during a titration study were determined for 21 patients in the oral group and 17 patients in the nasal group. Comparisons for nasal and oral interfaces were made for baseline patient characteristics, average hours of CPAP use, side effects from therapy, and among questionnaires evaluating patients' subjective responses to therapy at months 1 and 2.\n No significant difference was observed in the average hours of CPAP use between the oral (4.5+/-2.1; 5.5+/-2.6) and nasal groups (4.0+/-2.6; 4.8+/-2.5) for either month 1 or 2 (P>0.05). The dropout rates were similar for both groups after 8 weeks of therapy. However, patients in the nasal group had higher occurrences of side effects such as nasal congestion, dryness, and air leaks, whereas patients in the oral group experienced more oral dryness and gum pain.\n Oral delivery of CPAP with the Oracle is an effective and suitable alternative for patients with OSAHS.", "To evaluate the effect of interface on objective compliance, patient satisfaction, adverse effects, quality of life, and residual sleep-disordered breathing in patients with obstructive sleep apnea/hypopnea syndrome (OSAHS) using continuous positive airway pressure (CPAP).\n Randomized, cross-over.\n Two suburban community-based hospital sleep laboratories.\n Data were collected on 39 patients with OSAHS (mean age, 48.7 years), in whom CPAP was a novel treatment.\n Interventions were nasal pillows (Breeze; Mallinckrodt Corporation; Minneapolis, MN) and nasal mask (Contour; Respironics; Murrysville, PA).\n Outcomes assessed at the completion of each 3-week treatment period were objective compliance, adverse effects, and satisfaction with CPAP (CPAP questionnaire), daytime sleepiness (Epworth sleepiness scale [ESS]), quality of life (Functional Outcomes of Sleep Questionnaire [FOSQ]), sleep diary, and residual sleep-disordered breathing (apnea-hypopnea index [AHI]). Patients were randomly assigned to use the nasal pillows or the nasal mask following laboratory titration and initiated on CPAP (pressure range, 5 to 14 cm H(2)O). The percentage of days utilized favored the nasal pillows (94.1% vs 85.7%; p = 0.02), but minutes of use per night did not differ (nasal pillows, 223 min; nasal mask, 288 min). ESS scores were lower and the FOSQ total scores were higher following CPAP treatment (p < 0.001), but no differential treatment effects were noted. Fewer adverse effects, less trouble getting to sleep and staying asleep, and less air leak were reported with nasal pillows (p < 0.04). The mean +/- SD pretreatment AHI (47.1 +/- 35.1/h) was significantly lower following treatment with CPAP for both types of interface (nasal pillows, 10.2 +/- 9.8/h; nasal mask, 7.0 +/- 7.7/h; p < 0.001).\n Nasal pillows are a well-tolerated and effective interface for OSAHS patients receiving CPAP at < or = 14 cm H(2)O. Use of nasal pillows was associated with fewer adverse effects and better sleep quality during the first 3 weeks of CPAP therapy. Further investigation is needed to determine whether interface type affects long-term CPAP use.", "Many patients with sleep apnoea/hypopnoea syndrome (SAHS) find nasal continuous positive airway pressure (CPAP) treatment unsatisfactory due to side effects related to mouth air leakage. A study was performed to compare side effects with face mask and nose mask CPAP therapy in patients with SAHS, with and without uvulopalatopharyngoplasty (U3P).\n Twenty newly diagnosed patients with SAHS took part in a randomised double limb trial of face or nose mask CPAP therapy (four weeks per limb) in which CPAP compliance in terms of machine run time was measured and patients answered a symptom questionnaire on side effects resulting from the mask. Ten patients with SAHS with U3P (SAHS/U3P) who were already regular users of nasal CPAP were also given a four week trial of face mask CPAP to compare compliance and symptoms. Ten patients with SAHS were matched with the 10 SAHS/U3P patients for body mass index, age, apnoea/hypopnoea index, and CPAP pressure. Long term compliance was estimated one year after the mask comparison studies.\n For patients with SAHS nightly compliance was higher with a nose mask (mean (SE) 5.3 (0.4) hours/night CPAP) than with a face mask (4.3 (0.5) hours/night CPAP), p = 0.01 (mean difference 1.0 hour/night, 95% CI 1.8 to 0.3). Nose masks were rated more comfortable by 19 of 20 patients (p < 0.001) despite more mouth leak related symptoms. For SAHS/U3P patients compliance was marginally higher with nose masks (5.1 (0.7) hours/night CPAP) than with face masks (4.0 (0.8) hours/night CPAP), p = 0.07 (mean difference 1.1 hour/night, 95% CI 2.1 to 0.1). Nose masks were rated more comfortable by seven of 10 patients. There were no significant differences in side effect scores with face and nose masks. At one year nine of 10 SAHS patients and nine of 10 SAHS/U3P patients were still using CPAP. Compliance was 5.4 (0.6) hours/night for the SAHS patients and 3.5 (0.4) hours/night for the SAHS/U3P patients, p = 0.02 (mean difference 1.9 hour/night, 95% CI 3.6 to 0.3).\n Compliance is greater with nose mask CPAP than with face mask CPAP because the overall comfort is better and compensates for increased symptoms associated with mouth leakage. Improved face mask design is needed.", "To assess separately the effectiveness and safety of nasal-continuous positive airway pressure (N-CPAP) and that of surgery in comparison to conservative management in patients with obstructive sleep apnea syndrome (OSAS). DESIGN. A randomized study with 1-year follow-up.\n A university hospital acting as a referral center for OSAS.\n Symptomatic patients with OSAS (72 male and 4 female patients aged 18 to 65 years), who had oxygen desaturations in the overnight recording.\n After the initial diagnostic workup, patients were considered to be candidates for either N-CPAP (44 patients) or surgical treatment (uvulopalatopharyngoplasty [UPPP] with or without mandibular osteotomy) (32 patients). Within the groups, the patients were then randomized to either the assigned treatment or conservative management.\n The number of nocturnal oxygen desaturation events of 4% or more per hour in bed (ODI4); daytime somnolence; side effects.\n N-CPAP Group: Compliance with N-CPAP therapy at 1 year was 13 of 21. The most common reason for noncompliance was general intolerance of CPAP. All compliant patients had a normal ODI4 ( < 10), whereas 1 of 20 of their control subjects had a normal finding. Patients receiving active treatment were significantly less somnolent than their control subjects at 1 year (p < 0.05). SURGERY GROUP: At 1 year, 7 of 18 of the surgically treated and 1 of 14 of the conservatively treated patients had a normal ODI4 (p < 0.001). Daytime somnolence was significantly less severe in the surgically treated patients compared with their control subjects (p < 0.001) both at 3 and 12 months. The overall postoperative complication rate was 22%.\n N-CPAP is an effective therapy for OSAS, but compliance is a problem. Surgical therapy (UPPP with or without mandibular osteotomy) needs further evaluation." ]	Due to the limited number of studies available comparing various interface types, he optimum form of CPAP delivery interface remains unclear. The results of our review suggest that nasal pillows or the Oracle oral mask may be useful alternatives when a patient is unable to tolerate conventional nasal masks. The face mask can not be recommended as a first line interface, but may be considered if nasal obstruction or dryness limits the use of a nasal mask. Further randomised studies comparing the different forms of CPAP delivery interface now available for the treatment of OSA, in larger groups of patients and for longer durations, are required.
CD007434	[ "12694632", "19775439", "12014939", "9734786", "21924563", "14528540", "15066200", "15285276" ]	[ "Randomised controlled trial of a theoretically grounded tailored intervention to diffuse evidence-based public health practice [ISRCTN23257060].", "A randomized controlled trial evaluating the impact of knowledge translation and exchange strategies.", "General practitioners' use of magnetic resonance imaging: an open randomized trial comparing telephone and written requests and an open randomized controlled trial of different methods of local guideline dissemination.", "Using an office system intervention to increase breast cancer screening.", "Adoption, reach and effectiveness of computer-based, practitioner delivered and combined smoking interventions in general medical practices: a three-arm cluster randomized trial.", "The impact of tailored interventions on a community health center population.", "An outreach intervention to implement evidence based practice in residential care: a randomized controlled trial [ISRCTN67855475].", "A pilot study of mind-body changes in adults with asthma who practice mental imagery." ]	[ "Previous studies have shown that Norwegian public health physicians do not systematically and explicitly use scientific evidence in their practice. They work in an environment that does not encourage the integration of this information in decision-making. In this study we investigate whether a theoretically grounded tailored intervention to diffuse evidence-based public health practice increases the physicians' use of research information.\n 148 self-selected public health physicians were randomised to an intervention group (n = 73) and a control group (n = 75). The intervention group received a multifaceted intervention while the control group received a letter declaring that they had access to library services. Baseline assessments before the intervention and post-testing immediately at the end of a 1.5-year intervention period were conducted. The intervention was theoretically based and consisted of a workshop in evidence-based public health, a newsletter, access to a specially designed information service, to relevant databases, and to an electronic discussion list. The main outcome measure was behaviour as measured by the use of research in different documents.\n The intervention did not demonstrate any evidence of effects on the objective behaviour outcomes. We found, however, a statistical significant difference between the two groups for both knowledge scores: Mean difference of 0.4 (95% CI: 0.2-0.6) in the score for knowledge about EBM-resources and mean difference of 0.2 (95% CI: 0.0-0.3) in the score for conceptual knowledge of importance for critical appraisal. There were no statistical significant differences in attitude-, self-efficacy-, decision-to-adopt- or job-satisfaction scales. There were no significant differences in Cochrane library searching after controlling for baseline values and characteristics.\n Though demonstrating effect on knowledge the study failed to provide support for the hypothesis that a theory-based multifaceted intervention targeted at identified barriers will change professional behaviour.", "Significant resources and time are invested in the production of research knowledge. The primary objective of this randomized controlled trial was to evaluate the effectiveness of three knowledge translation and exchange strategies in the incorporation of research evidence into public health policies and programs.\n This trial was conducted with a national sample of public health departments in Canada from 2004 to 2006. The three interventions, implemented over one year in 2005, included access to an online registry of research evidence; tailored messaging; and a knowledge broker. The primary outcome assessed the extent to which research evidence was used in a recent program decision, and the secondary outcome measured the change in the sum of evidence-informed healthy body weight promotion policies or programs being delivered at health departments. Mixed-effects models were used to test the hypotheses.\n One hundred and eight of 141 (77%) health departments participated in this study. No significant effect of the intervention was observed for primary outcome (p < 0.45). However, for public health policies and programs (HPPs), a significant effect of the intervention was observed only for tailored, targeted messages (p < 0.01). The treatment effect was moderated by organizational research culture (e.g., value placed on research evidence in decision making).\n The results of this study suggest that under certain conditions tailored, targeted messages are more effective than knowledge brokering and access to an online registry of research evidence. Greater emphasis on the identification of organizational factors is needed in order to implement strategies that best meet the needs of individual organizations.\n The trial registration number and title are as follows: ISRCTN35240937 -- Is a knowledge broker more effective than other strategies in promoting evidence-based physical activity and healthy body weight programming?", "To determine the impact and cost-effectiveness of telephone versus written access to magnetic resonance imaging (MRI), and of different strategies for disseminating locally produced guidelines, upon requests by general practitioners (GPs) for knee and lumbar spine investigation.\n Two sequential pragmatic open cluster-randomized trials were conducted within 39 general practices. The outcome measure in each trial was concordance of request with local guidelines. Trial 1: practices requested MRI by telephone or in writing. Trial 2: all practices received guidelines, plus either: a practice-based seminar, practice-specific audit feedback, both seminar and feedback, or neither.\n A total of 414 requests were assessed in the two trials. Trial 1: telephone access cost pound4.86 more per request but rates of concordant requests were equivalent (65%/64%: telephone/written). Trial 2: compared to the control group, costs per practice were pound1911 higher in seminar group, pound1543 higher in feedback group and pound3578 higher for those receiving both. Concordance was greater following the intervention (74% vs 65%; P < 0.05), but there was no difference between the four study groups.\n Method of access did not affect concordance. Written access was more cost-effective. Seminars and feedback were no more effective in modifying practice than guidelines alone, which was thus the most cost-effective option.\n Copyright 2002 The Royal College of Radiologists.", "To evaluate an innovative approach to continuing medical education, an outreach intervention designed to improve performance rates of breast cancer screening through implementation of office systems in community primary care practices.\n Randomized, controlled trial with primary care practices assigned to either the intervention group or control group, with the practice as the unit of analysis.\n Twenty mostly rural counties in North Carolina.\n Physicians and staff of 62 randomly selected family medicine and general internal medicine practices, primarily fee-for-service, half group practices and half solo practitioners.\n Physician investigators and facilitators met with practice physicians and staff over a period of 12 to 18 months to provide feedback on breast cancer screening performance, and to assist these primary care practices in developing office systems tailored to increase breast cancer screening.\n Physician questionnaires were obtained at baseline and follow-up to assess the presence of five indicators of an office system. Three of the five indicators of office systems increased significantly more in intervention practices than in control practices, but the mean number of indicators in intervention practices at followup was only 2.8 out of 5. Cross-sectional reviews of randomly chosen medical records of eligible women patients aged 50 years and over were done at baseline (n = 2,887) and follow-up (n = 2,874) to determine whether clinical breast examinations and mammography, were performed. Results for mammography were recorded in two ways, mention of the test in the visit note and actual report of the test in the medical record. These reviews showed an increase from 39% to 51% in mention of mammography in intervention practices, compared with an increase from 41% to 44% in control practices (p = .01). There was no significant difference, however, between the two groups in change in mammograms reported (intervention group increased from 28% to 32.7%; control group increased from 30.6% to 34.0%, p = .56). There was a nonsignificant trend (p = .06) toward a greater increase in performance of clinical breast examination in intervention versus control practices.\n A moderately intensive outreach intervention to increase rates of breast cancer screening through the development of office systems was modestly successful in increasing indicators of office systems and in documenting mention of mammography, but had little impact on actual performance of breast cancer screening. At follow-up, few practices had a complete office system for breast cancer screening. Outreach approaches to assist primary care practices implement office systems are promising but need further development.", "Brief advice for smoking patients has not been sufficiently integrated in routine care. Computer-based interventions emerged as a time saving option that might help to exhaust the potential population impact of the general practice setting.\n 151 practices were randomly assigned to one of three intervention programs consisting in the delivery of: (1) brief advice by the practitioner; (2) individually tailored computer-generated letters; or (3) a combination of both interventions. We assessed three dimensions of population impact: (1) adoption, i.e., the rate of practices participating in the program; (2) reach, measured as the number of interventions provided within 7 months; (3) effectiveness, measured as smoking abstinence at 12-months follow-up.\n Among the practices, 70% adopted the program with no significant differences across study groups. Treatment was provided to 3086 adult smokers. Negative binomial regression analysis revealed that the number of interventions provided was higher in practices allocated to the tailored letter and combination intervention groups by 215% (p<.01) and 127% (p=.02), respectively, compared to the brief advice intervention group. Among the patients who received the combination of both intervention, the odds of point abstinence from smoking was increased by 65% (p=.02) and 32% (p=.01) compared to the brief advice and tailored letters intervention respectively. Comparing the number of abstinent patients at follow-up revealed that the tailored letter and combination interventions were superior to the brief advice intervention.\n Computer-based interventions alone or in addition to conventional practitioner-delivered advice can foster the participation of general medical practices in tobacco control.\n Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.", "We conducted a 4-year randomized study in a community health center that serves primarily low income Blacks in Durham, North Carolina. Patients (1318 at baseline) were assigned randomly to one of three study groups: provider prompting intervention alone, provider prompting and tailored print materials or the previous group and tailored telephone counseling. The purpose of the study was to determine whether increasingly intensive, tailored print and telephone interventions also were increasingly effective in promoting adherence to mammograms, Pap tests and overall cancer screening compliance. Thus, the combination of tailored print interventions (print and telephone) should have been more effective than the provider prompting intervention alone, or the print intervention and prompting combination. This is one of the few studies to examine a measure of overall cancer screening compliance and to assess the benefit of combinations of tailored interventions in promoting adherence to cancer screening. Patients gave extremely high ratings to the interventions. At the bivariate level, we found a significant effect of the most intensive group (provider prompting intervention, tailored print communications and tailored telephone counseling) on Pap test compliance (P = 0.05) and borderline significance at the multivariate level (P = 0.06) as well on overall screening compliance (P = 0.06). There was not a significant effect on mammography, probably because a majority of the patients were receiving regular mammograms. We also found some important subgroup differences. For example, a larger proportion of women reported Pap tests in the tailored print and counseling group when they believed the materials were 'meant for me.' These results show that a combination of tailored interventions may have potential for reaching the women who have too often been labeled the 'hard to reach.'", "The aim of this project was to assess whether outreach visits would improve the implementation of evidence based clinical practice in the area of falls reduction and stroke prevention in a residential care setting.\n Twenty facilities took part in a randomized controlled trial with a seven month follow-up period. Two outreach visits were delivered by a pharmacist. At the first a summary of the relevant evidence was provided and at the second detailed audit information was provided about fall rates, psychotropic drug prescribing and stroke risk reduction practices (BP monitoring, aspirin and warfarin use) for the facility relevant to the physician. The effect of the interventions was determined via pre- and post-intervention case note audit. Outcomes included change in percentage patients at risk of falling who fell in a three month period prior to follow-up and changes in use of psychotropic medications. Chi-square tests, independent samples t-test, and logistic regression were used in the analysis.\n Data were available from case notes at baseline (n = 897) and seven months follow-up (n = 902), 452 residential care staff were surveyed and 121 physicians were involved with 61 receiving outreach visits. Pre-and post-intervention data were available for 715 participants. There were no differences between the intervention and control groups for the three month fall rate. We were unable to detect statistically significant differences between groups for the psychotropic drug use of the patients before or after the intervention. The exception was significantly greater use of \"as required\" antipsychotics in the intervention group compared with the control group after the pharmacy intervention (RR = 4.95; 95%CI 1.69-14.50). There was no statistically significant difference between groups for the numbers of patients \"at risk of stroke\" on aspirin at follow-up.\n While the strategy was well received by the physicians involved, there was no change in prescribing patterns. Patient care in residential settings is complex and involves contributions from the patient's physician, family and residential care staff. The project highlights challenges of delivering evidence based care in a setting in which there is a paucity of well controlled trial evidence but where significant health outcomes can be attained.", "Despite the growing number of studies of imagery and the use of complementary and alternative modalities as treatments for asthma, research on mental imagery in adults with asthma is practically, nonexistent. The purpose of this feasibility study was to lay groundwork for a larger follow-up clinical trial.\n To determine whether pulmonary function, asthma symptoms, quality of life, depression, anxiety, and power differ over time in adults with asthma who do and do not practice mental imagery (MI). (Power is the ability to make aware choices with the intention of freely involving oneself in creating desired change.)\n Randomized controlled study using univariate repeated measures analysis of variance (ANOVA) and replacement through block design.\n Lenox Hill Hospital, an affiliate of New York University Medical School, New York, NY.\n Sixty-eight adults with symptomatic asthma, after 4 weeks of baseline data collection and analysis, met requirements for this randomized controlled study. Thirty-three completed pulmonary function as well as self-report tests at 4 time points over 17 weeks. The 16 experimental participants also completed the 4-session imagery protocol.\n Individual imagery instruction (week 1) and follow-up (weeks 4, 9, 15). Participants were given 7 imagery exercises to select from and practice 3 times a day for a total of 15 minutes.\n 1) Spirometry (FEV1); 2) medication use; 3) Asthma Quality of Life Questionnaire; 4) Beck Depression Inventory; 5) Spielberger Anxiety Scales (A-State and A-Trait); 6) Barrett Power as Knowing Participation in Change Tool, Version II; 7) Epstein Balloon Test of Ability to Image.\n There was little evidence of statistical change in this feasibility study; yet, valuable lessons were learned. Paired t-tests indicated there was a significant difference in the total power scores in the imagery group, and in the expected direction (two-tailed, t-statistic = -2.3, P = 0.035) and the choices sub-scale (two-tailed, tstatistic = -2.93, P = 0.01) of the power instrument from weeks one to 16 of the study. Eight of 17 (47%) participants in the MI group reduced or discontinued their medications. Three of 16 (19%) participants in the control group reduced their medications; none discontinued. Chi-square indicated differences between groups (X2 = 4.66, P = 0.05). Persons who reduced or discontinued their medications showed neither an increase in pulmonary function prior to medication discontinuation, nor a fall in these parameters following discontinuation.\n Findings related to major outcome measures must be viewed with caution due to the small sample size resulting from attrition related to labor intensiveness and, therefore, low statistical power. However, the study did provide significant data to plan a larger scale study of the use of mental imagery with adult asthmatics. The study also demonstrated that imagery is inexpensive, safe and, with training, can be used as an adjunct therapy by patients themselves. Its efficacy needs additional exploration. Further research for adults with asthma who practice imagery is important, as current treatments are not entirely efficacious. Lessons learned in this study may facilitate improvement in research designs." ]	Due to the limited nature of the available evidence and the mixed results that were found, no strong statements can be made about the effectiveness of communicating medical imaging results to change health behaviour. Only three trials in clinical populations were similar enough in term of setting, intervention and outcome to allow meta-analysis. We suggest, however, that targeted interventions using medical imaging technologies may be effective in certain contexts, or as applied to certain behaviours, but that this should be considered on an intervention by intervention basis, and not assumed as a general principle.
CD007545	[ "15786890", "14665488", "7841427", "3532585", "2516669", "7808991", "19017587", "10732934", "7548903", "9295239" ]	[ "Is the combination of pyrazinamide plus rifampicin safe for treating latent tuberculosis infection in persons not infected by the human immunodeficiency virus?", "Initial experience on rifampin and pyrazinamide vs isoniazid in the treatment of latent tuberculosis infection among patients with silicosis in Hong Kong.", "Rifabutin for the treatment of newly-diagnosed pulmonary tuberculosis: a multinational, randomized, comparative study versus Rifampicin. Rifabutin Study Group.", "[Daily ultrashort chemotherapy and intermittent short-term chemotherapy with 4 drugs of communicable pulmonary tuberculosis treated for the first time. Results of a cooperative multicenter study].", "Treatment of pulmonary tuberculosis with short course chemotherapy in south India--5-year follow up.", "[Compliance and tolerance of new antitubercular short-term chemopreventive regimens in childhood--a pilot project].", "Adverse events with 4 months of rifampin therapy or 9 months of isoniazid therapy for latent tuberculosis infection: a randomized trial.", "Rifampin and pyrazinamide vs isoniazid for prevention of tuberculosis in HIV-infected persons: an international randomized trial. Terry Beirn Community Programs for Clinical Research on AIDS, the Adult AIDS Clinical Trials Group, the Pan American Health Organization, and the Centers for Disease Control and Prevention Study Group.", "A pilot study of antituberculosis combinations comparing rifabutin with rifampicin in the treatment of HIV-1 associated tuberculosis. A single-blind randomized evaluation in Ugandan patients with HIV-1 infection and pulmonary tuberculosis.", "A trial of three regimens to prevent tuberculosis in Ugandan adults infected with the human immunodeficiency virus. Uganda-Case Western Reserve University Research Collaboration." ]	[ "Nine public health care centres in four Spanish cities.\n To evaluate the efficacy and safety of 2 months of rifampicin (R) plus pyrazinamide (Z) therapy (2RZ) compared with a 6-month course of isoniazid therapy (6H) for treating latent tuberculosis infection (LTBI).\n Multicentered, randomised, comparative and prospective trial conducted in HIV-seronegative contacts of infectious pulmonary TB cases.\n Of 352 individuals, 199 received 6H and 153 2RZ; 73% of contacts receiving 6H and 71% receiving 2RZ completed treatment (P = 0.73). Treatment interruption due to hepatotoxicity (ALT/AST > 5 times upper limit of normal) was observed in 10% of contacts in the 2RZ group and in 2.5% of the 6H group (P = 0.007). This higher than expected rate of hepatotoxicity in the 2RZ arm led to premature termination of the study. Severe or fatal liver injury was not detected. Liver function tests normalised after discontinuation of treatment. We conclude that the use of RZ should only be considered when other regimens are unsuitable and intensive monitoring of liver function is feasible.", "To compare the adverse effects and treatment adherence between 2 months of rifampin plus pyrazinamide (2RZ) and 6 months of isoniazid (6H).\n Patients with silicosis in Hong Kong are at high risk of acquiring tuberculosis. A previous study showed that treatment with 6H reduced the risk of silico-tuberculosis by one half.\n Patients with silicosis and a Mantoux skin test reaction > or =10 mm were randomized to receive either 2RZ or 6H daily. Liver function testing was done monthly during the initial 2 months. The adverse effects and treatment adherence were compared between the two regimens.\n Forty patients (mean age, 61.6 +/- 9.1 years) and 36 patients (mean age, 57.6 +/- 9.7 years) were randomized to the 2RZ and 6H arms, respectively (p > 0.05) [+/- SD]. Baseline characteristics were comparable. Nineteen patients in the 2RZ arm had peak alanine transaminase (ALT) levels > 1.5 times the upper limit of normal (ULN) in comparison with only five study subjects of the 6H arm (47.5% vs 13.9%, p < 0.01). Fourteen patients (35%) in the 2RZ arm and 1 patient (2.8%) in the 6H arm had peak ALT levels more than five times the ULN (p < 0.001). Only seven patients had symptoms suggestive of hepatitis; none of the patients had jaundice. All recovered after withholding treatment. In the 2RZ study arm, none of the baseline characteristics predicted hepatotoxicity. Other adverse effects were generally mild and comparable between both study arms. Treatment was stopped prematurely in 45% and 36.1% of patients in the 2RZ and 6H arms, respectively (p = 0.43). The main reasons were hepatotoxicity for the 2RZ arm and voluntary withdrawal after experiencing other minor adverse effects for the 6H arm.\n A higher incidence of hepatotoxicity was associated with rifampin plus pyrazinamide than isoniazid in the treatment of latent tuberculosis infection among patients with silicosis in Hong Kong.", "Patients with newly-diagnosed drug-sensitive, radiographically active and bacteriologically confirmed pulmonary tuberculosis recruited at 6 centres in Argentina, Brazil and Thailand.\n To assess the efficacy, tolerability and toxicity of two regimens containing different daily dosages of rifabutin in comparison with rifampicin.\n Multicentred, randomised, comparative study. In each group, study medications were administered daily for 6 months combined with isoniazid (6 months), and with pyrazinamide and ethambutol (both stopped after 2 months). Treatment success patients were followed-up for up to 2 years.\n A total of 520 patients were enrolled and randomly assigned to receive either rifampicin (n = 175), or rifabutin 150 mg (n = 174) or rifabutin 300 mg (n = 171). Considering all patients with positive baseline culture, the success rates at the last valid observation for each patient were 89%, 94% and 92% in the rifampicin, rifabutin 150 mg, and rifabutin 300 mg groups, respectively. The median time to culture conversion was comparable in the 3 groups and was 34 days for rifampicin and 37 days for each of the rifabutin groups. During the drug-free follow-up period, one relapse occurred in the rifampicin group, and two in each of the rifabutin groups. The 3 treatment schedules appeared well tolerated. No patients had to discontinue therapy because of an adverse event in the rifabutin 150 mg group, compared to one in the rifampicin and 5 in the rifabutin 300 mg group.\n All 3 regimens proved effective and well tolerated. Rifabutin at 150 mg/d showed the best risk-to-benefit ratio, in that this group had the highest proportion of patients completing treatment, the highest bacteriological conversion rates and the lowest incidence of adverse events.", "Three short-course regimens, all comprising isoniazide (H), rifampicine (R), streptomycine (S) and pyrazinamide (Z), are compared in a randomized prospective cooperative clinical trial. The drugs are given daily in a 3-month regimen (3-HRSZ), twice a week in a 6-month regimen (6-HRSZ2), and in a further two-phase 6-month regimen the 4 drugs are administered 3 times a week for the first 3 months followed by the administration of HSZ twice a week (without R) for further 3 months (3-HRSZ3/3-HSZ2). The number of patients admitted to study is 80, 144 and 139 respectively. The 3-month regimen has been stopped because of a high rate of relapses. 17 p.c. of the patients admitted have to be excluded from analysis for various reasons, out of these 5.8 p.c. because of adverse reactions. Two thirds of the patients had heavily positive sputum cultures at the start. 300 patients completed therapy. At the end of therapy cultures were negative in 94 p.c., 100 p.c. and 99 p.c. respectively. The rate of bacteriological relapses is 19 p.c. in 3-HRSZ, 9 p.c. in 3-HRSZ3/3-HSZ2 and 3 p.c. in 6-HRSZ2, during a follow-up period of 3-4 years after completing therapy. The acceptability was good in all treatment groups. Adverse reactions like \"flu\" were rarely observed. Increased blood urea was common but in general without clinical symptoms. Elevation of ALAT and ASAT was relatively frequent but mostly transient and without clinical importance. The results served as basis for the new \"Recommendation for Treatment of Tuberculosis\" and are interpreted with regard to practical consequences and possibilities for further rationalisation of treatment.", "A controlled clinical trial of three short-course chemotherapy regimens was undertaken in patients with newly diagnosed bacteriologically positive pulmonary tuberculosis. The patients were randomly allocated to receive one of three regimens: rifampicin, streptomycin, isoniazid and pyrazinamide daily for 2 months, followed by streptomycin, isoniazid and pyrazinamide twice weekly for 3 months (R/5) or for 5 months (R/7), or the same regimen as R/7 but without rifampicin (Z/7). A bacteriological relapse requiring retreatment occurred by 5 years in 7.1% of 126 R/5, 4.0% of 124 R/7 and 6.7% of 253 Z/7 patients with organisms initially sensitive to streptomycin and isoniazid; none of these differences is statistically significant. Of the 31 relapses, 16 occurred within 2 years of the completion of chemotherapy and the remaining 15 between 2 and 5 years. Among 65 patients with initial drug resistance to streptomycin or isoniazid or both, there were six bacteriological relapses requiring retreatment.", "Efficacy of preventive chemotherapy in tuberculosis-infected children depends to a great extend on medical compliance and drug tolerability. Two new short-course chemoprevention-regimes of tuberculosis--four months Rifampin (A) and two months Rifampin plus Pyrazinamide (B)--were compared with the well established regimen of six months Isoniacid (C). 150 children (mean age 3.6 years with Tb conversion) were randomly allocated to these three regimens. 13 patients were non-compliant, in terms of interview, urinary INH-test strips, urine colour and prescription frequency: 7 in group C and 3 in group A and B, respectively. Adverse effects were observed in 5 patients: 3 in group C and 1 in group A and B. 1 child (group B) developed tuberculosis two years after stopping short course chemoprevention. Good compliance (94%) as well as neglectable risks of adverse effects (2%) justify further controlled studies to evaluate the efficacy of short course chemoprevention in childhood.", "Treatment of latent tuberculosis infection with isoniazid for 9 months is complicated by poor patient adherence and the need for close follow-up of side effects, especially hepatotoxicity. Shorter and safer regimens are needed.\n To compare the frequency of adverse events and treatment completion in 2 treatment regimens for latent tuberculosis infection.\n Multicenter, randomized, open-label trial.\n Tuberculosis clinics located in university hospitals in Canada, Brazil, and Saudi Arabia.\n 847 patients without a contraindication for rifampin and requiring treatment for latent tuberculosis infection.\n Four months of daily rifampin therapy or 9 months of daily isoniazid therapy.\n Grade 3 to 4 drug-related adverse events resulting in drug discontinuation (primary outcome), and on-time treatment completion, grade 1 to 2 drug-related adverse events, and changes in liver enzymes and hematologic variables (secondary outcomes).\n Seventeen of 422 participants who started isoniazid therapy developed grade 3 to 4 adverse events compared with 7 of 418 who started rifampin therapy (risk difference [rifampin minus isoniazid], -2.3% [95% CI, -5% to -0.1%]; P = 0.040). Grade 3 or 4 hepatitis occurred in 16 of 422 isoniazid recipients compared with 3 of 418 rifampin recipients (risk difference, -3.1% [CI, -5% to -1%]; P = 0.003). Grade 1 or 2 adverse events attributed to study drugs occurred with similar frequency. Asymptomatic reduction in platelet and leukocyte counts were more frequent in rifampin recipients. More patients completed rifampin treatment (78%) than isoniazid treatment (60%) (difference, 18% [CI, 12% to 24%]; P < 0.001]).\n The study did not measure efficacy, and the open-label design may increase the chance of bias in ascertainment of adverse events.\n Treatment of latent tuberculosis with 4 months of rifampin leads to fewer serious adverse events and better adherence than 9 months of isoniazid. These findings justify a large-scale trial to compare the efficacy of rifampin with that of isoniazid.", "Because of problems with adherence, toxicity, and increasing resistance associated with 6- to 12-month isoniazid regimens, an alternative short-course tuberculosis preventive regimen is needed.\n To compare a 2-month regimen of daily rifampin and pyrazinamide with a 12-month regimen of daily isoniazid in preventing tuberculosis in persons with human immunodeficiency virus (HIV) infection.\n Randomized, open-label controlled trial conducted from September 1991 to May 1996, with follow-up through October 1997.\n Outpatient clinics in the United States, Mexico, Haiti, and Brazil.\n A total of 1583 HIV-positive persons aged 13 years or older with a positive tuberculin skin test result.\n Patients were randomized to isoniazid, 300 mg/d, with pyridoxine hydrochloride for 12 months (n = 792) or rifampin, 600 mg/d, and pyrazinamide, 20 mg/kg per day, for 2 months (n = 791).\n The primary end point was culture-confirmed tuberculosis; secondary end points were proven or probable tuberculosis, adverse events, and death, compared by treatment group.\n Of patients assigned to rifampin and pyrazinamide, 80% completed the regimen compared with 69% assigned to isoniazid (P<.001). After a mean follow-up of 37 months, 19 patients (2.4%) assigned to rifampin and pyrazinamide and 26 (3.3%) assigned to isoniazid developed confirmed tuberculosis at rates of 0.8 and 1.1 per 100 person-years, respectively (risk ratio, 0.72 [95% confidence interval, 0.40-1.31]; P = .28). In multivariate analysis, there were no significant differences in rates for confirmed or probable tuberculosis (P = .83), HIV progression and/or death (P = .09), or overall adverse events (P = .27), although drug discontinuation was slightly higher in the rifampin and pyrazinamide group (P = .01). Neither regimen appeared to lead to the development of drug-resistant tuberculosis.\n Our data suggest that for preventing tuberculosis in HIV-infected patients, a daily 2-month regimen of rifampin and pyrazinamide is similar in safety and efficacy to a daily 12-month regimen of isoniazid. This shorter regimen offers practical advantages to both patients and tuberculosis control programs.", "This pilot study was conducted at the Joint Clinical Research Centre (JCRC) in Kampala, Uganda, where tuberculosis (TB) is an epidemic health problem aggravated by the HIV-1 pandemic.\n To evaluate the feasibility of a larger phase III trial utilizing rifabutin as a substitute for rifampicin in short-course therapy for pulmonary TB.\n Single-blind randomized trial in 50 patients with new onset smear- and culture-positive pulmonary tuberculosis and HIV-1 infection. Comparison of daily, intermittently supervised 6-month treatment regimens of rifabutin versus rifampicin, together with isoniazid, ethambutol and pyrazinamide.\n Rifabutin- and rifampicin-containing regimens had comparable efficiency. However, rifabutin-treated patients had significantly more rapid clearance of acid-fast bacilli from sputum at 2 months (P < 0.05, Fisher exact test) and over the entire study period (P < 0.05, logrank test) than rifampicin-treated patients. The presence of cavitary disease was associated with a longer sputum conversion time for patients treated with either regimen. No major adverse events requiring dosage reduction or withdrawal of any study medication were seen in either treatment group. Mean absolute peripheral blood CD4 T lymphocyte counts increased by 28% from week 0 to week 12 in all subjects (334-427/microliters, respectively). An unexpected finding was the isolation of Mycobacterium africanum from 49% of the sputum cultures. This is the first report indicating a high prevalence of M. africanum in human TB in Uganda.\n Short-course antituberculosis regimens containing rifabutin or rifampicin are both safe and efficacious in the treatment of HIV-1 associated tuberculosis. Rifabutin-containing regimens were associated with earlier sputum smear and culture conversion.", "Infection with the human immunodeficiency virus (HIV) greatly increases the risk of reactivation tuberculosis. We evaluated the safety and efficacy of three preventive-therapy regimens in a setting where exposure to tuberculosis is common.\n We performed a randomized, placebo-controlled trial in 2736 HIV-infected adults recruited in Kampala, Uganda. Subjects with positive tuberculin skin tests (induration, > or =5 mm) with purified protein derivative (PPD) were randomly assigned to one of four regimens: placebo (464 subjects), isoniazid daily for six months (536), isoniazid and rifampin daily for three months (556), or isoniazid, rifampin, and pyrazinamide daily for three months (462). Subjects with anergy (0 mm induration in reaction to PPD and candida antigens) were randomly assigned to receive either placebo (323 subjects) or six months of isoniazid (395). The medications were dispensed monthly and were self-administered.\n Among the PPD-positive subjects, the incidence of tuberculosis in the three groups that received preventive therapy was lower than the rate in the placebo group (P=0.002 by the log-rank test). The relative risk of tuberculosis with isoniazid alone, as compared with placebo, was 0.33 (95 percent confidence interval, 0.14 to 0.77); with isoniazid and rifampin, 0.40 (0.18 to 0.86); and with isoniazid, rifampin, and pyrazinamide, 0.51 (0.24 to 1.08). Among the subjects with anergy, the relative risk of tuberculosis was 0.83 (95 percent confidence interval, 0.34 to 2.04) with isoniazid as compared with placebo. Side effects were more common with the multidrug regimens, and particularly with the regimen containing pyrazinamide. Survival did not differ among the groups, but the subjects with anergy had a higher mortality rate than the PPD-positive subjects.\n A six-month course of isoniazid confers short-term protection against tuberculosis among PPD-positive, HIV-infected adults. Multidrug regimens with isoniazid and rifampin taken for three months also reduce the risk of tuberculosis." ]	Trials to date of shortened prophylactic regimens using rifampicin alone have not demonstrated higher rates of active TB when compared to longer regimens with INH. Treatment completion is probably higher and adverse events may be fewer with shorter rifampicin regimens. Shortened regimens of rifampicin with INH may offer no advantage over longer INH regimens. Rifampicin combined with pyrazinamide is associated with more adverse events. A weekly regimen of rifapentine plus INH has higher completion rates, and less liver toxicity, though treatment discontinuation due to adverse events is probably more likely than with INH.
CD000333	[ "7710725", "1922205", "19452097", "12844212", "1435170", "16826020", "11149482", "17768587", "15889312", "2671517", "15129394", "8369985", "12879220", "11484097", "8931030", "12585781", "7990242", "17291843", "20101013", "12110425", "8213255", "15536539", "12510818", "1566165", "19521657", "8675921", "17613583", "21060992", "1611221", "15040821", "12919708", "19483372", "20220537", "19252142", "12525233", "9271287", "15774341", "16133653", "12663301", "10690445" ]	[ "Therapeutic exercise in the prevention of bone loss. A controlled trial with women after menopause.", "Prevention of postmenopausal osteoporosis. A comparative study of exercise, calcium supplementation, and hormone-replacement therapy.", "[Effects of a combined weight-bearing and non-weight-bearing ( warm water) exercise program on bone mass and quality in postmenopausal women with low bone-mineral density].", "Effects of exercise on bone mineral density in calcium-replete postmenopausal women with and without hormone replacement therapy.", "Bone density in postmenopausal women: high impact vs low impact exercise.", "Effect of exercise on bone mineral density and lean mass in postmenopausal women.", "Resistance training over 2 years increases bone mass in calcium-replete postmenopausal women.", "Physical training preserves bone mineral density in postmenopausal women with forearm fractures and low bone mineral density.", "Effect of impact exercise on bone mineral density in elderly women with low BMD: a population-based randomized controlled 30-month intervention.", "Efficacy of nonloading exercises in prevention of vertebral bone loss in postmenopausal women: a controlled trial.", "A randomized, prospective study of the effects of Tai Chi Chun exercise on bone mineral density in postmenopausal women.", "The effects of walking at the anaerobic threshold level on vertebral bone loss in postmenopausal women.", "Efficacy of home-based exercise for improving quality of life among elderly women with symptomatic osteoporosis-related vertebral fractures.", "Effect of exercise training and detraining on bone mineral density in postmenopausal women with osteoporosis.", "The effects of a community exercise program on fracture risk factors in older women.", "Effects of exercise on bone density, balance, and self-efficacy in older women.", "Effects of high-intensity strength training on multiple risk factors for osteoporotic fractures. A randomized controlled trial.", "The effects of hormone replacement therapy and resistance training on spine bone mineral density in early postmenopausal women.", "Exercise effects on bone mineral density, falls, coronary risk factors, and health care costs in older women: the randomized controlled senior fitness and prevention (SEFIP) study.", "Change in bone mass distribution induced by hormone replacement therapy and high-impact physical exercise in post-menopausal women.", "Effects of aerobic training on bone mineral density of postmenopausal women.", "Physical training and hormone replacement therapy reduce the decrease in bone mineral density in perimenopausal women: a pilot study.", "Regional specificity of exercise and calcium during skeletal growth in girls: a randomized controlled trial.", "The effect of high-intensity trunk exercise on bone mineral density of postmenopausal women.", "Unipedal standing exercise and hip bone mineral density in postmenopausal women: a randomized controlled trial.", "Impact of a 12-month exercise program on the physical and psychological health of osteopenic women.", "Effects of exercise and nutrition on postural balance and risk of falling in elderly people with decreased bone mineral density: randomized controlled trial pilot study.", "Effect of exercise on mobility, balance, and health-related quality of life in osteoporotic women with a history of vertebral fracture: a randomized, controlled trial.", "The effects of calcium supplementation and exercise on bone density in elderly Chinese women.", "Prevention of postmenopausal bone loss by a low-magnitude, high-frequency mechanical stimuli: a clinical trial assessing compliance, efficacy, and safety.", "Effect of alendronate and exercise on bone and physical performance of postmenopausal women: a randomized controlled trial.", "Effects on balance, falls, and bone mineral density of a home-based exercise program without home visits in community-dwelling elderly women: a randomized controlled trial.", "Effect of exercise and Cimicifuga racemosa (CR BNO 1055) on bone mineral density, 10-year coronary heart disease risk, and menopausal complaints: the randomized controlled Training and Cimicifuga racemosa Erlangen (TRACE) study.", "Strength training preserves the bone mineral density of postmenopausal women without hormone replacement therapy.", "Effect of exercise on total and intra-abdominal body fat in postmenopausal women: a randomized controlled trial.", "Randomized placebo-controlled trial of brisk walking in the prevention of postmenopausal osteoporosis.", "A pilot study of a supervised group exercise programme as a rehabilitation treatment for women with breast cancer receiving adjuvant treatment.", "A 1-year combined weight-bearing training program is beneficial for bone mineral density and neuromuscular function in older women.", "Effect of a calcium and exercise intervention on the bone mineral status of 16-18-y-old adolescent girls.", "Effects of one year of resistance training on the relation between muscular strength and bone density in elderly women." ]	[ "To evaluate the efficacy of therapeutic exercises in the prevention of bone loss, 146 untrained healthy postmenopausal women were prospectively controlled for (mean +/- SD) 3.0 +/- 1.3 yr. Eighty-two subjects aged (mean +/- SD) 61.5 +/- 6.1 yr participated in an exercise program (group 1) and sixty-four aged (mean +/- SD) 59.1 +/- 7.4 yr served as controls (group 2). Periodically during the study period, we measured women's bone density at two forearm sites and recorded their physical activities. Because bone loss differed insignificantly between the groups, group 1 was retrospectively subdivided into group 1a (regular exercise) and group 1b (nonregular exercise). The results showed that only 39 women (48 percent) of group 1 (group 1a) performed the exercise program regularly for the prescribed time. Regression slopes of forearm bone density (distal and proximal scans) v time were significantly less negative (P < 0.05) in group 1a (distal, -0.3 percent and proximal, -0.7 percent per year) than in group 1b (distal, -1.8 percent and proximal -1.6 percent per year) or group 2 (distal, -1.7 percent and proximal, -1.9 percent per year). We conclude that in untrained elderly women, poor compliance with regular physical activities is a main factor, explaining the lack of response to exercise treatment in prevention of osteoporosis.", "Osteoporosis among older women is a major public health problem. We studied the effects of three approaches to the prevention of osteoporosis in women with low bone density.\n One hundred twenty postmenopausal women (mean [+/- SD] age, 56 +/- 4) who were selected because they had low forearm bone density were enrolled in a double-blind, placebo-controlled, randomized study comparing the effects of an exercise regimen (exercise group, n = 41), exercise plus dietary calcium supplementation (exercise-calcium group, n = 39), and exercise plus continuous replacement of estrogen and progesterone (exercise-estrogen group, n = 40). Periodically during the two-year study period, we measured the women's bone density at three forearm sites, measured indexes of calcium metabolism, and recorded symptom scores. A comparison group of 42 women (mean age, 55.5 +/- 3.1) with normal bone density was also followed for two years.\n Significant bone loss in the distal forearm occurred in the group with normal bone density (control group) and the exercise group (change, -2.7 percent and -2.6 percent of the base-line value per year, respectively). Bone loss at the distal forearm site was significantly lower in the exercise-calcium group (-0.5 percent of the base-line value per year), and bone density increased at this site in the exercise-estrogen group (+2.7 percent of the base-line value per year). Bone loss at the median forearm site was significantly lower in the exercise-calcium group (-1.3 percent of the base-line value per year) than in the exercise group (-2.4 percent), and bone density at this site increased significantly in the exercise-estrogen group (+0.8 percent of the base-line value per year). Breast tenderness occurred in 47 percent of the women in the exercise-estrogen group but in only 20 percent in the other two treatment groups. Vaginal bleeding occurred at some time in 52 percent of the women who had not had a hysterectomy in the exercise-estrogen group, as compared with 11 percent and 12.5 percent, respectively, in the exercise and exercise-calcium groups.\n In postmenopausal women with low bone density, bone loss can be slowed or prevented by exercise plus calcium supplementation or estrogen-progesterone replacement. Although the exercise-estrogen regimen was more effective than exercise and calcium supplementation in increasing bone mass, it also caused more side effects.", "To evaluate the effects of a combined weight- and non weight-bearing (water) exercise program on bone mass and quality in postmenopausal women with low bone mineral density.\n 125 post-menopausal women with osteopenia/osteoporosis underwent a bone mass (Dual-Energy X-ray Absorbimetry, DEXA) and bone tissue quality (phalangeal osteosonography) evaluation. 58 of the participants took part in an 11-month specific exercise program (E). The other represented a control group (C) that did not exercise. At the end of the exercise program all the participants were re-evaluated.\n Concerning bone mass, within and between groups data analysis showed that t-score, measured at neck of femur, significantly increased in E (p < 0.05). No differences were instead detected for all the other parameters. With respect to osteosonography, group C showed a significant decrease of all bone quality parameters (p < 0.05), whereas E showed no differences after the exercise program.\n The results showed that a specific exercise program targeting osteoporosis is useful to reduce the physiological bone loss and to maintain a good bone quality in a group of postmenopausal women with low bone mineral density.", "Osteoporosis is a major public health concern. The combination of exercise, hormone replacement therapy, and calcium supplementation may have added benefits for improving bone mineral density compared to a single intervention. To test this notion, 320 healthy, non-smoking postmenopausal women, who did or did not use hormone replacement therapy (HRT), were randomized within groups to exercise or no exercise and followed for 12 months. All women received 800 mg calcium citrate supplements daily. Women who exercised performed supervised aerobic, weight-bearing and weight-lifting exercise, three times per week in community-based exercise facilities. Regional bone mineral density (BMD) was assessed by dual energy X-ray absorptiometry. Women who used HRT, calcium, and exercised increased femoral neck, trochanteric and lumbar spine bone mineral density by approximately 1-2%. Trochanteric BMD was also significantly increased by approximately 1.0% in women who exercised and used calcium without HRT compared to a negligible change in women who used HRT and did not exercise. The results demonstrate that regional BMD can be improved with aerobic, weight-bearing activity combined with weight lifting at clinically relevant sites in postmenopausal women. The response was significant at more sites in women who used HRT, suggesting a greater benefit with hormone replacement and exercise compared to HRT alone.", "This 1 year study examined the effect of high impact and low impact activities on bone mineral density (BMD) at the lumbar vertebrae (L2-L4) in healthy, sedentary, early postmenopausal women. Fifteen subjects whose postmenopausal status was verified by the blood levels of follicle stimulating hormone (FSH) and estradiol were chosen. These subjects were tested on the following variables: BMD via dual photon absorptiometry, heart rate response to the Balke treadmill test, percent fat via skinfolds, and a 3-d dietary analysis. Subjects were matched and then assigned randomly to one of three groups: (a) a control nonexercising group, (b) a low impact exercise group, and (c) a high impact exercise group. The control nonexercising group experienced a significant linear decrease in BMD during the study (F = 12.63, P = 0.002). Both the low and high impact exercise groups maintained BMD during the study (F = 0.04, P = 0.85; F = 1.08, P = 0.31, respectively). The difference in BMD between the low impact and the high impact exercise groups was not significant (F = 0.36, P = 0.55). In conclusion, 20 min of moderate intensity low impact or high impact exercise 3 d.wk-1 for 1 yr is effective in maintaining BMD in early postmenopausal women.", "To evaluate the effects of physical activity on bone mineral density, bone mineral content, and lean mass in postmenopausal, overweight/obese women.\n We conducted a 12-month randomized controlled aerobic exercise intervention versus control in 173 sedentary, overweight/obese, postmenopausal women, aged 50-75 yr. The exercise prescription consisted of >or=45 min of moderate-intensity aerobic exercise (60-75% of maximal heart rate), 5 d.wk for 12 months. Control participants attended 45-min stretching sessions once a week. Ninety-eight percent (N=170) completed the trial. Exercisers averaged 172 min.wk (SD=89) of exercise and expended 3828 kJ.wk (SD=2053). We assessed body fat, total lean mass, and total body bone mineral density and content using dual-energy x-ray absortiometry (DXA). We compared baseline with 12-month changes in exercisers versus controls.\n Exercisers lost significantly more weight than stretchers (1.3-kg loss vs 0.1-kg gain, P=0.01). However, no differences between exercisers and controls in the change from baseline to 12 months were detected: exercisers' average bone mineral density increased by 0.005 g.cm and controls' by 0.003 g.cm (P=0.61). Similarly, no significant differences were detected for bone mineral content. Lean mass increased by 0.2 kg in both groups (P=0.84).\n Overall, the results from this randomized controlled study suggest that a yearlong moderate-intensity aerobic exercise intervention does not affect total body bone mineral density, bone mineral content, or lean mass in overweight/obese postmenopausal women.", "Understanding the stress/strain relationship between exercise and bone is critical to understanding the potential benefit of exercise in preventing postmenopausal bone loss. This study examined the effect of a 2-year exercise intervention and calcium supplementation (600 mg) on bone mineral density (BMD) in 126 postmenopausal women (mean age, 60 +/- 5 years). Assignment was by block randomization to one of three groups: strength (S), fitness (F), or nonexercise control (C). The two exercise groups completed three sets of the same nine exercises, three times a week. The S group increased the loading, while the F group had additional stationary bicycle riding with minimal increase in loading. Retention at 2 years was 71% (59% in the S group, 69% in the F group, and 83% in the C group), while the exercise compliance did not differ between the exercise groups (S group, 74 +/- 13%; F group, 77 +/- 14%). BMD was measured at the hip, lumbar spine, and forearm sites every 6 months using a Hologic 4500. Whole body BMD also was measured every 6 months on a Hologic 2000. There was no difference between the groups at the forearm, lumbar spine, or whole body sites. There was a significant effect of the strength program at the total (0.9 +/- 2.6%; p < 0.05) and intertrochanter hip site (1.1 +/- 3.0%; p < 0.01). There was a significant time and group interaction (p < 0.05) at the intertrochanter site by repeated measures. This study shows the effectiveness of a progressive strength program in increasing bone density at the clinically important hip site. We concluded that a strength program could be recommended as an adjunct lifestyle approach to osteoporosis treatment or used in combination with other therapies.", "One hundred and twelve postmenopausal women with low bone mineral density (BMD) and forearm fractures were randomized to physical training or control group. After one year the total hip BMD was significantly higher in the women in the physical training group. The results indicate a positive effect of physical training on BMD in postmenopausal women with low BMD.\n The fivefold increase in hip fracture incidence since 1950 in Sweden may partially be due to an increasingly sedentary lifestyle. Our hypothesis was that physical training can prevent bone loss in postmenopausal women.\n One hundred and twelve postmenopausal women 45 to 65 years with forearm fractures and T-scores from -1.0 to -3.0 were randomized to either a physical training or control group. Training included three fast 30-minute walks and two sessions of one-hour training per week. Bone mineral density (BMD) was measured in the hip and the lumbar spine at baseline and after one year.\n A per protocol analysis was performed, including 48 subjects in the training group and 44 subjects in the control group. The total hip BMD increased in the training group +0.005 g/cm2 (+/-0.018), +0.58%, while it decreased -0.003 g/cm2 (+/-0.019), -0.36%, (p = 0.041) in the control group. No significant effects of physical training were seen in the lumbar spine. A sensitivity intention to treat analysis, including all randomized subjects, showed no significant effect of physical training on BMD at any site.\n The results indicate a small but positive effect of physical exercise on hip BMD in postmenopausal women with low BMD.", "Evidence of the effect of exercise on bone loss comes mainly from studies in voluntary postmenopausal women, and no population-based, long-term interventions have been performed. The purpose of this population-based, randomized, controlled trial was to determine the effect of long-term impact exercise on bone mass at various skeletal sites in elderly women with low bone mineral density (BMD) at the radius and hip. Participants (n=160) were randomly assigned to 30 months either of supervised and home-based impact exercise training or of no intervention. The primary outcome measures were femoral neck, trochanter and total hip BMD, and the secondary outcomes were bone density measures at the radius and calcaneum. Outcomes were assessed at baseline, 12 months and 30 months using blinded operators. The analyses were performed on an intention-to-treat analysis. Mean femoral neck and trochanter BMD decreased in the control group [-1.1%, 95% confidence interval (CI) -0.1% to -2.1% and -1.6%, 95% CI -0.4% to -2.7%], while no change occurred in the exercise group. Mean trochanter BMC decreased more in the control group (-7.7%, 95% CI -9.7% to -5.6% vs. -2.9%, 95% CI -5.3 to -0.9). There were six falls that resulted in fractures in the exercise group and 16 in the control group during the 30-month intervention (P=0.019). A significant bone loss occurred in both groups at the radius and calcaneum. In multivariate analysis, weight gain was associated with increased BMD and BMC at all femur sites both in the exercise group and in the pooled groups. In conclusion, impact exercise had no effect on BMD, while there was a positive effect on BMC at the trochanter. Exercise may prevent fall-related fractures in elderly women with low bone mass.", "A considerable increase in muscle strength and bone mass can be achieved in young adults through athletic exercise programs. We studied a less demanding nonloading exercise program for the back extensor muscles in postmenopausal women who were not on estrogen therapy. We randomly assigned 65 healthy Caucasian women without evidence of or risk factors for osteoporosis into an exercise group and a control group. The strength of the back extensor muscles and bone mineral density of the lumbar spine were measured at baseline and every 6 months for 2 years. In addition, a physical activity score was determined. Compliance was assessed by regular interviews and review of diaries. During the 2-year study, the mean rates of bone loss in the two groups were not statistically different. The strength of the back extensor muscles increased in both groups but significantly more (P = 0.002) in the exercise group. We conclude that postmenopausal bone loss is unaffected by a modest exercise program despite an increase in muscle strength. Nonloading muscle exercise may be ineffective in retarding vertebral bone loss in ambulatory, healthy postmenopausal women.", "To evaluate the potential benefits of programmed Tai Chi Chun (TCC) exercise on the weight-bearing bones of early postmenopausal women.\n Age-matched and randomized prospective intervention.\n University medical school.\n One hundred thirty-two healthy postmenopausal women (mean age, 54.0+/-3.5y) within 10 years of menopause onset were recruited and randomized into the TCC exercise group (n=67) or the sedentary control group (n=65).\n Supervised TCC exercise was performed by the TCC group for 45 minutes a day, 5 days a week, for 12 months; control subjects retained a sedentary life style. Main outcome measures Bone mineral density (BMD) was measured in the lumbar spine and proximal femur by using dual-energy x-ray absorptiometry and in the distal tibia by using multislice peripheral quantitative computed tomography (pQCT). All BMD measurements were repeated after 12 months in both groups. Fracture rate was also documented.\n Baseline measurements showed homogeneity in age, anthropometric variables, and menstruation status between the TCC and control groups. Exactly 81.6% of the subjects in the TCC group and 83.1% of subjects in the control group completed the 12-month follow-up study. BMD measurements revealed a general bone loss in both TCC and sedentary control subjects at all measured skeletal sites, but with a reportedly slower rate in the TCC group. A significant 2.6- to 3.6-fold retardation of bone loss (P<.01) was found in both trabecular and cortical compartments of the distal tibia in the TCC group as compared with the controls, as measured by pQCT. A total of 4 fracture cases were documented during follow-up, including 3 subjects in the control group and 1 in the TCC group.\n This is the first prospective and randomized study to show that a programmed TCC exercise intervention is beneficial for retarding bone loss in weight-bearing bones in early postmenopausal women. Long-term follow-up is needed to substantiate the role of TCC exercise in the prevention of osteoporosis and its related fracture.", "The purpose of this study was to determine the optimal intensity of exercise necessary to prevent the postmenopausal bone loss on the basis of anaerobic threshold (AT). Thirty-three postmenopausal women were randomized to control (group C: n = 12) or two exercise groups (group H and group M). All women performed a treadmill exercise test, and the AT was measured by expired gas analysis. The exercise regimen consisted mainly of walking at a speed that kept the exercise heart rate above the AT (group H: n = 12) or below the AT (group M: n = 9). Exercise was performed for 30 minutes, three times a week for 7 months. The bone mineral density (BMD) of the lumbar vertebrae was measured using dual energy X-ray absorptiometry. The BMD level in group C decreased by 1.7 +/- 2.7%, but there was a significant increase of 1.1 +/- 2.9% in group H. In group M there was a decrease of 1.0 +/- 3.1% which did not differ from group C. In group C, serum osteocalcin and urinary hydroxyproline excretion were significantly increased, but no changes were seen in either of the exercise groups. Urinary calcium significantly decreased in the exercise groups. We conclude that short-term (7 months) exercise with intensity above the AT is safe and effective in preventing postmenopausal bone loss.", "This randomized controlled trial was designed to investigate the effect of a 6-month home-based exercise program versus control (usual activities) on quality of life for postmenopausal women with osteoporosis who had at least one vertebral fracture. Twelve-month assessments of outcomes were completed to determine if women would continue exercising with minimal supervision and if benefit could be sustained. The home exercise program followed a \"lifestyle exercise\" approach where participants completed exercises 60 min per day, 3 days a week and could complete exercises in small periods of time throughout the day. Exercise activities included stretching, strength training and aerobics (i.e. walking). Participants were assessed at baseline, 6 months, and 12 months using the Osteoporosis Quality of Life Questionnaire (OQLQ), the Sickness Impact Profile (SIP), a balance test, and the Timed Up And Go test. Bone mineral density was assessed at baseline and 12 months for both the lumbar spine and femoral neck. Quality of life (OQLQ) improved over 6 months in the exercise group compared to the control group in the domains of symptoms (P=0.003), emotion (P=0.01) and leisure (P=0.03). Results from the balance test indicated a greater effect in the exercise group over 12 months (P<0.05). There were no significant differences between groups in measures of Timed Up and Go, SIP at 6 and 12 months, and femoral neck and lumbar spine bone mineral density at 12 months. Home-based exercise with minimal supervision improves quality of life in elderly women with vertebral fractures. Future research is needed to determine if home exercise programs reduce falls and fall-related injuries in the elderly.", "We examined the effect of exercise training and detraining on bone mineral density (BMD) in postmenopausal women with osteoporosis. Thirty-five postmenopausal women with osteoporosis, aged 53-77 years, were randomly assigned to three groups: a control group (n = 20), a 2-year exercise training group (n = 8), and an 1-year exercise training plus 1-year detraining group (n = 7). Exercise training consisted of daily brisk walking and gymnastic training. Calcium lactate, 2.0 g, and 1alpha-hydroxyvitamin D3, 1 microg were supplied daily to all subjects. No significant differences in initial lumbar BMD, measured by dual-energy X-ray absorptiometry (DXA) were found among the three groups. The mean percent change in BMD compared with the baseline was significantly higher at 1 and 2 years in the exercise training group and at 1 year in the detraining group than in the control group, and did not differ significantly at 2 years between the detraining and control groups. These findings indicate that our exercise training program led to a significant increase in lumbar BMD in postmenopausal women with osteoporosis compared with the control, but that the BMD reverted toward a level that was not significantly different from the control with detraining. Continued exercise training is needed to maintain the bone mass gained through exercise training.", "One hundred and seventy-nine women aged 60-85 years (mean age 71.6 years, SD 5.3 years) were randomly recruited from the community to participate in a 12-month randomized controlled trial to determine whether a program of twice-weekly structured exercise has beneficial effects on three factors associated with osteoporotic fractures: quadriceps strength, postural sway and bone density. At initial testing, there were no significant differences in the strength, sway and bone density measures (assessed at the hip and lumbar spine) between the exerciser and control groups. The exercise classes included strengthening, coordination and balance exercises, and approximately 35 min of each class comprised weight-bearing exercise. The mean number of classes attended for the 68 exercisers who completed the program was 59.8 of the 82 classes (72.9%). At the completion of the trial, the intervention group showed significant improvements in quadriceps strength and sway but not bone mineral density when compared with the control group. Indices of fracture risk, indicated by (i) the sum of standard score results and (ii) the sum of quartile grades of the femoral neck bone density, sway and strength measures, decreased significantly in the exercisers at the end of the trial compared with the controls. In conclusion, the program of general aerobic exercise may have reduced overall fracture risk, even though it did not significantly increase bone density. Further long-term studies are required that include acceptable weight-loaded exercises to determine optimal programs for reducing fracture risk factors by improving bone density as well as strength and balance.", "The effects of weighted vest walking and strength-training exercises on bone mineral density (BMD), balance, strength, and self-efficacy were tested in older women. Eighteen women, age 69.2 +/- 3.5 years, were randomly assigned to an exercise group (EG) (n = 9), or a sedentary control group (CG) (n = 9). The EG participated in 32 weeks (three 1-h sessions/week) of supervised strength training and walking, stair climbing, and balance exercises while wearing weighted vests. The CG did not exercise. All women took Ca2+ and vitamin D during the study period. Measures included 1) BMD of the hip and lumbar spine measured by dual-energy X-ray absorptiometry, 2) strength, 3) balance, and 4) scores on a self-efficacy instrument. The EG had significant improvements in bone density of the femoral neck and balance and a significant weight loss (P < 0.05). There were no changes in self-efficacy in either group.", "To determine how multiple risk factors for osteoporotic fractures could be modified by high-intensity strength training exercises in postmenopausal women.\n Randomized controlled trial of 1-year duration.\n Exercise laboratory at Tufts University, Boston, Mass.\n Forty postmenopausal white women, 50 to 70 years of age, participated in the study; 39 women completed the study. The subjects were sedentary and estrogen-deplete.\n High-intensity strength training exercises 2 days per week using five different exercises (n = 20) vs untreated controls (n = 19).\n Dual energy x-ray absorptiometry for bone status, one repetition maximum for muscle strength, 24-hour urinary creatinine for muscle mass, and backward tandem walk for dynamic balance.\n Femoral neck bone mineral density and lumbar spine bone mineral density increased by 0.005 +/- 0.039 g/cm2 (0.9% +/- 4.5%) (mean +/- SD) and 0.009 +/- 0.033 g/cm2 (1.0% +/- 3.6%), respectively, in the strength-trained women and decreased by -0.022 +/- 0.035 g/cm2 (-2.5% +/- 3.8%) and -0.019 +/- 0.035 g/cm2 (-1.8% +/- 3.5%), respectively, in the controls (P = .02 and .04). Total body bone mineral content was preserved in the strength-trained women (+2.0 +/- 68 g; 0.0% +/- 3.0%) and tended to decrease in the controls (-33+77 g; -1.2% +/- 3.4%, P = .12). Muscle mass, muscle strength, and dynamic balance increased in the strength-trained women and decreased in the controls (P = .03 to < .001).\n High-intensity strength training exercises are an effective and feasible means to preserve bone density while improving muscle mass, strength, and balance in postmenopausal women.", "This study evaluated the additive effects of hormone replacement therapy (HRT) and a 1-year site-specific resistance-training (RT) program involving two free weight exercises (i.e., squat and deadlift) 2 days/week as a strategy to reverse or attenuate bone loss at the lumbar spine in early postmenopausal women. Participants from a group of self-selected HRT or non-HRT (N=141) users were randomly assigned to RT (exercise) or no training, creating four groups: 1) non-HRT plus RT [NHRT plus exercise (n=35)]; 2) HRT plus RT [HRT plus exercise (n=37)]; 3) HRT no resistance training [HRT no exercise (n=35)]; or 4) control [non-HRT no resistance training group (n=34)]. Mean age and months past menopause did not differ between groups (52.1+/-3.0 years and 52.8+/-9.9 months, respectively). Post-menopausal status was confirmed by follicle-stimulating hormone levels > or =40 mIU/mL. Bone mineral density (BMD) of the spine was assessed by Dual Energy X-ray Absorptiometry (Hologic), at baseline and month 12. Data were analyzed using a 4 (experimental condition) x 2 (time) repeated measures multivariate analysis of variance to determine the effects of RT on HRT and non-HRT in early postmenopausal women. The main effects for group (P<0.007), time (P<0.001), and the group by time interaction (P<0.001) were each significant. Control participants experienced an average of -3.6% reduction of BMD at the spine. HRT treatment with no exercise showed bone loss of -0.66%. One year of RT produced increases in spine BMD of +0.43% and +0.70%, respectively for the NHRT plus exercise, and HRT plus exercise groups with no differences between the NHRT and HRT exercise groups. In conclusion, RT alone was as effective as HRT in preventing bone loss at the spine and was more effective than HRT alone in attenuating bone loss at the spine. Moreover, there was no additional benefit in combining HRT with RT for preventing bone loss at the spine in this group of early postmenopausal women.", "Physical exercise affects many risk factors and diseases and therefore can play a vital role in general disease prevention and treatment of elderly individuals and may reduce costs. We sought to determine whether a single exercise program affects fracture risk (bone mineral density [BMD] and falls), coronary heart disease (CHD) risk factors, and health care costs in community-dwelling elderly women.\n We conducted a randomized, single-blinded, controlled trial from May 1, 2005, through July 31, 2008, recruiting women 65 years or older who were living independently in the area of Erlangen-Nuremberg, Germany. In all, 246 women were randomly assigned to an 18-month exercise program (exercise group) or a wellness program (control group). The exercise group (n = 123) performed a multipurpose exercise program with special emphasis on exercise intensity; the controls (n = 123) focused on well-being with a low-intensity, low-frequency program. The main outcome measures were BMD, the number of falls, the Framingham-based 10-year CHD risk, and direct health care costs.\n For the 227 women who completed the 18-month study, significant exercise effects were observed for BMD of the lumbar spine (mean [95% confidence interval (CI)] percentage of change in BMD [baseline to follow-up] for the exercise group: 1.77% [1.26% to 2.28%] vs controls: 0.33% [-0.24% to 0.91%]; P < .001), femoral neck (exercise group: 1.01% [0.37% to 1.65%] vs controls: -1.05% [-1.70% to -0.40%]; P < .001), and fall rate per person during 18 months (exercise group: 1.00 [0.76 to 1.24] vs controls: 1.66 [1.33 to 1.99]; P = .002). The 10-year CHD risk was significantly affected in both subgroups (absolute change for the exercise group: -1.96% [95% CI, -2.69% to -1.23%] vs controls: -1.15% [-1.69% to -0.62%]; P = .22), with no significant difference between the groups. The direct health care costs per participant during the 18-month intervention showed nonsignificant differences between the groups (exercise group: 2255 euros[95% CI, 1791 euros-2718 euros] vs controls: 2780 euros [2187 euros-3372 euros]; P = .20).\n Compared with a general wellness program, our 18-month exercise program significantly improved BMD and fall risk, but not predicted CHD risk, in elderly women. This benefit occurred at no increase in direct costs.\n clinicaltrials.gov Identifier: NCT00267839.", "The purpose of this intervention trial was to determine whether changes in bone mass distribution could be observed in postmenopausal women following hormone replacement therapy (HRT) and/or high-impact physical exercise. Eighty healthy women, aged 50-57 years, at <5 years after the onset of menopause and with no previous use of HRT, were randomly assigned to one of four groups: HRT; exercise (Ex); HRT + Ex (ExHRT); and control (Co). HRT administration was conducted in a double-blind manner for 1 year using estradiol plus noretisterone acetate (Kliogest). The exercise groups participated in a 1 year progressive training program consisting of jumping and bounding activities. Subjects participated in two supervised sessions per week and were asked to perform a series of exercises at home 4 days/week. Bone measurements using a quantitative computed tomography scanner (Somatom DR, Siemens) were obtained from the proximal femur, midfemur, proximal tibia, and tibial shaft. Data were analyzed with a software program (BONALYSE 1.3) calculating density (g/cm(3)), cross-sectional area (CSA; mm(2)), and moments of inertia (I(max), I(min), I(polar)). In addition, the bone mass spectrum was determined as a function of the angular distribution around the bone mass center (polar distribution) and the distance from the bone mass center through the diaphyseal wall (radial distribution). After the 1 year period, there was an overall interaction of group x time in bone mineral density (BMD) at the proximal femur (p = 0.05) and tibial shaft (p = 0.035). Women in the ExHRT and HRT groups had increased proximal femur and tibial shaft BMD when compared with the change observed in the Co group (p = 0.024-0.011). The change was more pronounced in the cortical tibia, wherein the ExHRT group also differed from the Ex group (p = 0.038). No significant changes were found in bone CSA at any of the measured sites. The radial distribution indicated an increase of BMD in the endocortical part of the measured sites in the HRT and ExHRT groups and in the proximal tibia in the Ex group. The polar distribution showed that bone mass was redistributed in the anteroposterior direction. The changes in I(max), I(min), and I(polar) in the HRT and ExHRT groups differed from those in the Co group at the proximal femur, midfemur, and proximal tibia (p = 0.047-0.001). The Ex group also differed from the Co group in I(max) and I(polar) at the proximal tibia (p = 0.018 and 0.039, respectively). These results support the idea that HRT acts primarily at the bone-marrow interface. The exercise intervention chosen for this study contributed to the maintenance of bone mass. Our results suggest that both HRT and exercise have local effects on bone mass. The change in bone mass distribution induced by HRT and exercise may play an important role in the alteration of bone strength.", "A total of 76 women were enrolled and 55 naturally postmenopausal women completed a 12 month study investigating the effects of aerobic training plus calcium supplementation on lumbar (L2-4) bone mineral density (BMD) and forearm BMD. Training was conducted on treadmills at 70-85% of maximal heart rate for 30 or 45 minutes, three times per week for 12 months. Lumbar BMD was measured with dual-photon absorptiometry and forearm BMD with single-photon absorptiometry. Groups were similar with respect to age, weight, months since menopause, height, maximal oxygen uptake (VO2max), and lumbar and forearm BMD upon entering the study. Following training, percentage changes in VO2max were significantly different between the control and exercise groups but not between exercise groups. ANOVA evaluating lumbar BMD revealed a nonsignificant interaction effect and no significant changes (p > 0.05) between groups or times. The control (N = 19), 30 minute (N = 20), and 45 minute (N = 16) groups percentage lumbar BMD changes (X +/- SD) over 12 months were -0.61 +/- 3.40, -0.48 +/- 3.63, and 0.81 +/- 4.53%, respectively. The 95% confidence limits for percentage changes in lumbar BMD for the control, 30 minute, and 45 minute groups were -2.25 to 1.02, -2.18 to 1.22, and -1.16 to 3.22%, respectively. Forearm BMD changes were also not significant. Improvement in lumbar BMD was weakly but positively correlated with improvements in VO2max, r = 0.28, p < 0.05. Women < or = 6 years of the onset of menopause had an accelerated lumbar BMD loss compared to subjects who were > 6 years postmenopausal, and this subset's BMD changes were examined.(ABSTRACT TRUNCATED AT 250 WORDS)", "The effects of physical training and hormone replacement therapy (HRT) on bone mineral density in perimenopausal women were studied. Sixty perimenopausal women were randomized to either physical training (n = 20), HRT (n = 20), or control group (n = 20). The study period was 18 months. Bone mineral density (BMD) in the femoral neck and lumbar spine was measured using dual-energy X-ray absorptiometry (DXA). DXA was performed before treatment and after 6 and 18 months. Blood samples for analysis of the bone markers U-deoxypyridinoline and osteocalcin were collected at the same time points. After 18 months, BMD in the spine had not decreased in either the training group or in the HRT group. In the control group, spine BMD had significantly decreased (p = 0.0014). U-Deoxypyridinoline and osteocalcin were increased significantly in the control group (p = 0.0198, p = 0.0295, respectively). No significant changes in bone marker levels were found in the training group or the HRT group. We found that both HRT and physical training can prevent loss of spine BMD in perimenopausal women over a period of 18 months. HRT remains a cornerstone in the treatment of vasomotor symptoms and preservation of BMD. However, HRT can only be used for limited periods of time due to the potential serious adverse effects. This study indicates a beneficial effect of physical activity on spine BMD in the perimenopausal period, and highlights its potential as an alternative to HRT during this period.", "Combining exercise with calcium supplementation may produce additive or multiplicative effects at loaded sites; thus, we conducted a single blind, prospective, randomized controlled study in pre- and early-pubertal girls to test the following hypotheses. (1) At the loaded sites, exercise and calcium will produce greater benefits than exercise or calcium alone. (2) At non-loaded sites, exercise will have no benefit, whereas calcium with or without exercise will increase bone mass over that in exercise alone or no intervention. Sixty-six girls aged 8.8 +/- 0.1 years were randomly assigned to one of four study groups: moderate-impact exercise with or without calcium or low-impact exercise with or without calcium. All participants exercised for 20 minutes, three times a week and received Ca-fortified (434 +/- 19 mg/day) or non-fortified foods for 8.5 months. Analysis of covariance (ANCOVA) was used to determine interaction and main effects for exercise and calcium on bone mass after adjusting for baseline bone mineral content and growth in limb lengths. An exercise-calcium interaction was detected at the femur (7.1%, p < 0.05). In contrast, there was no exercise-calcium interaction detected at the tibia-fibula; however, there was a main effect of exercise: bone mineral content increased 3% more in the exercise than non-exercise groups (p < 0.05). Bone mineral content increased 2-4% more in the calcium-supplemented groups than the non-supplemented groups at the humerus (12.0% vs. 9.8%, respectively, p < 0.09) and radius-ulna (12.6% vs. 8.6%, respectively, p < 0.01). In conclusion, greater gains in bone mass at loaded sites may be achieved when short bouts of moderate exercise are combined with increased dietary calcium, the former conferring region-specific effects and the latter producing generalized effects.", "The purpose of this study was to determine the effect of a 1-year trunk resistive exercise program on bone mineral density at the lumbar spine and hip in postmenopausal women. Forty-nine subjects were divided into exercise and control groups. Dual photon absorptiometry was used to measure bone mineral density and the Muscle Examination and Exercise Dosimeter 3000 system was used to assess trunk muscle strength. Resistive exercise target levels for the exercise group were based on the results of the trunk muscle strength tests. The exercise group performed 3 sets of 10 repetitions for each of the sit-up, prone trunk extension, and double leg flexion exercises. The subjects were seen once per month and performed the exercises a minimum of three times per week. The bone mineral density and strength tests were done at baseline, at 6 months and at 12 months. The results of the study showed that 1) the dual photon absorptiometry method and the Muscle Examination and Exercise Dosimeter 3000 system were highly reliable in measuring bone mineral density and trunk muscle strength, respectively; and 2) no significant differences were found between the exercise and control groups at lumbar vertebrae L2, L3, L4, L2-L4, and the femoral neck, Ward's triangle, and trochanteric region of the proximal femur at baseline, 6-month, and 12-month evaluation sessions.", "The aim of this study was to test the effect of unipedal standing exercise on bone mineral density (BMD) of the hip in postmenopausal women. Japanese postmenopausal women (n = 94) were assigned at random to an exercise or control group (no exercise). The 6-month exercise program consisted of standing on a single foot for 1 min per leg 3 times per day. BMD of the hip was measured by dual-energy X-ray absorptiometry. There was no significant difference in age and baseline hip BMD between the exercise group (n = 49) and control group (n = 45). Exercise did not improve hip BMD compared with the control group. Stepwise regression analysis identified old age as a significant determinant (p = 0.034) of increased hip total BMD at 6 months after exercise. In 31 participants aged >/=70 years, the exercise group (n = 20) showed significant increase in the values of hip BMD at the areas of total (p = 0.008), intertrochanteric (p = 0.023), and Ward's triangle (p = 0.032). The same parameters were decreased in the control group (n = 11). The percent changes in hip BMD of the exercise group were not significantly different from those of the control group either in the participants with low baseline hip total BMD (<80% of the young adult mean) or high baseline hip total BMD (> or =80% of the young adult mean). In conclusion, unipedal standing exercise for 6 months did not improve hip BMD in Japanese postmenopausal women. Effect of exercise on hip total BMD was age dependent. In participants aged > or =70 years, the exercise significantly increased hip total BMD.", "To describe the effect of a supervised physical activity program on the physical and psychological health of osteopenic women.\n A randomized controlled trial.\n Sherbrooke, Quebec, Canada.\n A total of 124 community-living postmenopausal women, between 50 and 70 years of age, with low bone mass took part in the study.\n Subjects allocated to the experimental group performed weight-bearing exercises (walking, stepping up and down from benches), aerobic dancing, and flexibility exercises for 60 minutes, three times a week, over a period of 12 months. All subjects were invited to attend bi-monthly educational seminars covering topics related to osteoporosis.\n Spinal and femoral bone mineral density (BMD), functional fitness (flexibility, coordination, agility, strength/endurance, cardiorespiratory endurance), psychological well-being, back pain intensity, and self-perceived health.\n Spinal BMD stabilized in the exercisers while decreasing significantly in the controls (P = .031). No change in femoral BMD was observed in either group (P = .597). Four of the five parameters chosen to evaluate functional fitness, namely flexibility, agility, strength, and endurance, were affected positively by the exercise program (all P < .01). Adjusting for prescores by means of an analysis of covariance revealed a significant difference between the groups in psychological well-being, which favored the exercisers (P = .012). After 12 months, back pain reported by exercisers was lower than that reported by controls (P = .008). Finally, self-perceived health increased in the exercise group, whereas no difference was observed in the control group (P = .790).\n These results suggest that after 12 months, exercising can produce a significant increase above initial levels in the functional fitness, well-being, and self-perceived health of osteopenic women. Intensity of back pain can also be lowered by exercise. The exercise program succeeded in stabilizing spinal BMD but had no effect on femoral BMD.", "To compare the effect of calcium/vitamin D supplements with a combination of calcium/vitamin D supplements and exercise/protein on risk of falling and postural balance.\n Randomized clinical trial.\n University hospital physiotherapy department.\n Twenty-four independently living elderly females aged 65 years and older with osteopenia or osteoporosis and mean total hip T-score (SD) of -1.8 (0.8).\n A three-month programme consisting of exercise/protein including training of muscular strength, co-ordination, balance and endurance. Calcium/ vitamin D was supplemented in all participants for a 12-month period.\n Assessment took place prior to and following the months 3, 6, 9 and at the end of the study; primary dependent variables assessed were risk of falling (Berg Balance Test) and postural balance (forceplate). Secondary measures included body composition, strength, activity level, number of falls, bone mineral content, biochemical indices, nutritional status and general health.\n Significant reductions of risk of falling (repeated measures ANOVA F = 8.90, P = 0.008), an increase in muscular strength (ANOVA F = 3.0, P = 0.03), and an increase in activity level (ANOVA F = 3.38, P = 0.02) were found in the experimental group as compared to the control group. Further on, there was 89% reduction of falls reported in the experimental group (experimental pre/post 8/1 falls; control group pre/post 5/6 falls).\n This study provides support for our intervention programme aimed at reducing the risk of falling in elderly participants diagnosed with osteopenia or osteoporosis. The data obtained from the pilot study allow the calculation of the actual sample size needed for a larger randomized trial.", "The aim of this randomized controlled trial was to evaluate the effect of a 3-month course of exercises on mobility, balance, disease-specific, and generic health-related quality of life (HRQOL) for women with osteoporosis and a history of vertebral fractures. Our results showed that exercises improved their mobility, balance, and HRQOL.\n The aim was to evaluate the effect of a 3-month course of circuit exercises plus a 3-h lesson on how to cope with osteoporosis on mobility, balance, and the HRQOL for postmenopausal women (60-84 years) with osteoporosis and a history of vertebral fracture. Our hypothesis was that a 3-month course would have a significantly positive effect on the women's mobility and balance as well as on their HRQOL.\n The participants (89) were randomized to an intervention group (IT) or a control group (CT) and assessed at baseline at 3 months and at 12 months with measurement of maximum walking speed (MWS), Timed Up and GO (TUG), Functional Reach (FR), the Quality of Life Questionnaire issued by the European Foundation for Osteoporosis ('QUALEFFO-41') and the General Health Questionnaire (GHQ-20). The sample size was calculated with reference to walking speed (primary outcome), and the statistical approaches used were Student's t test or the chi-square test.\n At 3 months, better results were registered on the primary outcome, MWS as well as TUG, FR, sum score of GHQ-20, and \"QUALEFFO-41: mental function\" in the IT compared with the CT. At 12 months, those in the IT had a better result on the primary outcome, MWS as well as TUG, \"QUALEFFO-41: total score\" \"QUALEFFO-41: mental function\", \"QUALEFFO-41: physical function\", and \"QULEFFO-41: pain\" compared with CT.\n Circuit exercises will improve mobility and health-related quality of life of elderly women with osteoporosis and a history of vertebral fractures.", "A randomized controlled trial was carried out to determine whether calcium supplementation and load-bearing exercise can increase or maintain bone mass in the elderly. Fifty Chinese women, aged 62-92 years, living in a hostel for the elderly in Hong Kong were randomized to enter one of four treatment groups: (I) calcium supplementation of 800 mg (as calcium lactate gluconate) daily; (II) load-bearing exercise four times a week plus a daily placebo tablet; (III) calcium supplementation daily and load-bearing exercise four times a week; (IV) a placebo tablet daily. The interventions went on for 10 months. The bone mineral density (BMD) was measured at three sites in the hip (femoral neck, Ward's triangle and intertrochanteric area) and the L2-4 level of the spine. The percentage change in BMD in 10 months was used as the main outcome measurement. The parathyroid hormone level and indices of bone metabolism were also measured before and after 10 months of intervention. The BMD at Ward's triangle and the intertrochanteric area increased significantly in subjects on calcium supplement (p less than 0.05), but there was no significant change at the spine and femoral neck. Exercise had no effect on bone loss at any site. However, the results of two-way analysis of variance showed a significant joint effect of calcium supplements and exercise at the femoral neck (p less than 0.05), but not at the other sites. The parathyroid hormone levels fell significantly in subjects on calcium supplements (p less than 0.01). Calcium supplement in the form of calcium lactate gluconate was adequately absorbed in elderly Chinese women with a calcium intake of less than 300 mg per day. It was effective in reducing bone loss at the hip, and there may be interaction effects with exercise in maintaining bone density.", "A 1-year prospective, randomized, double-blind, and placebo-controlled trial of 70 postmenopausal women demonstrated that brief periods (<20 minutes) of a low-level (0.2g, 30 Hz) vibration applied during quiet standing can effectively inhibit bone loss in the spine and femur, with efficacy increasing significantly with greater compliance, particularly in those subjects with lower body mass.\n Indicative of the anabolic potential of mechanical stimuli, animal models have demonstrated that short periods (<30 minutes) of low-magnitude vibration (<0.3g), applied at a relatively high frequency (20-90 Hz), will increase the number and width of trabeculae, as well as enhance stiffness and strength of cancellous bone. Here, a 1-year prospective, randomized, double-blind, and placebo-controlled clinical trial in 70 women, 3-8 years past the menopause, examined the ability of such high-frequency, low-magnitude mechanical signals to inhibit bone loss in the human.\n Each day, one-half of the subjects were exposed to short-duration (two 10-minute treatments/day), low-magnitude (2.0 m/s2 peak to peak), 30-Hz vertical accelerations (vibration), whereas the other half stood for the same duration on placebo devices. DXA was used to measure BMD at the spine, hip, and distal radius at baseline, and 3, 6, and 12 months. Fifty-six women completed the 1-year treatment.\n The detection threshold of the study design failed to show any changes in bone density using an intention-to-treat analysis for either the placebo or treatment group. Regression analysis on the a priori study group demonstrated a significant effect of compliance on efficacy of the intervention, particularly at the lumbar spine (p = 0.004). Posthoc testing was used to assist in identifying various subgroups that may have benefited from this treatment modality. Evaluating those in the highest quartile of compliance (86% compliant), placebo subjects lost 2.13% in the femoral neck over 1 year, whereas treatment was associated with a gain of 0.04%, reflecting a 2.17% relative benefit of treatment (p = 0.06). In the spine, the 1.6% decrease observed over 1 year in the placebo group was reduced to a 0.10% loss in the active group, indicating a 1.5% relative benefit of treatment (p = 0.09). Considering the interdependence of weight, the spine of lighter women (<65 kg), who were in the highest quartile of compliance, exhibited a relative benefit of active treatment of 3.35% greater BMD over 1 year (p = 0.009); for the mean compliance group, a 2.73% relative benefit in BMD was found (p = 0.02). These preliminary results indicate the potential for a noninvasive, mechanically mediated intervention for osteoporosis. This non-pharmacologic approach represents a physiologically based means of inhibiting the decline in BMD that follows menopause, perhaps most effectively in the spine of lighter women who are in the greatest need of intervention.", "In this randomized, double-blind, placebo-controlled 12-month trial we evaluated effects of weight- bearing jumping exercise and oral alendronate, alone or in combination, on the mass and structure of bone, risk factors for falling (muscle strength and power, postural sway, and dynamic balance), and cardiorespiratory fitness in postmenopausal women. A total of 164 healthy, sedentary, early postmenopausal women were randomly assigned to one of four experimental groups: (1) 5 mg of alendronate daily plus progressive jumping exercise, (2) 5 mg alendronate, (3) placebo plus progressive jumping exercise, or (4) placebo. The primary endpoint was 12-month change in bone mass and geometry (measured with dual-energy X-ray absorptiometry and peripheral computed tomography at several axial and limb sites) and physical performance; the secondary endpoint was change in biochemical markers of bone turnover. The jumping exercise was conducted an average 1.6 +/- 0.9 (mean +/- SD) times a week. Alendronate daily was effective in increasing bone mass at the lumbar spine (alendronate vs placebo 3.5%; 95% CI, 2.2-4.9%) and femoral neck (1.3%; 95% CI, 0.2-2.4%) but did not affect other bone sites. Exercise alone had no effect on bone mass at the lumbar spine or femoral neck; it had neither an additive nor an interactive effect with alendronate at these bone sites. However, at the distal tibia the mean increase of 3.6% (0.3-7.1%) in the section modulus (that is, bone strength) and 3.7% (0.1-7.3%) increase in the ratio of cortical bone to total bone area were statistically significant in the exercise group compared to the nonexercise group, indicating exercise-induced thickening of the bone cortex. Bone turnover was reduced in alendronate groups only. Alendronate had no effect on physical performance while the jumping exercise improved leg extensor power, dynamic balance, and cardiorespiratory fitness. As conclusion Alendronate is effective in increasing bone mass at the lumbar spine and femoral neck, while exercise is effective in increasing the mechanical properties of bone at some of the most loaded bone sites, as well as improving the participants' muscular performance and dynamic balance. Together alendronate and exercise may effectively decrease the risk of osteoporotic fractures.", "The aim of the present study was to investigate the effects of home-based exercise without home visits on physical function, falls, and bone mineral density in community-dwelling elderly women. Sixty community-dwelling, elderly (> or =65 years of age) women were recruited from a Japanese community. Subjects were randomly assigned to a home-based exercise group or a control group. The subjects assigned to the home-based exercise group performed home-based exercise without home visits 3 times per week for 6 months in their homes. Assessments of physical function and bone mineral density were carried out before and after intervention in both groups. Muscle strength, gait velocity, the timed up and go test (TUGT), single leg stance time, the bend reach performance test, and reaction time were measured to assess physical function. The patients' history of falls was also assessed before and after the 12-month follow-up. To determine bone mineral density, the speed of sound (SOS) at the right calcaneus was measured using a quantitative ultrasound device. There were no significant differences between the two groups in baseline characteristics. 82.6% of subjects completed the prescribed exercise program in the home-based exercise group. Compared to the control group, TUGT improved significantly (p<0.05) in the home-based exercise group. Home-based exercise without home visits can be adopted for community-dwelling elderly women, particularly since no specific place or instructor is needed.", "The aim of this study was to determine the effect of periodized exercise training with and without Cimicifuga racemosa (CR) on bone mineral density (BMD) and 10-year coronary heart disease (CHD) risk in early postmenopausal women.\n A total of 128 women were randomly assigned to three subgroups: exercise (EG, n = 43), exercise and CR supplementation (EGCR, n = 43), and wellness control (control group [CG], n = 42). Both exercise groups performed a periodized exercise program with high-intensity-resistance/high-impact exercise dedicated to bone parameters interspersed by blocks of 10 weeks of training focusing on CHD parameters. In addition to the exercise program, the EGCR was supplemented with 40 mg/day of CR according to the specification of the manufacturer. A low-intensity exercise program of 60 minutes per week for a period of 10 weeks interspersed with 10-week blocks without exercise was performed in the CG. Primary endpoints were BMD and 10-year CHD risk proposed by Wilson. Secondary endpoints were body composition and menopausal symptoms.\n BMD at the lumbar spine was maintained in both exercise groups (EG, -0.1% +/- 2.2%, P = 0.74; EGCR, -0.4% +/- 2.4%, P = 0.40) and significantly decreased (P < 0.001) in the CG (2.0% +/- 2.0%). Both exercise groups significantly differed from the CG (P = 0.001 and 0.005 for the EG and EGCR, respectively); however, no differences between the exercise groups with and without CR was determined. Although slight increases in femoral neck BMD were determined in both exercise groups (EG, 0.5% +/- 3.0%, P = 0.36; EGCR, 0.4% +/- 3.1%, P = 0.52), a reduction was assessed in the CG (-0.6% +/- 2.7%, P = 0.29). No significant differences were determined between the groups. The 10-year CHD risk significantly increased in the EGCR (12.9% +/- 25.1%, P = 0.018) and in the CG (16.5% +/- 27.8%, P = 0.007). The EG did not show corresponding changes (-2.7% +/- 21.9%, P = 0.60). However, no significant between-group differences were observed.\n In conclusion our exercise program favorably affected bone, menopausal symptoms, lean body mass, and, to a smaller extent, 10-year CHD risk in early postmenopausal women. Adjuvant supplementation of CR did not enhance these positive effects.", "The study was designed to evaluate the effects of strength training (ST) on the bone mineral density (BMD) of postmenopausal women without hormone replacement therapy.\n Subjects were randomized into untrained (UN) or trained (TR) groups. The TR group exercised three ST sessions per week for 24 weeks, and body composition, muscular strength, and BMD of the lumbar spine and femur neck were evaluated.\n Body weight, mass index, and fat percentage were lower after 24 weeks only in the TR group (p < .05). SR also improved the one repetition maximum test in 46% and 39% of upper and lower limbs, respectively. The percentage of demineralization was higher in the UN group than in the TR group at the lumbar spine and femoral neck (p < .05).\n Results indicated that 24 weeks of ST improved body composition parameters, increased muscular strength, and preserved BMD in postmenopausal women.", "The increasing prevalence of obesity is a major public health concern. Physical activity may promote weight and body fat loss.\n To examine the effects of exercise on total and intra-abdominal body fat overall and by level of exercise.\n Randomized controlled trial conducted from 1997 to 2001.\n A total of 173 sedentary, overweight (body mass index > or =24.0 and >33% body fat), postmenopausal women aged 50 to 75 years who were living in the Seattle, Wash, area.\n Participants were randomly assigned to an intervention consisting of exercise facility and home-based moderate-intensity exercise (n = 87) or a stretching control group (n = 86).\n Changes in body weight and waist and hip circumferences at 3 and 12 months; total body, intra-abdominal, and subcutaneous abdominal fat at 12 months.\n Twelve-month data were available for 168 women. Women in the exercise group participated in moderate-intensity sports/recreational activity for a mean (SD) of 3.5 (1.2) d/wk for 176 (91) min/wk. Walking was the most frequently reported activity. Exercisers showed statistically significant differences from controls in baseline to 12-month changes in body weight (-1.4 kg; 95% confidence interval [CI], -2.5 to -0.3 kg), total body fat (-1.0%; 95% CI, -1.6% to -0.4%), intra-abdominal fat (-8.6 g/cm2; 95% CI, -17.8 to 0.9 g/cm2), and subcutaneous abdominal fat (-28.8 g/cm2); 95% CI, -47.5 to -10.0 g/cm2). A significant dose response for greater body fat loss was observed with increasing duration of exercise.\n Regular exercise such as brisk walking results in reduced body weight and body fat among overweight and obese postmenopausal women.", "to evaluate the effects of brisk walking on bone mineral density in women who had suffered an upper limb fracture.\n randomized placebo-controlled trial. Assessments of bone mineral density were made before and at 1 and 2 years after intervention. Standardized and validated measures of physical capacity, self-rated health status and falls were used.\n district general hospital outpatient department.\n 165 women drawn from local accident and emergency departments with a history of fracture of an upper limb in the previous 2 years. Women were randomly allocated to intervention (self-paced brisk walking) or placebo (upper limb exercises) groups.\n both groups were seen at 3-monthly intervals to assess progress, measure physical capacity and maintain enthusiasm. The brisk-walking group were instructed to progressively increase the amount and speed of walking in a manner that suited them. The upper limb exercise placebo group were asked to carry out a series of exercises designed to improve flexibility and fine hand movements, appropriate for a past history of upper limb fracture.\n drop-outs from both intervention and placebo groups were substantial (41%), although there were no significant differences in bone mineral density, physical capacity or health status between drop-outs and participants. At 2 years, among those completing the trial, bone mineral density at the femoral neck had fallen in the placebo group to a greater extent than in the brisk-walking group [mean net difference between intervention and placebo groups 0.019 g/cm2, 95% confidence interval (CI) -0.0026 to +0.041 g/cm2, P = 0.056]. Lumbar spine bone mineral density had increased to a similar extent (+0.017 g/cm2) in both groups. The cumulative risk of falls was higher in the brisk-walking group (excess risk of 15 per 100 person-years, 95% CI 1.4-29 per 100 person-years, P < 0.05). There were no significant differences in clinical or spinal x-ray fracture risk or self-rated health status between intervention and placebo groups.\n the promotion of exercise through brisk-walking advice given by nursing staff may have a small, but clinically important, impact on bone mineral density but is associated with an increased risk of falls. Self-paced brisk walking is difficult to evaluate in randomized controlled trials because of drop-outs, placebo group exercise, limited compliance and lack of standardization of the duration and intensity of walking. Further work is needed to evaluate the best means of safely achieving increased activity levels in different groups, such as older women and those at high risk of fractures.", "This pilot study examined whether exercise as an adjunctive rehabilitation therapy could benefit women who have early stage breast cancer and are currently receiving chemotherapy/radiotherapy. The study was designed as a randomised controlled trial (RCT). Physical functioning, fatigue and Quality of Life (QoL) outcomes were evaluated pre and post a 12-week intervention. The results showed that after 12 weeks the women who participated in the exercise programme (n = 12) displayed significantly higher levels of physical functioning and reported higher QoL scores than the controls (n = 10). Changes in fatigue and satisfaction with life favoured the intervention group but did not reach significance. These results are encouraging and suggest that a structured group exercise programme during adjuvant treatment is a safe, well tolerated and effective way of providing physical and psychological health benefits to women during treatment for early stage breast cancer. Since this was a pilot study the numbers did not allow appropriately powered analyses of some variables of interest and favoured relatively young and socio-economically advantaged women. Future studies need to address these issues and determine if these short-term benefits can be sustained.", "Forty-eight community living women 66-87 years old volunteered to participate in a 12-month prospective, randomized, controlled, trial. The aim was to determine if a combined weight-bearing training program twice a week would be beneficial to bone mineral density and neuromuscular function. The participants were pairwise age-matched and randomly assigned to either an exercise group (n=24) or a control group (n=24). Twenty-one subjects in the intervention group and 19 in the control group completed the study. The exercise program lasted for 50 min and consisted of a combination of strengthening, aerobic, balance and coordination exercises. The mean percentage of scheduled sessions attended for the exercise group was 67%. At the completion of the study, the intervention group showed significant increments in bone mineral density of the Ward's triangle (8.4%, P<0.01) as well as improvement in maximum walking speed (11.4%, P<0.001) and isometric grip strength (9.9%, P<0.05), as compared to the control group. The conclusion was that a combined weight-bearing training program might reduce fracture risk factors by improving bone density as well as muscle strength and walking ability. This program could be suitable for older community living women in general, and might, therefore, have important implications for fracture prevention.", "Osteoporosis may be prevented or delayed by maximizing peak bone mass through diet modification and physical activity during adolescence.\n We studied whether increases in calcium intake and physical activity effectively increase the bone mineral status of adolescent girls aged 16-18 y.\n We conducted a 15.5-mo study of calcium supplementation (1000 mg Ca/d as carbonate) in 144 adolescent girls aged 17.3 +/- 0.3 y ( +/- SD). The subjects were randomly allocated to an exercise (three 45-min exercise-to-music classes/wk during term time) or nonexercise group. Dual-energy X-ray absorptiometry of the whole body, spine, forearm, and hip was performed before and after intervention.\n The mean (+/- SD) percentage of subjects compliant with supplement taking was 70 +/- 27% and with exercise class attendance was 36 +/- 25%. Baseline calcium intake was 938 +/- 411 mg/d. Calcium supplementation significantly increased size-adjusted bone mineral content. The effect was stronger in subjects with good compliance (percentage difference +/- SE): whole body, 0.8 +/- 0.3% (P < or = 0.01); lumbar spine, 1.9 +/- 0.5% (P < or = 0.001); ultradistal radius, 1.3 +/- 0.6% (P < or = 0.05); total hip, 2.7 +/- 0.6% (P < or = 0.001); femoral neck, 2.2 +/- 0.7% (P < or = 0.001); trochanter, 4.8 +/- 0.9% (P < or = 0.001). Attendance at > 50% of the exercise sessions was significant at the total hip (1.4 +/- 0.7%; P < or = 0.05) and trochanter (2.6 +/- 1.2%; P < or = 0.05).\n Calcium supplementation and exercise enhanced bone mineral status in adolescent girls. Whether this is a lasting benefit, leading to the optimization of peak bone mass and a reduction in fracture risk, needs to be determined.", "There is a paucity of long term studies on exercise training in elderly women. The purpose of this study was to investigate the effects of one year of progressive resistance exercise (PRE) on dynamic muscular strength and the relations to bone mineral density (BMD) in elderly women.\n Forty four healthy sedentary women (mean age 68.8 years) volunteered for this study and were randomly assigned to either an exercise group or a control group. The exercise group were involved in three one hour sessions a week for 52 weeks of supervised PRE to strengthen the large muscle groups of the body, while the control group were instructed to continue their normal lifestyle. The exercise circuit included three sets of eight repetitions at 75% of one repetition maximum focused on the large muscle groups. BMD was measured by dual energy x ray absoptiometry (Lunar DPX) at the lumbar spine and at three sites in the proximal femur. Other selected parameters of physical fitness were also measured.\n Statistical analyses (analysis of covariance) showed significant strength gains (p < 0.01) in bilateral bench press (> 29%), bilateral leg press (> 19%), and unilateral biceps curl (> 20%). No significant difference between groups was evident in body weight, grip strength, flexibility, waist to hip ratio, or the sum of eight skinfolds. Significant relations (p < 0.05) were recorded between dynamic leg strength and the BMD of the femoral neck, Ward's triangle, and the lumbar spine.\n Significant strength changes, after one year of PRE, were evident in elderly women, and the muscle increases may parallel changes in BMD; however, correlation coefficients were moderate." ]	Our results suggest a relatively small statistically significant, but possibly important, effect of exercise on bone density compared with control groups. Exercise has the potential to be a safe and effective way to avert bone loss in postmenopausal women.
CD000104	[ "8951252", "10051081", "16163366", "9310511", "16137357", "15717206", "8463913", "19321507", "11098980", "12373475", "17405870", "9506636" ]	[ "The Provo multicenter early high-frequency oscillatory ventilation trial: improved pulmonary and clinical outcome in respiratory distress syndrome.", "A prospective randomized comparison of conventional mechanical ventilation and very early high frequency oscillatory ventilation in extremely premature newborns with respiratory distress syndrome.", "Randomized, multicenter trial of conventional ventilation versus high-frequency oscillatory ventilation for the early management of respiratory failure in term or near-term infants in Colombia.", "Multicenter controlled clinical trial of high-frequency jet ventilation in preterm infants with uncomplicated respiratory distress syndrome.", "High frequency oscillatory ventilation compared with conventional mechanical ventilation in adult respiratory distress syndrome: a randomized controlled trial [ISRCTN24242669].", "HFOV in premature neonates: effects on pulmonary mechanics and epithelial lining fluid cytokines. A randomized controlled trial.", "Randomized study of high-frequency oscillatory ventilation in infants with severe respiratory distress syndrome. HiFO Study Group.", "Long term follow-up of very low birthweight infants from a neonatal volume versus pressure mechanical ventilation trial.", "Inhaled nitric oxide reduces the need for extracorporeal membrane oxygenation in infants with persistent pulmonary hypertension of the newborn.", "Early versus delayed surfactant administration in extremely premature neonates with respiratory distress syndrome ventilated by high-frequency oscillatory ventilation.", "Volume guarantee versus high-frequency ventilation: lung inflammation in preterm infants.", "A prospective, randomized, multicenter trial of high-frequency oscillatory ventilation compared with conventional ventilation in preterm infants with respiratory distress syndrome receiving surfactant." ]	[ "To compare the hospital course and clinical outcome of preterm infants with respiratory distress syndrome treated with surfactant and managed with high-frequency oscillatory ventilation (HFOV) or conventional mechanical ventilation (CV) as their primary mode of ventilator support.\n A prospective randomized clinical trial.\n Three community-based level III neonatal intensive care units.\n A total of 125 neonates who were 35 weeks or less estimated gestation requiring intubation and assisted ventilation for respiratory distress syndrome with arterial to alveolar oxygen ratio less than .50.\n Patients were randomized to continue CV (61 patients) or be changed to HFOV (64 patients) after exogenous surfactant administration (100 mg/kg). HFOV was used in a strategy to promote lung recruitment and maintain lung volume. Protocol respiratory care guidelines were followed; otherwise routine care was provided by each neonatal intensive care unit.\n No differences were noted in demographic features between the two study groups. The study population birth weight was 1.51 +/- .47 kg (mean +/- SD), gestational age was 30.9 +/- 2.5 weeks, and study entry age was 2 to 3 hours. Patients randomized to HFOV demonstrated the following significant findings compared with CV-treated patients: vasopressor support was less intensive; surfactant redosing was not as frequent; oxygenation improved more rapidly and remained higher during the first 7 days; fewer infants required prolonged supplemental oxygen or ventilator support; treatment failure was reduced; more patients survived without chronic lung disease at 30 days; need for continuous supplemental oxygen at discharge was less; frequency of necrotizing enterocolitis illness was lower; there were fewer abnormal hearing tests; and hospital costs were decreased. No differences were seen between the two study groups in the frequency or severity of patent ductus arteriosus, air leak, retinopathy of prematurity, or intraventricular hemorrhage. Length of hospital stay and survival to discharge were similar for HFOV- and CV-treated infants.\n When used early with a lung recruitment strategy, HFOV after surfactant replacement resulted in clinical outcomes consistent with a reduction in both acute and chronic lung injury. Benefit was evident for preterm infants both less than or equal to 1 kg and more than 1 kg. In addition, early HFOV treatment may have had a more global effect on patient health throughout the hospitalization, resulting in reduced morbidity and decreased health care cost.", "To compare the effectiveness and safety of very early high-frequency oscillatory ventilation (HFOV) with conventional mechanical ventilation (CMV) in treatment of the respiratory distress syndrome (RDS) and to evaluate their impact on the incidence of chronic pulmonary disease and early and late morbidity of very low-birthweight neonates.\n A prospective randomized clinical trial.\n Tertiary neonatal intensive care unit in the Perinatology Center in Prague.\n 43 premature newborns, delivered in the Department of Obstetrics in the Perinatology Center, were randomly divided into two groups (HFOV and CMV) immediately after delivery; 2 patients in each group died, 2 fulfilled crossover criteria from CMV to HFOV, and 2 were excluded because of congenital malformations. Nineteen patients treated with HFOV were therefore compared with 18 infants in the CMV group.\n The two contrasting modes of ventilation were introduced immediately after intubation. Maintenance of optimal lung volume in HFOV to optimize oxygenation and the therapeutic administration of surfactant after fulfilling defined criteria are important points of the strategy and design of the study.\n Except for a higher proportion of males in the HFOV group (p<0.02), the basic clinical characteristics (gestational age, birthweight, Apgar score at 5 min, umbilical arterial pH), the two groups were similar. In the acute stage of RDS, infants treated with HFOV had higher proximal airway distending pressure with HFOV for 6 h after delivery (p<0.05). For a period of 12 h after delivery lower values for the alveolar-arterial oxygen difference (p<0.03) were noted. The number of patients who did not require surfactant treatment was higher in the HFOV group (11 vs. 1, p<0.001). In the HFOV group the authors found a lower roentgenographic score at 30 days of age (p<0.03) and a lower clinical score in the 36th postconceptional week (p<0.05), using these two scoring systems for assessing chronic lung disease according to Toce scale. The incidence of pneumothorax, pulmonary interstitial emphysema, intraventricular hemorrhage and retinopathy of prematurity in both groups was the same.\n HFOV, when applied early and when the clinical strategy of maintenance of optimal lung volume is used, improves oxygenation in the acute stage of RDS, reduces the need of surfactant administration, and can decrease the injury to lung tissue even in extremely immature newborns to whom surfactant is administered therapeutically.", "To determine the efficacy and safety of high-frequency oscillatory ventilation (HFOV) compared to conventional ventilation (CV) for the treatment of respiratory failure in term and near-term infants in Colombia.\n Eligible infants with moderate to severe respiratory failure were randomized to early treatment with CV or HFOV. Ventilator management and general patient care were standardized. The main outcome was neonatal death or pulmonary air leak.\n A total of 119 infants were enrolled (55 in the HFOV group; 64 in the CV group) during the study period. Six infants in the HFOV group (11%) and two infants in the CV group (3%) developed the primary outcome (RR: 3.6, 95% CI: 0.8-16.9). Five infants in the HFOV group (9%) and one infant in the CV (2%) died before 28 days of life (RR: 5.9 CI: 0.7-48.2). Secondary outcomes were similar between groups.\n HFOV may not be superior to CV as an early treatment for respiratory failure in this age group. Standardization of ventilator management and general patient care may have a greater impact on the outcome in Colombia than mode of ventilation.\n Journal of Perinatology (2005) 25, 720-724. doi:10.1038/sj.jp.7211386; published online 15 September 2005.", "To test the hypothesis that high-frequency jet ventilation (HFJV) will reduce the incidence and/or severity of bronchopulmonary dysplasia (BPD) and acute airleak in premature infants who, despite surfactant administration, require mechanical ventilation for respiratory distress syndrome.\n Multicenter, randomized, controlled clinical trial of HFJV and conventional ventilation (CV). Patients were to remain on assigned therapy for 14 days or until extubation, whichever came first. Crossover from CV to HFJV was allowed if bilateral pulmonary interstitial emphysema or bronchopleural fistula developed. Patients could cross over to the other ventilatory mode if failure criteria were met. The optimal lung volume strategy was mandated for HFJV by protocol to provide alveolar recruitment and optimize lung volume and ventilation/perfusion matching, while minimizing pressure amplitude and O2 requirements. CV management was not controlled by protocol.\n Eight tertiary neonatal intensive care units.\n Preterm infants with birth weights between 700 and 1500 g and gestational age <36 weeks who required mechanical ventilation with FIO2 >0.30 at 2 to 12 hours after surfactant administration, received surfactant by 8 hours of age, were <20 hours old, and had been ventilated for <12 hours. Outcome Measures. Primary outcome variables were BPD at 28 days and 36 weeks of postconceptional age. Secondary outcome variables were survival, gas exchange, airway pressures, airleak, intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), and other nonpulmonary complications.\n A total of 130 patients were included in the final analysis; 65 were randomized to HFJV and 65 to CV. The groups were of comparable birth weight, gestational age, severity of illness, postnatal age, and other demographics. The incidence of BPD at 36 weeks of postconceptional age was significantly lower in babies randomized to HFJV compared with CV (20.0% vs 40.4%). The need for home oxygen was also significantly lower in infants receiving HFJV compared with CV (5.5% vs 23.1%). Survival, incidence of BPD at 28 days, retinopathy of prematurity, airleak, pulmonary hemorrhage, grade I-II IVH, and other complications were similar. In retrospect, it was noted that the traditional HFJV strategy emphasizing low airway pressures (HF-LO) rather than the prescribed optimal volume strategy (HF-OPT) was used in 29/65 HFJV infants. This presented a unique opportunity to examine the effects of different HFJV strategies on gas exchange, airway pressures, and outcomes. HF-OPT was defined as increase in positive end-expiratory pressure (PEEP) by >/=1 cm H2O from pre-HFJV baseline and/or use of PEEP of >/=7 cm H2O. Severe neuroimaging abnormalities (PVL and/or grade III-IV IVH) were not different between the CV and HFJV infants. However, there was a significantly lower incidence of severe IVH/PVL in HFJV infants treated with HF-OPT compared with CV and HF-LO. Oxygenation was similar between CV and HFJV groups as a whole, but HF-OPT infants had better oxygenation compared with the other two groups. There were no differences in PaCO2 between CV and HFJV, but the PaCO2 was lower for HF-LO compared with the other two groups. The peak inspiratory pressure and DeltaP (peak inspiratory pressure-PEEP) were lower for HFJV infants compared with CV infants.\n HFJV reduces the incidence of BPD at 36 weeks and the need for home oxygen in premature infants with uncomplicated RDS, but does not reduce the risk of acute airleak. There is no increase in adverse outcomes compared with CV. HF-OPT improves oxygenation, decreases exposure to hypocarbia, and reduces the risk of grade III-IV IVH and/or PVL.", "To compare the safety and efficacy of high frequency oscillatory ventilation (HFOV) with conventional mechanical ventilation (CV) for early intervention in adult respiratory distress syndrome (ARDS), a multi-centre randomized trial in four intensive care units was conducted.\n Patients with ARDS were randomized to receive either HFOV or CV. In both treatment arms a priority was given to maintain lung volume while minimizing peak pressures. CV ventilation strategy was aimed at reducing tidal volumes. In the HFOV group, an open lung strategy was used. Respiratory and circulatory parameters were recorded and clinical outcome was determined at 30 days of follow up.\n The study was prematurely stopped. Thirty-seven patients received HFOV and 24 patients CV (average APACHE II score 21 and 20, oxygenation index 25 and 18 and duration of mechanical ventilation prior to randomization 2.1 and 1.5 days, respectively). There were no statistically significant differences in survival without supplemental oxygen or on ventilator, mortality, therapy failure, or crossover. Adjustment by a priori defined baseline characteristics showed an odds ratio of 0.80 (95% CI 0.22-2.97) for survival without oxygen or on ventilator, and an odds ratio for mortality of 1.15 (95% CI 0.43-3.10) for HFOV compared with CV. The response of the oxygenation index (OI) to treatment did not differentiate between survival and death. In the HFOV group the OI response was significantly higher than in the CV group between the first and the second day. A post hoc analysis suggested that there was a relatively better treatment effect of HFOV compared with CV in patients with a higher baseline OI.\n No significant differences were observed, but this trial only had power to detect major differences in survival without oxygen or on ventilator. In patients with ARDS and higher baseline OI, however, there might be a treatment benefit of HFOV over CV. More research is needed to establish the efficacy of HFOV in the treatment of ARDS. We suggest that future studies are designed to allow for informative analysis in patients with higher OI.", "Ventilation strategies for preterm neonates may influence the severity of pulmonary dysfunction and later development of chronic lung disease. The objective of this report is to compare the effects of high-frequency oscillatory ventilation (HFOV) versus synchronized intermittent mandatory ventilation (sIMV) from the points of views of biochemical and functional variables.\n Randomized controlled trial.\n Third level NICU.\n Forty preterm neonates with a gestational age of 24-29 weeks were randomly assigned to one of the two above-mentioned ventilation strategies within 30 min from birth.\n At 1, 3, 5, and 7 days, the babies were monitored by means of ventilator indices, pulmonary function, and eight pro-inflammatory or anti-inflammatory cytokines measured in bronchoalveolar lavage fluid. The neonates assigned to the HFOV procedure benefited from early and sustained improvement in pulmonary mechanics and gas exchange-significantly higher dynamic respiratory compliance values, significantly lower expiratory airway resistance and oxygenation index values-with earlier extubation as compared to the neonates assigned to sIMV treatment, and showed significantly lower transforming growth factor-beta1 concentrations in bronchoalveolar lavage fluid.\n The results of this randomized clinical trial support the hypothesis that early and exclusive use of HFOV, combined with optimum volume strategy, has a beneficial effect during the acute phase of lung injury.", "We conducted a multicenter, prospective, noncrossover, randomized study to determine whether high-frequency oscillatory ventilation (HFOV) would decrease the development or progression of air leak syndrome in infants with severe respiratory distress syndrome. Air leak syndrome was defined as pulmonary interstitial emphysema or gross air leak such as pneumothorax. Infants were eligible for study entry if they were less than 48 hours of age and had severe respiratory distress syndrome, defined by peak inspiratory pressure or the presence of air leak syndrome. Infants who weighed > or = 0.5 kg at birth were randomly assigned to receive either conventional ventilation (CV) or HFOV. HFOV was provided by a ventilator that operated at 15 Hz, with a 1:2 inspiratory/expiratory ratio and no background tidal breaths. Severity of pulmonary interstitial emphysema was scored independently by two neonatologists unaware of the infants' ventilatory group. Gross air leak severity was scored according to the number of chest tubes required and duration of air leak. Eighty-six infants received HFOV; 90 received CV. During the first 24 hours of the study, patients in the HFOV group received significantly higher mean airway pressure and lower inspired oxygen concentration, had significantly lower arterial carbon dioxide tension, and had a higher ratio of arterial to alveolar oxygen tension. When the HFOV and CV groups were compared with control for birth weight strata, study site, and inborn versus outborn status, HFOV significantly reduced the development of air leak syndrome in those patients who entered the study without the syndrome. We conclude that HFOV, when the strategy employed in this study is used, provides effective ventilation, improves oxygenation, and significantly reduces the development of air leak syndrome in infants with severe respiratory distress syndrome.", "A previous randomised trial showed volume controlled ventilation (VCV) was efficacious in ventilating very preterm and extremely low birthweight babies.\n To compare long term survival, pulmonary morbidities and gross neurodevelopmental outcomes of babies randomised to either VCV or pressure limited ventilation (PLV) for treatment of respiratory distress syndrome.\n Masked evaluation of health status, including frequency of respiratory illness, use of medications, hospital admissions, and gross neurodevelopmental status were obtained using a structured parental questionnaire and verification from medical records.\n 94 of 109 children (86%) survived to discharge. Three died after discharge (2 VCV, 1 PLV). Modality of ventilation did not affect overall mortality; seven VCV children died (12%) versus 11 PLV (21%) (OR 0.5 (95% CI 0.1 to 1.4), p = 0.13). Respiratory abnormalities were present in 32 (37%), and 26 (30%) required hospital readmission. There was no significant difference in readmission rates between the two groups: VC 13/45 (29%) and PLV 19/40 (47%) (OR 0.4 (0.1 to 1.1), p = 0.07). Modality of ventilation did not affect frequency of respiratory illness: VC 12 (27%) and PLV 14 (35%) (OR 0.46 (0.1 to 1.1), p = 0.09). However, significantly fewer VCV children (13%, n = 6) compared to PLV children (32%, n = 13) required treatment with inhaled steroids/bronchodilators (OR 0.3 (0.1 to 0.9), p = 0.04). Nine children had severe neurodevelopmental disability (cerebral palsy, blindness, deafness) (9.8%; 3 VCV, 6 PLV 6) (OR 0.4 (0.09 to 1.7)).\n The efficacy of VCV in very preterm and low birth babies appears to be maintained on longer term evaluation.", "We previously reported improved oxygenation, but no change, in rates of extracorporeal membrane oxygenation (ECMO) use or death among infants with persistent pulmonary hypertension of the newborn who received inhaled nitric oxide (NO) with conventional ventilation, irrespective of lung disease. The goal of our study was to determine whether treatment with inhaled NO improves oxygenation and clinical outcomes in infants with persistent pulmonary hypertension of the newborn and associated lung disease who are ventilated with high-frequency oscillatory ventilation (HFOV).\n Single-center, prospective, randomized, controlled trial.\n Newborn intensive care unit of a tertiary care teaching hospital.\n We studied infants with a gestational age of > or =34 wks who were receiving mechanical ventilatory support and had echocardiographic and clinical evidence of pulmonary hypertension and hypoxemia (PaO2 < or =100 mm Hg on FIO2 = 1.0), despite optimal medical management Infants with congenital heart disease, diaphragmatic hernia, or other major anomalies were excluded.\n The treatment group received inhaled NO, whereas the control group did not. Adjunct therapies and ECMO criteria were the same in the two groups of patients. Investigators and clinicians were not masked as to treatment assignment, and no crossover of patients was permitted.\n Primary outcome variables were mortality and use of ECMO. Secondary outcomes included change in oxygenation and duration of mechanical ventilatory support and supplemental oxygen therapy. Forty-two patients were enrolled. Baseline oxygenation and clinical characteristics were similar in the two groups of patients. Infants in the inhaled NO group (n = 21) had improved measures of oxygenation at 15 mins and 1 hr after enrollment compared with infants in the control group (n = 20). Fewer infants in the inhaled NO group compared with the control group were treated with ECMO (14% vs. 55%, respectively; p = .007). Mortality did not differ with treatment assignment.\n Among infants ventilated by HFOV, those receiving inhaled NO had a reduced need for ECMO. We speculate that HFOV enhances the effectiveness of inhaled NO treatment in infants with persistent pulmonary hypertension of the newborn and associated lung disease.", "To determine whether early surfactant administration is superior to selective delayed treatment in terms of improving survival and/or reducing chronic lung disease in extremely premature neonates with respiratory distress syndrome (RDS) treated by high-frequency oscillatory ventilation (HFOV).\n Prospective randomized clinical trial.\n Tertiary neonatal intensive care unit (NICU) in the Perinatology Center of Prague.\n Forty-three extremely premature infants who needed artificial ventilation within 3 h after delivery.\n Patients were randomly assigned to either early ( n=21) or delayed (n=22) administration of surfactant. All were ventilated by HFOV as the primary mode of ventilation using the high volume strategy aimed at optimizing lung volume. Curosurf at a dose of 100 mg/kg was given as a single bolus via the endotracheal tube within 1 min immediately after intubation in the early group (EARL), or during HFOV only when defined criteria were reached in the delayed (DEL) group.\n No differences were noted in demographic data between the two groups. Fewer infants randomized to the EARL group required oxygen use or died at 36 weeks (combined outcome 29% vs 64%, p=0.021), and there was a lower incidence of any intraventricular hemorrhage in this group (43 vs 82%, p=0.008).\n When compared to delayed dosing, early administration of surfactant followed by HFOV facilitates and accelerates respiratory stabilization during the acute phase of severe RDS, may reduce the incidence of chronic lung disease or death and may positively influence the incidence of severe intracranial pathology in extremely premature infants with primary surfactant insufficiency.", "Appropriate ventilation together with improvement of clinical care of premature babies can contribute to reducing lung inflammation, known to represent the \"primum movens\" of bronchopulmonary dysplasia (BPD). High-frequency oscillatory ventilation (HFOV) and volume-guarantee (VG) ventilation are effective in the treatment of neonatal respiratory distress syndrome (RDS).\n To assess the potential of HFOV and VG to prevent BPD in the acute phase of RDS, by a randomised clinical study evaluating lung inflammation in premature infants. Study design: Forty infants (gestational age 25-32 weeks) with RDS were assigned to assist-control ventilation plus VG (Vt = 5 ml/kg) or HFOV (both with a Dräger Babylog 8000 plus ventilator). Levels of interleukin (IL) 6, IL8 and tumour necrosis factor were determined in tracheal aspirate on days 1, 3 and 7 of life.\n In the HFOV group IL6 levels were significantly higher on day 3 (0.5 (0.2) vs assisted-control ventilation plus VG group 0.1 (0.2) ng/ml) and oxygen dependency was significantly longer (36 (23) vs assisted-control ventilation plus VG group 19 (11) days).\n VG ventilation is an effective lung-protective strategy to be used in acute RDS, inducing a lower expression of early inflammation markers than HFOV. Whether the use of this initial ventilatory strategy contributes to the prevention of BPD requires further studies.", "To compare high-frequency oscillatory ventilation (HFOV) and intermittent positive pressure ventilation (IPPV) as a primary ventilation mode in preterm infants with respiratory distress syndrome. Primary end points were survival and maintenance of the randomized ventilation mode.\n Prospective, multicenter, randomized clinical trial.\n Level III neonatal intensive care units at three university children's hospitals.\n Ninety-six premature infants (gestational age < 32 weeks) randomly assigned to HFOV or IPPV within the first 2 hours of life. All patients received a natural surfactant. No differences were found between the study groups with respect to the demographic data or the severity of respiratory distress syndrome. Infants were stratified at randomization, by birth weight, into two groups: 750 to 1000 gm (n = 32) and 1001 to 1500 gm (n = 64). The centers involved complied with a study protocol that planned a reduction in respiratory pressures when the infant's oxygen requirement had reached a fractional concentration of inspired oxygen of 0.6.\n Five patients in the HFOV group died, and eight patients did not respond to the randomized ventilation mode; whereas four patients in the IPPV group died, and nine were switched to HFOV. No differences were found in gas exchange or ventilator support over the first 72 hours. Premature infants with a birth weight < 1000 gm had a significantly shorter course to reach fractional concentration of inspired oxygen of 0.21 while receiving IPPV than those receiving HFOV (9.3+/-4.5 days vs 27.5+/-10.2 days, p = 0.01). No differences were found between the groups in extraalveolar air (HFOV seven; IPPV, seven) and intracranial bleeding (HFOV, nine; IPPV, eight).\n After surfactant treatment, HFOV, as a primary ventilation mode in premature infants with respiratory distress syndrome, is as safe and efficacious as conventional ventilation." ]	There is no clear evidence that elective HFOV offers important advantages over CV when used as the initial ventilation strategy to treat preterm infants with acute pulmonary dysfunction. There may be a small reduction in the rate of CLD with HFOV use, but the evidence is weakened by the inconsistency of this effect across trials and the overall borderline significance. Future trials on elective HFOV should target those infants who are at most risk of CLD (extremely preterm infants), compare different strategies for generating HFOV and CV, and report important long-term neurodevelopmental outcomes.
CD003817	[ "3302144", "9070555", "11678486", "9540015", "9803696", "16801586", "10888969", "11743061", "12941710", "9086690", "18227359", "16472039", "7593872", "19637289", "8559961", "8280188", "3071485", "16507343", "8990415", "2368376", "14633807", "15805347", "9279482", "10703876", "4032130", "11874926", "20003224", "8296738", "9929086", "1925430", "17331082", "20854564", "11828224", "3100910", "8612437", "14500058", "9314625", "7960690", "9028689", "21108032" ]	[ "Effects of diet and exercise interventions on control and quality of life in non-insulin-dependent diabetes mellitus.", "Comparison of single versus multiple lifestyle interventions: are the antihypertensive effects of exercise training and diet-induced weight loss additive?", "Computerized weight loss intervention optimizes staff time: the clinical and cost results of a controlled clinical trial conducted in a managed care setting.", "Lifestyle intervention in overweight individuals with a family history of diabetes.", "Use of personal trainers and financial incentives to increase exercise in a behavioral weight-loss program.", "Promoting physical activity in a low-income multiethnic district: effects of a community intervention study to reduce risk factors for type 2 diabetes and cardiovascular disease: a community intervention reducing inactivity.", "Exercise and weight loss reduce blood pressure in men and women with mild hypertension: effects on cardiovascular, metabolic, and hemodynamic functioning.", "Men gain additional psychological benefits by adding exercise to a weight-loss program.", "One-year outcome of a combination of weight loss therapies for subjects with type 2 diabetes: a randomized trial.", "Exercise in the treatment of obesity: effects of four interventions on body composition, resting energy expenditure, appetite, and mood.", "Clinic-based support to help overweight patients with type 2 diabetes increase physical activity and lose weight.", "Effects of a CHANGE intervention to increase exercise maintenance following cardiac events.", "Long-term effects of interventions for weight loss using food provision and monetary incentives.", "Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without weight loss.", "Physical activity within a community-based weight control program: program evaluation and predictors of success.", "Diet and exercise are equally effective in reducing risk for cardiovascular disease. Results of a randomized controlled study in men with slightly to moderately raised cardiovascular risk factors.", "Exercise in a behavioural weight control programme for obese patients with Type 2 (non-insulin-dependent) diabetes.", "A cognitive/behavioral group intervention for weight loss in patients treated with atypical antipsychotics.", "A worksite program for overweight middle-aged men achieves lesser weight loss with exercise than with dietary change.", "Coronary risk factors in type II diabetes: response to low-intensity aerobic exercise.", "The Finnish Diabetes Prevention Study (DPS): Lifestyle intervention and 3-year results on diet and physical activity.", "Short- and long-term beneficial effects of a combined dietary-behavioral-physical activity intervention for the treatment of childhood obesity.", "Will older sedentary people with non-insulin-dependent diabetes mellitus start exercising? A health promotion model.", "The effect of weight loss with or without exercise training on large artery compliance in healthy obese men.", "Effect of diet and controlled exercise on weight loss in obese children.", "Effects of an energy-restrictive diet with or without exercise on abdominal fat, intermuscular fat, and metabolic risk factors in obese women.", "Aerobic exercise in obese diabetic patients with chronic kidney disease: a randomized and controlled pilot study.", "Exercise testing and training in physically disabled men with clinical evidence of coronary artery disease.", "Effects of lifestyle activity vs structured aerobic exercise in obese women: a randomized trial.", "The effect of a weight reduction program on cardiovascular risk factors among overweight hypertensives in primary health care.", "Combined diet and exercise intervention reverses the metabolic syndrome in middle-aged males: results from the Oslo Diet and Exercise Study.", "LiFE Pilot Study: A randomised trial of balance and strength training embedded in daily life activity to reduce falls in older adults.", "The effect of exercise, cognitive therapy, and nutritional counseling in treating bulimia nervosa.", "The independent effects of dietary weight loss and aerobic training on high density lipoproteins and apolipoprotein A-I concentrations in obese men.", "Effects of a behavioral weight loss program stressing calorie restriction versus calorie plus fat restriction in obese individuals with NIDDM or a family history of diabetes.", "Look AHEAD (Action for Health in Diabetes): design and methods for a clinical trial of weight loss for the prevention of cardiovascular disease in type 2 diabetes.", "A randomized controlled trial of weight reduction and exercise for diabetes management in older African-American subjects.", "Moderate exercise improves glucose metabolism in uncontrolled elderly patients with non-insulin-dependent diabetes mellitus.", "Lifestyle changes may reverse development of the insulin resistance syndrome. The Oslo Diet and Exercise Study: a randomized trial.", "Directive and nondirective e-coach support for weight loss in overweight adults." ]	[ "Evidence suggests that diet and exercise are associated with improved glucose tolerance for patients with non-insulin-dependent diabetes mellitus (NIDDM). Seventy-six volunteer adult patients with NIDDM were each assigned to one of four programs: diet, exercise, diet plus exercise, or education (control). Each program required ten weekly meetings. Detailed evaluations were completed prior to the program and after three, six, 12, and 18 months. Evaluations included various psychosocial measures, measures of the quality of life, and fasting blood glucose, glycosylated hemoglobin, and relative weight determinations. Of the 76 original participants, 70 completed the 18-month follow-up study. At 18 months, the combination diet-and-exercise group had achieved the greatest reductions in glycosylated hemoglobin measures. In addition, this group showed significant improvements on a general quality of life measure. These improvements were largely uncorrelated with changes in weight. The authors conclude that the combination of dietary change and physical conditioning benefits NIDDM patients, and that the benefits may be independent of substantial weight loss.", "Although aerobic exercise training and diet-induced weight loss each have been shown to individually lower elevated blood pressure (BP), it is currently not known whether their combined use produces an additive antihypertensive effect. In this randomized clinical trial we therefore compared the effect on resting BP of exercise training only and dietary modification only with that of exercise training plus dietary modification in 55 sedentary, overweight patients with high normal BP or stage 1 or 2 hypertension. After baseline testing, patients were randomized to 1 of the following 3 interventions for 12 weeks: exercise training only (aerobic exercise; 30 to 45 minutes; 3 to 5 days/week; 60% to 85% of maximal heart rate), dietary modification only (aimed primarily at weight loss via restriction of energy intake and dietary fat), or exercise training plus dietary modification. Forty-eight patients completed the study. In these patients, exercise training plus dietary modification elicited a greater reduction (p < or = 0.001) in body weight (-7.1 +/- 2.9 vs -1.0 +/- 1.8 kg) than exercise training only, and a greater increase (p < or = 0.05) in maximal oxygen uptake (4.3 +/- 2.6 vs 1.9 +/- 2.0 ml/kg/min) versus dietary modification only. However, the reduction in BP with exercise training plus dietary modification (-12.5 +/- 6.3/7.9 +/- 4.3 mm Hg) did not differ significantly from that with exercise training only (-9.9 +/- 6.4/5.9 +/- 4.6 mm Hg) or dietary modification only (-11.3 +/- 12.1/7.5 +/- 4.3 mm Hg). These data indicate that the antihypertensive effects of exercise training and diet-induced weight loss are not additive. This finding has important public health and clinical implications for the millions of overweight persons with high normal BP or stage 1 or 2 hypertension.", "To evaluate the costs and effects of incremental components of a weight-loss program.\n A 3-arm, 12-month randomized controlled clinical trial to evaluate 3 incremental levels of intervention intensity.\n The study included 588 individuals (BMI > 25 kg/m2) in a freestanding health maintenance organizalion and achieved an 81% completion rate.\n Using a cognitive behavioral approach for tailoring lifestyle modification goals, the incremental levels of intervention included a) a workbook alone, b) the addition of computerized tailoring using onsite computer kiosks with touch screen monitors, and c) the addition of both computers and staff consultation.\n Endpoints included weight parameters, lipid profile, plasma glucose, blood pressure, intervention costs, dietary intake, and physical activity.\n Study endpoints were analyzed using analysis of variance for normally distributed variables and analysis of covariance to control for any baseline differences. Regression and correlation analysis assessed the relationship between weight loss and other variables.\n For the increasing levels of intervention intensity, the mean 12-month weight losses were 2.2, 4.7, and 7.4 pounds, with the respective cost per participant being $12.33, $41.99, and $133.74. The decreases in mean BMIs for these respective intervelation levels were 0.4, 0.9 and 1.2. All groups reported a decrease in energy and fat intake and an increase in blocks walked (P<.01). Intervention variables that correlated with weight loss included more computer log-ons, achieving computer-selected goals, more self-monitoring, increased walking, and decreased energy and fat intake, as well as higher attendance in staff consultation group sessions for that treatment condition. Weight loss correlated with decreases in fasting glucose and blood pressure.\n In a weight-loss program, computers can facilitate selecting behavioral change goals. More frequent usage resulted in greater weight loss. Staff counseling to augment the computer intervention achieved the most weight loss.", "To assess the effect of lifestyle intervention over 2 years on changes in weight, coronary heart disease (CHD) risk factors, and incidence of diabetes in overweight individuals with a parental history of diabetes.\n Participants (n = 154), who were 30-100% over ideal body weight, had one or both parents with diabetes, and were currently nondiabetic, were randomly assigned to 2-year treatments focused on diet (decreasing calories and fat intake), exercise (goal of 1,500 kcal/week of moderate activity), or the combination of diet plus exercise or to a no-treatment control group. Subjects were reassessed at 6 months, 1 year, and 2 years.\n At 6 months, the groups differed significantly on measures of eating, exercise, and fitness; weight losses in the diet and diet-plus-exercise groups were significantly greater than in the exercise and control conditions. Weight losses were associated with positive changes in CHD risk factors. After 6 months, there was gradual deterioration of behavioral and physiological changes, so that at 2 years, almost no between-group differences were maintained. Differences between groups in risk of developing diabetes were of borderline significance (P = 0.08). Strongest predictors were impaired glucose tolerance at baseline, which was positively related to risk of developing diabetes, and weight loss from baseline to 2 years, which was negatively related; in all treatment groups, a modest weight loss of 4.5 kg reduced the risk of type 2 diabetes by approximately 30% compared with no weight loss.\n Although initially successful, the interventions studied here were not effective in producing long-term changes in behavior, weight, or physiological parameters. However, weight loss from 0 to 2 years reduced the risk of developing type 2 diabetes. Since modest weight loss significantly reduced risk of type 2 diabetes, further research is needed to determine how best to increase the percentage of subjects achieving at least a modest weight loss.", "Exercise is the best predictor of long-term weight loss. This study evaluated two strategies for improving exercise adherence and long-term weight loss in obese outpatients. Obese men and women (N = 193) were randomized to 1 of 5 treatment groups for 18 months: standard behavior therapy (SBT); SBT with supervised walks (SW) 3 times per week; SBT + SW with personal trainers (PT), who walked with participants, made phone reminders, and did make-up SW; SBT + SW with monetary incentives (I) for completing SW; and SBT + SW + PT + I. Both PT and I enhanced attendance at SWs, the combination producing the best adherence. Increased walk attendance did not result in higher overall energy expenditure, however, and long-term weight loss was also not improved. Post hoc analyses suggest that the level of exercise needed for successful long-term weight loss is much higher than that usually recommended in behavioral treatment programs.", "The aim was to assess the net effects on risk factors for type 2 diabetes and cardiovascular disease of a community-based 3-year intervention to increase physical activity.\n A pseudo-experimental cohort design was used to compare changes in risk factors from an intervention and a control district with similar socioeconomic status in Oslo, Norway, using a baseline investigation of 2,950 30- to 67-year-old participants and a follow-up investigation of 1,776 (67% of those eligible, 56% women, 18% non-Western immigrants) participants. A set of theory-based activities to promote physical activity were implemented and tailored toward groups with different psychosocial readiness for change. All results reported are net changes (the difference between changes in the intervention and control districts). At both surveys, the nonfasting serum levels of lipids and glucose were adjusted for time since last meal.\n The increase in physical activity measured by two self-reported questionnaires was 9.5% (P = 0.008) and 8.1% (P = 0.02), respectively. The proportion who increased their body mass was 14.2% lower in the intervention district (P < 0.001), implying a 50% relative reduction compared with the control district, and was lower across subgroups. Beneficial effects were seen for triglyceride levels (0.16 mmol/l [95% CI 0.06-0.25], P = 0.002), cholesterol-to-HDL cholesterol ratio (0.12 [0.03-0.20], P = 0.007), systolic blood pressure (3.6 mmHg [2.2-4.8], P < 0.001), and for men also in glucose levels (0.35 mmol/l [0.03-0.67], P = 0.03). The net proportion who were quitting smoking was 2.9% (0.1-5.7, P = 0.043).\n Through a theory-driven, low-cost, population-based intervention program, we observed an increase in physical activity levels, reduced weight gain, and beneficial changes in other risk factors for type 2 diabetes and cardiovascular disease.", "Lifestyle modifications have been recommended as the initial treatment strategy for lowering high blood pressure (BP). However, evidence for the efficacy of exercise and weight loss in the management of high BP remains controversial.\n One hundred thirty-three sedentary, overweight men and women with unmedicated high normal BP or stage 1 to 2 hypertension were randomly assigned to aerobic exercise only; a behavioral weight management program, including exercise; or a waiting list control group. Before and following treatment, systolic and diastolic BPs were measured in the clinic, during daily life, and during exercise and mental stress testing. Hemodynamic measures and metabolic functioning also were assessed.\n Although participants in both active treatment groups exhibited significant reductions in BP relative to controls, those in the weight management group generally had larger reductions. Weight management was associated with a 7-mm Hg systolic and a 5-mm Hg diastolic clinic BP reduction, compared with a 4-mm Hg systolic and diastolic BP reduction associated with aerobic exercise; the BP for controls did not change. Participants in both treatment groups also displayed reduced peripheral resistance and increased cardiac output compared with controls, with the greatest reductions in peripheral resistance in those in the weight management group. Weight management participants also exhibited significantly lower fasting and postprandial glucose and insulin levels than participants in the other groups.\n Although exercise alone was effective in reducing BP, the addition of a behavioral weight loss program enhanced this effect. Aerobic exercise combined with weight loss is recommended for the management of elevated BP in sedentary, overweight individuals.", "Adding exercise to a comprehensive weight-loss program might not only attenuate any psychological distress associated with weight-loss attempts but also may provide psychological benefits. This study examined whether a diet-plus-exercise weight-loss program improved psychological outcomes more than a diet-only weight-loss program or an assessment-only control group.\n This study was part of a larger 1-year randomized weight-loss trial examining the effects of diet and exercise on cardiovascular disease risk factors in 264 overweight adults. Psychological measures specific to weight control (e.g., cognitive restraint, disinhibition, hunger, and body dissatisfaction) as well as traditional measures of psychological distress (e.g., symptoms of depression, anxiety, and stress) were obtained at baseline and 1 year.\n Men and women in either weight-loss program reported greater restraint, less disinhibition, and less hunger at 1 year than those in no program. Men in the diet-plus-exercise program experienced additional increases in restraint and decreases in hunger than did men in the diet-only program. Women in the diet-plus-exercise program did not experience additional psychological benefits specific to weight control than those in the diet-only program, despite increases in aerobic capacity.\n The pattern seen for overweight men in the diet-plus-exercise program at 1 year-greater restraint, less disinhibition, and less hunger-is similar to the pattern seen in successful weight maintainers. These results underscore the need for innovative strategies that will enhance and sustain the pattern of psychological benefits specific to weight control associated with successful weight loss, especially for overweight women.", "The purpose of this study was to evaluate the effects of a combination weight loss program using intermittent low-calorie diets, energy-controlled meal replacement products, and sibutramine on weight loss, diabetes control, and cardiovascular risk factors in overweight or obese subjects with type 2 diabetes.\n Overweight or obese individuals with type 2 diabetes treated with diet or oral medication were randomly assigned to either a standard therapy or combination therapy group. Both groups received a standardized program to facilitate weight loss. The combination therapy group also received 10-15 mg sibutramine daily, low-calorie diets using meal replacement products for 1 week every 2 months, and between low-calorie diet weeks, once daily use of meal replacement product and snack bars to replace one usual meal and snack. Primary outcome measures were changes in body weight, glycemic control, plasma lipids, blood pressure, pulse, and body composition at 1 year.\n At 1 year, combination therapy, compared with standard therapy, resulted in significantly more weight loss (-7.3 +/- 1.3 kg vs. -0.8 +/- 0.9 kg, P < 0.001) and reduction in HbA(1c) (-0.6 +/- 0.3 vs. 0.0 +/- 0.2%, P = 0.05). Combination therapy resulted in reduced requirement for diabetes medications and decreased fat mass and lean body mass. A 5-kg decrease in weight at 1 year was associated with a decrease of 0.4% in HbA(1c) (P = 0.006). Changes in fasting glucose, lipids, pulse, and blood pressure did not differ between groups.\n This combination weight loss program resulted in greater weight loss and improved diabetes control compared with a standard weight loss program in overweight or obese subjects with type 2 diabetes.", "This study investigated changes in body composition, resting energy expenditure (REE), appetite, and mood in 128 obese women who were randomly assigned to 1 of 4 treatment conditions: diet alone, diet plus aerobic training, diet plus strength training, or diet combined with aerobic and strength training (i.e., combined training). All women received the same 48-week group behavioral program and were prescribed the same diet. Exercising participants were provided 3 supervised exercise sessions per week for the first 28 weeks and 2 sessions weekly thereafter. Participants across the 4 conditions achieved a mean weight loss of 16.5 +/- 6.8 kg at Week 24, which decreased to 15.1 +/- 8.4 kg at Week 48. There were no significant differences among conditions at any time in changes in weight or body composition. Women who received aerobic training displayed significantly smaller reductions in REE at Week 24 than did those who received strength training. There were no other significant differences among conditions at any time on this variable or in changes in appetite and mood.", "Our objective was to test the effect of physicians providing brief health lifestyle counseling to patients with type 2 diabetes mellitus during usual care visits.\n We conducted a randomized controlled trial of a 12-month intervention at 2 large community health centers, enrolling 310 patients with a body mass index (calculated as weight in kilograms divided by height in meters squared) of 25 or greater. In the intervention group, self-management goals for nutrition and physical activity were set using a tailored computer program. Goals were then reviewed at each clinic visit by physicians. The control group received only printed health education materials. The main outcome measures included change in physical activity and body weight.\n In the intervention group, recommended levels of physical activity increased from 26% at baseline to 53% at 12 months (P< .001) compared with controls (30% to 37%; P= .27), and 32% of patients in the intervention group lost 6 or more pounds at 12 months compared with 18.9% of controls (odds ratio, 2.2; P= .006).\n A brief intervention to increase the dialogue between patients and health care providers about behavioral goals can lead to increased physical activity and weight loss.", "Despite participation in a cardiac rehabilitation program, there is a downward trajectory of exercise participation during the year following a cardiac event.\n The purpose of this study was to test the effectiveness of CHANGE (Change Habits by Applying New Goals and Experiences), a lifestyle modification program designed to increase exercise maintenance in the year following a cardiac rehabilitation program. The CHANGE intervention consists of 5 small-group cognitive-behavioral change counseling sessions in which participants are taught self-efficacy enhancement, problem-solving skills, and relapse prevention strategies to address exercise maintenance problems.\n Participants (N = 250) were randomly assigned to the CHANGE intervention (supplemental to usual care) or a usual-care-only group. Exercise was measured using portable wristwatch heart rate monitors worn during exercise for 1 year. Cox proportional hazards regression was used to determine differences in exercise over the study year between the study groups.\n Participants in the usual-care group were 76% more likely than those in the CHANGE group to stop exercising during the year following a cardiac rehabilitation program (hazard ratio = 1.76, 95% confidence interval = 1.08-2.86, p = .02) when adjusting for the significant covariates race, gender, comorbidity, muscle and joint pain, and baseline motivation. Most participants, however, had less than recommended levels of exercise amount and intensity.\n Counseling interventions that use contemporary behavior change strategies, such as the CHANGE intervention, can reduce the number of individuals who do not exercise following cardiac events.", "One hundred seventy-seven men and women who had participated in an 18-month trial of behavioral interventions involving food provision and financial incentives were examined 12 months later. Food provision, but not financial incentives, led to better weight loss than standard behavioral treatment during the 18-month trial, but over 12 additional months of no-treatment follow-up, all treated groups gained weight, maintained only slightly better weight losses than a no-treatment control group, and did not differ from each other. Weight loss success during both active treatment and maintenance was associated with increase in exercise, decrease in percentage of energy from fat, increase in nutrition knowledge, and decrease in perceived barriers to adherence. Obesity treatment research should focus on developing better ways to maintain changes in the diet and exercise behaviors needed for sustained weight loss.", "Weight loss remains the most common therapy advocated for reducing hepatic lipid in obesity and nonalcoholic fatty liver disease. Yet, reduction of body weight by lifestyle intervention is often modest, and thus, therapies which effectively modulate the burden of fatty liver but are not contingent upon weight loss are of the highest practical significance. However, the effect of aerobic exercise on liver fat independent of weight loss has not been clarified. We assessed the effect of aerobic exercise training on hepatic, blood, abdominal and muscle lipids in 19 sedentary obese men and women using magnetic resonance imaging and proton magnetic resonance spectroscopy ((1)H-MRS). Four weeks of aerobic cycling exercise, in accordance with current physical activity guidelines, significantly reduced visceral adipose tissue volume by 12% (P < 0.01) and hepatic triglyceride concentration by 21% (P < 0.05). This was associated with a significant (14%) reduction in plasma free fatty acids (P < 0.05). Exercise training did not alter body weight, vastus lateralis intramyocellular triglyceride concentration, abdominal subcutaneous adipose tissue volume, (1)H-MRS-measured hepatic lipid saturation, or HOMA-IR (homeostasis model assessment of insulin resistance; P > 0.05).\n These data provide the first direct experimental evidence demonstrating that regular aerobic exercise reduces hepatic lipids in obesity even in the absence of body weight reduction. Physical activity should be strongly promoted for the management of fatty liver, the benefits of which are not exclusively contingent upon weight loss.", "To assess the feasibility and effectiveness of adding physical activity sessions to a weight control program in a community health center and to identify individuals suitable for outpatient group treatment with and without physical activity.\n The study population included 42 overweight women who were randomly divided into treatment groups. Both treatment groups received guidance in nutrition and behavior modification and the exercise group also participated in physical activity sessions. Both treatments included 20 sessions and participants were followed up for eight months.\n In both treatments, significant improvements were seen in physical fitness, anthropometric measurements, nutritional knowledge, food consumption, and eating behaviors. Weight loss following three months of weekly sessions did not differ by treatment group. At follow-up there was a trend towards increased maintenance of weight loss in the exercise group, however differences were not statistically significant. Attrition rates were low in both treatments and participant satisfaction was high. Lower baseline BMI predicted larger weight losses, in particular in the exercise group. Other predictors of weight loss included poorer baseline eating behaviors and employment outside of the home. Perceived spouse support predicted continual participation.", "To study the impact of diet and exercise and the combination thereof on cardiovascular risk factors, 157 healthy men aged 35-60 years (mean +/- S.D.; 46.2 +/- 5.0) with slightly to moderately raised cardiovascular risk factors, were randomized to 4 groups, diet (D, n = 40), exercise (E, n = 39), diet plus exercise (DE, n = 39), and no active intervention (controls (C, n = 39)), and investigated at baseline and after 6 months. BMI was significantly reduced in Groups E and DE (mean difference and 95% confidence intervals (CI), -0.3 (-0.5, -0.01) and -0.6 (-0.9, -0.3) kg/m2, respectively). Waist circumference was reduced in all 3 intervention groups (D, E, and DE), -1.3 (-2.5, -0.1), -2.2 (-3.2, -1.3) and -3.0 (-3.9, -2.0) cm, but not in the control group. Blood pressure (BP) was reduced in all 3 intervention groups, systolic BP 4-7 mmHg and diastolic BP 2-6 mmHg. Serum cholesterol was reduced in Group DE, -0.45 (-0.77, -0.13) mmol/l. VLDL-cholesterol was reduced in Groups E and DE, -0.14 (-0.26, -0.03) and -0.09 (-0.18, -0.01) mmol/l, whereas LDL-cholesterol was reduced in Groups D and DE -0.30 (-0.54, -0.06) and -0.35 (-0.64, -0.05) mmol/l. In contrast, neither HDL-cholesterol nor serum triglycerides were influenced by the interventions. According to the coronary risk profile derived from the Framingham study, all 3 intervention groups (D, E, and DE) significantly reduced their estimated 10-year risk (-13, -12, and -14%, respectively). We conclude that even with rather moderate changes in diet and exercise, several important cardiovascular risk factors can be affected and that diet and exercise were about equally effective in reducing cardiovascular risk.", "Two studies were conducted to determine whether adding exercise to a diet programme promotes weight loss or glycaemic control in Type 2 (non-insulin-dependent) diabetic subjects. In Study 1, 25 subjects were randomly assigned to diet plus moderate exercise or diet plus placebo exercise. All subjects exercised twice a week as a group and once a week on their own; the diet plus moderate exercise group walked a 3-mile route at each session while the diet plus placebo exercise group did very low intensity exercises such as stretching and light calisthenics. All subjects followed a calorie-counting diet and were taught behaviour modification strategies. Weight losses and improvements in glycaemic control did not differ significantly between the two treatment groups at the end of the 10-week treatment or at 1-year follow-up. In Study 2, more extreme conditions were compared: a diet only group and a diet plus exercise group. The diet plus exercise group walked a 3-mile route with the group 3 times/week and once a week on their own, while the diet only group was instructed to maintain their current low level of activity. Both groups received comparable diet and behaviour modification instruction and therapist contacts. The diet plus exercise group had significantly (p less than 0.01) better weight losses than the diet only condition at the end of the 10 week programme (-9.3 kg vs -5.6 kg) and at 1 year follow-up (-7.9 kg vs -3.8 kg).(ABSTRACT TRUNCATED AT 250 WORDS)", "Obesity and diabetes have caused problems for individuals with schizophrenia long before atypical antipsychotic agents. The prevalence of obesity, insulin resistance, impaired glucose tolerance, type 2 diabetes mellitus, dyslipidemia, and the Metabolic Syndrome has increased in people with schizophrenia as compared to the general population. Risk reduction studies for persons with obesity, diabetes, and cardiovascular disease indicate that cognitive/behavioral interventions that promote motivation and provide strategies to overcome the barriers in adherence to diet and activity modification are effective interventions for weight management and risk reduction. In the landmark multi-center randomized-controlled trial study, the Diabetes Prevention Project (DPP), a cognitive/behavioral intervention, was more successful in producing weight loss and preventing diabetes than the drugs metformin, troglitazone or placebo. This pilot study examined the effectiveness of a cognitive/behavioral group intervention, modified after the DPP program, in individuals with schizophrenia or schizoaffective disorder taking atypical antipsychotics in a large urban public mental health system. Outcome measures included body weight, body mass index, waist-hip ratios, and fasting glucose levels. Both groups demonstrated elevated fasting glucose levels and were obese with a mean BMI of 33. The group that received the cognitive/behavioral group intervention lost more weight than the treatment as usual group. The CB group participants lost an average of 5.4 lb or 2.9% of body weight, and those in the control group lost 1.3 lb or 0.6% body weight. The range of weight loss for the treatment group was from 1 to 20 lb. This pilot study has demonstrated that weight loss is possible with cognitive/behavioral interventions in a population with a psychotic disorder.", "To compare changes in total and regional body composition using dual energy X-ray absorptiometry (DEXA) after subjects lost weight through change in diet or exercise.\n A 12-month, randomized, controlled study of two weight-loss interventions-low-fat diet ad libitum or moderate, unsupervised exercise-in free-living, middle-aged men. Compliance was determined at monthly measurement sessions through food records and activity logs; DEXA scans were performed every 3 months.\n Fifty-eight overweight men (mean body mass index = 29.0 +/- 2.6; mean age = 43.4 +/- 5.7 years) recruited from a national corporation were assigned randomly to diet, exercise, or control groups.\n One group reduced dietary fat to 26.4% of energy intake but kept activity unchanged; another group self-selected aerobic exercise (three sessions per week at 65% to 75% maximum heart rate) but kept diet unchanged. A control group maintained weight.\n At 12 months, measurements of weight, total and regional fat mass and lean mass, energy intake, and percentage dietary fat; physical activity indexes.\n Results were analyzed using paired t tests and analysis of variance.\n Mean weight loss was 6.4 +/- 3.3 kg in dieters and 2.6 +/- 3.0 kg in exercisers; control subjects maintained weight. DEXA scans revealed that 40% of dieters' weight loss was lean tissue; more than 80% of weight lost by exercisers was fat. Exercisers maintained limb lean tissue and lost fat mass.\n Greater total weight and lean tissue loss occurred when subjects lost weight through a low-fat diet consumed ad libitum than when subjects participated in unsupervised aerobic exercise. Use of DEXA enabled identification of progressive total and regional changes in fat and lean tissue.", "Patients with non-insulin-dependent diabetes are at greatly increased risk for coronary artery disease. Although exercise training has been shown to decrease risk factors, the presence of obesity, older age, and a sedentary lifestyle make a high-intensity exercise program an unrealistic choice of therapy. Therefore, we examined the effect of a low-to-moderate-intensity (mean 69 per cent of maximal heart rate) walking program on lipids, glucose, insulin, glycosylated hemoglobin and cardiovascular fitness. Nine women and seven men, mean age 56, were randomly assigned to a control or an exercise group which exercised three times per week for two months. Supervised exercise sessions consisted of 40-45 minutes of walking and/or slow jogging. Subjects continued on their usual diets. The trained group showed a significant improvement in VO2max from 1.65 to 1.95 L/min. Resting systolic blood pressure decreased from 141 to 130 mm Hg after training, and resting heart rate decreased from 88 to 81. Glycosylated hemoglobin decreased in the exercise group in seven or eight subjects and in only two of eight controls. Triglycerides decreased in the exercise group from 285 to 223 mg/dl. Body weight, total and HDL cholesterol, glucose, and insulin did not change in either group. These data indicate that a low-to-moderate level of aerobic training, independent of dietary changes, is an effective and feasible method of improving cardiovascular risk factors: physical fitness, systolic blood pressure, plasma triglycerides, and glycemic control in non-insulin-dependent diabetic subjects.", "To describe the 1) lifestyle intervention used in the Finnish Diabetes Prevention Study, 2) short- and long-term changes in diet and exercise behavior, and 3) effect of the intervention on glucose and lipid metabolism.\n There were 522 middle-aged, overweight subjects with impaired glucose tolerance who were randomized to either a usual care control group or an intensive lifestyle intervention group. The control group received general dietary and exercise advice at baseline and had an annual physician's examination. The subjects in the intervention group received additional individualized dietary counseling from a nutritionist. They were also offered circuit-type resistance training sessions and advised to increase overall physical activity. The intervention was the most intensive during the first year, followed by a maintenance period. The intervention goals were to reduce body weight, reduce dietary and saturated fat, and increase physical activity and dietary fiber.\n The intervention group showed significantly greater improvement in each intervention goal. After 1 and 3 years, weight reductions were 4.5 and 3.5 kg in the intervention group and 1.0 and 0.9 kg in the control group, respectively. Measures of glycemia and lipemia improved more in the intervention group.\n The intensive lifestyle intervention produced long-term beneficial changes in diet, physical activity, and clinical and biochemical parameters and reduced diabetes risk. This type of intervention is a feasible option to prevent type 2 diabetes and should be implemented in the primary health care system.", "Obesity has become the most common pediatric chronic disease in the modern era. Early prevention and treatment of childhood and adolescent obesity is mandated. Surprisingly, however, only a minor fraction of obese children participate in weight reduction interventions, and the longer-term effects of these weight-reduction interventions among children have not been elucidated.\n To examine prospectively the short- and long-term effects of a 3-month, combined dietary-behavioral-physical activity intervention on anthropometric measures, body composition, dietary and leisure-time habits, fitness, and lipid profiles among obese children.\n In this randomized prospective study, 24 obese subjects completed the 3-month intervention and were compared with 22 obese, age- and gender-matched, control subjects.\n At 3 months, there were significant differences in changes in body weight (-2.8 +/- 2.3 kg vs 1.2 +/- 2.2 kg), BMI (-1.7 +/- 1.1 kg/m2 vs -0.2 +/- 1.0 kg/m2), body fat percentage (from skinfold tests; -3.3 +/- 2.6% vs 1.4 +/- 4.7%), serum total cholesterol level (-24.6 +/- 15.1 mg/dL vs 0.8 +/- 18.7 mg/dL), low-density lipoprotein cholesterol level (-23.3 +/- 15.2 mg/dL vs -3.7 +/- 17.3 mg/dL), and fitness (215 +/- 107 seconds vs 50 +/- 116 seconds) in the intervention group versus the control group. After a 1-year follow-up period, there were significant differences between the intervention group (n = 20) and the control group (n = 20) in body weight (0.6 +/- 6.0 kg vs 5.3 +/- 2.7 kg), BMI (-1.7 +/- 2.3 kg/m2 vs 0.6 +/- 0.9 kg/m2), and body fat percentage. There was a significant increase in leisure-time physical activity among the intervention participants, compared with a decrease among the control subjects.\n Our data demonstrate the short- and longer-term beneficial effects of a combined dietary-behavioral-physical activity intervention among obese children. These results highlight the importance of multidisciplinary programs for the treatment of childhood obesity and emphasize their encouraging long-term effects.", "Exercise and diet are the cornerstones of management of non-insulin-dependent diabetes mellitus (NIDDM). Many older people have difficulty in exercising, missing benefits on glycaemic control, weight, cardiac disease and mood. We report the outcomes of a 6 month structured exercise and support programme based on a health promotion model, on physical activity, glycaemic control and parameters of cardiovascular risk in non-exercisers, compared with standard outpatient clinic education. A total of 26 non-exercising patients were randomised to an intervention or control group (ten men, 16 women; mean age (+/- S.D.) 60 +/- 8 years). Programme participation was not associated with any significant increase in activity. Glycated hemoglobin (HbAtc) levels tended to stabilise in the intervention group during the 6 month programme and to deteriorate in the control group (P = 0.03); by 12 months HbA1C levels deteriorated to a similar level in both. Programme participation did not cause significant change in anthropometric or metabolic parameters. Examining the cohort as a whole, increased activity over 6 months was associated with improvements in weight, body mass index (BMI), body fat and fasting insulin. Activity increases over 12 months were associated with improvements in weight and BMI. These changes could not be attributed to changes in energy intake or dietary composition. We conclude that while exercise can benefit older people with NIDDM, a programme based on a model of health promotion was not effective in increasing physical activity.", "Obesity is an independent risk factor for cardiovascular morbidity and mortality. Large artery compliance is thought to be associated with cardiovascular risk. The effect of weight loss on large artery compliance is not yet clarified.\n To investigate the effect of weight loss, with or without exercise, on vessel wall properties in healthy obese men.\n This was a pair-matched randomized intervention study. All subjects were on an energy-restricted diet. One subject from each pair was also on an exercise programme. Measurements were performed before and at the end of the study period. The study lasted for 3 months.\n The vessel wall properties of the brachial and common carotid artery were assessed using a vessel wall movement detector system in combination with applanation tonometry.\n The mean body mass index was 32.3+/-0.4 kg/m2 and decreased (P < 0.001) to 27.6+/-0.4 kg/mm2 during the study. The mean blood pressure decreased (P < 0.001) by 6%. At operating pressures, carotid artery distensibility was 27.5+/-1.7 x 10(-3)/kPa at the start of the study and 31.1+/-1.8 x 10(-3)/kPa (P < 0.04) at the end of the study. Brachial and carotid artery compliances were 0.11+/-0.01 and 1.35+/-0.08 mm2/kPa at the start of the study and tended to increase to 0.12+/-0.001 (P = 0.06) and 1.48+/-0.08 mm2/kPa (P = 0.057), respectively, at the end of the study. Isobaric compliance did not change. The diet-and-exercise group did not differ statistically from the only-diet group in the effects on weight loss, blood pressure and arterial compliance.\n This study shows that weight loss increased carotid artery distensibility at operating pressures, but not under isobaric conditions. This increase is probably due to the decrease in blood pressure. The addition of exercise did not result in an additional effect within 3 months.", "The effects of adding exercise to diet for weight control in obese children were evaluated by randomizing obese girls to one of two groups: diet and diet plus exercise. During the first 6 weeks of the treatment, children exercised in a supervised three times a week exercise program, in which they walked or ran 3 miles. Significant decreases from baseline weight and in percent overweight were observed for both groups during the year of treatment. Significant decreases in percent overweight were observed at 0 to 2 months and then at 2 to 6 months for the children who were exercising, whereas percent overweight in children in the diet-alone group decreased only from 0 to 2 months. In addition, a significant improvement in fitness was observed only for children in the diet plus exercise group.", "The primary objective was to examine whether the combination of diet and aerobic exercise (DA) or diet and resistance exercise (DR) is associated with greater improvements in metabolic risk factors by comparison to diet only (DO) in obese women. A second objective considered whether reductions in metabolic risk factors are related to concurrent changes in abdominal and/or intermuscular fat distribution.\n A total of 38 premenopausal obese women were randomly assigned to one of three 16-week treatments: DO (n=13), DA (n=11), or DR (n=14). Plasma glucose, insulin, and lipid levels were measured in a fasting state and after a 75-g oral glucose challenge (oral glucose tolerance test [OGTT]). Total, abdominal subcutaneous, visceral, and intermuscular fat were measured by magnetic resonance imaging.\n Significant reductions (P < 0.02) in body weight (approximately 10 kg or 10%) and in total, abdominal subcutaneous, visceral, and intermuscular fat were observed within each group. Fasting and OGTT insulin, total cholesterol, LDL cholesterol, and apolipoprotein B also decreased within each group (P < or = 0.02). The changes in the body fat and metabolic variables were not different across treatment (P > 0.05). Visceral fat alone was related to the metabolic risk factors both before and after the treatment.\n Weight loss was associated with reductions in metabolic risk factors in obese women. The improvement in the metabolic profile was not enhanced by the addition of aerobic or resistance exercise. The findings reinforce the importance of diminished visceral fat in the treatment of insulin resistance.", "Patients with obesity, diabetes, and chronic kidney disease (CKD) are generally physically inactive, have a high mortality rate, and may benefit from an exercise program.\n We performed a 24-week randomized controlled feasibility study comparing aerobic exercise plus optimal medical management to medical management alone in patients with type 2 diabetes, obesity (body mass index [BMI] > 30 kg/m2), and stage 2-4 CKD (estimated glomerular filtration rate [eGFR] 15-90 mL/min/1.73 m2 with persistent proteinuria). Subjects randomized to exercise underwent thrice weekly aerobic training for 6 followed by 18 weeks of supervised home exercise. The primary outcome variable was change in proteinuria.\n Seven subjects randomized to exercise and 4 control subjects completed the study. Exercise training resulted in an increase in exercise duration during treadmill testing, which was accompanied by slight but insignificant decreases in resting systolic blood pressure and 24-hour proteinuria. Exercise did not alter GFR, hemoglobin, glycated hemoglobin, serum lipids, or C-reactive protein (CRP). Caloric intake and body weight and composition also did not change with exercise training.\n Exercise training in obese diabetic patients with CKD is feasible and may have clinical benefits. A large-scale randomized controlled trial to determine the effects of exercise on renal functions, cardiovascular fitness, inflammation, and oxidative stress in diabetic patients with CKD is planned.", "A prospective, randomized, controlled clinical trial in patients with coronary artery disease (CAD) and a concurrent physical disability evaluated the effects of a home exercise training program on cardiovascular function and blood lipids. Eighty-eight men between the ages of 42 and 72 years (mean 62) with documented CAD and a physical disability with functional use of > or = 2 extremities including 1 arm were randomized to either a 6-month home exercise training program using wheelchair ergometry or to a control group that received usual and customary care. Both groups received dietary instructions and were requested to follow a fat-controlled diet. Exercise test variables with echocardiography and blood lipids were measured at baseline and at 6 months. The home exercise training group significantly improved both peak exercise left ventricular ejection fraction (p = 0.007) and fractional shortening (p = 0.01) between baseline to 6 months, whereas the control group showed no significant changes. Exercise training effects of decreased resting heart rate (p = 0.03) and decreased peak rate pressure product (p = 0.03) were also found in the treatment group. No exercise-related cardiac complications occurred. Both groups significantly (p < or = 0.01) increased high-density lipoprotein cholesterol levels. These results indicate that physically disabled men with CAD can safely participate in a home exercise training program which may result in intrinsic cardiac benefits. The metabolic cost of activities of daily living imposed on this disabled population may also have a positive effect on high-density lipoprotein cholesterol levels.", "Physical inactivity contributes to weight gain, but only 22% of Americans are regularly active.\n To examine short- and long-term changes in weight, body composition, and cardiovascular risk profiles produced by diet combined with either structured aerobic exercise or moderate-intensity lifestyle activity.\n Sixteen-week randomized controlled trial with 1-year follow-up, conducted from August 1995 to December 1996.\n Forty obese women (mean body mass index [weight in kilograms divided by the square of height in meters], 32.9 kg/m2; mean weight, 89.2 kg) with a mean age of 42.9 years (range, 21-60 years) seen in a university-based weight management program.\n Structured aerobic exercise or moderate lifestyle activity; low-fat diet of about 1200 kcal/d.\n Changes in body weight, body composition, cardiovascular risk profiles, and physical fitness at 16 weeks and at 1 year.\n Mean (SD) weight losses during the 16-week treatment program were 8.3 (3.8) kg for the aerobic group and 7.9 (4.2) kg for the lifestyle group (within groups, P<.001; between groups, P = .08). The aerobic group lost significantly less fat-free mass (0.5 [1.3] kg) than the lifestyle group (1.4 [1.3] kg; P = .03). During the 1-year follow-up, the aerobic group regained 1.6 [5.5] kg, while the lifestyle group regained 0.08 (4.6) kg. At week 16, serum triglyceride levels and total cholesterol levels were reduced significantly (P<.001) from baseline (16.3% and 10.1% reductions, respectively) but did not differ significantly between groups and were not different from baseline or between groups at week 68.\n A program of diet plus lifestyle activity may offer similar health benefits and be a suitable alternative to diet plus structured aerobic activity for obese women.", "The aim of the study was to test the effect of a nonpharmacological weight reduction program on cardiovascular risk factors among overweight hypertensives in a primary health care setting. Forty-nine overweight hypertensive patients completed the 12-month program. The patients were randomly allocated into either intervention or control groups. The examinations included interviews by a nutritionist, pertinent laboratory tests, and a medical examination. The intervention involved an individually planned energy-restricted diet of 1000-1500 kcal per day, weekly discussions, and various leaflets on diet modification and on increase of physical activity. The mean body weight was reduced by 5 kg in the intervention group, but remained unchanged in the control group. The intervention group reduced their fat intake by 14 g/day while the control group increased it by 9 g/day on the average. In the intervention group, the total serum cholesterol decreased, HDL-cholesterol increased and triglycerides decreased significantly. The systolic blood pressure fell by 8 mm Hg and 15 mm Hg in the intervention and control groups, respectively. The diastolic blood pressure fell on average by 11 mm Hg in both groups. The results demonstrate the comprehensive weight reduction program to be effective in the control of cardiovascular risk factors.", "We examined the single and combined effects of a 1-year diet and exercise intervention on the International Diabetes Federation (IDF) metabolic syndrome among middle-aged males. The study was a randomized, controlled, 2 x 2 factorial intervention study. Participants included 137 men with metabolic syndrome according to the IDF criteria aged 40-49 years randomly allocated to four intervention groups: diet alone (n=34), exercise alone (n=34), the combination of the diet and exercise intervention (n=43) or control (n=26). The main outcome measure was metabolic syndrome as defined by IDF criteria (2005). In the combined diet and exercise group, 14 participants (32.6%) (P<0.0001 as compared with control) had the metabolic syndrome after 1-year intervention. In the diet-only group, 22 participants (64.7%) (P=0.023 vs control) and in the exercise-only group 26 participants (76.5%) (P=0.23 vs control) had the metabolic syndrome following the intervention. Utilizing the factorial design, both dietary and exercise intervention had significant effects (P<0.005) on the resolution of the metabolic syndrome. Both exercise and dietary intervention reduced metabolic syndrome prevalence compared with control after 1 year of intervention. However, the combined diet and exercise intervention was significantly more effective than diet or exercise alone in the treatment of the metabolic syndrome.", "Exercise as a falls prevention strategy is more complex with people at risk than with the general population. The Lifestyle approach to reducing Falls through Exercise (LiFE) involves embedding balance and lower limb strength training in habitual daily routines.\n A total of 34 community-residing people aged ≥70 years were randomised either into the LiFE programme or into a no-intervention control group and followed up for six months. Inclusion criteria were two or more falls or an injurious fall in the past year.\n There were 12 falls in the intervention group and 35 in the control group. Therelative risk (RR) analysis demonstrated a significant reduction in falls (RR = 0.23; 0.07-0.83). There were indications that dynamic balance (P = 0.04 at three months) and efficacy beliefs (P = 0.04 at six months) improved for the LiFE programme participants. In general, secondary physical and health status outcomes, which were hypothesised as potential mediators of fall risk, improved minimally and inconsistently.\n LiFE was effective in reducing recurrent falls in this at-risk sample. However, there were minimal changes in secondary measures. The study was feasible in terms of recruitment, randomisation, blinding and data collection. A larger randomised trial is needed to investigate long-term efficacy, mechanisms of benefit and clinical significance of this new intervention.", "The aim of this treatment study on bulimia nervosa was (i) to examine the effect of physical exercise as an experimental treatment condition against the well-documented effect of cognitive-behavioral therapy (CBT), and (ii) to compare the effect of CBT versus the effect of nutritional advice as one single treatment component of CBT.\n Normal weight female bulimic patients aged 18-29 yr were randomly assigned to a physical exercise program (N = 15), CBT (N = 16), nutritional advice (N = 17), or a waiting list control group (N = 16). Seventeen healthy female control subjects were also included. Treatment effects were determined by the frequency of binge eating and purging, scores on the Eating Disorder Inventory subscales \"Drive for thinness,\" \"Bulimia,\" and \"Body dissatisfaction\" and by a clinical interview to measure symptom severity. Assessments were made before and after treatment and at 6- and 18-month follow-up after the end of treatment.\n Nutritional counseling did not prove more effective than CBT. Physical exercise appeared more effective than CBT in reducing pursuit of thinness; change in body composition; aerobic fitness; and frequency of bingeing, purging, and laxative abuse.\n Physical exercise is important in the treatment of normal weight bulimic patients. Further studies should address possible additive effects of CBT and physical exercise.", "Several studies have demonstrated that high density lipoprotein cholesterol (HDL-C) is increased after either dietary weight loss or aerobic exercise training, but it is unclear whether the effects of these two interventions are separate and independent, or just related to the amount of weight or fat lost. The effect of dietary weight loss or aerobic training on apolipoprotein A1 (Apo-A-I) has not been extensively studied. In the present study we evaluated the effects of either dietary weight loss or aerobic exercise training on lipoproteins and Apo A-I, and assessed whether they are related to changes in body composition. Twenty-six obese, otherwise healthy, untrained, nonsmoking, male subjects were weight stabilized for ten days, during which maximal aerobic capacity, body composition, and fat cell size were measured. At the end of this ten-day period lipoproteins and Apo A-I were measured. Subjects were then randomized into either a dietary weight loss (n = 12) or aerobic exercise group (n = 14). At the end of three months the groups were restabilized and restudied. Although both groups lost weight, the weight loss was greater in the diet group (-13.1 v -2.8 kg, P less than 0.001). Important differences in body composition were also detected after the two interventions with 25% of the total weight loss in the diet group coming from fat free mass. Significant decrements in triglyceride (-54 +/- 67 mg/dL, P less than 0.05), total cholesterol (-29 +/- 27 mg/dL, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)", "The aim of this randomized trial was to compare the effects of a behavioral intervention focusing on either calorie restriction alone or calorie plus fat restriction on weight loss and changes in lipids and glycemic control in individuals with non-insulin-dependent diabetes mellitus (NIDDM) or a family history of diabetes.\n We recruited 44 obese women with NIDDM and 46 obese women with a family history of NIDDM and randomly assigned these subjects to calorie restriction (CAL) or to calorie plus fat restriction (CAL + FAT). All subjects participated in a 16-week behavioral weight loss program, with training in diet, exercise, and behavior modification. Subjects assigned to the CAL condition were given a 1,000-1,500 kcal/day goal and self-monitored calories consumed. Subjects assigned to the CAL+FAT condition had the same calorie goal, but were also given a fat goal (grams of fat/day), to produce a diet with < 20% of calories from fat; this group monitored both calories and fat grams.\n Among NIDDM subjects, weight loss of the subjects in the CAL+FAT condition was significantly greater than subjects in the CAL condition (7.7 vs. 4.6 kg) and the CAL+FAT condition group also maintained their weight loss better at the 1-year follow-up (5.2 vs. 1.0 kg). Significant decreases in glucose, high-density lipoprotein (HDL) cholesterol, and total cholesterol were seen after 16 weeks of treatment among NIDDM subjects; these changes were similar in CAL and CAL+FAT groups, but a greater proportion of subjects in CAL condition required oral hypoglycemic medication. At the 1-year follow-up, all parameters had returned to baseline. No significant differences in weight loss or physiological changes were seen between CAL and CAL+FAT conditions in subjects with a family history of diabetes.\n These results suggest that using the combination of calorie and fat restriction may help promote weight loss in obese NIDDM patients. No other long-term benefits of this regimen were observed.", "Overweight and obesity are major contributors to both type 2 diabetes and cardiovascular disease (CVD). Moreover, individuals with type 2 diabetes who are overweight or obese are at particularly high risk for CVD morbidity and mortality. Although short-term weight loss has been shown to ameliorate obesity-related metabolic abnormalities and CVD risk factors, the long-term consequences of intentional weight loss in overweight or obese individuals with type 2 diabetes have not been adequately examined. The primary objective of the Look AHEAD clinical trial is to assess the long-term effects (up to 11.5 years) of an intensive weight loss program delivered over 4 years in overweight and obese individuals with type 2 diabetes. Approximately 5000 male and female participants who have type 2 diabetes, are 45-74 years of age, and have a body mass index >or=25 kg/m(2) will be randomized to one of the two groups. The intensive lifestyle intervention is designed to achieve and maintain weight loss through decreased caloric intake and increased physical activity. This program is compared to a control condition given diabetes support and education. The primary study outcome is time to incidence of a major CVD event. The study is designed to provide a 0.90 probability of detecting an 18% difference in major CVD event rates between the two groups. Other outcomes include components of CVD risk, cost and cost-effectiveness, diabetes control and complications, hospitalizations, intervention processes, and quality of life.", "To evaluate a weight loss and exercise program designed to improve diabetes management in older African-Americans.\n Overweight African-Americans (n = 64) ages 55-79 years with NIDDM were randomized to either an intervention (12 weekly group sessions, 1 individual session, and 6 biweekly group sessions) or usual care (1 individual session, and 6 biweekly group sessions) or usual care (1 class and 2 informational mailings). Clinical and behavioral variables were assessed at 0, 3, and 6 months of treatment.\n Significant net differences in the intervention versus usual care were observed for weight (-2.0 kg, P = 0.006), physical activity, and dietary intake of fat, saturated fat, cholesterol, and nutrition knowledge at 3 months (all P < 0.05) and for weight at 6 months (-2.4 kg; P = 0.006) and mean HbA1c values at 3 and 6 months (respectively, -1.6 and -2.4%, both P < 0.01). After the adjustment for changes in weight and activity, the intervention participants were approximately twice as likely to have a one unit decrease in HbA1c value as those in usual care. Blood pressure increase sin usual care participants resulted in net differences (intervention minus control) at 3 and 6 months of -3.3 (P = 0.09) and -4.0 (P = 0.05) mmHg diastolic, respectively, and -8.4 (P = 0.06) and -5.9 (P > 0.10) mmHg systolic, respectively. Blood lipid profiles improved more in intervention than usual care participants, but not significantly.\n The intervention program was effective in improving glycemic and blood pressure control. The decrease in HbA1c values was generally independent of the relatively modest changes in dietary intake, weight, and activity and may reflect indirect program effects on other aspects of self-care.", "Exercise should be an integral part of the treatment in non-insulin-dependent (NIDDM) diabetic patients, yet most of these patients' performance is low, mainly because of their obesity and concomitant macrovascular disease. We studied the influence of a moderate exercise training on parameters of glucose control in NIDDM patients. Forty patients aged 56.6 +/- 6.6 years were assigned randomly according to age and sex into exercise and control groups. The exercise group trained for 45 min 3 times weekly for 12 weeks, while the control group did not change their lifestyle. At the end of the study the exercise group had a significant reduction in plasma levels of triglycerides, fructosamine and glycohemoglobin. The improvement in metabolic control persisted significantly in patients who continued to exercise at varying levels at home during 1 year of follow-up.", "To compare and assess the single and joint effect of diet and exercise intervention for 1 year on insulin resistance and the development leading toward the insulin resistance syndrome.\n An unmasked, randomized 2 x 2 factorial intervention trial was applied with a duration of 1 year for each participant. The trial comprised 219 men and women with diastolic blood pressure of 86-99 mmHg, HDL cholesterol < 1.20 mmol/l, triglycerides > 1.4 mmol/l, total cholesterol of 5.20-7.74 mmol/l, and BMI > 24 kg/m2. Participants were randomly allocated to diet group (n = 35), diet and exercise group (n = 67), exercise group (n = 54), and control group (n = 43). The diet included increased intake of fish and reduced total fat intake. The exercise program entailed supervised endurance exercise three times a week. Baseline cross-sectional changes and 1-year changes in insulin resistance, fasting serum levels of insulin, C-peptide, proinsulin, glucose, and lipids as well as weight, mean blood pressure, and plasminogen activator inhibitor 1 (PAI-1) values were recorded.\n The cross-sectional results at baseline showed significant correlations between the calculated insulin resistance and BMI (r = 0.54) and correlations between the mean blood pressure (mBP) (r = 0.26) and PAI-1 (r = 0.40). The 1-year diet intervention gave a significant decrease in the calculated insulin resistance from 4.6 to 4.2 and a positive correlation between the changes in insulin resistance and changes in BMI (r = 0.40). The diet and exercise intervention also led to significantly decreased insulin resistance (from 5.0 to 4.0). The exercise intervention did not significantly change insulin resistance.\n The cross-sectional and 1-year intervention results supported each other and underscored the important connection between increased BMI and the development leading toward the insulin resistance syndrome.", "Although e-coach support increases the effectiveness of Internet weight loss interventions, no studies have assessed influence of type of e-coach support.\n The effects of nondirective (collaborative, flexible) and directive (prescriptive, protocol driven) e-coach support on weight loss, dietary behavior, physical activity, and engagement were assessed in a 12-week weight loss e-coaching program.\n Overweight adults (N = 104) were randomly assigned to nondirective, directive, or minimal support. All received weekly lessons and feedback graphs via e-mail. Participants in the nondirective and directive support conditions received individualized nondirective or directive weight loss support.\n For females, weight loss (η(2) = 0.10) and changes in waist circumference (η(2) = 0.07) were greater in the directive than in the nondirective and minimal support conditions.\n Differences in type of e-coach support are salient to participants. Directive support is beneficial to females in a 12-week e-coach weight loss program." ]	The results of this review support the use of exercise as a weight loss intervention, particularly when combined with dietary change. Exercise is associated with improved cardiovascular disease risk factors even if no weight is lost.
CD005527	[ "12829988", "12948399", "12072596", "12558913", "9581698", "11008222", "14988824", "11051370", "9695995", "9131395", "8720287" ]	[ "Maintenance therapy with ribavirin in patients with chronic hepatitis C who fail to respond to combination therapy with interferon alfa and ribavirin.", "Retreatment of hepatitis C non-responsive to interferon. A placebo controlled randomized trial of ribavirin monotherapy versus combination therapy with Ribavirin and Interferon in 121 patients in the Benelux [ISRCTN53821378].", "High sustained response rate in patients with histologically mild (low grade and stage) chronic hepatitis C infection. A randomized, double blind, placebo controlled trial of interferon alpha-2b with and without ribavirin.", "The safety and tolerability of daily infergen plus ribavirin in the treatment of naíïve chronic hepatitis C patients.", "A randomized study comparing ribavirin and interferon alfa monotherapy for hepatitis C recurrence after liver transplantation.", "A prospective and randomized study using ribavirin as monotherapy for the treatment of naïve patients with chronic hepatitis C.", "Antiviral action of ribavirin in chronic hepatitis C.", "Treatment of chronic hepatitis C in patients who failed interferon monotherapy: effects of higher doses of interferon and ribavirin combination therapy. The Virginia Cooperative Hepatitis Treatment Group.", "Sequential versus concomitant administration of ribavirin and interferon alfa-n3 in patients with chronic hepatitis C not responding to interferon alone: results of a randomized, controlled trial.", "Pilot study of a short course of ribavirin and alpha interferon in the treatment of chronic active hepatitis C not responding to alpha-interferon alone.", "The effect of interferon alfa and ribavirin combination therapy in naive patients with chronic hepatitis C." ]	[ "To assess the efficacy and safety of maintenance therapy with ribavirin alone in chronic hepatitis C, 108 patients were treated with the combination of interferon alfa and ribavirin for 24 weeks; those who failed to have a virologic response were offered enrollment in a randomized, double-blind, controlled trial of ribavirin (1,000-1,200 mg daily) versus placebo for the subsequent 48 weeks. Patients were monitored at regular intervals with symptom questionnaires, serum aminotransferase levels, hepatitis C virus (HCV) RNA levels, and complete blood counts and underwent liver biopsy at the completion of therapy. Among 108 patients, 50 were still HCV RNA positive after 24 weeks of treatment, of whom 34 agreed to be randomized to continue either ribavirin monotherapy or placebo. Among 17 patients who received placebo, there was no overall improvement in symptoms, serum alanine aminotransferase (ALT) levels, HCV RNA levels, or hepatic histology. Among the 17 patients who received ribavirin, serum ALT levels and necroinflammatory features of liver histology were improved, whereas symptoms, HCV RNA levels, and hepatic fibrosis scores were not changed significantly from baseline. Responses to ribavirin seemed to be categorical, such that 8 patients (47%) had definite improvement in liver histology. Patients with improved histology had improvements in serum ALT levels both on combination therapy and after switching to ribavirin monotherapy. In conclusion, continuation of ribavirin monotherapy may maintain serum biochemical improvements that occur during interferon-ribavirin combination therapy in some patients and that these improvements are often associated with decreases in necroinflammatory changes in the liver. Whether these improvements will ultimately result in prevention of progression of hepatitis C requires further study.", "Evidence based medicine depends on unbiased selection of completed randomized controlled trials. For completeness it is important to publish all trials. This report describes the first large randomised controlled trial where combination therapy was compared to placebo therapy and to ribavirin monotherapy, which has not been published until now.\n One hundred and twenty one patients with chronic hepatitis C and elevated transaminases who did not respond to previous treatment with standard interferon monotherapy, were included from 16 centers in Belgium, the Netherlands and Luxembourg between 1992 and 1996. Patient poor-response characteristics were: genotype 1 (69%), HCV RNA above 2 x 10(6) copies/ml (55%) and cirrhosis (38%). Patients were randomized to 6 months combination therapy with interferon alpha-2b (3 MU tiw) and ribavirin (1000-1200 mg/day), 6 months ribavirin monotherapy (1000-1200 mg/day) or 6 months ribavirin placebo. The study was double blinded for the ribavirin/placebo component. One patient did not fit the entry criteria, and 3 did not start. All 117 patients who received at least one dose of treatment were included in the intention to treat analysis.\n At the end of treatment, HCV RNA was undetectable in 35% of patients on combination therapy and in none of the patients treated with ribavirin monotherapy or placebo. The sustained virological response rate at 6 months after therapy was 15% for patients treated with interferon and ribavirin. During the 6 months treatment period 13% of patients on interferon ribavirin combination therapy, 13% of patients on ribavirin monotherapy and 11% of patients on placebo withdrew due to side effects or noncompliance. At 24 weeks of treatment the mean Hb level was 85% of the baseline value, which means a mean decrease from 9.1 mmol/l to 7.8 mmol/l. The Hb levels at the end of treatment were not significantly different from patients treated with ribavirin monotherapy (p = 0.76). End of treatment WBC was significantly lower in patients treated with combination therapy, compared to ribavirin (p < 0.01) as well as for patients treated with ribavirin monotherapy compared to placebo (p < 0.01).\n This belated report on the only placebo controlled study of interferon ribavirin combination therapy in non responders to standard doses of interferon monotherapy documents the effectiveness, be it limited, of this approach as well as the dynamics of the effects on blood counts.", "To evaluate the efficacy and safety of therapy for patients with histologically mild hepatitis C virus (HCV) liver disease.\n A randomized, double blind, placebo controlled trial of interferon alpha-2b with or without ribavirin.\n Regional and university hospitals.\n One hundred and sixteen treatment naive patients with mild chronic HCV infection. Mild HCV infection was defined according to Knodell as a grade score of > or = 1 and < or = 6 and a stage score of < or = 1.\n Interferon alpha-2b (3 MU three times weekly) for 52 weeks in combination with either ribavirin or a matched placebo.\n The study endpoint was the absence of HCV RNA in plasma and liver tissue 26 weeks post-treatment. In addition, liver histology was compared pre- and post-treatment.\n Combination therapy was superior to interferon monotherapy, with a virological sustained response rate of 54% (31/57) and 20% (12/59), respectively, in both serum and liver tissue (P = 0.001). The sustained response rate was higher with combination therapy than monotherapy both in genotype non-1 (81% vs 36%) and in genotype 1 (28% vs 4%). There was a significant improvement in mean grade score in all sustained responders, irrespective of treatment arm.\n Combination therapy with interferon and ribavirin was safe and as effective in patients with histologically mild HCV infection as previously reported for more advanced disease.", "The treatment of chronic hepatitis C patients was enhanced when the combination of interferon alfa-2b and ribavirin was shown to be safe and more effective than interferon monotherapy. To date, no published reports have addressed the use of consensus interferon (CIFN) when combined with ribavirin. We conducted a pilot study to compare the safety and tolerability of daily CIFN plus ribavirin to CIFN monotherapy for the initial treatment of chronic hepatitis C patients. Forty subjects were randomized to two treatment groups; CIFN 9 microg daily, or CIFN 9 microg daily plus ribavirin 1000 or 1200 mg daily. All subjects received 48 weeks of therapy except for nongenotype 1 subjects in the combination treatment group who received only 24 weeks of therapy. The results show that at baseline, age, gender, risk factors, race, RNA titres, and liver histology were not different between the two groups. The proportion of subjects with genotype 1 infection was 50% (10/20) and 55% (11/20) for the monotherapy and combination therapy groups, respectively. Fifty (10/20) and sixty-five (13/20) per cent of subjects in the monotherapy and combination therapy groups exhibited a 2-log or greater decrease in viral titre at week 12 (P = NS). Using intent-to-treat analysis, 20% and 40% of enrolled subjects exhibited a sustained viral response in the monotherapy and combination therapy groups, respectively (P = NS). The proportion of subjects requiring dose reduction was 55% (11/20) and 65% (13/20), respectively. Study discontinuations for any reason were 25% (5/20) and 35% (7/20) for the monotherapy and combination groups, respectively. Discontinuations due to adverse events related to study drug were 20% (4/20) and 25% (5/20), respectively. A total of four serious adverse events occurred, two in each treatment group, only one of which was determined to be study-drug related. It is concluded that the safety and tolerability profiles of the two treatments were similar suggesting that daily dosing of CIFN may be difficult to tolerate resulting in discontinuation of therapy in a significant proportion of patients. The combination regimen resulted in a trend towards a higher viral response rate than monotherapy treatment. These data suggest that CIFN may be safely combined with ribavirin and may enhance the sustained response rate but is not well tolerated in US patients when given in a daily dosing regimen.", "Hepatitis C virus (HCV) infection usually recurs after orthotopic liver transplantation (OLT), and most patients develop graft damage. This study compared the efficacy of interferon alfa (IFN-alpha) and ribavirin monotherapies in liver transplant recipients with chronic hepatitis C in the graft. Thirty OLT recipients with chronic hepatitis C were randomized to receive either IFN-alpha (3 MU three times a week) or ribavirin (up to 1.2 g daily) for 24 weeks. Virological, biochemical, and histological responses to treatment were assessed. Twenty-eight patients completed the treatment regimen, two ribavirin-treated patients being withdrawn because of severe hemolysis. Normalization of serum aspartate aminotransferase was achieved in 13 of 14 patients receiving ribavirin (93%) and 6 of 14 patients receiving IFN-alpha (43%; P=.01). Lobular inflammation was reduced in 9/14 ribavirin-treated (64%) and 3 of 14 IFN-alpha-treated patients (21%; P=.05), each of whom had a biochemical response. However, the total histological activity index did not improve in either the interferon (P=.43) or the ribavirin (P=.96) group. Posttreatment viremia levels were significantly reduced in IFN-alpha-treated (P=.05) but not in ribavirin-treated (P=.88) patients. Hemolysis occurred in all ribavirin-treated patients, with serum hemoglobin decreasing to < 10 g/dL in 50%. Total leukocyte and lymphocyte counts decreased significantly during ribavirin treatment (P=.02 and P=.004, respectively). We concluded that in patients with chronic hepatitis C after OLT, IFN-alpha retains an antiviral effect whereas ribavirin is superior in achieving normalization of serum aspartate aminotransferase levels and reducing lobular inflammation, but not the total histological activity index. These findings provide a rationale for combination therapy in the post-OLT setting, although patients must be carefully monitored for hemolysis.", "In order to evaluate the response to ribavirin in previously untreated patients with chronic hepatitic C, 39 patients were selected for a double-blind prospective and randomized trial, and divided into two groups: ribavirin-group (19 patients) and placebo-group (20 patients). Ribavirin was administered orally for 24 weeks (600 mg/day, followed by 1,000 mg/day and 1,200 mg/day each one for 8 weeks). After 3 months of drug administration, the patients were evaluated by measuring biochemical, virologic and histologic responses. After this phase, ribavirin was offered to the patients who had received placebo (second phase). The results showed that the patients who received ribavirin showed a higher reduction in serum alanine aminotransferase (ALT) activity than patients in the placebo group. Among the patients in the ribavirin-group, a complete biochemical response (ALT levels normalized) was observed in 3 patients (16%), and a partial response (reduction greater than 50% of the initial value of ALT activity) in 4 (21%). In the 20 patients in the placebo group, only 1 showed a partial response (5%). In the second phase of the study, among 16 patients who received ribavirin, 4 (25%) showed a complete and 5 (31%) a partial biochemical response. HCV-RNA did not become negative in any patient during the two phases. A reduction in the score of portal and lobular activity was observed in patients who received ribavirin, but statistical analysis did not identify differences. This study showed that ribavirin alone induces a biochemical response (ALT reduction) in some patients with chronic hepatitis C, which may be associated with a reduction in hepatic inflammatory activity reduction, but the changes are not sufficient to recommend initial monotherapy with ribavirin.", "In the patients with chronic hepatitis C, the addition of ribavirin to interferon (IFN)-alpha significantly increases the virologic responses. Our aim was to assess the antiviral action of ribavirin on hepatitis C virus (HCV) as a function of ribavirin pharmacokinetics and to evaluate the influence of this antiviral effect on IFN-alpha efficacy.\n Forty-five patients with chronic hepatitis C (genotype 1b) received various schedules of IFN-alpha and/or ribavirin administration. Frequent blood sampling was performed for HCV RNA kinetics and ribavirin pharmacokinetics assessment.\n Ribavirin monotherapy induced a significant, moderate, early, and transient viral load decrease in approximately half of the patients. The occurrence of this effect was associated with longer ribavirin clearance half-lives and higher serum ribavirin concentrations. Ribavirin antiviral effect partly reduced the rebound preceding the second IFN-alpha injection in patients receiving standard IFN-alpha 3 times per week plus ribavirin. The magnitude of the rebound was inversely related to ribavirin concentrations. These patients subsequently experienced a slow, but significant, second slope of viral decrease and cleared HCV RNA. The addition of ribavirin to daily IFN-alpha monotherapy did not have any impact on the second phase of viral decline.\n Ribavirin exerts a significant, moderate, and transient antiviral effect in a significant proportion of patients with chronic hepatitis C. The antiviral effect of ribavirin correlates with ribavirin pharmacokinetics and is partly responsible for the improved efficacy of the combination of standard IFN-alpha and ribavirin compared with IFN-alpha monotherapy by increasing the incidence of the initial response.", "The present study was designed to evaluate the effectiveness of interferon-ribavirin combination therapy for treatment of chronic hepatitis C virus (HCV) in patients who failed previous treatment with interferon monotherapy.\n A total of 140 patients with well-documented chronic HCV who failed to achieve a virological (if HCV-RNA was assessed) or biochemical response (if HCV-RNA was not assessed) to interferon monotherapy, 3 mU three times weekly (TIW) for 3-18 months, were randomly assigned to one of three treatment groups. Group A patients were treated with 5 mU interferon TIW for 6 months. Ribavirin (1000-1200 mg daily) was added in those patients HCV-RNA positive at month 3. Group B patients were treated with 3 mU interferon TIW plus ribavirin (1000-1200 mg daily) for 6 months. The dose of interferon was increased to 5 mU TIW in those patients HCV-RNA positive at month 3. Group C patients were treated with 5 mU interferon TIW plus ribavirin (1000-1200 mg daily) for 6 months. Serum ALT and HCV-RNA were monitored during and after treatment for a total of 15 months.\n Seventeen percent of patients in group A became HCV-RNA negative by treatment month 3. Adding ribavirin resulted in one additional patient becoming HCV-RNA negative. However, none of the patients in this group achieved sustained virological response. Twenty-six percent of patients in group B became HCV-RNA negative by treatment month 3. Increasing the dose of interferon from 3 to 5 mU TIW increased virological response to 30%. However, sustained virological response was observed in only 14%. Thirty percent of patients in group C became HCV-RNA negative, but sustained virological response was observed in only 12%. Sustained virological response was found to be significantly greater in patients with a nontype I HCV genotype (p < 0.002) and in patients who had a decline in HCV-RNA titer to a value < 100,000 copies/ml during their previous course of interferon monotherapy (p < 0.0001). None of the 12 sustained responders were African Americans (p < 0.013).\n Retreatment of nonresponders with interferon-ribavirin combination therapy results in limited benefit; only 13% of patients achieved sustained virological response. Response was extremely poor in African Americans and those with HCV genotype 1.", "We conducted a three-arm, randomized trial in 96 patients with chronic hepatitis C who did not respond to interferon alfa to compare treatments. Group 1 (33 patients) received ribavirin alone (1,000 mg/daily for 6 months) followed by interferon alfa n-3 alone (3 MU thrice weekly for 6 months); group 2 (33 patients) received ribavirin plus interferon alfa n-3 for 6 months at the above doses; and group 3 (30 patients) received interferon alfa n-3 alone (3 MU thrice weekly for 6 months). At the end of treatment, 3 patients (10%) in group 1, 13 (41%) in group 2, and 5 (17%) in group 3 had normal alanine transaminase (ALT) levels (group 2 vs. groups 1 and 3, P = .008). After 6 months of follow-up, only 4 patients (12.5%) in group 2 still had normal ALT values (P = .03). At the end of therapy, hepatitis C virus (HCV) RNA was no longer detectable by polymerase chain reaction in 4 (13%), 9 (27%), and 2 (7%) patients, respectively, in groups 1, 2, and 3 (P = NS). Six months posttherapy, only 5 (15%) patients in group 2 were still HCV RNA negative (P = .02). At the time of follow-up liver biopsy, performed 6 months after the end of treatment, a significant improvement of the necroinflammatory scores was observed among group 2 patients (P = .01) but not in the other two groups. Side effects reflected the profile of each drug as monotherapy; mild hemolytic anemia was the most frequent side effect caused by ribavirin. In conclusion, concomitant administration of ribavirin and interferon alfa n-3 was significantly superior to the sequential schedule or interferon alfa n-3 monotherapy in inducing a sustained response in patients with chronic hepatitis C who had not responded to interferon alone. However, combination therapy at the dose and duration adopted in this study is capable of modifying the natural course of the disease in only a minority of these patients.", "Chronic active hepatitis due to HCV represents a severe progressive disorder of the liver, At present, Interferon seems to be the most efficacious treatment available, however, only 20-25% of the patients treated achieve complete remission. The efficacy has, therefore, been evaluated of Ribavirin, a nucleoside analogue active both on DNA and RNA viruses, in the treatment of non responders to a previous course of interferon. Twenty patients were randomly assigned to two groups: A) received the association R (800 mg/day for 2 months)+interferon (9 Mu/week for 6 months); B) received IFN (9 Mu/week for 6 months). All patients completed the study without important side effects. Four patients in group A presented reduced ALT and loss of viraemia during treatment with Ribavirin. Only one patient in group B had reduced indices of cell lysis and was negative for HCV-RNA during the course of the study. However, viremia and an increase of ALT values were observed in all of these subjects once treatment was interrupted. The results emerging from this study indicate that Ribavirin therapy, at the dose and duration of treatment employed, is not sufficient to change the natural course of events of chronic active hepatitis from HCV.", "Chronic hepatitis C may lead to cirrhosis and hepatocellular carcinoma in a subset of patients. Because response rates with interferon alfa therapy are unsatisfactory, new therapies are needed.\n We conducted a three-arm, randomized trial in 45 interferon-naive men (mean age 40.6 +/- 12 years) with chronic hepatitis C to compare treatments: group A, ribavirin alone (15 mg/kg daily for 6 months); group B, interferon alone (3 MU thrice weekly for 6 months); and group C, interferon plus ribavirin at the above doses. Histologic outcomes of therapy were assessed by pretreatment and post-treatment liver biopsies.\n In group A, alanine aminotransferase levels normalized during therapy in 66% of those with HCV-1b and 34% of those with HCV-2a, but all patients relapsed after treatment ended. In group B, alanine aminotransferase levels normalized during treatment in 66%, 75%, and 100% of patients infected with HCV-1b, HCV-2a, and HCV-3, respectively; however, a sustained response was noted in only 25% of those with HCV-3. In group C, a sustained normalization of alanine aminotransferase with negative serum HCV RNA was seen in 20% of those with HCV-1b, 40% of those with HCV-2a, and 75% of those with HCV-3 12 months after therapy. One year after therapy ended, group C demonstrated a significant sustained response (47%) as well as a significant reduction in piecemeal necrosis and portal inflammation (p < 0.05).\n Combination therapy was significantly superior to ribavirin or interferon monotherapy in producing a sustained response in interferon-naive patients with chronic hepatitis C (p < 0.05). The results of our study suggest that ribavirin potentiates the effect of interferon therapy in chronic hepatitis C." ]	Ribavirin seems without beneficial effects on serum virological response and liver-related morbidity or mortality, and significantly increased the risk of adverse reactions. Ribavirin monotherapy seems significantly inferior to interferon monotherapy. The total number of included patients is small, and more trials are perhaps needed. The use of ribavirin monotherapy for chronic hepatitis C cannot be recommended outside randomised trials.
CD004592	[ "3220789" ]	[ "Effectiveness of single versus double volume exchange transfusion in newborn infants with AB0 hemolytic disease." ]	[ "The effectiveness of early single volume exchange transfusion (ET; 80 ml/kg) was compared with that of early double volume exchange transfusion (160 ml/kg) for treatment of hemolytic disease of the newborn caused by AB0 incompatibility. Twenty full-term infants with AB0 hemolytic disease were randomized into the two treatment groups. The groups were comparable for gestational age, body weight, hemoglobin values, reticulocyte count, maximum serum bilirubin levels, rate of rise of serum bilirubin before ET, antibody titer, and age at time of ET (all p greater than 0.05). The efficacy of treatment was similar in both groups taking into account the mean bilirubin level after ET, post-ET bilirubin, duration of phototherapy following ET, and frequency of second ET (all p greater than 0.05). However, platelet count immediately after ET was lower in the double volume ET group as compared to the single volume ET group (p less than 0.01). Hemoglobin values immediately after ET were higher in the double volume ET group (p less than 0.01). At ten days of life no differences were detectable. The results of this study indicate that the effectiveness of single volume ET for treatment of full-term infants with jaundice due to AB0 incompatibility is at least comparable to that of double exchange ET. Furthermore, the lesser aggressive approach determines less complications such as a decrease of platelet count." ]	There was insufficient evidence to support or refute the use of single volume exchange transfusion as opposed to double volume exchange transfusion in jaundiced newborns. A change from the current practice of double volume exchange transfusions for severe jaundice in newborns infant, cannot be recommended on current evidence.
CD002984	[ "2142915", "12890374" ]	[ "Severe exacerbations of COPD and asthma. Incremental benefit of adding ipratropium to usual therapy.", "Inhaling beta(2)-agonist with heliox-driven in bronchial asthma." ]	[ "Single dose studies have assessed the utility of ipratropium bromide alone or with beta agonists in the short- and long-term management of chronic obstructive lung disease and asthma. We performed a randomized, double-blind trial to assess the incremental benefit over 24 hours of adding ipratropium vs placebo to a standardized regimen of medications commonly used in the acute and subsequent hospital management of COPD and asthma. Sixty-eight subjects received nebulized salbutamol, intravenous methylprednisolone, intravenous aminophylline, and antibiotics and were randomized to receive either 80 micrograms of ipratropium or placebo via metered dose inhaler and spacing device with each salbutamol treatment (6 to 8 times per day). Among the 50 patients who completed the study, there were no significant differences between ipratropium and placebo groups with respect to baseline FEV1, FVC, and PaCO2. The improvement of FEV1 from baseline to 24 hours was 294 (SD = 568) ml in the ipratropium group vs 393 (SD = 622) ml in placebo group. Adjusting FEV1 by age, gender, and smoking did not significantly alter the findings. Those with an admission diagnosis of asthma showed larger 24 hour FEV1 responses (487 ml in ipratropium vs 801 ml in placebo) than those with COPD (149 ml ipratropium vs 102 ml in placebo). However, within these two strata, there were no significant differences in FEV1 improvement between ipratropium and placebo groups. This study suggests that if ipratropium is used in the initial emergency treatment of COPD or asthma, it could safely be discontinued by 24 hours in order to reduce the cost and complexity of therapy.", "To evaluate the effectiveness of a helium-oxygen mixture (79%He- 21%O(2)) as an aerosolizing compressed gas for beta(2)-agonist therapy in patients with an asthma exacerbation.\n Twenty-four patients in the outpatient department with a mild to moderate exacerbation of asthma were enrolled. The patients were randomly divided into an experimental group (13 cases) and a control group (11 cases). The experimental group inhaled Berotec with heliox-driven, and the control group inhaled Berotec with compressed air-driven. Eight hospitalized patients in the respiratory department with severe exacerbation of asthma were enrolled. The patients inhaled Berotec with heliox-driven or compressed air-driven in a random order.\n The results of spirometric parameters and arterial blood-gas analysis were measured. In the mild to moderate asthma patients, no statistical differences between the two groups for forced vital capacity (FVC), forced expired volume in one second (FEV(1)), and expiratory flow in 50% forced vital capacity (FEF(50)) were presented. But the severe patients showed significant differences between heliox-driven and compressed air-driven for FVC, FEV(1), FEF(50) and partial pressure of oxygen (PaO(2)).\n Compared with the traditional inhalation of beta(2)-agonist therapy using compressed air-driven, the method of inhaling beta(2)-agonist with heliox-driven has more obvious benefits for those suffering from severe asthma. This is likely due to the cooperative effects between inhaling heliox on its physical gas properties and improving delivery of beta(2)-agonist in the treatment of exacerbation of severe asthma." ]	There are few controlled trial data concerning the use of inhaled beta2-agonist agents in acute exacerbations of COPD and none that have compared these agents directly with placebo. None of the studies used the more modern beta2-agonists used most widely in this setting (salbutamol and terbutaline). Beta2-agonists and ipratropium both produce small improvements in FEV1, but beta2-agonists may worsen PaO2 for a period. We could not draw conclusions concerning possible additive effects.
CD007297	[ "15113492" ]	[ "Exploratory cluster randomised controlled trial of shared care development for long-term mental illness." ]	[ "Primary care clinicians have a considerable amount of contact with patients suffering from long-term mental illness. The United Kingdom's National Health Service now requires general practices to contribute more systematically to care for this group of patients.\n To determine the effects of Mental Health Link, a facilitation-based quality improvement programme designed to improve communication between the teams and systems of care within general practice. Design of study: Exploratory cluster randomised controlled trial.\n Twenty-three urban general practices and associated community mental health teams.\n Practices were randomised to service development as usual or to the Mental Health Link programme. Questionnaires and an audit of notes assessed 335 patients' satisfaction, unmet need, mental health status, processes of mental and physical care, and general practitioners' satisfaction with services and beliefs about service development. Service use and intervention costs were also measured.\n There were no significant differences in patients' perception of their unmet need, satisfaction or general health. Intervention patients had fewer psychiatric relapses than control patients (mean = 0.39 versus 0.71, respectively, P = 0.02) but there were no differences in documented processes of care. Intervention practitioners were more satisfied and services improved significantly for intervention practices. There was an additional mean direct cost of pound 63 per patient with long-term mental illness for the intervention compared with the control.\n Significant differences were seen in relapse rates and practitioner satisfaction. Improvements in service development did not translate into documented improvements in care. This could be explained by the intervention working via the improvements in informal shared care developed through better link working. This type of facilitated intervention tailored to context has the potential to improve care and interface working." ]	No firm conclusions can be drawn at present about the effects of shared decision making interventions for people with mental health conditions. There is no evidence of harm, but there is an urgent need for further research in this area.
MR000026	[ "15649836", "16230312", "15318916", "12701949", "9836655", "16085190", "12701945", "11237924", "16100321", "8021373" ]	[ "Searching multiple databases for systematic reviews: added value or diminishing returns?", "Effectiveness and efficiency of search methods in systematic reviews of complex evidence: audit of primary sources.", "Developing methods for systematic reviewing in health services delivery and organization: an example from a review of access to health care for people with learning disabilities. Part 1. Identifying the literature.", "Beyond Medline: reducing bias through extended systematic review search.", "Review of the usefulness of contacting other experts when conducting a literature search for systematic reviews.", "Searching one or two databases was insufficient for meta-analysis of observational studies.", "Publication bias and meta-analyses: a practical example.", "Lessons for search strategies from a systematic review, in The Cochrane Library, of nutritional supplementation trials in patients after hip fracture.", "Systematic reviews of health effects of social interventions: 1. Finding the evidence: how far should you go?", "Reference accuracy in the dermatologic literature." ]	[ "To explore whether searching specialised bibliographic databases identified additional relevant papers to those located by a Medline search for a systematic review of exercise therapy.\n Searches were performed in Medline, two further generalised medical databases (Embase, Cochrane Library) and four specialised databases (CancerLit, Cinahl, PsychInfo, SportDiscus) to identify controlled trials of exercise interventions for cancer patients.\n A total of 749 different publications were located through the search, of which 18 met inclusion criteria. Fifteen (83%) of these were identified through Medline and three (17%) from three individual specialised databases. A further seven studies meeting inclusion criteria were located through reference lists and contact with experts.\n In this example, searching Medline and additional specialised databases along with checking reference lists and contacting experts was the most effective means of ensuring that all relevant papers were included in the review. Searching Medline alone for systematic reviews of exercise or other unconventional therapies is likely to be inadequate.", "To describe where papers come from in a systematic review of complex evidence. Method Audit of how the 495 primary sources for the review were originally identified.\n Only 30% of sources were obtained from the protocol defined at the outset of the study (that is, from the database and hand searches). Fifty one per cent were identified by \"snowballing\" (such as pursuing references of references), and 24% by personal knowledge or personal contacts.\n Systematic reviews of complex evidence cannot rely solely on protocol-driven search strategies.", "Our objectives were to identify literature on: (i) theory, evidence and gaps in knowledge relating to the help-seeking behaviour of people with learning disabilities and their carers; (ii) barriers experienced by people with learning disabilities in securing access to the full range of health services; (iii) interventions which improve access to health services by people with learning disabilities.\n twenty-eight bibliographic databases, research registers, organizational websites or library catalogues; reference lists from identified studies; contact with experts; current awareness and contents alerting services in the area of learning disabilities.\n Inclusion criteria were English language literature from 1980 onwards, relating to people with learning disabilities of any age and all study designs. The main criteria for assessment was relevance to the Guilliford et al. model of access to health care (Gulliford et al. Access to health care. Report of a Scoping Exercise for the National Co-ordinating Centre for NHS Service Delivery and Organisation R & D (NCCSDO). London: NCCSDO, 2001), which was modified to the special needs of people with learning disabilities. Inclusion criteria focused on relevance to the model with initial criteria revised in light of literature identified and comments from a consultation exercise with people with learning disabilities, family and paid carers and experts in the field. Data abstraction was completed independently and selected studies were evaluated for scientific rigour and the results synthesized.\n In total, 2221 items were identified as potentially relevant and 82 studies fully evaluated.\n The process of identifying relevant literature was characterized by a process of clarifying the concept under investigation and sensitive search techniques which led to an initial over-identification of non-relevant records from database searches. Thesaurus terms were of limited value, forcing a reliance on using free-text terms and alternative methods of identifying literature to supplement and improve the recall of the database searches. A key enabler in identifying relevant literature was the depth and breadth of knowledge built up by the reviewers whilst engaged in this process.", "To evaluate the sensitivity and precision of various extended search methods in identifying randomized controlled trials (RCTs) for systematic reviews.\n Prospective analysis of extended search methods (specialized databases or trial registries, reference lists, hand-searching, personal communication, and Internet) used in two systematic reviews of RCTs. The gold standard was the total number of RCTs identified by major databases (MEDLINE, EMBASE, etc.) and extended search strategies combined. Sensitivity was the proportion of all known RCTs identified by any extended search method. Precision reflected the proportion of all items uncovered by any extended search method that actually were RCTs.\n The extended search identified 94 additional RCTs for the systematic reviews beyond those identified with the major databases. Specialized databases and trial registries had the highest sensitivity and precision for the lipid-lowering project (13.6% and 52.7%, respectively; p < .05) followed by scanning of reference lists (7.2% sensitivity and 41.9% precision; p <.05). Hand-searching was more effective than personal communication and Internet searching (1.7% sensitivity and 12.2% precision; p < .05). The acupuncture project had slightly different results, with the specialized databases and trial registries tied with the review of reference lists for highest sensitivity (14.2%). The precision followed the same trend as the lipid-lowering project (17.6% specialized databases; 8.3% reference lists; p < .05). A post-hoc analysis showed that 75 of the 94 RCTs were indexed in the major databases but missed by the major database search.\n Extended searching identified additional RCTs for the systematic reviews beyond those found in major databases. Specialized databases and trial registries were most effective. An important number of RCTs were missed by the major database search. Timing and accuracy of indexing may explain this finding. The definitive measure, whether there is an association between the method used to uncover RCTs, the quality of the items uncovered and their impact on systematic review results, is yet to be determined.", "nan", "To address methodologic issues in searching for observational studies by presenting database search methods and results.\n Results of two literature searches for publications reporting on observational studies of alcohol consumption and the risk of breast cancer and large bowel cancer were compared, to evaluate the sensitivity of various bibliographic databases and search strategies, including hand-searching reviews and meta-analyses.\n The target sensitivity of 90% of publications in the breast cancer search was achieved by starting with Medline, then adding Biosis, Embase, and SCI EXPANDED-SSCI, which provided a total of 72 (91%) of the 79 relevant publications. To reach a similar 89% sensitivity for large bowel cancer, at least Biosis, Dissertation Abstracts Online, Embase, ETOH, and Medline had to be searched, with the addition of hand search of reviews and meta-analyses.\n Limiting a search to one or two databases when conducting meta-analyses of observational studies will not provide a thorough summary of the existing literature. The findings support recommendations to implement a comprehensive search of electronic databases and the reference lists of recent review articles and meta-analyses.", "Publication bias is widely appreciated, but considerable time and effort are needed to locate and obtain data from unpublished randomized controlled trials (RCTs), those published in non-English language journals or those reported in the gray literature; for this publication, we will call this collection of trials the \"gray+literature.\" However, excluding such trials from systematic reviews could introduce bias and give rise to misleading conclusions.\n We aimed to explore and quantify the impact of inclusion of gray+ literature on the results of all completed individual patient data (IPD) reviews coordinated by our group (13 meta-analyses). For each IPD review, results were calculated for RCTs fully published in English language journals and RCTs fully published in English language journals and the gray+literature.\n The IPD meta-analyses based only on RCTs that were fully published in English language journals tended to give more favorable results than those that included RCTs from the gray+literature. Although in most cases the addition of gray+data gave less encouraging results, moving the estimated treatment effect toward a null result, the direction of effect was not always predictable.\n We recommend that all systematic reviews should at least attempt to identify trials reported in the gray+literature and, where possible, obtain data from them.", "A key aim when conducting systematic reviews of randomized controlled trials (RCTs) is to include all of the evidence, if possible. Serious bias may result if trials are missed through inadequate search strategies.\n The objective was to evaluate the search plan for identifying RCTs in nutrition as part of a systematic review, in The Cochrane Library, of nutritional supplementation trials in patients after hip fracture.\n We identified potential studies by searching the electronic databases BIOSIS, CABNAR, CINAHL, EMBASE, HEALTHSTAR, and MEDLINE; reference lists in trial reports; and other relevant articles. We also contacted investigators and other experts for information and searched 4 nutrition journals by hand.\n We identified 15 RCTs that met the predefined inclusion criteria. The search plan identified 8 trials each in EMBASE, HEALTHSTAR, and MEDLINE and 7 in BIOSIS and CABNAR. BIOSIS was the only electronic database source of 2 trials. Eleven trials were identified by searching electronic databases and 2 unpublished trials were identified via experts in the field. We found one trial, published only as a conference abstract, by searching nutrition journals by hand. After publication of the protocol for the review in The Cochrane Library, we were informed of another unpublished trial.\n We found that a limited search plan based on only MEDLINE or one of the other commonly available databases would have failed to locate nearly one-half of the studies. To protect against bias, the search plan for a systematic review of nutritional interventions should be comprehensive.", "There is little guidance on how to identify useful evidence about the health effects of social interventions. The aim of this study was to assess the value of different ways of finding this type of information.\n Retrospective analysis of the sources of studies for one systematic review.\n Case study of a systematic review of the effectiveness of interventions in promoting a population shift from using cars towards walking and cycling.\n Only four of the 69 relevant studies were found in a \"first-line\" health database such as Medline. About half of all relevant studies were found through the specialist Transport database. Nine relevant studies were found through purposive internet searches and seven relevant studies were found by chance. The unique contribution of experts was not to identify additional studies, but to provide more information about those already found in the literature.\n Most of the evidence needed for this review was not found in studies indexed in familiar literature databases. Applying a sensitive search strategy across multiple databases and interfaces is very labour intensive. Retrospective analysis suggests that a more efficient method might have been to search a few key resources, then to ask authors and experts directly for the most robust reports of studies identified. However, internet publications and serendipitous discoveries did make a significant contribution to the total set of relevant evidence. Undertaking a comprehensive search may provide unique evidence and insights that would not be obtained using a more focused search.", "The reference list is an important part of a scientific article. To be useful it must be accurate.\n The purpose of this study was to evaluate the accuracy of references in the dermatologic literature.\n We randomly selected 240 references (60 per journal) from the Archives of Dermatology, the British Journal of Dermatology, this Journal, and the Journal of Investigative Dermatology and checked them against the original articles.\n The overall rate of citation error (the information identifying the source) was 41%, and the quotation error (inconsistency between the statement referenced and the original source) was 35%. Only 36% of references were free of error.\n This study shows that the rate of citation and quotation errors is unacceptably high in the dermatologic literature, which significantly diminishes the value of the reference list." ]	There is some evidence to support the use of checking reference lists for locating studies in systematic reviews. However, this evidence is derived from weak study designs. In situations where the identification of all relevant studies through handsearching and database searching is difficult, it would seem prudent that authors of reviews check reference lists to supplement their searching. The challenge, therefore, is for review authors to recognize those situations.
CD004445	[ "11928968", "11928967", "11593439", "17567977", "9126518", "15044414" ]	[ "Evaluation of a child safety program based on the WHO safe community model.", "Controlled evaluation of a community based injury prevention program in Australia.", "Evaluation of an inter-organizational prevention program against injuries among the elderly in a WHO Safe Community.", "Quantifying the effect of a community-based injury prevention program in Queensland using a generalized estimating equation approach.", "A controlled evaluation of a community injury prevention project in two Greek islands.", "Impact of social standing on injury prevention in a World Health Organization Safe Community--intervention outcome by household employment contract." ]	[ "To evaluate the outcome of the World Health Organization (WHO) Safe Community model with respect to child injuries.\n A population based quasiexperimental design was used. Cross sectional pre-implementation and post-implementation data were collected in intervention (Motala municipality) and control (Mjölby municipality) areas, both in Ostergötland county, Sweden.\n The total relative risk of child injury in the intervention community decreased more (odds ratio 0.74; 95% confidence interval (CI) 0.68 to 0.81) than in a control community exposed only to national level injury prevention programs (0.93; 95% CI 0.82 to 1.05). The relative risk of moderately (abbreviated injury scale (AIS) 2) severe injury in the study area was reduced to almost a half (odds ratio 0.49; 95% Cl 0.41 to 0.57), whereas the risk of minor (AIS 1) injuries decreased only slightly (odds ratio 0.89; 95% CI 0.80 to 0.99). The risk of severe or fatal (AIS 3-6) injuries remained constant.\n After introduction of an injury prevention program based on the WHO Safe Community model, the relative risk for child injury in the intervention community decreased significantly more than in a control community exposed only to national injury prevention programs.", "To evaluate the effects of a community based, all age, all injury prevention program, the Safe Living Program, on injury risk and injury rates.\n A quasiexperimental population based evaluation using an intervention and comparison community design.\n The intervention community (Shire of Bulla, n = 37,257) is an outer metropolitan area of Melbourne, Australia. The demographically matched comparison community (Shire of Melton, n=33,592) is located nearby.\n The Safe Living Program in the Shire of Bulla targeted injury reduction in all settings with a focus on high risk groups. Strategies included program publicity, education and training, injury hazard reduction, and environmental change. Baseline and follow up measures of program reach, risk factors, and injury rates in both communities were used to evaluate program process, impact, and outcome.\n Increase in program awareness was moderate and similar to other community based programs. The program achieved injury hazard reduction on the road, in schools, and, to a more limited extent, in the home. Other changes in injury risk factors could not necessarily be attributed to the program as similar changes were observed in the comparison community. No significant changes were found in rates of injury deaths, hospitalisations, or emergency department presentations in the Shire of Bulla after six years. Self reported household injuries, mostly minor, were reduced in the intervention community, but had been higher at program launch than in the comparison community.\n The Safe Living Program was unable to replicate the significant reductions in injuries reported in other community based interventions. Replication of apparently successful community based injury prevention programs in different settings and populations requires evidence based interventions, sustained and effective program penetration, reliable data systems to measure change, at least one control community, and sufficient budget and time for effects to be observable.", "The aim of the study was to evaluate the outcome of a participatory community-based prevention program against injuries among the elderly. A population-based quasi-experimental design was used with pre- and post-implementation measurements in an intervention and a control area. The program was based on cross-sectoral participation in detecting and taking action against injuries among the elderly. Change in the relative risk of injury was estimated by the odds ratio. Morbidity in moderately (AIS 2) severe injury in the study area was reduced from 46 per 1000 population years to 25 per 1000 population years (odds ratio 0.55; 95% confidence interval 0.46-0.65), while the minor (AIS 1) injuries increased (odds ratio 1.55; 95% confidence interval 1.21-1.91). The risk of severe or fatal (AIS 3-6) injuries remained constant. In the study area, only a slight decrease in the total morbidity rate was observed (odds ratio 0.87; 95% confidence interval 0.77-0.99). In the control area, there was no evident change in the total morbidity rates. Falls decreased or showed a tendency to decrease in the age groups 65 to 79-y-old in the study area, while they increased in the older age group. The results indicate that no sharp boundaries should be drawn between safety education, physical conditioning, environmental adjustments and secondary prevention measures when planning safety promotion among the elderly. Future studies should address these issues along with the methodological complexity associated with assessment of participatory community-based safety promotion programs.", "To develop a generalized estimating equation (GEE) model of childhood injury rates to quantify the effectiveness of a community-based injury prevention program implemented in 2 communities in Australia, in order to contribute to the discussion of community-based injury prevention program evaluation.\n An ecological study was conducted comparing injury rates in two intervention communities in rural and remote Queensland, Australia, with those of 16 control regions. A model of childhood injury was built using hospitalization injury rate data from 1 July 1991 to 30 June 2005 and 16 social variables. The model was built using GEE analysis and was used to estimate parameters and to test the effectiveness of the intervention.\n When social variables were controlled for, the intervention was associated with a decrease of 0.09 injuries/10,000 children aged 0-4 years (95% CI -0.29 to 0.11) in logarithmically transformed injury rates; however, this decrease was not significant (p = 0.36).\n The evaluation methods proposed in this study provide a way of determining the effectiveness of a community-based injury prevention program while considering the effect of baseline differences and secular changes in social variables.", "During the 20-month period September 1993 to April 1995, a health education injury prevention programme focusing on home injuries among the young (< or = 18 years old) and elderly (> or = 65 years old) on the Greek island of Naxos was undertaken, its effectiveness was evaluated by comparing the subsequent injury experience in sentinel population groups in Naxos as well as in Spetses, another island of similar sociodemographic profile, where no such intervention programme had been formally implemented.\n On the island-of Naxos an injury prevention campaign was initially undertaken involving virtually all opinion leaders and implemented through lectures, workshops and publicity in the local media. The main intervention focused on 172 households on the island of Naxos and was done by trained local collaborators who visited each household weekly to provide injury prevention advice and assess home safety. Similar visits were done by untrained collaborators in 177 households on the island of Spetses in order to assure collaboration of household members in the comparative evaluation stage of the programme. The process evaluation was based on ascertained changes of safety features and attitudes in the participating households, whereas the outcome evaluation was based on the incidence of injuries among members of the participating households in the two islands over a period of 8.5 months (255 days).\n On the intervention island of Naxos there were statistically significant improvements with respect to 11 of the 28 examined variables, whereas on the island of Spetses, such improvement was only noted for one variable. The age-adjusted incidence rate ratio of injuries overall among the target groups, contrasting the intervention and the control households was 0.85 with 90% confidence interval (CI): 0.69-1.05. With respect to home accidents the corresponding ratio was 0.79 with 90% CI: 0.60-1.04.\n An intensive and focused injury prevention intervention had only modest success when injuries themselves were the outcome variable.", "Although social inequality in health has been an argument for community-based injury prevention programmes, intervention outcomes with regard to differences in social standing have not been analysed. The objective of this study was to investigate rates of injuries treated in health-care among members of households at different levels of labour market integration before and after the implementation of a WHO Safe Community programme.\n A quasi-experimental design was used with pre- and post-implementation data collection covering the total populations <65 years of age during one year in the programme implementation municipality (population 41 000) and in a control municipality (population 26 000). Changes in injury rates were studied using prospective registration of all acute care episodes with regard to social standing in both areas during the study periods.\n Male members of households categorized as not vocationally active displayed the highest pre-intervention injury rates. Also after the intervention, males in households classified as not vocationally active displayed notably elevated injury rates in both the control and study areas. Households in the study area in which the significant member was employed showed a post-intervention decrease in injury rate among both men (P < 0.001) and women (P < 0.01). No statistically significant change was observed in households in which the significant member was self-employed or not vocationally active. In the control area, only an aggregate-level decrease (P < 0.05) among members of households in which the significant member was employed was observed.\n The study displayed areas for improvement in the civic network-based WHO Safe Community model. Even though members of non-vocationally active households, in particular men, were at higher pre-intervention injury risk, they were not affected by the interventions. This fact has to be addressed when planning future community-based injury prevention programmes." ]	There is marked inconsistency in the results of the studies included in this systematic review. While the frequency of injury in some study communities did reduce following their designation as a WHO Safe Community, there remains insufficient evidence from which to draw definitive conclusions regarding the effectiveness of the model. The lack of consistency in results may be due to the heterogeneity of the approaches to implementing the model, varying efficacy of activities and strategies, varying intensity of implementation and methodological limitations in evaluations. While all communities included in the review fulfilled the WHO Safe Community criteria, these criteria were too general to prescribe a standardised programme of activity or evaluation methodology. Adequate documentation describing how various Safe Communities implemented the model was limited, making it unclear which factors affected success. Where a reduction in injury rates was not reported, lack of information makes it difficult to distinguish whether this was due to problems with the model or with the way in which it was implemented.
CD006794	[ "8605126", "1732771", "17654188", "1396258", "9442174", "18715415", "8605125", "12742329", "14744822", "19250364", "18450604", "7485346" ]	[ "A randomised controlled trial of early versus delayed use of amniotomy and oxytocin infusion in nulliparous labour.", "A controlled trial of a program for the active management of labor.", "A trial of amniotomy in a Palestinian hospital.", "Evaluation of different policies for the management of labour.", "Dysfunctional labour: a randomised trial.", "A randomised controlled trial of early versus delayed oxytocin augmentation to treat primary dysfunctional labour in nulliparous women.", "Induction of labour: a randomised clinical trial of amniotomy versus amniotomy with oxytocin infusion.", "Aggressive or expectant management of labour: a randomised clinical trial.", "Randomised controlled trial of labouring in water compared with standard of augmentation for management of dystocia in first stage of labour.", "Early versus delayed oxytocin augmentation in nulliparous women with prolonged labour--a randomised controlled trial.", "A behavioral intervention to improve obstetrical care.", "Early versus late amniotomy for labor induction: a randomized trial." ]	[ "To compare routine amniotomy and early intravenous oxytocin (active management of labour) with a more selective use of amniotomy and oxytocin in women in true labour who received comparable continuous supportive midwifery care.\n Randomised controlled trial of nulliparous clinic patients in spontaneous labour at term.\n Labour and delivery ward of a university teaching hospital.\n Three hundred and six parturients: 152 received active management of labour; 154 were more selectively managed.\n 1. Active management: early amniotomy, early use of oxytocin. 2. Selective intervention management: no routine amniotomy and more selective use of oxytocin.\n Use of oxytocin and amniotomy. Labour duration, mode of delivery.\n Maternal characteristics were comparable in both groups. Amniotomy was more often performed (91% versus 57%, P <0.01) and oxytocin more often used (53% versus 27%, P < 0.01) in the active management group. The first stage of labour, however, was only shortened by half an hour in the active management group (254 min versus 283 min, P = 0.087). Caesarean section rate (3.9% versus 2.6%), spontaneous vaginal delivery rate (78% versus 79%) and neonatal outcome were not significantly different between groups.\n Within a set-up of strict labour diagnosis and supportive midwifery care, routine amniotomy and early use of oxytocin offered no advantage over a more selective use of amniotomy and oxytocin in terms of mode of delivery and labour duration.", "Over the past two decades, the rate of cesarean section in the United States has risen from 5 percent to 25 percent of deliveries, primarily because of the increased frequency of dystocia (arrest of labor). One strategy that has been proposed for increasing the rate of vaginal delivery is a program of active management of labor that encourages early amniotomy, early diagnosis of slow progress in labor, and the use of higher than usual doses of oxytocin; the efficacy and safety of this approach are uncertain, however.\n We conducted a randomized trial in which nulliparous women in spontaneous labor at term were randomly assigned to either active management of labor or traditional management. With active management, amniotomy was performed within one hour of the diagnosis of labor, and when the rate of cervical dilation was less than 1 cm per hour, oxytocin was infused at an initial rate of 6 mU per minute. The dose was increased by 6 mU per minute every 15 minutes (to a maximum of 36 mU per minute) until there were seven contractions every 15 minutes.\n For the women assigned to active management (n = 351), the cesarean-section rate was 10.5 percent, as compared with 14.1 percent for those assigned to traditional management (n = 354, P = 0.18). The 26 percent reduction in the cesarean-section rate was due primarily to a decrease in dystocia. After we controlled for potential confounding variables, the reduction in the rate of delivery by cesarean section was statistically significant (odds ratio for women given active as compared with traditional management, 0.57; 95 percent confidence interval, 0.36 to 0.95). With active management, the average length of labor was shortened by 1.66 hours, principally because of earlier amniotomy and earlier use of oxytocin. There was no increase in maternal or neonatal morbidity, and there were significantly fewer infectious complications in the mothers.\n The program we studied for the active management of labor reduces the incidence of dystocia and increases the rate of vaginal delivery without increasing maternal or neonatal morbidity.", "This randomised controlled trial of routine amniotomy was carried out in a developing country setting to investigate the effect of this common procedure on the duration of labour, intra-partum interventions and selected newborn and maternal outcomes. In a Jerusalem teaching hospital, 533 multiparous and 157 nulliparous low-risk women were randomised to either amniotomy or intent to conserve membranes. For multiparae, the median duration from randomisation to full dilatation was 95 and 160 min, respectively in the intervention and control arms (p < 0.001); for nulliparae it was 210 and 270 min, respectively (p < 0.001). In both groups, oxytocin was used less in the intervention arms (p < 0.001), and no difference in mode of delivery and immediate outcomes was detected. However, given the risks of this intervention and these study findings indicating an overall short duration of childbirth, amniotomy should be limited to cases of abnormal progress of labour.", "Various policies of management of prolonged labour have been proposed to prevent its two main consequences--caesarean section and fetal distress. Two randomised controlled trials were organised; the first to assess the value of amniotomy with oxytocin compared to a more conservative approach. The second trial compared the effect of continuous professional support during labour with the intermittent presence of a member of staff. These were multicentre studies in several countries of Europe. Preliminary results of early amniotomy suggested no difference in the rate of operative delivery. Continuous professional support was associated with a significant reduction in operative deliveries.", "Sixty-one women making slow progress in the active phase of spontaneous labour with intact membranes were randomised to oxytocin and amniotomy, amniotomy only or expectant management. The data show that oxytocin significantly increases the rate of cervical dilatation and shortens prolonged labour, when compared with amniotomy alone and expectant management (P = 0.0144 and 0.0006, respectively). The impact on the operative delivery rate and neonatal outcome is difficult to assess due to the small number of relevant adverse outcomes. Women reported higher satisfaction score in the two groups where intervention followed the diagnosis of dysfunctional labour.", "Oxytocin is widely used to speed up slow labour, especially in nulliparous women, but randomised trials, apart from one reported only in abstract, have been too small to exclude important effects.\n To test the hypothesis that early use of oxytocin reduces the need for caesarean delivery.\n A randomised controlled trial.\n Twelve obstetric units within the Northern and Yorkshire regions in the North East of England.\n A total of 412 low-risk nulliparous women in spontaneous labour at term, who had been diagnosed with primary dysfunctional labour were recruited from January 1999 to December 2001.\n Immediate oxytocin administration (active group) or oxytocin withheld for up to 8 hours (conservative group).\n Caesarean section and operative vaginal delivery rates. The length of labour measured from the time of randomisation to delivery. The rate of maternal Edinburgh Postnatal Depression Scale (EPDS) greater than 12 (major depression) within 48 hours of delivery.\n The caesarean section rates were 13.5% active versus 13.7% controls (OR 0.98, 95% CI 0.6-1.7). Operative delivery, 24.5% versus 30.9% (OR 0.73, 95% CI 0.5-1.1). The median (interquartile range) randomisation to delivery interval in the active group was 5 hours 52 minutes (3:57-8:28) and in the conservative group 9 hours 8 minutes (5:06-13:16) (P < 0.001). The rate of EPDS >12 was 20% in the active arm versus 15% among controls (OR 1.26, 95% CI 0.7-2.2). There was one perinatal death in each group and no major differences in perinatal outcomes.\n Among nulliparous women with primary dysfunctional labour, early use of oxytocin does not reduce caesarean section or short-term postnatal depression. However, it shortens labour considerably and may reduce operative vaginal deliveries.", "To compare two methods of induction of labour-amniotomy with oxytocin infusion versus amniotomy alone.\n Prospective randomised clinical trial.\n The department of obstetrics in a Swedish central hospital.\n One hundred and ninety-six pregnant women with indication for induction of labour at term and a favourable cervix (modified Bishop score > or = 6).\n The women were randomised to amniotomy followed by oxytocin infusion after 1 h (group A, n = 98) or amniotomy alone (group B, n = 98). If labour had not ensued on the following morning, after approximately 24 h, the women in group B were given an oxytocin infusion.\n Induction-delivery interval, duration of labour, time spent in delivery ward, oxytocin use, maternal and neonatal clinical outcome.\n Amniotomy combined with early oxytocin infusion resulted in shorter induction-delivery interval (median 6.0 h; 95% confidence interval (CI) 5.0 to 6.5 h) than amniotomy alone (median 9.0 h; 95% CI 7.5 to 10.0 h). This was due to a shorter latent period in the former group (median 2.3 h; 95% CI 2.0 to 3.0 h) compared to the latter (median 4.3 h; 95% CI 3.0 to 5.5 h). The duration of labour stages 1 and 2 were similar in both groups. The time spent in the delivery ward was slightly reduced for women managed by amniotomy alone (median 5.0 h; 95% CI 4.5 to 6.0 h) compared with those managed by the combination of amniotomy and oxytocin infusion (median 6.0 h; 95% CI 5.0 to 6.5 h). Eighty-seven percent in group A and 32% in group B were given oxytocin, and the total oxytocin infusion time was nearly five times longer in group A. No other important effect on maternal or fetal outcomes was demonstrated.\n With regard to safety the results do not warrant recommending either type of labour induction. The minor differences observed between the induction groups justify an individual management policy, with attention paid to both the indication for induction of labour and the woman's choice.", "To compare labour outcomes using aggressive or expectant management protocols.\n Randomised trial.\n Pretoria Academic Complex, South Africa. It serves an indigent urban population.\n Healthy nulliparous women in active labour, at term, with a health singleton pregnancy and cephalic presentation.\n The women were randomised to either aggressive (n = 344) or expectant (n = 350) management protocols. Aggressive management entailed using a single line partogram, a vaginal examination every two hours and use of an oxytocin infusion if the line was crossed. Expectant management entailed using a two line partogram, with the alert line and a parallel action line four hours to the right, with a vaginal examination every four hours. If the action line was reached, oxytocin was started. The women were reassessed every two hours thereafter. Analgesia was prescribed on request.\n Mode of birth, use of oxytocin and analgesia and neonatal outcome.\n The groups were similar with respect to maternal age, cervical dilation at trial entry, number crossing the alert line and birthweight of the infants. Significantly fewer women managed aggressively had caesarean sections (16.0%) than those managed expectantly (23.4%) (relative risk [RR] 0.68, 95% confidence intervals [CI] 0.50, 0.93). Significantly more oxytocin was used in the aggressive management group, but there was no difference with respect to the use of analgesia or episiotomy or in neonatal outcome with respect to the Apgar score at 1 or 10 minutes. There were three perinatal deaths. One woman was found to have an intrauterine death before trial entry and the other two were in the aggressive management group but did not receive oxytocin. Compliance by staff was poor in the aggressive management group.\n Aggressive management of labour reduces the caesarean section rate in nulliparous women but requires more intensive nursing.", "To evaluate the impact of labouring in water during first stage of labour on rates of epidural analgesia and operative delivery in nulliparous women with dystocia.\n Randomised controlled trial.\n University teaching hospital in southern England.\n 99 nulliparous women with dystocia (cervical dilation rate < 1 cm/hour in active labour) at low risk of complications. Interventions Immersion in water in birth pool or standard augmentation for dystocia (amniotomy and intravenous oxytocin).\n Primary: epidural analgesia and operative delivery rates. Secondary: augmentation rates with amniotomy and oxytocin, length of labour, maternal and neonatal morbidity including infections, maternal pain score, and maternal satisfaction with care.\n Women randomised to immersion in water had a lower rate of epidural analgesia than women allocated to augmentation (47% v 66%, relative risk 0.71 (95% confidence interval 0.49 to 1.01), number needed to treat for benefit (NNT) 5). They showed no difference in rates of operative delivery (49% v 50%, 0.98 (0.65 to 1.47), NNT 98), but significantly fewer received augmentation (71% v 96%, 0.74 (0.59 to 0.88), NNT 4) or any form of obstetric intervention (amniotomy, oxytocin, epidural, or operative delivery) (80% v 98%, 0.81 (0.67 to 0.92), NNT 5). More neonates of women in the water group were admitted to the neonatal unit (6 v 0, P = 0.013), but there was no difference in Apgar score, infection rates, or umbilical cord pH.\n Labouring in water under midwifery care may be an option for slow progress in labour, reducing the need for obstetric intervention, and offering an alternative pain management strategy.", "To study the effects of early versus delayed oxytocin augmentation on the obstetrical and neonatal outcome in nulliparous women with spontaneous but prolonged labour.\n Randomised controlled study.\n Two delivery units in Sweden.\n Healthy nulliparous women with normal pregnancies, spontaneous onset of active labour, a cervical dilatation of 4-9 cm and no progress in cervical dilatation for 2 hours and for an additional hour if amniotomy was performed due to slow progress.\n Women (n = 630) were randomly allocated either to labour augmentation by oxytocin infusion (early oxytocin group) or to postponement of oxytocin augmentation for another 3 hours (expectant group).\n Mode of delivery (spontaneous vaginal or instrumental vaginal delivery or caesarean section) and time from randomisation to delivery.\n The caesarean section rate was 29 of 314 (9%) in the early oxytocin group and 34 of 316 (11%) in the expectant group (OR 0.8, 95% CI 0.5-1.4), and instrumental vaginal delivery 54 of 314 (17%) in the early oxytocin versus 38 of 316 (12%) in the expectant group (OR 1.5, 95% CI 0.97-2.4). Early initiation of oxytocin resulted in a mean decrease of 85 minutes in the randomisation to delivery interval.\n Early administration of oxytocin did not change the rate of caesarean section or instrumental vaginal delivery but shortened labour duration significantly in women with a 2-hour arrest in cervical dilatation. No other clear benefits or harms were seen between early and delayed administration of oxytocin.", "Implementation of evidence-based obstetrical practices remains a significant challenge. Effective strategies to disseminate and implement such practices are needed.\n We randomly assigned 19 hospitals in Argentina and Uruguay to receive a multifaceted behavioral intervention (including selection of opinion leaders, interactive workshops, training of manual skills, one-on-one academic detailing visits with hospital birth attendants, reminders, and feedback) to develop and implement guidelines for the use of episiotomy and management of the third stage of labor or to receive no intervention. The primary outcomes were the rates of prophylactic use of oxytocin during the third stage of labor and of episiotomy. The main secondary outcomes were postpartum hemorrhage and birth attendants' readiness to change their behavior with regard to episiotomies and management of the third stage of labor. The outcomes were measured at baseline, at the end of the 18-month intervention, and 12 months after the end of the intervention.\n The rate of use of prophylactic oxytocin increased from 2.1% at baseline to 83.6% after the end of the intervention at hospitals that received the intervention and from 2.6% to 12.3% at control hospitals (P=0.01 for the difference in changes). The rate of use of episiotomy decreased from 41.1% to 29.9% at hospitals receiving the intervention but remained stable at control hospitals, with preintervention and postintervention values of 43.5% and 44.5%, respectively (P<0.001 for the difference in changes). The intervention was also associated with reductions in the rate of postpartum hemorrhage of 500 ml or more (relative rate reduction, 45%; 95% confidence interval [CI], 9 to 71) and of 1000 ml or more (relative rate reduction, 70%; 95% CI, 16 to 78). Birth attendants' readiness to change also increased in the hospitals receiving the intervention. The effects on the use of episiotomy and prophylactic oxytocin were sustained 12 months after the end of the intervention.\n A multifaceted behavioral intervention increased the prophylactic use of oxytocin during the third stage of labor and reduced the use of episiotomy. (ClinicalTrials.gov number, NCT00070720 [ClinicalTrials.gov]; Current Controlled Trials number, ISRCTN82417627 [controlled-trials.com].).\n Copyright 2008 Massachusetts Medical Society.", "Our purpose was to determine the impact of early and late amniotomy on labor induction with continuous oxytocin infusion at term.\n A total of 209 women admitted for labor induction were randomized to early or late amniotomy. The early amniotomy group (n = 106) had membranes ruptured as soon as it was deemed safe and feasible. The late amniotomy group (n = 103) had membrane rupture performed at > or = 5 cm dilatation. The first 103 women received a continuous oxytocin infusion with incremental adjustments at 60-minute intervals as required. The next 106 women had adjustments every 30 minutes as required. Statistical analysis was confined to concurrent groups.\n Early amniotomy was associated with shorter labor (13.3 vs 17.8 hours, p = 0.001), chorioamnionitis (22.6% vs 6.8%, p = 0.002), and significant fetal umbilical cord compression (12.3% vs 2.9%, p = 0.017). The benefit regarding shortening of labor was limited to women having oxytocin increments every 30 minutes as required (13.3 vs 17.8 hours, p = 0.001). Alternatively, the increase in chorioamnionitis was confined to the 60-minute group (39% vs 11%, p < 0.001), which also demonstrated a trend toward increased moderate and severe variable decelerations (19.6% vs 6.4%, p = 0.08).\n When a protocol of 60-minute increments in oxytocin infusion rate is desired, amniotomy should be performed late in labor to reduce chorioamnionitis and significant umbilical cord compression. Alternatively, if early amniotomy is necessary, oxytocin should be adjusted every 30 minutes as tolerated." ]	In prevention trials, early intervention with amniotomy and oxytocin appears to be associated with a modest reduction in the rate of caesarean section over standard care.
CD004332	[ "9328500", "9519495", "7662044", "8694680", "10787398", "15000513", "12768462", "11524307", "8475472", "12107041", "9622434", "10787394", "12511176", "8676626", "16546214", "12634260", "16968347", "2085344", "8786520", "11916372" ]	[ "Efficacy and safety of acamprosate in the treatment of detoxified alcohol-dependent patients. A 90-day placebo-controlled dose-finding study.", "Acamprosate treatment in a long-term community-based alcohol rehabilitation programme.", "Double-blind randomized multicentre trial of acamprosate in maintaining abstinence from alcohol.", "Relapse prevention by acamprosate. Results from a placebo-controlled study on alcohol dependence.", "Acamprosate and relapse prevention in the treatment of alcohol dependence: a placebo-controlled study.", "Acamprosate in alcohol dependence: a randomized controlled efficacy study in a standard clinical setting.", "Acamprosate and its efficacy in treating alcohol dependent adolescents.", "Acamprosate during and after acute alcohol withdrawal: a double-blind placebo-controlled study in Spain.", "[Acamprosate--a stabilizing factor in long-term withdrawal of alcoholic patients].", "Does psychosocial treatment enhance the efficacy of acamprosate in patients with alcohol problems?", "Combined efficacy of acamprosate and disulfiram in the treatment of alcoholism: a controlled study.", "United Kingdom Multicentre Acamprosate Study (UKMAS): a 6-month prospective study of acamprosate versus placebo in preventing relapse after withdrawal from alcohol.", "Comparing and combining naltrexone and acamprosate in relapse prevention of alcoholism: a double-blind, placebo-controlled study.", "Comparison of acamprosate and placebo in long-term treatment of alcohol dependence.", "Effect of oral acamprosate on abstinence in patients with alcohol dependence in a double-blind, placebo-controlled trial: the role of patient motivation.", "Acamprosate in Korean alcohol-dependent patients: a multi-centre, randomized, double-blind, placebo-controlled study.", "Naltrexone versus acamprosate in the treatment of alcohol dependence: A multi-centre, randomized, double-blind, placebo-controlled trial.", "Acamprosate appears to decrease alcohol intake in weaned alcoholics.", "[Does acamprosate diminish the appetite for alcohol in weaned alcoholics?].", "Divalproex sodium (Depakote) for alcohol withdrawal and relapse prevention." ]	[ "Acamprosate is a newly registered drug that appears to reduce alcohol-drinking in both animal models and clinical conditions.\n In order to assess the efficacy and safety of the drug in the treatment of detoxified alcoholics, we performed a 90-day double-blind trial comparing two dosages of acamprosate (1332 mg/day and 1998 mg/day).\n For all efficacy parameters, acamprosate appeared to be significantly superior to placebo, with a trend towards a better effect at the higher dosage. Furthermore, acamprosate appeared to be extremely safe.\n This study confirms that acamprosate could be an interesting adjuvant for maintaining abstinence in detoxified alcoholics.", "To evaluate the efficacy of acamprosate in maintaining abstinence in weaned alcohol-dependent patients.\n A multicentre, double-blind, randomized control trial. Patients were individually randomly allocated to active or placebo conditions. Abstinence was assessed during a 6-month treatment period and after a 6-month follow-up period.\n A community-based, outpatient alcohol rehabilitation programme.\n Two hundred and forty-six alcohol-dependent patients between the ages of 18 and 65 years were recruited immediately following acute, inpatient withdrawal treatment.\n The primary outcome measure was self-reported abstinence from alcohol since the previous sessions at 3, 6, 9 and 12 months following the start of treatment, with treatment taking place for a period of 6 months.\n A significantly higher proportion of patients in the acamprosate group were abstinent after 3 months and 6 months of treatment. The percentage of patients with continuous abstinence at the end of the treatment period was almost double for the acamprosate group than for the placebo group (40.7% vs. 20.8%, respectively). Acamprosate significantly increased the retention of patients in the treatment programme. Six months after drug treatment ceased, the criterion of abstinence since the previous visit was reached by significantly more patients from the acamprosate group (43.4%) than from the placebo group (29.8%), but this difference was not statistically significant at the 3-month point after cessation of study medication.\n Acamprosate may be a useful pharmacological compound for the long-term treatment of alcohol-dependence when applied in a community-based rehabilitation programme.", "A prospective placebo-controlled, randomized double-blind study of Acamprosate at two dose levels in alcohol-dependent patients followed up for 12 months was performed. After detoxification, each of the 538 patients included was randomly assigned to one of three groups: 177 patients received placebo, 188 received Acamprosate at 1.3 g/day (low dose group) and 173 received 2.0 g/day (high dose group) for 12 months. This was followed by a single blind 6 month period on placebo. The patients' mean age was 43.2 +/- 8.6 years. Their mean daily alcohol intake was high (nearly 200 g/day) and of long duration (9.5 +/- 7.1 years). Abstinence figures followed the order high dose > low dose > placebo. The difference was significant at 6 months (P < or = 0.02) but not at 12 months (P = 0.096). The number of days of continuous abstinence after detoxification was 153 +/- 197 for the high-dose group versus 102 +/- 165 for the placebo group (P = 0.005), with the lose-dose group reporting 135 +/- 189 days. Clinic attendance was significantly better in the Acamprosate groups than in the placebo group at 6 months (P = 0.002) and 12 months (P = 0.005). During the 6-month post-treatment period, no increased relapse rate or residual drug effect was observed. The side effect profile for Acamprosate was good compared with controls with only diarrhoea being reported more frequently (P < 0.01). This study confirms the pharmacological efficacy of Acamprosate and its good acceptability. As an adjunct to psychotherapy, this study supports the inclusion of Acamprosate in a strategy for treating alcoholism.", "The effectiveness of acamprosate (calcium bisacetylhomotaurinate) as a treatment to maintain abstinence in alcohol-dependent patients was assessed for 1 year.\n After short-term detoxification, 272 patients participated in a randomized, double-blind, placebo-controlled study. Patients received routine counseling and either the study medication or placebo for 48 weeks; they were followed up for another 48 weeks without medication. Statistical analysis was performed according to the intention-to-treat principle.\n Patients who were receiving acamprosate showed a significantly higher continuous abstinence rate within the first 60 days of treatment compared with patients who were assigned to placebo treatment (67% vs 50%) until completion of the treatment period (43% vs 21%, log rank P = .005), and they had a significantly longer mean abstinence duration of 224 vs 163 days, or 62% vs 45% days abstinent (P < .001); however, there was no difference in psychiatric symptoms. Of the patients who were receiving acamprosate, 41% had dropped out, whereas 60% of the placebo-treated patients dropped out of the study. Few side effects (mainly diarrhea and headache) were recorded. At the end of a further 48 weeks without receiving study medication, 39% and 17% of the acamprosate- and placebo-treated patients, respectively, had remained abstinent (P = .003).\n Acamprosate proved to be a safe and effective aid in treating alcohol-dependent patients and in maintaining the abstinence of patients during 2 years.", "The objective of this study was to compare acamprosate with placebo in the treatment of alcohol-dependent patients during a 6-month post-detoxification treatment and a 3-month medication-free follow-up. Patients (n = 330) were detoxified and randomized to treatment with acamprosate (1998 mg/day) or placebo within an out-patient programme including medical counselling, psychotherapy and self-help groups. The main outcome criterion was drinking behaviour as assessed by: abstinence/relapse ratio, cumulative abstinence duration (CAD) and the period of continued abstinence. Anxiety, depression and craving were also monitored. Intention to treat (ITT) statistical principles were followed. Twenty-five per cent of patients dropped out over the first 6 months. At the end of the treatment period, the abstinence rate was 57.9% for acamprosate and 45.2% for placebo (P = 0.03). The CAD was 110+/-77 days for acamprosate and 89+/-77 days for placebo (P = 0.016). Patients on acamprosate had a higher continuous abstinence rate and experienced less severe relapses. No differential effect was noted for anxiety, depression or craving. Treatment remained positive, but not significant, 3 months after termination of study medication. No significant difference in adverse events was noted between treatment groups. Acamprosate treatment over 180 days was consistently more effective than placebo to maintain abstinence and to diminish relapse severity.", "This study was undertaken to evaluate the efficacy and safety of acamprosate in the treatment of alcohol dependence.\n The investigation was a double-blind, placebo-controlled, 24-week study carried out at the University of São Paulo, Brazil. The sample comprised 75 patients, 18-60 years of age, with an International Classification of Diseases (ICD-10) diagnosis of alcohol dependence. After a 1-week detoxification period the patients were randomly divided into two groups: the first received acamprosate (1.998 mg/day) and the second received placebo. After the first 12 weeks, the patients continued follow-up for a similar length of time without medication. The main outcome measures were relapse rates, side effects and time to first relapse.\n On an intention-to-treat basis, the Kaplan-Meier survival curve showed an advantage in relapse rates for acamprosate over placebo (log-rank test, p = .02), and acamprosate was well tolerated.\n Acamprosate seems to be an effective treatment for alcohol dependence in a Brazilian population.", "About 50 % of adult alcoholic patients relapse within 3 months of treatment. Previous studies have suggested that acamprosate may help to prevent such relapse. The aim of our study was to assess the efficacy and safety of long-term acamprosate treatment in alcohol dependence of adolescents.\n In this, double-blind, placebo-controlled study, we recruited 26 patients, aged 16-19 years, with chronic or episodic alcohol dependence. Patients were randomly allocated treatment with acamprosate (1332 mg daily) or placebo for 90 days. Patients were assessed on the day treatment started and on days 30, and 90 by interview, self report, questionnaire, and laboratory screening.\n 13 acamprosate-treated and 13 placebo-treated patients completed the treatment phase: of those withdrawn, 11 (1 vs 6) relapsed, 5 (3 vs 2) refused to continue treatment, 3 (1 vs 2) had concurrent illness, and 2 (1 vs 1) had adverse side-effects. At the end of treatment, 7 acamprosate treated and 2 placebo-treated patients had been continuously abstinent (p = 0.0076). Mean cumulative abstinence duration was significantly greater in the acamprosate group than in the placebo group (79.8 [SD 37.5] vs 32.8 [19.0] days; p = 0.012).\n Acamprosate is an effective and well-tolerated pharmacological adjunct to psychosocial treatment programmes.", "To test acamprosate's role as an aid in preventing relapse after detoxification, 296 alcohol-dependent patients entered a prospective, multicentre, randomized, double-blind, parallel comparison of acamprosate treatment consisting of two 333 mg tablets given three times daily for 180 days with matching placebo treatment. Unlike previous studies, acamprosate was prescribed from the start of alcohol withdrawal, rather than after the detoxification process. During the treatment period, 110 patients dropped out. The two treatment groups were balanced with regard to baseline values and reasons for discontinuation. There was no difference between the groups in the severity of withdrawal symptoms as measured by the CIWA-Ar (Clinical Institute Withdrawal Assessment for Alcohol scale). Acamprosate given during withdrawal did not cause unwanted effects. The cumulative abstinence duration (CAD, main end-point) was 19 days longer in the acamprosate treatment group than the placebo treatment group (analysis of variance on ranks, P = 0.0006) and the stable recovery duration, defined as the number of abstinent days between the last relapse into any drinking and the end of the trial, was 16 days longer in the acamprosate treatment group (P = 0.021). Continuous abstinence, estimated by survival analysis on time to first relapse, was achieved by 35% of acamprosate-treated patients and 26% of placebo-treated patients (log rank P = 0.068). The geometric mean of the ratio final/baseline values for serum carbohydrate-deficient transferrin was 0.802 (placebo) and 0.733 (acamprosate) (P = 0.059). The geometric mean of the ratio final/baseline values for serum gamma-glutamyltransferase was 0.496 (placebo) and 0.415 (acamprosate) (P = 0.024) which corroborated the greater abstinence reported by the acamprosate group.", "In a one-year double-blind-treatment study with acamprosat (six months with and six months without substance) the efficiency of this new medicament could be proved. The number of relapses in the treatment group was significantly lower during the first 30 days with a trend to further 150 days. The substance caused very few side effects.", "Acamprosate in combination with psychosocial treatment has been shown to be effective for the treatment of alcohol dependence. The goal of the present study was to determine whether the addition of psychosocial intervention to the medical prescription of acamprosate contributes to treatment outcome.\n Patients (n = 248) meeting DSM-IV criteria for alcohol dependence or abuse were recruited in 14 outpatient treatment centres and randomized into one of three treatment conditions: acamprosate; acamprosate plus minimal intervention aimed at motivational enhancement (3-weekly sessions of 20 min); and acamprosate plus brief cognitive behavioural therapy (7-weekly sessions of 60 min). Acamprosate was prescribed for 28 weeks, medically monitored by a physician on six occasions lasting 10 min. Drinking behaviour, medication compliance and psychological distress were assessed throughout the treatment period. Follow-up assessment was undertaken 6 months after termination of pharmacological treatment.\n Of 241 patients with intention to treat (ITT), 114 (47.3%) remained in treatment for the full 28 weeks; 169 of the ITT population (70.1%) were seen for follow-up. No statistically significant differences were found between treatment groups for any of the drinking outcomes either at the end of the 28 weeks of treatment or at 6-month follow-up. There were no statistically significant differences in medication compliance, drop-out rates, or psychological distress. However, a significant interaction effect was observed between treatment centre and treatment group, indicating that brief interventions were differentially effective in different treatment centres.\n A clear supplemental value of minimal and brief psychosocial interventions to the prescription of acamprosate was not demonstrated. The widely held belief that pharmacotherapy for alcohol dependence should always be combined with psychosocial intervention is debatable and merits further research.", "This study presents the results of a multicenter investigation of the efficacy of acamprosate in the treatment of patients with chronic or episodic alcohol dependence. One hundred eighteen patients were randomly assigned to either placebo or acamprosate, and both groups were stratified for concomitant voluntary use of disulfiram. Treatment lasted for 360 days, with an additional 360-day follow-up period. The primary efficacy parameters evaluated were: relapse rate and cumulative abstinence duration (CAD). Results were analyzed according to Intention-To-Treat principles using chi2, t, and multiple regression analyses where appropriate. After 30 days on study medication, 40 of 55 (73%) acamprosate-treated patients were abstinent, compared with 26 of 55 (43%) placebo-treated patients (p = 0.019). The treatment advantage remained throughout the study medication period and was statistically significant until day 270 (p = 0.028). Twenty-seven percent of patients on acamprosate and 53% of patients on placebo had a first drink within the first 30 days of the study. The mean CAD was 137 days (40% abstinent days) for the patients treated with acamprosate and 75 days (21% abstinent days) for the placebo group (p = 0.013). No adverse interaction between acamprosate and disulfiram occurred, and the subgroup who received both medications had a better outcome on CAD than the those on only one or no medication. Acamprosate was well tolerated. Diarrhea was the only significant treatment-induced effect. It was concluded that acamprosate was a useful and safe pharmacotherapy in the long-term treatment of alcoholism. Concomitant administration of disulfiram improved the effectiveness of acamprosate.", "A 6-month randomized controlled study of acamprosate versus placebo in preventing relapse following withdrawal from alcohol was undertaken in 20 centres throughout the UK. Patients diagnosed as alcohol-dependent and detoxified within the preceding 5 weeks were randomly assigned to treatment with either acamprosate (A) 666 mg three times/day or identical placebo (P). A total of 664 patients were screened; 581 were entered into the treatment phase. One-third were episodic drinkers, 84% were male, 44% were unmarried and 48% were unemployed. Medication was first taken on average 24 days after the start of detoxification; 32% of patients had already relapsed by this time. The 6-month study period was completed by 35% of patients; adverse events led to withdrawal of a further 14% (A) and 9% (P) respectively. Compliance was poor in that, by the end of the second week, only 57% of patients were judged to be taking at least 90% of their tablets. The mean total of abstinent days achieved was 77 (A) and 81 (P). Complete abstinence for 6 months was achieved by 12% (A) and 11% (P); drinking remained within controlled limits in a further 3% (A) and 6% (P). An effect of acamprosate on consumption was not seen when subgroups, including those defined by the Lesch typology, were analysed separately. However, the mean percentage reduction in craving for alcohol measured on a visual analogue scale was greater in the acamprosate, than placebo, patients at week 2 and week 4 (P<0.001) and the mean decrease in the Hamilton Anxiety score at the 4th week was greater in the acamprosate than placebo patients (P = 0.017). In comparison with other published trials of acamprosate, patients started study medication after a longer time following detoxification, had more often recommenced drinking before medication was started and had a higher drop-out rate, and this might have contributed to the lack of a treatment effect in this study.", "Naltrexone and acamprosate have been shown to be effective in relapse prevention of alcoholism via different pharmacologic mechanisms. Since it remains uncertain whether both substances are equally efficient and whether a combination of both drugs potentiates the efficacy, we conducted the first published controlled study comparing and combining both compounds.\n After detoxification, 160 patients with alcoholism participated in a randomized, double-blind, placebo-controlled protocol. Patients received naltrexone, acamprosate, naltrexone plus acamprosate, or placebo for 12 weeks. Patients were assessed weekly by interview, self-report, questionnaires, and laboratory screening. Time to first drink, time to relapse, and the cumulative abstinence time were the primary outcome measures.\n Naltrexone, acamprosate, and the combined medication were significantly more effective than placebo. Comparing the course of nonrelapse rates between naltrexone and acamprosate, the naltrexone group showed a tendency for a better outcome regarding time to first drink and time to relapse. The combined medication was most effective with significantly lower relapse rates than placebo and acamprosate but not naltrexone.\n The results of this study support the efficacy of pharmacotherapeutic strategies in the relapse prevention of alcoholism. Naltrexone and acamprosate, especially in combination, considerably enhance the potential of relapse prevention.", "About 50% of alcoholic patients relapse within 3 months of treatment. Previous studies have suggested that acamprosate may help to prevent such relapse. The aim of our study was to assess the efficacy and safety of long-term acamprosate treatment in alcohol dependence.\n In this multicentre, double-blind, placebo-controlled study, we recruited 455 patients, aged 18-65 years, with chronic or episodic alcohol dependence. Patients were randomly allocated treatment with acamprosate (1998 mg daily for bodyweight > 60 kg; 1332 mg daily for < or = kg) or placebo for 360 days. Patients were assessed on the day treatment started and on days 30, 90, 180, 270, and 360 by interview, self-report, questionnaire, and laboratory screening. Patients were classified as abstinent, relapsing, or non-attending. Time to first treatment failure (relapse or non-attendance) was the primary outcome measure.\n Seven patients were excluded from the intention-to-treat analysis because they did not attend on the first treatment day and therefore received no medication. The acamprosate (n = 224) and placebo (n = 224) groups were well matched in terms of baseline demographic and alcohol-related variables. 94 acamprosate-treated and 85 placebo-treated patients completed the treatment phase: of those withdrawn, 104 (52 in each group) relapsed, 69 (33 vs 36, respectively) were lost to follow-up, 63 (31 vs 32) refused to continue treatment, 16 (15 vs 11) had concurrent illness, three (two vs one) died, ten (six vs four) had adverse side-effects, one (acamprosate treated) received the wrong medication, and three (placebo treated) were non-compliant. The proportion without treatment failure was higher in the acamprosate than in the placebo group throughout the treatment period (p < 0.001, Mantel-Cox). At the end of treatment, 41 (18.3%) acamprosate-treated and 16 (7.1%) placebo-treated patients had been continuously abstinent (p = 0.007). Mean cumulative abstinence duration was significantly greater in the acamprosate group than in the placebo group (138.8 [SD 137.5] vs 103.8 [119.0] days; p = 0.012). 148 patients (79 acamprosate, 69 placebo) completed 27 months follow-up: 27 (11.9%) acamprosate-treated and 11 (4.9%) placebo-treated patients remained continuously abstinent, and the mean cumulative abstinence duration was 230.8 days (259.1) and 183.0 days (235.2), respectively. Apart from occasional diarrhoea, there was no difference in side-effects between groups.\n Acamprosate is an effective and well-tolerated pharmacological adjunct to psychosocial and behavioural treatment programmes for treatment of alcohol-dependent patients.", "This is the first US study to evaluate the clinical efficacy of acamprosate (Campral), a newly FDA-approved medication for maintaining abstinence in patients with alcohol dependence following alcohol withdrawal. We compared effects of the standard 2 g dose (n=258) and an exploratory 3 g dose of acamprosate (n=83) versus placebo (n=260), and evaluated drug safety in a double-blind, placebo-controlled 6-month trial conducted in 21 outpatient clinics across the US. Participants were 601 volunteers with current alcohol dependence recruited primarily by advertisement. All patients concomitantly received eight sessions of brief manual-guided counseling (www.alcoholfree.info). The main outcome measure was the percentage of alcohol-free days over the 6-month study. Self-report was validated by breath alcohol concentration, gamma-glutamyltransferase (GGT) and collateral informant interviews. The percentage of abstinent days did not differ significantly across groups in a priori analysis (54.3% for placebo, 56.1% for 2 g, 60.7% for 3 g). Post-hoc analysis controlling for baseline variables and treatment exposure found acamprosate was associated with a significantly higher percentage of abstinent days than placebo (52.3% for placebo, 58.2% for 2 g, 62.7% for 3 g; P=0.01), with an even greater effect in the subgroup of 241 patients having a baseline goal of abstinence (58.1% for placebo, 70.0% for 2 g, 72.5% for 3 g; P=0.02). There were no deaths or serious drug-related adverse events. The US study findings suggest that acamprosate is safe and well tolerated in a broadly inclusive sample of alcoholics and appears effective in populations of patients motivated to have a treatment goal of abstinence.", "A multi-centre, randomized, double-blind, placebo-controlled trial was conducted to evaluate the efficacy and the safety of acamprosate over 8 weeks in Korean alcohol-dependent patients.\n One hundred and forty-two alcohol-dependent patients in 12 centres were randomized to 8 weeks treatment with either acamprosate (n = 72) or a placebo (n = 70) in combination with out-patient psychosocial intervention. They were predominantly male (95.8%), with a mean age of 44.3 +/- 8.3 years; 76.1% were married; 59.9% were employed; 58.5% had received previous alcoholism treatment (previous mean number of admissions in alcoholism in-patient programmes 4.6 +/- 6.9). At visits to the clinic (weekly for 4 weeks, then biweekly for 4 weeks), a record was made of alcohol use (Time-Line Follow-Back), alcohol craving using a Korean version of the Obsessive Compulsive Drinking Scale and a visual analogue scale, and adverse events. Serum aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase (GGT), blood urea nitrogen and creatinine levels were measured on weeks 0, 2, 4 and 8.\n In the acamprosate group (A), 71.4% had had alcohol within the 2 days prior to starting medication, against 65.2% of patients in the placebo group (P); (P > 0.05). One hundred and one subjects (71.1%) completed 8-weeks of treatment (A, 73.6%; P, 68.6%; P > 0.05). During the 8-week treatment period, 37, (A) (n = 72) and 32% (P) (n = 70) achieved continuous abstinence (P > 0.05), and 40, (A) and 39% (P) remained without relapse (P > 0.05) (defined as a day when a man consumed five or more drinks or a woman four or more drinks). The percentage of days abstinent during the 8-week treatment period was 81.2, (A) and 78.5% (P) (P > 0.05), and the percentage of days without heavy drinking 86.1 (A) and 84.9% (P) (P > 0.05). The mean amount drunk per drinking occasion was 7.2, (A) and 8.6 standard drinks (P) (P > 0.05). No statistically significant differences in changes in the serum GGT level or craving scores from baseline to the end-point of treatment were found between the two groups. Recency of drinking prior to commencing study drug predicted percentage of days abstinent in the first 2 weeks on treatment; however, when ANOVAs were conducted using treatment outcomes as a dependent variable, medication condition as an independent variable and the period of abstinence prior to treatment as a covariate, a significant effect of medication condition was still not seen.\n Acamprosate was ineffective in reducing drinking in this Korean sample. The result differs from that of most European acamprosate trials. This might be explained by our sample's relatively severe alcohol dependence, and low social support, or the fact that many patients were still drinking near to their first medication. The variability of the psychosocial support, ethnicity (which might also affect acamprosate pharmacokinetics) and the Korean drinking style, which differs from that of Europeans, might have contributed to our negative result.", "To compare the efficacy of acamprosate and naltrexone in the treatment of alcohol dependence.\n A double-blind, placebo-controlled trial.\n Three treatment centres in Australia.\n A total of 169 alcohol dependent subjects were given naltrexone (50 mg/day), acamprosate (1998 mg/day) or placebo for 12 weeks.\n All subjects were offered manualized compliance therapy, a brief intervention that targets problems that may affect treatment compliance such as ambivalence and misperceptions about medication.\n Time to the first drink, time to first relapse, drinks per drinking day and cumulative abstinence.\n In intention-to-treat analyses, there were no differences between groups on outcome measures of drinking, craving or biochemical markers. Similarly, analyses of the 94 subjects that completed the study in full and demonstrated 80% compliance, revealed no significant treatment effects. Differential treatment effects were identified after stratification according to scores on the Alcohol Dependence Scale (ADS) and Depression Anxiety and Stress Scale (DASS). A significant beneficial treatment effect on time to first relapse was revealed for subjects with 'no depression' allocated to naltrexone (n = 56; P < 0.01). In addition, a significant beneficial treatment effect was revealed in subjects with 'low dependence' allocated to naltrexone (n = 34; P < 0.05).\n The results of this study support the efficacy of naltrexone in the relapse prevention of alcoholism amongst those with low levels of clinical depression and alcohol dependence severity. No effect of acamprosate was found in our sample.", "Five hundred and sixty-nine alcoholics were included in a double-blind placebo-controlled randomized multicenter study of the effects of Acamprosate (calcium acetylhomotaurinate (CA), 1.3 g/day) on indicators of alcoholic relapse after withdrawal. One hundred and eighty-one patients in the CA group versus 175 in the placebo group completed the three-month study. The major efficacy criterion was plasma gamma-glutamyl transpeptidase (GGT), as an indicator of recent alcohol ingestion. This analysis was completed by criteria concordance analysis on a number of indicators of alcohol intake. Patients in both groups were similar initially. After 3 months of treatment, the patients in the CA group had significantly lower GGT (1.4 +/- 1.56 versus 2.0 +/- 3.19 times normal, P = 0.016). All significant differences (P less than 0.05) or trends (0.10 greater than P greater than 0.05) were in favor of a superior effect of CA over placebo. The major side-effect of CA was diarrhea (present in 13% of CA patients versus 7% of placebo, P = 0.04). CA proved superior to placebo on the evolution of markers of alcohol ingestion at three months, in this large-scale multicenter study. It could be a new modality in the drug therapy of alcoholism, not involving an antabuse effect, an antidepressant action, or conditioning.", "A population of 127 alcoholics of both sexes, hospitalized and weaned (DSM III diagnose: Alcohol Abuse and Alcohol Dependence) received Acamprosate (n = 63) or placebo (n = 64) in a double blind randomized therapeutic trail. The patients were followed during three months and anamnestic as well as biological data were recorded. It appeared no significant differences between the two groups of patients. This negative result could perhaps be explained by the heaviness of the pathology of this hospitalized alcoholic population.", "This pilot study evaluates the safety and efficacy of divalproex sodium (Depakote) for alcohol withdrawal and relapse prevention. Sixteen patients in moderate alcohol withdrawal were randomized to receive a standard benzodiazepine detoxification, depakote detoxification, or depakote detox plus maintenance. Symptom reduction occurred more rapidly and consistently in the depakote treated patients than in the benzodiazepine control group, and at six-week follow up a greater percentage of patients in the depakote maintenance group were completely abstinent than either detox-only group. There were no significant differences in sociodemographic or drinking data amongst the three cohort samples at baseline. Our findings suggest that the anticonvulsant divalproex sodium (Depakote) may be a safe and efficacious alternative to benzodiazepines for the treatment of alcohol withdrawal. It may be an advantageous alternative for outpatient detoxification, as it has no abuse potential, pharmacologic synergy with alcohol, or substantial cognitive or psychomotor side effects." ]	Acamprosate appears to be an effective and safe treatment strategy for supporting continuous abstinence after detoxification in alcohol dependent patients. Even though the sizes of treatment effects appear to be rather moderate in their magnitude, they should be valued against the background of the relapsing nature of alcoholism and the limited therapeutic options currently available for its treatment.
CD006471	[ "19374691" ]	[ "The impact of pressure ulcer risk assessment on patient outcomes among hospitalised patients." ]	[ "To determine whether use of a risk assessment scale reduces nosocomial pressure ulcers.\n There is contradictory evidence concerning the validity of risk assessment scales. The interaction of education, clinical judgement and use of risk assessment scales has not been fully explored. It is not known which of these is most important, nor whether combining them results in better patient care.\n Pretest-posttest comparison.\n A risk assessment scale namely the Braden was implemented in a group of wards after appropriate education and training of staff in addition to mandatory wound care study days. Another group of staff received the same education programme but did not implement the risk assessment scale and a third group carried on with mandatory study days only.\n Nosocomial Pressure Ulcer was reduced in all three groups, but the group that implemented the risk assessment scale showed no significant additional improvement. Allowing for age, gender, medical speciality, level of risk and other factors did not explain this lack of improvement. Clinical judgement seemed to be used by nurses to identify patients at high risk to implement appropriate risk reduction strategies such as use of pressure relieving beds. Clinical judgement was not significantly different from the risk assessment scale score in terms of risk evaluation.\n It is questioned whether the routine use of a risk assessment scale is useful in reducing nosocomial pressure ulcer. It is suggested clinical judgement is as effective as a risk assessment scale in terms of assessing risk (though neither show good sensitivity and specificity) and determining appropriate care.\n Clinical judgement may be as effective as employing a risk assessment scale to assess the risk of pressure ulcers. If this were true it would be simpler and release nursing time for other tasks." ]	One small RCT was identified which evaluated the effect of risk assessment on patient outcomes; there was no statistically significant difference in pressure ulcer incidence between patients who were assessed using structured risk assessment compared with those receiving unstructured risk assessment. Methodological limitations of this study prevent firm conclusions regarding whether the use of structured, systematic pressure ulcer risk assessment tools, in any healthcare setting, reduces the incidence of pressure ulcers. The effect of structured risk assessment tools on pressure ulcer incidence needs to be evaluated.
CD004996	[ "9228372", "8825017", "22009916", "19276620", "1617983" ]	[ "A trial of antioxidants N-acetylcysteine and procysteine in ARDS. The Antioxidant in ARDS Study Group.", "Multicenter ophthalmic and nutritional age-related macular degeneration study--part 2: antioxidant intervention and conclusions.", "Carotenoids in Age-related Maculopathy Italian Study (CARMIS): two-year results of a randomized study.", "Is antioxidant and n-3 supplementation able to improve functional status in poststroke patients? Results from the Nutristroke Trial.", "Antioxidant treatment with N-acetylcysteine during adult respiratory distress syndrome: a prospective, randomized, placebo-controlled study." ]	[ "To determine the levels of glutathione and cysteine in patients with ARDS and examine the effect of treatment with N-acetylcysteine (NAC) and L-2-oxothiazolidine-4-carboxylate (Procysteine; Clintec Technologies Inc; Chicago [OTZ]) on these levels and on common physiologic abnormalities, and organ dysfunction associated with ARDS.\n Randomized, double-blind, placebo-controlled, prospective clinical trial.\n ICUs in five clinical centers in the United States and Canada.\n Patients meeting a predetermined definition of ARDS and requiring mechanical ventilation.\n Standard care for ARDS and I.V. infusion, every 8 h for 10 days, of one of the following: NAC (70 mg/kg, n=14), OTZ (63 mg/kg, n=17), or placebo (n=15).\n Both antioxidants effectively repleted RBC glutathione gradually over the 10-day treatment period (47% and 49% increases from baseline values for NAC and OTZ, respectively). There was no difference in mortality among groups (placebo, 40%; NAC, 36%; OTZ, 35%). However, the number of days of acute lung injury was decreased and there was also a significant increase in cardiac index in both treatment groups (NAC/OTZ [+]14%; placebo [-]6%).\n Our findings suggest that repletion of glutathione may safely be accomplished with NAC or OTZ in patients with acute lung injury/ARDS. Such treatment may shorten the duration of acute lung injury, but larger studies are needed to confirm this.", "The experimental design, subjects, procedures and baseline data for the prospective double blind dry ARMD-antioxidant intervention study have been described in Part 1.\n At eight DVA medical centers, 32 patients (group one) were assigned a placebo and 39 patients (group two) a \"broad spectrum\" antioxidant capsule. Data was collected in five areas: demographic; ophthalmic; dietary analysis of daily food intake; serum analysis; and adverse gastrointestinal symptoms. Data was serially acquired at baseline, 6 months, 12 months and 18 months, and was analyzed by univariate repeated factors ANOVA, p = 0.05.\n Group two (antioxidant po BID) maintained their distance LogMAR visual acuity (p = 0.03), while there was a trend toward both stabilized near M print (p = 0.07) and 6 cycle/degree contrast sensitivity (p approximately 0.10), in left eyes. However, group two (antioxidant) also had increased cortical opacification of the right lens (p = 0.04), compared to group one (placebo). Self perceived stabilization of vision was reported by subjects in group two and supported the objective data (Pearson chi square; p = 0.05).\n A specific 14 component antioxidant capsule taken twice daily stabilized but did not improve dry ARMD over the study period of 1.5 years. The ARMD stabilized eyes had less advanced disease functionally but not by fundus appearance. Decreased intake of cardioprotective nutrients (vitamin E, zinc, magnesium, B6 and folate) in ARMD patients remained constant over the course of the trial.", "The high concentration of carotenoids in the macula, plus evidence linking oxidative stress to age-related macular degeneration (AMD) and carotenoids to antioxidation, generated the hypothesis that higher antioxidant intakes can prevent AMD. The aim of this study was to determine whether nutritional supplementation with a targeted nutritional supplement improves visual acuity and visual function in AMD.\n In this multicenter, prospective open-label randomized study, 145 patients were randomly assigned to 2 different treatment groups. Interventions were lutein (10 mg), zeaxanthin (1 mg), astaxanthin (4 mg; AZYR SIFI, Catania, Italy), and antioxidants/vitamins supplementation formula or no dietary supplementation for 2 years. Primary outcome was mean changes in visual acuity (VA) at 12 and 24 months. Other measures included contrast sensitivity (CS) and National Eye Institute visual function questionnaire (NEI VFQ-25) scores at 12 and 24 months.\n Patients in the treated group showed stabilization of VA with significantly (p=0.003) better VA scores (81.4 ± 7.2) compared to the nontreated group (76.8 ± 8.9) at 24-month follow-up. An improvement in CS (p=0.001) and final mean NEI VFQ-25 composite scores at 12 and 24 months higher in treated group compared to nontreated group were also shown (p<0.001).\n Patients treated with lutein/zeaxanthin and astaxanthin together with other nutrients were more likely to report clinically meaningful stabilization/improvements in VA, CS, and visual function through 24 months compared with nontreated subjects. Further studies are needed with more patients and for longer periods of time.", "To test whether supplementary antioxidants and n-3 fatty acids, alone or in combination, could improve functional status in stroke survivors.\n We performed a randomized, double-blind, placebo-controlled clinical trial in 72 stroke patients (47 males; age 65.3 +/- 12.9 years) admitted to a rehabilitation hospital for sequelae of first-ever ischemic stroke, and divided them into 4 subgroups. Group 1 patients received daily oral antioxidants, group 2 received n-3 polyunsaturated fatty acids, group 3 both supplements, and group 4 placebo, all for 12 months. No difference at baseline was observed among groups in neurological severity or in disability. All measures were repeated after 6 and 12 months of treatment. All major clinical events were recorded.\n At baseline, 25% of the patients had a low plasma vitamin status, and 48.5% was at risk of undernutrition. At the 1-year follow-up, we observed a trend for lower mortality (p = 0.060) in subgroups treated with n-3 fatty acids, but without significant differences in rehabilitation result status among groups.\n Malnutrition is widely observed in patients admitted to a rehabilitative hospital for stroke rehabilitation, and dietary supplementation, even if not able to improve rehabilitation results, is likely to reduce mortality at the 1-year follow-up.\n Copyright 2009 S. Karger AG, Basel.", "To examine whether the antioxidant N-acetylcysteine could ameliorate the course of the adult respiratory distress syndrome (ARDS) in man.\n Randomized, double-blind, placebo-controlled study.\n Medical and surgical ICU in a regional hospital.\n Sixty-six ICU patients with ARDS.\n Patients with ARDS (PaO2/FiO2 ratio less than 250 torr) were treated with either the antioxidant N-acetylcysteine 150 mg/kg as a loading dose and then 20 mg/kg/hr, or with placebo for 6 days.\n No improvement could be demonstrated in the PaO2/FiO2 ratio in the study group as compared with the control group on any day. Pulmonary compliance was higher in the N-acetylcysteine group than in the placebo group on all days, but this difference did not reach the chosen 5% level of significance. No difference between the two groups could be demonstrated on chest radiograph or on survival rate. We documented that N-acetylcysteine acts as an anticoagulant and perhaps decreases pulmonary fibrin uptake during ARDS.\n N-acetylcysteine might be of benefit in ARDS. Before further clinical studies are started, problems with N-acetylcysteine and coagulation have to be elucidated in order to find out whether N-acetylcysteine could have a beneficial effect in the treatment of ARDS." ]	There is insufficient data to either support or refute the use of antioxidant supplements for patients with NAFLD. It may be advisable to carry out large prospective randomised clinical trials on this topic.
CD003397	[ "6849350", "3904818" ]	[ "The effect of maternal glucose administration on the specificity of the nonstress test.", "Non-stress antenatal cardiotocography--a prospective randomized clinical trial." ]	[ "To determine whether maternal glucose administration can decrease the incidence of false positive nonstress tests, 296 nonstress tests were performed on 235 high-risk obstetric patients in a prospective controlled study. Patients were alternately given a 50 gm oral glucose drink or an equal volume of water 30 minutes prior to the commencement of each test. Among \"fed\" patients (last meal within 2 hour of the nonstress test) whether receiving glucose or water, and \"fasted\" patients who received glucose, there was no significant difference in the percentage of reactive tests at either 20 minutes (65.2%) or 40 minutes (87.3%) of testing. However, patients fasting and receiving water had a significantly decreased percentage of reactive tests, both at 20 minutes (48.3%, P less than 0.01) and at 40 minutes (76.7%, P less than 0.05). Glucose administered to fasted patients resulted in an increase in the incidence of reactive tests, although this was not statistically significant. Glucose administration had no effect on the nonstress test results when administered to fed patients.", "A randomized controlled trial examined the effects of non-stress antepartum cardiotocography on obstetric management and assessed its usefulness as a diagnostic test of fetal compromise. Daily cardiotocograph recordings were made in 396 antenatal patients at increased risk of fetal compromise but were withheld from the clinicians responsible for care in half the cases. The frequency of intrapartum fetal distress and low Apgar score was similar in the two groups. The three normally-formed perinatal deaths all occurred in the revealed group but in only one case could earlier obstetric intervention have altered the outcome. Availability of non-stress cardiotocography was not associated with an increased rate of induction of labour or caesarean section." ]	Antenatal maternal glucose administration has not been shown to reduce non-reactive cardiotocography. More trials are needed to further substantiate this and to determine not only the optimum dose, but also to evaluate the efficacy, predictive reliability, safety and perinatal outcome of glucose administration in conjunction with cardiotocography and also other tests of fetal wellbeing.
CD008413	[ "18193194", "19793927", "19509412", "21610263", "19323939", "18237696", "20434660", "15174545", "21316972", "20734043", "19557391", "20668835", "19794165", "17560476", "18208432", "20934698" ]	[ "Reconstruction of the ACL with a semitendinosus tendon graft: a prospective randomized single blinded comparison of double-bundle versus single-bundle technique in male athletes.", "Comparison between single-and double-bundle anterior cruciate ligament reconstruction: a prospective, randomized, single-blinded clinical trial.", "Prospective comparative study of anterior cruciate ligament reconstruction using the double-bundle and single-bundle techniques.", "Double-bundle versus single-bundle anterior cruciate ligament reconstruction: randomized clinical and magnetic resonance imaging study with 2-year follow-up.", "Clinical evaluation of double-bundle anterior cruciate ligament reconstruction procedure using hamstring tendon grafts: a prospective, randomized and controlled study.", "Prospective randomized comparison of double-bundle versus single-bundle anterior cruciate ligament reconstruction.", "Outcome of arthroscopic single-bundle versus double-bundle reconstruction of the anterior cruciate ligament: a preliminary 2-year prospective study.", "Reconstruction of the anterior cruciate ligament. Single- versus double-bundle multistranded hamstring tendons.", "Evaluation of tibial rotational stability of single-bundle vs. anatomical double-bundle anterior cruciate ligament reconstruction during a high-demand activity - a quasi-randomized trial.", "A prospective randomised study of anatomical single-bundle versus double-bundle anterior cruciate ligament reconstruction: quantitative evaluation using an electromagnetic measurement system.", "Double-bundle versus single-bundle ACL reconstruction using the horizontal femoral position: a prospective, randomized study.", "Single-bundle patellar tendon versus non-anatomical double-bundle hamstrings ACL reconstruction: a prospective randomized study at 8-year minimum follow-up.", "Anterior cruciate ligament reconstruction using autologous hamstring double bundle graft compared with single bundle procedures.", "A prospective randomized study of 4-strand semitendinosus tendon anterior cruciate ligament reconstruction comparing single-bundle and double-bundle techniques.", "ST/G ACL reconstruction: double strand plus extra-articular sling vs double bundle, randomized study at 3-year follow-up.", "ACL reconstruction in sports active people: transtibial DB technique with ST/G vs. transtibial SB technique with BPTB: preliminary results." ]	[ "Anterior cruciate ligament (ACL) reconstruction in double-bundle technique is advocated to more closely restore the anatomy and function of the native ligament than conventional single-bundle technique. But up to now there are only a few clinical investigations comparing both techniques in a prospective manner. We hypothesized that double-bundle ACL reconstruction reveals superior clinical and subjective results compared to single-bundle technique in a high-demand collective. A total of 50 male patients (mean age 29.4 years) were prospectively randomized consecutively into one of the two reconstruction techniques. Group 1 (SB) underwent a 4-stranded single-bundle reconstruction with a ST graft in femoral position at 10:00 and 02:00 o'clock, respectively. In group 2 (DB), reconstruction was performed by using a 2-stranded ST graft with double-bundle, four tunnel technique. Before surgery and at a 2 year follow-up (range 23-25 months) patients were evaluated by the same blinded observer. There was no significant difference in the side-to-side anterior laxity-measurement with the KT-1000 between both groups. As evaluated by the pivot shift, no significant correlation could be noted (Fisher exact test P = 0.098) between rotational stability and any of the both reconstruction techniques. However, the anterior and rotational stability improved significantly at 2-year follow-up compared to preoperatively (P = 0.003) in both groups. The statistical analysis showed a significant increase for the IKDC (subjective, objective) and the Lysholm Score at final follow-up among each single technique, while we found no significant difference between the two reconstruction methods. On the basis of our investigation, we conclude that reconstruction of the ACL by a double-bundle ST graft with an extracortical anchorage can achieve excellent clinical results. But in contrast to our initial hypothesis, we could not quote any significant advantages by creating two independent bundles. Reconstruction of the anterior cruciate ligament in conventional single-bundle technique with a more horizontal femoral tunnel placement obtains comparable clinical results in the present high-demand collective.", "Double-bundle ACL reconstruction popularity is increasing with the aim to reproduce native ACL anatomy and improve ACL reconstruction outcome. However, to date, only a few randomized clinical studies have been published.\n The aim of this study was to prospectively compare the clinical results of single- and double-bundle ACL reconstruction.\n Randomized controlled clinical trial; Level of evidence, 1.\n Seventy patients with a chronic unilateral ACL rupture who underwent arthroscopically assisted ACL reconstruction using a hamstring graft were randomized to receive a single- (SB) or double-bundle (DB) reconstruction. Both groups were comparable with regard to preoperative data. A double-incision surgical technique was adopted in both groups. The graft was fixed by looping the hamstring tendons around a bony (DB) or a metallic (SB) bridge on the tibial side and with interference screws reinforced with a staple on the femur. The same rehabilitation protocol was adopted. Outcome assessment was performed by a blinded, independent observer using the visual analog scale (VAS) score, the new International Knee Documentation Committee (IKDC) form, the Knee Injury and Osteoarthritis Outcome Score (KOOS), and KT-1000 arthrometer evaluation.\n All the patients reached a minimum follow-up of 2 years. No differences between the 2 groups were observed in terms of KOOS and IKDC subjective score. A statistically significant difference in favor of the DB group was found with the VAS (P < .03). The objective IKDC final scores showed statistically significantly more \"normal knees\" in the DB group than in the SB group (P = .03). There was 1 stability failure in the DB group and 3 in the SB group. The KT-1000 arthrometer data showed a statistically significant decrease in the average anterior tibial translation in the DB group (1.2 mm DB vs 2.1 mm SB; P < .03). The incidence of a residual pivot-shift glide was 14% in DB and 26% in SB (P = .08).\n In the 2-year minimum follow-up, DB ACL reconstructions showed better VAS, anterior knee laxity, and final objective IKDC scores than SB. However, longer follow-up and accurate instrumented in vivo rotational stability assessment are needed.", "The intent of double-bundle anterior cruciate ligament reconstruction is to reproduce the normal anterior cruciate ligament anatomy and improve knee joint rotational stability. However, no consensus has been reached on the advantages of this technique over the single-bundle technique.\n We hypothesized that double-bundle anterior cruciate ligament reconstruction could provide better intraoperative stability and clinical outcome than single-bundle reconstruction.\n Cohort study; Level of evidence, 2.\n Forty patients with anterior cruciate ligament injury in one knee were recruited; 20 were allocated to a double-bundle anterior cruciate ligament reconstruction group and 20 to a single-bundle anterior cruciate ligament reconstruction group. Intraoperative stabilities at 30 degrees of knee flexion were compared between the 2 groups using a navigation system. Clinical outcomes including Lysholm knee scores, Tegner activity scores, Lachman and pivot-shift test results, and radiographic stabilities were also compared between the 2 groups after a minimum of 2 years of follow-up.\n Intraoperative anterior and rotational stabilities after anterior cruciate ligament reconstruction in the double-bundle group were significantly better than those in single-bundle group (P = .020 and P < .001, respectively). Nineteen patients (95%) in each group were available at a minimum 2-year follow-up. Clinical outcomes including Lysholm knee and Tegner activity scores were similar in the 2 groups at 2-year follow-up (P > .05). Furthermore, stability results of the Lachman and pivot-shift tests, and radiologic findings at 2-year follow-up failed to reveal any significant intergroup differences (P > .05).\n Although double-bundle anterior cruciate ligament reconstruction produces better intraoperative stabilities than single-bundle anterior cruciate ligament reconstruction, the 2 modalities were found to be similar in terms of clinical outcomes and postoperative stabilities after a minimum of 2 years of follow-up.", "One aspect of the debate over the reconstruction of the anterior cruciate ligament is whether it should be carried out with the single-bundle or double-bundle technique.\n The double-bundle technique results in fewer graft failures than the single-bundle technique in anterior cruciate ligament reconstruction.\n Randomized controlled trial; Level of evidence, 1.\n A total of 153 patients were prospectively randomized into 2 groups of anterior cruciate ligament reconstruction with hamstring autografts using aperture interference screw fixation: single-bundle technique (SB group, n = 78) and double-bundle technique (DB group, n = 75). The evaluation methods were clinical examination, KT-1000 arthrometric measurement, the International Knee Documentation Committee (IKDC) and the Lysholm knee scores, and magnetic resonance imaging (MRI) evaluation. All of the operations were performed by 1 experienced orthopaedic surgeon, and all clinical assessments were made by 2 blinded and independent examiners. A musculoskeletal radiologist blinded to the clinical data made the MRI interpretation.\n There were no differences between the study groups preoperatively. Ninety percent of patients (n = 138) were available at a minimum 2-year follow-up (range, 24-37 months). Eight patients (7 in the SB group and 1 in the DB group) had graft failure during the follow-up and had anterior cruciate ligament revision surgery (P = .04). In addition, 7 patients (5 in the SB group and 2 in the DB group) had an invisible graft on the MRI assessment at the 2-year follow-up. Also, the anteromedial bundle was partially invisible in 2 patients and the posterolateral bundle in 9 patients. Together, the total number of failures and invisible grafts were significantly higher in the SB group (12 patients, 15%) than the DB group (3 patients, 4%) (P = .024). No significant group differences were found in the knee scores or stability evaluations at the follow-up.\n This 2-year randomized trial showed that the revision rate of the anterior cruciate ligament reconstruction was significantly lower with the double-bundle technique than that with the single-bundle technique. However, additional years of follow-up are needed to reveal the long-term results.", "In clinical studies there is still a lot of controversy about the increased anterior and rotational stability between double-bundle (DB) and single-bundle (SB) anterior cruciate ligament (ACL) reconstruction. The aim of this study was to evaluate the clinical results of four-tunnel DB ACL reconstruction.\n Sixty-four consecutive patients with ACL ruptures from May 2005 to May 2006 were randomly assigned into two groups: 32 cases for SB ACL reconstruction and 32 cases for DB ACL reconstruction. Clinical data, including KT 2000, Biodex test, Lysholm score, Tegner score and IKDC score, were prospectively collected until at least 10 months post-operative.\n The average values of KT 2000 were (1.47 +/- 1.17) mm and (1.68 +/- 1.14) mm for the SB and DB ACL reconstruction groups at 30 degrees of knee flexion (P > 0.05), and were (1.04 +/- 0.98) mm and (1.13 +/- 0.98) mm at 90 degrees of knee flexion (P > 0.05). There were also no significant differences in Lysholm score, Tegner score, IKDC score and Biodex test scores between the two groups (P > 0.05). The operation time of DB ACL reconstruction was 20 minutes longer than the SB ACL reconstruction (P < 0.05).\n Double bundle ACL reconstructions have no obvious clinical advantages over single bundle ACL reconstructions.", "Biomechanical studies show increased anterior and rotational stability with double-bundle (DB) compared to single-bundle (SB) anterior cruciate ligament (ACL) reconstruction. The aim of this study was to evaluate the clinical results of four-tunnel DB ACL reconstruction.\n Seventy patients undergoing arthroscopic hamstring ACL reconstruction were prospectively randomized to DB (n = 35) or SB (n = 35) groups. Each bundle fixation was by means of a femoral EndoButton CL and a tibial biodegradable interference screw. Demographic data were comparable between groups, and the average age of all patients was 29 years. The average follow-up was 19 months for both groups and included a history, clinical evaluation with knee scores, and radiographs.\n The subjective results were similar in groups. The subjective International Knee Documentation Committee (IKDC) 2000 score was 88 P for DB versus 90 P for SB; the Lysholm score was 90 P for DB versus 93 P for SB; and the Cincinnati knee score was 91 P for DB versus 92 P for SB. The objective IKDC was significantly higher for DB: 78% \"A\" (P < .000) and 19% \"B\" compared to 24% \"A\" and 68% \"B\" for SB. The average KT-1000 side-to-side difference was 1.0 mm for DB and 1.6 mm for SB (P = .054) and the pivot shift test was negative in 97% for DB (P = .01) and 71% for SB. The range of motion was comparable for both groups.\n Our study shows a significant advantage in anterior and rotational stability as well as objective IKDC for four-tunnel DB ACL reconstruction compared to SB ACL reconstruction. The subjective Cincinnati knee score, the Lysholm score, and the subjective IKDC 2000 did not show any statistical difference for one or the other technique.\n Level I, randomized controlled trial.", "The purpose of this study was to compare the clinical results of arthroscopic single-bundle and double-bundle anterior cruciate ligament (ACL) reconstruction.\n We designed a prospective study that included patients with an isolated ACL injury. From April 2004 to February 2007, of 147 patients who underwent ACL reconstruction, 113 were included in this study. We serially obtained clinical and radiologic data preoperatively and postoperatively. We compared preoperative data and data at 2 years postoperatively in patients who had undergone single-bundle ACL reconstruction versus patients who had undergone double-bundle ACL reconstruction. There were 50 single-bundle reconstructions and 63 double-bundle reconstructions. Anteroposterior stability was assessed objectively by anterior stress radiographs with the telos device (telos, Marburg, Germany) and the maximal manual test with the KT-2000 arthrometer (MEDmetric, San Diego, CA). Rotational stability was determined by lateral pivot-shift test. The clinical results were assessed by International Knee Documentation Committee and Orthopadische Arbeitsgruppe Knie scores and Tegner activity scale. In addition, we evaluated postoperative thigh circumference and range of motion.\n Residual anteroposterior laxity determined at 2 years postoperatively by telos and KT-2000 was 1.74mm +/- 1.67mm and 1.79mm +/- 1.56mm, respectively, in the single-bundle reconstruction group and 1.63mm +/- 1.50mm and 1.61mm +/- 1.22mm, respectively, in the double-bundle reconstruction group. There were no statistically significant differences. For the lateral pivot-shift test done at 2 years postoperatively, there was no statistically significant difference. In addition, clinical results such as International Knee Documentation Committee score, Orthopadische Arbeitsgruppe Knie score, Tegner activity scale, thigh circumference, and range of motion showed no significant differences between the 2 groups.\n Double-bundle reconstruction of the ACL by a method using 2 femoral tunnel and 2 tibial tunnels showed no differences in stability results or any other clinical aspects or in terms of patient satisfaction.\n Level II, prospective comparative study.", "A total of 108 patients with unilateral instability of the knee, associated with rupture of the anterior cruciate ligament, was prospectively randomised for arthroscopic single- or double-bundle reconstruction of the ligament using hamstring tendons. The same post-operative rehabilitation protocol was used for all. The patients were followed up for a mean of 32 months (24 to 36). We measured the anterior laxity and joint position sense at different angles of flexion of the knee to determine whether both bundles in the double-bundle reconstruction contributed to the stability of the joint and proprioception. No significant difference was found between the two groups with regard to anterior laxity measured by the KT-2000 arthrometer with the knee at 20 degrees or 70 degrees flexion nor with regard to proprioception. A notchplasty was required less often in the double- compared with the single-bundle reconstruction. We did not find any advantage in a double-bundle as opposed to a single-bundle reconstruction in terms of stability or proprioception.", "The purpose of this study was to compare the tibial rotational stability of anatomical double-bundle anterior cruciate ligament reconstructed knees with single-bundle anterior cruciate ligament reconstructed knees during a high-demand activity. Total of 66 subjects, (22 with double-bundle anterior cruciate ligament reconstruction, 22 with single-bundle anterior cruciate ligament reconstruction, and 22 healthy control individuals) were examined in this study. Using a 9-camera motion analysis system, motion subjects were recorded performing during a drop landing and cutting. Using the point cluster technique, the internal-external tibial rotation of both knees was calculated. The mean maximum range of motion for each knee was evaluated for 3 groups (double-bundle group, single-bundle group, and control group). Clinical assessment, including Tegner score, Lysholm score, and knee arthrometric measurement, revealed restoration of the reconstructed knee stability with no differences between the two anterior cruciate ligament reconstruction groups. The results showed that both groups resulted in tibial rotation values that were significantly smaller than those in the intact legs and those in the healthy controls. There were no significant differences in tibial rotation between the DB group and the SB group. Therefore anatomical double-bundle reconstruction restores normal tibial rotation no more than single-bundle reconstruction during this high-demand dynamic activity. These results suggest a trend towards dynamic overcorrection after the ACL reconstruction.\n Copyright © 2010 Elsevier B.V. All rights reserved.", "We conducted a prospective randomised study of anatomical single-bundle (A-SB group) versus double-bundle (A-DB group) anterior cruciate ligament (ACL) reconstruction using the hamstrings tendons. Twenty patients with unilateral ACL deficiency were randomised into two groups. We created the bone tunnels at the position of the original insertion of the anteromedial bundle footprint and posterolateral bundle footprint in the A-DB group and at the central position between these two bundles in the A-SB group. All of the patients were tested before ACL reconstruction and one year after surgery. The KT-1000 measurements, isokinetic muscle peak torque and heel-height difference were evaluated and the general knee condition was assessed by Lysholm score. For pre- and postoperative stability assessment, we used the six-degrees-of-freedom of knee kinematic measurement system using an electromagnetic device (the EMS) for quantitative assessment during the Lachman test and the pivot shift test. There were no significant differences in the KT-1000 measurements, isokinetic muscle peak torque, heel-height difference, and Lysholm score at one-year follow-up between these two groups. The EMS data showed there were significant differences in the acceleration of the pivot shift test between the operated knee and the contralateral normal knees in the A-SB group. In conclusion, clinical outcomes were equally good in both groups. However, the EMS data showed the anatomical double-bundle ACL reconstruction tended to be biomechanically superior to the single-bundle reconstruction.", "The aim of this study was to evaluate whether anterior cruciate ligament (ACL) reconstruction using the double bundle technique (DB) improves stability in the knee compared with the single bundle technique (SB) with the femoral tunnel in a more horizontal position (2 or 10 o'clock). We conducted a randomized, prospective study. Forty patients were randomized to the DB group (20 patients) and the SB group (20 patients). Four-stranded semitendinosus and gracilis autologous grafts were used in the SB group and in the DB group the conventional four tunnel technique was carried out using the same tendons. The IKDC complete form was used for the preoperative evaluation, and in the follow-up the IKDC subjective knee evaluation form, IKDC current health assessment form and IKDC knee examination form were used. Anteroposterior (AP) laxity was evaluated by standardised and forced radiology in all patients. No significant preoperative between-group differences were found. During the follow-up, no differences were found between groups, except for significant between-group differences (P < 0.05) between the preoperative and postoperative evaluations. The IKDC index also showed significant differences in the 2-year follow-up. Median scores increased from 48 (range 41-54) to 81 (range 75-87) (P = 0.01) in the SB group and from 52 (range 46-58) to 80 (range 72-88) (P = 0.02) in the DB group. There were no significant differences between the groups in terms of functional scores. In conclusion, the 2 and 10 o'clock placements showed no significant differences between SB and DB techniques in the pivot-shift test, manual and radiological anterior posterior laxity and IKDC scores. However, significant between-group differences were found between the preoperative and postoperative evaluations.", "The purpose of this study was to compare subjective, objective and radiographic outcome of the lateralized single-bundle bone-patellar tendon-bone autograft with a non-anatomical double-bundle hamstring tendons autograft anterior cruciate ligament (ACL) reconstruction technique at long-term follow-up.\n Seventy-nine non-consecutive randomized patients (42 men; 37 women) with unilateral ACL insufficiency were prospectively evaluated, before and after ACL reconstruction by means of the above-mentioned techniques, with a minimum follow-up of 8 years (range 8-10 years; mean 8.6 years). In the double-bundle hamstrings technique, we used one tibial and one femoral tunnel combined with one \"over-the-top\" passage, cortical staple's fixation and we left intact hamstrings' tibial insertion. Patients were evaluated subjectively and objectively, using IKDC score, Tegner level, manual maximum displacement test with KT-2000™ arthrometer. Radiographic evaluation was performed according to IKDC grading system, and re-intervention rate for meniscal lesions was also recorded.\n The subjective and objective IKDC were similar in both groups while double-bundle hamstrings group showed significantly higher Tegner level (P = 0.0007), higher passive range of motion recovery (P = 0.0014), faster sport resumption (P = 0.0052), lower glide pivot-shift phenomenon (P = 0.0302) and lower re-intervention rate (P = 0.0116) compared with patellar tendon group. Radiographic evaluation showed significant lower objective degenerative changes in double-bundle hamstrings group at final follow-up (P = 0.0056).\n Although both techniques provide satisfactory results, double-bundle ACL reconstruction shows better functional results, with a faster return to sport activity, a lower re-operation rate and lower degenerative knee changes.", "A total of 218 patients with unilateral anterior cruciate ligament deficiency were randomly assigned to one of four groups. In group A an anatomical double bundle anterior cruciate ligament reconstruction was performed; group B were treated by a single bundle using an Endobutton for femoral fixation; in group C by a single bundle using RigidFix cross pins for femoral fixation; and in group D by a single bundle using a bioabsorbable TransFix II screw for femoral fixation. For tibial fixation a bioabsorbable Intrafix interference screw was used for all the groups and the graft was fashioned from the semitendinosus and gracilis tendons in all patients. In all, 18 patients were lost to follow-up. The remaining 200 were subjected to a clinical evaluation, with assessment of the anterior drawer, Lachman's and the pivot-shift tests, and KT-1000 arthrometer measurement. They also completed the International Knee Documentation Committee, Lysholm knee and Tegner activity scores. At a mean of 29 months (25 to 38) follow-up there were no significant differences concerning time between injury and range of movement and Lysholm knee scores among the four groups. However, the double bundle method showed significantly better results for the pivot-shift test (p = 0.002). The KT 1000 measurements showed a mean difference between the reconstructed knee and the patients' normal knee of 1.4 mm in the double bundle group and 2.4 mm in the single bundle group; which was statistically significant. The Lachman and anterior drawer tests also showed superior results for the double bundle method. The International Knee Documentation Committee scale showed no significant difference among the groups (p < 0.001). On clinical evaluation the double bundle group showed less laxity than the single bundle groups. However, regardless of the technique, all knees were improved by anterior cruciate ligament reconstruction compared with their pre-operative status.", "A randomized clinical study was conducted to compare the outcome between double-bundle (DB) and single-bundle (SB) anterior cruciate ligament (ACL) reconstructions with 4-strand semitendinosus tendon (ST).\n We divided 68 patients with unilateral ACL injury into 2 groups according to their birth date, and they were followed up in person for a mean of 25 months (range, 18 to 41 months). Each group of 34 patients underwent either DB or SB ACL reconstruction using 4-strand ST with EndoButton femoral fixation (Smith & Nephew Endoscopy, Andover, MA) and anchor staple tibial fixation. There was no difference between the 2 groups with regard to age at surgery, sex, follow-up period, period before surgery, combined meniscus injuries, and athletic activity level. All patients followed the same postoperative program. They were evaluated using manual knee laxity tests, instrumented anterior laxity measurements (KT-1000 arthrometer [MEDmetric, San Diego, CA]), knee extension and flexion strength testing, and so on. General knee condition was evaluated by use of the Lysholm knee score and subjective rating scale.\n There were no significant differences between the 2 groups with regard to range of motion, thigh girth, muscle strength, and Lysholm score. Manual knee laxity testing revealed that negative Lachman and pivot-shift test results were found in more patients in the DB group than in the SB group. KT measurements averaged 2.4 mm in the SB group and 1.4 mm in the DB group, which was statistically significantly different. Statistical analysis showed no significant difference regarding all of the modified International Knee Documentation Committee-categorized data between the 2 groups.\n This randomized controlled trial indicated that DB ACL reconstruction via 4-strand ST is superior to the SB technique with regard to anterior and rotational stability; however, it fails to show any subjective difference.\n Level I, prospective randomized controlled clinical study.", "Several investigators have reported the presence of biomechanical, kinematic, anatomic, fiber orientation patterns and biological differences between the anteromedial bundle and the posterolateral bundle of ACL. The purpose of this prospective randomized study was to compare the clinical, instrumental and X-ray outcome of two ACL reconstruction techniques with hamstring tendons: one with a single intra-articular bundle associated to an extra-articular sling, the second with a more anatomic double-bundle technique that reproduces better the native ACL function. From an initial group of 100 patients who underwent ACL reconstruction, 72 patients (35 single bundle plus lateral plasty and 37 double bundle) were evaluated with IKDC, Tegner score, KT2000 arthrometer, Activity Rating Scale, Psychovitality Questionnaire and Ahlback radiographic score at a mean 3 years follow-up. Double-bundle group showed significantly better results regarding IKDC, ROM, Activity Rating Scale and time to return to sport. Also KT 2000 showed significant differences in objective stability. The double-bundle technique for ACL reconstruction described in this paper has demonstrated significantly better subjective, objective and functional results compared with a double-stranded hamstrings plus extra-articular sling at a minimum 3-year follow-up.", "The single-bundle ACL reconstruction ensures good outcomes and it is a well-established and widespread technique. Nevertheless, some patients still present residual pain and instability. Recent studies have showed that the double-bundle technique restores better natural ACL-fitting kinematics. Long-term clinical studies comparing the two surgical techniques are not frequent and there is no instrument to evaluate function and kinematics during the knee rotation in vivo. In this randomised prospective study performed on sportive people, we compare the BPTB single-bundle ACL reconstruction technique, which is the most common surgical technique performed on these patients' category, with the ACL double-bundle reconstruction technique (DB), in order to evaluate possible differences between the groups. Comparing the two groups, no statistically significant difference regarding the post-operative Lysholm score (p=0.368) the Tegner activity scale (p=0.519) and the arthrometric evaluation with KT-1000 (p=0.74) have been observed. On the contrary, the IKDC evaluation showed a statistically significant difference (p=0.004) better results of the DB group. Moreover, as assessed by the Tegner activity scale, only patients of the DB group were able to return to sports at a pre-injury level. Our data suggest that the double bundle ST/G ACL reconstruction technique results into slightly better outcome than the traditional technique of single-bundle BPTB. The verification and quantification of the advantages of this technique is anticipated with future studies focusing to the accurate measurement of knee rotation during different activities.\n Copyright © 2010 Elsevier Ltd. All rights reserved." ]	There is insufficient evidence to determine the relative effectiveness of double-bundle and single-bundle reconstruction for anterior cruciate ligament rupture in adults, although there is limited evidence that double-bundle ACL reconstruction has some superior results in objective measurements of knee stability and protection against repeat ACL rupture or a new meniscal injury. High quality, large and appropriately reported randomised controlled trials of double-bundle versus single-bundle reconstruction for anterior cruciate ligament rupture in adults appear justified.
CD006162	[ "17098084", "16291982", "16478899" ]	[ "Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study.", "Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia.", "Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial." ]	[ "Rimonabant, a selective cannabinoid type 1 receptor blocker, reduces bodyweight and improves cardiovascular and metabolic risk factors in non-diabetic overweight or obese patients. The aim of the RIO-Diabetes trial was to assess the efficacy and safety of rimonabant in overweight or obese patients with type 2 diabetes that was inadequately controlled by metformin or sulphonylureas.\n 1047 overweight or obese type 2 diabetes patients (body-mass index 27-40 kg/m2) with a haemoglobin A1c (HbA1c) concentration of 6.5-10.0% (mean 7.3% [SD 0.9] at baseline) already on metformin or sulphonylurea monotherapy were given a mild hypocaloric diet and advice for increased physical activity, and randomly assigned placebo (n=348), 5 mg/day rimonabant (360) or 20 mg/day rimonabant (339) for 1 year. Two individuals in the 5 mg/day group did not receive double-blind treatment and were thus not included in the final analysis. The primary endpoint was weight change from baseline after 1 year of treatment. Analyses were done on an intention-to-treat basis. This trial is registered at ClinicalTrials.gov, number NCT00029848.\n 692 patients completed the 1 year follow-up; numbers in each group after 1 year were much the same. Weight loss was significantly greater after 1 year in both rimonabant groups than in the placebo group (placebo: -1.4 kg [SD 3.6]; 5 mg/day: -2.3 kg [4.2], p=0.01 vs placebo; 20 mg/day: -5.3 kg [5.2], p<0.0001 vs placebo). Rimonabant was generally well tolerated. The incidence of adverse events that led to discontinuation was slightly greater in the 20 mg/day rimonabant group, mainly due to depressed mood disorders, nausea, and dizziness.\n These data indicate that 20 mg/day rimonabant, in combination with diet and exercise, can produce a clinically meaningful reduction in bodyweight and improve HbA1c and a number of cardiovascular and metabolic risk factors in overweight or obese patients with type 2 diabetes inadequately controlled by metformin or sulphonylureas.", "Rimonabant, a selective cannabinoid-1 receptor (CB1) blocker, has been shown to reduce body weight and improve cardiovascular risk factors in obese patients. The Rimonabant in Obesity-Lipids (RIO-Lipids) study examined the effects of rimonabant on metabolic risk factors, including adiponectin levels, in high-risk patients who are overweight or obese and have dyslipidemia.\n We randomly assigned 1036 overweight or obese patients (body-mass index [the weight in kilograms divided by the square of the height in meters], 27 to 40) with untreated dyslipidemia (triglyceride levels >1.69 to 7.90 mmol per liter, or a ratio of cholesterol to high-density lipoprotein [HDL] cholesterol of >4.5 among women and >5 among men) to double-blinded therapy with either placebo or rimonabant at a dose of 5 mg or 20 mg daily for 12 months in addition to a hypocaloric diet.\n The rates of completion of the study were 62.6 percent, 60.3 percent, and 63.9 percent in the placebo group, the group receiving 5 mg of rimonabant, and the group receiving 20 mg of rimonabant, respectively. The most frequent adverse events resulting in discontinuation of the drug were depression, anxiety, and nausea. As compared with placebo, rimonabant at a dose of 20 mg was associated with a significant (P<0.001) mean weight loss (repeated-measures method, -6.7+/-0.5 kg, and last-observation-carried-forward analyses, -5.4+/-0.4 kg), reduction in waist circumference (repeated-measures method, -5.8+/-0.5 cm, and last-observation-carried-forward analyses, -4.7+/-0.5 cm), increase in HDL cholesterol (repeated-measures method, +10.0+/-1.6 percent, and last-observation-carried-forward analyses, +8.1+/-1.5 percent), and reduction in triglycerides (repeated-measures method, -13.0+/-3.5 percent, and last-observation-carried-forward analyses, -12.4+/-3.2 percent). Rimonabant at a dose of 20 mg also resulted in an increase in plasma adiponectin levels (repeated-measures method, 57.7 percent, and last-observation-carried-forward analyses, 46.2 percent; P<0.001), for a change that was partly independent of weight loss alone.\n Selective CB1-receptor blockade with rimonabant significantly reduces body weight and waist circumference and improves the profile of several metabolic risk factors in high-risk patients who are overweight or obese and have an atherogenic dyslipidemia.\n Copyright 2005 Massachusetts Medical Society.", "Rimonabant, a selective cannabinoid-1 receptor blocker, may reduce body weight and improve cardiometabolic risk factors in patients who are overweight or obese.\n To compare the efficacy and safety of rimonabant with placebo each in conjunction with diet and exercise for sustained changes in weight and cardiometabolic risk factors over 2 years.\n Randomized, double-blind, placebo-controlled trial of 3045 obese (body mass index > or =30) or overweight (body mass index >27 and treated or untreated hypertension or dyslipidemia) adult patients at 64 US and 8 Canadian clinical research centers from August 2001 to April 2004.\n After a 4-week single-blind placebo plus diet (600 kcal/d deficit) run-in period, patients were randomized to receive placebo, 5 mg/d of rimonabant, or 20 mg/d of rimonabant for 1 year. Rimonabant-treated patients were rerandomized to receive placebo or continued to receive the same rimonabant dose while the placebo group continued to receive placebo during year 2.\n Body weight change over year 1 and prevention of weight regain during year 2. Additional efficacy measures included changes in waist circumference, plasma lipid levels, and other cardiometabolic risk factors.\n At year 1, the completion rate was 309 (51%) patients in the placebo group, 620 (51%) patients in the 5 mg of rimonabant group, and 673 (55%) patients in the 20 mg of rimonabant group. Compared with the placebo group, the 20 mg of rimonabant group produced greater mean (SEM) reductions in weight (-6.3 [0.2] kg vs -1.6 [0.2] kg; P<.001), waist circumference (-6.1 [0.2] cm vs -2.5 [0.3] cm; P<.001), and level of triglycerides (percentage change, -5.3 [1.2] vs 7.9 [2.0]; P<.001) and a greater increase in level of high-density lipoprotein cholesterol (percentage change, 12.6 [0.5] vs 5.4 [0.7]; P<.001). Patients who were switched from the 20 mg of rimonabant group to the placebo group during year 2 experienced weight regain while those who continued to receive 20 mg of rimonabant maintained their weight loss and favorable changes in cardiometabolic risk factors. Use of different imputation methods to account for the high rate of dropouts in all 3 groups yielded similar results. Rimonabant was generally well tolerated; the most common drug-related adverse event was nausea (11.2% for the 20 mg of rimonabant group vs 5.8% for the placebo group).\n In this multicenter trial, treatment with 20 mg/d of rimonabant plus diet for 2 years promoted modest but sustained reductions in weight and waist circumference and favorable changes in cardiometabolic risk factors. However, the trial was limited by a high drop-out rate and longer-term effects of the drug require further study. Clinical Trials Registration ClinicalTrials.gov Identifier: NCT00029861." ]	The use of rimonabant after one year produces modest weight loss of approximately 5%. Even modest amounts of weight loss may be potentially beneficial. The observed results should be interpreted with some caution, though, since the evaluated studies presented some deficiencies in methodological quality. Studies with longer follow-ups after the end of treatment and of more rigorous quality should be done before definitive recommendations can be made regarding the role of this new medication in the management of overweight or obese patients.
CD005947	[ "15798461", "15325681" ]	[ "Glutamine supplementation of parenteral nutrition does not improve intestinal permeability, nitrogen balance, or outcome in newborns and infants undergoing digestive-tract surgery: results from a double-blind, randomized, controlled trial.", "Glutamine supplementation in infants with gastrointestinal disease: a randomized, placebo-controlled pilot trial." ]	[ "To assess the effect of isocaloric isonitrogenous parenteral glutamine supplementation on intestinal permeability and nitrogen loss in newborns and infants after major digestive-tract surgery.\n Glutamine supplementation in critically ill and surgical adults may normalize intestinal permeability, attenuate nitrogen loss, improve survival, and lower the incidence of nosocomial infections. Previous studies in critically ill children were limited to very-low-birthweight infants and had equivocal results.\n Eighty newborns and infants were included in a double-blind, randomized trial comparing standard parenteral nutrition (sPN; n = 39) to glutamine-supplemented parenteral nutrition (GlnPN; glutamine target intake, 0.4 g kg day; n = 41), starting on day 2 after major digestive-tract surgery. Primary endpoints were intestinal permeability, as assessed by the urinary excretion ratio of lactulose and rhamnose (weeks 1 through 4); nitrogen balance (days 4 through 6), and urinary 3-methylhistidine excretion (day 5). Secondary endpoints were mortality, length of stay in the ICU and the hospital, number of septic episodes, and usage of antibiotics and ICU resources.\n Glutamine intake plateaued at 90% of the target on day 4. No differences were found between patients assigned sPN and patients assigned GlnPN regarding any of the endpoints. Glutamine supplementation was not associated with adverse effects.\n In newborns and infants after major digestive-tract surgery, we did not identify beneficial effects of isonitrogenous, isocaloric glutamine supplementation of parenteral nutrition. Glutamine supplementation in these patients therefore is not warranted until further research proves otherwise.", "Glutamine (Gln) is a non-essential amino acid that plays an important role in energy metabolism for gastrointestinal epithelia and other cells with rapid turnover. We evaluated the effects of enteral supplementation with Gln in infants undergoing surgery for congenital or acquired gastrointestinal disease.\n This was a randomized, double-masked, controlled clinical trial.\n Twenty infants were randomly assigned to receive Gln (n = 9) or placebo amino acid (n = 11), with a goal of supplemental amino acid intake of 0.4 g.kg(-1).d(-1). Infants were weaned from parenteral nutrition, and enteral feeds were started according to a standardized feeding protocol. Median (interquartile range) durations of parenteral nutrition were 39 d (12 to 99) in the Gln group and 21 d (6 to 59) in the control group (P = 0.201). Median (interquartile range) durations needed to reach 80% of the US recommended dietary allowance for energy with enteral nutrition were 24 d (8 to 55) in the Gln group and 12.5 d (5 to 32) in the control group (P = 0.313). There were no differences in the occurrence of infections between groups. Among all infants enrolled, significant correlations were found between duration of parenteral nutrition and residual small bowel length, peak concentrations of direct bilirubin, and alanine aminotransferase. Peak direct bilirubin was associated with longer duration of parenteral nutrition, shorter gestation, older age before feeds were started, shorter bowel length, and larger amounts of parenteral energy and protein intake.\n In this pilot trial, enteral Gln supplementation was well tolerated among infants with surgical gastrointestinal disease. There was no effect observed on the duration of parenteral nutrition, tolerance of enteral feeds, or intestinal absorptive or barrier function. Larger, multicenter trials in infants with surgical gastrointestinal disease are needed due to the variability in important outcome measurements." ]	The available data from randomised controlled trials are insufficient to determine whether glutamine supplementation has any important benefits for young infants with severe gastrointestinal disease.
CD001922	[ "7717832", "19477503", "18212034", "20947859" ]	[ "Deep vein thrombosis: prevention in stroke patients during rehabilitation.", "Effectiveness of thigh-length graduated compression stockings to reduce the risk of deep vein thrombosis after stroke (CLOTS trial 1): a multicentre, randomised controlled trial.", "A pilot randomized controlled trial to evaluate the benefit of the cardiac rehabilitation paradigm for the non-acute ischaemic stroke population.", "AXIS: a trial of intravenous granulocyte colony-stimulating factor in acute ischemic stroke." ]	[ "Deep vein thrombosis (DVT) and subsequent pulmonary embolism (PE) is a major source of mortality and morbidity in stroke patients. This study was designed to determine the effectiveness of different prophylactic treatments in the prevention of DVT after a stroke in patients undergoing rehabilitation. An additional objective was the identification of risk factors for DVT in stroke in patients during rehabilitation. Three hundred and sixty patients, over a 3-year period, were randomly assigned to one of four groups: adjusted dose heparin, intermittent pneumatic compression (IPC), functional electrical stimulation (FES), or control. There was no significant difference in the development of DVT by treatment group. Patients with DVT on admission (prevalent, n = 61) were compared with the study patients (n = 360). Time interval (from stroke to admission) and lactic dehydrogenase (LDH) concentration were significant risk factors, as well as predictors, for development of DVT (p < .000). These results suggest that the longer a patient remains without DVT prophylaxis after a stroke, the greater the risk of developing DVT and this supports early prophylaxis before rehabilitation.", "Deep vein thrombosis (DVT) and pulmonary embolism are common after stroke. In small trials of patients undergoing surgery, graduated compression stockings (GCS) reduce the risk of DVT. National stroke guidelines extrapolating from these trials recommend their use in patients with stroke despite insufficient evidence. We assessed the effectiveness of thigh-length GCS to reduce DVT after stroke.\n In this outcome-blinded, randomised controlled trial, 2518 patients who were admitted to hospital within 1 week of an acute stroke and who were immobile were enrolled from 64 centres in the UK, Italy, and Australia. Patients were allocated via a central randomisation system to routine care plus thigh-length GCS (n=1256) or to routine care plus avoidance of GCS (n=1262). A technician who was blinded to treatment allocation undertook compression Doppler ultrasound of both legs at about 7-10 days and, when practical, again at 25-30 days after enrolment. The primary outcome was the occurrence of symptomatic or asymptomatic DVT in the popliteal or femoral veins. Analyses were by intention to treat. This study is registered, number ISRCTN28163533.\n All patients were included in the analyses. The primary outcome occurred in 126 (10.0%) patients allocated to thigh-length GCS and in 133 (10.5%) allocated to avoid GCS, resulting in a non-significant absolute reduction in risk of 0.5% (95% CI -1.9% to 2.9%). Skin breaks, ulcers, blisters, and skin necrosis were significantly more common in patients allocated to GCS than in those allocated to avoid their use (64 [5%] vs 16 [1%]; odds ratio 4.18, 95% CI 2.40-7.27).\n These data do not lend support to the use of thigh-length GCS in patients admitted to hospital with acute stroke. National guidelines for stroke might need to be revised on the basis of these results.\n Medical Research Council (UK), Chief Scientist Office of Scottish Government, Chest Heart and Stroke Scotland, Tyco Healthcare (Covidien) USA, and UK Stroke Research Network.", "To evaluate risk factor reduction and health-related quality of life following a 10-week cardiac rehabilitation programme in non-acute ischaemic stroke subjects.\n Single-blinded randomized control trial.\n Outpatient rehabilitation.\n Forty-eight community-dwelling ischaemic stroke patients (38 independently mobile, 9 requiring assistance, 1 non-ambulatory) were randomly assigned to intervention or control groups by concealed allocation.\n The trial consisted of a 10-week schedule with measures taken at weeks 1 and 10. Both groups continued usual care (excluding aerobic exercise); intervention subjects attended 16 cycle ergometry sessions of aerobic-training intensity and two stress-management classes.\n Cardiac risk score (CRS); VO(2) (mL O(2)/kg per minute) and Borg Rate of Perceived Exertion (RPE) assessed during a standardized ergometry test; Hospital Anxiety and Depression Scale (HADS); Frenchay Activity Index; Fasting Lipid Profiles and Resting Blood Pressure.\n Group comparison with independent t-tests showed significantly greater improvement at follow-up by intervention subjects than controls in VO(2) (intervention 10.6 +/-1.6 to 12.0 +/- 2.2, control 11.1 +/-1.8 to 11.1 +/-1.9 t=4.734, P<0.001) and CRS (intervention 13.4 +/-10.1 to 12.4 +/-10.5, control 9.4 +/-6.7 to 15.0 +/-6.1 t=-2.537, P<0.05). RPE rating decreased in intervention subjects (13.4 +/-12.2 to 12.4 +/-2.0) and increased in controls (13.8 +/-1.8 to 14.4 +/-1.6); Mann-Whitney U (U = 173.5, P<0.05). Within-group comparison showed significant decrease in the HADS depression subscale in the intervention group alone (5.1 +/-3.4 to 3.0 +/-2.8) (Wilcoxon signed ranks test Z=-3.278, P<0.001).\n Preliminary findings suggest non-acute ischaemic stroke patients can improve their cardiovascular fitness and reduce their CRS with a cardiac rehabilitation programme. The intervention was associated with improvement in self-reported depression.", "Granulocyte colony-stimulating factor (G-CSF) is a promising stroke drug candidate. The present phase IIa study assessed safety and tolerability over a broad dose range of G-CSF doses in acute ischemic stroke patients and explored outcome data.\n Four intravenous dose regimens (total cumulative doses of 30-180 μg/kg over the course of 3 days) of G-CSF were tested in 44 patients in a national, multicenter, randomized, placebo-controlled dose escalation study (NCT00132470; www.clinicaltrial.gov). Main inclusion criteria were a 12-hour time window after stroke onset, infarct localization to the middle cerebral artery territory, a baseline National Institutes of Health Stroke Scale range of 4 to 22, and presence of diffusion-weighted imaging/perfusion-weighted imaging mismatch.\n Concerning the primary safety end points, we observed no increase of thromboembolic events in the active treatment groups, and no increase in related serious adverse events. G-CSF led to expected increases in neutrophils and monocytes that resolved rapidly after end of treatment. We observed a clinically insignificant drug-related decrease of platelets. As expected from the low number of patients, we did not observe significant differences in clinical outcome in treatment vs. placebo. In exploratory analyses, we observed an interesting dose-dependent beneficial effect of treatment in patients with DWI lesions > 14-17 cm³.\n We conclude that G-CSF was well-tolerated even at high dosages in patients with acute ischemic stroke, and that a substantial increase in leukocytes appears not problematic in stroke patients. In addition, exploratory analyses suggest treatment effects in patients with larger baseline diffusion-weighted imaging lesions. The obtained data provide the basis for a second trial aimed to demonstrate safety and efficacy of G-CSF on clinical end points." ]	Evidence from randomised trials does not support the routine use of GCS to reduce the risk of DVT after acute stroke. There is insufficient evidence to support the routine use of IPC to reduce the risk of DVT in acute stroke and further larger randomised studies of IPC are needed to reliably assess the balance of risks and benefits of this intervention.
CD008344	[ "1727754", "7916398", "2105256", "20698232", "8768018", "3142949", "12679945", "12358242", "8838831", "8455312", "14734433", "3148039", "9739036", "10798755", "1909085", "3932509", "3082733", "9448611", "16839996", "14526151", "9351723", "20602497", "20005375", "6406649", "6803118", "8748357", "10553972" ]	[ "Accelerated improvement of alcoholic liver disease with enteral nutrition.", "Comparison of enteral feeding and total parenteral nutrition after liver transplantation.", "Effect of total enteral nutrition on the short-term outcome of severely malnourished cirrhotics. A randomized controlled trial.", "Prospective randomized controlled study of short-term perioperative oral nutrition with branched chain amino acids in patients undergoing liver surgery.", "[Total enteral nutrition versus mixed enteral and parenteral nutrition in patients at an intensive care unit].", "A randomized controlled study of peripheral parenteral nutrition in moderate and severe alcoholic hepatitis.", "The influence of Enteral Nutrition in postoperative patients with poor liver function.", "Hypocaloric jejunal feeding is better than total parenteral nutrition in acute pancreatitis: results of a randomized comparative study.", "Enteral versus parenteral nutrition: effects on gastrointestinal function and metabolism.", "Controlled trial on nutrition supplementation in outpatients with symptomatic alcoholic cirrhosis.", "Multicentre, cluster-randomized clinical trial of algorithms for critical-care enteral and parenteral therapy (ACCEPT).", "Improvement of nutritional measures during preoperative parenteral nutrition in patients selected by the prognostic nutritional index: a randomized controlled trial.", "A randomized, controlled, a single-blind trial of nutritional supplementation after acute stroke.", "A prospective randomized study of preoperative nutritional supplementation in patients awaiting elective orthotopic liver transplantation.", "A randomized, controlled trial of treatment of alcoholic hepatitis with parenteral nutrition and oxandrolone. I. Short-term effects on liver function.", "Controlled trial of nutritional supplementation, with and without branched chain amino acid enrichment, in treatment of acute alcoholic hepatitis.", "A randomized clinical trial of supplementary parenteral nutrition in jaundiced alcoholic cirrhotic patients.", "Enteral nutrition is superior to parenteral nutrition in severe acute pancreatitis: results of a randomized prospective trial.", "Perioperative nutritional support: a randomised clinical trial.", "A randomised clinical trial to assess the effect of total enteral and total parenteral nutritional support on metabolic, inflammatory and oxidative markers in patients with predicted severe acute pancreatitis (APACHE II > or =6).", "A prospective, randomized trial of early enteral feeding after resection of upper gastrointestinal malignancy.", "Randomized clinical trial of laxatives and oral nutritional supplements within an enhanced recovery after surgery protocol following liver resection.", "Nutrition support with glutamine dipeptide in patients undergoing liver transplantation.", "The favorable effect of early parenteral feeding on survival in head-injured patients.", "A prospective randomized clinical trial of total parenteral nutrition in children with cancer.", "Early enteral nutrition support in patients undergoing liver transplantation.", "Prospective randomized control study on the effect of branched-chain amino acids in patients with liver resection for hepatocellular carcinoma." ]	[ "This prospective study compared the effects of tube-fed nutrition with those of a regular diet in alcoholic liver disease. The high prevalence of malnutrition in patients with alcoholic liver disease requires clarification of the benefits of aggressive nutritional support. Patients were randomly assigned a regular diet without or with tube-fed supplementation, delivering 1.5 g/kg protein and 167 kJ/kg daily. Comparisons of encephalopathy, antipyrine clearance, metabolic rate, and biochemical parameters were performed weekly for 4 weeks. Sixteen patients receiving enteral supplementation had antipyrine half-life (50% vs. 3% reduction), serum bilirubin (25% vs. 0% reduction), and median encephalopathy scores that improved more rapidly than those of controls. Initially, 15 controls did not consume adequate calories to meet measured resting energy expenditure. Aggressive nutritional intervention accelerated improvement in alcoholic liver disease. Adverse effects did not offset the demonstrated benefits of a 2-cal/mL, casein-based tube-fed supplement. These findings support the use of standard, casein-based solutions in the treatment of alcoholic liver disease and as the control condition for future studies.", "Total parenteral nutrition is used for nutritional support in patients undergoing orthotopic liver transplantation but is associated with complications. We compared the efficacy and tolerability of early enteral feeding with total parenteral nutrition after liver transplantation. 24 patients were studied: 14 received enteral feeding and 10 total parenteral nutrition. A double-lumen enteral tube was used to deliver the feed directly into the jejunum with the second lumen of the tube being used for gastric aspiration. Enteral feeding was started post-operatively within 18 h, was well-tolerated, and of comparable efficacy to total parenteral nutrition. The median number of days for patients to start eating (4) and to achieve 70% of estimated requirements orally (5) did not differ significantly between the two groups. Mid-arm circumference, triceps skinfold thickness, and biceps skinfold thickness were, by comparison with pre-operative values, maintained on the tenth postoperative day in both groups. Early postoperative absorptive capacity, as assessed by a combined carbohydrate test, was reduced significantly in both groups but insufficiently to be of nutritional concern. Intestinal mucosal integrity, as assessed by an intestinal permeability test, was maintained throughout. We conclude that the practical aspects of enteral feeding after liver transplantation are surmountable and that enteral feeding is as effective at maintaining nutritional status as total parenteral nutrition, and has potential benefits in terms of reduced complications and costs.", "Thirty-five severely malnourished cirrhotic patients were randomized to receive either enteral-tube feeding as the sole nutritional support (n = 16) or an isocaloric, isonitrogenous, low-sodium standard oral diet (n = 19). Both groups were homogeneous regarding age, sex distribution, etiology of liver cirrhosis, history of previous complications, clinical status, liver and renal function, modified Child's score, and nutritional status at admission. The enteral formula diet was energy dense, containing 40 mmol Na/day, whole protein plus branched-chain amino acids, medium- and long-chain triglycerides, and maltodextrin. It supplied 2115 kcal/day. The amount of vitamins and trace elements was at the upper limit of the recommended dietary allowances. The orally fed patients were encouraged to eat all meals served. Total enteral nutrition was well tolerated without major complications. Serum albumin and Child's score improved in the enterally fed patients but not in controls. Mortality rate while in the hospital was lower in patients on enteral feeding than in controls (12% vs 47%). These results show that total enteral nutrition is safe and effective in improving the short-term clinical outcome in severely malnourished cirrhotics.", "Early prospective randomized clinical trials demonstrated that perioperative parenteral nutrition (PN) with branched chain amino acids (BCAA) is beneficial in cirrhotic patients with hepatocellular carcinoma who undergo hepatectomy. However, PN support is expensive and requires a long hospital stay. Moreover, PN support has not been evaluated in patients with a normal liver who undergo hepatectomy. It was studied the benefits of perioperative oral nutrition (ON) with BCAA in patients who underwent hepatectomy, including those with a non-hepatitis liver.\n In this prospective, randomized, controlled trial, 38 patients were assessed for eligibility. Fourteen patients were excluded because they had received intraoperative blood transfusions or incomplete resections. The 24 eligible patients (20 with malignant liver tumors and 4 with benign liver tumors) were randomly assigned to receive perioperative ON with BCAA (11 patients, BCAA group) or a usual diet (13 patients, control group). The BCAA group received a BCAA supplement twice daily plus a usual diet for 14 days before operation and on days 1 to 7 after operation. The control group received a usual diet alone. The primary end point was the improvement in postoperative biochemical measurements.\n Two of the 11 patients in the BCAA group developed postoperative complications, as compared with 3 of the 13 patients in the control group (18.2% vs. 23.1%, p = 0.7686). Serum levels of alanine aminotransferase, aspartate aminotransferase, and ammonia did not differ significantly between the BCAA group and control group; however, peak values were lower in the BCAA group. There was no difference between the groups in serum hemoglobin levels after operation. Among patients with hepatitis, serum erythropoietin (EPO) levels on POD 3, 5, and 7 were slightly but not significantly higher in the BCAA group than in the control group. Among patients with non-hepatitis, serum EPO levels on POD 3, 5, and 7 were significantly higher in the BCAA group than in the control group (p = 0.0174, p = 0.0141, and p = 0.0328, respectively).\n Short-term ON support with BCAA was associated with higher serum EPO levels than was a normal diet in patients with non-hepatitis who underwent curative hepatic resection. Higher EPO levels might be beneficial in protecting liver cells from ischemic injury and preventing intraoperative hemorrhage associated with lower perioperative levels of alanine aminotransferase and aspartate aminotransferase in serum. This is the first study to demonstrate an effect of EN support with BCAA in patients with non-hepatitis, as well as those with hepatitis.", "To compare metabolic, nutritional and epidemiological data in two groups of patients, one receiving total enteral nutrition, via nasoenteric tube, and one receiving both enteral and parenteral nutrition.\n A prospective, randomized study.\n A general ICU, with both medical and surgical patients, in a big regional University and National Health Service hospital.\n 24 patients requiring Intensive Care after major surgery or because suffering from severe head injury or major neurological impairment.\n All patients initially received total parenteral nutrition: after 4 days 12 patients were \"weaned\" to total enteral nutrition and 12 stayed on mixed parenteral and enteral nutrition. LABORATORY INVESTIGATIONS AND OBSERVATIONAL DATA: Blood levels of albumin, prealbumin, transferrin, ALT, AST, bilirubin, blood urea, blood glucose, total linfocite count, and nutritional and epidemiological data such as nitrogen balance, calorie intake, diarrhea incidence, blood and sputum cultures and radiologic evidence of pneumonia are analysed.\n At T1, NET patients were able to reduce their nitrogen losses (0.27.1 g/kg +/-0.12 vs 0.35 +/- 0.13 at TO; p < 0.05) and improve nitrogen balance (-9 +/- 7 vs -2 +/- 6 at T0; p < 0.05); they also had a better total linfocite count (2034 +/- 304 vs. 1413 +/- 360 of the MISTA group; p < 0.05), and a lower incidence of pneumonia as documented by sputum cultures and radiograms.\n Patients fed with both parenteral and enteral nutrition did no better than those on total enteral nutrition as far as nutritional and metabolic indices were concerned; they also seemed more prone to infections than those on total enteral nutrition, indicating that mixed nutrition may result in more stable feeding, but this does not seem to have any beneficial nutritional, immunological and metabolic effect.", "We performed a controlled trial of peripheral hyperalimentation in moderate and severe alcoholic hepatitis to determine whether improvement in survival and liver function could be obtained. Twelve patients with moderate and 22 with severe alcoholic hepatitis were randomized to 28 days of peripheral parenteral nutrition (PPN) or standard therapy (ST). In the moderate group, six were treated with each therapy. In the severe group, 10 were treated with PPN and 12 with ST. Routine liver tests, hepatocyte function (galactose elimination capacity), estimated hepatic blood flow (galactose clearance) and assessment of ascites and encephalopathy were performed at randomization and at 28 days. Groups were equally matched at randomization. In the moderate group PPN produced no improvement in morbidity (liver tests) and mortality (no deaths). In the severe group there were seven deaths (4 PPN, 3 ST). PPN produced greater improvement than ST in serum bilirubin and transferrin concentrations and a trend toward greater improvement in prothrombin time, serum albumin and galactose elimination capacity. PPN had no deleterious effect on encephalopathy or ascites as only ST patients developed ascites or encephalopathy after randomization. We conclude that PPN compared to ST (1) provides no benefit in moderate alcoholic hepatitis, but (2) did more rapidly improve morbidity (liver tests) and probably liver function in severe alcoholic hepatitis; (3) PPN did not improve early mortality, and (4) it had no deleterious effect on encephalopathy or ascites.", "To investigate the safety, rationality and the practicality of enteral nutritional (EN) support in the postoperative patients with damaged liver function and the protective effect of EN on the gut barrier.\n 135 patients with liver function of Child B or C grade were randomly allocated to enteral nutrition group (EN, 65 cases), total parenteral nutrition group (TPN, 40 cases) and control group (CON, 30 cases). Nutritional parameters, hepatic and kidney function indexes were measured at the day before operation, 5th and 10th day after the operation respectively. Comparison was made to evaluate the efficacy of different nutritional support. Urinary concentrations of lactulose(L) and mannitol(M) were measured by pulsed electrochemical detection(HPLC-PED) and the L/M ratio calculated to evaluate their effectiveness on protection of gut barrier.\n No significant damages in hepatic and kidney function were observed in both EN and TPN groups between pre- and postoperatively. EN group was the earliest one reaching the positive nitrogen balance after operation and with the lowest loss of body weight and there was no change in L/M ratio after the operation (0.026+/-0.004) at the day 1 before operation, 0.030+/-0.004 at the day 5 postoperative and 0.027+/-0.005 at the day 10 postoperative), but the change in TPN group was significant at the day 5 postoperative (0.027+/-0.003 vs 0.038+/-0.009,P<0.01).\n EN is a rational and effective method in patients with hepatic dysfunction after operation and has significant protection effect on the gut barrier.", "The aims of this study were to define the indications for, and to evaluate the cost-effectiveness of, nutritional support in patients with acute pancreatitis.\n All admissions during the 12-month period from January through December 2000, were entered into a common management protocol consisting of an initial 48-h fast with i.v. fluids and analgesics. After 48 h, those patients who were improving were restarted on oral feeding (group O). The remaining patients were randomized to receive nasojejunal (group EN) or parenteral feeding (group TPN). The randomization study was continued until 50 patients had been accrued. Outcomes in the three groups were compared with respect to length of hospital stay, duration of feeding, complications, and hospital costs.\n A total of 156 admissions were evaluated in the first 12 months. Of these, 87% patients had mild disease, 10% moderate, and 3% severe; 62% were related to alcohol abuse, 18% gallstones, and 8% idiosyncratic drug reactions. Of the patients, 75% improved on 48 h bowel rest and i.v. fluids, and were discharged within 4 days. The remainder were randomized to jejunal elemental (n = 26) or parenteral (n = 27) feeding. Duration of feeding was shorter with EN (6.7 vs 10.8 days, p < 0.05) and nutrition costs were lower, representing an average cost saving of $2362.00 per patient fed. EN was less effective in meeting estimated nutritional requirements (54 vs 88%, p < 0.0001), but metabolic (p < 0.003) and septic complications (p = 0.01) were lower. Subgroup analysis of patients with severe disease showed similar findings.\n Despite concerns that metabolic expenditure is increased and that food-stimulated pancreatic secretion might exacerbate the disease process, hypocaloric enteral feeding seems to be safer and less expensive than parenteral feeding and bowel rest in patients with acute pancreatitis.", "The effects of total parenteral nutrition (TPN) versus enteral nutrition (TEN) were studied in 34 patients following major neurosurgery. Measurements were made of resting energy expenditure (REE), urea production rate (UPR), visceral proteins, parameters of liver and pancreas function, as well as gastrointestinal absorption. To predict nutritional status, nutritional index (NI) was calculated. UPR revealed no significant differences between the groups. After 12 days of TEN, however, synthesis of visceral proteins increased significantly. In addition, NI improved after TEN (p < 0.05), whereas it remained unchanged after TPN. Thrombocyte and lymphocyte counts rose predominately during enteral nutrition. Only in the TEN group was REE increased by 18% and Glasgow Coma Scale (GCS) enhanced from Day 6 on. Exogenous insulin demand was enhanced in the parenterally fed group, and bilirubin (p < 0.05), amylase (p < 0.05), and lipase (p < 0.01) rose significantly, as did gamma-glutamyl-transferase (p < 0.0005) and alkaline phosphatase (p < 0.0005). After 12 d of TPN, vitamin A absorption was significantly attenuated, indicating reduced fat absorption compared to TEN. Carbohydrate absorption did not show significant changes between the groups. Only during TPN did mean values of xylose absorption remain below the normal range. Therefore, enteral nutrition following neurosurgical procedures is associated with an accelerated normalization of nutritional status and an improved substrate tolerance. TEN opposes early postoperative absorption disturbances of the small intestine.", "A controlled trial on nutrition supplementation in ambulatory patients with decompensated alcoholic liver disease was carried out during 1 year. Fifty-one patients were studied; 26 were assigned to an experimental group receiving a daily supplement of 1000 kcal and 34 g of proteins given as a casein-based enteral nutrition product and 25 to a control group receiving one placebo capsule. Patients were examined in a special clinic once a month or more if required. Sixty-eight percent of patients admitted to alcohol ingestion or had alcohol in urine samples on at least one occasion. Dietary recalls showed a significantly higher protein and caloric intake in case patients subjects (p < .0001). Nine patients died during the study, three case patients and six control patients (p = NS). The frequency of hospitalizations was significantly less in the experimental group. This difference was attributed to a reduction in severe infections. Mid-arm circumference, serum albumin concentration, and hand grip strength improved earlier in case patients, although both groups had a significant improvement in these parameters. Bilirubin and aspartate aminotransferase decreased and prothrombin time increased significantly in both groups during the study period, without differences between groups. It is concluded that nutrition support decreases nutrition-associated complications in patients with alcoholic liver disease.", "The provision of nutritional support for patients in intensive care units (ICUs) varies widely both within and between institutions. We tested the hypothesis that evidence-based algorithms to improve nutritional support in the ICU would improve patient outcomes.\n A cluster-randomized controlled trial was performed in the ICUs of 11 community and 3 teaching hospitals between October 1997 and September 1998. Hospital ICUs were stratified by hospital type and randomized to the intervention or control arm. Patients at least 16 years of age with an expected ICU stay of at least 48 hours were enrolled in the study (n = 499). Evidence-based recommendations were introduced in the 7 intervention hospitals by means of in-service education sessions, reminders (local dietitian, posters) and academic detailing that stressed early institution of nutritional support, preferably enteral.\n Two hospitals crossed over and were excluded from the primary analysis. Compared with the patients in the control hospitals (n = 214), the patients in the intervention hospitals (n = 248) received significantly more days of enteral nutrition (6.7 v. 5.4 per 10 patient-days; p = 0.042), had a significantly shorter mean stay in hospital (25 v. 35 days; p = 0.003) and showed a trend toward reduced mortality (27% v. 37%; p = 0.058). The mean stay in the ICU did not differ between the control and intervention groups (10.9 v. 11.8 days; p = 0.7).\n Implementation of evidence-based recommendations improved the provision of nutritional support and was associated with improved clinical outcomes.", "Patients undergoing major gastrointestinal surgery who had a prognostic nutritional index (PNI) score of greater than 30% were randomized to receive a preoperative course of 10 days of intravenous nutrition or to undergo surgery at the next convenient operation list. Two groups of 17 patients were well matched for age, sex, and nutritional status. Although they underwent diverse operations, the extent of these was similar: 12 +/- 3 days of parenteral nutrition resulted in weight gain, 3.2 +/- 2.3 kg p less than 0.01; increased triceps skinfold, 0.6 +/- 1.2 mm p less than 0.05; improved immunological state, p less than 0.02; and improved PNI, 5.5 +/- 10.1% p less than 0.05. The changes in serum albumin and transferrin were not significant. There were only three major complications with one death in the treatment group but this was not significantly different from the control group which had six major complications and three deaths. This study suggests that patients with demonstrable nutritional depletion who require major gastrointestinal surgery will benefit from a preoperative course of parenteral nutrition, but to conclusively prove this a large and probably multicentre study will be required.", "Although stroke patients who do not have difficulty swallowing may be at risk of undernutrition and worsening nutritional status during hospitalization, optimum methods for nutrition intervention in stroke patients have not been established.\n To examine the feasibility of enteral sip feeding as an effective nutrition intervention after acute stroke.\n Forty-two acute ischemic stroke inpatients with impaired nutritional status who did not have difficulty swallowing within 1 week after the stroke were entered into a single-blind, randomized, controlled, prospective study of enteral sip feeding. Twenty-one patients were randomized to receive daily oral food supplements for 4 weeks in addition to the hospital food, and 21 patients received only the hospital food for the same period. Main outcome measures were energy and protein intakes during the intervention period, change in nutritional status, disability, infective complications, length of stay, and mortality during hospitalization and at 3 months.\n Two patients, one from each group, were lost to follow-up immediately after randomization. Twenty patients received oral nutritional supplementation. The energy intake was significantly greater in the supplemented group: 1807 +/- 318 vs 1084 +/- 343 kcal/d (mean +/- SD; p < .0001) (estimated treatment effect, 723 kcal/d; 95% confidence interval [CI], 498 to 947), as was protein intake: 65.1 +/- 13.8 vs 44.1 +/- 12.8 g/d (p < .001) (estimated treatment effect, 21.0 g/d; 95% CI, 11.7 to 30.3). There also were significant differences between the two groups in the changes in serum albumin and serum iron concentrations between randomization and at follow-up. There was a trend to lower mortality at 3 months in the supplemented group with two deaths (10%) compared with seven deaths (35%) in the control group (p = .127, relative risk, 0.29; 95% CI, 0.07 to 1.21).\n This study suggests that enteral sip feeding is effective in improving nutritional intake and status in stroke patients who do not have swallowing difficulties. There also may be some beneficial effects on clinical outcome, but larger studies are required to confirm this observation and define more precisely the magnitude of any favorable effects.", "Poor nutritional status is common among patients awaiting orthotopic liver transplantation and is associated with poor outcome.\n This prospective randomized controlled trial examined the effect of pretransplant nutritional supplementation on the outcome of patients undergoing liver transplantation. Of 82 consecutive patients with mid-arm muscle circumference <25th percentile, 42 received enteral supplementation, and the remainder acted as the control group. The supplemented group received a calorie-dense enteral feed taken daily (in addition to diet) until transplantation. Nutritional status was monitored by upper arm anthropometric measurements and handgrip strength. Dietary intake was calculated from 5-day food diaries.\n Supplementation improved mid-arm circumference, mid-arm muscle circumference, and grip strength. Pretransplant nutritional status was not associated with posttransplant sepsis or major complications. Preoperative grip strength of <85% of normal values was predictive of increased incidence of posttransplant major complications. Supplementation did not affect outcome, although there were more deaths in the control group (seven deaths before and two deaths after transplant) than there were in the supplemented group (two deaths before and three deaths after transplant). There was no difference in overall survival (P = 0.075).\n Enteral supplementation improved some parameters of nutritional status pretransplant. Dietary intake of patients in the two groups was similar at transplant. Nutritional supplementation has not increased nutritional intake, although this may reflect the importance of regular dietetic input and support, rather than suggesting that nutritional supplementation is ineffective. Supplementation had no effect on outcome of liver transplantation.", "The present studies were designed to provide careful measures of effects of oxandrolone, an anabolic steroid, intravenous nutritional supplementation, and the combination of these two treatments on liver functions, metabolic balances, nitrogen metabolism, and nutritional status in patients with moderate to severe alcoholic hepatitis. Of 43 patients originally recruited, 39 (19 men, 20 women) with typical clinical and laboratory features of alcoholic hepatitis (11 Child's-Pugh class B; 28 class C) were admitted to a metabolic unit and completed a 35-day three-phase protocol. Phase I was a 10-day baseline period of observation, during which routine and special quantitative tests of liver function (galactose and antipyrine metabolism), a 7-day elemental balance study, and a 15N, 13C-leucine metabolism study were done. Phase II was a 21-day treatment period during which patients were randomly assigned to receive one of four regimens: 1) standard therapy, consisting of abstinence, a balanced, nutritionally adequate diet, and multivitamins; 2) oxandrolone (20 mg orally four times a day) plus standard therapy; 3) nutritional supplementation, consisting of 2 L daily of 3.5% crystalline amino acids (in 5% dextrose), given by peripheral vein; or 4) a combination of oxandrolone and nutritional supplementation, along with standard therapy. Metabolic balances were repeated during phase II. Phase III was 2 or 3 days posttreatment, during which special studies of liver functions and volumes and leucine metabolism were repeated. All patients who completed phase I of study and were randomly allocated to one of the four treatment groups completed the subsequent two phases. Overall, with time, patients showed highly significant improvements in most clinical and laboratory features. For most standard laboratory tests (e.g., serum albumin, transferrin, prothrombin time) improvements were more marked in patients treated with nutritional supplementation and/or oxandrolone than in those given standard therapy alone. Liver volumes fell in all treatment groups, with greater improvement in those treated with nutritional supplementation. Improvements in galactose and antipyrine metabolism rates were significant only in those treated with nutritional supplementation or oxandrolone. Effects of treatments on metabolic balances, nitrogen metabolism, and measures of nutrition are described in this issue in a companion paper. We conclude that the addition of nutritional supplementation and oxandrolone to standard therapy of moderately severe or severe alcoholic hepatitis is well tolerated, and leads to more rapid improvement in the laboratory parameters measured.", "Sixty-four patients admitted with acute alcoholic hepatitis, with or without underlying cirrhosis, were randomized regardless of encephalopathy to receive a controlled diet either alone, or supplemented orally, nasogastrically, or intravenously as necessary, with 2000 kCal and 10 g nitrogen daily. Whether this came from a conventional protein source or a branched chain amino acid enriched formulation was also randomly determined. In the absence of renal failure, nitrogen intakes of 10 g or more daily were invariably associated with positive nitrogen balance, but complications of liver dysfunction prevented the attainment of significantly more positive balance in the supplemented groups than in controls. Neither in the series as a whole, nor in any identifiable subgroup of patients, was mortality affected by treatment. Changes in prothrombin time and in measured nutritional parameters during the study did not differ between supplemented and control groups, and the observed changes in midarm muscle circumference appeared to reflect changes in degree of fluid retention. Neither enteral nor parenteral branched chain amino acids showed any consistent effect upon encephalopathy.", "Between March 1982 and September 1983, 40 inpatients (25 men and 15 women, mean age 53 years) with alcoholic cirrhosis and total serum bilirubin greater than or equal to 5 mg per dl were studied. Those with hepatocellular carcinoma, renal failure, hyponatremia, septicemia, spontaneous bacterial peritonitis, gastrointestinal bleeding, and hepatic coma were excluded. Patients were studied for 28 days. The two groups were offered an oral diet containing 40 kcal per kg per day. Patients in the supplementary parenteral nutrition group received 40 kcal per kg per day and 200 mg nitrogen per kg per day using a central catheter. The major endpoint was total serum bilirubin on Day 28. On admission, serum bilirubin was not significantly different in the two groups: oral group, 12.5 +/- 6.6 mg per dl; supplementary parenteral nutrition group, 12.3 +/- 8.5 mg per dl. On Day 28, serum bilirubin was lower in the supplementary parenteral nutrition group (2.5 +/- 1.4 mg per dl) than in the oral group (4.1 +/- 2.2 mg per dl) (p less than 0.02). Serum bilirubin was also lower in the supplementary parenteral nutrition group than in the oral group on Days 7, 14 and 21 (p less than 0.05). Analysis of covariance, considering serum bilirubin on admission and at randomization and time between admission and randomization, confirmed these results. On Day 28, anthropometric parameters, serum transferrin, prealbumin and retinol-binding protein were higher in the supplementary parenteral nutrition group, but the differences were not significant. Serum albumin was significantly lower in the supplementary parenteral nutrition group. The incidence of encephalopathy and sepsis was not significantly different between the two groups.", "Parenteral nutrition is well established for providing nutritional support in acute pancreatitis while avoiding pancreatic stimulation. However, it is associated with complications and high cost. Benefits of enteral feeding in other disease states prompted a comparison of early enteral feeding with total parenteral nutrition in this clinical setting.\n Thirty-eight patients with acute severe pancreatitis were randomized into two groups. The first (n = 18) received enteral nutrition through a nasoenteric tube with a semi-elemental diet, while the second group (n = 20) received parenteral nutrition through a central venous catheter. Safety was assessed by clinical course of disease, laboratory findings and incidence of complications. Efficacy was determined by nitrogen balance. The cost of nutritional support was calculated.\n Enteral feeding was well tolerated without adverse effects on the course of the disease. Patients who received enteral feeding experienced fewer total complications (P < 0.05) and were at lower risk of developing septic complications (P < 0.01) than those receiving parenteral nutrition. The cost of nutritional support was three times higher in patients who received parenteral nutrition.\n This study suggests that early enteral nutrition should be used preferentially in patients with severe acute pancreatitis.", "Ever since methods of artificial nutritional support became available, attempts have been made using this form of treatment to reduce mortality and morbidity in surgical patients. Many trials have addressed this question, but very few have given a meaningful answer because of conceptual and methodological flaws. We therefore undertook a prospective randomised trial investigating the effects of at least 10 days pre-operative total parenteral nutrition (TPN) (n = 51) or total enteral nutrition (TEN) (n = 50) providing 150% basal energy expenditure (BEE) non-protein energy, to reduce major postoperative complications and mortality in a homogeneous patient group with signs of depletion. 50 patients served as a depleted control group (D) and 49 patients served as a non-depleted reference group (ND) and were operated upon without delay. Depleted control patients suffered significantly more septic complications than did patients in the non-depleted reference group (p < 0.05). There was no significant difference, however, in septic complications between either of the nutritional support groups and the non-depleted control group. In high risk patients, with weight loss >10% of body weight and over 500 ml blood loss during operation, a significant decrease in major complications was observed (p < 0.05) as a result of nutritional support. We conclude that pre-operative nutritional support, in patients with severe depletion, results in a reduction in major complications to a degree that justifies its routine use in this selected group of patients.", "Total enteral nutrition (TEN) within 48 h of admission has recently been shown to be safe and efficacious as part of the management of severe acute pancreatitis. Our aim was to ascertain the safety of immediate TEN in these patients and the effect of TEN on systemic inflammation, psychological state, oxidative stress, plasma glutamine levels and endotoxaemia.\n Patients admitted with predicted severe acute pancreatitis(APACHE II score >5) were randomised to total enteral (TEN; n = 8) or total parenteral nutrition (TPN; n = 9). Measurements of systemic inflammation (C-reactive protein), fatigue (visual analogue scale), oxidative stress (plasma thiobarbituric acid-reactive substances), plasma glutamine and anti-endotoxin IgG and IgM antibody concentrations were made on admission and repeated on days 3 and 7 thereafter. Clinical progress was monitored using APACHE II score. Organ failure and complications were recorded.\n All patients tolerated the feeding regime well with few nutrition-related complications. Fatigue improved in both groups but more rapidly in the TEN group. Oxidative stress was high on admission and rose by similar amounts in both groups. Plasma glutamine concentrations did not change significantly in either group. In the TPN group, 3 patients developed respiratory failure and 3 developed non-respiratory single organ failure. There were no such complications in the TEN group. Hospital stay was shorter in the TEN group [7(4-14) vs. 10 (7-26) days; p = 0.05] as was time to passing flatus and time to opening bowels [1 (0-2) vs. 2 (1-5)days; p = 0.01]. The cost of TEN was considerably less than of TPN.\n Immediate institution of nutritional support in the form of TEN is safe in predicted severe acute pancreatitis. It is as safe and as efficacious as TPN and may be beneficial in the clinical course of this disease.", "The purpose of the study was to determine whether early postoperative enteral feeding with an immune-enhancing formula (IEF) decreases morbidity, mortality, and length of hospital stay in patients with upper gastrointestinal (GI) cancer.\n Early enteral feeding with an IEF has been associated with improved outcome in trauma and critical care patients. Evaluable data documenting reduced complications after major upper GI surgery for malignancy with early enteral feeding are limited.\n Between March 1994 and August 1996, 195 patients with a preoperative diagnosis of esophageal (n = 23), gastric (n = 75), peripancreatic (n = 86), or bile duct (n = 11) cancer underwent resection and were randomized to IEF via jejunostomy tube or control (CNTL). Tube feedings were supplemented with arginine, RNA, and omega-3 fatty acids, begun on postoperative 1, and advanced to a goal of 25 kcal/kg per day. The CNTL involved intravenous crystalloid solutions. Statistical analysis was by t test, chi square, or logistic regression.\n Patient demographics, nutritional status, and operative factors were similar between the groups. Caloric intake was 61% and 22% of goal for the IEF and CNTL groups, respectively. The IEF group received significantly more protein, carbohydrate, lipids and immune-enhancing nutrients than did the CNTL group. There were no significant differences in the number of minor, major, or infectious wound complications between the groups. There was one bowel necrosis associated with IEF requiring reoperation. Hospital mortality was 2.5% and median length of hospital stay was 11 days, which was not different between the groups.\n Early enteral feeding with an IEF was not beneficial and should not be used in a routine fashion after surgery for upper GI malignancies.", "Routine laxatives may expedite gastrointestinal recovery and early tolerance of food within an enhanced recovery after surgery (ERAS) programme. Combined with carbohydrate loading and oral nutritional supplements (ONS), it may further enhance recovery of gastrointestinal function and promote earlier overall recovery.\n Seventy-four patients undergoing liver resection were randomized in a two-by-two factorial design to receive either postoperative magnesium hydroxide as a laxative, preoperative carbohydrate loading and postoperative ONS, their combination or a control group. Patients were managed within an ERAS programme of care. The primary outcome measure was time to first passage of stool. Secondary outcome measures were gastric emptying, postoperative oral calorie intake, time to functional recovery and length of hospital stay.\n Sixty-eight patients completed the trial. The laxative group had a significantly reduced time to passage of stool: median (interquartile range) 4 (3-5) versus 5 (4-6) days (P = 0.034). The ONS group showed a trend towards a shorter time to passage of stool (P = 0.076) but there was no evidence of interaction in patients randomized to the combination regimen. Median length of hospital stay was 6 (4-7) days. There were no differences in secondary outcomes between groups.\n Within an ERAS protocol for patients undergoing liver resection, routine postoperative laxatives result in an earlier first passage of stool but the overall rate of recovery is unaltered.\n Copyright (c) 2010 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.", "The effect of total parenteral nutrition (TPN) support supplemented with alanyl-glutamine (Ala-Gln) dipeptide was investigated in a randomized, controlled clinical trial.\n Sixty-five patients with the diagnosis of end-stage liver disease or hepatic cellular carcinoma admitted for orthotopic liver transplantation were randomly divided into 3 groups: diet group (n = 21), TPN group (n = 22), and Gln group (n = 22). Patients in the TPN and Gln groups received isocaloric and isonitrogenous TPN for 7 days. Venous heparin blood samples were obtained for assay on days 2 and 9 after surgery; we performed routine pathologic tests.\n Compared with the results on day 9 in the TPN group, there was a significant increase in the prognostic nutrition index and in prealbumin among the Gln group. Aspartate aminotransferase improved significantly by Gln treatment compared with traditional TPN support (P < .05). The pathologic results also showed Gln supplementation to reduce hepatic cell injury. A significant decrease in postoperative hospital stay was observed in the Gln group.\n Posttransplant TPN support greatly improved protein metabolism and nutritional state of patients. TPN with Ala-Gln helped to improve synthetic function and to reduce the injury to a transplanted liver.", "This prospective randomized controlled clinical trial compares the effects of early parenteral nutrition and traditional delayed enteral nutrition upon the outcome of head-injured patients. Thirty-eight head-injured patients were randomly assigned to receive total parenteral nutrition (TPN) or standard enteral nutrition (SEN). Clinical and nutritional data were collected on all patients until death or for 18 days of hospitalization. Survival and functional recovery were monitored in survivors for 1 year. Of the 38 patients, 18 were randomized to the SEN group and 20 to the TPN group. Demographically, the two groups of patients were similar on admission. There was no significant difference in the severity of head injury between the two groups as measured by the Glasgow Coma Scale (p = 0.52). The outcome for the two groups was quite different, with eight of the 18 SEN patients dying within 18 days of injury, whereas no patient in the TPN group died within this period (p less than 0.0001). The basis for the improved survival in the TPN patients appears to be improved nutrition. The TPN patients had a more positive nitrogen balance (p less than 0.06), and a higher serum albumin level and total lymphocyte count. More adequate nutritional status may have improved the patients' immunocompetence, resulting in decreased susceptibility to sepsis. The data from this study strongly support the favorable effect of early TPN on survival from head injury.", "A prospective randomized clinical trial was undertaken to test the efficacy of total parenteral nutrition (TPN) among previously untreated children receiving abdominal/pelvic irradiation with or without adjuvant chemotherapy who were at risk for weight loss, malnutrition, and complications from treatment. Children were evaluated by weight/height determinations, anthropomorphic measurements, and laboratory studies. TPN was associated with an improved nutritional status during therapy as compared with control patients on ad libitum intake. However, when TPN was discontinued, weight declined and there were no differences among treated and control patients detected at three-month follow-up. Likewise there was no obvious effect from TPN on tolerance to therapy in the adequately nourished child. TPN as initial supportive therapy should be reserved for those children who are malnourished or marginally malnourished at the time of presentation. Close nutritional assessment during treatment is essential since approximately 25% of children undergoing abdominal/pelvic radiotherapy with chemotherapy can be expected to become malnourished during an initial course of therapy.", "The purpose of this study was to determine the effects of early postoperative tube feeding on outcomes of liver transplant recipients.\n Fifty transplant patients were randomized prospectively to receive enteral formula via nasointestinal feeding tubes (tube-feeding [TF] group) or maintenance i.v. fluid until oral diets were initiated (control group). Thirty-one patients completed the study. Resting energy expenditure, nitrogen balance, and grip strength were measured on days 2, 4, 7, and 12 after liver transplantation. Calorie and protein intakes were calculated for 12 days posttransplant.\n Tube feeding was tolerated in the TF group (n = 14). The TF patients had greater cumulative 12-day nutrient intakes (22,464 +/- 3554 kcal, 927 +/- 122 g protein) than did the control patients (15,474 +/- 5265 kcal, 637 +/- 248 g protein) (p < .002). Nitrogen balance was better in the TF group on posttransplant day 4 than in the control group (p < .03). There was a rise in the overall mean resting energy expenditure in the first two posttransplant weeks from 1487 +/- 338 to 1990 +/- 367 kcal (p = .0002). Viral infections occurred in 17.7% of control patients compared with 0% of TF patients (p = .05). Although other infections tended to occur more frequently in the control group vs the TF group (bacterial, 29.4% vs 14.3%; overall infections, 47.1% vs 21.4%), these differences were not statistically significant. Early posttransplant tube feeding did not influence hospitalization costs, hours on the ventilator, lengths of stay in the intensive care unit and hospital, rehospitalizations, or rejection during the first 21 posttransplant days.\n Early posttransplant tube feeding was tolerated and promoted improvements in some outcomes and should be considered for all liver transplant patients.", "Aminoleban EN contains branched-chain amino acids (BCAA) and is known to be beneficial for the protein-energy malnutrition in cirrhotic patients. Patients suffering from hepatocellular carcinoma often have background cirrhosis, and the present study investigates the effect of Aminoleban EN on these patients after hepatic resection for the primary disease.\n A prospective randomized controlled clinical trial, to which 50 patients were recruited, was carried out. The study group received Aminoleban EN in addition to normal diet for 12 weeks and the control group received an isonitrogenous and isocaloric diet only.\n After exclusions, there were 21 patients in the study group and 23 patients in the control. The study group had a shorter hospital stay, and had a significantly higher haemoglobin level, higher sodium level, higher albumin level and lower bilirubin during the postoperative course. There was no significant difference in terms of neuropsychiatric symptoms or Karnofsky performance score. There was no difference in gastrointestinal symptoms or other signs. No adverse reaction was associated with the administration of Aminoleban, and there was no significant difference in terms of morbidity and mortality between the two groups of patients.\n Aminoleban EN is safe to administer and does not have significant adverse effects. It contributes to a shorter hospital stay and quicker improvement of liver function in the early postoperative period. These beneficial results require only a 12-week period of administration of BCAA after operation." ]	The data do not compellingly justify the routine use of parenteral nutrition, enteral nutrition, or oral nutritional supplements in patients with liver disease. The fact that all but one of these trials were at high risks of bias even casts doubt on the few benefits that were demonstrated. Data from well-designed and executed randomised trials that include an untreated control group are needed before any such recommendation can be made. Future trials have to be powered adequately to see small, but clinically important, differences.
CD007726	[ "12243210", "15450054", "9322135", "14744180", "19138567", "22121861", "18162017", "12083600" ]	[ "A randomized, placebo-controlled trial of the discontinuation of long-term antipsychotics in dementia.", "Effect of antipsychotic withdrawal on behavior and sleep/wake activity in nursing home residents with dementia: a randomized, placebo-controlled, double-blinded study. The Bergen District Nursing Home Study.", "Withdrawal of neuroleptic medications from institutionalized dementia patients: results of a double-blind, baseline-treatment-controlled pilot study.", "A 3-month, randomized, placebo-controlled, neuroleptic discontinuation study in 100 people with dementia: the neuropsychiatric inventory median cutoff is a predictor of clinical outcome.", "The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial.", "Antipsychotic prophylaxis is needed after remission from a first psychotic episode in schizophrenia patients: results from an aborted randomised trial.", "Ethyl-eicosapentaenoic acid in first-episode psychosis: a randomized, placebo-controlled trial.", "No long-term effect of behavioral treatment on psychotropic drug use for agitation in Alzheimer's disease patients." ]	[ "The objectives of this randomized clinical trial were to investigate the impact of the discontinuation of long-term antipsychotics in residents with dementia in chronic care institutions and to identify clinical predictors of safe discontinuation. Subjects included 34 residents with dementia who were on antipsychotics for more than 6 months and whose behavior was currently stable. Subjects were randomized to either continue receiving their regular dosage of antipsychotics or to receive placebo for 6 months. Early withdrawal from the study was not statistically different between the groups (relative risk [RR] = 1.57, 95% confidence interval [CI] 0.76-3.26), and though not significantly different, subjects in the placebo group were more likely to be withdrawn from the study because of worsening behavior (RR = 1.25, 95% Cl 0.33-4.76). Three subjects in the placebo group were withdrawn from the study due to worsening of extrapyramidal symptoms. The active treatment group had more behavioral problems (e.g., physical aggression towards others, p < .05) compared to the placebo group. The placebo group developed more apathy, but balancing this outcome was a relative improvement in cognitive functioning. Baseline antipsychotic dose was predictive of behavioral worsening upon discontinuation of long-term antipsychotic drugs. The primary limitation of the study was the small sample size. In conclusion, a trial of discontinuation of antipsychotics should be considered in this population.", "To explore the effect on sleep/wake activity and on behavioral and psychological symptoms of the withdrawal of antipsychotic medications from nursing home (NH) patients with dementia.\n Randomized, placebo-controlled, double-blind trial.\n NHs in Bergen, Norway.\n Thirty patients (mean age 83.5) taking haloperidol, risperidone, or olanzapine for nonpsychotic symptoms. Intervention: Study participants were randomly assigned to withdrawal (intervention group) or continued treatment with antipsychotic medications (reference group) for 4 consecutive weeks.\n Behavioral rating using the Neuropsychiatric Inventory Questionnaire (NPI-Q) and actigraphy.\n After antipsychotic withdrawal, behavioral scores remained stable or improved in 11 of 15 patients, whereas four had worsening scores. Actigraphy revealed decreased sleep efficiency after drug discontinuation and increased 24-hour and night activity in both groups. Actigraphy records of nighttime and daytime activity indicated sleep problems and restlessness, in terms of the NPI-Q. One patient was restarted on antipsychotics.\n Antipsychotic drug withdrawal affected activity and sleep efficiency over the short term. Increases in total activity and impaired sleep quality after drug discontinuation should be monitored, because the long-term effect of these changes is not known. The NPI-Q and actigraphy are feasible tools that disclose relevant changes occurring during antipsychotic withdrawal in NH patients with dementia. Their use in clinical practice should be substantiated by larger studies.", "Among dementia patients in long-term care facilities, neuroleptics (NL) are frequently prescribed for the treatment of agitation. Although good clinical practice and federal law mandate attempts at withdrawal of these medications, empiric data regarding the cessation of NL treatment are limited in this population. The objective of the present study was to assess through direct observation the effects of short-term NL withdrawal on physically aggressive behavior and other aspects of agitation. We carried out a randomized, double-blind, baseline NL-controlled 4-week trial of the effects of NL withdrawal in 36 institutionalized patients with possible or probable Alzheimer's disease. Patients were directly observed for four 2-hour sessions during baseline, a prerandomization week, and during weeks 1, 2, and 4 of the double-blind portion of the study. Completion of the 4 weeks of double-blind medication and number of observed episodes of physically aggressive behavior (PAB) were the two primary outcome measures. Of the 22 patients who were withdrawn from NL, 20 (91%) completed the 4-week double-blinded withdrawal. Two patients were discontinued from the study due to unacceptable levels of agitation at the request of their nursing staff. Of the 14 patients not withdrawn, all completed the 4-week trial. The chi-square test for the difference between groups was not significant (P > .05). Based on the observed instances of PAB, there was no significant difference (P > .05) between withdrawn and not-withdrawn subjects. Half of the withdrawn patients remained off NLs for an extended period of time after the end of the study, even after the blind was broken. Withdrawing institutionalized dementia patients from NLs was successful in most but not all study patients. Generalization of these results is limited by the highly selected nature of the participants. Unmasking of unmanageable agitation and physical aggressiveness in a small minority must be weighed against the benefits of removing unnecessary medication in the majority of dementia patients in whom NL withdrawal is attempted. PAB itself should not drive continuing NL use without regard to objective assessment of efficacy of the NL treatment.", "Although few placebo-controlled neuroleptic discontinuation studies have been conducted in people with dementia, such studies are essential to inform key clinical decisions.\n A 3-month, double-blind, placebo-controlled, neuroleptic discontinuation study (June 2000 to June 2002) was completed in 100 care-facility residents with probable or possible Alzheimer's disease (according to National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria) who had no severe behavioral disturbances and had been taking neuroleptics for longer than 3 months. The Neuropsychiatric Inventory (NPI) was used to measure changes in behavioral and psychiatric symptoms. Quality of life was evaluated using Dementia Care Mapping.\n Eighty-two patients completed the 1-month assessment (36 placebo, 46 active). The number of participants withdrawing overall (N = 14 [30%] placebo, N = 14 [26%] active treatment) and because of exacerbation of behavioral symptoms (N = 6 [13%] placebo, N = 5 [9%] active treatment) was similar in the neuroleptic- and placebo-treated patients. As hypothesized, patients with baseline NPI scores at or below the median (< or = 14) had a particularly good outcome, with a significantly greater reduction of agitation in the patients receiving placebo (Mann-Whitney U test, z = 2.4, p =.018), while patients with higher baseline NPI scores were significantly more likely to develop marked behavioral problems if discontinued from neuroleptics (chi(2) = 6.8, p =.009). There was no overall difference in the change of quality of life parameters between groups.\n A standardized evaluation with an instrument such as the NPI may be a clinical indicator of which people with dementia are likely to benefit from discontinuation of neuroleptic treatment.", "Data from 12-week placebo-controlled trials have led to mounting concerns about increased mortality in patients with Alzheimer's disease (AD) who are prescribed antipsychotics; however, there are no mortality data from long-term placebo-controlled trials. We aimed to assess whether continued treatment with antipsychotics in people with AD is associated with an increased risk of mortality.\n Between October, 2001, and December, 2004, patients with AD who resided in care facilities in the UK were enrolled into a randomised, placebo-controlled, parallel, two-group treatment discontinuation trial. Participants were randomly assigned to continue with their antipsychotic treatment (thioridazine, chlorpromazine, haloperidol, trifluoperazine, or risperidone) for 12 months or to switch their medication to an oral placebo. The primary outcome was mortality at 12 months. An additional follow-up telephone assessment was done to establish whether each participant was still alive 24 months after the enrollment of the last participant (range 24-54 months). Causes of death were obtained from death certificates. Analysis was by intention to treat (ITT) and modified intention to treat (mITT). This trial is registered with the Cochrane Central Registry of Controlled Trials/National Research Register, number ISRCTN33368770.\n 165 patients were randomised (83 to continue antipsychotic treatment and 82 to placebo), of whom 128 (78%) started treatment (64 continued with their treatment and 64 received placebo). There was a reduction in survival in the patients who continued to receive antipsychotics compared with those who received placebo. Cumulative probability of survival during the 12 months was 70% (95% CI 58-80%) in the continue treatment group versus 77% (64-85%) in the placebo group for the mITT population. Kaplan-Meier estimates of mortality for the whole study period showed a significantly increased risk of mortality for patients who were allocated to continue antipsychotic treatment compared with those allocated to placebo (mITT log rank p=0.03; ITT p=0.02). The hazard ratio for the mITT group was 0.58 (95% CI 0.35 to 0.95) and 0.58 (0.36 to 0.92) for the ITT population. The more pronounced differences between groups during periods of follow up longer than 12 months were evident at specific timepoints (24-month survival 46%vs 71%; 36-month survival 30%vs 59%).\n There is an increased long-term risk of mortality in patients with AD who are prescribed antipsychotic medication; these results further highlight the need to seek less harmful alternatives for the long-term treatment of neuropsychiatric symptoms in these patients.\n UK Alzheimer's Research Trust.", "To assess the effect of withdrawal of antipsychotic treatment on relapse risk in remitted first-episode schizophrenia patients.\n First-episode 1-year stable and remitted outpatients with a schizophrenic disorder were randomly allocated to continuation of their antipsychotic regimen for at least 6 months (N = 9), or gradual withdrawal (N = 11). Primary outcome was the difference in cumulative relapse-free survival at 9 months.\n Recruitment was terminated prematurely on 26 October 2005. The cumulative relapse-free survival was 88% (SE = 0.12) in the continuation and 18% (SE = 0.12) in the discontinuation group (P = 0.001) at 9 months follow-up.\n Discontinuation of antipsychotic medication markedly increases the risk of relapse in stable remitted first-episode schizophrenia patients. In future studies the topics of safety monitoring and sampling of patients should receive extra attention.", "To investigate if ethyl-eicosapentaenoic acid (E-EPA) augmentation improves antipsychotic efficacy and tolerability in first-episode psychosis (FEP).\n We performed a 12-week, randomized, double-blind, placebo-controlled trial of 2-g E-EPA augmentation in 80 FEP patients. Sixty-nine patients were eligible for analysis; a post hoc analysis was computed for a subgroup of nonaffective FEP patients (N = 53). The first participant was included in November 2000 and the last participant completed the trial in August 2003. Primary outcome measures were symptom change scores and time to first response, while tolerability measures and cumulative antipsychotic dose were secondary outcome measures.\n Analysis of covariance controlling for baseline symptoms found no significant mean difference between E-EPA and placebo at week 12 for symptom change scores. Cox regression analysis revealed a significant treatment by diagnosis interaction (p = .024) for time to first response favoring E-EPA in nonaffective psychosis. Post hoc analysis for cumulative response rates further confirmed a higher response rate at week 6 (42.9% [15/35] vs. 17.6% [6/34] for all participants, p = .036; 54.2% [13/24] vs. 17.2% [5/29] for the nonaffective psychosis subset, p = .008); however, the difference at week 12 was no longer significant. Analysis of secondary outcome measures revealed that E-EPA-augmented participants needed 20% less antipsychotic medication between weeks 4 through 6 (p = .03), had less extrapyramidal side effects in the initial 9 weeks (p < .05 for all participants and for all timepoints), and reported less constipation (p = .011) and fewer sexual side effects (p = .016) than those treated with antipsychotic medication alone.\n The findings suggest that E-EPA may accelerate treatment response and improve the tolerability of antipsychotic medications. However, it was not possible to demonstrate a sustained symptomatic benefit of E-EPA in early psychosis, possibly due to a ceiling effect, since a high proportion of first-episode patients already achieve symptomatic remission with antipsychotic medication alone. Further controlled trials in nonaffective early psychosis seem warranted.\n Australian Clinical Trials Registry identifier 12605000267651 (http://actr.org.au).", "Th determine if teaching caregivers behavior management techniques (BMTs) reduces long-term psychotropic use in Alzheimer's disease (AD) patients, we examined 12-month follow-up data from a 4-month randomized study comparing placebo, BMTs, trazodone, and haloperidol for the treatment of agitated behaviors in persons with AD. After 4 months, treatment was allowed with any agent. Between 42.8% and 51% of AD patients received additional psychotropics between 4 and 12 months. The relative risk of being prescribed any psychotropic drug after the 4-month trial was at or about 1.0 for subjects in each drug arm or placebo arm versus BMTs. We concluded that teaching caregivers BMTs did not diminish long-term prescription of psychotropic drugs." ]	Our findings suggest that many older people with Alzheimer's dementia and NPS can be withdrawn from chronic antipsychotic medication without detrimental effects on their behaviour. It remains uncertain whether withdrawal is beneficial for cognition or psychomotor status, but the results of this review suggest that discontinuation programmes could be incorporated into routine practice. However, two studies of people whose agitation or psychosis had previously responded well to antipsychotic treatment found an increased risk of relapse or shorter time to relapse after discontinuation. Two other studies suggest that people with more severe NPS at baseline could benefit from continuing their antipsychotic medication. In these people, withdrawal might not be recommended.
CD004876	[ "7966893", "2200894", "15542184", "8241913", "15530669", "19395948", "9076288", "17596805", "1530193", "19149900", "15195237", "14656755", "14508426", "9652613", "8648202", "2968738", "9302748", "18097856", "3553874", "17142512", "11517426", "14506120", "16171903", "12236274", "20723631", "11382801", "8653819", "14575760", "11599691", "15189916", "15629993", "10493337", "14687310", "21219979", "11717569", "1415151", "9382120", "2975452", "9580647", "7666874", "10411194", "16651286", "8160445", "15056235", "11015795", "7963201", "12271720", "8669146", "16883677", "1245939", "12145718", "9042032", "9744187", "8557090", "20629771", "3093045", "3341857", "7080769", "16720062", "8259810", "21263970", "3565663", "18187561", "9269055", "12457048", "20855940", "10930686", "11447049", "8065407" ]	[ "The efficacy of influenza vaccination in elderly individuals. A randomized double-blind placebo-controlled trial.", "Frequency of adverse reactions to influenza vaccine in the elderly. A randomized, placebo-controlled trial.", "Is influenza vaccination cost effective for healthy people between ages 65 and 74 years? A randomised controlled trial.", "Adverse reactions to influenza vaccine in elderly people: randomised double blind placebo controlled trial.", "Effectiveness of the MF59-adjuvanted influenza vaccine in preventing emergency admissions for pneumonia in the elderly over 64 years of age.", "Efficacy and safety of 1 and 2 doses of live attenuated influenza vaccine in vaccine-naive children.", "A randomised intervention study to examine the effect on immunisation coverage of making influenza vaccine available at no cost.", "Efficacy and safety of a live attenuated, cold-adapted influenza vaccine, trivalent against culture-confirmed influenza in young children in Asia.", "Protective efficacy of combined live intranasal and inactivated influenza A virus vaccines in the elderly.", "Challenge of conducting a placebo-controlled randomized efficacy study for influenza vaccine in a season with low attack rate and a mismatched vaccine B strain: a concrete example.", "A cohort study of the effectiveness of influenza vaccine in older people, performed using the United Kingdom general practice research database.", "Influenza vaccination in children with asthma: randomized double-blind placebo-controlled trial.", "The influence of health professionals on the uptake of the influenza immunization.", "Randomised placebo-controlled crossover trial on effect of inactivated influenza vaccine on pulmonary function in asthma.", "Evaluation of live attenuated influenza vaccines in children 6-18 months of age: safety, immunogenicity, and efficacy. National Institute of Allergy and Infectious Diseases, Vaccine and Treatment Evaluation Program and the Wyeth-Ayerst ca Influenza Vaccine Investigators Group.", "[The results of state trials of inactivated influenza vaccines for children].", "Evaluation of bivalent live attenuated influenza A vaccines in children 2 months to 3 years of age: safety, immunogenicity and dose-response.", "Influenza vaccination in adults with asthma: safety of an inactivated trivalent influenza vaccine.", "Age-related responses to influenza vaccination in the Newcastle region during 1983 and 1984.", "Safety, efficacy, and effectiveness of cold-adapted influenza vaccine-trivalent against community-acquired, culture-confirmed influenza in young children attending day care.", "Influenza vaccine effectiveness in preventing hospitalizations and deaths in persons 65 years or older in Minnesota, New York, and Oregon: data from 3 health plans.", "Effectiveness of inactivated influenza vaccine in preventing acute otitis media in young children: a randomized controlled trial.", "Inactivated influenza vaccine effectiveness in children under 6 years of age during the 2002-2003 season.", "Improving uptake of influenza vaccination among older people: a randomised controlled trial.", "Effectiveness of pneumococcal polysaccharide vaccine against pneumonia and cost analysis for the elderly who receive seasonal influenza vaccine in Japan.", "Efficacy of Influenza Vaccine in Elderly Persons in Welfare Nursing Homes: Reduction in Risks of Mortality and Morbidity During an Influenza A (H3N2) Epidemic.", "Clinical and epidemiological evaluation of a live, cold-adapted influenza vaccine for 3-14-year-olds.", "A prospective, Internet-based study of the effectiveness and safety of influenza vaccination in the 2001-2002 influenza season.", "Effectiveness of influenza vaccination in the elderly in a community in Italy.", "Acute respiratory illness in patients with COPD and the effectiveness of influenza vaccination: a randomized controlled study.", "Implementation of universal influenza immunization recommendations for healthy young children: results of a randomized, controlled trial with registry-based recall.", "Randomized, placebo-controlled double blind study on the efficacy of influenza immunization on absenteeism of health care workers.", "Can a short period of micronutrient supplementation in older institutionalized people improve response to influenza vaccine? A randomized, controlled trial.", "Influenza A (H1N1) 2009 two-dose immunization of US children: an observer-blinded, randomized, placebo-controlled trial.", "Influenza vaccination, hospitalizations, and costs among members of a Medicare managed care plan.", "Influenza vaccine effectiveness in preventing hospitalization for pneumonia in the elderly.", "Clinical efficacy of pneumococcal vaccine in the elderly: a randomized, single-blind population-based trial.", "[Characteristics of the clinical and immunologic safety of inactivated influenza vaccines in children undergoing multiple immunizations].", "The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children.", "The effectiveness of vaccination against influenza in healthy, working adults.", "Effectiveness of live, attenuated intranasal influenza virus vaccine in healthy, working adults: a randomized controlled trial.", "The safety of trivalent influenza vaccine among healthy children 6 to 24 months of age.", "[The immunogenic properties and prophylactic efficacy of a live polyvalent influenza vaccine in children 5 to 14 years old].", "Failure of inactivated influenza A vaccine to protect healthy children aged 6-24 months.", "Effectiveness and cost-benefit of influenza vaccination of healthy working adults: A randomized controlled trial.", "Improving compliance with immunization in the older adult: results of a randomized cohort study.", "[The investigation of the safety, genetic stability and immunogenicity of live influenza vaccine for adults in vaccination of 3-6 years old children].", "[Prophylactic effectiveness of a live recombinant influenza type A vaccine in immunizing children aged 3-14 years].", "[Immunization program against influenza for adults 65 years or older at a community pharmacy in Puerto Rico].", "Clinical reactions and serologic response following inactivated monovalent influenza type B vaccine in young children and infants.", "Influence of high-risk medical conditions on the effectiveness of influenza vaccination among elderly members of 3 large managed-care organizations.", "Effectiveness of influenza vaccine in reducing hospital admissions during the 1989-90 epidemic.", "Postcard reminders from GPs for influenza vaccine: are they more effective than an ad hoc approach?", "Study of the effectiveness of influenza vaccination in the elderly in the epidemic of 1989-90 using a general practice database.", "Protective effect of single-dose adjuvanted pandemic influenza vaccine in children.", "Comparison of three methods of recalling patients for influenza vaccination.", "Association of influenza immunization with reduction in mortality in an elderly population. A prospective study.", "[Evaluation of the safety, reactogenicity and antigenic activity of inactivated chromatographic influenza vaccine in school children].", "Effectiveness of influenza vaccination in preventing influenza-like illness among community-dwelling elderly: population-based cohort study in Japan.", "The impact of a public health nurse intervention on influenza vaccine acceptance.", "The telephone: an overlooked technology for prevention in family medicine.", "Increasing influenza vaccination among high-risk elderly: a randomized controlled trial of a mail cue in an HMO setting.", "Influenza vaccination in secondary prevention from coronary ischaemic events in coronary artery disease: FLUCAD study.", "Efficacy of repeated annual immunization with inactivated influenza virus vaccines over a five year period.", "A randomised, clinical trial comparing the effectiveness of hospital and community-based reminder systems for increasing uptake of influenza and pneumococcal vaccine in hospitalised patients aged 65 years and over.", "Vaccine effectiveness against laboratory-confirmed influenza in infants: A matched case control study.", "Immunogenicity and efficacy of Russian live attenuated and US inactivated influenza vaccines used alone and in combination in nursing home residents.", "Influenza vaccine effectiveness among elderly nursing home residents: a cohort study.", "The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community." ]	[ "To determine the efficacy of influenza vaccination in elderly people.\n Randomized double-blind placebo-controlled trial.\n Fifteen family practices in the Netherlands during influenza season 1991-1992.\n A total of 1838 subjects aged 60 years or older, not known as belonging to those high-risk groups in which vaccination was previously given.\n Purified split-virion vaccine containing A/Singapore/6/86(H1N1), A/Beijing/353/89(H3N2), B/Beijing/1/87, and B/Panama/45/90 (n = 927) or intramuscular placebo containing physiological saline solution (n = 911).\n Patients presenting with influenzalike illness up to 5 months after vaccination; self-reported influenza in postal questionnaires 10 weeks and 5 months after vaccination; serological influenza (fourfold increase of antibody titer between 3 weeks and 5 months after vaccination).\n The incidence of serological influenza was 4% in the vaccine group and 9% in the placebo group (relative risk [RR], 0.50; 95% confidence interval [CI], 0.35 to 0.61). The incidences of clinical influenza were 2% and 3%, respectively (RR, 0.53; 95% CI, 0.39 to 0.73). The effect was strongest for the combination of serological and clinical influenza (RR, 0.42; 95% CI, 0.23 to 0.74). The effect was less pronounced for self-reported influenza.\n In the elderly, influenza vaccination may halve the incidence of serological and clinical influenza (in periods of antigenic drift).", "Concern about side effects constitutes a major deterrent to patient compliance with influenza vaccination, yet there is a paucity of data about the occurrence of adverse reactions in the population targeted for immunization. We conducted a randomized, double-blind, crossover trial to compare the frequency of adverse reactions following administration of 1988-1989 trivalent split-antigen influenza vaccine and saline placebo. Outpatient veterans 65 years of age or over (n = 336) were recruited by mail and were randomly assigned to receive vaccine followed 2 weeks later by placebo injection or placebo followed 2 weeks later by vaccine. There was no significant difference between influenza vaccine and placebo with respect ot the proportion of subjects reporting disability or systemic symptoms.", "The aim of this study was to determine the cost effectiveness of influenza vaccination for healthy people aged 65-74 years living in the UK. People without risk factors for influenza (chronic heart, lung or renal disease, diabetic, immunosuppressed or those living in an institution) were identified from 20 general practitioner (GP) practices in Liverpool in September 1999. 729/5875 (12.4%) eligible individuals were recruited and randomised to receive either influenza vaccine or placebo (ratio 3:1), with all participants receiving 23-valent-pneumococcal polysaccharide vaccine unless already administered. The primary analysis was the frequency of influenza as recorded by a GP diagnosis of pneumonia or influenza like illness. In 2000, the UK vaccination policy was changed with influenza vaccine becoming available for all people aged 65 years and over irrespective of risk. As a consequence of this policy change, the study had to be fundamentally restructured and only results obtained over a one rather than the originally planned two-year randomised controlled trial framework were used. Results from 1999/2000 demonstrated no significant difference between groups for the primary outcome (relative risk 0.8, 95% CI 0.16-4.1). In addition, there were no deaths or hospitalisations for influenza associated respiratory illness in either group. The subsequent analysis, using both national and local sources of evidence, estimated the following cost effectiveness indicators: (1) incremental NHS cost per GP consultation avoided = 2000 pound sterling; (2) incremental NHS cost per hospital admission avoided = 61,000 pound sterling; (3) incremental NHS cost per death avoided = 1,900,000 pound sterling and (4) incremental NHS cost per QALY gained = 304,000 pound sterling. The analysis suggested that influenza vaccination in this population would not be cost effective.", "To assess the frequency and type of side effects after influenza vaccination in elderly people.\n Randomised double blind placebo controlled study.\n 15 general practices in the southern Netherlands.\n 1806 patients aged 60 or older, of whom 904 received influenza vaccine and 902 placebo.\n Adverse reactions reported on postal questionnaire completed four weeks after vaccination.\n 210 (23%) patients given vaccine reported one or more adverse reactions compared with 127 (14%) given placebo. The frequency of local adverse reactions were 17.5% in the vaccine group and 7.3% in the placebo group (p < 0.001). There was no difference in systemic adverse reactions (11% v 9.4%; p = 0.34). In general, men reported fewer side effects than women.\n Only local side effects were more common in vaccinated patients and all side effects were mild.", "Case-control study designed to determine the effectiveness of an MF59-adjuvanted influenza vaccine in the population aged 65 years and older living in the community. Detailed health histories were obtained on both cases and controls that included a functional measure of co-morbidity (Barthel Index). Subjects were all eligible persons admitted to various hospitals with a diagnosis of pneumonia during the winter months and were matched by sex, hospital and admission week to controls admitted for non-medical reasons. The influenza vaccination programme using the MF59-adjuvanted influenza vaccine significantly reduced the probability of being hospitalised for pneumonia in the elderly over 64 years of age, even in a season with a low influenza activity, during which the predominant circulating strains were types B and A (H1N1).", "We investigated the efficacy and safety of 1 versus 2 doses of live attenuated influenza vaccine (LAIV) in influenza vaccine-naive children aged 6 to <36 months.\n Subjects were randomized to 1 of 4 regimens in year 1: 2 doses LAIV, 1 dose LAIV, excipient placebo, or saline placebo. In year 2, LAIV recipients were to receive 1 dose of LAIV and placebo recipients were to receive saline placebo. Because of an unintended treatment allocation error in year 2, 1 block of subjects who were randomized to LAIV received saline placebo and 1 block who were randomized to placebo received LAIV.\n In year 1, vaccine efficacy versus placebo among recipients of 2 and 1 doses of LAIV was 73.5% and 57.7%, respectively, against antigenically similar strains. In year 2, absolute efficacy of a single dose of LAIV was 73.6% and 65.2%, respectively, in recipients of 2 and 1 doses of LAIV in year 1. Year 2 efficacy was 57.0% in subjects who received 2 doses of LAIV in year 1 and placebo in year 2. Safety and tolerability of LAIV were consistent with previous studies. Reactogenicity was similar between placebo groups. Seroconversion rates were significantly higher in the 2-dose versus the 1-dose LAIV group in year 1 and in both LAIV groups versus placebo in years 1 and 2.\n One dose of LAIV provided clinically significant protection against influenza in young children previously unvaccinated against influenza; 2 doses provided additional protection. Protection after 2 doses in year 1 persisted through a second season without revaccination. LAIV excipients were not a major contributor to reactogenicity. These benefits provide support for increased use of LAIV in children > or =2 years of age.", "This study aims to assess the effects of two interventions on influenza vaccination coverage: a simple organisational strategy, and making the vaccine available free.\n Sixteen general practitioners in the Auckland region were randomly selected to participate. Patients over 65 years of these general practitioners were randomly allocated to control, letter of invitation for a flu vaccine, or offer of a free flu vaccine. Administration of a flu vaccine for each person in the study was documented in each general practitioner surgery. Vaccine coverage for each of the three groups was measured.\n Results were available for 15 of the 16 participating general practitioners, a total of 2791 subjects. Immunisation coverage rates for control, letter of invitation and vaccine at no cost, were 17%, 27% and 45% respectively. Statistical analysis, allowing for the cluster method used to obtain subjects, showed risk ratios of 1.55 and 2.65 for the two interventions, with p values of < 0.00001.\n A potential source of bias in this study is underreporting of administration of vaccine to people in group 1. Notwithstanding this potential bias, both interventions were highly effective at increasing the uptake of influenza vaccine in the elderly population. General practitioners should be recommended to routinely invite patients over 65 years to have a flu vaccine. Given the commitment of the Ministry of Health to the vaccination against influenza of people over 65, this study would suggest that serious consideration should be given to making the vaccine available at no cost to this age group.", "This study was designed to evaluate the efficacy and safety of cold-adapted influenza vaccine, trivalent (CAIV-T) against culture-confirmed influenza in children 12 to <36 months of age during 2 consecutive influenza seasons at multiple sites in Asia.\n In year 1, 3174 children 12 to <36 months of age were randomized to receive 2 doses of CAIV-T (n = 1900) or placebo (n = 1274) intranasally > or =28 days apart. In year 2, 2947 subjects were rerandomized to receive 1 dose of CAIV-T or placebo.\n Mean age at enrollment was 23.5 +/- 7.4 months. In year 1, efficacy of CAIV-T compared with placebo was 72.9% [95% confidence interval (CI): 62.8-80.5%] against antigenically similar influenza subtypes, and 70.1% (95% CI: 60.9-77.3%) against any strain. In year 2, revaccination with CAIV-T demonstrated significant efficacy against antigenically similar (84.3%; 95% CI: 70.1-92.4%) and any (64.2%; 95% CI: 44.2-77.3%) influenza strains. In year 1, fever, runny nose/nasal congestion, decreased activity and appetite, and use of fever medication were more frequent with CAIV-T after dose 1. Runny nose/nasal congestion after dose 2 (year 1) and dose 3 (year 2) and use of fever medication after dose 3 (year 2) were the only other events reported significantly more frequently in CAIV-T recipients.\n CAIV-T was well tolerated and effective in preventing culture-confirmed influenza illness over multiple and complex influenza seasons in young children in Asia.", "To evaluate the efficacy of adding intranasal live attenuated cold-adapted influenza A vaccine to inactivated influenza vaccine to prevent influenza A in elderly residents of long-term-care institutions.\n Randomized, double-blind, placebo-controlled study conducted over 3 years.\n Three large nursing homes.\n A total of 523 residents of nursing homes (mean age, 84.2 years).\n All participants received trivalent inactivated influenza vaccine parenterally and were randomly assigned to receive either live attenuated influenza A (H3N2) virus vaccine or placebo intranasally.\n Laboratory-documented influenza A was defined as a respiratory illness plus isolation of influenza A virus from nasal secretions, significant serologic response, or both. Participants were considered to have been exposed to influenza A if they resided in an institution in which cases of influenza A were documented. Outbreak-associated illnesses were defined as those occurring between the first and last isolation of influenza virus from within the institution, +/- 3 days.\n Participants who received intranasal vaccine and were subsequently exposed to influenza A had significantly lower rates of laboratory-documented influenza A (9 of 162 vaccine recipients compared with 24 of 169 placebo recipients; vaccine protective efficacy, 60.6%; 95% CI, 18% to 82%), outbreak-associated respiratory illnesses (13 of 162 vaccine recipients compared with 34 of 169 placebo recipients; vaccine protective efficacy, 56.8%; CI 23% to 76%), and outbreak-associated influenza-like illnesses (6 of 162 vaccine recipients compared with 18 of 169 placebo recipients; vaccine protective efficacy, 65.0%; CI 17% to 86%).\n Intranasal immunization with live attenuated influenza A virus vaccine provided additional protection against influenza A when added to parenteral trivalent inactivated influenza vaccine among elderly nursing home residents.", "Our aim was to determine the efficacy of a trivalent inactivated split virus influenza vaccine (TIV) against culture-confirmed influenza A and/or B in adults 18 to 64 years of age during the 2005/2006 season in the Czech Republic.\n 6203 subjects were randomized to receive TIV (N = 4137) or placebo (N = 2066). The sample size was based on an assumed attack rate of 4% which provided 90% power to reject the hypothesis that vaccine efficacy (VE) was > or = 45%. Cases of influenza like illness (defined as fever (oral temperature > or =37.8 degrees C) plus cough and/or sore throat) were identified both by active (biweekly phone contact) and passive (self reporting) surveillance and nasal and throat swabs were collected from subjects for viral culture.\n TIV was well tolerated and induced a good immune response. The 2005/2006 influenza season was exceptionally mild in the study area, as it was throughout Europe, and only 46 culture-confirmed cases were found in the study cohort (10 influenza A and 36 influenza B). Furthermore among the B isolates, 35 were identified as B/Hong Kong 330/2001-like (B/Victoria/2/87 lineage) which is antigenically unrelated to the vaccine B strain (B/Yamagata/16/88 lineage). The attack rate in the vaccine group (0.7%) was not statistically significantly different from the attack rate in the placebo group (0.9%).\n Due to the atypical nature of the influenza season during this study we were unable to assess TIV efficacy. This experience illustrates the challenge of conducting a prospective influenza vaccine efficacy trial during a single season when influenza attack rates and drift in circulating strains or B virus lineage match can be difficult to estimate in advance.\n Clinical trial registery: NCT00197223.", "The effectiveness of influenza vaccination against hospitalization and death can only ethically be assessed in observational studies. A concern is that individuals who are vaccinated are healthier than individuals who are not vaccinated, potentially biasing estimates of effectiveness upward.\n We conducted a historical cohort study of individuals >64 years of age, for whom there were data available in the General Practice Research Database for 1989 to 1999 in England and Wales. Rates of admissions for acute respiratory diseases and rates of death due to respiratory disease were compared over 692,819 person-years in vaccine recipients and 1,534,280 person-years in vaccine nonrecipients.\n The pooled effectiveness of vaccine against hospitalizations for acute respiratory disease was 21% (95% confidence interval [CI], 17%-26%). The rate reduction attributable to vaccination was 4.15 hospitalizations/100,000 person-weeks in the influenza season. Among vaccine recipients, no important reduction in the number of admissions to the hospital was seen outside influenza seasons. The pooled effectiveness of vaccine against deaths due to respiratory disease was 12% (95% CI, 8%-16%). A greater proportionate reduction was seen among people without medical disorders, but absolute rate reduction was higher in individuals with medical disorders, compared with individuals without such disorders (6.14 deaths due to respiratory disease/100,000 person-weeks vs. 3.12 deaths due to respiratory disease/100,000 person-weeks). Clear protection against death due to all causes was not seen.\n Influenza vaccination reduces the number of hospitalizations and deaths due to respiratory disease, after correction for confounding in individuals >64 years of age who had a high risk or a low risk for influenza. For elderly people, untargeted influenza vaccination is of confirmed benefit against serious outcomes.", "There is little evidence that influenza vaccination reduces asthma exacerbations. We determined whether influenza vaccination is more effective than placebo in 6-18-year-old children with asthma. We performed a randomized, double-blind, placebo-controlled trial. Parenteral vaccination with inactivated influenza vaccine or placebo took place approximately November 1, and children were followed until April 1 of the next year. Airway symptoms were reported in a diary. When symptom scores reached a predefined level, a pharyngeal swab was taken. Primary outcome was the number of asthma exacerbations associated with virologically proven influenza infection. Three hundred forty-nine children were assigned placebo, and 347 were assigned vaccine. Pharyngeal swabs positive for influenza were related to 42 asthma exacerbations, 24 in the vaccine group and 18 in the placebo group, a difference of 33% favoring placebo (31% after adjustment for confounders; 95% confidence interval, -34% to 161%). Influenza-related asthma exacerbations were of similar severity in both groups; they lasted 3.1 days shorter in the vaccine group (95% confidence interval, -6.2 to 0.002 days, p = 0.06). We conclude that influenza vaccination did not result in a significant reduction of the number, severity, or duration of asthma exacerbations caused by influenza. Additional studies are warranted to justify routine influenza vaccination of children with asthma.", "Influenced by the Department of Health's aim to increase the uptake of the influenza immunization to 70% among those eligible, this study aimed to compare three methods of promoting influenza immunization among over 65 year old patients in a GP practice, and to identify if a particular promotion method was more effective among either of two defined age groups. The sample (n = 90) was randomly allocated into three intervention groups, and then subdivided into two age groups. A different subject experimental design was used to compare the groups. Statistical analysis of the data showed no significant difference in influenza immunization uptake between the three intervention groups, or the age-defined sub-groups. However, although not significant at 5% significance level, participants aged 72 years and over showed a greater uptake among those visited by a health professional. The findings suggest that a larger study using the same interventions would produce significant results.", "Despite current recommendations, many people with asthma do not receive annual vaccination against influenza, partly because of concern that vaccine may trigger exacerbations. Colds can trigger exacerbations, which may be mistaken for vaccine-related adverse events. We undertook a double-blind placebo-controlled multicentre crossover study to assess the safety of influenza vaccine in patients with asthma, with allowance for the occurrence of colds.\n We studied 262 patients, aged 18-75 years, who recorded daily peak expiratory flow (PEF), respiratory symptoms, medication, medical consultations, and hospital admissions for 2 weeks before the first injection and until 2 weeks after the second injection. Order of injection (vaccine and placebo) was assigned randomly. There was an interval of 2 weeks between injections. The main outcome measure was an exacerbation of asthma within 72 h of injection (defined as a fall in PEF of >20%).\n Among 255 participants with paired data, 11 recorded a fall in PEF of more than 20% after vaccine compared with three after placebo (McNemar's test p=0.06); a fall of more than 30% was recorded by eight after vaccine compared with none after placebo (binomial test p=0.008). However, when participants with colds were excluded, there was no significant difference in the numbers with falls of more than 20% between vaccine and placebo (six vs three; binomial test p=0.51), although the difference for PEF decreases of more than 30% approached significance (five vs none; binomial test, p=0.06). This association was confined to first-time vaccinees.\n Our findings indicate that pulmonary-function abnormalities may occur as a complication of influenza vaccination. However, the risk of pulmonary complications is very small and outweighed by the benefits of vaccination.", "Live attenuated, cold-adapted (ca) monovalent and bivalent influenza A vaccines were evaluated in seronegative infants (ages 6-18 months) in a double-blind placebo-controlled trial to assess safety and immunogenicity. A total of 182 seronegative subjects received a single intranasal dose (10(6.2) TCID50) of ca A/Kawasaki/9/86 (H1N1) or ca A/Los Angeles/2/87 (H3N2), both as a bivalent vaccine, or placebo. Respiratory and systemic symptoms did not differ between groups after vaccination. Hemagglutination antibody seroconversions (> or = 1:8) to H3N2 exceeded 90%. In contrast, seroconversions to A/Kawasaki/9/86 (H1N1) were significantly less frequent in bivalent ca vaccine recipients (31%) than in monovalent ca H1N1 recipients (83%) (P < .002). During a subsequent H3N2 epidemic, nasal washes were cultured for viruses from any subject with respiratory illness. H3N2 infections documented by virus isolation were reduced by 65% in ca H3N2 recipients compared with placebo or ca HIM recipients (P = .01).", "Controlled epidemiological surveillance covering the total number of 13,355 schoolchildren aged 11-14 years and adolescents was carried out with a view to compare the efficacies of inactivated influenza vaccines. The children were immunized intradermally in a single injection with inactivated influenza vaccines containing A (H3N2) and A (H1N1) hemagglutinins, 3.5 micrograms per 0.2 ml of the preparation each. The studies demonstrated the safety and low reactogenicity of these vaccines, as well as their high antigenic potency. In 1984 during mixed influenza B + A (H1N1) epidemic the preparations produced a pronounced prophylactic effect: the efficacy indices were 1.6-1.9 (p less than 0.001). The results obtained in these studies made it possible to recommend two inactivated influenza vaccines (chromatographic and centrifugal) for practical medicine with the aim of protecting children aged 11 years and over from influenza.", "1126 children, 2 months to 3 years old, received a single intranasal dose of 10(4), 10(6), or 10(7) TCID50 of cold adapted (ca) A/Kawasaki/9/86 (H1N1) and A/Beijing/352/89 (H3N2) or placebo, in a double blind, placebo-controlled, safety and immunogenicity trial. No reactogenicity attributable to vaccine was demonstrated. A single bivalent 10(6) or 10(7) dose produced high rates of seroconversion to H1N1 (77%) and H3N2 (92%) in seronegative children > 6 months old; serologic responses were lower to H1N1 (P < 0.001) and H3N2 (P = 0.01) in younger infants. A single 10(6) dose of bivalent ca influenza A vaccine can be immunogenic in children, but response is age dependent.", "Despite recommendations in most countries for giving inactivated influenza vaccine to people with asthma, only a minority currently receive it. One reason for low vaccine coverage has been concern that vaccination may induce exacerbations of asthma. In this randomized trial, 291 patients between 18 and 65 years of age received either an inactivated influenza vaccine followed 14 days later by a saline placebo or placebo followed by the vaccine. Each patient received 1 dose of vaccine and 1 dose of placebo. The percentage of patients reporting at least one asthma exacerbation within 14 days after injection was similar following vaccine or placebo (28.3% and 25.5%, respectively). The combined exacerbation rate during the first 14-day interval was higher (31.5%) than that during the second 14-day interval (22.4%, P = 0.0135), indicating that the occurrence of exacerbations was not likely to be related to the sequence of injections. The percentages of individuals with solicited systemic symptoms were 56.6% and 44.8% after vaccine or placebo injection, respectively. We conclude that influenza vaccination did not increase the incidence of asthma exacerbations compared to placebo in this study and the vaccine was well tolerated. The results thus support annual influenza vaccination in patients with asthma.", "A study was carried out in Newcastle to assess responses to influenza vaccines in elderly nursing home patients and in younger adults during 1983 and 1984. The decision to vaccinate the elderly subjects was made by their general practitioners. A concurrent randomized placebo-controlled trial of the same vaccine was performed in young adult volunteers. Elderly subjects generally possessed higher levels of pre-existing antibody to the influenzal haemagglutinins that were present in the vaccines than did younger subjects. The highest levels were observed in the 52-63 years' age group. Younger subjects showed significantly greater responses to vaccines compared with elderly subjects (P less than 0.05). Peak responses were noted in the 16-24 years' age group. Of a total of 326 elderly subjects (70% of whom had been vaccinated), six participants, two of whom had been vaccinated, contracted laboratory-proven influenza during 1983. Only one unvaccinated subject of a total of 365 subjects (50% of whom had been vaccinated) contracted influenza during 1984. In both years illness was produced by strain A/Philippines/2/82.", "The goal was to evaluate the safety, tolerability, and efficacy of an investigational, refrigerator-stable formulation of live attenuated influenza vaccine (cold-adapted influenza vaccine-trivalent) against culture-confirmed influenza, acute otitis media, and effectiveness outcomes in young children in day care over 2 consecutive influenza seasons.\n Children 6 to <36 months of age who were attending day care were assigned randomly in year 1 to receive 2 doses of vaccine or placebo intranasally, 35 +/- 7 days apart. In year 2, subjects received 1 dose of the same treatment as in year 1.\n A total of 1616 subjects (vaccine: 951 subjects; placebo: 665 subjects) in year 1 and 1090 subjects (vaccine: 640 subjects; placebo: 450 subjects) in year 2 were able to be evaluated for efficacy. The mean age at first vaccination was 23.4 +/- 7.9 months. In year 1, the overall efficacy of the vaccine against influenza subtypes similar to the vaccine was 85.4%; efficacy was 91.8% against A/H1N1 and 72.6% against B. In year 2, the overall efficacy was 88.7%; efficacy was 90.0% against H1N1, 90.3% against A/H3N2, and 81.7% against B. Efficacy against all episodes of acute otitis media associated with culture-confirmed influenza was 90.6% in year 1 and 97.0% in year 2. Runny nose or nasal discharge after dose 1 in year 1 was the only reactogenicity event that was significantly more frequent with cold-adapted influenza vaccine-trivalent (82.3%) than placebo (75.4%).\n Cold-adapted influenza vaccine-trivalent was well tolerated and effective in preventing culture-confirmed influenza illness in children as young as 6 months of age who attended day care.", "This study developed methods and determined the impact of influenza vaccination on elderly persons in 3 large health plans: Kaiser Permanente Northwest, HealthPartners, and Oxford Health Plans. Data for the 1996-1997 and 1997-1998 seasons were extracted from administrative databases. Subjects were health plan members > or = 65 years old. Comorbid conditions collected from the preceding year were used for risk adjustment with logistic regression. The virus-vaccine match was excellent for year 1 and fair for year 2. Both years, during peak and total periods, vaccination reduced all causes of death and hospitalization for pneumonia and influenza: hospitalizations were reduced by 19%-20% and 18%-24% for years 1 and 2, respectively, and deaths were reduced by 60%-61% and 35%-39% for the same periods. These results show that all elderly persons should be immunized annually for influenza. The methods used in this study are an efficient cost-effective way to study vaccine impact and similar questions.", "Acute otitis media (AOM) frequently complicates influenza infection. Previous studies have found influenza vaccine effective in reducing the occurrence of AOM in children mainly older than 2 years.\n To evaluate the effectiveness of inactivated influenza vaccine in preventing AOM in children aged 6 to 24 months.\n Randomized, double-blind, placebo-controlled trial of 786 children aged 6 to 24 months enrolled at Children's Hospital of Pittsburgh before the 1999-2000 (411 children) and 2000-2001 (375 children) respiratory seasons (defined as December 1 through March 31 of the respective following year). Children received influenza vaccine or placebo in a 2:1 ratio. The first cohort was observed for 1 year and the second cohort until the end of the ensuing respiratory season.\n Two doses (0.25 mL each) of inactivated trivalent subvirion influenza vaccine or placebo were administered intramuscularly approximately 4 weeks apart.\n Proportion of children who developed AOM, monthly occurrence rate of AOM, estimated proportion of time with middle ear effusion, and utilization of selected health care and related resources.\n Of the 66 children in the vaccine group from whom serum samples were collected, seroconversion against strains in the vaccine formulations developed in 88.6% to 96.8%, depending on the specific strain. The efficacy of the vaccine against culture-confirmed influenza was 66% (95% confidence interval [CI], 34%-82%) in 1999-2000 and -7% (95% CI, -247% to 67%) in 2000-2001; however, influenza attack rates differed between these 2 periods (in the placebo group, 15.9% and 3.3%, respectively). Compared with placebo, influenza vaccine did not reduce the proportion of children who had at least 1 episode of AOM during the respiratory season (in the first cohort: vaccine, 49.2% vs placebo, 52.2%; P =.56 ]; in the second cohort: vaccine, 55.8% vs placebo, 48.3%; P =.17). The vaccine also did not reduce the monthly rate of AOM; the estimated proportion of time with middle ear effusion; or the utilization of selected health care and related resources. There were also no differences between the vaccine and placebo groups regarding any of these outcomes during peak influenza periods. The vaccines administered to both cohorts of children were well tolerated.\n Administration of inactivated trivalent influenza vaccine to children aged 6 to 24 months did not reduce their burden of AOM or their utilization of selected health care and related resources.", "This study was carried out to investigate the effectiveness of influenza vaccine among 2913 children (1512 vaccinees and 1401 nonvaccinees) under 6 years of age during the 2002-2003 season. Study subjects were recruited from 54 paediatric clinics, located in eight areas in Japan. Maximum body temperatures were obtained weekly from parents between 2002 December 16 and 2003 April 13. Influenza-like illness (ILI) was defined as an acute febrile illness (> or =38.0 degrees C) during the peak epidemic period in each study area. The vaccine antigens included were A/New Caledonia/20/99(H1N1), A/Panama/2007/99(H3N2) and B/Shandong/7/97. Vaccine effectiveness was analyzed by comparing the frequencies of ILI between vaccinees and nonvaccinees. The adjusted odds ratio (OR) and its 95% confidence interval (95% CI) were calculated by the proportional odds model using logistic regression with three-level outcome variables (<38.0/38.0-38.9/> or =39.0 degrees C). A significantly decreased OR of vaccination was observed (OR: 0.76; 95% CI: 0.66-0.88), corresponding to a vaccine effectiveness (1-OR) of 24% (95% CI: 12%-34%). When the analysis was confined to those aged > or =2 years, a more pronounced OR (0.67, 0.56-0.79) was obtained with a vaccine effectiveness of 33% (21%-44%). On the other hand, no significant vaccine effectiveness was detected among very young children; the ORs were 1.84 (0.81-4.19) for those <1 year of age and 0.99 (0.72-1.36) for those 1.0-1.9 years of age and 1.07 (0.80-1.44) when these two age groups were combined. Thus, among very young children vaccine effectiveness could not be demonstrated.", "The uptake of influenza vaccination among older people is suboptimal. Contact with a doctor or nurse is associated with older people deciding to accept influenza vaccination.\n To compare different forms of approach in improving uptake of influenza vaccination among patients aged 75 years and over in primary care.\n Randomised controlled trial.\n One large rural general practice serving the town and surrounding area of Melton Mowbray, Leicestershire.\n All 2,052 patients aged 75 years and over, registered with the practice and not living in nursing/residential homes or sheltered accommodation, were included in the study. One-third of patients were randomised to receive an offer of influenza vaccination as part of an over-75 health check administered by a practice nurse in the patient's home, and two-thirds of patients were randomised to receive a personal letter of invitation to attend an influenza vaccination clinic held at the surgery. The main outcome measure was uptake of influenza vaccination.\n Six hundred and eighty patients were randomised to the health check arm of the trial and 1,372 were randomised to receive a personal letter. Of those randomised to the health check arm, 468 received the health check from the nurse. Overall, the difference in influenza vaccination uptake was 6.4% (95% confidence interval [CI] = 2.2% to 10.4%) with 67.9% (n = 932) of those who were sent a personal letter actually receiving the vaccine, compared with 74.3% (n = 505) of those offered a combined health check and influenza vaccination (P = 0.003).\n Combining home-based over- 75 health checks with influenza vaccination can improve uptake among older patients. However this intervention is likely to be costly and its effect on influenza vaccination rates is modest. The difference in uptake is greater among those who do not routinely comeforwardfor vaccination and a more viable option may be to target these patients.", "To determine the clinical efficacy and cost-saving effect of pneumococcal polysaccharide vaccine (PPV) against community-acquired pneumonia (CAP), an open-label, randomized clinical trial was conducted involving 786 Japanese subjects older than 65 years of age receiving a routine influenza vaccine during the 2-year period. Study subjects were randomly assigned to either a PPV group (n=394) or to a non-PPV group (n=392). The incidence, admission and the medical cost for all-cause pneumonia were compared between these two groups. PPV vaccination significantly reduced the incidence of admission for all-cause pneumonia for subjects older than 75 years of age (41.5%, P=0.039) and for those who had difficulty walking (62.7%, P=0.005), but not for all study subjects older than 65 years of age (P=0.183), for the 2-year period. The Kaplan-Meier survival curves for subjects who had difficulty walking free from all-cause pneumonia demonstrated a significant difference (P=0.0146) between the two groups. PPV vaccination significantly reduced medical costs for all study subjects during the first year period (P=0.027). Our present data demonstrated that PPV was effective for all-cause pneumonia for study subjects older than 75 years of age, although the effect was not significant for all study subjects older than 65 years of age.\n Copyright © 2010 Elsevier Ltd. All rights reserved.", "The effect of influenza vaccination on the occurrence and severity of influenza virus infection in a population residing in nursing homes was studied through a program by the Osaka Prefectural Government, which is the first and official support for influenza vaccination of the elderly population during an influenza A (H3N2) epidemic in JAPAN:\n A cohort study located in the Osaka Prefecture, Japan, followed the outcomes of elderly nursing home residents who received influenza vaccinations (n = 10,739) in comparison with control subjects who did not receive influenza vaccinations (n = 11,723) and monitored clinically the onset of serious morbidity and mortality of influenza illness. Subjects were 22,462 persons older than 65 years who resided in 301 welfare nursing homes in the Osaka Prefecture, Japan during an influenza A (H3N2) epidemic in 1998 to 1999.\n Of 22,462 individuals living in 301 nursing homes, 10,739 received either one dose (2027 subjects) or two doses (8712 subjects) of inactivated, subunit trivalent influenza vaccine. Through the period from November 1998 to March 1999, there were 950 cases of influenza infection diagnosed clinically with cases by virus isolation and/or serology. There were statistically significantly fewer clinical cases of influenza, hospital admissions due to severe infection, and deaths due to influenza in the vaccinated cohort (256 cases, 32 hospital admissions, and one death) compared with the unvaccinated controls (694 cases, 150 hospital admissions, and five deaths). Vaccination was equally effective in those who received one dose of vaccine as in those who received two doses. No serious adverse reactions to vaccination were recorded. Thus, influenza vaccination is safe and effective in this population and should be an integral part of the routine care of persons aged 65 years and older residing in nursing homes.\n This study provides an analysis of the clinical efficacy of influenza vaccination in a large cohort of nursing home residents in JAPAN: Annual influenza vaccine administration requires the attention of all nursing home attendants, physicians, and public health organizations.", "Reported is a study of live, cold-adapted (CA) reassortant mono-, di-, and trivalent influenza type A and B vaccines in a series of controlled clinical and epidemiological investigations involving nearly 130 000 children aged 3-15 years. The results of clinical, immunological, and morbidity investigations of the vaccinees and a control group over 6-months' follow-up indicated that the vaccines were completely attenuated by the children. Transient febrile reactions occurred in < 1% of the children after vaccination, including double seronegative individuals with low antibody titres. The type A reisolates examined were genetically stable. The reassortants did not suppress each other after simultaneous inoculation of children and stimulated antibody response to influenza virus strains A1, A3, and B. The incidence of influenza-like diseases was approximately 30-40% lower among the vaccinated group than among the control group. The study demonstrates, for the first time, the efficacy of CA vaccine against infections caused by influenza B virus.", "The effectiveness of the influenza vaccine used in the 2001-2002 influenza season in Japan was investigated in a large-scale, geographically widely distributed, Internet-based study. Data were collected from 8841 of 9902 subjects registered by 38 clinics prior to the start of influenza season. Subjects were categorized into three groups by vaccination regimen: unvaccinated, vaccinated once, and vaccinated twice. Efficacy was also analyzed for three age groups: 0-15, 16-64, and 65-104 years. Influenza-like illness (ILI) was diagnosed according to Ministry of Health (MWH, Labor and Welfare in Japan) criteria. Laboratory-confirmed influenza cases were analyzed separately. The respective vaccine efficacy in the 0-15 years group for the one- and two-dose regimens was 67.6 and 84.5% for ILI and 54.0 and 79.8% for laboratory-confirmed influenza. Influenza vaccination was also shown to be effective in subjects 16-64 years. Vaccine effectiveness was not able to be determined for the over 65 years group, probably due to an insufficient number of infected patients. These results suggest that influenza vaccination is effective for children and adults and that a two-dose regimen is superior to a single dose in children 0-15 years.", "Assess the effectiveness of influenza vaccination in reducing hospitalization due to pneumonia and influenza among elderly subjects in a community in central Italy. Estimate the hospitalization fraction preventable by extending the vaccination program.\n Case-control study. Cases were subjects aged 65+ at hospital admission (1 December 1994-31 March 1995). For each case two population controls were randomly chosen, matched by sex, age and residence. Variables of interest were recorded through a postal questionnaire and telephone interview. A matched-set analysis was carried out adjusting for concomitant chronic diseases, education, type of home heating, and smoking habits. The preventable fraction of hospitalization was computed through the application of the attributable risk estimate. The setting was 33 municipalities in central Italy including 169,370 residents aged 65 years or more.\n Two hundred and seventy-five cases 550 controls were analyzed. Influenza vaccination was effective in preventing 33% of hospitalization due to pneumonia/influenza. The fraction of hospital admissions preventable by extending the vaccination was 17%. When the analysis was limited to self-respondents to the questionnaire (excluding next-of-kin) and to pneumonia/influenza as primary discharge diagnosis, protection from hospitalization by vaccination almost reached 50%, a better result in comparison with most case-control studies.\n Influenza vaccination was shown to be successful in reducing hospital admissions due to pneumonia and influenza. A large number of hospitalizations could be reduced extending the vaccination campaign.", "To determine the effectiveness of influenza vaccination on influenza-related acute respiratory illness (ARI) and overall ARI in patients with COPD, and its relationship to the degree of airflow obstruction.\n Stratified, randomized, double-blind, placebo-controlled trial.\n From June 1997 to November 1998 at a single university hospital. Patients and interventions: One hundred twenty-five patients with COPD were stratified based on their FEV(1) as having mild, moderate, and severe COPD. Within each group, they were randomized to the vaccine group (62 patients who received purified, trivalent, split-virus vaccine) or the placebo group (63 patients).\n The number of episodes and severity of total ARI, classified as outpatient treatment, hospitalization, and requirement of mechanical ventilation; and the number of episodes and severity of influenza-related ARI.\n The incidence of influenza-related ARI was 28.1 per 100 person-years and 6.8 per 100 person-years in the placebo group and vaccine group, respectively (relative risk [RR], 0.24 [p = 0.005]; vaccine effectiveness, 76%). The incidences were 28.2, 23.8, and 31.2 per 100 person-years in the patients with mild, moderate, and severe COPD, respectively, in the placebo group, and 4.5, 13.2, and 4.6 per 100 person-years in the patients with mild, moderate, and severe COPD, respectively, in the vaccine group (RR, 0.16 [p = 0.06]; vaccine effectiveness, 84%; RR, 0.55 [p = 0.5]; vaccine effectiveness, 45%; and RR, 0.15 [p = 0.04]; vaccine effectiveness, 85%, in the patients with mild, moderate, and severe COPD, respectively). Bivariate analysis revealed that the effectiveness of influenza vaccination was not modified by the severity of COPD, comorbid diseases, age, gender, or current smoking status. There was no difference in the incidence or severity of total ARI between the placebo group and the vaccine group.\n Influenza vaccination is highly effective in the prevention of influenza-related ARI regardless of the severity of COPD. Influenza vaccination does not prevent other ARIs unrelated to influenza. The effectiveness of influenza vaccination in the prevention of overall ARI in patients with COPD will depend on how much the proportion of influenza-related ARI contributes to the incidence of total ARI. Influenza vaccination should be recommended to all patients with COPD.", "An Advisory Committee on Immunization Practices policy of encouraging influenza vaccination for healthy 6- to 23-month-old children was in effect during the 2003-2004 influenza season, which was unusually severe in Colorado. We collaborated with 5 pediatric practices to attempt universal influenza immunization in this age group.\n The objectives were (1) to assess the maximal influenza immunization rates that could be achieved for healthy young children in private practice settings, (2) to evaluate the efficacy of registry-based reminder/recall for influenza vaccination, and (3) to describe methods used by private practices to implement the recommendations.\n The study was conducted in 5 private pediatric practices in Denver, Colorado, with a common billing system and immunization registry. Although recommendations by the Advisory Committee on Immunization Practices included children who were 6 to 23 months of age at any point during the influenza season, our practices chose not to recall children 22 to 23 months of age, because they would have become >24 months of age during the study period. Therefore, our study population consisted of all healthy children 6 to 21 months of age from the 5 practices (N = 5193), who were randomized to intervention groups (n = 2595) that received up to 3 reminder/recall letters or to control groups (n = 2598) that received usual care. The primary outcome was receipt of >or=1 influenza immunization, as noted either in the immunization registry or in billing data.\n Immunization rates for >or=1 dose of influenza vaccine for the intervention groups in the 5 practices were 75.9%, 75.4%, 68.1%, 55.6%, and 44.3% at the end of the season. Overall, 62.4% of children in the intervention groups and 58.0% of children in the control groups were immunized (4.4% absolute difference), with absolute differences, compared with control values, ranging from 1.0% to 9.1% according to practice. However, before intensive media coverage of the influenza outbreak began (November 15, 2003), absolute differences, compared with control values, ranged from 5.1% to 15.3% and were 9.6% overall. Before November 15, significant effects of recall were seen for children in the intervention groups, in both the 12- to 21-month age category (10.4% increase over control) and the 6- to 11-month category (8.1% increase over control); at the end of the season, however, significant effects of recall were seen only for the older age group (6.2% increase over control). The rates of receipt of 2 vaccine doses >or=1 month apart for eligible children ranged from 21% to 48% among the practices. Four of the 5 practices held influenza immunization clinics during office hours, evenings, or weekends, and these clinics achieved higher coverage rates.\n These results demonstrated that, in an epidemic influenza year, private practices were able to immunize the majority of 6- to 21-month-old children in a timely manner. Although media coverage regarding the epidemic blunted the effect of registry-based recall, recall was effective in increasing rates early in the epidemic, especially for children between 1 and 2 years of age. The practices that achieved the highest immunization rates were proactive in planning influenza clinics to handle the extra volume of immunizations required.", "In healthy adults influenza immunization reduces absenteeism caused by respiratory infections, but data on its efficacy among health care workers are scarce.\n To determine the effect of the conventional inactivated influenza A vaccine on reducing absenteeism related to respiratory infections among pediatric health care providers.\n A randomized, placebo-controlled, double blind study on vaccine efficacy was conducted in two pediatric hospitals during the winter season 1996 to 1997. The primary endpoint was days of work lost from the hospital because of respiratory infections. The documentation of absenteeism was based on personal sickness logs.\n Of the 547 randomized vaccinees 427 (78%) persons completed the 4-month follow-up and returned the sickness logs. Immunization failed to reduce episodes of respiratory infections (1.8 episodes/study period among vaccinees vs. 2.0 among controls). Similarly the vaccine failed to affect the total number of days the vaccinees suffered from respiratory infections (13.5 days vs. 14.6 days, respectively). However, days of work lost because of respiratory infections (1.0 days vs. 1.4 days, respectively, P = 0.02) and especially total numbers of days the study persons felt themselves unable to work when either on or off duty (2.5 days vs. 3.5 days, P 0.02) were significantly decreased.\n Influenza vaccination reduced absenteeism related to respiratory infections by 28%. We therefore believe that routine annual influenza immunizations should be recommended to health care providers working in pediatric settings.", "To test the hypothesis that a micronutrient supplement can improve seroconversion after influenza immunization in older institutionalized people.\n : Randomized, double-blind, placebo-controlled study.\n Nursing and residential homes in Liverpool, United Kingdom.\n One hundred sixty-four residents aged 60 and older from 31 homes were initially randomized; of these, 119 (72.6%) completed the study.\n Participants were randomized to receive a micronutrient supplement providing the reference nutrient intake for all vitamins and trace elements or identical placebo. Tablets were taken over an 8-week period during September and October 2000; influenza vaccine was administered 4 weeks after their commencement.\n The hemagglutination-inhibiting antibody response as defined by a fourfold or greater titer rise over 4 weeks and assessed separately for each of the three antigens contained in the 2000/2001 influenza vaccine (A/New Caledonia/20/99 (H1N1), A/Moscow/10/99 (H3N2), B/Beijing/184/93 (B)).\n Despite a significant increase in serum concentrations of vitamins A, C, D3, E, folate, and selenium in the supplemented group, there was no significant difference between groups (supplemented vs placebo, respectively) in the proportion of participants seroconverting to H1N1 (41% vs 49%, P=.374), H3N2 (49% vs 58%, P=.343), or B (41% vs 40%, P=.944).\n A micronutrient supplement providing the reference nutrient intake administered over 8 weeks had no beneficial effect on antibody response to influenza vaccine in older people living in long-term care.", "The goal of this pediatric clinical trial was to assess the safety and immunogenicity of two different doses of a monovalent inactivated pandemic (H1N1) 2009 vaccine in US children aged 6 months to 9 years of age. Randomized, observer-blinded, US multicenter phase 2 study assessing 2 doses of vaccine given 21 days apart in 474 children aged 6-35 months or 3-9 years. Children in each age group were randomly assigned to receive either a pandemic (H1N1) 2009 vaccine containing 7.5 or 15 μg of hemagglutinin (HA) or placebo in a 4:4:1 ratio. Primary outcome was hemagglutination inhibition (HI) antibody responses 21 days following each vaccination. Safety was monitored throughout the study. The first dose of either A H1N1 vaccine formulation was more immunogenic in children older than 3 years than in younger children. 45-50% of children aged 6-35 months and 69-75% of children aged 3-9 year-old attained HI titers of ≥ 1:40. A second dose of A H1N1 vaccine further increased HI antibody responses with seroprotection and seroconversion rates reaching 90-99% in both age groups. Interestingly, the pandemic (H1N1) 2009 vaccine formulations elicited similar rates of solicited and unsolicited injection site and systemic reactions as the placebo. The data therefore demonstrate the high level immunogenicity in infants and children of an (H1N1) 2009 influenza vaccine displaying a safety and reactogenicity profile similar to placebo.\n Copyright © 2011 Elsevier Ltd. All rights reserved.", "To evaluate the effectiveness and possible cost savings of influenza vaccination.\n Members age 65 and older in a Medicare managed care plan during the 1994-1995, 1995-1996, and 1996-1997 influenza seasons.\n The study examined administrative data on influenza vaccination and subsequent hospitalizations. Outcomes included hospitalization with pneumonia or influenza, with any respiratory condition, and with congestive heart failure (CHF).\n Vaccinated subjects experienced fewer hospitalizations with respiratory conditions or CHF than had unvaccinated subjects (OR=0.8 (95% CI, 0.7, 0.9) in analyses adjusted for age, sex, pneumococcal vaccination, health utilization, and morbidity). Analyses adjusted in addition for ethnicity obtained similar results among the subgroup of members whose ethnicity was known. Subjects without major disease in the previous 12 months had lower odds ratios for vaccination than subjects with major disease (OR values of 0.5 [95% CI, 0.4, 0.7] and 0.9 [95% CI, 0.8, 1.1], respectively). Subjects ages 65 to 79 had lower odds ratios for vaccination than subjects ages 80 and older (OR values of 0.7 [95% CI, 0.6, 0.9] and 0.9 [95% CI, 0.8, 1.1], respectively). Estimated cost savings averaged about $80 per vaccinated subject.\n Subjects ages 65 to 79 who had received influenza vaccination experienced fewer hospitalizations and had lower costs than had unvaccinated subjects. Associations were weaker for subjects age 80 and older. The results, consistent with recommendations for the use of influenza vaccine, suggest that people ages 65 to 79 should be heavily targeted for vaccination.", "During the winter of 1989-1990, influenza type A(H3N2) circulated widely, causing excess morbidity and mortality nationwide. From November through April, 1989-1990, hospitalized cases of pneumonia and influenza occurring among noninstitutionalized individuals 65 or more years of age were identified by 20 acute care hospitals in southern lower Michigan. These cases were group matched on age, sex, race, and zip code to randomly sampled, community-based controls from a comprehensive listing of Medicare beneficiaries residing in the study area. Self-reported data were collected from cases and controls on influenza vaccine status for the 1989-1990 season and on a number of other factors which could have influenced vaccination status or outcome. Questionnaires were completed by 1,907 individuals, 449 of whom were cases, resulting in an overall response rate of 76%. A community-based influenza surveillance system was implemented to determine the timing and intensity of viral activity and influenza-like illness. Vaccine effectiveness in preventing overall pneumonia and influenza hospitalizations was estimated by logistic regression. During the 3-month period of surveillance-confirmed peak influenza type A(H3N2) circulation, vaccine effectiveness was 45% (95% confidence interval 14-64, p = 0.009). However, during the 3-month period of low or absent virus activity, identical methodology and model specification resulted in an effectiveness estimate of 21% that was not statistically different from zero (p = 0.36). The effectiveness determined during the peak period of virus circulation is felt to be a conservative estimate, since agents other than influenza are responsible for pneumonia and influenza hospitalizations, even during times of peak influenza activity.", "To study the efficacy of pneumococcal capsular polysaccharide vaccine among the elderly by use of a population-based intervention in one township, Varkaus, Eastern Finland.\n A randomized, controlled trial in which elderly inhabitants (aged 60 years or older) of the catchment area were randomized to receive either pneumococcal and influenza vaccines (PI group = vaccinated) or influenza vaccine alone (I group = controls) and offered participation. The response rate was 67.4%. The PI group consisted of 1,364 persons and the I group of 1,473 persons. The vaccinations were performed in the municipal health center in the fall of 1982, and all elderly inhabitants were followed for 3 years for the development of radiologically confirmed pneumonia. Pneumococcal etiology was identified by serological methods.\n The incidence of pneumonia was 18.8 per 1,000 person-years in the PI group (73 pneumonia episodes) and 16.6 per 1,000 person-years in the I group (69 episodes). Pneumococcal etiology was found in 27 episodes in the PI group (incidence 7.0 per 1,000 person-years) and in 36 episodes in the I group (incidence 8.6 per 1,000 person-years). In controls (I group) the incidence of pneumococcal pneumonia was significantly higher among persons with increased risk for contracting pneumonia (19 per 1,000 person-years) than among controls with low risk status (4 per 1,000 person-years). No significant protection from pneumococcal pneumonia was found in the study group as a whole (vaccine efficacy 15%, 95% CI -43% to 50%). However, in persons with medical risk factors for contracting pneumonia, there was a statistically significant protective efficacy of 59% (95% CI, 6% to 82%).\n Pneumococcal vaccination significantly reduced the incidence of pneumococcal pneumonia in elderly persons at increased risk for contracting pneumonia. This increased/high-risk category comprised 34% of the population aged 60 years or older. Because targeted vaccination of this large group may be difficult to organize in an efficient manner, vaccinating all elderly persons may be the best strategy to prevent this rather common and often fatal disease.", "In a strictly controlled epidemiological trial on 12,643 school children aged 11-14 years the reactogenic properties and safety of killed influenza chromatographic vaccine under the conditions of multiple immunization were studied. A single immunization dose of the vaccine (0.2 ml) contained the hemagglutinins of influenza viruses A/Philippines/82 (H3N3) and A/Kiev/59/79 (H1N1), 3.5 micrograms each. The preparation was introduced by means of a jet injector. The vaccine was shown to be clinically and immunologically safe under the conditions of the regular multiple immunization of children over the period of 4 years.", "Influenzavirus vaccine is used infrequently in healthy children, even though the rates of influenza in this group are high. We conducted a multicenter, double-blind, placebo-controlled trial of a live attenuated, cold-adapted, trivalent influenzavirus vaccine in children 15 to 71 months old.\n Two hundred eighty-eight children were assigned to receive one dose of vaccine or placebo given by intranasal spray, and 1314 were assigned to receive two doses approximately 60 days apart. The strains included in the vaccine were antigenically equivalent to those in the inactivated influenzavirus vaccine in use at the time. The subjects were monitored with viral cultures for influenza during the subsequent influenza season. A case of influenza was defined as an illness associated with the isolation of wild-type influenzavirus from respiratory secretions.\n The intranasal vaccine was accepted and well tolerated. Among children who were initially seronegative, antibody titers increased by a factor of four in 61 to 96 percent, depending on the influenza strain. Culture-positive influenza was significantly less common in the vaccine group (14 cases among 1070 subjects) than the placebo group (95 cases among 532 subjects). The vaccine efficacy was 93 percent (95 percent confidence interval, 88 to 96 percent) against culture-confirmed influenza. Both the one-dose regimen (89 percent efficacy) and the two-dose regimen (94 percent efficacy) were efficacious, and the vaccine was efficacious against both strains of influenza circulating in 1996-1997, A(H3N2) and B. The vaccinated children had significantly fewer febrile illnesses, including 30 percent fewer episodes of febrile otitis media (95 percent confidence interval, 18 to 45 percent; P<0.001).\n A live attenuated, cold-adapted influenzavirus vaccine was safe, immunogenic, and effective against influenza A(H3N2) and B in healthy children.", "Although influenza causes substantial morbidity and mortality in all age groups, current recommendations emphasize annual immunization for people at high risk for complications of influenza. We conducted a double-blind, placebo-controlled trial of vaccination against influenza in healthy, working adults.\n In the fall of 1994, we recruited working adults from 18 to 64 years of age from in and around the Minneapolis-St. Paul area and randomly assigned them to receive either influenza vaccine or placebo injections. The primary study outcomes included upper respiratory illnesses, absenteeism from work because of upper respiratory illnesses, and visits to physicians' offices for upper respiratory illnesses. The economic benefits of vaccination were analyzed by estimating the direct and indirect costs associated with immunization and with upper respiratory illnesses.\n We enrolled a total of 849 subjects. Baseline characteristics were similar in the two groups. During the follow-up period, consisting of the 1994-1995 influenza season (December 1, 1994, through March 31, 1995), those who received the vaccine reported 25 percent fewer episodes of upper respiratory illness than those who received the placebo (105 vs. 140 episodes per 100 subjects, P < 0.001), 43 percent fewer days of sick leave from work due to upper respiratory illness (70 vs. 122 days per 100 subjects, P = 0.001), and 44 percent fewer visits to physicians' offices for upper respiratory illnesses (31 vs. 55 visits per 100 subjects, P = 0.004). The cost savings were estimated to be $46.85 per person vaccinated.\n Vaccination against influenza has substantial health-related and economic benefits for healthy, working adults.", "Influenza virus is a major cause of illness, disruption to daily life, and increased use of health care in all age groups.\n To assess the safety and effectiveness of intranasally administered trivalent, live, attenuated influenza virus (LAIV) vaccine for reducing illness, absenteeism, and health care use among healthy, working adults.\n Randomized, double-blind, placebo-controlled trial conducted from September 1997 through March 1998.\n Thirteen centers across the United States.\n A total of 4561 healthy, working adults aged 18 to 64 years recruited through health insurance plans, at work sites, and from the general population.\n Participants were randomized 2:1 to receive intranasally administered trivalent LAIV vaccine (n = 3041) or placebo (n = 1520) in the fall of 1997.\n Episodes of febrile illness, severe febrile illness, febrile upper respiratory tract illness, work loss, and health care use during the peak and total influenza outbreak periods, and adverse events.\n Recipients of LAIV vaccine were as likely to experience 1 or more febrile illnesses as placebo recipients during peak outbreak periods (13.2% for vaccine vs 14.6% for placebo; P=.19). However, vaccination significantly reduced the numbers of severe febrile illnesses (18.8% reduction; 95% confidence interval [CI], 7.4%-28.8%) and febrile upper respiratory tract illnesses (23.6% reduction; 95% CI, 12.7%-33.2%). Vaccination also led to fewer days of illness across all illness syndromes (22.9% reduction for febrile illnesses; 27.3% reduction for severe febrile illnesses), fewer days of work lost (17.9% reduction for severe febrile illnesses; 28.4% reduction for febrile upper respiratory tract illnesses), and fewer days with health care provider visits (24.8% reduction for severe febrile illnesses; 40.9% reduction for febrile upper respiratory tract illnesses). Use of prescription antibiotics and over-the-counter medications was also reduced across all illness syndromes. Vaccine recipients were more likely to experience runny nose or sore throat during the first 7 days after vaccination, but serious adverse events between the groups were not significantly different. The match between the type A(H3N2) vaccine strain and the predominant circulating virus strain (A/Sydney/05/97[H3N2]) for the 1997-1998 season was poor, suggesting that LAIV provided substantial cross-protection against this variant influenza A virus strain.\n Intranasal trivalent LAIV vaccine was safe and effective in healthy, working adults in a year in which a drifted influenza A virus predominated.", "The objective of this study was to assess the safety of routine trivalent influenza vaccine (TIV) administration among healthy children 6 through 23 months of age, after the Advisory Committee on Immunization Practices recommendation.\n The study was a retrospective case-control study of children receiving TIV in the first 2 seasons after the Advisory Committee on Immunization Practices recommendation. We assessed outcomes in the 42 days after vaccination in a population of 13,383 children. Each case subject was matched, according to age and gender, with 3 control subjects. Hazard ratios were calculated with conditional logistic regression analysis.\n We found no statistically significantly elevated hazard ratios for the first TIV dose. An elevated risk of pharyngitis was found for children receiving a second TIV dose. No elevated risk of seizure was found.\n These results, for a population of healthy children, showed no medically significant adverse events related to TIV among children 6 to 23 months of age.", "Production lots of a live influenza vaccine made of strains A/47/T (N1H1), A/47/6/2 (H3N2), and B/60/32 were used for vaccination of 3663 children aged from 5 to 14 years inoculated twice with monovaccines, a trivaccine made of the above strains, or placebo. Both mono- and polyvaccine were practically areactogenic. An average per cent of subjects with a significant rise in antibody titres to the respective three antigens was 60%. The efficacy of the vaccination was 31.0-42.8% for monopreparations and 36.3% for the trivaccine. The studies showed the possibility and expedience of using for children the live influenza vaccine in the form of a polyvalent preparation including current influenza type A and B viruses.", "The efficacy of inactivated influenza vaccine in healthy infants and children younger than 24 months has not been confirmed. The aim of the present study was to determine the prophylactic effect of inactivated influenza vaccine against influenza A in healthy children aged 6-24 months.\n Healthy infants and young children (6-24 months old) were immunized by subcutaneous injection of inactivated influenza vaccine before influenza seasons. Age matched children were randomly assigned as the control. These children were followed up from January to April in each year (2000, 2001 and 2002). The attack rates of influenza A infection was compared and statistically assessed.\n The attack rate of influenza A virus infection in the vaccine group and the control group were 14.8% (n = 27) vs 12.5% (n = 32) in 2000 (P = 0.526); 2.8% (n = 72) vs 7.2% (n = 69) in 2001 (P = 0.203); and 3.4% (n = 52) vs 8.9% (n = 56) in 2002 (P = 0.205). The attack rates of influenza A between the two groups were not significantly different.\n Inactivated influenza vaccine did not reduce the attack rate of influenza A infection in 6-24 month old children.", "Although the cost-effectiveness and cost-benefit of influenza vaccination are well established for persons aged 65 years or older, the benefits for healthy adults younger than 65 years are less clear.\n To evaluate the effectiveness and cost-benefit of influenza vaccine in preventing influenza-like illness (ILI) and reducing societal costs of ILI among healthy working adults.\n Double-blind, randomized, placebo-controlled trial conducted during 2 influenza seasons.\n Healthy adults aged 18 to 64 years and employed full-time by a US manufacturing company (for 1997-1998 season, n = 1184; for 1998-1999 season, n = 1191).\n For each season, participants were randomly assigned to receive either trivalent inactivated influenza vaccine (n = 595 in 1997-1998 and n = 587 in 1998-1999) or sterile saline injection (placebo; n = 589 in 1997-1998 and n = 604 in 1998-1999). Participants in 1997-1998 were rerandomized if they participated in 1998-1999.\n Influenza-like illnesses and associated physician visits and work absenteeism reported in biweekly questionnaires by all participants, and serologically confirmed influenza illness among 23% of participants in each year (n = 275 in 1997-1998; n = 278 in 1998-1999); societal cost of ILI per vaccinated vs unvaccinated person.\n For 1997-1998 and 1998-1999, respectively, 95% (1130/1184) and 99% (1178/1191) of participants had complete follow-up, and 23% in each year had serologic testing. In 1997-1998, when the vaccine virus differed from the predominant circulating viruses, vaccine efficacy against serologically confirmed influenza illness was 50% (P =.33). In this season, vaccination did not reduce ILI, physician visits, or lost workdays; the net societal cost was $65.59 per person compared with no vaccination. In 1998-1999, the vaccine and predominant circulating viruses were well matched. Vaccine efficacy was 86% (P =.001), and vaccination reduced ILI, physician visits, and lost workdays by 34%, 42%, and 32%, respectively. However, vaccination resulted in a net societal cost of $11.17 per person compared with no vaccination.\n Influenza vaccination of healthy working adults younger than 65 years can reduce the rates of ILI, lost workdays, and physician visits during years when the vaccine and circulating viruses are similar, but vaccination may not provide overall economic benefits in most years. JAMA. 2000;284:1655-1663.", "To compare three approaches for improving compliance with influenza and pneumococcal vaccination of elderly patients.\n Randomized controlled trial using three parallel group practices at a public urban teaching hospital.\n Public teaching hospital.\n All patients 65 years of age and older (n = 1202) seen by resident physicians (n = 66) attending three ambulatory medical practices from October 1, 1989 to March 31, 1990.\n All three provider groups received intensive education in immunization standards. The control group received no further intervention. Staff in the second group offered education to patients at their visits. In the third group, the prevention team, a flowsheet was used, patient education offered, and staff had their tasks redefined to facilitate compliance; for vaccinations, eg, nurses could vaccinate independent of MD initiative.\n Medical records were reviewed for the 1202 patients seen, including 756 patients seen during both the 1988-89 and 1989-90 influenza seasons, to determine documented offering and receipt of vaccinations. During the intervention period (1989-90), influenza vaccinations were offered significantly more frequently to prevention team patients (68.3%) than to patients in either the patient education (50.4%) or control (47.6%) groups (P = 0.006), even after adjusting for the patients' prior vaccination status, age, gender, race, and high-risk co-morbidity and for physicians' level of training. Likewise, pneumococcal vaccinations were offered more frequently to previously unvaccinated prevention team patients (28.3%) than to patient education (6.5%) or control (5.4%) group patients (P = 0.001), even after adjusting for the factors using multivariate analysis. Compliance rates did not differ between patient education and control subjects for either vaccine. Pre-intervention physician surveys documented higher perceived than actual compliance for both vaccines, with 89.0% and 52.8% of physicians believing that they complied with influenza and pneumococcal vaccination guidelines, respectively.\n The results of this trial provide strong support for organizational changes that involve non-physician personnel to enhance vaccination rates among older adults.", "The study of the based on the A/Leningrad/134/17/57/(H2N2) attenuated adult live influenza vaccine (LIV) investigated features for immunization of the children, aged 3-6 years. During autumn, 1999, out of 256 children, aged 3-6 years, residents of the Leningrad region, who attended the kindergarten, 184 children were immunized with 1 or 2 doses of the live influenza vaccine, and 72 ones were given placebo. There were no any moderate or strong temperature reactions revealed after the inoculation. The LIV was shown to be genetically stable. After a single dose of the vaccine seroconversion to influenza type A virus and to influenza type B virus was observed respectively in 58% and in 39% of seronegative 3-6 year old vaccinees. The twofold LIV administration failed to give any advantages in stimulation of the immune response. During 6 months after immunization the morbidity rate in vaccinees did not exceed the morbidity rate in unvaccinated children. Thus LIV for adults proved safe and immunogenic and can be recommended for single dose immunization both of adults and children.", "Children aged 3 to 14 were immunized with live recombinant influenza A vaccine; about 120,000 children were followed up for 6 months. Analysis of the morbidity (excepting ARVI and influenza) of the immunized and control groups permitted a conclusion about the safety of the preparation. The protective index of vaccine efficacy during influenza epidemic caused by A/Taiwan/1/86(H1N1) virus was 1.3 to 1.42. Live recombinant influenza vaccine is recommended for public health to be used for protection of children aged 3 to 14 from influenza.", "Evaluate the educational needs of adults over 65 years or more with regards to the vaccine, vaccination and immunization against the influenza, design strategies to assist the educational needs and implant and evaluate an immunization program at an independent community pharmacy. A study divided into three phases: Phase I--evaluation of the educational needs related to the vaccine, vaccination and immunization. Phase II--designing of strategies to assist the needs. Phase III--a random longitudinal controlled study to evaluate an immunization program against the influenza implanted at an independent community pharmacy. One hundred (100) patients participated, randomly assigned to a controlled and experimental group. Three months into the study's Phase III, a 68% of the experimental group had been vaccinated and showed a tendency to improvement in knowledge; in the controlled group, a 32% had been vaccinated and did not show a tendency in improvement of knowledge. A year into the study's Phase III, a 76% of the experimental group had been vaccinated and 24% of the controlled group was vaccinated. The satisfaction average of the experimental group towards the pharmacist was 3.94 +/- 0.18 and, in the controlled group was 3.98 +/- 0.20, whiting a scale of 0-04. People who participated in an educational activity offered by a pharmacist showed: more knowledge, remembered what they learned and an increase in influenza vaccination.", "A monovalent, zonally purified, inactivated influenza B vaccine was administered to 29 children, 3 to 6 years of age, and 16 infants, 12 to 28 months of age, as a single dose of 0.25 ml containing 250 chick cell agglutinating units. The vaccine was both antigenic and well tolerated in the older group of preschool children. In the infants the vaccine was also antigenic but poorly tolerated clinically. Febrile reactions to 102 or greater were seen in 9 of the 16 infants, and two of these infants experienced a seizure following vaccination. The clinical reactions observed with the administration of influenza B vaccine in the dose used in this study would suggest significant limitations on its use in children under 3 years of age.", "This serial cohort study assessed the risk of hospitalization or death associated with influenza and the effectiveness of influenza vaccination among subgroups of elderly members of 3 managed-care organizations in the United States. Data on baseline characteristics and outcomes were obtained from computerized databases. A total of 122,974 (1996-1997 season) and 158,454 (1997-1998 season) persons were included in the cohorts. Among unvaccinated persons, hospitalizations for pneumonia/influenza or death occurred in 8.2 of 1000 healthy and 38.4 of 1000 high-risk persons in year 1, and in 8.2 of 1000 healthy and 29.3 of 1000 high-risk persons in year 2. After adjustments, vaccination was associated with a 48% reduction in the incidence of hospitalization or death (95% confidence interval [CI], 42-52) in year 1 and 31% (95% CI, 26-37) in year 2. Effectiveness estimates were statistically significant and generally consistent across the healthy and high-risk subgroups. The absolute risk reduction, however, was 2.4- to 4.7-fold higher among high-risk than among healthy elderly persons. All elderly individuals may substantially benefit from vaccination. However, the impact of influenza is greater in persons with high-risk medical conditions.", "The effectiveness of influenza vaccine in reducing hospital admissions for pneumonia, influenza, bronchitis, or emphysema was assessed by a case-control study of people aged 16 years and older who were admitted to 10 Leicestershire hospitals between 1 December 1989 and 31 January 1990. Hospital and general practitioners' records for 156 admissions (the cases) and 289 controls matched for age and sex were reviewed. Information was collected on demography, the usual place of residence (institutional or non-institutional), the existence of chronic illness, and vaccination during the 5 years before admission. The odds ratio for hospital admission among vaccinees was 0.67 (95% CI 0.39-1.12) giving an estimate of vaccine effectiveness in this setting of 33% (95% CI 0-61). However, multivariate logistic regression, adjusting for the effects of institutional care and chronic illness, revealed that influenza vaccination reduced hospital admissions by 63% (95% CI 17-84%). There was a strong trend towards improved vaccine effectiveness when used in institutional settings. Influenza vaccine is effective in reducing hospital admissions for influenza, pneumonia, bronchitis and emphysema, and effectiveness is comparable to that observed for influenza and pneumonia admissions in North America.", "All persons 65 years and older are recommended to be immunised against influenza each autumn. As immunisation rates remain low, we conducted a randomised control trial in a three-partner urban general practice to evaluate the differential effectiveness of a single postcard reminder in a general practice setting compared to usual care. All non-residential patients aged 65 years and over were identified from the age/sex/disease register. After exclusions, 325 patients were stratified by sex (125 men and 200 women) and randomised to receive either a postcard reminder in large print mailed in April or usual care. General practitioners (GPs) were blind to the randomisation. A blinded record audit performed in July demonstrated that the postcard was effective in increasing immunisation for men (chi(2)1df = 3.85; p = 0.05) but not for women (chi(2)1df = 0.45; p = 0.50). After adjusting for 1995 immunisation status, the effect of the postcard on immunisation rates was even stronger in men (Wald chi(2)1df = 6.20; p = 0.01) but remained non-significant in women (Wald chi(2)1df = 1.38; p = 0.24). With this adjustment, the odds of having the 1996 flu vaccine for men sent the postcard reminder were three times that of men in the control group (OR = 3.0; 95% CI 1.3-6.9). In a general practice setting, a single postcard reminder appears to be a promising way to boost influenza immunisation rates among ageing men. Replication of the study is recommended.", "The effectiveness of influenza vaccination in preventing serious illness and death was determined in an elderly population during the influenza epidemic of was determined in an elderly population during the influenza epidemic of was determined in an elderly population during the influenza epidemic of 1989-90. A retrospective cohort study was carried out using computerized general practitioner records on nearly 10,000 patients aged 55 years and over. After adjustment for potential confounding factors, recent immunization was found to have a protective effect of 75% (95% confidence intervals: 21-92%) against death. Protection did not appear to vary with either age or the presence of underlying chronic disease. As the complications of influenza are most common in those with underlying chronic disease, the study findings are consistent with the recommended policy for the use of influenza vaccine in the UK. Further work is necessary to determine the cost-effectiveness of extending immunization to other groups.", "During the first wave of A/California/7/2009(H1N1) influenza, high rates of hospitalization in children under 5 years were seen in many countries. Subsequent policies for vaccinating children varied in both type of vaccine and number of doses. In Canada, children 36 months to <10 years received a single dose of 0.25 ml of the GSK adjuvanted vaccine (Arepanrix) equivalent to 1.9 microg HA. Children 6 months to 35 months received two doses as did those 36-119 months with chronic medical conditions.\n We conducted a community-based case-control vaccine effectiveness (VE) review of children under 10 years with influenza like illness who were tested for H1N1 infection at the central provincial laboratory. Laboratory-confirmed influenza was the primary outcome, and vaccination status the primary exposure to assess VE after a single 0.25-ml dose.\n If vaccination was designated to be effective after 14 days, no vaccinated child had laboratory-confirmed influenza compared to 38% of controls. The VE of 100% was statistically significant for children <10 years of age and <5 years considered separately. If vaccination was considered effective after 10 days, VE dropped to 96% overall but was statistically significant and over 90% in all age subgroups, including those under 36 months.\n A single 0.25-ml dose of the GSK adjuvanted vaccine (Arepanrix) protects children against laboratory-confirmed pandemic influenza potentially avoiding any increased reactogenicity associated with second doses. Adjuvanted vaccines offer hope for improved seasonal vaccines in the future.", "Despite recommendations supporting annual influenza vaccination for people aged 65 years or older, vaccination rates remain low. Several studies have evaluated the effect of sending mailed reminders, but few have compared alternative ways of reminding patients to receive the vaccine. In a randomized trial of 939 patients aged 65 years or older in four family practices carried out between Oct. 23 and Dec. 31, 1984, we compared three ways of reminding elderly patients to receive the vaccine: personal reminder by the physician, telephone reminder by the nurse and reminder by letter. The vaccination rates for the three groups were 22.9%, 37% and 35.1% respectively. No reminder was issued to a control group, and the rate was 9.8%. Some patients could not be reached by telephone, and some did not see the physician during the specified time. Among the patients whom the nurse actually contacted, the vaccination rate was 43.5%; the rate for patients whom the doctor actually saw was 45.1%. Overall, a telephone reminder by the nurse was the most effective method, and at an hourly salary of $16 or less this method would also be the most cost-effective. The reminders used in this study were automatically generated from a computerized medical record system. The study shows how a computerized system can be used to identify patients for whom preventive procedures are due.", "We prospectively studied the efficacy of influenza vaccine during an influenza A/Arizona/80 (H3N2) outbreak at the Jewish Home and Hospital for the Aged in New York in the winter season of 1982 to 1983. All patients had been offered influenza vaccine before the outbreak; 181 chose to be vaccinated and 124 refused vaccination but agreed to participate in the study. Among those with serologic evidence of influenza infection, respiratory illness was significantly more common in the unvaccinated group (six of 14 vs one of 22). The overall mortality was 13 (7.2%) of 181 in the vaccinated group and 22 (17.7%) of 124 in the control group. The vaccinated and the control groups were examined for comparability. A logistic regression analysis, which controlled for differences in sex and level of nursing care, indicated that the difference in mortality was still significant, with a summary odds ratio of 2.7. The relative risk of death in the unvaccinated group was comparable at 2.18. Influenza vaccine reduced the mortality by 59% in the vaccinated group compared with the control group.", "To evaluate the safety, reactogenicity and immunogenicity of inactivated chromatographic influenza vaccine A(H3N2) produced by the Pasteur Research Institute of Epidemiology and Microbiology in Leningrad, children aged 7-15 years received the vaccine intradermally in doses of 114-228 IU, and 152 children received placebo. In this study inactivated influenza vaccine introduced parenterally to children aged 11-15 years in a dose of 228 IU proved to be nonreactogenic. The reactogenicity index of the preparation injected in a dose of 114 IU to children aged 7-10 years was 0.6%. Immunization in a single injection was accompanied by significant seroconversions in 87.5%-96.0% of children with the highly pronounced growth of antibody titers (21.1-34.6 times). The complex of clinico-laboratory tests showed the safety of this preparation for both age groups.", "A population-based cohort study was conducted during the 2003-2004 season to examine the effectiveness of influenza vaccine among community-dwelling elderly. The subjects consisted of 4787 elderly, ranging from 65 to 79 years. We either interviewed the elderly directly or their families regarding acute febrile illness, hospital visits, hospitalization and death by telephone every month. The vaccination status and physician-diagnosed clinical influenza (hereinafter referred as clinical influenza) were determined based on data obtained from the city office and hospitals, respectively. Influenza-like illness (ILI) was defined as an acute febrile illness (> or = 38.5 degrees C) during the epidemic period. After adjusting for confounders, vaccination decreased ILI significantly (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.17-0.85), but not clinical influenza (OR, 0.76; 95% CI, 0.28-2.06). The results were inconclusive for preventing hospitalization for influenza or pneumonia (OR, 0.37; 95% CI, 0.09-1.47) and death (OR, 3.68; 95% CI, 0.75-18.12), due to the inadequate sample size. In conclusion, the influenza vaccination was thus found to be associated with a decreased ILI during the epidemic period in community-dwelling elderly.", "Public health clients in an Ontario community 65 years of age or older were randomly allocated to receive an intervention by a public health nurse during a home visit promoting either influenza immunization or safety measures. There was no statistically significant differences in influenza immunization rates between these two groups (56.1% vs 56.6%). Men were significantly more likely to receive immunization.", "Annual influenza vaccination has long been recommended for the elderly population. Despite this recommendation, immunization rates have remained very low. This study measured the effects of two approaches to the provision of influenza immunization to the 65-years-and-over age group in a single family practice. The \"drop-in\" group (N=123) was informed of the availability of the vaccine at visits made during the vaccination period. The \"phone\" group (N=120) was notified of the availability of the vaccine by telephone and was invited to come in for the shot. An immunization rate of 50.8% for the \"phone\" group and 26.8% for the \"drop-in\" group was obtained (P=.0002). These results contrast strongly with the overall immunization rates of 5.9% and 9.5% obtained during the previous two years, when no active immunization policy was in place. The telephone approach was found to benefit the type of patient at greatest risk from influenza: the chronically ill and the aged. It is clear that having a defined immunization policy substantially improves the provision of influenza vaccination. The authors discuss the effectiveness and practicality of these approaches to the delivery of influenza vaccine and their applicability to other forms of prevention in family medicine.", "A randomized controlled trial demonstrated that a single mailed influenza vaccination cue increased the vaccination rate among elderly HMO members with high-risk chronic conditions (n = 2217) from 30 per cent to 39 per cent during the fall and winter of 1984/85.", "To evaluate the effect of influenza vaccination on the coronary events in patients with confirmed coronary artery disease (CAD).\n Randomized, double-blind, placebo controlled study. We included 658 optimally treated CAD patients; 477 men, mean age 59.9+/-10.3 years. Three hundred and twenty-five patients received the influenza vaccine, and 333 patients placebo. Median follow-up was 298 (interquartile range 263-317) days. Primary endpoint was the cardiovascular death. Its estimated 12-month cumulative event rate was 0.63% in the vaccine vs. 0.76% in controls (HR 1.06 95% CI: 0.15-7.56, P = 0.95). There were two secondary composite endpoints: (i) the MACE (cardiovascular death, myocardial infarction, coronary revascularization) tended to occur less frequently in the vaccine group vs. placebo with the event rate 3.00 and 5.87%, respectively (HR 0.54;95% CI: 0.24-1.21, P = 0.13). (ii) Coronary ischaemic event (MACE or hospitalization for myocardial ischaemia) estimated 12-month event rate was significantly lower in the vaccine group 6.02 vs. 9.97% in controls (HR 0.54; 95% CI: 0.29-0.99, P = 0.047).\n In optimally treated CAD patients influenza vaccination improves the clinical course of CAD and reduces the frequency of coronary ischaemic events. Large-scale studies are warranted to evaluate the effect of influenza vaccination on cardiovascular mortality. (ClinicalTrials.gov: NCT 00371098).", "Some reports have suggested that influenza virus vaccine is less effective in persons that have received prior annual vaccination(s) than in those receiving it for the first time. This issue was addressed by evaluating the efficacy of annual influenza vaccinations over a 5 year period in healthy adults employing commercially-available, inactivated whole-virus vaccine. Influenza vaccination had minimal effects on overall respiratory illnesses during epidemic periods. However, it reduced influenza virus shedding by an average of 38.8% and conferred protection against influenza virus infection during each epidemic. Some variation in infection rates were noted between vaccine groups given one or more than one annual immunization, and between years, but no consistent pattern of differences was noted in relation to number of successive years of vaccination. These results suggest that the current recommendation for annual influenza vaccination of persons at special risk of serious disease and complications is appropriate, but that continued efforts to improve the effectiveness of our prophylactic measures against influenza are needed.", "Hospitalisation represents an opportunity to identify unimmunised people at risk for the complications of influenza and pneumococcal disease. We conducted a randomised controlled trial of two strategies to increase uptake of influenza and pneumococcal vaccines in eligible, hospitalised subjects aged 65 years or more, admitted between May and September 1998 to a Melbourne hospital. Unvaccinated participants were allocated randomly to alert systems for hospital staff or community general practitioners (GPs). Follow-up occurred at 1 and 3 months. The baseline vaccination rates were 70% for influenza (426/606) and 41% (248/606) for pneumococcal disease. For unvaccinated subjects, the hospital alert resulted in 67% uptake compared to 55% following a GP alert for pneumococcal vaccine; and 63% in hospital compared to 53% following a GP alert for influenza vaccine. Although there was a trend toward a higher uptake in hospital, neither of these differences was statistically significant. The majority (75%) of vaccinations following a GP alert occurred within 1 month of discharge. Despite hospital and community-based reminder systems, there are still significant missed opportunities for vaccination. We did not demonstrate significant differences between hospital and GP reminder systems, but there was a trend towards higher uptake with opportunistic vaccination in hospital.\n Copyright 2003 S. Karger AG, Basel", "Influenza is a common and potentially serious infection in infants. Previous studies of influenza vaccine in this age group have reported widely varying estimates of vaccine effectiveness, and few have used laboratory confirmation of influenza diagnoses. We evaluated the effectiveness of 1 and 2 doses of the trivalent inactivated vaccine against laboratory-confirmed influenza in children aged 6 to 23 months within the Kaiser Permanente Northern California Medical Care Program for the 2003-2004, 2004-2005 and 2005-2006 influenza seasons. 1,648 children were included in the analyses, with an average of 4.5 controls matched to each of the 300 cases (213, 29 and 58 cases identified for each of the influenza seasons, respectively) based on birth month/year and zip code. Vaccination status was determined as of 14 days prior to the case patient's positive test result. Conditional logistic regression was used to calculate vaccine effectiveness for each season, adjusting for chronic medical conditions and other possible confounders. During the 2005-2006 influenza season, when predominant circulating virus strains and vaccine strains were well matched, vaccination was 76% [95% CI: 37-91%] effective against laboratory-confirmed infection. There was no statistically significant effect of vaccination, however, for the 2003-2004 or 2004-2005 seasons. Our results highlight the need for further study of influenza vaccine effectiveness in this age group.", "The immunogenicity and efficacy of Russian live attenuated and US inactivated trivalent influenza vaccines administered alone or in three different combinations were evaluated in a randomized, placebo-controlled, double-blinded study of 614 elderly or chronically ill nursing home residents in St. Petersburg, Russia during the 1996-97 influenza season. Postvaccination serum antibody responses were more frequent among individuals administered the combination vaccines than among those vaccinated with live or inactivated vaccine alone. Only individuals who received live vaccine, alone or in combination with inactivated vaccine, achieved significant postvaccination increases in virus-specific nasal IgA. Efficacy in preventing laboratory-confirmed influenza in vaccinated versus nonvaccinated individuals was 67% (95%CI, 36-81%) for recipients of a combination of the vaccines compared with 51% (95%CI, -17-79%) for recipients of live vaccine alone and 50% (95%CI, -26-80%) for recipients of inactivated vaccine alone. These results suggest that administration of a combination of influenza vaccines may provide a strategy for improved influenza vaccination of elderly people.", "Outbreaks of influenza in nursing homes still occur, even when a large portion of residents have been inoculated with inactivated vaccine. Data were collected in 1991--1992 from 83 eligible skilled nursing homes located in southern Lower Michigan to determine the effectiveness of inactivated influenza vaccine in preventing influenza-like illness and influenza-associated pneumonia. Surveillance was conducted to identify the occurrence of influenza in the homes and, at the end of the season, specific data were gathered on all residents of homes with influenza activity. Age- and sex-adjusted estimates of vaccine effectiveness were calculated using Cox proportional hazards models for each nursing home. Estimates were pooled using precision-based weights calculated from data for each home. Vaccine was found to be 33% effective in preventing total respiratory illness (influenza-like illness and clinically diagnosed pneumonia). In prevention of pneumonia alone, vaccine was 43% effective. The estimate for prevention of pneumonia rose to 55% if the period under consideration was limited to the time of peak influenza activity. Given the number of eligible homes and the cohort methodology used, the results support continuation of current policy, encouraging use of vaccine in all nursing home residents.", "Despite recommendations for annual vaccination against influenza, more than half of elderly Americans do not receive this vaccine. In a serial cohort study, we assessed the efficacy and cost effectiveness of influenza vaccine administered to older persons living in the community.\n Using administrative data bases, we studied men and women over 64 years of age who were enrolled in a large health maintenance organization in the Minneapolis-St. Paul area. We examined the rate of vaccination and the occurrence of influenza and its complications in each of three seasons: 1990-1991, 1991-1992, and 1992-1993. Outcomes were adjusted for age, sex, diagnoses indicating a high risk, use of medications, and previous use of health care services.\n Each cohort included more than 25,000 persons 65 years of age or older. Immunization rates ranged from 45 percent to 58 percent. Although the vaccine recipients had more coexisting illnesses at base line than those who did not receive the vaccine, during each influenza season vaccination was associated with a reduction in the rate of hospitalization for pneumonia and influenza (by 48 to 57 percent, P < or = 0.002) and for all acute and chronic respiratory conditions (by 27 to 39 percent, P < or = 0.01). Vaccination was also associated with a 37 percent reduction (P = 0.04) in the rate of hospitalization for congestive heart failure during the 1991-1992 season, when influenza A was epidemic. The costs of hospitalization for all types of illness studied were lower in the vaccinated group during 1991-1992 (range of reduction, 47 to 66 percent; P < 0.005) and for acute and chronic respiratory conditions and congestive heart failure in 1990-1991 (reductions of 37 percent and 43 percent, respectively; P < or = 0.05). Direct savings per year averaged $117 per person vaccinated (range, $21 to $235), with cumulative savings of nearly $5 million. Vaccination was also associated with reductions of 39 to 54 percent in mortality from all causes during the three influenza seasons (P < 0.001).\n For elderly citizens living in the community, vaccination against influenza is associated with reductions in the rate of hospitalization and in deaths from influenza and its complications, as compared with the rates in unvaccinated elderly persons, and vaccination produces direct dollar savings." ]	The available evidence is of poor quality and provides no guidance regarding the safety, efficacy or effectiveness of influenza vaccines for people aged 65 years or older. To resolve the uncertainty, an adequately powered publicly-funded randomised, placebo-controlled trial run over several seasons should be undertaken.
CD003556	[ "11189545", "14534844" ]	[ "Vacuum-assisted closure versus saline-moistened gauze in the healing of postoperative diabetic foot wounds.", "A prospective randomized evaluation of negative-pressure wound dressings for diabetic foot wounds." ]	[ "Diabetic foot wounds present a great challenge to wound care practitioners. The objective of this pilot study was to determine whether vacuum-assisted closure (V.A.C.) therapy would afford quicker wound resolution as compared to saline-moistened gauze in the treatment of postoperative diabetic foot wounds. Ten patients were randomized into either the experimental V.A.C. group or control saline gauze group. Included in the study were diabetic patients 18 to 75 years of age who had a nonhealing foot ulceration. Excluded were those patients with venous disease, coagulopathy, or those who had active infections not resolved by initial surgical debridement. All foot ulcers were surgically debrided prior to initiation of V.A.C. or gauze treatment. In the experimental group, V.A.C. dressings were applied in accordance with manufacturer's protocol for chronic wounds and changed every 48 hours. In the control group, saline gauze dressings were applied at the time of surgical debridement and changed twice a day thereafter. Measurements and photos were obtained to document wound progress. Main outcome measures included: 1) time to satisfactory healing (calculated from date of initial debridement to date of definitive closure, and 2) change in wound surface area (calculated from initial wound tracing to final tracing). Satisfactory healing in the V.A.C. group was achieved in 22.8 (+/- 17.4) days, compared to 42.8 (+/- 32.5) days in the control group. Surface area changes of 28.4% (+/- 24.3) average decrease in wound size in the V.A.C. group, compared to a 9.5% (+/- 16.9) average increase in the control group during measurement period.", "Optimal treatment for large diabetic foot wounds is ill defined. The purpose of this study was to compare the rate of wound healing with the Vacuum Assisted Closure device trade mark (VAC) to conventional moist dressings in the treatment of large diabetic foot wounds. Diabetics with significant soft tissue defects of the foot were considered for enrollment. Patients were randomized to receive either moist gauze dressings or VAC treatments for 2 weeks, after which they were treated with the alternative dressing for an additional 2 weeks. Wounds were photographed weekly and wound dimensions calculated in a blinded fashion with spatial analysis software. Percent change in wound dimensions were calculated and compared for each weekly assessment and over 2 weeks of therapy with each dressing type. Ten patients were enrolled in the trial, but two were lost to follow-up and two were withdrawn. Complete data were available for analysis on seven wounds in six patients. Average length, width, and depth of the wounds at initiation of the trial was 7.7, 3.5, and 3.1 cm, respectively. Only the wound depth was significantly decreased over the weeks of the trial to 1.2 cm ( p < 0.05). VAC dressings decreased the wound volume and depth significantly more than moist gauze dressings (59% vs. 0% and 49% vs. 8%, respectively). VAC dressings were associated with a decrease in all wound dimensions while wound length and width increased with moist dressings. In summary, over the first several weeks of therapy, VAC dressings decreased wound depth and volume more effectively than moist gauze dressings. Negative-pressure wound treatment may accelerate closure of large foot wounds in the diabetic patient." ]	There is evidence to suggest that hydrogel increases the healing rate of diabetic foot ulcers compared with gauze dressings or standard care. There is insufficient evidence (one small trial, abstract only) of the effects of larval therapy on diabetic foot ulcers. More research is needed to evaluate the effects of a range of widely used debridement methods and of debridement per se.
CD009660	[ "19695776", "20216531", "15944167", "17076751", "18443390", "19457471", "14566163", "19108951", "19091806", "14560166", "12456542", "16456392", "10596504", "10517054", "19318990", "19794200", "18515890", "8567611", "9303253", "21681863", "11434842", "2504794", "20181120", "17885567", "19968378", "19076262", "15279533", "11473908", "2266221", "19309326", "8640423" ]	[ "Randomized controlled trial of an Internet-delivered family cognitive-behavioral therapy intervention for children and adolescents with chronic pain.", "Cognitive-behavioral therapy for children with functional abdominal pain and their parents decreases pain and other symptoms.", "A randomized controlled trial of a cognitive-behavioral family intervention for pediatric recurrent abdominal pain.", "Randomised controlled trial of a parenting intervention in the voluntary sector for reducing child conduct problems: outcomes and mechanisms of change.", "Randomized controlled comparison of two cognitive behavioral therapies for obese children: mother versus mother-child cognitive behavioral therapy.", "Cognitive-behavioural therapy for young children with anxiety disorders: Comparison of a Child + Parent condition versus a Parent Only condition.", "Cognitive-behavioral therapy for children with anxiety disorders in a clinical setting: no additional effect of a cognitive parent training.", "Evaluating the effectiveness of exposure and acceptance strategies to improve functioning and quality of life in longstanding pediatric pain--a randomized controlled trial.", "Conducting a randomized clinical trial of an psychological intervention for parents/caregivers of children with cancer shortly after diagnosis.", "Brief psychoeducational parenting program: an evaluation and 1-year follow-up.", "Improving mental health through parenting programmes: block randomised controlled trial.", "Putting the pieces together: preliminary efficacy of a family problem-solving intervention for children with traumatic brain injury.", "The effectiveness of a parenting skills program for parents of middle school students in small communities.", "Cognitive-behavioral group treatments in childhood anxiety disorders: the role of parental involvement.", "Cognitive-behavioral treatment versus an active control for children and adolescents with anxiety disorders: a randomized trial.", "Long-term effectiveness of a parenting intervention for children at risk of developing conduct disorder.", "Cognitive--behavioural therapy and family intervention for relapse prevention and symptom reduction in psychosis: randomised controlled trial.", "A treatment outcome study for sexually abused preschool children: initial findings.", "Brief cognitive-behavioral group treatment for children's headache.", "Cognitive-behavioral treatment of persistent functional somatic complaints and pediatric anxiety: an initial controlled trial.", "Maternal outcomes of a randomized controlled trial of a community-based support program for families of children with chronic illnesses.", "The long-term effectiveness and clinical significance of three cost-effective training programs for families with conduct-problem children.", "Effectiveness of a single-session early psychological intervention for children after road traffic accidents: a randomised controlled trial.", "Effectiveness of behavioral parent training for children with ADHD in routine clinical practice: a randomized controlled study.", "Randomized controlled trial of a family cognitive-behavioral preventive intervention for children of depressed parents.", "Immediate and short-term outcomes of the 'COPEing with Toddler Behaviour' parent group.", "Parent-child interaction therapy with physically abusive parents: efficacy for reducing future abuse reports.", "Multicentre controlled trial of parenting groups for childhood antisocial behaviour in clinical practice.", "Enhancing the effectiveness of self-administered videotape parent training for families with conduct-problem children.", "Cognitive behavioral therapy for anxiety in children with autism spectrum disorders: a randomized, controlled trial.", "Clinical monitoring of treatment course in child physical abuse: psychometric characteristics and treatment comparisons." ]	[ "Cognitive-behavioral therapy (CBT) interventions show promise for decreasing chronic pain in youth. However, the availability of CBT is limited by many factors including distance to major treatment centers and expense. This study evaluates a more accessible treatment approach for chronic pediatric pain using an Internet-delivered family CBT intervention. Participants included 48 children, aged 11-17 years, with chronic headache, abdominal, or musculoskeletal pain and associated functional disability, and their parents. Children were randomly assigned to a wait-list control group or an Internet treatment group. Primary treatment outcomes were pain intensity ratings (0-10 NRS) and activity limitations on the Child Activity Limitations Interview, both completed via an online daily diary. In addition to their medical care, the Internet treatment group completed 8 weeks of online modules including relaxation training, cognitive strategies, parent operant techniques, communication strategies, and sleep and activity interventions. Youth randomized to the wait-list control group continued with the current medical care only. Findings demonstrated significantly greater reduction in activity limitations and pain intensity at post-treatment for the Internet treatment group and these effects were maintained at the three-month follow-up. Rate of clinically significant improvement in pain was also greater for the Internet treatment group than for the wait-list control group. There were no significant group differences in parental protectiveness or child depressive symptoms post-treatment. Internet treatment was rated as acceptable by all children and parents. Findings support the efficacy and acceptability of Internet delivery of family CBT for reducing pain and improving function among children and adolescents with chronic pain.", "Unexplained abdominal pain in children has been shown to be related to parental responses to symptoms. This randomized controlled trial tested the efficacy of an intervention designed to improve outcomes in idiopathic childhood abdominal pain by altering parental responses to pain and children's ways of coping and thinking about their symptoms.\n Two hundred children with persistent functional abdominal pain and their parents were randomly assigned to one of two conditions-a three-session intervention of cognitive-behavioral treatment targeting parents' responses to their children's pain complaints and children's coping responses, or a three-session educational intervention that controlled for time and attention. Parents and children were assessed at pretreatment, and 1 week, 3 months, and 6 months post-treatment. Outcome measures were child and parent reports of child pain levels, function, and adjustment. Process measures included parental protective responses to children's symptom reports and child coping methods.\n Children in the cognitive-behavioral condition showed greater baseline to follow-up decreases in pain and gastrointestinal symptom severity (as reported by parents) than children in the comparison condition (time x treatment interaction, P<0.01). Also, parents in the cognitive-behavioral condition reported greater decreases in solicitous responses to their child's symptoms compared with parents in the comparison condition (time x treatment interaction, P<0.0001).\n An intervention aimed at reducing protective parental responses and increasing child coping skills is effective in reducing children's pain and symptom levels compared with an educational control condition.", "To investigate whether the combination of standard medical care (SMC) and short-term cognitive-behavioral family treatment (CBT) in the treatment of recurrent abdominal pain (RAP) was more effective than SMC alone.\n Children recently diagnosed with RAP via physician examination were randomized into SMC (n = 29) and SMC plus CBT (n = 40) groups. Outcome measures included multiple dimensions of child and parent reported child pain, somatization, and functional disability, and school absences and physician contacts.\n Children and parents participating in the combined SMC + CBT intervention reported significantly less child and parent reported child abdominal pain than children in the SMC intervention immediately following the intervention and up to 1 year following study entry, as well as significantly fewer school absences. Significant differences in functional disability and somatization were not revealed.\n These results, in combination with previous studies, add support to the effectiveness of CBT intervention in reducing the sensory aspects of RAP. Results are discussed with respect to the cost-benefit of integrated medical and short-term psychological services.", "To test effectiveness of a parenting intervention, delivered in a community-based voluntary-sector organisation, for reducing conduct problems in clinically-referred children.\n Randomised controlled trial, follow-up at 6, 18 months, assessors blind to treatment status. Participants--76 children referred for conduct problems, aged 2-9, primarily low-income families, randomised to treatment vs. 6-month wait-list group. Retention was 93% at 6 months, 90% at 18 months. Interventions--Webster-Stratton Incredible Years video-based 14-week group programme, teaches cognitive-behavioural principles for managing behaviour, using a collaborative, practical, problem-solving approach. Primary outcomes--child problem behaviour by parent-report (Eyberg) and home-based direct observation; secondary outcomes--observed positive and negative parenting; parent-reported parenting skill, confidence and depression.\n Post-treatment improvements were found in child problem behaviour, by parent-report (effect size (ES) .48, p = .05) and direct observation (ES .78, p = .02); child independent play (ES .77, p = .003); observed negative (ES .74, p = .003) and positive (ES .38, p = .04) parenting; parent-reported confidence (ES .40, p = .03) and skill (ES .65, p =.01), using ANCOVA to control for baseline scores. Maternal depression did not change. Consumer satisfaction was high. At 18-month follow-up, although no randomised comparison was possible, changes appeared to maintain, with no significant change toward baseline level on any measure. Change in observed positive parenting appeared to mediate change in child problem behaviour (p < .025).\n Findings suggest that a group-based cognitive-behavioural parenting programme, delivered by well-trained and supervised staff, can be effective in a community voluntary-sector setting, for reducing conduct problems and enhancing parenting skills. Change in parenting skill appears to be a key mechanism for change in child behaviour. Findings have implications for feasibility of translating evidence-based programmes, even for clinically-referred conduct problems, into less specialised community settings, likely to have lower costs and be more accessible for families.", "Parent-child treatments have been shown to be superior to child-focused treatments of childhood obesity. Yet until now, the comparative effectiveness of parent-only and parent-child approaches has been little studied.\n Fifty-six obese children and their families were randomly assigned to a 16-session cognitive behavioral therapy (CBT) for the parents only or for a combined treatment of parents and children. Children's percent overweight, the body mass index of their mothers, and behavioral and psychological problems of children and mothers were assessed.\n Both treatments reduced children's percent overweight significantly and equally by 6-month follow-up. Also both treatments provided similar results in reducing general behavior problems (externalizing and internalizing behavior problems), global and social anxiety, and depression.\n Our results point to a comparable efficacy of the two treatments. Further, psychological well-being of both mothers and children can be improved in a CBT for obese children and their parents. Future studies should focus on finding ways to improve the adherence of families to long-term treatment of obesity in childhood.\n (c) 2008 S. Karger AG, Basel.", "The present study compared the efficacy of a group-based cognitive-behavioural treatment (GCBT) delivered exclusively to parents of young anxious children (between 4 and 8 years of age) with the same intervention delivered to both children and parents, relative to a Wait-list Control condition. Parents of children in the Parent Only condition (N = 25) received 10 weekly sessions of GCBT whereas children and parents in the Parent + Child condition (N = 24) each received 10 weekly sessions of GCBT. Intent-to-treat analyses indicated that both active treatment conditions were superior to the Wait-list condition (N = 11), with 55.3% of children in the Parent Only condition and 54.8% of children in the Parent + Child condition no longer meeting criteria for their principal diagnosis at post-treatment. These treatment gains were maintained in both treatment conditions at six-month and 12-month follow-up assessments. There were no significant differences between the two active conditions on other outcome measures including parental psychopathology and parenting style. However, an unexpected finding was that parenting satisfaction and to some extent parenting competence reduced significantly from pre- to post-treatment regardless of the active treatment condition. The present results suggest that GCBT delivered exclusively to parents of young anxious children may be a viable treatment alternative for improving accessibility to efficacious treatments for children with anxiety disorders and for reducing costs associated with mental health care delivery.", "To evaluate a 12-week cognitive-behavioral treatment program for children with anxiety disorders and the additional value of a seven-session cognitive parent training program.\n Seventy-nine children with an anxiety disorder (aged 7-18 years) were randomly assigned to a cognitive behavioral treatment condition or a wait-list control condition. Families in the active treatment condition were randomly assigned to an additional seven-session cognitive parent training program. Semistructured diagnostic interviews were conducted with parents and children separately, before and after treatment and at 3 months follow-up. Questionnaires included child self-reports on anxiety and depression and parent reports on child's anxiety and behavioral problems.\n Children with anxiety disorders showed more treatment gains from cognitive-behavioral therapy than from a wait-list control condition. These results were substantial and significant in parent measures and with regard to diagnostic status, but not in child self-reports. In the active treatment condition, children improved on self-reported anxiety and depression, as well as on parent reports on their child's anxiety problems. These results were equal for clinically referred and recruited children. Child self-reports decreased to the normal mean, whereas parents reported scores that were lower than before treatment but were still elevated from the normal means. No significant outcome differences were found between families with or without additional parent training.\n Children with anxiety disorders profited from cognitive-behavioral therapy. Children improved equally whether or not additional parent training was offered.", "Although several studies have illustrated the effectiveness of cognitive behavior therapy (CBT) on adult pain patients, there are few randomized controlled trials on children and adolescents. There is particularly a need for studies on pediatric patients who are severely disabled by longstanding pain syndromes. Acceptance and Commitment Therapy, as an extension of traditional CBT, focuses on improving functioning and quality of life by increasing the patient's ability to act effectively in concordance with personal values also in the presence of pain and distress. Following a pilot study, we sought to evaluate the effectiveness of an ACT-oriented intervention based on exposure and acceptance strategies and to compare this with a multidisciplinary treatment approach including amitriptyline (n=32). The ACT condition underwent a relatively brief treatment protocol of approximately 10 weekly sessions. Assessments were made before and immediately after treatment, as well as at 3.5 and 6.5 months follow-up. Prolonged treatment in the MDT group complicated comparisons between groups at follow-up assessments. Results showed substantial and sustained improvements for the ACT group. When follow-up assessments were included, ACT performed significantly better than MDT on perceived functional ability in relation to pain, pain intensity and to pain-related discomfort (intent-to-treat analyses). At post-treatment, significant differences in favor of the ACT condition were also seen in fear of re/injury or kinesiophobia, pain interference and in quality of life. Thus, results from the present study support previous findings and suggest the effectiveness of this ACT-oriented intervention for pediatric longstanding pain syndromes.", "To report acceptability, feasibility, and outcome data from a randomized clinical trial (RCT) of a brief intervention for caregivers of children newly diagnosed with cancer.\n Eighty-one families were randomly assigned following collection of baseline data to Intervention or Treatment as Usual (TAU). Recruitment and retention rates and progression through the protocol were tracked. Measures of state anxiety and posttraumatic stress symptoms served as outcomes.\n Difficulties enrolling participants included a high percentage of newly diagnosed families failing to meet inclusion criteria (40%) and an unexpectedly low participation rate (23%). However, movement through the protocol was generally completed in a timely manner and those completing the intervention provided positive feedback. Outcome data showed no significant differences between the arms of the RCT.\n There are many challenges inherent in conducting a RCT shortly after cancer diagnosis. Consideration of alternative research designs and optimal timing for interventions are essential next steps.", "Despite recognition of the need for parenting interventions to prevent childhood behavioral problems, few community programs have been evaluated. This report describes the randomized controlled evaluation of a four-session psychoeducational group for parents of preschoolers with behavior problems, delivered in community agencies.\n In 1998, 222 primary caregivers, recruited through community ads, filled out questionnaires on parenting practices and child behavior. Parents were randomly assigned to immediate intervention or a wait-list control. The intervention comprised three weekly group sessions and a 1-month booster, the focus being to support effective discipline (using the video 1-2-3 Magic) and to reduce parent-child conflict.\n Using an intent-to-treat analysis, repeated-measures analyses of variance indicated that the parents who received the intervention reported significantly greater improvement in parenting practices and a significantly greater reduction in child problem behavior than the control group. The gains in positive parenting behaviors were maintained at 1-year follow-up in a subset of the experimental group.\n This brief intervention program may be a useful first intervention for parents of young children with behavior problems, as it seems both acceptable and reasonably effective.", "To assess the effectiveness of a parenting programme, delivered by health visitors in primary care, in improving the mental health of children and their parents among a representative general practice population.\n Parents of children aged 2-8 years who scored in the upper 50% on a behaviour inventory were randomised to the Webster-Stratton 10 week parenting programme delivered by trained health visitors, or no intervention. Main outcome measures were the Eyberg Child Behaviour Inventory and the Goodman Strengths and Difficulties Questionnaire to measure child behaviour, and the General Health Questionnaire, Abidin's Parenting Stress Index, and Rosenberg's Self Esteem Scale to measure parents' mental health. These outcomes were measured before and immediately after the intervention, and at six months follow up.\n The intervention was more effective at improving some aspects of the children's mental health, notably conduct problems, than the no intervention control condition. The Goodman conduct problem score was reduced at immediate and six month follow up, and the Eyberg Child Behaviour Inventory was reduced at six months. The intervention also had a short term impact on social dysfunction among parents. These benefits were seen among families with children scoring in the clinical range for behaviour problems and also among children scoring in the non-clinical (normal) range.\n This intervention could make a useful contribution to the prevention of child behaviour problems and to mental health promotion in primary care.", "To describe a family-centered problem-solving intervention (FPS) for pediatric traumatic brain injury (TBI), and to assess the efficacy of the intervention in a randomized clinical trial.\n Families of 32 school-aged children with moderate to severe TBI randomly assigned to FPS or usual care (UC) group.\n Child Behavior Checklist, Brief Symptom Inventory, Conflict Behavior Questionnaire.\n Seven-session problem-solving/skill-building intervention delivered over a 6-month period for the participating families.\n Parents in the FPS group reported significantly greater improvements in their children in internalizing symptoms, anxiety/depression, and withdrawal than did parents in the UC comparison group.\n FPS holds promise for reducing child behavior problems, the most common and persistent sequelae of TBI.", "This study provides evidence of the effectiveness of behaviorally based parenting skills classes provided by carefully trained and supervised group leaders who were not mental health clinicians. A program for parents of at-risk middle school students was evaluated in a randomized controlled trial in 8 small Oregon communities. Parents (N = 303) were randomly assigned to immediate treatment or a wait-list condition. Data were analyzed using latent growth modeling. Participation in the program led to significant improvements in problem-solving interactions as indicated by parent reports and a Taped Situations Test. Parents' over-reactivity and laxness toward their children's behavior were reduced and their feelings toward their children improved significantly as a function of treatment. Parent-reported child antisocial behavior was also reduced.", "This study examined (1) the effect of a cognitive-behavioral group intervention on anxiety, depression, and coping strategies in school-age children (aged 7-12 years) with Axis I anxiety disorders; and (2) the effect of parental involvement on treatment outcomes.\n Parents and children (N = 62) were randomly assigned to one of three 12-week treatment conditions: parent and child intervention, child-only intervention, and parent-only intervention. Child anxiety, depression, and coping strategies were assessed before and after treatment.\n All treatment groups reported fewer symptoms of anxiety and depression posttreatment and changes in their use of coping strategies. Children in the parent and child intervention used more active coping strategies posttreatment compared with children in the other 2 treatment conditions. Parents in this treatment condition reported a significantly greater improvement in their children's emotional well-being than parents in the other treatment conditions.\n Cognitive-behavioral group interventions reduced symptoms of anxiety and depression in school-age children with anxiety disorders. Concurrent parental involvement enhanced the effect on coping strategies. Further investigation is needed to corroborate the effectiveness of such short-term interventions and the maintenance of treatment effects.", "The current trial examined whether a specific cognitive-behavioral treatment package was more efficacious in treating childhood anxiety disorders than a nonspecific support package.\n One hundred twelve children (aged 7-16 years) with a principal anxiety disorder were randomly allocated to either a group cognitive-behavioral treatment (CBT) program or a control condition (group support and attention [GSA]).\n Overall, results showed that CBT was significantly more efficacious compared with the GSA condition: 68.6% of children in the CBT condition did not meet diagnostic criteria for their principal anxiety diagnosis at 6-month follow-up compared with 45.5% of the children in the GSA condition. The results of the child- and parent-completed measures indicated that, although mothers of CBT children reported significantly greater treatment gains than mothers of GSA children, children reported similar improvements across conditions.\n Specific delivery of cognitive-behavioral skills is more efficacious in the treatment of childhood anxiety than a treatment that includes only nonspecific therapy factors.", "The typical pattern for intervention outcome studies for conduct problems has been for effect sizes to dissipate over time with decreasing effects across subsequent follow-ups.\n To establish whether the short-term positive effects of a parenting programme are sustained longer term. To observe trends, and costs, in health and social service use after intervention.\n Parents with children aged 36-59 months at risk of developing conduct disorder (n = 104) received intervention between baseline and first follow-up (6 months after baseline n = 86) in 11 Sure Start areas in North Wales. Follow-ups two (n = 82) and three (n = 79) occurred 12 and 18 months after baseline. Child problem behaviour and parenting skills were assessed via parent self-report and direct observation in the home.\n The significant parent-reported improvements in primary measures of child behaviour, parent behaviour, parental stress and depression gained at follow-up one were maintained to follow-up three, as were improved observed child and parent behaviours. Overall, 63% of children made a minimum significant change (0.3 standard deviations) on the Eyberg Child Behavior Inventory problem scale between baseline and follow-up (using intention-to-treat data), 54% made a large change (0.8 standard deviations) and 39% made a very large change (1.5 standard deviations). Child contact with health and social services had reduced at follow-up three.\n Early parent-based intervention reduced child antisocial behaviour and benefits were maintained, with reduced reliance on health and social service provision, over time.", "Family intervention reduces relapse rates in psychosis. Cognitive-behavioural therapy (CBT) improves positive symptoms but effects on relapse rates are not established.\n To test the effectiveness of CBT and family intervention in reducing relapse, and in improving symptoms and functioning in patients who had recently relapsed with non-affective psychosis.\n A multicentre randomised controlled trial (ISRCTN83557988) with two pathways: those without carers were allocated to treatment as usual or CBT plus treatment as usual, those with carers to treatment as usual, CBT plus treatment as usual or family intervention plus treatment as usual. The CBT and family intervention were focused on relapse prevention for 20 sessions over 9 months.\n A total of 301 patients and 83 carers participated. Primary outcome data were available on 96% of the total sample. The CBT and family intervention had no effects on rates of remission and relapse or on days in hospital at 12 or 24 months. For secondary outcomes, CBT showed a beneficial effect on depression at 24 months and there were no effects for family intervention. In people with carers, CBT significantly improved delusional distress and social functioning. Therapy did not change key psychological processes.\n Generic CBT for psychosis is not indicated for routine relapse prevention in people recovering from a recent relapse of psychosis and should currently be reserved for those with distressing medication-unresponsive positive symptoms. Any CBT targeted at this acute population requires development. The lack of effect of family intervention on relapse may be attributable to the low overall relapse rate in those with carers.", "Treatment outcome for sexually abused preschool-age children and their parents was assessed, comparing the effectiveness of a cognitive-behavioral intervention to nondirective supportive treatment.\n Sixty-seven sexually abused preschool children and their parents were randomly assigned to either (1) cognitive-behavioral therapy adapted for sexually abused preschool children (CBT-SAP) or (2) nondirective supportive therapy (NST). Treatment consisted of 12 individual sessions for both the child and parent, monitored for integrity with the therapeutic model through intensive training and supervision, use of treatment manuals, and rating of audiotaped sessions. Parents completed the Child Behavior Checklist, the Child Sexual Behavior Inventory, and the Weekly Behavior Report to measure a variety of emotional and behavioral symptoms.\n Within-group comparison of pretreatment and posttreatment outcome measures demonstrated that while the NST group did not change significantly with regard to symptomatology, the CBT-SAP group had highly significant symptomatic improvement on most outcome measures. Repeated-measures analyses of variance demonstrated group x time interactions on some variables as well. Clinical findings also supported the effectiveness of the CBT-SAP intervention over NST.\n Findings provide strong preliminary evidence for the effectiveness of a specific cognitive-behavioral treatment model for sexually abused preschool children and their parents.", "Using a randomized design with a waiting list control condition, we assessed the effectiveness of an abbreviated cognitive therapy group program for headaches in children 7 to 12 years of age. In the treatment condition, small groups of five to eight children were taught relaxation, distraction, visualization, and stress management skills in two 90-minute sessions. Parent groups, seen concurrently, reviewed the children's program and addressed parenting strategies. The waiting list control groups were treated 5 weeks later. Thirty-six children meeting inclusion criteria were included in the study; complete data were available for 29 participants (mean age, 9.4 years; 66% female). DEPENDENT MEASURES: We obtained children's ratings of headache frequency, intensity, duration, and five other variables in a diary kept for 3 weeks before and 3 weeks after treatment. Parent measures were collected once before treatment and once at 3-month follow-up.\n CHILD RATINGS: The control condition showed a significant reduction in children's self-rated headache frequency, while the treatment condition did not. On all other self-reported variables, there were no significant differences between the control and treatment conditions. Two participants in each condition achieved a 50% or greater reduction in a self-rating headache index.\n PARENT RATINGS: Follow-up ratings, obtained over the telephone from parents after the children in both conditions had been treated, indicated that the children in both conditions had experienced reduced intensity, frequency, and duration of headaches and that 82% of the children were using the techniques taught in the program. Fourteen children achieved a 50% or greater reduction in a headache index based on parent ratings.\n Although parents were very positive about the effectiveness of the program, the results for children's self-ratings do not support the use of this highly abbreviated treatment method.", "Children and adolescents who seek medical treatment for persistent physical distress often suffer from co-occurring anxiety disorders. Treatment options for this impaired population are limited. This study tests the feasibility and potential efficacy of a cognitive-behavioral intervention targeting pain and anxiety for youth with impairing functional physical symptoms and anxiety disorders presenting to pediatricians for medical care.\n Children and adolescents (aged 8-16) experiencing somatic complaints, without an explanatory medical disorder (i.e., functional), were recruited from primary care and specialty (gastroenterologists and cardiologists) pediatricians. Forty children, primarily with gastrointestinal symptoms, who met criteria for a co-occurring anxiety disorder, were randomly assigned to a cognitive-behavioral treatment addressing pain and anxiety, Treatment of Anxiety and Physical Symptoms (TAPS), or to a waiting list control.\n TAPS was found to be an acceptable treatment for this population and was superior to the waiting list condition. Eighty percent of children in TAPS were rated as treatment responders by independent evaluators compared with none of the controls. Overall, self- and parent ratings indicated reductions in children's somatic discomfort and anxiety following intervention. TAPS participants maintained clinical gains 3 months following treatment.\n The study supports the feasibility and preliminary efficacy of a cognitive-behavioral intervention targeting co-occurring physical distress and anxiety in youth presenting for medical treatment. Such an approach has the potential to exert broad impact on children's dysfunction and to minimize exposure to invasive, ineffective, and costly medical procedures and treatments.\n © 2011 Wiley-Liss, Inc.", "Parents of children with chronic illnesses are at high risk for secondary mental health problems, such as anxiety and depression.\n To evaluate maternal outcomes of a support intervention for families of children with selected chronic illnesses.\n A randomized controlled clinical trial design with repeated measures 1 year apart.\n A community-based family support intervention linked to subspecialty and general pediatric clinics and practices in a metropolitan area.\n A population-based sample of 193 mothers of children aged 7 to 11 years; the children were diagnosed as having diabetes, sickle cell anemia, cystic fibrosis, or moderate to severe asthma. About 15% of the persons contacted refused to participate in the research, and 14% of the families were lost to follow-up.\n The 15-month intervention, the Family-to-Family Network, was designed to enhance mothers' mental health by linking mothers of school-aged children with selected chronic illnesses with mothers of older children with the same condition. The program included telephone contacts, face-to-face visits, and special family events.\n Beck Depression Inventory score and the Psychiatric Symptom Index.\n Maternal anxiety scores for participants in the experimental group decreased during the intervention period for all diagnostic groups and for the total group; scores for the control group increased (F = 5.07, P =.03). In multiple regression analyses, the intervention group was a significant predictor of posttest anxiety scores (P =.03). Effects were greater for mothers with high baseline anxiety (P<.001) and for those who were themselves in poor health (P<.01).\n A family support intervention can have beneficial effects on the mental health status of mothers of children with chronic illnesses. This type of intervention can be implemented in diverse pediatric settings.", "We evaluated the long-term effectiveness of three cost-effective parent training programs for conduct-problem children. One year posttreatment, 93.1% of families (94 mothers and 60 fathers) were assessed on the basis of teacher and parent reports and home observations. Results indicated that all the significant improvement reported immediately posttreatment were maintained one year later. Moreover, approximately two thirds of the entire sample showed \"clinically significant\" improvements. There were very few differences between the three treatment conditions except for the \"consumer satisfaction\" measure indicating that the treatment combining group discussion and video-tape modeling was superior to treatments without both components.", "Road traffic accidents (RTAs) are the leading health threat to children in Europe, resulting in 355,000 injuries annually. Because children can suffer significant and long-term mental health problems following RTAs, there is considerable interest in the development of early psychological interventions. To date, the research in this field is scarce, and currently no evidence-based recommendations can be made.\n To evaluate the effectiveness of a single-session early psychological intervention, 99 children age 7-16 were randomly assigned to an intervention or control group. The manualised intervention was provided to the child and at least one parent around 10 days after the child's involvement in an RTA. It included reconstruction of the accident using drawings and accident-related toys, and psychoeducation. All of the children were interviewed at 10 days, 2 months and 6 months after the accident. Parents filled in questionnaires. Standardised instruments were used to assess acute stress disorder (ASD), posttraumatic stress disorder (PTSD), depressive symptoms and behavioural problems.\n The children of the two study groups showed no significant differences concerning posttraumatic symptoms and other outcome variables at 2 or at 6 months. Interestingly, analyses showed a significant intervention x age-group effect, indicating that for preadolescent children the intervention was effective in decreasing depressive symptoms and behavioural problems.\n This study is the first to show a beneficial effect of a single-session early psychological intervention after RTA in preadolescent children. Therefore, an age-specific approach in an early stage after RTAs may be a promising way for further research. Younger children can benefit from the intervention evaluated here. However, these results have to be interpreted with caution, because of small subgroup sizes. Future studies are needed to examine specific approaches for children and adolescents. Also, the intervention evaluated here needs to be studied in other groups of traumatised children.\n Clinical Trial Registry: ClinicalTrials.gov: NCT00296842.", "To investigate the effectiveness of behavioral parent training (BPT) as adjunct to routine clinical care (RCC).\n After a first phase of RCC, 94 children with attention-deficit/hyperactivity disorder (ADHD) ages 4-12, all referred to a Dutch outpatient mental health clinic, were randomly assigned to 5 months of BPT plus concurrent RCC (n = 47) or to 5 months of RCC (n = 47) alone. BPT consisted of 12 sessions in group format; RCC included family support and pharmacotherapy when appropriate. Exclusionary criteria were minimized, and children with and without medication could participate. Parent-reported behavioral problems, ADHD symptoms, internalizing problems, and parenting stress were assessed before and after treatment. Follow-up assessment of the BPT + RCC group was completed 25 weeks post-BPT intervention. Repeated-measures analyses of variance were carried out on an intention-to-treat basis.\n Both groups showed improvements over time on all measures. BPT + RCC was superior to RCC alone in reducing behavioral (p = .017) and internalizing (p = .042) problems. No outcome differences were found in ADHD symptoms (p = .161) and parenting stress (p = .643). These results were equal for children with and without medication. Children allocated to RCC alone received more polypharmaceutical treatment.\n Adjunctive BPT enhances the effectiveness of routine treatment of children with ADHD, particularly in decreasing behavioral and internalizing problems, but not in reducing ADHD symptoms or parenting stress. Furthermore, adjunctive BPT may limit the prescription of polypharmaceutical treatment.", "A family cognitive-behavioral preventive intervention for parents with a history of depression and their 9-15-year-old children was compared with a self-study written information condition in a randomized clinical trial (n = 111 families). Outcomes were assessed at postintervention (2 months), after completion of 4 monthly booster sessions (6 months), and at 12-month follow-up. Children were assessed by child reports on depressive symptoms, internalizing problems, and externalizing problems; by parent reports on internalizing and externalizing problems; and by child and parent reports on a standardized diagnostic interview. Parent depressive symptoms and parent episodes of major depression also were assessed. Evidence emerged for significant differences favoring the family group intervention on both child and parent outcomes; strongest effects for child outcomes were found at the 12-month assessment with medium effect sizes on most measures. Implications for the prevention of adverse outcomes in children of depressed parents are highlighted.", "Controlling, uninvolved, and rejecting parenting in early childhood are strong predictors of later disruptive behavior disorders. However, there have been no evaluations of non-targeted groups for parents of very young children, despite their potential advantages.\n We randomly assigned 79 mothers of 12- to 36-month-olds to an 8-session parent training program (called 'COPEing with Toddler Behaviour') or to a waiting list control condition. We investigated the immediate and short-term impact on parent-reported child behavior problems, observed parent-child interaction, and self-reported parenting behavior and parent functioning.\n In an intent-to-treat design, the program yielded significant effects on child behavior problems, positive parent-child interaction, and parental overreactivity and depression but not observed negative child behavior or parental laxness. Most effects were significant at both post-test and 1-month follow-up and effects sizes were small to medium for the intervention group and inverse to small for the control group.\n The potential of the program to prevent later behavior problems is supported by improvements in six of the eight outcomes. As part of a community strategy, groups such as COPEing with Toddler Behaviour may promote positive parent-child interaction and children's mental health.", "A randomized trial was conducted to test the efficacy and sufficiency of parent-child interaction therapy (PCIT) in preventing re-reports of physical abuse among abusive parents. Physically abusive parents (N=110) were randomly assigned to one of three intervention conditions: (a) PCIT, (b) PCIT plus individualized enhanced services, or (c) a standard community-based parenting group. Participants had multiple past child welfare reports, severe parent-to-child violence, low household income, and significant levels of depression, substance abuse, and antisocial behavior. At a median follow-up of 850 days, 19% of parents assigned to PCIT had a re-report for physical abuse compared with 49% of parents assigned to the standard community group. Additional enhanced services did not improve the efficacy of PCIT. The relative superiority of PCIT was mediated by greater reduction in negative parent-child interactions, consistent with the PCIT change model.\n (c) 2004 APA, all rights reserved", "To see whether a behaviourally based group parenting programme, delivered in regular clinical practice, is an effective treatment for antisocial behaviour in children.\n Controlled trial with permuted block design with allocation by date of referral.\n Four local child and adolescent mental health services.\n 141 children aged 3-8 years referred with antisocial behaviour and allocated to parenting groups (90) or waiting list control (51).\n Webster-Stratton basic videotape programme administered to parents of six to eight children over 13-16 weeks. This programme emphasises engagement with parental emotions, rehearsal of behavioural strategies, and parental understanding of its scientific rationale.\n Semistructured parent interview and questionnaires about antisocial behaviour in children administered 5-7 months after entering trial; direct observation of parent-child interaction.\n Referred children were highly antisocial (above the 97th centile on interview measure). Children in the intervention group showed a large reduction in antisocial behaviour; those in the waiting list group did not change (effect size between groups 1.06 SD (95% confidence interval 0.71 to 1.41), P<0.001). Parents in the intervention group increased the proportion of praise to ineffective commands they gave their children threefold, while control parents reduced it by a third (effect size between groups 0.76 (0.16 to 1.36), P=0.018). If the 31 children lost to follow up were included in an intention to treat analysis the effect size on antisocial behaviour was reduced by 16%.\n Parenting groups effectively reduce serious antisocial behaviour in children in real life conditions. Follow up is needed to see if the children's poor prognosis is improved and criminality prevented.", "Parents of 43 conduct-problem children, aged 3-8 years, were randomly assigned to one of two treatments: an individually self-administered video-tape modeling treatment (IVM) and IVM treatment plus therapist consultation (IVMC). Randomization also included a waiting-list control group (CON). Compared with the control group, both treatment groups of mothers reported significantly fewer child behavior problems, reduced stress levels, and less use of spanking. Home visit data indicated that both treatment groups exhibited significant behavioral changes. There were relatively few differences between the two treatment conditions. However, the IVMC children were significantly less deviant than the IVM children, suggesting that the IVMC (with therapist consultation) treatment was superior to self-administered treatment with no therapist involvement. The added benefits of therapist involvement are discussed.", "Children with autism spectrum disorders often present with comorbid anxiety disorders that cause significant functional impairment. This study tested a modular cognitive behavioral therapy (CBT) program for children with this profile. A standard CBT program was augmented with multiple treatment components designed to accommodate or remediate the social and adaptive skill deficits of children with ASD that could pose barriers to anxiety reduction.\n Forty children (7-11 years old) were randomly assigned to 16 sessions of CBT or a 3-month waitlist (36 completed treatment or waitlist). Therapists worked with individual families. The CBT model emphasized behavioral experimentation, parent-training, and school consultation. Independent evaluators blind to treatment condition conducted structured diagnostic interviews and parents and children completed anxiety symptom checklists at baseline and posttreatment/postwaitlist.\n In intent-to-treat analyses, 78.5% of the CBT group met Clinical Global Impressions-Improvement scale criteria for positive treatment response at posttreatment, as compared to only 8.7% of the waitlist group. CBT also outperformed the waitlist on diagnostic outcomes and parent reports of child anxiety, but not children's self-reports. Treatment gains were maintained at 3-month follow-up.\n The CBT manual employed in this study is one of the first adaptations of an evidence-based treatment for children with autism spectrum disorders. Remission of anxiety disorders appears to be an achievable goal among high-functioning children with autism.", "Weekly reports of high-risk indicators designed to monitor the course of treatment were obtained from physically abused, school-aged children and their parents/guardians who were randomly assigned to Individual Child and Parent Cognitive-Behavioral Treatment (CBT) or Family Therapy (FT). Measures of parental anger and physical discipline/force, and family problems were obtained each session. The measures showed moderate stability and parent-child correspondence. Between 20% and 23% of the two informant's reports acknowledged high levels of physical discipline/force during the early and late phases of treatment, respectively, and an even higher percentage of cases reported heightened parental anger and family problems. Early treatment reports from both informants predicted late period reports, but only parent reports were related to validity measures. The overall levels of parental anger and physical discipline/force were lower in CBT than FT families, though each group showed a reduction on these items from the early to late treatment sessions. The importance of routine monitoring of clinical course during intervention, especially in the identification of cases at-risk of reabuse, is discussed." ]	There is no evidence on the effectiveness of psychological therapies that include parents in most outcome domains of functioning, for a large number of common chronic illnesses in children. There is good evidence for the effectiveness of including parents in psychological therapies that reduce pain in children with painful conditions. There is also good evidence for the effectiveness of CBT that includes parents for improving the primary symptom complaints when available data were included from chronic illness conditions. Finally, there is good evidence for the effectiveness of problem solving therapy delivered to parents on improving parent problem solving skills and parent mental health. All effects are immediately post-treatment. There are no significant findings for any treatment effects in any condition at follow-up.
CD006410	[ "15066200", "17296417", "15161896", "12694632", "9746022" ]	[ "An outreach intervention to implement evidence based practice in residential care: a randomized controlled trial [ISRCTN67855475].", "A critical assessment of the quality of reporting of randomized, controlled trials in the urology literature.", "Empirical evidence for selective reporting of outcomes in randomized trials: comparison of protocols to published articles.", "Randomised controlled trial of a theoretically grounded tailored intervention to diffuse evidence-based public health practice [ISRCTN23257060].", "Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses?" ]	[ "The aim of this project was to assess whether outreach visits would improve the implementation of evidence based clinical practice in the area of falls reduction and stroke prevention in a residential care setting.\n Twenty facilities took part in a randomized controlled trial with a seven month follow-up period. Two outreach visits were delivered by a pharmacist. At the first a summary of the relevant evidence was provided and at the second detailed audit information was provided about fall rates, psychotropic drug prescribing and stroke risk reduction practices (BP monitoring, aspirin and warfarin use) for the facility relevant to the physician. The effect of the interventions was determined via pre- and post-intervention case note audit. Outcomes included change in percentage patients at risk of falling who fell in a three month period prior to follow-up and changes in use of psychotropic medications. Chi-square tests, independent samples t-test, and logistic regression were used in the analysis.\n Data were available from case notes at baseline (n = 897) and seven months follow-up (n = 902), 452 residential care staff were surveyed and 121 physicians were involved with 61 receiving outreach visits. Pre-and post-intervention data were available for 715 participants. There were no differences between the intervention and control groups for the three month fall rate. We were unable to detect statistically significant differences between groups for the psychotropic drug use of the patients before or after the intervention. The exception was significantly greater use of \"as required\" antipsychotics in the intervention group compared with the control group after the pharmacy intervention (RR = 4.95; 95%CI 1.69-14.50). There was no statistically significant difference between groups for the numbers of patients \"at risk of stroke\" on aspirin at follow-up.\n While the strategy was well received by the physicians involved, there was no change in prescribing patterns. Patient care in residential settings is complex and involves contributions from the patient's physician, family and residential care staff. The project highlights challenges of delivering evidence based care in a setting in which there is a paucity of well controlled trial evidence but where significant health outcomes can be attained.", "Randomized, controlled trials are the gold standard for evidence based assessment of therapeutic interventions. In 1996 the Consolidated Standards of Reporting Trials statement was published in an effort to standardize the reporting of clinical trials. To our knowledge we report the first systematic assessment of randomized, controlled trial quality in the urology literature by Consolidated Standards of Reporting Trials standards.\n All human subject randomized, controlled trials published in 4 leading urology journals in 1996 and 2004 were identified for formal review. A standardized evaluation form was developed based on the Consolidated Standards of Reporting Trials statement. Each article was evaluated by 2 independent reviewers and discrepancies were settled by consensus. A Consolidated Standards of Reporting Trials criteria summary score was calculated on a scale of 0 to 22.\n A total of 152 randomized, controlled trials met inclusion criteria. The mean+/-SEM Consolidated Standards of Reporting Trials summary score was 10.2+/-0.3 (median 10.3) and 12.0+/-0.3 (median 12.2) in 1996 and 2004, respectively, with a mean difference of 1.8 (95% CI 1.0, 2.6; p=0.001). Reporting of important methodological criteria, eg sample size justification and randomization implementation, improved from 1996 to 2004. Improvement notwithstanding, reporting of key methodological criteria remained consistently below 50% in 2004.\n This formal review suggests that randomized, controlled trial reporting in the urology literature has improved since the publication of the Consolidated Standards of Reporting Trials statement in 1996. Certain areas, such as reporting of trial methods, continue to meet Consolidated Standards of Reporting Trials criteria in fewer than half of publications. Ongoing graduate and postgraduate education in trial design and evidence based practice may result in further improvement in randomized, controlled trial reporting.", "Selective reporting of outcomes within published studies based on the nature or direction of their results has been widely suspected, but direct evidence of such bias is currently limited to case reports.\n To study empirically the extent and nature of outcome reporting bias in a cohort of randomized trials.\n Cohort study using protocols and published reports of randomized trials approved by the Scientific-Ethical Committees for Copenhagen and Frederiksberg, Denmark, in 1994-1995. The number and characteristics of reported and unreported trial outcomes were recorded from protocols, journal articles, and a survey of trialists. An outcome was considered incompletely reported if insufficient data were presented in the published articles for meta-analysis. Odds ratios relating the completeness of outcome reporting to statistical significance were calculated for each trial and then pooled to provide an overall estimate of bias. Protocols and published articles were also compared to identify discrepancies in primary outcomes.\n Completeness of reporting of efficacy and harm outcomes and of statistically significant vs nonsignificant outcomes; consistency between primary outcomes defined in the most recent protocols and those defined in published articles.\n One hundred two trials with 122 published journal articles and 3736 outcomes were identified. Overall, 50% of efficacy and 65% of harm outcomes per trial were incompletely reported. Statistically significant outcomes had a higher odds of being fully reported compared with nonsignificant outcomes for both efficacy (pooled odds ratio, 2.4; 95% confidence interval [CI], 1.4-4.0) and harm (pooled odds ratio, 4.7; 95% CI, 1.8-12.0) data. In comparing published articles with protocols, 62% of trials had at least 1 primary outcome that was changed, introduced, or omitted. Eighty-six percent of survey responders (42/49) denied the existence of unreported outcomes despite clear evidence to the contrary.\n The reporting of trial outcomes is not only frequently incomplete but also biased and inconsistent with protocols. Published articles, as well as reviews that incorporate them, may therefore be unreliable and overestimate the benefits of an intervention. To ensure transparency, planned trials should be registered and protocols should be made publicly available prior to trial completion.", "Previous studies have shown that Norwegian public health physicians do not systematically and explicitly use scientific evidence in their practice. They work in an environment that does not encourage the integration of this information in decision-making. In this study we investigate whether a theoretically grounded tailored intervention to diffuse evidence-based public health practice increases the physicians' use of research information.\n 148 self-selected public health physicians were randomised to an intervention group (n = 73) and a control group (n = 75). The intervention group received a multifaceted intervention while the control group received a letter declaring that they had access to library services. Baseline assessments before the intervention and post-testing immediately at the end of a 1.5-year intervention period were conducted. The intervention was theoretically based and consisted of a workshop in evidence-based public health, a newsletter, access to a specially designed information service, to relevant databases, and to an electronic discussion list. The main outcome measure was behaviour as measured by the use of research in different documents.\n The intervention did not demonstrate any evidence of effects on the objective behaviour outcomes. We found, however, a statistical significant difference between the two groups for both knowledge scores: Mean difference of 0.4 (95% CI: 0.2-0.6) in the score for knowledge about EBM-resources and mean difference of 0.2 (95% CI: 0.0-0.3) in the score for conceptual knowledge of importance for critical appraisal. There were no statistical significant differences in attitude-, self-efficacy-, decision-to-adopt- or job-satisfaction scales. There were no significant differences in Cochrane library searching after controlling for baseline values and characteristics.\n Though demonstrating effect on knowledge the study failed to provide support for the hypothesis that a theory-based multifaceted intervention targeted at identified barriers will change professional behaviour.", "Few meta-analyses of randomised trials assess the quality of the studies included. Yet there is increasing evidence that trial quality can affect estimates of intervention efficacy. We investigated whether different methods of quality assessment provide different estimates of intervention efficacy evaluated in randomised controlled trials (RCTs).\n We randomly selected 11 meta-analyses that involved 127 RCTs on the efficacy of interventions used for circulatory and digestive diseases, mental health, and pregnancy and childbirth. We replicated all the meta-analyses using published data from the primary studies. The quality of reporting of all 127 clinical trials was assessed by means of component and scale approaches. To explore the effects of quality on the quantitative results, we examined the effects of different methods of incorporating quality scores (sensitivity analysis and quality weights) on the results of the meta-analyses.\n The quality of trials was low. Masked assessments provided significantly higher scores than unmasked assessments (mean 2.74 [SD 1.10] vs 2.55 [1.20]). Low-quality trials (score < or = 2), compared with high-quality trials (score > 2), were associated with an increased estimate of benefit of 34% (ratio of odds ratios [ROR] 0.66 [95% CI 0.52-0.83]). Trials that used inadequate allocation concealment, compared with those that used adequate methods, were also associated with an increased estimate of benefit (37%; ROR=0.63 [0.45-0.88]). The average treatment benefit was 39% (odds ratio [OR] 0.61 [0.57-0.65]) for all trials, 52% (OR 0.48 [0.43-0.54]) for low-quality trials, and 29% (OR 0.71 [0.65-0.77]) for high-quality trials. Use of all the trial scores as quality weights reduced the effects to 35% (OR 0.65 [0.59-0.71]) and resulted in the least statistical heterogeneity.\n Studies of low methodological quality in which the estimate of quality is incorporated into the meta-analyses can alter the interpretation of the benefit of intervention, whether a scale or component approach is used in the assessment of trial quality." ]	The quality of the evidence base currently provides very little guidance for the development of services. If randomised controlled trials are not feasible then consideration should be given to alternative study designs, such as prospective systems of audit conducted across several centres, as this has the potential to improve the current level of evidence. These studies should include baseline measurement at admission along with demographic data, and outcomes measured using a few standardised robust instruments.
CD005481	[ "20515418", "12001042", "14526206" ]	[ "Abacavir/lamivudine/zidovudine maintenance after standard induction in antiretroviral therapy-naïve patients: FREE randomized trial interim results.", "A randomized trial of simplified maintenance therapy with abacavir, lamivudine, and zidovudine in human immunodeficiency virus infection.", "Impact of an educational program on efficacy and adherence with a twice-daily lamivudine/zidovudine/abacavir regimen in underrepresented HIV-infected patients." ]	[ "Maintenance with a triple nucleoside reverse transcriptase Inhibitor (NRTI) regimen after successful induction with a dual NRTI/protease inhibitor (PI) combination may be advantageous, because of low pill burden, favorable lipids, and less drug interactions. This strategy to become free of PI-related problems without losing viral efficacy has not been formally tested. We performed a randomized, open-label, multicenter, 96-week comparative study in antiretroviral therapy (ART)-naïve patients with CD4 <or=350 cells/mm(3) and HIV-1 RNA concentrations (viral load [VL]) greater than 30,000 copies per milliliter. Patients were randomized after reaching VL less than 50 copies per milliliter on two consecutive occasions between 12 and 24 weeks after start of zidovudine/lamuvidine and lopinavir/ritonavir combination. Eligible subjects switched to abacavir/lamivudine/zidovudine (TZV) or continued the PI-containing regimen. Here we present the 48-week data with virologic success rate (failure: VL > 50 copies per milliliter). Two hundred seven patients had similar baseline (BL) characteristics: median CD4 180 cells/mm(3), median VL 5.19 log(10) copies per milliliter. One hundred twenty subjects (58%) met randomization criteria. Baseline VL differed significantly between dropouts and randomized subjects (median 5.41 versus 5.06 log(10) copies per milliliter, p = 0.017), as did CD4 cells (median 160 and 200 cells/mm(3), p = 0.044). Sixty-one subjects received TZV and 59 subjects continued NRTIs/PI. At week 48, 2 patients in the TZV group and 5 in the PI group did not have a sustained virologic suppression (log rank test; p = 0.379). CD4 counts increased significantly in both arms. In ART-naïve patients, TZV maintenance had similar antiviral efficacy compared to continued standard ART at 48 weeks after baseline. Patients on successful standard ART can be safely switched to a NRTI-only regimen, at least for the tested time period.", "This randomized study evaluated the efficacy and tolerability of continued treatment with protease inhibitor plus nucleoside-analogue combination regimens (n=79) or a change to the simplified regimen of abacavir-lamivudine-zidovudine (n=84) in patients with suppressed human immunodeficiency virus type 1 (HIV-1) RNA for > or = 6 months who did not have the reverse transcriptase 215 mutation. After a median follow-up of 84 weeks, virologic failure was 6% in the continuation and 15% in the simplified group (P=.081). Previous zidovudine monotherapy or dual therapy and archived reverse transcriptase resistance mutations in HIV-1 DNA at baseline were significant predictors of failure. Study treatment was discontinued because of adverse events in 20% of the continuation and 7% of the simplified group (P=.021). Simplification to abacavir-lamivudine-zidovudine significantly decreased nonfasting cholesterol and triglyceride levels; however, this switch strategy carries a risk of virologic failure when treatment history or resistance testing suggest the presence of archived resistance mutations to the simplified regimen.", "A 24-week open-label clinical trial was conducted in 195 HIV-infected adults commonly underrepresented in research (35% female, 71% African American, 21% Hispanic, and 20% injection drug users [IDUs]) to evaluate the effect of an HIV educational program on efficacy and adherence with a simple, compact, twice-daily triple nucleoside regimen containing a lamivudine (150 mg)/zidovudine (300 mg) combination (COM) tablet plus abacavir (ABC), 300 mg. At baseline, the patients' median plasma HIV-1 RNA level was 4.18 log10 copies/mL and the median CD4+ cell count was 379 cells/mm3. Patients were randomized 1:1 to 4 modules of the Tools for Health and Empowerment HIV education intervention plus routine counseling (EI + RC; n = 96) or to routine counseling alone (RC; n = 99). No differences between the EI + RC and RC treatment arms were observed with respect to the proportion of patients achieving plasma HIV-1 RNA levels <40 copies/mL (60% [33/55] vs. 55% [38/69]; P = 0.529) or <400 copies/mL (80% [44/55] vs. 80% [55/69]; P = 0.689) at week 24 (intent-to-treat observed analysis), increase in median CD4 cell count above baseline at week 24 (78.3 vs. 104.8 cells/mm3; P = 0.498), or mean overall adherence rates as measured by the Medication Event Monitoring System (MEMS) (70% vs. 74%). COM + ABC was generally well tolerated, and no association was observed between interruptions in treatment and the development of ABC hypersensitivity (5 suspected cases). In conclusion, in underrepresented patients, the EI used in this study did not affect the efficacy and adherence results with ABC + COM to any greater degree than did RC." ]	This review provides evidence that co-formulated abacavir-lamivudine-zidovudine remains a viable option for initiating antiretroviral therapy, especially in HIV-infected patients with pre-existing hyperlipidaemia. The varied geographical locations of the included trials augment the external validity of these findings. We are moderately confident in our estimate of the treatment effects of the triple NRTI regimen as initial therapy for HIV infection. In the context of the GRADE approach, such moderate quality of evidence implies that the true effects of the regimen are likely to be close to the estimate of effects found in this review; but there is a possibility that they could be substantially different. Further research should be geared towards defining the subgroup of HIV patients for whom this regimen will be most beneficial.
CD004634	[ "1633902", "1955546", "12832372", "2193071" ]	[ "A prospective randomized study comparing aspiration only with aspiration and flushing for transvaginal ultrasound-directed oocyte recovery.", "Is follicular flushing necessary for oocyte retrieval? A randomized trial.", "Electro-acupuncture as a peroperative analgesic method and its effects on implantation rate and neuropeptide Y concentrations in follicular fluid.", "Is analgesia required for transvaginal single-follicle aspiration in in vitro fertilization? A double-blind study." ]	[ "To compare aspiration only with aspiration and flushing of ovarian follicles during transvaginal ultrasound (US)-directed oocyte recovery.\n Prospective randomized study.\n One hundred patients who were undergoing an in vitro fertilization (IVF) treatment cycle.\n All patients underwent pituitary desensitization before the administration of gonadotropins. Monitoring of ovarian stimulation and the criteria for the administration of human chorionic gonadotropin were similar in both groups. In patients in whom aspiration alone was used, each follicle was aspirated until it was empty. The US probe was then rotated until every drop of follicular fluid had been aspirated before the next follicle was aspirated and the procedure repeated. For patients who had aspiration and flushing, each follicle was aspirated and then flushed up to a maximum of six times before moving to the next follicle. In both groups, all follicles greater than 10 mm were aspirated.\n The indication for IVF and mean age of the patients were comparable in the two groups. There were no significant differences between the aspiration and the aspiration and flushing groups in terms of the number of oocytes retrieved (11 versus 9), the oocyte recovery rates (77.5% versus 77.0%), the fertilization rates (55.6% versus 60.0%), the number of embryos transferred (2 versus 2), or the number of clinical pregnancies (12 versus 13). The time taken for oocyte recovery was significantly shorter (15 versus 30 minutes, P less than 0.00001), and the dose of pethidine required significantly less (50 mg versus 100 mg, P less than 0.00001) in the aspiration only group.\n Aspiration alone produces comparable oocyte recovery rates as aspiration and flushing while significantly reducing the length of the procedure and the dose of analgesia required. Aspiration alone suffices for virtually all cases during transvaginal US-directed oocyte recovery.", "A prospective randomized trial was performed to evaluate the necessity of follicular flushing during transvaginal, ultrasonically guided oocyte recovery under mild sedation. Patients with tubal damage as the sole cause of their infertility were randomized into one of two groups. Group one had their follicles aspirated only. Follicles of patients in Group 2 were aspirated and flushed with a total of 10 ml of flushing medium. There was no significant difference in the number of oocytes retrieved, fertilization rate or pregnancy rate in each group. There was, however, a significant shortening of operating time in the aspiration only group.", "In a previous study on the effect of electro-acupuncture (EA) in combination with a paracervical block (PCB) as an analgesic method during oocyte aspiration in IVF treatment, EA appeared to increase the pregnancy rate. This study was designed to test the hypothesis that EA as an analgesic during oocyte aspiration would result in: (i) a better IVF pregnancy rate than with alfentanil; (ii) peroperative analgesia that was as good as that produced by alfentanil; (iii) less postoperative abdominal pain, nausea and stress; and (iv) a reduction in the use of additional analgesics. Neuropeptide Y (NPY) concentrations in follicular fluid (FF) were analysed when possible.\n In this prospective, randomized, multicentre clinical trial, 286 women undergoing oocyte aspiration were randomly allocated to the EA group (EA plus a PCB) or to the alfentanil group (alfentanil plus a PCB). No significant differences were found between the EA and alfentanil groups in any of the IVF variables. NPY concentrations in FF were significantly higher in the EA group compared with the alfentanil group. No correlation between pregnancy rate and NPY concentrations was found in either analgesic group. Both EA plus a PCB and alfentanil plus a PCB induced adequate peroperative analgesia during oocyte aspiration evaluated using the visual analogue scale. After 2 h, the EA group reported significantly less abdominal pain, other pain, nausea and stress than the alfentanil group. In addition, the EA group received significantly lower amounts of additional alfentanil than the alfentanil group.\n EA does not improve pregnancy rate in the present clinical situation. The observation that NPY concentrations in FF were higher in the EA group may be important for human ovarian steroidogenesis. The analgesic effects produced by EA are as good as those produced by conventional analgesics, and the use of opiate analgesics with EA is lower than when conventional analgesics alone are used.", "High oocyte retrieval rates using transvaginal follicular aspiration for single follicles and improved laboratory techniques have engendered renewed interest in natural-cycle in vitro fertilization (IVF). To assess analgesia requirements during single-follicle aspiration, a double-blind study was set up in 30 patients comparing intraprocedure intravenous fentanyl with normal saline as a placebo. Analysis of pain perception using visual analogue scoring showed a similar pain tolerance in both groups for the procedures of vaginal ultrasound scanning, needle insertion, and follicular aspiration. A correlation between each patient's tolerance of common pain-producing experiences with that for the procedure was not well defined (r = 0.5). We conclude that one of the benefits of natural-cycle IVF using transvaginal single-follicle aspiration is that it can be performed without analgesia." ]	There is no evidence that follicular aspiration and flushing is associated with improved clinical or ongoing pregnancy rates, nor an increase in oocyte yield. The operative time is significantly longer and more opiate analgesia is required for pain relief during oocyte retrieval. There is a lack of evidence regarding the effect of follicular aspiration and flushing on live birth rates in the identified data.
CD008456	[ "16570467", "12455427", "17689192", "15967762", "16078340", "16819378", "20686425", "19695776", "7892015", "16139778", "8066514", "8907093", "10029400", "18086516", "17449998", "16564618" ]	[ "Efficacy of an early intervention for patients with acute temporomandibular disorder-related pain: a one-year outcome study.", "A randomized clinical trial of a tailored comprehensive care treatment program for temporomandibular disorders.", "Hypnosis in the management of persistent idiopathic orofacial pain--clinical and psychosocial findings.", "Should treatment of (sub)acute low back pain be aimed at psychosocial prognostic factors? Cluster randomised clinical trial in general practice.", "Efficacy of cognitive-behavioral intervention for juvenile primary fibromyalgia syndrome.", "Treatment of nonorganic recurrent abdominal pain: cognitive-behavioral family intervention.", "A family-based randomized controlled trial of pain intervention for adolescents with sickle cell disease.", "Randomized controlled trial of an Internet-delivered family cognitive-behavioral therapy intervention for children and adolescents with chronic pain.", "Brief group cognitive-behavioral intervention for temporomandibular disorders.", "Individually tailored treatment targeting activity, motor behavior, and cognition reduces pain-related disability: a randomized controlled trial in patients with musculoskeletal pain.", "Intensive physical and psychosocial training program for patients with chronic low back pain. A controlled clinical trial.", "Dysfunctional patients with temporomandibular disorders: evaluating the efficacy of a tailored treatment protocol.", "The efficacy of developmentally sensitive interventions and sucrose for relieving procedural pain in very low birth weight neonates.", "Results of a randomized controlled trial to examine the efficacy of a chronic pain self-management group for older adults [ISRCTN11899548].", "Does systematic graded exposure in vivo enhance outcomes in multidisciplinary chronic pain management groups?", "A sham-controlled, phase II trial of transcranial direct current stimulation for the treatment of central pain in traumatic spinal cord injury." ]	[ "The authors conducted a randomized clinical trial to evaluate the efficacy of a biopsychosocial intervention for patients who were at high risk (HR) of progressing from acute to chronic temporomandibular disorder (TMD)-related pain.\n The authors classified subjects' risk using a predictive algorithm and randomized them into an early-intervention (EI) or a nonintervention (NI) group. The EI included cognitive behavioral skills training and biofeedback. The authors assessed pain and psychosocial measures at intake and at a one-year follow-up. Subjects' self-reported pain levels were measured on an analog scale and as a response to palpation.\n At one year, EI-group subjects had significantly lower levels of self-reported pain and depression. At one year, more NI-group subjects than EI-group subjects had utilized health care for jaw-related pain. NI-group subjects were 12.5 times as likely to have a somatoform disorder, more than seven times as likely to have an anxiety disorder, and 2.7 times more likely to have an affective disorder at one year, compared with EI-group subjects.\n EI-group subjects had reduced pain levels, improved coping abilities and reduced emotional distress at one year.\n The TMD-related pain experience is complex and requires early identification with a biopsychosocial EI to achieve maximal, sustainable results.", "To test the usefulness of tailoring cognitive-behavioral therapy (CBT) for patients with temporomandibular disorders (TMD) who demonstrated poor psychosocial adaptation to their TMD condition, independent of physical diagnosis.\n A randomized clinical trial compared a 6-session CBT intervention delivered in conjunction with the usual TMD treatment to the usual conservative treatment by TMD specialist dentists. For study inclusion, Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD), Axis II criteria, were used to target patients with elevated levels of TMD pain-related interference with daily activities, independent of physical diagnosis (i.e., Axis I).\n At the post-treatment assessment, about 4 months after the baseline evaluations, the comprehensive care group, when compared to the usual treatment group, showed significantly lower levels of characteristic pain intensity, significantly higher self-reported ability to control their TMD pain, and a strong trend (P = .07) toward lower pain-related interference in daily activities. From post-intervention to 1-year follow-up, all subjects showed improvement. At the 1-year follow-up, the comprehensive care group, while not losing any of its early gains, was not significantly different from the usual care group with regard to reported levels of pain, ability to control pain, and levels of interference in activities. For many of these psychosocially disabled TMD patients, pain and interference 1 year after treatment remained at the same or higher levels than those observed at baseline among a group of patients selected for a separate randomized clinical trial on the basis of better psychosocial adaptation.\n The 6-session CBT intervention for patients with heightened psychologic and psychosocial disability was effective in improving pain-related variables over the course of the CBT in conjunction with usual treatment, but was too brief an intervention to result in further improvement after the sessions ended. Patient ratings of treatment satisfaction and helfulness were high for both groups, but they were significantly higher for the comprehensive care group.", "This controlled and patient blinded study tested the effect of hypnosis on persistent idiopathic orofacial pain (PIOP) in terms of clinical and psychosocial findings. Forty-one PIOP were randomized to active hypnotic intervention or simple relaxation as control for five individual 1-h sessions. Primary outcome was average pain intensity scored three times daily in a pain diary using visual analogue scale (VAS). Secondary outcome measures were pain quality assessed by McGill pain questionnaire (MPQ), psychological symptoms assessed by symptom check list (SCL), quality of life assessed by SF36, sleep quality, and consumption of analgesic. Data were compared between groups before and after treatment using ANOVA models and paired t-tests. The change in VAS pain scores from baseline to the last treatment (t4) was (33.1+/-7.4%) in the hypnosis group and (3.2+/-5.4%) in the control group (P<0.03). In the hypnosis group, highly hypnotic susceptible patients had greater decreases in VAS pain scores (55.0+/-12.3%) when compared to less susceptible patients (17.9+/-6.7%) (P<0.02). After the last treatment there were also statistically significant differences between groups in perceived pain area (MPQ) and the use of weak analgesics (P<0.03). There were no statistically significant changes in SCL or SF36 scores from baseline to t4. In conclusion, hypnosis seems to offer clinically relevant pain relief in PIOP, particularly in highly susceptible patients. However, stress coping skills and unresolved psychological problems need to be included in a comprehensive management plan in order also to address psychological symptoms and quality of life.", "To compare the effects of a minimal intervention strategy aimed at assessment and modification of psychosocial prognostic factors and usual care for treatment of (sub)acute low back pain in general practice.\n Cluster randomised clinical trial.\n 60 general practitioners in 41 general practices.\n 314 patients with non-specific low back pain of less than 12 weeks' duration, recruited by their general practitioner.\n In the minimal intervention strategy group the general practitioner explored the presence of psychosocial prognostic factors, discussed these factors, set specific goals for reactivation, and provided an educational booklet. The consultation took about 20 minutes. Usual care was not standardised.\n Functional disability (Roland-Morris disability questionnaire), perceived recovery, and sick leave because of low back pain assessed at baseline and after 6, 13, 26, and 52 weeks.\n The dropout rate was 8% in the minimal intervention strategy group and 9% in the usual care group. Multilevel analyses showed no significant differences between the groups on any outcome measure during 12 months of follow-up in the whole group or in relevant subgroups (patients with high scores on psychosocial measures at baseline or a history of frequent or prolonged low back pain).\n This study provides no evidence that (Dutch) general practitioners should adopt our new treatment strategy aimed at psychosocial prognostic factors in patients with (sub)acute low back pain. Further research should examine why our new strategy was not more effective than usual care.", "There are currently no controlled studies of behavioral interventions for juvenile primary fibromyalgia syndrome (JPFM). In this small-sample randomized study, we tested the efficacy of a behavioral intervention, i.e., coping skills training (CST), for the treatment of adolescents with JPFM. Outcomes tested in this study were functional disability, pain intensity, pain-coping efficacy, and depressive symptoms.\n Thirty patients with JPFM were randomly assigned to 8 weeks of either CST or self-monitoring. Adolescents in the CST condition received training in active pain-coping techniques, while those in the self-monitoring condition monitored daily pain intensity and sleep quality with no instructions about behavior change. After posttreatment assessment, subjects were crossed over into the opposite treatment arm for 8 weeks (so that all adolescents eventually received both CST and self-monitoring) and were reassessed at Week 16.\n At Week 8, adolescents in both conditions showed significant decrease in depressive symptoms and functional disability. Those who received CST showed significantly greater ability to cope with pain than those in the self-monitoring condition and a trend toward decreased pain intensity. At Week 16, adolescents had significantly lower levels of disability and depressive symptoms compared to baseline, but those who received self-monitoring followed by CST seemed to receive the most benefit.\n CST can lead to improved functioning among JPFM patients. Although some of the improvement may be due to increased monitoring and attention, CST provides the specific benefit of improving adolescents' ability to cope with pain.", "We evaluated the efficacy of cognitive-behavioral family intervention in the treatment of crises of pain in children with nonorganic recurrent abdominal pain (RAP) and the thresholds of pain for 17 body surface areas in these children.\n A randomized clinical trial was undertaken with 32 children between the ages of 5.1 and 13.9 years with nonorganic RAP. A group of 15 patients, aged 9.9 +/- 2.2 years (11 girls), received standard pediatric care and cognitive-behavioral family intervention for treatment of pain crises. The control group of 17 children, aged 8.4 +/- 2.0 years (11 girls), received only standard pediatric care. These procedures were undertaken by general pediatricians over 4 monthly sessions. An analog visual scale was used to measure the frequency and intensity of the pain crises per month and a mechanical pressure algometer for the measurement of pain threshold.\n The median frequency of pain crises per month reported by patients at the 3 monthly cognitive-behavioral family intervention sessions was 15, 5, 2 and 2, respectively. In contrast, the median frequency for pain crises per month reported by the control group was 12, 8, 10 and 8, respectively. The difference between the intervention group and the controls was statistically significant for frequency of pain at the second, third and fourth visits. There was no statistical difference for intensity of pain or for measured pain thresholds between the control and the intervention group.\n The cognitive-behavioral family intervention reduced the frequency of pain crises of children with nonorganic RAP. This successful intervention was carried out by the intervention of general pediatricians.", "The study had 2 aims---to determine the efficacy of a family-based cognitive-behavioral pain management intervention for adolescents with sickle cell disease (SCD) in (1) reducing pain and improving health-related variables and (2) improving psychosocial outcomes. Each adolescent and a family support person were randomly assigned to receive a brief pain intervention (PAIN) (n=27) or a disease education attention control intervention (DISEASE ED) (n=26) delivered at home. Assessment of primary pain and health-related variables (health service use, pain coping, pain-related hindrance of goals) and secondary psychosocial outcomes (disease knowledge, disease self-efficacy, and family communication) occurred at baseline (before randomization), postintervention, and 1-year follow-up. Change on outcomes did not differ significantly by group at either time point. When groups were combined in exploratory analyses, there was evidence of small to medium effects of intervention on health-related and psychosocial variables. Efforts to address barriers to participation and improve feasibility of psychosocial interventions for pediatric SCD are critical to advancing development of effective treatments for pain. Sample size was insufficient to adequately test efficacy, and analyses did not support this focused cognitive-behavioral pain management intervention in this sample of adolescents with SCD. Exploratory analyses suggest that comprehensive interventions, that address a broad range of skills related to disease management and adolescent health concerns, may be more effective in supporting teens during healthcare transition.", "Cognitive-behavioral therapy (CBT) interventions show promise for decreasing chronic pain in youth. However, the availability of CBT is limited by many factors including distance to major treatment centers and expense. This study evaluates a more accessible treatment approach for chronic pediatric pain using an Internet-delivered family CBT intervention. Participants included 48 children, aged 11-17 years, with chronic headache, abdominal, or musculoskeletal pain and associated functional disability, and their parents. Children were randomly assigned to a wait-list control group or an Internet treatment group. Primary treatment outcomes were pain intensity ratings (0-10 NRS) and activity limitations on the Child Activity Limitations Interview, both completed via an online daily diary. In addition to their medical care, the Internet treatment group completed 8 weeks of online modules including relaxation training, cognitive strategies, parent operant techniques, communication strategies, and sleep and activity interventions. Youth randomized to the wait-list control group continued with the current medical care only. Findings demonstrated significantly greater reduction in activity limitations and pain intensity at post-treatment for the Internet treatment group and these effects were maintained at the three-month follow-up. Rate of clinically significant improvement in pain was also greater for the Internet treatment group than for the wait-list control group. There were no significant group differences in parental protectiveness or child depressive symptoms post-treatment. Internet treatment was rated as acceptable by all children and parents. Findings support the efficacy and acceptability of Internet delivery of family CBT for reducing pain and improving function among children and adolescents with chronic pain.", "Temporomandibular disorders (TMD) are currently viewed as an interrelated set of clinical conditions presenting with signs and symptoms in masticatory and related muscles of the head and neck, and the soft tissue and bony components of the temporomandibular joint. Epidemiologic and clinical studies of TMD confirm its status as a chronic pain problem. In this report we present results from a randomized clinical trial which compared, at 3- and 12-month follow-ups, the effects of usual TMD treatment on TMD pain and related physical and psychological variables with the effects of a cognitive-behavioral (CB) intervention delivered to small groups of patients before usual TMD treatment began. The purpose of this study was to determine whether a minimal CB intervention followed by dental TMD treatment enhanced the effects of usual clinical dental treatment. A second purpose of the study was to determine whether patients classified as high in somatization and psychosocial dysfunction would respond less favorably to this minimal intervention than would those low in somatization and dysfunction. Patients who participated in the CB intervention followed by usual treatment showed greater long-term decreases in reported pain level and pain interference in daily activities than did patients who received only usual treatment. The benefits of CB intervention were not seen when the CB and UT groups were compared at 3-month follow-up. During the 3-12-month follow-up interval, however, the UT group maintained essentially the same level of improvement in characteristic pain while the CB group continued to improve, as hypothesized. During this same follow-up interval, the CB group also showed a strong trend toward continued improvement in pain interference. Such effects were not observed for depression, somatization, or clinical measures of jaw range of motion. Additionally, as hypothesized, dysfunctional chronic pain patients did not appear to benefit from the brief CB intervention. Intent to treat analyses were also performed to assess generalizability of the results.", "This study compares the outcomes of an individually tailored behavioral medicine intervention (experimental) with physical exercise therapy (control). The experimental intervention was systematically individualized according to each participant's behavioral treatment goals and functional behavioral analyses. One hundred twenty-two patients seeking care at 3 primary health care clinics because of musculoskeletal pain were randomized. Ninety-seven completed the trial. Data were collected at baseline, immediately after treatment, and at a 3-month follow-up. Analyses of data from completers, as well as intention-to-treat analyses, showed that the experimental group experienced lower levels of disability (P = .01), lower maximum pain intensity (P = .02), higher levels of pain control (P = .001), and lower fear of movement (P = .022) as a result of treatment condition. Self-efficacy (P = .0001) and physical performance (P = .0001) increased over time for both groups. Participants in the experimental group generally reported more positive effects after treatment. Treatment fidelity was maintained during the course of the study. Activity can be resumed and pain might be managed by the patients themselves if treatment incorporates the biopsychosocial explanatory model of pain and strategies are tailored according to individual's priorities of everyday life activities and empirically derived determinants of pain-related disability.\n This study shows that the biomedical and the psychosocial perspectives of the experiences and consequences of pain complement rather than contradict each other. Primary health care patients with persistent musculoskeletal pain benefit more from a systematic tailoring of treatments according to biopsychosocial factors than from a physically based exercise intervention.", "The authors conducted a controlled clinical trial with 1-year follow-up to define the effectiveness of an intensive physical and psychosocial training program on patients with low back pain.\n The intervention group included 152 patients (mean age 40.5 yr, Million index 45.1/100), and the reference group included 141 patients (mean age 40.4 yr, Million-index 44.5/100).\n The progressive intervention program consisted of intensive physical training and psychosocial activation. The outcomes were physical and psychosocial measures, the pain and disability index (Million), sick leaves, and occupational handicap.\n The intervention was more efficient with respect to physical measures and pain and disability index. There were only mild or no differences in changes between the study groups in psychologic variables, sick leaves, or retirement.\n The intervention program could improve physical disability, but to improve occupational handicap, activities of the whole society (social legislation, labor market policy) are needed.", "Forty-eight dysfunctional patients (i.e., high levels of pain, interference, and affective distress and low levels of perceived control) with temporomandibular disorders (TMDs) were randomly assigned either to a treatment consisting of an intraoral appliance (IA) and stress management with biofeedback (SM) plus nondirective, supportive counseling (SC) -- IA + SM + SC -- or to a customized treatment that included cognitive therapy (CT) with the IA and SM--IA + SM + CT. Both treatment groups reported statistically significant reductions on a set of physical, psychosocial, and behavioral measures posttreatment and at a 6-month follow-up. However, the intervention that included CT demonstrated significantly greater reductions in pain, depression, and medication use. Only the groups receiving the treatment that included the CT demonstrated continued improvements to the follow-up on pain associated with muscle palpation, self-reported pain severity, depression, and use of medications. These results support the efficacy of the tailored treatment for dysfunctional TMD.", "Procedural pain management for very low birth weight (VLBW) neonates has been minimal or nonexistent in most neonatal intensive care units (NICUs).\n To compare the efficacy of developmentally sensitive behavioral interventions (nonnutritive sucking via a pacifier, positioning) and sucrose for relieving procedural pain in VLBW infants and to determine the influence of contextual factors (gestational age, postnatal age, birth weight, severity of illness, frequency of painful procedures) on pain response.\n In a prospective randomized crossover trial, pain was assessed in 122 VLBW neonates using the Premature Infant Pain Profile following four randomly ordered interventions during consecutive routine heel lance procedures.\n Significant differences in pain existed among treatment interventions (F = 16.20, p < .0001). The pacifier with sucrose (F = 24.09, p < .0001) and pacifier with sterile water (F = 9.00, p = .003) significantly reduced pain. Prone positioning did not decrease pain (F = 2.24, p = .137). Frequency of painful procedures approached significance in influencing pain response (F = 3.59, p = .01).\n The most efficacious interventions for reducing pain from single painful events were the pacifier with sucrose and the pacifier with sterile water. Research on the efficacy and safety of implementing these interventions, alone and in combination, for repeated painful procedures is needed. In addition, research is needed on the influence of implementing these interventions on pain response and clinical outcomes (e.g., health status and neurodevelopmental status) in VLBW neonates in the NICU.", "Chronic pain is a common, disabling problem in older adults. Pain self-management training is a multimodal therapy that has been found to be effective in young to middle-aged adult samples; however, few studies have examined the effectiveness of this therapy in older adults. In this randomized, controlled trial, we evaluated a pain self-management training group (SMG) intervention as compared with an education-only (BOOK) control condition. Participants, 65 years of age or older who experienced persistent, noncancer pain that limited their activities, were recruited from 43 retirement communities in the Pacific Northwest of the United States. The primary outcome was physical disability, as measured by the Roland-Morris Disability Questionnaire. Secondary outcomes were depression (Geriatric Depression Scale), pain intensity (Brief Pain Inventory), and pain-related interference with activities (Brief Pain Inventory). Randomization occurred by facility to minimize cross-contamination between groups. Two-hundred and fifty-six individuals, mean age=81.8 (SD: 6.5), enrolled and 218 completed the study. No significant differences in outcomes were found between groups at post-intervention, 6-month follow-up, or 12-month follow-up. The SMG group showed a significantly greater increase over time, relative to the BOOK group, in two process measures, as measured by the Chronic Pain Coping Inventory: use of relaxation and use of exercise/stretching. In both cases, the increase was greatest from baseline to the post-intervention assessment. Study findings indicate that additional research is needed to determine the most effective content and delivery methods for self-management therapies targeted at older adults with chronic pain.", "Graded exposure in vivo (GEXP) treatment has been successfully used to reduce levels of pain-related fear and disability in some chronic pain patients, but its effectiveness has not been evaluated in general clinical settings using group-design studies. The purpose of this study was to determine if the systematic incorporation of GEXP into a multidisciplinary chronic pain management group (PMG) treatment program would result in better treatment outcomes than usual PMG treatment.\n One hundred forty-three chronic pain patients who were assessed as suitable for an outpatient multidisciplinary chronic PMG program were randomly allocated to 3 experimental conditions; usual PMG, PMG incorporating systematic graded exposure, and wait-list control.\n The clinical outcomes of the 2 treatment conditions were not significantly different, suggesting that the systematic incorporation of GEXP into a multidisciplinary PMG program did not result in better treatment outcomes than usual PMG treatment. Both group treatment programs were associated with significant treatment effects when compared with the wait-list control on measures of pain intensity, fear of movement/(re)injury, pain self-efficacy, activity level, and depression. No treatment effects were found on self-report measures of pain disability or anxiety.\n The addition of systematic graded exposure into a multidisciplinary chronic pain management program did not result in better clinical outcomes than the usual group treatment program. The validity of GEXP to the broader population of chronic pain patients warrants further investigation.", "Past evidence has shown that motor cortical stimulation with invasive and non-invasive brain stimulation is effective to relieve central pain. Here we aimed to study the effects of another, very safe technique of non-invasive brain stimulation--transcranial direct current stimulation (tDCS)--on pain control in patients with central pain due to traumatic spinal cord injury. Patients were randomized to receive sham or active motor tDCS (2mA, 20 min for 5 consecutive days). A blinded evaluator rated the pain using the visual analogue scale for pain, Clinician Global Impression and Patient Global Assessment. Safety was assessed with a neuropsychological battery and confounders with the evaluation of depression and anxiety changes. There was a significant pain improvement after active anodal stimulation of the motor cortex, but not after sham stimulation. These results were not confounded by depression or anxiety changes. Furthermore, cognitive performance was not significantly changed throughout the trial in both treatment groups. The results of our study suggest that this new approach of cortical stimulation can be effective to control pain in patients with spinal cord lesion. We discuss potential mechanisms for pain amelioration after tDCS, such as a secondary modulation of thalamic nuclei activity." ]	There is weak evidence to support the use of psychosocial interventions for chronic orofacial pain. Although significant effects were observed for outcome measures where pooling was possible, the studies were few in number and had high risk of bias. However, given the non-invasive nature of such interventions they should be used in preference to other invasive and irreversible treatments which also have limited or no efficacy. Further high quality trials are needed to explore the effects of psychosocial interventions on chronic orofacial pain.
CD000095	[ "8508009" ]	[ "Effects of garlic coated tablets in peripheral arterial occlusive disease." ]	[ "For the first time, a weak clinical efficacy of a 12-week therapy with garlic powder (daily dose, 800 mg) is demonstrated in patients with peripheral arterial occlusive disease stage II. The increase in walking distance in the verum group by 46 m (from 161.0 +/- 65.1 to 207.1 +/- 85.0 m) was significantly higher (P < 0.05) than in the placebo group (by 31 m, from 172.0 +/- 60.9 to 203.1 +/- 72.8). Both groups received physical therapy twice a week. The diastolic blood pressure, spontaneous thrombocyte aggregation, plasma viscosity, and cholesterol concentration also decreased significantly. Body weight was maintained. It is quite interesting that the garlic-specific increase in walking distance did not appear to occur until the 5th week of treatment, connected with a simultaneous decrease in spontaneous thrombocyte aggregation. Therefore, garlic may be an appropriate agent especially for the long-term treatment of an incipient intermittent claudication." ]	One small trial of short duration found no statistically significant effect of garlic on walking distance.
CD005992	[ "18815714", "19165321", "18669427", "16728756", "19369895", "16966957", "18676987", "12873245", "16319361", "19398142", "18653490", "16754947", "17482249", "17901438", "17204724", "18089625", "18268149", "15066887", "17652238", "18047180", "17760974", "19208693", "11433049", "16046685", "16940340", "19032538", "17827487", "18319698", "12195637", "16671973", "7740017", "3615040", "15530588", "9551726", "17827485", "12200104", "19151105", "9851475", "21800642", "6527988", "7852062", "11906689", "15586837", "1956104" ]	[ "Exposure to environmental tobacco smoke and health effects among hospitality workers in Sweden--before and after the implementation of a smoke-free law.", "Impact of the Spanish smoking law on exposure to second-hand smoke and respiratory health in hospitality workers: a cohort study.", "Smoke-free legislation and hospitalizations for acute coronary syndrome.", "Decline in respiratory symptoms in service workers five months after a public smoking ban.", "Impact of an indoor smoking ban on bar workers' exposure to secondhand smoke.", "Effects of a smoke-free law on hair nicotine and respiratory symptoms of restaurant and bar workers.", "Study of the impact of laws regulating tobacco consumption on the prevalence of passive smoking in Spain.", "Four-year follow-up of smoke exposure, attitudes and smoking behaviour following enactment of Finland's national smoke-free work-place law.", "Secondhand smoke exposure and risk following the Irish smoking ban: an assessment of salivary cotinine concentrations in hotel workers and air nicotine levels in bars.", "Does the workplace-smoking ban eliminate differences in risk for environmental tobacco smoke exposure at work?", "Changes in air quality and second-hand smoke exposure in hospitality sector businesses after introduction of the English Smoke-free legislation.", "Reductions in tobacco smoke pollution and increases in support for smoke-free public places following the implementation of comprehensive smoke-free workplace legislation in the Republic of Ireland: findings from the ITC Ireland/UK Survey.", "The impact of a smoking ban on hospital admissions for coronary heart disease.", "Declines in hospital admissions for acute myocardial infarction in New York state after implementation of a comprehensive smoking ban.", "Effects of the Irish smoking ban on respiratory health of bar workers and air quality in Dublin pubs.", "Changes in smoking among restaurant and bar employees following Norway's comprehensive smoking ban.", "Effect of the Italian smoking ban on population rates of acute coronary events.", "Reduced incidence of admissions for myocardial infarction associated with public smoking ban: before and after study.", "Legislation reduces exposure to second-hand tobacco smoke in New Zealand bars by about 90%.", "Reduced admissions for acute myocardial infarction associated with a public smoking ban: matched controlled study.", "Impact of the \"Tobacco control law\" on exposure to environmental tobacco smoke in Spain.", "Bar workers' health and environmental tobacco smoke exposure (BHETSE): symptomatic improvement in bar staff following smoke-free legislation in Scotland.", "A randomized trial to reduce passive smoke exposure in low-income households with young children.", "Changes in hospitality workers' exposure to secondhand smoke following the implementation of New York's smoke-free law.", "Short-term effects of Italian smoking regulation on rates of hospital admission for acute myocardial infarction.", "Scottish smoke-free legislation and trends in smoking cessation.", "Changes in child exposure to environmental tobacco smoke (CHETS) study after implementation of smoke-free legislation in Scotland: national cross sectional survey.", "Reduction incidence of myocardial infarction associated with a national legislative ban on smoking.", "A comprehensive worksite cancer prevention intervention: behavior change results from a randomized controlled trial (United States).", "Protecting sick children from exposure to passive smoking through mothers' actions: a randomized controlled trial of a nursing intervention.", "Evaluation of a Dutch community-based smoking cessation intervention.", "Trial of an intervention to reduce passive smoking in infancy.", "Smoking reduction intervention in a large population-based study. The Inter99 study.", "Effectiveness of postal smoking cessation advice: a randomized controlled trial in young men with reduced FEV1 and asbestos exposure.", "Changes in exposure of adult non-smokers to secondhand smoke after implementation of smoke-free legislation in Scotland: national cross sectional survey.", "A minimal-contact intervention for cardiac inpatients: long-term effects on smoking cessation.", "The impact of smokefree legislation in Scotland: results from the Scottish ITC: Scotland/UK longitudinal surveys.", "Bartenders' respiratory health after establishment of smoke-free bars and taverns.", "[A pre assessment for nursing intervention to support tobacco cessation in patients hospitalized for cardiac problems: a pilot study (So-Live)].", "Effects of physician counseling on the smoking behavior of asbestos-exposed workers.", "A comparison of nursing interventions for smoking cessation in adults with cardiovascular health problems.", "Pilot evaluation of a population-based health intervention for reducing use of smokeless tobacco.", "Results of a randomized controlled trial of intervention to implement smoking guidelines in Veterans Affairs medical centers: increased use of medications without cessation benefit.", "Active enforcement of cigarette control laws in the prevention of cigarette sales to minors." ]	[ "This study attempted to identify changes in exposure to environmental tobacco smoke, as well as symptoms and attitudes among hospitality workers after the introduction of extended smoke-free workplace legislation.\n A total of 37 volunteers working in bingo halls and casinos (gaming workers) and 54 bars and restaurant employees (other workers) in nine Swedish communities participated in the study. Altogether 71 of 91 persons (14 daily smokers and 57 nonsmokers) participated in both the pre-ban baseline survey and the follow-up 12 months after the ban. Exposure to environmental tobacco smoke, smoking habits, respiratory and sensory symptoms, and attitudes towards the ban were recorded, and spirometry was carried out.\n The frequency of reported respiratory and sensory symptoms was approximately halved among the nonsmokers in both occupational groups after the introduction of the ban. Initially 87% had exposure to environmental tobacco smoke that was over the nicotine cut-off level chosen to identify possible health risk ( <0.5 microg/m3) while, after the ban, it was only 22%, a relative risk of 0.25 (95% confidence interval 0.15-0.41). The risk decreased in both occupational groups, but gaming workers experienced the highest pre-ban exposure levels. Attitudes towards the legislation were largely positive, particularly after the ban. However, there was no notable change in lung function, and there was no notable reduction in the number of cigarettes consumed by smokers.\n The introduction of smoke-free legislation was associated with a substantial reduction in respiratory and sensory symptoms, as well as reduced exposure to environmental tobacco smoke at work, particularly among gaming workers.", "A smoke-free law came into effect in Spain on 1st January 2006, affecting all enclosed workplaces except hospitality venues, whose proprietors can choose among totally a smoke-free policy, a partial restriction with designated smoking areas, or no restriction on smoking on the premises. We aimed to evaluate the impact of the law among hospitality workers by assessing second-hand smoke (SHS) exposure and the frequency of respiratory symptoms before and one year after the ban.\n We formed a baseline cohort of 431 hospitality workers in Spain and 45 workers in Portugal and Andorra. Of them, 318 (66.8%) were successfully followed up 12 months after the ban, and 137 nonsmokers were included in this analysis. We obtained self-reported exposure to SHS and the presence of respiratory symptoms, and collected saliva samples for cotinine measurement. Salivary cotinine decreased by 55.6% after the ban among nonsmoker workers in venues where smoking was totally prohibited (from median of 1.6 ng/ml before to 0.5 ng/ml, p<0.01). Cotinine concentration decreased by 27.6% (p = 0.068) among workers in venues with designated smoking areas, and by 10.7% (p = 0.475) among workers in venues where smoking was allowed. In Portugal and Andorra, no differences between cotinine concentration were found before (1.2 ng/ml) and after the ban (1.2 ng/ml). In Spain, reported respiratory symptom declined significantly (by 71.9%; p<0.05) among workers in venues that became smoke-free. After adjustment for potential confounders, salivary cotinine and respiratory symptoms decreased significantly among workers in Spanish hospitality venues where smoking was totally banned.\n Among nonsmoker hospitality workers in bars and restaurants where smoking was allowed, exposure to SHS after the ban remained similar to pre-law levels. The partial restrictions on smoking in Spanish hospitality venues do not sufficiently protect hospitality workers against SHS or its consequences for respiratory health.", "Previous studies have suggested a reduction in the total number of hospital admissions for acute coronary syndrome after the enactment of legislation banning smoking in public places. However, it is unknown whether the reduction in admissions involved nonsmokers, smokers, or both.\n Since the end of March 2006, smoking has been prohibited by law in all enclosed public places throughout Scotland. We collected information prospectively on smoking status and exposure to secondhand smoke based on questionnaires and biochemical findings from all patients admitted with acute coronary syndrome to nine Scottish hospitals during the 10-month period preceding the passage of the legislation and during the same period the next year. These hospitals accounted for 64% of admissions for acute coronary syndrome in Scotland, which has a population of 5.1 million.\n Overall, the number of admissions for acute coronary syndrome decreased from 3235 to 2684--a 17% reduction (95% confidence interval, 16 to 18)--as compared with a 4% reduction in England (which has no such legislation) during the same period and a mean annual decrease of 3% (maximum decrease, 9%) in Scotland during the decade preceding the study. The reduction in the number of admissions was not due to an increase in the number of deaths of patients with acute coronary syndrome who were not admitted to the hospital; this latter number decreased by 6%. There was a 14% reduction in the number of admissions for acute coronary syndrome among smokers, a 19% reduction among former smokers, and a 21% reduction among persons who had never smoked. Persons who had never smoked reported a decrease in the weekly duration of exposure to secondhand smoke (P<0.001 by the chi-square test for trend) that was confirmed by a decrease in their geometric mean concentration of serum cotinine from 0.68 to 0.56 ng per milliliter (P<0.001 by the t-test).\n The number of admissions for acute coronary syndrome decreased after the implementation of smoke-free legislation. A total of 67% of the decrease involved nonsmokers. However, fewer admissions among smokers also contributed to the overall reduction.\n 2008 Massachusetts Medical Society", "To evaluate the effect of a total ban on smoking indoors in restaurants and other hospitality business premises in Norway, on respiratory symptoms among workers in the industry.\n Phone interviews with 1525 employees in the hospitality business were conducted immediately before the enacting of the law. In a follow-up study five months later, 906 of the workers from the baseline sample participated. Questions were asked on demographic variables, passive smoking exposure, personal smoking, attitudes towards the law, and five respiratory symptoms. Change in symptom prevalence was analysed with McNemar's test and with analysis of variance (ANOVA) for repeated measures.\n The prevalence of all five symptoms declined after the ban; for morning cough from 20.6% to 16.2% (p < 0.01); for daytime cough from 23.2% to 20.9%; for phlegm cough from 15.3% to 11.8% (p < 0.05); for dyspnoea from 19.2% to 13.0% (p < 0.01); and for wheezing from 9.0% to 7.8%. ANOVA showed that the largest decline in symptom prevalence was seen among workers who themselves gave up smoking, and subjects with a positive attitude towards the law before it took effect.\n A significant decrease in respiratory symptoms among service industry workers was found five months after the enacting of a public smoking ban.", "To evaluate the impact of an indoor smoke-free bylaw in Toronto, Ontario, implemented June 2004.\n We used a pre-post comparison design to assess secondhand smoke (SHS) exposure among 79 eligible bar workers in Toronto, Ontario (bylaw enacted), and 49 eligible bar workers in a control community, Windsor, Ontario (no bylaw change), at four times: preban, and 1, 2, and 9 months postban.\n SHS exposure time and urinary cotinine level were substantially reduced in Toronto bar workers immediately after the ban by 94% (from 7.8 to 0.5 hours) and 68% (from 24.2 to 7.8 ng/mL), respectively. The reduction was sustained throughout follow-up. There was no change among Windsor bar workers before and after the ban.\n Compliance with the ban was high, and the ban led to a substantial reduction in SHS exposure.", "Bar and restaurant workers' exposure to secondhand smoke (SHS) was compared before and 3 and 6 months after implementation of a smoke-free ordinance.\n Hair nicotine, self-reported exposure to SHS, and respiratory symptoms were assessed on 105 smoking and nonsmoking workers from randomly selected establishments in Lexington, Kentucky. Thirty-eight percent were current smokers with more than half smoking 10 or fewer cigarettes per day. Workers provided a hair sample at baseline and at the 3-month interview.\n There was a significant decline in hair nicotine 3 months postlaw when controlling for cigarettes smoked per day. Bar workers showed a significantly larger decline in hair nicotine compared with restaurant workers. The only significant decline in SHS exposure was in the workplace and other public places. Regardless of smoking status, respiratory symptoms declined significantly postlaw.\n Hospitality workers demonstrated significant declines in hair nicotine and respiratory symptoms after the law. Comprehensive smoke-free laws can provide the greatest protection to bar workers who are the most vulnerable to SHS exposure at work.", "In 2005, the Spanish parliament passed the Spanish anti-smoking law. This legislation restricted tobacco smoking in public places, including recreation venues (bars and restaurants), but smoking was not completely prohibited in bars and restaurants. The law was enforced in January 2006. With the objective of analysing the impact that this law has had on the general Spanish population, the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) designed and implemented a survey of a representative sample of the general Spanish population on two separate occasions: in 2005 and in 2007 (12 months after the ban came into effect).\n Two epidemiological, observational and cross-sectional surveys were performed among a random and representative sample of the general Spanish population, using the Computer-Assisted Telephone Interview system.\n In the first survey, a total of 6533 subjects were interviewed, of whom 3907 (59.8%) were non-smokers and in the second, a total of 3289 subjects were interviewed, of whom 2174 (65.9%) were non-smokers. The overall prevalence of exposure to environmental tobacco smoke (ETS) decreased from 49.5% in 2005 to 37.9% in 2007 (22% reduction). The greatest reduction in prevalence of ETS exposure was in workplaces (from 25.8% to 11%, a decrease of 58.8%). Smaller reductions occurred in the home (from 29.5% to 21.4%, a decrease of 27%) and in recreation venues (from 37.4% to 31.8%, a decrease of 8%).\n Implementation of the smoking ban resulted in a significant decrease in exposure to ETS.", "This study evaluated the possible impact of national smoke-free work-place legislation on employee exposure to environmental tobacco smoke (ETS), employee smoking habits and attitudes on work-place smoking regulations.\n Repeated cross-sectional questionnaire surveys and indoor air nicotine measurements were carried out before, and 1 and 3 years after the law had come into effect.\n Industrial, service sector and office work-places from the Helsinki metropolitan area, Finland.\n A total of 880, 940 and 659 employees (response rates 70%, 75% and 75%) in eight work-places selected from a register kept by the Uusimaa Regional Institute of Occupational Health to represent various sectors of public and private work-places.\n Reported exposure to ETS, smoking habits, attitudes on smoking at work and measurements of indoor air nicotine concentration.\n Employee exposure to ETS for at least 1 hour daily decreased steadily during the 4-year follow-up, from 51% in 1994 to 17% in 1995 and 12% in 1998. Respondents' daily smoking prevalence and tobacco consumption diminished 1 year after the enforcement of legislation from 30% to 25%, and remained at 25% in the last survey 3 years later. Long-term reduction in smoking was confined to men. Both smokers' and non-smokers' attitudes shifted gradually towards favouring a total ban on smoking at work. Median indoor airborne nicotine concentrations decreased from 0.9 micro g/m3 in 1994-95 to 0.1 micro g/m3 in 1995-96 and 1998.\n This is the first follow-up study on a nationally implemented smoke-free work-place law. We found that such legislation is associated with steadily reducing ETS exposure at work, particularly at work-places, where the voluntary smoking regulations have failed to reduce exposure. The implementation of the law also seemed to encourage smokers to accept a non-smoking work-place as the norm.", "To investigate whether the Irish smoking ban has had an impact on secondhand smoke (SHS) exposures for hospitality workers.\n Before and after the smoking ban a cohort of workers (n = 35) from a sample of city hotels (n = 15) were tested for saliva cotinine concentrations and completed questionnaires. Additionally, a random sample (n = 20) of city centre bars stratified by size (range 400-5000 square feet), were tested for air nicotine concentrations using passive samplers before and after the ban.\n Salivary cotinine concentrations (ng/ml), duration of self reported exposures to secondhand smoke, air nicotine (microg/cubic metre).\n Cotinine concentrations reduced by 69%, from 1.6 ng/ml to 0.5 ng/ml median (SD 1.29; p < 0.005). Overall 74% of subjects experienced decreases (range 16-99%), with 60% showing a halving of exposure levels at follow up. Self reported exposure to SHS at work showed a significant reduction from a median 30 hours a week to zero (p < 0.001). There was an 83% reduction in air nicotine concentrations from median 35.5 microg/m3 to 5.95 microg/m3 (p < 0.001). At baseline, three bars (16%) were below the 6.8 microg/m3 air nicotine significant risk level for lung cancer alone; at follow up this increased to 10 (53%).\n Passive smoking and associated risks were significantly reduced but not totally eliminated. Exposure to SHS is still possible for those working where smoking is still allowed and those working where smoke may migrate from outdoor areas. Further research is required to assess the true extent and magnitude of these exposures.", "A workplace-smoking ban in the Netherlands was introduced on January 1, 2004. Before the ban male and low educated employees were at higher risk for exposure to environmental tobacco smoke (ETS). Effective implementation of the ban should result not only in an overall decline of exposure, but also in the disappearance of systematic differences in exposure between subgroups of employees.\n Data from a Dutch continuous Internet survey were used. From July 2003 through June 2005, 200 respondents were randomly selected each week. The sample consisted of 11,291 non-smoking, working respondents, aged 16-65 years.\n ETS exposure decreased among all employees and among subgroups at higher risk before the ban. However, also after the ban, males and low educated employees were still most likely to be exposed to ETS.\n The workplace-smoking ban was effective in reducing ETS exposure among employees. However, after the ban still 52.2% of non-smoking workers reported to be exposed. We did not find the expected stronger effect among employees who were at higher risk. Both before and after implementation of the ban, males and lower educated employees were about two times more likely to be exposed to ETS.", "To monitor and disseminate the short-term effects of the English Smoke-free legislation on air quality and employee exposure in businesses of the hospitality industry.\n Indoor particle concentrations and salivary cotinine levels were measured in businesses in the hospitality sector and non-smoking employees one month before and after the implementation of the legislation. Results were immediately released to the media to announce the improvements in air quality and employee exposure to the wider public.\n Measurements were collected in 49 businesses and from 75 non-smoking individuals. Indoor PM(2.5) concentrations decreased by 95% from 217 microg/m(3) at baseline to 11 microg/m(3) at follow-up (P < 0.001). Salivary cotinine in employees was reduced by 75%, from 3.6 ng/ml at baseline to 0.9 ng/ml at follow-up (P < 0.001). The findings were presented to the public through press releases and interviews and were cited in over 20 media articles.\n The project demonstrates the positive effects of the English Smoke-free legislation on air quality and second-hand smoke exposure in the hospitality industry sector. We believe that quick and positive feedback to the public on the effects of smoking restrictions is essential when introducing public health legislation such as the Smoke-free legislation.", "To evaluate the psychosocial and behavioural impact of the first ever national level comprehensive workplace smoke-free law, implemented in Ireland in March 2004.\n Quasi-experimental prospective cohort survey: parallel cohort telephone surveys of national representative samples of adult smokers in Ireland (n = 769) and the UK (n = 416), surveyed before the law (December 2003 to January 2004) and 8-9 months after the law (December 2004 to January 2005).\n Respondents' reports of smoking in key public venues, support for total bans in those key venues, and behavioural changes due to the law.\n The Irish law led to dramatic declines in reported smoking in all venues, including workplaces (62% to 14%), restaurants (85% to 3%), and bars/pubs (98% to 5%). Support for total bans among Irish smokers increased in all venues, including workplaces (43% to 67%), restaurants (45% to 77%), and bars/pubs (13% to 46%). Overall, 83% of Irish smokers reported that the smoke-free law was a \"good\" or \"very good\" thing. The proportion of Irish homes with smoking bans also increased. Approximately 46% of Irish smokers reported that the law had made them more likely to quit. Among Irish smokers who had quit at post-legislation, 80% reported that the law had helped them quit and 88% reported that the law helped them stay quit.\n The Ireland smoke-free law stands as a positive example of how a population-level policy intervention can achieve its public health goals while achieving a high level of acceptance among smokers. These findings support initiatives in many countries toward implementing smoke-free legislation, particularly those who have ratified the Framework Convention on Tobacco Control, which calls for legislation to reduce tobacco smoke pollution.", "In March 2002, the city of Bowling Green, Ohio, implemented a clean indoor air ordinance banning smoking in workplaces and public places. This study evaluates the effect of this ordinance on hospital admissions for smoking-related diseases.\n A quasi-experimental design with interrupted time-series was used including a matched control city (Kent, Ohio) with no clean indoor air ordinance. Data on hospital admissions during the period of January 1999 to June 2005 were analyzed using Autoregressive Integrated Moving Average (ARIMA) models.\n A reduction in admission rates for smoking-related diseases was achieved in Bowling Green compared to the control city. The largest reduction was for coronary heart disease, where rates were decreased significantly by 39% after 1 year and by 47% after 3 years following the implementation of the ordinance. ARIMA models revealed a statistically significant downward trend in monthly admission rates for coronary heart disease (Bowling Green, omega=-1.69, p=0.036 vs. Kent, omega=-1.14, p=0.183) and support the hypothesis that the ordinance had a significant impact on admission rates for coronary heart disease.\n The findings of this study suggest that clean indoor air ordinances lead to a reduction in hospital admissions for coronary heart disease, thus reducing health care costs.", "Reductions in exposure to environmental tobacco smoke have been shown to attenuate the risk of cardiovascular disease. We examined whether the 2003 implementation of a comprehensive smoking ban in New York State was associated with reduced hospital admissions for acute myocardial infarction and stroke, beyond the effect of moderate, local and statewide smoking restrictions, and independent of secular trends.\n We analyzed trends in county-level, age-adjusted, monthly hospital admission rates for acute myocardial infarction and stroke from 1995 to 2004 to identify any association between admission rates and implementation of the smoking ban. We used regression models to adjust for the effects of pre-existing smoking restrictions, seasonal trends in admissions, differences across counties, and secular trends.\n In 2004, there were 3813 fewer hospital admissions for acute myocardial infarction than would have been expected in the absence of the comprehensive smoking ban. Direct health care cost savings of $56 million were realized in 2004. There was no reduction in the number of admissions for stroke.\n Hospital admission rates for acute myocardial infarction were reduced by 8% as a result of a comprehensive smoking ban in New York State after we controlled for other relevant factors. Comprehensive smoking bans constitute a simple, effective intervention to substantially improve the public's health.", "Environmental tobacco smoke (ETS) causes disease in nonsmokers. Workplace bans on smoking are interventions to reduce exposure to ETS to try to prevent harmful health effects. On March 29, 2004, the Irish government introduced the first national comprehensive legislation banning smoking in all workplaces, including bars and restaurants. This study examines the impact of this legislation on air quality in pubs and on respiratory health effects in bar workers in Dublin.\n Exposure study. Concentrations of particulate matter 2.5 microm or smaller (PM(2.5)) and particulate matter 10 microm or smaller (PM(10)) in 42 pubs were measured and compared before and after the ban. Benzene concentrations were also measured in 26 of the pubs. Health effects study. Eighty-one barmen volunteered to have full pulmonary function studies, exhaled breath carbon monoxide, and salivary cotinine levels performed before the ban and repeated 1 year after the ban. They also completed questionnaires on exposure to ETS and respiratory symptoms on both occasions.\n Exposure study. There was an 83% reduction in PM(2.5) and an 80.2% reduction in benzene concentration in the bars. Health effects study. There was a 79% reduction in exhaled breath carbon monoxide and an 81% reduction in salivary cotinine. There were statistically significant improvements in measured pulmonary function tests and significant reductions in self-reported symptoms and exposure levels in nonsmoking barmen volunteers after the ban.\n A total workplace smoking ban results in a significant reduction in air pollution in pubs and an improvement in respiratory health in barmen.", "Norway implemented a nationwide ban on indoor smoking in June 2004. This study documents the smoking patterns of Norway's restaurant and bar workers before and after the ban, to determine changes in smoking prevalence and explore which individual and environmental characteristics were related to cessation. A national sample of food service workers was surveyed by telephone or Internet immediately before the ban and at 4 and 11 months post-implementation. Results showed that between baseline measurement and 4 months post-implementation, there were significant declines in prevalence of daily smoking (-3.6% points, p < 0.005), daily smoking at work (-6.2% points, p < 0.001), number of cigarettes smoked by continuing smokers (-1.55, p < 0.001) and number of cigarettes smoked at work by continuing smokers (-1.63, p < 0.001). No significant changes occurred in any of these variables between 4 and 11 months post-implementation. Logistic regression analysis revealed that only smokers' intentions at baseline to quit within 30 days predicted cessation at both follow-up time points. In addition, cessation at 4 months was predicted by lower daily cigarette consumption at baseline, whereas cessation at 11 months was predicted by baseline attitude toward ETS and exposure to ETS as measured at follow-up. In sum, Norway's smoking ban was accompanied by a reduction in smoking in the period immediately following the ban, and the reduction was maintained almost a year later. The finding that smoking cessation was consistently associated with smokers' intentions to quit within 30 days suggests that motivational and support programs could play a significant role in boosting cessation rates. It is recommended that targeted interventions be used to supplement the benefits of a comprehensive ban to achieve tobacco control objectives.", "Several countries in the world have not yet prohibited smoking in public places. Few studies have been conducted on the effects of smoking bans on cardiac health. We evaluated changes in the frequency of acute coronary events in Rome, Italy, after the introduction of legislation that banned smoking in all indoor public places in January 2005.\n We analyzed acute coronary events (out-of-hospital deaths and hospital admissions) between 2000 and 2005 in city residents 35 to 84 years of age. We computed annual standardized rates and estimated rate ratios by comparing the data from prelegislation (2000-2004) and postlegislation (2005) periods. We took into account several time-related potential confounders, including particulate matter (PM10) air pollution, temperature, influenza epidemics, time trends, and total hospitalization rates. The reduction in acute coronary events was statistically significant in 35- to 64-year-olds (11.2%, 95% CI 6.9% to 15.3%) and in 65- to 74-year-olds (7.9%, 95% CI 3.4% to 12.2%) after the smoking ban. No evidence was found of an effect among the very elderly. The reduction tended to be greater in men and among lower socioeconomic groups.\n We found a statistically significant reduction in acute coronary events in the adult population after the smoking ban. The size of the effect was consistent with the pollution reduction observed in indoor public places and with the known health effects of passive smoking. The results affirm that public interventions that prohibit smoking can have enormous public health implications.", "To determine whether there was a change in hospital admissions for acute myocardial infarction while a local law banning smoking in public and in workplaces was in effect.\n Analysis of admissions from December 1997 through November 2003 using Poisson analysis.\n Helena, Montana, a geographically isolated community with one hospital serving a population of 68 140.\n All patients admitted for acute myocardial infarction.\n Number of monthly admissions for acute myocardial infarction for people living in and outside Helena.\n During the six months the law was enforced the number of admissions fell significantly (- 16 admissions, 95% confidence interval - 31.7 to - 0.3), from an average of 40 admissions during the same months in the years before and after the law to a total of 24 admissions during the six months the law was effect. There was a non-significant increase of 5.6 (- 5.2 to 16.4) in the number of admissions from outside Helena during the same period, from 12.4 in the years before and after the law to 18 while the law was in effect.\n Laws to enforce smoke-free workplaces and public places may be associated with an effect on morbidity from heart disease.", "To measure exposure to second-hand smoke (SHS) in New Zealand bars before and after comprehensive smoke-free legislation enacted on 10 December 2004.\n Cotinine is the main specific metabolite of nicotine and a well-established biomarker for SHS exposure. We measured cotinine levels in saliva of non-smoking volunteers before and after a 3 h visit to 30 randomly selected bars in 3 cities across the country. Two measures of cotinine before the smoke-free law change during winter and spring 2004, and two follow-up measurements in the same volunteers and venues during winter and spring 2005, were included.\n Before the smoke-free law change, in all bars and in all volunteers, exposure to SHS was evident with an average increase in saliva cotinine of 0.66 ng/ml (SE 0.03 ng/ml). Increases in cotinine correlated strongly with the volunteers' subjective observation of ventilation, air quality and counts of lit cigarettes. However, even venues that were judged to be \"seemingly smoke free\" with \"good ventilation\" produced discernable levels of SHS exposure. After the law change, there remained some exposure to SHS, but at much lower levels (mean saliva cotinine increase of 0.08 ng/ml, SE 0.01 ng/ml). Smoking indoors in bars was almost totally eliminated: in 2005 only one lit cigarette was observed in 30 visits.\n Comprehensive smoke-free legislation in New Zealand seems to have reduced exposure of bar patrons to SHS by about 90%. Residual exposures to SHS in bars do not result from illicit smoking indoors.", "There has been no research linking implementation of a public smoking ban and reduced incidence of acute myocardial infarction (AMI) among nonsmoking patients. An ex post facto matched control group study was conducted to determine whether there was a change in hospital admissions for AMI among nonsmoking patients after a public smoking ban was implemented in Monroe County compared with Delaware County, Indiana without such a ban. Poisson analysis was conducted for 44 months of hospital admissions. A significant drop occurred in the number of admissions among nonsmoking patients in Monroe County after the ban whereas a nonsignificant decrease in the number of admissions occurred in Delaware County. The changes in the number of smoking-patient admissions before and after the ban were not significant.", "The initial evaluations of the introduction of legislation that regulates smoking in enclosed public places in European countries, describe an important effect in the control of exposure to environmental tobacco smoke. However, the evidence is still limited. The objective of this study is to estimate the short-term effects of the comprehensive \"Tobacco control law\" introduced in Spain on January 2006, which includes a total ban of smoking in workplaces and a partial limitation of smoking in bars and restaurants.\n Cross-sectional, population-based study. The self-reported exposure to environmental tobacco smoke at home, at work, in bars and restaurants of the population aged 18 to 64 years in the Madrid Region during a period prior to the law (October and November 2005; n = 1750) was compared to that of the period immediately after the law came into force (January-July 2006; n = 1252). Adjusted odds ratios (OR) were calculated using logistic regression models.\n Passive exposure to tobacco smoke at home has hardly changed. However, at indoor workplaces there has been a considerable reduction: after the law came into force the OR for daily exposure > 0-3 hours versus non-exposure was 0.11 (95% CI: 0.07 to 0.17) and for more than 3 hours, 0.12 (95% CI: 0.09 to 0.18). For fairly high exposure in bars and restaurants versus non-exposure, the OR in the former was 0.30 (95% CI: 0.20 to 0.44) and in the latter was 0.24 (95% CI: 0.18 to 0.32); for very high exposure versus non-exposure they were 0.16 (95% CI: 0.10 to 0.24) and 0.11 (95% CI: 0.07 to 0.19), respectively. These results were similar for the smoking and non-smoking populations.\n A considerable reduction in exposure to environmental tobacco smoke in the workplace and, to a lesser extent, in bars and restaurants, is related to the implementation of the \"Tobacco control law\". Although only initial figures, these results already demonstrate the effectiveness of strategies that establish control measures to guarantee smoke-free places.", "To examine changes in the health of bar workers after smoke-free legislation was introduced.\n Longitudinal study following bar workers from before legislation introduction, at 2 months after introduction and at 1 year to control for seasonal differences.\n Bars across a range of socio-economic settings in Scotland.\n 371 bar workers recruited from 72 bars.\n Introduction of smoke-free legislation prohibiting smoking in enclosed public places, including bars. Main outcomes measures: Change in prevalence of self-reported respiratory and sensory symptoms.\n Of the 191 (51%) workers seen at 1-year follow-up, the percentage reporting any respiratory symptom fell from 69% to 57% (p = 0.02) and for sensory symptoms from 75% to 64% (p = 0.02) following reductions in exposure, effects being greater at 2 months, probably partly due to seasonal effects. Excluding respondents who reported having a cold at either baseline or 1 year, the reduction in respiratory symptoms was similar although greater for \"any\" sensory symptom (69% falling to 54%, p = 0.011). For non-smokers (n = 57) the reductions in reported symptoms were significant for phlegm production (32% to 14%, p = 0.011) and red/irritated eyes (44% to 18%, p = 0.001). Wheeze (48% to 31%, p = 0.006) and breathlessness (42% to 29%, p = 0.038) improved significantly in smokers. There was no relationship between change in salivary cotinine levels and change in symptoms.\n Bar workers in Scotland reported significantly fewer respiratory and sensory symptoms 1 year after their working environment became smoke free. As these improvements, controlled for seasonal variations, were seen in both non-smokers and smokers, smoke-free working environments may have potentially important benefits even for smokers.", "Passive smoke exposure among children is widespread in the United States; estimates suggest that almost 40% of children who are younger than 5 years live with a smoker. Few randomized studies of passive smoke exposure reduction among children have been conducted, and the impact of interventions that have been evaluated has been limited. The objective of this study was to determine whether a motivational intervention for smoking parents of young children will lead to reduced household passive smoke exposure.\n Project KISS (Keeping Infants Safe From Smoke), a theory-driven exposure reduction intervention targeting low-income families with young children, was a randomized controlled study in which participants-smoking parents/caregivers (N = 291) who had children who were younger than 3 years and who were recruited through primary care settings-were randomly assigned to either the motivational intervention (MI) or a self-help (SH) comparison condition was used. Follow-up assessments were conducted at 3 and 6 months. The MI condition consisted of a 30- to 45-minute motivational interviewing session at the participant's home with a trained health educator and 4 follow-up telephone counseling calls. Feedback from baseline household air nicotine assessments and assessment of the participant's carbon monoxide level was provided as part of the intervention. Participants in the SH group received a copy of the smoking cessation manual, the passive smoke reduction tip sheet, and the resource guide in the mail. Household nicotine levels were measured by a passive diffusion monitor.\n The 6-month nicotine levels were significantly lower in MI households. Repeated measures analysis of variance across baseline, 3-month, and 6-month time points showed a significant time-by-treatment interaction, whereby nicotine levels for the MI group decreased significantly and nicotine levels for the SH group increased but were not significantly different from baseline.\n This study targeted a large sample of racially and ethnically diverse low-income families, in whom both exposure and disease burden is likely to be significant. This is the first study to our knowledge that has been effective in reducing objective measures of passive smoke exposure in households with healthy children. These findings have important implications for pediatric health care providers, who play an important role in working with parents to protect children's health. Providers can help parents work toward reducing household passive smoke exposure using motivational strategies and providing a menu of approaches regardless of whether the parents are ready to quit.", "To assess the impact on hospitality workers' exposure to secondhand smoke of New York's smoke-free law that prohibits smoking in all places of employment, including restaurants, bars, and bowling facilities.\n Pre-post longitudinal follow up design.Settings: Restaurants, bars, and bowling facilities in New York State.\n At baseline, 104 non-smoking workers in restaurants, bars, and bowling facilities were recruited with newspaper ads, flyers, and radio announcements. Of these, 68 completed a telephone survey and provided at least one saliva cotinine specimen at baseline. At three, six, and 12 month follow up studies, 47, 38, and 32 workers from the baseline sample of 68 completed a telephone survey and provided at least one saliva cotinine specimen.\n The smoke-free law went into effect 24 July 2003.\n Self reported sensory and respiratory symptoms and exposure to secondhand smoke; self administered saliva cotinine specimens. Analyses were limited to subjects in all four study periods who completed a telephone survey and provided at least one saliva cotinine specimen.\n All analyses were limited to participants who completed both an interview and a saliva specimen for all waves of data collection (n = 30) and who had cotinine concentrations < or = 15 ng/ml (n = 24). Hours of exposure to secondhand smoke in hospitality jobs decreased from 12.1 hours (95% confidence interval (CI) 8.0 to 16.3 hours) to 0.2 hours (95% CI -0.1 to 0.5 hours) (p < 0.01) and saliva cotinine concentration decreased from 3.6 ng/ml (95% CI 2.6 to 4.7 ng/ml) to 0.8 ng/ml (95% CI 0.4 to 1.2 ng/ml) (p < 0.01) from baseline to the 12 month follow up. The prevalence of workers reporting sensory symptoms declined from 88% (95% CI 66% to 96%) to 38% (95% CI 20% to 59%) (p < 0.01); there was no change in the overall prevalence of upper respiratory symptoms (p < 0.16).\n New York's smoke-free law had its intended effect of protecting hospitality workers from exposure to secondhand smoke within three months of implementation. One year after implementation, the results suggest continued compliance with the law.", "We used the hospital discharge records of Piedmont region (northern Italy) to evaluate whether a national law banning smoking in public resulted in a short-term reduction in hospital admissions for acute myocardial infarction (AMI).\n Rates of admission for AMI before the ban (October-December 2004) and during the ban (February-June 2005) were analysed. Each period was compared with the corresponding period 12 months before. Among persons aged under 60, the number of admissions for AMI decreased significantly after the introduction of the ban: from 922 cases in February-June 2004 to 832 cases in February-June 2005 (sex- and age-adjusted rate ratio, 0.89; 95% confidence interval, 0.81-0.98). No decrease was seen before the ban. No effect was found among persons aged at least 60. We estimated that the observed reduction in active smoking after the introduction of the ban could account for a 0.7% decrease in admissions for AMI during the study period, suggesting that most of the observed effect (11%) might be due to the reduction of passive smoking.\n Our study, based on a population of about 4 million inhabitants, suggests that smoke-free policies may result in a short-term reduction in admissions for AMI.", "To investigate trends in smoking cessation before and after the introduction of Scottish smoke-free legislation and to assess the perceived influence of the legislation on giving up smoking and perceptions of the legislation in smokers.\n Longitudinal data on smoking cessation were obtained from 1998 to 2007 on a cohort of 3350 Scottish adults aged between 50 and 75 years at baseline. All members of the cohort were participating in a clinical trial of aspirin in people at moderately increased risk of cardiovascular events. A subgroup of 474 participants who had smoked in the year prior to the introduction of legislation in March 2006 also completed a questionnaire on the influence and perceptions of the smoke-free legislation following its introduction.\n Smoking status was recorded yearly, including dates of quitting and restarting. Participants who gave up smoking for at least 3 months were recorded as having quit smoking. The questionnaire included scales on whether the smoke-free legislation had helped/influenced cessation, made the individual think about/prompt them to quit and perceptions of the legislation.\n The odds of smokers quitting annually increased throughout the 7-year period prior to introduction of the smoke-free legislation to 2 years afterwards (odds ratio 1.09, 95% confidence interval 1.05-1.12, P<0.001). During 2006, the pattern of quarterly quitting rates changed, with an increase in quit rates (to 5.1%) in the 3-month period prior to introduction of the legislation (January-March 2006). Socio-economic status was not related to smoking cessation. In the subgroup completing the questionnaire (n=474), 57 quit smoking between June 2005 and May 2007 and 43.9% of these said that the smoke-free legislation had helped them to quit. Most (>70%) smokers were positive about the legislation, especially those from more affluent compared with more deprived communities (P=0.01).\n The Scottish smoke-free legislation was associated with an increase in the rate of smoking cessation in the 3-month period immediately prior to its introduction. Overall quit rates in the year the legislation was introduced and the subsequent year were consistent with a gradual increase in quit rates prior to introduction of the legislation. Socio-economic status was not related to smoking cessation, but individuals from more affluent communities were more positive about the legislation.", "To detect any change in exposure to secondhand smoke among primary schoolchildren after implementation of smoke-free legislation in Scotland in March 2006.\n Comparison of nationally representative, cross sectional, class based surveys carried out in the same schools before and after legislation.\n Scotland.\n 2559 primary schoolchildren (primary 7; mean age 11.4 years) surveyed in January 2006 (before smoke-free legislation) and 2424 in January 2007 (after legislation).\n Salivary cotinine concentrations, reports of parental smoking, and exposure to tobacco smoke in public and private places before and after legislation.\n The geometric mean salivary cotinine concentration in non-smoking children fell from 0.36 (95% confidence interval 0.32 to 0.40) ng/ml to 0.22 (0.19 to 0.25) ng/ml after the introduction of smoke-free legislation in Scotland-a 39% reduction. The extent of the fall in cotinine concentration varied according to the number of parent figures in the home who smoked but was statistically significant only among pupils living in households in which neither parent figure smoked (51% fall, from 0.14 (0.13 to 0.16) ng/ml to 0.07 (0.06 to 0.08) ng/ml) and among pupils living in households in which only the father figure smoked (44% fall, from 0.57 (0.47 to 0.70) ng/ml to 0.32 (0.25 to 0.42) ng/ml). Little change occurred in reported exposure to secondhand smoke in pupils' own homes or in cars, but a small decrease in exposure in other people's homes was reported. Pupils reported lower exposure in cafes and restaurants and in public transport after legislation.\n The Scottish smoke-free legislation has reduced exposure to secondhand smoke among young people in Scotland, particularly among groups with lower exposure in the home. We found no evidence of increased secondhand smoke exposure in young people associated with displacement of parental smoking into the home. The Scottish smoke-free legislation has thus had a positive short term impact on young people's health, but further efforts are needed to promote both smoke-free homes and smoking cessation.", "The aim of the present study was to assess change in admissions for acute myocardial infarction (AMI) in the period immediately subsequent to the coming into force of law no. 3/2003 ''Protection of the health of non-smokers''.\n Four Italian regions (Piedmont, Friuli Venezia Giulia, Lazio and Campania) took part in the study. Data regarding admissions for AMI were taken from the daily discharge papers of patients aged between 40 and 64 (cod. ICD9-CM 410.), in the period 10 January-10 March 2001-2005. Repeated admissions were excluded. Admission rates standardised by age and overall total, and specifically by region, age and gender were calculated. The hypothesis of a significant reduction between 2005 and 2004 was also checked.\n The results showed a decrease in the number of cases and in the standardised rates between 2004 and 2005. The number of admissions estimated with a linear regression model for 2005 was significantly higher than that really observed (+13%). The decrease between the 2005 and 2004 rates was noteworthy for all four regions. Analysis by gender shows that the effect is observed only in male patients and in the age classes 45-49 and 50-54.\n This study shows that there has been an appreciable reduction in the incidence of heart attacks in the period immediately subsequent to the coming into force of the non-smoking Law in the populations surveyed, and that this reduction mainly regards men of working age. The reduction reverses a trend that has been evident for a number of years, namely that of a decidedly upward trend in the number of admissions for AMI.", "Workplace cancer prevention initiatives have been least successful with blue-collar workers. This study assess whether an intervention integrating health promotion with occupational health and safety results in significant and meaningful increases in smoking cessation and consumption of fruits and vegetables, compared to a standard health promotion intervention, for workers overall and for blue-collar workers in particular.\n A randomized controlled design was used, with 15 manufacturing worksites assigned to a health promotion (HP) or a health promotion plus occupational health and safety intervention (HP/OHS), and compared from baseline (1997) to final (1999). The response rates to the survey were 80% at baseline (n = 9019) and 65% at final (n = 7327). Both groups targeted smoking and diet; the HP/OHS condition additionally incorporated reduction of occupational exposures.\n Smoking quit rates among blue-collar workers in the HP/OHS condition more than doubled relative to those in the HP condition (OR = 2.13, p = 0.04), and were comparable to quit rates of white-collar workers. No statistically significant differences between groups were found for mean changes in fruits and vegetables.\n Integration of occupational health and safety and health promotion may be an essential means of enhancing the effectiveness of worksite tobacco control initiatives with blue-collar workers.", "The aim of this study was to evaluate the effectiveness of a nursing educational intervention with mothers of sick children to decrease passive smoking exposure.\n Passive smoking represents a serious health hazard and is a substantial threat to child health causing major risk factors for acute respiratory illness in children. Nurses are in a vital position to conduct health education to improve children's health, which is a legitimate activity in a pediatric ward.\n A randomized controlled trial was conducted in the general paediatric wards of four major hospitals in Hong Kong. The participants were non-smoking mothers of sick children admitted to the paediatric ward and with smoking husbands living in the same household.\n A total of 1483 women were randomized into the intervention (n = 752) and control (n = 731) group. The intervention group received from the nurses (1) standardized health advice; (2) two purpose-designed booklets about preventing exposure to passive smoking and helping fathers quit; (3) a no smoking sticker; and (4) a telephone reminder 1 week later. No intervention was given to the controls. Baseline comparison showed no significant differences between the two groups in the mothers' actions to protect the children from passive smoking exposure. More mothers in the intervention group than the control group had always moved the children away when they were exposed to the fathers' smoke at home at 3-month follow up (78.4% vs. 71.1%; P = 0.01) but became non-significant at 6 and 12 months.\n A simple health education intervention provided by nurses to the mothers in a busy clinical setting can be effective in the short-term to motivate the mothers to take actions to protect the children from exposure to passive smoking produced by the fathers.", "Until 1990, smoking cessation interventions in the Netherlands were limited. The utility and effectiveness of community-based smoking cessation programs have not been examined.\n In a treatment city (Den Bosch) a multicomponent community-based smoking cessation intervention was implemented in which local mass media and general practitioners draw smokers' attention to a local quit line. Telephone counselors advised applicants on their choice between self-help and group treatment and optional telephone counseling. Another Dutch city (Apeldoorn) served as a control. Population samples of smokers (n = 547 and n = 546) were interviewed three times at approximately 7-month intervals. Self-help manual requesters (n = 84) and group participants (n = 83) were interviewed before and 6 months after treatment.\n Treatment modalities were successful; 13% of self-help manual requesters and 22% of group participants were abstinent after 6 months. On a population level the intervention resulted in significantly higher recall of self-help manual and group program in the treatment city. A modest intervention effect on prevalence of abstinence was found at the community level.\n Treatment modalities were effective within their participants, but the intervention effectiveness on a community level was limited. No significant difference was found between quit rates after 14 months (7% in treatment city and 9% in control city). Several system failures could be identified. However, probably the intervention effect was seriously confounded by two national governmental publicity campaigns introducing and reinforcing a mandatory smoking ban and a series of national campaigns initiated by the united Dutch tobacco producers opposing the ban.", "We tested a health education intervention program to reduce passive smoking in infancy. The aim was to develop an instrument for study of tobacco smoke exposure and childhood respiratory illness. One hundred and eighty-four women who had smoked during pregnancy were allocated by month of delivery to an intervention group, to a minimal contact group, or to a follow-up only comparison group. Exposure to smoke was assessed 3 months later by questionnaire and by measurement of cotinine in samples of maternal and infant urine. There was a reduction in maternal smoking associated with contact with research staff, but this was not statistically significant. There were no differences between the groups in the exposure of infants to tobacco smoke. Reasons for this finding may include the timing of the intervention, the heterogeneity of the target group, and the manner in which information was presented on health risks caused by parental smoking.", "Smoking reduction has been introduced as an alternative to smokers unable or unwilling to quit but has never been implemented in a population-based intervention.\n Two thousand four hundred eight daily smokers in all motivational stages were included in a randomised population-based intervention study, in Copenhagen, Denmark. Smokers, unwilling or unable to quit, were encouraged to reduce their tobacco consumption. Furthermore, smokers in the high-intensity intervention were offered participation in smoking reduction groups.\n Twenty-three percent of those who attended both baseline and 1 year visit reported reduction by at least 5 g and 8% reported a halving or more. Halving of tobacco consumption was achieved significantly more often than in the background population, OR = 2.6 (1.6-4.4), even when assuming that non-participants had not reduced, OR = 1.7 (1.0-2.8). Reduction of at least 5 g doubled the probability of increased motivation to quit and a halving increased it more than four times. The reductions were not validated. Less than 2% attended the smoking reduction groups.\n The smoking reduction intervention was significant in self-reported reduction of tobacco consumption and subsequently increased motivation to quit. This may open new perspectives, with reduction as a first step towards cessation, a possible supplement to smoking cessation strategies.", "There have been few community-based randomized, controlled intervention trials for cessation in high-risk smokers. In such a trial we evaluated the effects of postal smoking cessation advice in smokers with asbestos exposure and/or reduced forced expiratory volume in one second (FEV1). All men aged 30-45 yrs (n=22,392) living in 34 municipalities in western Norway were invited to a cross-sectional community survey. Information on smoking habits and occupational asbestos exposure were obtained from self-administered questionnaires and measurements of FEV1 were performed with dry-wedge bellow spirometers. Among 16,393 participants we identified a group of 2,610 smokers with previous occupational asbestos exposure and/or adjusted FEV1 in the lowest quartile. A random half (n=1,300) received a mailed personal letter from a respiratory physician with a person-specific health advice to quit smoking and a pamphlet on smoking cessation. The remaining smokers (n=1,310) acted as controls and did not receive any information. Twelve months after the intervention, information on smoking habits was re-examined using a postal questionnaire. Among the respondents (n=2,282), smoking cessation was reported altogether by 13.7% in the intervention group versus 9.9% in the control group (p<0.01). The 1 yr sustained quit rate (no smoking at all during the last year) was 5.6 versus 35% (p<0.05), respectively. Measurements of carbon monoxide in expired air (with < or = 10 parts per million) confirmed self-reported nonsmoking in samples of the two groups. In a community this simple postal smoking cessation advice from a respiratory physician based on person-specific risk factors improved the 1 yr sustained success rate by 60% in identified high-risk smokers.", "To measure change in adult non-smokers' exposure to secondhand smoke in public and private places after smoke-free legislation was implemented in Scotland.\n Repeat cross sectional survey.\n Scotland.\n Scottish adults, aged 18 to 74 years, recruited and interviewed in their homes.\n Comprehensive smoke-free legislation that prohibits smoking in virtually all enclosed public places and workplaces, including bars, restaurants, and cafes.\n Salivary cotinine, self reported exposure to smoke in public and private places, and self reported smoking restriction in homes and in cars.\n Overall, geometric mean cotinine concentrations in adult non-smokers fell by 39% (95% confidence interval 29% to 47%), from 0.43 ng/ml at baseline to 0.26 ng/ml after legislation (P<0.001). In non-smokers from non-smoking households, geometric mean cotinine concentrations fell by 49% (40% to 56%), from 0.35 ng/ml to 0.18 ng/ml (P<0.001). The 16% fall in cotinine concentrations in non-smokers from smoking households was not statistically significant. Reduction in exposure to secondhand smoke was associated with a reduction after legislation in reported exposure to secondhand smoke in public places (pubs, other workplaces, and public transport) but not in homes and cars. We found no evidence of displacement of smoking from public places into the home.\n Implementation of Scotland's smoke-free legislation has been accompanied within one year by a large reduction in exposure to secondhand smoke, which has been greatest in non-smokers living in non-smoking households. Non-smokers living in smoking households continue to have high levels of exposure to secondhand smoke.", "This study examined the 1-year effects of a minimal-contact smoking cessation intervention for cardiac inpatients.\n The multicenter study included cardiac inpatients who had smoked prior to hospitalization. A pretest-posttest quasi-experimental design was used. Patients' experimental condition depended on the hospital they were assigned to. The design was partially randomized: 4 of the 11 hospitals selected the experimental condition themselves (2 experimental, 2 control), while the remaining 7 hospitals were randomly assigned. The experimental group consisted of patients of 5 hospitals (N = 388). Patients of 6 other hospitals served as the control group (N = 401). The intervention included stop-smoking advice by the cardiologist, brief counseling by the nurse, the provision of self-help materials, and aftercare by the cardiologist.\n Logistic regression analyses controlling for baseline differences and covariates did not show significant intervention effects on point prevalence and continuous abstinence. The study also showed that the outcomes were not significantly related to the way hospitals were assigned to the experimental condition.\n While short-term effects were found, the minimal-contact intervention did not result in significant effects after 12 months, at least if patients lost to follow-up were treated as posttest smokers. Efforts should be made to improve the intervention, especially the aftercare.", "To evaluate how Scotland's smokefree law impacted self-reported secondhand smoke (SHS) exposure in hospitality venues, workplaces and in people's homes. In addition, we examine changes in support for the law, pub and restaurant patronage, smoking cessation indicators and whether any observed changes varied by socioeconomic status.\n A quasi-experimental longitudinal telephone survey of nationally representative samples of smokers and non-smokers interviewed before the Scottish law (February to March 2006) and 1 year later after the law (March 2007) in Scotland (n = 705 smokers and n = 417 non-smokers) and the rest of the UK (n = 1027 smokers and n = 447 non-smokers) where smoking in public places was not regulated at the time.\n Dramatic declines in the observance of smoking in pubs, restaurants and workplaces were found in Scotland relative to the rest of the UK. The change in the percent of smokers reporting a smokefree home and number of cigarettes smoked inside the home in the evening was comparable in Scotland and the rest of the UK. Support for smokefree policies increased to a greater extent in Scotland than in the rest of the UK. Self-reported frequency of going to pubs and restaurants was generally comparable between Scotland and the rest of the UK; however, non-smokers in Scotland were more likely to frequent pubs more often. No differences in smoking cessation indicators were observed between countries.\n The Scottish smokefree law has been successful in decreasing secondhand smoke exposure while causing none of the hypothesized negative outcomes.", "The association between environmental tobacco smoke (ETS) exposure and respiratory symptoms has not been well established in adults.\n To study the respiratory health of bartenders before and after legislative prohibition of smoking in all bars and taverns by the state of California.\n Cohort of bartenders interviewed before and after smoking prohibition.\n Bartenders at a random sample of bars and taverns in San Francisco.\n Interviews assessed respiratory symptoms, sensory irritation symptoms, ETS exposure, personal smoking, and recent upper respiratory tract infections. Spirometric assessment included forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) measurements.\n Fifty-three of 67 eligible bartenders were interviewed. At baseline, all 53 bartenders reported workplace ETS exposure. After the smoking ban, self-reported ETS exposure at work declined from a median of 28 to 2 hours per week (P<.001). Thirty-nine bartenders (74%) initially reported respiratory symptoms. Of those symptomatic at baseline, 23 (59%) no longer had symptoms at follow-up (P<.001). Forty-one bartenders (77%) initially reported sensory irritation symptoms. At follow-up, 32 (78%) of these subjects had resolution of symptoms (P<.001). After prohibition of workplace smoking, we observed improvement in mean FVC (0.189 L; 95% confidence interval [CI], 0.082-0.296 L; 4.2% change) and, to a lesser extent, mean FEV1 (0.039 L; 95% CI, -0.030 to 0.107 L; 1.2% change). Complete cessation of workplace ETS exposure (compared with continued exposure) was associated with improved mean FVC (0.287 L; 95% CI, 0.088-0.486; 6.8% change) and mean FEV1 (0.142 L; 95% CI, 0.020-0.264 L; 4.5% change), after controlling for personal smoking and recent upper respiratory tract infections.\n Establishment of smoke-free bars and taverns was associated with a rapid improvement of respiratory health.", "The aim of this study was to evaluate the effect of a smoking cessation intervention provided after discharge from a specialized cardiac hospital.\n A randomized pilot study (N = 40); after discharge, the experimental group (EG) received 6 phone calls from a nurse specialized in tobacco cessation counselling.\n Patients in the EG showed improved scores on two aspects of illness representations (perceive their illness as chronic and reported less negative emotional representations). No significant difference in smoking cessation was observed at 6 months (p = 0.72).\n The non-significant difference may be explained in part by the smoking characteristics within this sample exemplifying the more nicotine dependent \"hard core\" smokers who persist in their smoking habits despite the serious health consequences incurred by continued smoking. This population of smokers may require a more intensive, specialized intervention to achieve smoking cessation.", "Physician antismoking advice has been shown to increase smoking cessation, particularly among patients who have medical problems or perceive themselves to be at risk. The present study tested three hypotheses: (a) providing 3 to 5 min of behavioral counseling regarding a cessation strategy would be more effective than simply warning the smoker to quit smoking; (b) smokers with abnormal pulmonary function would be more likely to comply with medical advice than would smokers with normal pulmonary function; and (c) that smokers with abnormal pulmonary function who receive behavioral counseling would be the group most likely to achieve prolonged abstinence. Asbestos-exposed smoking men undergoing screening in a mandated program for naval shipyard workers were categorized as having normal or abnormal pulmonary status on the basis of chest X ray and pulmonary function tests (PFT). They were then randomly assigned within PFT categories to receive either a simple warning or 3 to 5 min of behavioral cessation counseling from the physician who gave them the results of their pulmonary tests. Subjects' smoking status was evaluated at 3- and 11-month intervals following the physician intervention. Smokers who received behavioral counseling were more likely to quit and remain abstinent over the 11-month period (8.4% abstinent) than were smokers given a minimal warning (3.6% abstinent). Prolonged abstinence rates among abnormal PFT subjects (3.7%) did not differ from those of normals (5.9%). The group with normal PFT who received behavioral counseling achieved the highest level of abstinence (9.5%). Maintaining adequate physician compliance with the counseling protocol proved difficult; implications of this for future efforts are discussed.", "To examine the relative effectiveness of three different presentations of a smoking cessation program on the smoking behavior of adults with cardiovascular health problems.\n A 2 x 2 x 2 x 4 experimental design with stratification by sex, smoking history, and a cardiovascular event, and randomization to Individual, Group, Written, or No Intervention groups.\n Six community hospital classrooms.\n 255 nonhospitalized adults. THEORETIC FRAMEWORK: Interaction Model of Client Health Behavior.\n Study Intake: Professional referral form, demographic questionnaire, smoking habits questionnaire, health history, perceived threat survey, perceived health status. Follow up: smoking cessation and health questionnaire, saliva thiocyanate testing.\n At 12-month follow-up, a nurse-client interaction was more effective than written self-help materials; however, smoking cessation rates were highest in the No Intervention control group, possibly related to having had coronary artery bypass graft surgery. Variables positively related to quitting were being male and married and having a higher income. With baseline factors considered, a quitter was most likely to be male and less than 48 years of age, have a high degree of perceived threat relative to medical diagnosis, and be in the individual intervention group. Only partial support for the study hypotheses was found.", "Smokeless tobacco (ST) use has been associated with numerous negative health consequences, yet the prevalence of ST has increased dramatically since the 1970s. Young males in the military are at an elevated risk for ST use relative to the general population. Sixty active-duty male participants were identified as ST users during their annual preventive health screening and randomly assigned to minimal-contact intervention or usual care. Intervention participants were proactively contacted by phone and recruited, using a motivational interviewing style, for a cessation program consisting of a treatment manual, video, and two supportive phone calls from a cessation counselor. Sixty-five per cent (20/31) agreed to participate in the minimal-contact intervention. Three- and 6-month follow-up contacts found that the cessation rates reported by intervention participants were double those reported by participants receiving usual care (41% vs. 17% at 3 months, 37% vs. 19% at 6 months). These pilot study data suggest that proactive recruitment using a motivational interviewing approach to offer a treatment provides a good opportunity to reduce the use of ST in military settings.", "The AHRQ Clinical Practice Guideline for Treating Tobacco Use and Dependence recommends screening and treatment of all tobacco users. Effective methods to implement recommendations are needed because simple guideline dissemination does not necessarily result in changes in practice.\n The Guideline Implementation for Tobacco (GIFT) study tested an organizational intervention to improve Guideline implementation.\n GIFT randomized 20 Veterans Affairs medical centers to intervention or control conditions. We trained prime movers at each site to improve identification of smoking status, promote primary care interventions and increase availability of smoking cessation medications. Sites and patients were evaluated before and after intervention.\n GIFT included 20 Veterans Affairs medical centers and 5678 subjects.\n Data regarding smoking status, delivery of treatment, medication use, and smoking cessation were collected from participant surveys, medical record review, survey of site leaders, and Pharmacy Benefits Management.\n The intervention did not increase participant report of being asked about smoking status or receipt of counseling. It did increase the rate of identification of smoking status in the medical record (P = 0.0001) but did not increase the rate of counseling to stop smoking. Site level data showed no increase in the number of patients receiving smoking cessation medications or dollars spent on medications. Individual smoker data showed a significant increase in the use of medications for smoking cessation in intervention sites (odds ratio = 6.89, P < 0.0001); however, only a small minority of smokers received medication even after the intervention. There was no difference in smoking cessation rates between participants at the intervention and treatment sites.\n We conclude that improvements in smoking cessation rates are likely to require more intensive intervention in this population.", "To assess the effect that cigarette legislation would have on reducing merchant sales rates of cigarettes to minors and the affect on adolescent smoking behavior.\n Observational survey of merchant selling behaviors and adolescent smoking habits before and after passage of legislation.\n The setting for the merchant survey was Woodridge, Ill (population 25,200), a suburban community of Chicago. The surveys were distributed to adolescents in the local junior high school.\n Convenience sample of both merchants and adolescent students.\n Passage of community antismoking legislation.\n Percentage of stores selling cigarettes to minors in Woodridge and percentage of students who had experimented with cigarettes or were regular smokers.\n Merchant sales rates in Woodridge decreased from a baseline of 70% before legislation to less than 5% in 1.5 years of compliance checking after legislation. Student surveys showed that the rates of cigarette experimentation and regular use of cigarettes by adolescents were reduced by over 50%.\n Cigarette control laws can be effective in significantly reducing the rate of cigarettes sold by merchants and rates of cigarette use by adolescents. Key elements of successful legislation implementation are consistent compliance checking and heightened community awareness of the problems and prevalence of adolescent smoking." ]	Introduction of a legislative smoking ban does lead to a reduction in exposure to passive smoking. Hospitality workers experienced a greater reduction in exposure to SHS after implementing the ban compared to the general population. There is limited evidence about the impact on active smoking but the trend is downwards. There is some evidence of an improvement in health outcomes. The strongest evidence is the reduction seen in admissions for acute coronary syndrome. There is an increase in support for and compliance with smoking bans after the legislation.
CD006173	[ "11641669", "9236641", "12179676" ]	[ "A randomized controlled trial comparing oxytocin administration before and after placental delivery in the prevention of postpartum hemorrhage.", "Routine oxytocin in the third stage of labour: a placebo controlled randomised trial.", "A randomized controlled trial of oxytocin administered at the end of the second stage of labor versus oxytocin administered at the end of the third stage of labor in the prevention of postpartum hemorrhage." ]	[ "To determine if the timing of the administration of prophylactic oxytocin influences the incidence of postpartum hemorrhage caused by uterine atony, retained placenta, and third-stage duration.\n Parturients who presented for vaginal delivery were randomized in a double-blinded fashion to receive oxytocin, 20 units in a 500-mL crystalloid intravenous bolus, beginning upon delivery of either the fetal anterior shoulder or placenta. For all patients, the third stage of labor was managed with controlled cord traction until placental expulsion, followed by at least 15 seconds of fundal massage. Patients were excluded if they had a previous cesarean section, multiple gestation, antepartum hemorrhage, or bleeding disorder.\n A total of 1486 patients were enrolled: 745 in the before-placenta group and 741 in the after-placenta group. The groups were similar with respect to gestational age, fetal weight, labor duration, maternal age, parity, and ethnicity. The incidence of postpartum hemorrhage did not differ significantly between the two groups (5.4% vs 5.8%; crude OR, 0.92; 95% CI, 0.59 to 1.43). There were no significant differences between the two groups with respect to incidence of retained placenta (2.4% vs 1.6%; OR, 1.49; 95% CI, 0.72 to 3.08), or third-stage duration (7.7 minutes vs 8.1 minutes; P =.23).\n The administration of prophylactic oxytocin before placental delivery does not reduce the incidence of postpartum hemorrhage or third-stage duration, when compared with giving oxytocin after placental delivery. Early administration, however, does not increase the incidence of retained placenta.", "To compare intravenous oxytocin administration (Partocon 10 IU) with saline solution in the management of postpartum haemorrhage in the third stage of labour.\n A double-blind, randomised controlled trial involving 1000 parturients with singleton fetuses in cephalic presentation and undergoing vaginal delivery, randomly allocated to treatment with oxytocin (n = 513) or 0.9% saline solution (n = 487).\n Labour ward at a central county hospital.\n Mean blood loss (total, and before and after placenta delivery); frequencies of blood loss > 800 mL, need of additional oxytocic treatment, postpartum haemoglobin < 10 g/dL; and duration of postpartum hospitalisation.\n As compared with saline solution, oxytocin administration was associated with significant reduction in mean total blood loss (407 versus 527 mL), and in frequencies of postpartum haemorrhage > 800 mL (8.8% versus 5.2%), additional treatment with metylergometrine (7.8% versus 13.8%), and postpartum Hb < 10 g/dL (9.7% versus 15.2%), and a nonsignificant increase in the frequency of manual placenta removal (3.5% versus 2.3%). There was no group difference in the mean duration of postpartum hospitalisation (4.6 versus 4.5 days, respectively).\n Administration of intravenous oxytocin in the third stage of labour is associated with an approximately 22% reduction in mean blood loss, and approximately 40% reductions in frequencies of postpartum haemorrhage (> 500 mL or > 800 mL) and of postpartum haemoglobin < 10 g/dL. Identification of risk groups for oxytocin treatment does not seem worthwhile. Oxytocin is a cheap atoxic drug and should be given routinely after vaginal delivery.", "The general objective was to determine the incidence of postpartum hemorrhage when oxytocin was administered at the end of the second stage of labor compared to when oxytocin was administered at the end of the third stage. The specific objectives were to determine the mean amount of blood loss, duration of the third stage of labor, need for additional uterotonics and blood transfusion, incidence of hypotension and retained placenta, and mean difference in hemoglobin levels. A randomized controlled trial was conducted in a tertiary care training hospital. 130 women with term, singleton, live pregnancies in cephalic presentation who delivered vaginally were included. Patients were randomly allocated to receive oxytocin after the second stage or after the third stage of labor. Oxytocin was administered as a continuous intravenous infusion. The placenta was delivered by controlled cord traction after placental separation. Blood loss was measured by weight, and the corresponding volume was computed. Relative risk was calculated. Incidence of postpartum hemorrhage, volume of blood loss, duration of the third stage of labor, need for additional uterotonics and blood transfusion, incidence of hypotension and retained placenta, and difference in hemoglobin levels were the main outcome measures. There was a decreased incidence of postpartum hemorrhage (39.66% vs. 48.61%, relative risk [RR] = 0.82, 95% confidence interval [CI] = 0.55-1.21) and less amount of blood loss (557.93 ml vs. 636.84 ml, p = 0.352) when oxytocin was administered at the end of the second stage of labor. There was less need for additional uterotonics (12.07% vs. 13.89%, RR = 0.87, 95% CI = 0.35-2.14), and blood transfusion (5.17% vs. 5.56%, RR = 0.87, 95% CI = 0.22-3.99). There was a smaller mean difference in hemoglobin (16.20 g/dl vs. 20.29 g/dl, p = 0.145). Mean duration of the third stage of labor were comparable (7.93 minutes vs. 7.96 minutes, p = 0.863). However, more patients developed hypotension (3.45% vs. 1.39%, RR = 2.48, 95% CI = 0.23-26.70). All results were not statistically significant. There was no incidence of retained placenta. There is a trend towards a reduction of the risk of postpartum hemorrhage when oxytocin is administered at the end of the second stage of labor. This is not accompanied by an increased risk for any morbidity." ]	Administration of oxytocin before and after the expulsion of placenta did not have any significant influence on many clinically important outcomes such as the incidence of postpartum haemorrhage, rate of placental retention and the length of the third stage of labour. However, the number of available studies were limited. The only uterotonic drug used was oxytocin, mainly through intravenous infusion, therefore its extrapolation to other routes of administration should be interpreted cautiously. More studies are required to examine other maternal and neonatal outcomes using consistent approaches.
CD003828	[ "16888706", "21873370", "11558012", "19430829" ]	[ "Randomized clinical trial assessing the effect of Doppler-optimized fluid management on outcome after elective colorectal resection.", "Randomized controlled trial of intraoperative goal-directed fluid therapy in aerobically fit and unfit patients having major colorectal surgery.", "Laparoscopic versus open appendectomy in children: a prospective randomised study.", "Randomized clinical trial of laparoscopic versus open repair of the perforated peptic ulcer: the LAMA Trial." ]	[ "Protocolized fluid administration using oesophageal Doppler monitoring may improve the postoperative outcome in patients undergoing surgery.\n A total of 108 patients undergoing elective colorectal resection were recruited into a double-blind prospective randomized controlled trial. An oesophageal Doppler probe was placed in all patients. The control group received perioperative fluid at the discretion of the anaesthetist, whereas the intervention group received additional colloid boluses based on Doppler assessment. Primary outcome was length of postoperative hospital stay. Secondary outcomes were morbidity, return of gastrointestinal function and cytokine markers of the systemic inflammatory response. Standard preoperative and postoperative management was used in all patients.\n Demographic and surgical details were similar in the two groups. Aortic flow time, stroke volume, cardiac output and cardiac index during the intraoperative period were higher in the intervention group (P<0.050). The intervention group had a reduced postoperative hospital stay (7 versus 9 days in the control group; P=0.005), fewer intermediate or major postoperative complications (2 versus 15 percent; P=0.043) and tolerated diet earlier (2 versus 4 days; P=0.029). There was a reduced rise in perioperative level of the cytokine interleukin 6 in the intervention group (P=0.039).\n A protocol-based fluid optimization programme using intraoperative oesophageal Doppler monitoring leads to a shorter hospital stay and decreased morbidity in patients undergoing elective colorectal resection.\n Copyright (c) 2006 British Journal of Surgery Society Ltd.", "Intraoperative fluid therapy regimens using oesophageal Doppler monitoring (ODM) to optimize stroke volume (SV) (goal-directed fluid therapy, GDT) have been associated with a reduction in length of stay (LOS) and complication rates after major surgery. We hypothesized that intraoperative GDT would reduce the time to surgical readiness for discharge (RfD) of patients having major elective colorectal surgery but that this effect might be less marked in aerobically fit patients.\n In this double-blinded controlled trial, 179 patients undergoing major open or laparoscopic colorectal surgery were characterized as aerobically 'fit' (n=123) or 'unfit' (n=56) on the basis of their performance during a cardiopulmonary exercise test. Within these fitness strata, patients were randomized to receive a standard fluid regimen with or without ODM-guided intraoperative GDT.\n GDT patients received an average of 1360 ml of additional intraoperative colloid. The mean cardiac index and SV at skin closure were significantly higher in the GDT group than in controls. Times to RfD and LOS were longer in GDT than control patients but did not reach statistical significance (median 6.8 vs 4.9 days, P=0.09, and median 8.8 vs 6.7 days, P=0.09, respectively). Fit GDT patients had an increased RfD (median 7.0 vs 4.7 days; P=0.01) and LOS (median 8.8 vs 6.0 days; P=0.01) compared with controls.\n Intraoperative SV optimization conferred no additional benefit over standard fluid therapy. In an aerobically fit subgroup of patients, GDT was associated with detrimental effects on the primary outcome.\n UK NIHR CRN 7285, ISRCTN 14680495. http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=7285.", "43 children between the ages of 7 and 15 years with clinical symptoms of acute appendicitis were randomised to an open appendectomy (OA) or a laparoscopic appendectomy (LA). There were 15 acute cases of appendicitis and 5 perforated appendices in the OA group and 17 acute appendicitis, 3 cases of perforated appendices and 3 other diagnoses in the LA group. The operative time was a little shorter in the OA group. There were no differences in hospital stay or the postoperative course of the patients. In the LA group, there were two minor complications, no other complications were seen. When comparing the two surgical methods in the consistent group of patients with non-perforated acute appendicitis no statistical differences were seen in the operative time, hospital stay or in the recovery of the patients between the OA and the LA groups.We conclude that LA has no significant benefit over OA in routine use. In paediatric patients we recommend an open approach for clinically typical acute appendicitis, but there should be no hesitation to choose laparoscopic approach when the clinical diagnosis is unclear.", "Laparoscopic surgery has become popular during the last decade, mainly because it is associated with fewer postoperative complications than the conventional open approach. It remains unclear, however, if this benefit is observed after laparoscopic correction of perforated peptic ulcer (PPU). The goal of the present study was to evaluate whether laparoscopic closure of a PPU is as safe as conventional open correction.\n The study was based on a randomized controlled trial in which nine medical centers from the Netherlands participated. A total of 109 patients with symptoms of PPU and evidence of air under the diaphragm were scheduled to receive a PPU repair. After exclusion of 8 patients during the operation, outcomes were analyzed for laparotomy (n = 49) and for the laparoscopic procedure (n = 52).\n Operating time in the laparoscopy group was significantly longer than in the open group (75 min versus 50 min). Differences regarding postoperative dosage of opiates and the visual analog scale (VAS) for pain scoring system were in favor of the laparoscopic procedure. The VAS score on postoperative days 1, 3, and 7 was significant lower (P < 0.05) in the laparoscopic group. Complications were equally distributed. Hospital stay was also comparable: 6.5 days in the laparoscopic group versus 8.0 days in the open group (P = 0.235).\n Laparoscopic repair of PPU is a safe procedure compared with open repair. The results considering postoperative pain favor the laparoscopic procedure." ]	The quality and quantity of information extracted from the trials performed to date are insufficient to make any firm conclusion on the optimum choice of surgical approach in adult patients undergoing primary THA for OA.
CD001347	[ "12631097", "2892989", "11254817", "8633378", "9059953", "7653482", "9552083" ]	[ "Zoledronic acid to prevent bone loss in the first 6 months after renal transplantation.", "Prevention of steroid-induced osteoporosis with (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD).", "Bone mineral density in subjects with mild asthma randomised to treatment with inhaled corticosteroids or non-corticosteroid treatment for two years.", "Prevention of bone loss in cardiac transplant recipients. A comparison of biphosphonates and vitamin D.", "Cyclical etidronate in the prevention of bone loss in corticosteroid-treated primary biliary cirrhosis. A prospective, controlled pilot study.", "Cyclical etidronate reverses bone loss of the spine and proximal femur in patients with established corticosteroid-induced osteoporosis.", "A four-year randomized controlled trial of hormone replacement and bisphosphonate, alone or in combination, in women with postmenopausal osteoporosis." ]	[ "Bisphosphonates can prevent bone mineral density loss after renal transplantation, but their effect on trabecular mineralization and bone morphology, two key factors of bone stability, remains unknown.\n In a 6-month, randomized, placebo-controlled study, 20 kidney transplant recipients received either 4 mg zoledronic acid or placebo twice within 3 months after engraftment. At transplantation and after 6 months, mean trabecular calcium concentration and trabecular morphometry were measured in bone biopsies. Bone mineral density (BMD) of the femoral neck and the lumbar spine were evaluated by dual-energy x-ray absorptiometry, and serum biochemical markers of bone metabolism were determined monthly.\n Trabecular calcium content increased significantly in the zoledronic acid group, but remained unchanged in the placebo group. BMD at femoral neck showed no change in the zoledronic acid group, but decreased in the placebo group. BMD of the lumbar spine was increased in the zoledronic acid group without change in the placebo group. High-turnover bone disease resolved similarly in both groups, as evidenced by a significant decrease of eroded bone surface, osteoclast and osteoblast surface. Serologic markers of bone formation and resorption were significantly lower in zoledronic acid-treated patients throughout the study. Kidney transplant function was stable after zoledronic acid therapy.\n Our results show that administration of zoledronic acid improves the calcium content of cancellous bone after kidney transplantation. The beneficial effect of bisphosphonate therapy is further evidenced by an increase of lumbar spine BMD, and stabilization of femur BMD.", "In a prospective, randomised, placebo-controlled trial comparing the effect of (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) (150 mg/day) plus calcium (1 g/day) with that of calcium alone on the bone mass of patients receiving long-term glucocorticoid therapy, the mean metacarpal cortical area in patients receiving APD increased by 1.2% between 0 and 6 months (p less than 0.06) and then remained stable between 6 and 12 months. In contrast, this index progressively declined in the placebo group (p less than 0.05 at 12 months). The two groups differed significantly in the changes at both 6 and 12 months (p less than 0.01). Mean vertebral mineral density, as measured by quantitative computed tomography, increased by 19.6% over 12 months in the APD group (p less than 0.02) but showed a non-significant decline of 8.8% in controls. The differences between the changes were again significant (p less than 0.005). Biochemical indices and bone histomorphometry indicated a reduction in bone resorption and bone formation but there was no evidence of osteomalacia. APD may thus prevent bone loss in glucocorticoid-treated patients over a year.", "Inhaled corticosteroids are clearly beneficial for patients with asthma of moderate severity, but the risks and benefits of using them in patients with milder asthma are less clear. We have compared the change in bone mineral density over 2 years in adults with mild asthma randomised to receive an inhaled corticosteroid or non-corticosteroid treatment.\n Subjects with mild asthma (mean forced expiratory volume in one second (FEV(1)) 86% predicted, mean age 35 years, taking beta agonists only) were randomised to receive inhaled budesonide, inhaled beclomethasone dipropionate, or non-corticosteroid treatment for 2 years in a prospective randomised open study in 19 centres in France, New Zealand, Spain, and the UK. The corticosteroid dose was adjusted according to a written self-management plan. The main outcome measure-change in bone mineral density after 6, 12, and 24 months-was measured \"blind\". Secondary outcomes included lung function, the relation between change in bone density and inhaled steroid dose and change in biochemical markers of bone metabolism.\n Of 374 subjects randomised, 239 (64%) completed the study and were included in the analysis. The median daily doses of inhaled budesonide (n=87) and beclomethasone (n=74) were 389 microg and 499 microg, respectively. Subjects treated with an inhaled corticosteroid had better asthma control than those in the reference group (n=78). Change in bone mineral density did not differ between the three groups over the 2 years, nor did it correlate with changes in markers of bone metabolism. The mean change in bone mineral density over 2 years in the budesonide, beclomethasone dipropionate, and reference groups was 0.1%, -0.4%, and 0.4% for the lumbar spine and -0.9%, -0.9%, and -0.4% for neck of the femur. Mean daily dose of inhaled steroid was related to reduction in bone mineral density at the lumbar spine but not at the femoral neck.\n In subjects with mild asthma an inhaled corticosteroid provided better asthma control than alternative non-corticosteroid treatment with no difference in change in bone mineral density over 2 years. The relation between dose of inhaled corticosteroid and change in bone density at the lumbar spine may be due to a direct effect of inhaled corticosteroids on bone. Since inhaled steroid dose is also related inversely to lung function, an effect of asthma severity on bone density was also possible.", "Bone mineral density is already abnormally reduced at the moment of cardiac transplantation and bone loss occurs at an impressive rate in the first postoperative year. The aim of the study was to compare two prophylactic medical regimens as to their efficacy in mitigating bone loss after transplantation. Forty-eight consecutive recipients were randomized to receive either alternating calcium carbonate and disodium etidronate (group A) or a daily supplement of calcium carbonate and alphacalcidol (group B). Bone mineral density measurements were performed immediately before hospital discharge and 6, 12, and 24 months after surgery using dual energy X-ray absorptiometry. Clinical events were recorded and roentgenograms of the spine were performed postoperatively and 1 and 2 years later. In both treatment groups bone loss remained significant at the level of the lumbar spine in the first postoperative year (P<0.005) and at the level of the femoral neck in the first (P<0.005) and the second (P<0.06) year after transplantation. Six months after transplantation, however, patients receiving alphacalcidol had a significant reduction in bone loss at the level of the lumbar spine (P=0.047) and at the level of the femoral neck (P=0.043). At the level of the femoral neck this decrease in bone loss was even more pronounced in the second postoperative year (P<0.001). In the group of patients treated with disodium etidronate, 4 recipients needed additional hospitalizations for treatment of symptomatic fractures at the level of the lumbar spine or the femoral neck. No such events happened in recipients receiving vitamin D supplements. Prophylactic administration of calcium carbonate and alphacalcidol after cardiac transplantation reduces bone loss and seems to decrease osteoporotic complications.", "Recently, promising disease modifying effects of low dose corticosteroid treatment in primary biliary cirrhosis have been reported. However, steroid-induced bone loss constitutes a potential drawback of this treatment option.\n To assess whether etidronate can reduce bone loss during corticosteroid treatment.\n Twelve primary biliary cirrhosis patients (all Child-Pugh Class A), treated with prednisone in the context of a 1-year placebo-controlled pilot study with prednisone (maintenance dose 10 mg daily), and azathioprine (50 mg daily), were randomized to receive either cyclical etidronate (400 mg daily, during 2 weeks) alternated with calcium 500 mg daily during 11 weeks or calcium alone. All patients had been receiving ursodeoxycholic acid during at least 1 year and this treatment was continued. Bone mass was measured in the lumbar spine and the femoral neck by dual energy X-ray absorptiometry before and after 3 and 12 months of treatment. Markers of bone formation (serum osteocalcin, procollagen-I-propeptide) and bone resorption (urinary deoxypyridinoline and calcium) were also monitored.\n The mean lumbar bone mineral density did not significantly change in the patients taking etidronate + calcium, in contrast to patients treated with calcium alone (+0.4 vs. -3.0%; p = 0.01). Changes in femoral bone mineral density and markers of bone turnover did not significantly differ between both groups. No adverse effects of etidronate were noted.\n Cyclical etidronate appears to prevent bone loss associated with prednisone treatment in patients with primary biliary cirrhosis. These preliminary results encourage the further evaluation of long term prednisone treatment and concurrent bisphosphonate therapy in primary biliary cirrhosis.", "To compare the bone-mass effects of calcium supplementation and intermittent cyclic etidronate in patients with established corticosteroid-induced osteoporosis.\n Eighteen male and 21 female patients who had established corticosteroid-induced osteoporosis and were receiving chronic prednisone therapy (> or = 10 mg/d) were enrolled in a prospective 12-month, open-label study. In addition to continuing prednisone therapy, patients received continuous calcium supplementation 500 mg/d (n = 20) or four cycles of intermittent cyclic etidronate therapy consisting of etidronate 400 mg/d for 14 days followed by calcium 500 mg/d for 76 days (n = 19). Bone mineral density (BMD) of the spine (L1 through L4) and proximal femur (total hip, femoral neck, trochanter, Ward's triangle) was measured by dual-energy x-ray absorptiometry at baseline, 6 months, and 12 months by staff blinded to the treatment. Serum calcium, phosphorus, and alkaline phosphatase were also measured at these times.\n Treatment with intermittent cyclic etidronate for 12 months resulted in significant increases of 5.7% and 6.8% in BMD of the spine and proximal femur (total hip), respectively (P < 0.02 versus baseline; P < 0.001 versus calcium group). Calcium supplementation alone did not prevent significant losses of 3.4% and 4.1% in BMD at the respective sites (P < 0.02 versus baseline). At the end of the study Z scores reflected significant increases in BMD of the spine and proximal femur (all regions) in the etidronate group (P < 0.01), and significant decreases at the spine, proximal femur, and trochanter in the calcium group (P < 0.01). After 12 months, the difference between the groups was 9.1% (P < 0.01; 95% CI 6.3% to 11.9%) at the spine and 10.9% (P < 0.01; 95% CI 7.8% to 14.1%) at the proximal femur (total hip). Seventeen (89%) of the etidronate-treated patients had increases in BMD of both skeletal sites, whereas only 2 (10%) and 3 (15%) of the calcium-treated patients had positive changes in BMD of the spine and proximal femur (total hip), respectively (P < 0.01). Serum calcium, phosphorus, and alkaline phosphatase levels did not change significantly during the study in either treatment group. Both treatment regimens were well tolerated, with no interactions between prednisone therapy and the study medications. Analyses of response by subgroups (female/male, pulmonary/nonpulmonary indication for prednisone) showed no significant attribute-dependent changes during the 12-month study. At baseline, women had significantly lower BMD of the spine and proximal femur (total hip) (P < 0.01), and patients with pulmonary disease had significantly longer duration of prednisone therapy and cumulative prednisone dose (P < 0.03).\n Intermittent cyclic etidronate reversed the progressive loss of bone mineral density of the spine and proximal femur in female and male patients with established osteoporosis secondary to chronic corticosteroid (prednisone) therapy for pulmonary and nonpulmonary diseases. Calcium supplementation alone did not prevent or attenuate corticosteroid-induced losses.", "Hormone replacement therapy (HRT) with estrogen and treatment with bisphosphonates have been shown to increase bone mineral density (BMD) in postmenopausal women. This 4-year prospective randomized study was carried out to assess the effectiveness of the combined HRT plus etidronate on BMD in postmenopausal women with established osteoporosis.\n Seventy-two postmenopausal women (mean age 64.9+/-0.5 years) attending metabolic bone disease outpatient clinics with established osteoporosis were randomly allocated into one of four treatment groups and monitored for 4 years. All patients enrolled in this study including the control group (n=18) received 1.0 g elemental calcium and 400 units vitamin D per day. The HRT group (n=18) received cyclical estrogen and progesterone; the etidronate group (n=17) received intermittent cyclical etidronate; and the combined therapy group (n=19) received both HRT and etidronate. BMD was measured in the lumbar spine and the hip before treatment and at 2 and 4 years after treatment. Changes in height were recorded, and the occurrence of new vertebral fractures were documented in comparison with the baseline radiographic evaluation. In 40 patients (10 patients per group), analysis of bone histomorphometry was carried out after 4 years of treatment.\n In patients who received the combined therapy, BMD increased in the lumbar spine by 10.4% (P <0.001) and in the hip by 7.0% (P <0.001) at 4 years. For patients treated with ICE, these increases were 7.3% (P <0.001) and 0.9% (P <0.05), and with HRT, the increases were 7.0% (P <0.001) and 4.8% (P <0.01) in the vertebrae and femora, respectively. The group treated with calcium and vitamin D lost 2.5% (P <0.05) and 4.4% (P <0.01) of BMD in the vertebrae and femora, respectively, after 4 years. Patients who received combined therapy had significantly higher BMD in both the vertebrae and in the femora (P <0.05) in comparison with patients who were treated with HRT or etidronate alone after 4 years. In comparison with patients in the control group, there was a trend toward a lower rate of new vertebral fractures in the treatment groups. Height loss was significantly less in all three active treatment groups (HRT [P <0.001], etidronate [P <0.02], and combined therapy group [P <0.0001]), in comparison with the control group. The combined therapy group did not have a significant height loss, in comparison with the HRT (P <0.02) and the etidronate (P <0.001) groups. None of the patients had histomorphometric evidence of osteomalacia.\n This 4-year randomized study showed an additive effect of etidronate and HRT on hip and spine BMD in postmenopausal women with established osteoporosis." ]	Bisphosphonates are effective at preventing and treating corticosteroid-induced bone loss at the lumbar spine and femoral neck. Efficacy regarding fracture prevention cannot be concluded from this analysis, although bone density changes are correlated with fracture risk.
CD005182	[ "7373255", "12004637", "3958683", "16880458", "15522983", "48832", "7436639", "17261454", "6377291", "3980239", "761334", "10100064", "8908893", "91901", "3870921", "9374947", "7795830", "8840744", "6545038", "8722429", "1173830", "7059257", "9008249", "9824519", "369673", "12473876", "16737346", "8263895", "6908098", "6153057", "7114339", "15154946", "2001777", "7748631", "7110301", "16280273", "16115830", "8467308", "6341724", "11294376", "16647628", "8960857", "11079287", "19920081", "18626028", "20413121", "10358675", "16595786", "3092976", "73694", "7854076", "430732", "3624815", "3503941", "3122919", "6849473", "15485755", "16513919", "16331115", "15866255", "2258874", "10229991", "1899945", "15894901", "356078", "11714206", "10710578", "1599343", "12624611" ]	[ "Effectiveness of patient education and psychosocial counseling in promoting compliance and control among hypertensive patients.", "Improving blood pressure control in diabetes: limitations of a clinical reminder in influencing physician behavior.", "A randomized trial of special packaging of antihypertensive medications.", "Improving blood pressure control through provider education, provider alerts, and patient education: a cluster randomized trial.", "Pharmacist involvement in primary care improves hypertensive patient clinical outcomes.", "Randomised clinical trial of strategies for improving medication compliance in primary hypertension.", "Increasing compliance. Patient-operated hypertension groups.", "Electronic monitoring of adherence as a tool to improve blood pressure control. A randomized controlled trial.", "A controlled trial of health education in the physician's office.", "Evaluation of family health education to build social support for long-term control of high blood pressure.", "Improving compliance with therapeutic regimens in hypertensive patients in a community health center.", "Antihypertensive drug treatment: a comparison of usual care with self blood pressure measurement.", "A randomized trial to improve follow-up care in severe uncontrolled hypertensives at an inner-city walk-in clinic.", "Work-site treatment of hypertension by specially trained nurses. A controlled trial.", "An appointment reminder system's effect on reducing the number of hypertension patients who drop out from care.", "Patterns of compliance with once versus twice daily antihypertensive drug therapy in primary care: a randomized clinical trial using electronic monitoring.", "Trial of Nonpharmacologic Intervention in the Elderly (TONE). Design and rationale of a blood pressure control trial.", "Comprehensive pharmaceutical care in the chain setting.", "Screening, treatment and adherence to treatment for hypertension.", "A telecommunications system for monitoring and counseling patients with hypertension. Impact on medication adherence and blood pressure control.", "Management of hypertension. Effect of improving patient compliance for follow-up care.", "Improving hypertension control in a private medical practice.", "A randomized study comparing a patient-directed hypertension management strategy with usual office-based care.", "Comparing standard care with a physician and pharmacist team approach for uncontrolled hypertension.", "Self-recording of blood pressure in the management of hypertension.", "Non-pharmacological treatment of hypertension in primary health care: a 2-year open randomized controlled trial of lifestyle intervention against hypertension in eastern Finland.", "Rational prescribing in primary care (RaPP): a cluster randomized trial of a tailored intervention.", "Effect of value-added utilities on prescription refill compliance and health care expenditures for hypertension.", "Influencing adherence among hypertensives.", "Improving hypertension control: impact of computer feedback and physician education.", "The effects of family involvement and practitioner home visits on the control of hypertension.", "Educational outreach in diabetes to encourage practice nurses to use primary care hypertension and hyperlipidaemia guidelines (EDEN): a randomized controlled trial.", "Weight reduction in obese hypertensive patients.", "Coordinating and standardizing long-term care: evaluation of the west of Scotland shared-care scheme for hypertension.", "The effect of treatment on mortality in \"mild\" hypertension: results of the hypertension detection and follow-up program.", "Self-monitoring of blood pressure promotes achievement of blood pressure target in primary health care.", "Targets and self monitoring in hypertension: randomised controlled trial and cost effectiveness analysis.", "Evaluation of a structured treatment and teaching programme on hypertension in general practice.", "A computer-based monitoring system for follow-up of elevated blood pressure.", "Feedback on prescribing rate combined with problem-oriented pharmacotherapy education as a model to improve prescribing behaviour among general practitioners.", "Pharmaceutical care program for patients with uncontrolled hypertension. Report of a double-blind clinical trial with ambulatory blood pressure monitoring.", "Appropriate Blood Pressure Control in NIDDM (ABCD) Trial.", "Effect of pharmacist intervention and initiation of home blood pressure monitoring in patients with uncontrolled hypertension.", "Hypertension improvement project: randomized trial of quality improvement for physicians and lifestyle modification for patients.", "Integration of depression and hypertension treatment: a pilot, randomized controlled trial.", "Effects of 8 weeks sustained follow-up after a nurse consultation on hypertension: a randomised trial.", "Linking community-based blood pressure measurement to clinical care: a randomized controlled trial of outreach and tracking by community health workers.", "Effect of nurse-directed hypertension treatment among First Nations people with existing hypertension and diabetes mellitus: the Diabetes Risk Evaluation and Microalbuminuria (DREAM 3) randomized controlled trial.", "Randomised controlled trial of computer assisted management of hypertension in primary care.", "Improvement of medication compliance in uncontrolled hypertension.", "Use of a standardized personal medical record by patients with hypertension: a randomized controlled prospective trial.", "Health education for hypertensive patients.", "Compliance to treatment for hypertension in elderly patients: the SHEP pilot study. Systolic Hypertension in the Elderly Program.", "A randomized controlled trial of an information booklet for hypertensive patients in general practice.", "Can general practitioners use training in relaxation and management of stress to reduce mild hypertension?", "Five-year blood pressure control and mortality following health education for hypertensive patients.", "Nurse management for hypertension. A systems approach.", "Randomized controlled trial on lifestyle modification in hypertensive patients.", "Efficacy of a home blood pressure monitoring programme on therapeutic compliance in hypertension: the EAPACUM-HTA study.", "Group versus individual academic detailing to improve the use of antihypertensive medications in primary care: a cluster-randomized controlled trial.", "Evaluation of two educative models in a primary care hypertension programme.", "Implementing clinical guidelines in the treatment of hypertension in general practice. Evaluation of patient outcome related to implementation of a computer-based clinical decision support system.", "Home blood pressure monitoring for mild hypertensives.", "Effects of a lifestyle programme on ambulatory blood pressure and drug dosage in treated hypertensive patients: a randomized controlled trial.", "Treatment of hypertension with biofeedback and relaxation techniques.", "Pharmacoeconomic evaluation of a pharmacist-managed hypertension clinic.", "Evaluation of computer based clinical decision support system and risk chart for management of hypertension in primary care: randomised controlled trial.", "Nonpharmacologic intervention to reduce blood pressure in older patients with mild hypertension.", "Effectiveness of multidisciplinary lifestyle intervention for hypertension: a randomised controlled trial." ]	[ "Compliance with physician recommendations among long-term hypertensive patients can be a chronic and difficult treatment problem. This study evaluated the relative effectiveness of additional patient education and psychosocial counseling in improving patient compliance. At a family practice clinic, 123 low income, rural, black hypertensive patients were pretested on several psychological characteristics and randomly assigned to one of three groups: vigorous, group patient education and family physician appointments; supportive, individualized psychosocial counseling and family physician appointments; or family physician appointments only, which was the baseline medical care. Intervention and follow-up each lasted three months, and the intervention was in addition to the patients' baseline medical care. Compliance was measured by: keeping follow-up appointments; bringing antihypertension medications to each appointment; consuming these medications; and diastolic blood pressure. Analysis of variance of group mean and change scores, t tests, and chisquare analysis indicated that neither additional patient education nor additional psychosocial counseling improved compliance or blood pressure control significantly better than regular family physician visits alone.", "Hypertension should be aggressively treated, especially in diabetic patients. But studies of physician prescribing habits reveal that physicians often delay making medication changes or initiating antihypertensive therapy. A chart-based reminder was designed to improve physician medication prescribing in this clinical situation.\n A randomized controlled trial was conducted at the Veterans Affairs Medical Center in Richmond, Virginia. Patients with diabetes and hypertension were selected. A highly visible chart reminder was applied to the front of outpatient charts in the intervention group practice. A chart review was conducted to assess physician-directed medication changes. A successful outcome was defined as any antihypertensive medication increase or addition at that same visit.\n Physicians were more likely to intensify antihypertensive medication as the blood pressure increased regardless of the reminder. Overall, only 33% of visits resulted in a medication change, even though 93% of patients had elevations over target blood pressure at the follow-up visit. Physicians in the intervention and control groups made changes to medication at similar rates (chi 2 = 0.621, p = .511).\n In this study, a chart reminder failed to improve physician compliance with the clinical guideline for hypertension management in diabetics, Sixth Report of the Joint National Committee on the Detection, Evaluation, Prevention and Treatment of High Blood Pressure. To inform the design of effective intervention strategies, further research should explore specific barriers to guideline adherence in this clinical situation.", "This article reports a randomized controlled trial designed to test the effects of special packaging of antihypertensive medication on compliance and blood pressure control. One hundred eighty subjects who had exhibited elevated blood pressure greater than 90 mmHg in the two years prior to the study were recruited from patients receiving care at a community hospital-based family medicine practice. After completing preenrollment interviews and blood pressure measurements, subjects were randomly assigned to receive their antihypertensive medications either in the usual vials or in special unit dose-reminder packaging. Follow-up interviews, pill counts, and blood pressure measurements were performed at three-month intervals. There were no statistically significant differences between the control and experimental groups with regard to age, sex, race, employment, education, marital status, insurance coverage, or blood pressure regimens. Prior to the intervention, the experimental group had slightly lower diastolic blood pressure and reported better compliance than the control group. Analyses performed on 165 subjects completing the first follow-up visit revealed no significant improvements in blood pressure control or compliance for patients receiving special medication packaging. While some patients found it easy to remember to take pills packaged using this format, they also found the packages somewhat more difficult and inconvenient to use. In contrast to previously reported work, this study did not demonstrate any significant improvement in compliance with special packaging of antihypertensive medications.", "Inadequate blood pressure control is a persistent gap in quality care.\n To evaluate provider and patient interventions to improve blood pressure control.\n Cluster randomized, controlled trial.\n 2 hospital-based and 8 community-based clinics in the Veterans Affairs Tennessee Valley Healthcare System.\n 1341 veterans with essential hypertension cared for by 182 providers. Eligible patients had 2 or more blood pressure measurements greater than 140/90 mm Hg in a 6-month period and were taking a single antihypertensive agent.\n Providers who cared for eligible patients were randomly assigned to receive an e-mail with a Web-based link to the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) guidelines (provider education); provider education and a patient-specific hypertension computerized alert (provider education and alert); or provider education, hypertension alert, and patient education, in which patients were sent a letter advocating drug adherence, lifestyle modification, and conversations with providers (patient education).\n Proportion of patients with a systolic blood pressure less than 140 mm Hg at 6 months; intensification of antihypertensive medication.\n Mean baseline blood pressure was 157/83 mm Hg with no differences between groups (P = 0.105). Six-month follow-up data were available for 975 patients (73%). Patients of providers who were randomly assigned to the patient education group had better blood pressure control (138/75 mm Hg) than those in the provider education and alert or provider education alone groups (146/76 mm Hg and 145/78 mm Hg, respectively). More patients in the patient education group had a systolic blood pressure of 140 mm Hg or less compared with those in the provider education or provider education and alert groups (adjusted relative risk for the patient education group compared with the provider education alone group, 1.31 [95% CI, 1.06 to 1.62]; P = 0.012).\n Follow-up blood pressure measurements were missing for 27% of study patients. The study could not detect a mechanism by which patient education improved blood pressure control.\n A multifactorial intervention including patient education improved blood pressure control compared with provider education alone.", "The practice of pharmaceutical care in primary care settings in Thailand is currently not generally accepted.\n To evaluate the effect of pharmacist involvement in treatment with hypertensive patients in primary care settings.\n The treatment objective was to stabilize the blood pressure (BP) of hypertensive patients in accordance with the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure guidelines. Patients were randomly assigned to a pharmacist-involved group (treatment) or a group with no pharmacist involvement (control). Pre- and post-test BPs, tablet counts, lifestyle modifications, and pharmacists' recommendations were recorded. The 6-month study was carried out in Mahasarakham University pharmacy and 2 primary care units. Patients were monitored monthly by reviewing their medications and supported by providing pharmaceutical care and counseling.\n From a total of 235 patients, the treatment group (n = 118) had a significant reduction in both systolic (S) and diastolic (D) BP compared with the 117 patients of the control group (p = 0.037, 0.027, respectively). The 158 patients (76 treatment, 82 control) with BPs >or=140/90 mm Hg at the beginning of the study showed significant BP reductions (p = 0.002 SBP, 0.008 DBP). The proportion of 158 patients whose BP became stabilized was higher in the treatment group (p = 0.017). The treatment group showed significantly better adherence (p = 0.014) and exercise control (p = 0.012) at the end of the study. Physicians accepted 42.72% of medication modifications and 5.34% of the suggestions for additional investigations.\n Hypertensive patients who received pharmacist input achieved a significantly greater benefit in BP reduction, BP control, and improvement in adherence rate and lifestyle modification.", "230 Canadian steelworkers with hypertension took part in a randomised trial to see if compliance with antihypertensive drug regimens could be improved. For care and follow-up these men were randomly allocated to see either their own family doctors outside working-hours or industrial physicians during work shifts; the same men were randomly allocated to receive or not receive an educational programme aimed at instructing them about hypertension and its treatment. Surprisingly, the convenience of follow-up at work had no effect upon these men's compliance with antihypertensive drug regimens. Similarly, although men receiving health education learned a lot about hypertension, they were not more likely to take their medicine.", "Compliance was compared in 52 previously noncompliant hypertensive patients randomly assigned for eight weeks to either a nurse-operated hypertension clinic (control) or a patient-operated hypertension group] (experimental). Control patients listened to audiotapes on hypertension and its management and met individually with a nurse who adjusted their drug regimens. Experimental patients were trained to take their own blood pressure (BP) and select their own drugs in a group program emphasizing informed self-help. After the eight-week training period and at two- and six-month follow-up visits, both groups had significantly lower BPs. Compared with control patients, experimental patients had lower diastolic BPs, better pill counts, and better attendance (all P < .05). This study suggests that training noncompliant patients in groups to manage their own hypertension may achieve better results than traditional management programs.", "Poor adherence to antihypertensive drug regimens is believed to be a major contributor to treatment failure. Electronic monitoring of adherence may improve adherence and allow differentiation between those who are nonadherent and those who are pharmacologically nonresponsive. This study was designed to evaluate the effectiveness of electronic monitoring of adherence in lowering blood pressure (BP) in comparison with usual care.\n A total of 258 patients with high BP despite use of antihypertensive medication were randomly assigned to either continuation of usual care (with adjustment in antihypertensive medication if necessary) or to the introduction of electronic monitoring. Adherence to antihypertensive medication was monitored for 2 months without medication changes. The primary outcome measure was the proportion of patients who reached target BP levels after a 5-month follow-up period.\n At 5 months, 50.6% of the patients in the usual care group reached adequate BP, v 53.7% in the electronic monitoring group (P = .73). The percentages of patients with drug additions or increases in dosage were higher in the usual care group compared with those in whom adherence was monitored (P < .01).\n These data show that electronic monitoring in comparison to usual care results in similar BP control but leads to fewer drug changes and less drug use. This result is likely to be achieved by improving adherence. Hence a strategy that includes electronic monitoring has the potential to prevent unnecessary treatment escalation in patients with poor adherence.", "Screening of 6,144 patients in a general practice clinic to assist physician case-finding uncovered 983 (16%) who were uncontrolled hypertensives. Following physician recommendation, 115 patients volunteered for a controlled trial to test the effectiveness of supplementary strategies to the pharmaceutical management of high blood pressure. A study of nonparticipants indicated that about 7% of the practice population was eligible for cardiovascular health education. One group received a health education program, a second was allocated to self-monitor their blood pressure for 6 months, a third group was allocated to both strategies, and the final group, acting as a control, continued to receive their usual care. Physician monitoring of patients continued for the duration of the study and blood pressures decreased in all patients. The study's most important outcome was the joint reduction of blood pressure and medication strength. These were assessed by a \"blind\" clinician before and after the interventions according to criteria set out in the \"stepped-care\" approach to management of high blood pressure. People allocated to a health education program conducted in the doctor's common room did twice as well on this measure as those who were not so educated. Daily self-monitoring of blood pressure for 6 months proved to be too much for the majority of those so instructed. It is concluded that the general practice setting remains an important place for health education to prevent cardiac disease and suggestions are made for incorporating this into everyday practice.", "Sustaining patient motivation for long-term adherence to drug therapies remains a substantial problem for physicians, other health care providers, the patients themselves, and their families. Other therapeutic requests such as dietary changes and weight control may be even more difficult to maintain than taking pills. As part of a controlled experimental design implemented in an outpatient teaching hospital, an educational program was implemented to improve family member support for medical compliance among hypertensive patients. Family members were interviewed, counseled, and provided with a booklet for the purpose of educating and involving them in the home management of high blood pressure. The booklet identified ways the family member could assist the patient with medication compliance, appointment keeping, as well as diet and weight control. These items were identified and recorded as behavioral objectives in the booklet. Patients were followed for three years to assess long-term outcomes. Results showed a strong statistically significant difference between the experimental and control groups, with the experimental group demonstrating higher levels of appointment-keeping behavior, weight control, and BP under control (all p values less than .001). Analysis of the main effects of the educational program demonstrated that the family member support intervention accounted for the greatest decrease in diastolic blood pressure variability, R2 = .20, p less than .001.", "A 1-year, randomized study was conducted to test the possibility of improving compliance with therapeutic regimens in hypertensives by means of certain simple arrangements. Patients were given written treatment instructions concerning hypertension, a personal blood-pressure follow-up card, and, for those who failed to attend their blood-pressure check-up, an invitation for a new check-up. Using matched pairs, 202 Finnish hypertensives were randomly allocated either to an ordinary or a reorganized treatment group. By means of the latter system, patient compliance could be significantly (p less than 0.01) improved: Only 4% of the patients in this group dropped out of treatment, compared with 19% in the ordinary treatment group. By the end of the year, blood pressure had been lowered by at least 10% in 95% of the patients in the reorganized group and in 78% of those in the ordinary group (p less than 0.01). This was achieved in approximately 60% of cases using chlorthalidone alone.", "Blood pressure self-measurement is increasing in most communities and yet its role in the management of hypertension is poorly understood. This study was devised to evaluate the behaviour of doctors in general practice when treating patients with poorly controlled essential hypertension who use self-measurement. Patients, most of whom were already taking antihypertensive medications were commenced on perindopril or indapamide at their doctor's discretion and were randomly allocated to self-measurement (SM) using an OMRON HEM706 oscillometric device or a continuation of their usual care (UC) over an 8-week period. This was an observational study without any specific or set treatment goals for the doctor to follow. Sixty of 62 subjects completed the study and the two groups were equally matched for age, body mass index, gender, and blood pressure (BP). While additional perindopril or indapamide produced a significant fall in BP in both groups over the study period, the systolic pressure remained significantly higher in the SM group (sitting 148 +/- 3 compared with 142 +/- 3; 145 +/- 3 compared with 138 +/- 3 mm Hg respectively; P < 0.05). Twenty-four hour and daytime ambulatory monitor systolic pressures were also significantly higher in the SM group. Differences in diastolic BP were not statistically significant. Furthermore, SM patients were less likely to have their medications increased and more likely to have them reduced or ceased. Doctors and patients found self-measurement convenient and useful. This study suggests that doctors prescribing decisions are influenced by evidence from self-measurement of BP with consequential increases in office BP related to reduced drug use. While self-BP measurement can offer reassurance about adequacy of control when away from a physicians office, our best evidence of understanding target blood pressures comes from large randomised studies using office blood pressures as an end-point. There is an urgent need for further study to provide arbitration between self-measurement and office blood pressures although each measurement must contribute to the management of hypertension.", "A single-blinded, randomized trial was conducted to determine whether a mailed postcard improved follow-up in uncontrolled hypertensives. One hundred and seven patients with a systolic blood pressure (BP) of 180 or more or a diastolic blood pressure of 110 or more at an inner-city, hospital-based walk-in clinic were enrolled; mean age was 56 years, 95 percent were African American, 73 percent were female, and mean BP was 193/106. Patients were required to be aware of their diagnosis and to have been informed of their need for medication at least a month before the trial. Of those who received postcard reminders, 45 percent followed up within 10 days, compared with 47 percent of controls (p = 0.93). At 30 days, 64 percent of the intervention group followed up, compared with 55 percent of controls (p = 0.36). In an adjusted logistic regression model, there was no difference in follow-up. Correlates of appointment noncompliance at one month included alcoholism and lack of insurance in an adjusted logistic regression model. Follow-up in severe hypertensives was poor, and a mailed postcard reminder had no effect in a walk-in setting.", "The clinical efficacy of using specially trained nurses to treat hypertension at the patient's place of work was compared in a controlled trial with management by the patient's family doctor. The 457 study participants were selected from 21 906 volunteers in industry and government whose blood-pressure was screened. The nurses were allowed to prescribe and change drug therapy at the work site without prior physician approval. Patients randomly allocated to receive care at work were significantly more likely to be put on antihypertensive medications (94.7% vs 62.7%, to reach goal blood-pressure in the first six months (48.5% vs 27.5%), and to take the drugs prescribed (67.6% vs 49.1%). Only 6% of patients were dissatisfied with the care provided by the nurses. Thus provision of care at work by specially tranined nurses was well accepted and resulted in significantly improved blood-pressure control and medication compliance among employees with asymptomatic and uncomplicated hypertension.", "We evaluated the effects of an appointment reminder system on the appointment-keeping behavior and blood pressure control status of hypertensive patients receiving care in an urban medical clinic. The study population consisted of 973 adult hypertensive patients receiving medical care at a family practice clinic affiliated with the Wayne State University School of Medicine, Detroit, Michigan. Of the 973 patients enrolled in the study, 486 were randomly assigned to a group that received appointment reminder cards and telephone calls to reschedule missed appointments, and 487 were assigned to a nonintervention control group. Patients were followed-up with regard to their appointment-keeping behavior and blood pressure control status, five to eight months after being entered in the study. The study results indicate that patients in the appointment reminder group kept significantly more appointments and were less likely to drop out of treatment than patients in the control group. The dropout rate was 46 percent lower among patients in the appointment reminder group than in the control group. Patients in the appointment reminder group also demonstrated slightly better blood pressure control at the end of the study compared with patients in the control group, although none of the differences in blood pressure levels between groups were statistically significant at the 5 percent level.", "To evaluate patterns of compliance with once versus twice daily administration of antihypertensive therapy (primary-outcome measure) and relevance of partial compliance for blood pressure control (secondary outcome measure).\n Multicentre, nonblinded, parallel group randomized design.\n Nonacademic primary care practices across Canada.\n Patients with mild essential hypertension (diastolic blood pressure 95 to 110 mmHg) of either sex (40% women), age 18 to 80 years (average 55 years). One hundred and ninety-eight patients were randomized to active treatment; 14 patients discontinued the study because of side effects.\n After a four-week placebo run-in period, patients were randomized to amlodipine 5 mg once-a-day or diltiazem slow release formulation (SR) 90 mg twice daily. Doses were increased to 10 mg and 180 mg to achieve sitting diastolic blood pressure of 90 mmHg or less.\n During 20 weeks on active treatment, compliance was assessed by pill counts and medication event monitoring system (MEMS), assessing percentage of prescribed doses taken, percentage days correct doses taken, percentage prescribed doses taken on time and blood pressure control as determined by office blood pressure measurement.\n The percentage prescribed doses taken (by either pill count of MEMS) showed a high degree of compliance, similar for the two treatments. However, other parameters of compliance were significantly better with once versus twice daily therapy. Partial compliance (less than 80% by pill count) led to less blood pressure control with the short acting diltiazem, but did not affect blood pressure control for the long acting amlodipine. Side effects profiles did not differ between the two treatments.\n Within the constraints of a clinical trial, hypertensive patients in primary care show a high degree of overall compliance with once or twice daily pill-taking, but patterns of pill-taking are more erratic with twice versus once daily medication, particularly in men. The results suggest that the negative consequences of partial compliance for blood pressure control can be offset by choosing agents with a duration of action well beyond the dosing interval.", "National and international policy-making organizations advocate nonpharmacologic therapies to reduce blood pressure (BP). However, data to support such recommendations in older persons are virtually nonexistent. The Trials of Nonpharmacologic Intervention in the Elderly (TONE) is a randomized, controlled trial that will test whether weight loss or a reduced sodium (Na) intake or both can maintain satisfactory BP control, without unacceptable side effects, after withdrawal of antihypertensive drug therapy. Medication-treated hypertensives (aged 60 to 80 years) with a systolic BP less than 145 mm Hg and a diastolic BP less than 85 mm Hg who are taking one antihypertensive medication are randomly assigned to one of four groups: (1) weight loss alone, (2) reduced Na intake alone, (3) combined weight loss and reduced Na intake, or (4) usual life-style (control group). Overweight participants are randomized to one of these four groups, while nonoverweight individuals are assigned to either the reduced Na intake or the usual life-style group. The interventions, tailored to the needs of older persons, use behavioral approaches to accomplish intervention-specific goals (weight loss > or = 10 lb, daily Na intake < or = 80 mEqa). Three months after the start of intervention, antihypertensive drug therapy is withdrawn. The primary trial end point is a BP of 150/90 mm Hg or higher, resumption of antihypertensive drug therapy, or the occurrence of a BP-related clinical complication during 2 to 3 years of follow-up. It is anticipated that TONE findings may identify an effective and acceptable nonpharmacologic approach to control hypertension in the increasingly large number of older persons treated with antihypertensive drug therapy.", "A controlled, randomized study was conducted in two chain pharmacies to determine the clinical value of comprehensive pharmacy services for hypertensive patients in a chain pharmacy setting. Twenty-seven patients were enrolled as intervention participants with 26 control subjects. Monthly services for the intervention group included blood pressure and heart rate assessments and counseling on lifestyle modifications and drug therapy. Control patients received initial and final blood pressure measurements and minimal counseling. Both study and control groups completed quality-of-life questionnaires upon entering and completing the study. Results showed that blood pressure control was significantly improved in the study group. Compliance rates as well as energy/fatigue scores (a quality-of-life scale) improved in the study group compared with the control population. Community pharmacists in chain stores could have a beneficial effect on the health care of large numbers of patients if pharmaceutical care programs were developed.", "The population aged 40 to 64 years of the municipality of Köyliö, situated in southwestern Finland, was screened for hypertension in 1973-74; a total of 1018 persons (92%) participated in the program. On the basis of two separate blood pressure measurements a total of 147 hypertensive individuals who were not under treatment were identified. These individuals were divided into two groups by randomization of matched pairs. One group (the control group) was merely advised by letter to see a physician for raised blood pressure, while the other group (the experimental group), in addition to being so notified, received written information explaining the nature of hypertension and the importance of its treatment. After two years, the individuals in both groups were invited for a follow-up blood-pressure measurement, with the object of investigating the number of individuals who had sought treatment and who had continued it, and the differences between the groups in treatment seeking and adherence. A total of 79% of those who were notified to seek medical care had done so. Antihypertensive drug therapy had been begun for 85% of these. After two years, 56% of those who had been found initially to be hypertensive and who were seen in the follow-up were still under treatment. In 43% of these the blood pressure was at the target level. No statistically significant differences in treatment seeking and adherence to it were found between the experimental and control groups, nor were differences found in the decline in the blood pressure or its target levels. Comparing with other studies shows, that results can be better if the health care system that carries out the screening procedure for hypertension also take active steps to bring the patient under treatment and keep him on the regimen.", "This study was conducted to evaluate the effect of automated telephone patient monitoring and counseling on patient adherence to antihypertensive medications and on blood pressure control. A randomized controlled trial was conducted in 29 greater Boston communities. The study subjects were 267 patients recruited from community sites who were >or= 60 years of age, on antihypertensive medication, with a systolic blood pressure (SBP) of >or= 160 mm Hg and/or a diastolic blood pressure (DBP) of >or= 90 mm Hg. The study compared subjects who received usual medical care with those who used a computer-controlled telephone system in addition to their usual medical care during a period of 6 months. Weekly, subjects in the telephone group reported self-measured blood pressures, knowledge and adherence to antihypertensive medication regimens, and medication side-effects. This information was sent to their physicians regularly. The main study outcome measures were change in antihypertensive medication adherence, SBP and DBP during 6 months, satisfaction of patient users, perceived utility for physicians, and cost-effectiveness. The mean age of the study population was 76.0 years; 77% were women; 11% were black. Mean antihypertensive medication adherence improved 17.7% for telephone system users and 11.7% for controls (P = .03). Mean DBP decreased 5.2 mm Hg in users compared to 0.8 mm Hg in controls (P = .02). Among nonadherent subjects, mean DBP decreased 6.0 mm Hg for telephone users, but increased 2.8 mm Hg for controls (P = .01). For telephone system users, mean DBP decreased more if their medication adherence improved (P = .03). The majority of telephone system users were satisfied with the system. Most physicians integrated it into their practices. The system was cost-effective, especially for nonadherent patient users. Therefore, weekly use of an automated telephone system improved medication adherence and blood pressure control in hypertension patients. This system can be used to monitor patients with hypertension or with other chronic diseases, and is likely to improve health outcomes and reduce health services utilization and costs.", "A radomized controlled trial was conducted in a metropolitan teaching hospital to determine whether improving follow-up of emergency room patients who had hypertension led to improvements in their medical care and blood pressure control. One hundred fourty four patients were randomly assigned into an intervention group and a control group. In the former, a follow-up clerk assigned patients in returning for follow-up care. Eighty-four percent of patients in this group and 63% of control patients returned to the clinic (P less than 0.1). However, five months after the patients' emergency room visits, 51% of patients in the intervention group and 53% of control patients were normotensive. There were more diagnostic and therapeutic measures in the intervention group, but long-term management was similar in both groups. Improvement in follow-up may not be by itself lead to blood pressure control among hypertensive patients.", "Hypertension is one of the most common diseases seen by the practicing physician. Yet, because of noncompliance, conditions of many hypertensive patients are not effectively controlled by treatment. The purpose of this study was to test the efficacy of a patient education program in reducing the blood pressure (BP) of hypertensive patients in a private, solo medical practice. The intervention program focused on three behavioral objectives-pill taking, appointment keeping, and dietary sodium reduction while stressing the need for taking responsibility for one's own care. It was hypothesized that patients receiving an educational intervention stressing self-care would benefit more than those receiving the usual medical care. A substantial reduction in BP was considered to be the measure of successful treatment. Thirty-nine hypertensive patients receiving drug therapy from a private, solo medical practice were randomized into either a treatment group or a control group. A comparison of means disclosed no pretreatment differences between the groups' average BPs. After following up both groups for six months, mean changes in BP were compared for both treatment and control patients using a two-sample t test for independent samples. The BP fell in the treatment group (-13 mm Hg, systolic; -8 mm Hg, diastolic) but rose slightly in the control group (3 mm Hg, systolic 0.5 mm Hg, diastolic). The difference in changes was significant for both the systolic and diastolic BP.", "This study aimed to compare the efficacy of a patient-directed management strategy with office-based management in maintaining blood pressure control in patients with chronic stable hypertension using a randomized trial of two months duration. The subjects had chronic stable essential hypertension without secondary causes or unstable cardiovascular disease and were selected through the offices of 11 family physicians and a tertiary care hypertension research unit. Patients were randomly assigned (2:1 ratio) to either a patient-directed management strategy using home blood pressure monitoring to adjust drug therapy if readings consistently exceeded defined limits, or office-based management through physician visits. The primary endpoint was the change from baseline in mean arterial pressure as determined by automatic ambulatory blood pressure monitoring. Secondary endpoints were changes in compliance, quality of life, and health care resource use. Ninety-one potential subjects were screened and 31 were randomized. Subjects in the patient-directed management group employed the drug adjustment protocols appropriately without complications. A significant difference in change in mean blood pressure was observed, favoring the patient-directed management (-0.95 mm Hg and +1.90 mm Hg, respectively, for patient-directed management and office-based management, P = .039). Compliance rates and quality of life scores were not significantly different between groups. Physician visits were more frequent in the patient-directed management group (1.05 v 0.20 visits/8 weeks, respectively, for patient-directed management and office-based management groups, P = .045). A patient-directed hypertensive management strategy may be feasible for patients with chronic stable hypertension. Such a strategy may improve blood pressure control compared with usual office-based care. However, physician visits may be increased using this strategy, at least in the short term.", "To assess the effect of a physician and pharmacist teamwork approach to uncontrolled hypertension in a medical resident teaching clinic, for patients who failed to meet the recommended goals of the fifth Joint National Commission on Detection, Evaluation and Treatment of High Blood Pressure.\n Physician and pharmacist teamwork can improve the rate of meeting national blood pressure goals in patients with previously uncontrolled hypertension.\n A single-blinded randomized controlled trial lasting 6 months.\n A primary care outpatient teaching clinic.\n A sample of 95 adult hypertensive patients who failed to meet national blood pressure goals based on three consecutive visits over a 6-month period.\n Patients were randomly assigned to a control arm of standard medical care or to an intervention arm in which a physician and pharmacist worked together as a team.\n At study completion, the percentage of patients achieving national goals due to intervention was more than double the percentage in the control arm (55% vs 20%, p < .001). Systolic blood pressure declined 23 mm Hg in the intervention arm versus 11 mm Hg in the control arm (p < .01). Diastolic blood pressure declined 14 and 3 mm Hg in the intervention and control arms, respectively (p < .001). The intervention worked equally as well in men and women and demonstrated noticeable promise in a minority of mixed-ancestry Hawaiians in whom hypertension is of special concern.\n Patients who fail to achieve national blood pressure goals under standard outpatient medical care may benefit from a program that includes a physician and pharmacist teamwork approach.", "The efficacy of self-recording of blood pressure in the management of hypertension was assessed in a randomized clinical trial involving 140 persons who had been receiving antihypertensive therapy for a year or more, but whose diastolic blood pressure had remained at 95 mm Hg or higher. To control for the increased attention implicit in self-recording, which might affect blood pressure, the patients were assigned at random to one of the four groups: self-recording and monthly home visits, self-recording only, monthly home visits only, and neither self-recording nor monthly home visits. This design also permitted assessment of the effect of home visits. During the 6-month experiment no significant differences were apparent between the groups in either compliance or diastolic blood pressure. However, both self-recording and monthly home visits produced a reduction in blood pressure among patients who admitted to difficulty remembering to take their pills; a reduction was not seen among patients who said they had no such difficulty. This confirmed an earlier observation suggesting that this easily identified group of patients may be the most responsive to intervention programs.", "To assess whether lifestyle counselling is effective in non-pharmacological treatment of hypertension in primary health care.\n Open randomized controlled trial.\n Ten municipal primary health care centres in eastern Finland.\n Seven hundred and fifteen subjects aged 25-74 years with systolic blood pressure 140-179 mmHg and/or diastolic blood pressure 90-109 mmHg or antihypertensive drug treatment.\n Systematic health counselling given by local public health nurses for 2 years.\n Blood pressure, lipids and lifestyle data were collected annually.\n Among participants with no antihypertensive drug treatment, the net reductions after 1 year both in systolic blood pressure [-2.6 mmHg; 95% confidence interval (CI), -4.7 to -0.5 mmHg] and in diastolic blood pressure (-2.7 mmHg; 95% CI, -4.0 to -1.4 mmHg) were significant in favour of the intervention group. This difference in blood pressure change was maintained during the second year. In participants with antihypertensive drug treatment, no significant difference in blood pressure reduction was seen between the groups during the study.\n A relatively modest, but systematic counselling in primary health care can, at least among untreated hypertensive subjects, produce reductions in blood pressure levels that are modest for the individual, but very important from the public health point of view.", "A gap exists between evidence and practice regarding the management of cardiovascular risk factors. This gap could be narrowed if systematically developed clinical practice guidelines were effectively implemented in clinical practice. We evaluated the effects of a tailored intervention to support the implementation of systematically developed guidelines for the use of antihypertensive and cholesterol-lowering drugs for the primary prevention of cardiovascular disease.\n We conducted a cluster-randomized trial comparing a tailored intervention to passive dissemination of guidelines in 146 general practices in two geographical areas in Norway. Each practice was randomized to either the tailored intervention (70 practices; 257 physicians) or control group (69 practices; 244 physicians). Patients started on medication for hypertension or hypercholesterolemia during the study period and all patients already on treatment that consulted their physician during the trial were included. A multifaceted intervention was tailored to address identified barriers to change. Key components were an educational outreach visit with audit and feedback, and computerized reminders linked to the medical record system. Pharmacists conducted the visits. Outcomes were measured for all eligible patients seen in the participating practices during 1 y before and after the intervention. The main outcomes were the proportions of (1) first-time prescriptions for hypertension where thiazides were prescribed, (2) patients assessed for cardiovascular risk before prescribing antihypertensive or cholesterol-lowering drugs, and (3) patients treated for hypertension or hypercholesterolemia for 3 mo or more who had achieved recommended treatment goals. The intervention led to an increase in adherence to guideline recommendations on choice of antihypertensive drug. Thiazides were prescribed to 17% of patients in the intervention group versus 11% in the control group (relative risk 1.94; 95% confidence interval 1.49-2.49, adjusted for baseline differences and clustering effect). Little or no differences were found for risk assessment prior to prescribing and for achievement of treatment goals.\n Our tailored intervention had a significant impact on prescribing of antihypertensive drugs, but was ineffective in improving the quality of other aspects of managing hypertension and hypercholesterolemia in primary care.", "A randomised trial was undertaken to discern the effect of pharmacy-based value-added utilities on prescription refill compliance with antihypertensive therapy and subsequent health care expenditures. The subjects were 304 Medicaid beneficiaries from the state of Florida, previously untreated for mild to moderate hypertension, prescribed 240 mg of calcium channel antagonist verapamil once daily and monitored regarding prescription refill compliance and health service utilisation for one year. Subjects provided informed consent and were randomly assigned to one of four experimental groups: (1) the control cohort received standard pharmaceutical care with each dispensing of antihypertensive therapy, (2) the second cohort received standard pharmaceutical care and was mailed a medication-refill reminder ten days prior to each sequential refill date, (3) the third cohort received standard pharmaceutical care and was provided unit-of-use packaging with each prescription-refill request and (4) the fourth cohort received standard pharmaceutical care, mailed medication-refill reminders and unit-of-use packaging. Analysis of variance (ANOVA) procedures revealed that patients receiving mailed prescription-refill reminders, unit-of-use packaging or a combination of both interventions achieved a significant (P < or = 0.05) increase in the Medication Possession Ratio (MPR) for antihypertensive therapy relative to controls. Receipt of both interventions resulted in a significant (P < or = 0.05) improvement in the MPR for antihypertensive therapy relative to all other groups no significant difference was discerned between groups receiving either mailed prescription-refill reminders or unit-of-use packaging.(ABSTRACT TRUNCATED AT 250 WORDS)", "In the treatment of hypertension, problems of nonadherence and consequent poor blood pressure control are particularly severe. Alternative intervention strategies were compared to explore means of improving adherence and lowering blood pressures. In a 3 x 4 repeated measures analysis of variance design, 115 patients were randomly selected and randomly assigned to one of three treatment modalities (routine clinic care, patient education, and contingency contracting) and were followed over four clinic visits. Subjects' knowledge about hypertension and its management, adherence to requests for regular medical follow-up, and blood pressure levels were measured. Patient education was not effective in lowering blood pressures; it produced an untoward outcome, a dropout rate higher than that for patients receiving only routine clinic care. However, contingency contracting was an effective intervention strategy for improving patient knowledge, F (1,59) = 51.32, p less than .0001; adherence to requests for regular medical care, Max L (2) = 25.9, p less than .0001; and decreasing diastolic blood pressures, F (2,49) = 3.39, p less than .05.", "Two interventions designed to help physicians manage hypertensive patients were evaluated in a controlled trial: 1) computer-generated feedback to facilitate identification of poorly controlled patients; and 2) a physician education program on clinical management strategies, emphasizing patient compliance. Four physician practice teams received either computer feedback, the education program, both, or neither. Feedback team physicians received seven monthly listings of the latest visits and blood pressures of their hypertensive patients. The self-administered learning program included written clinical stimulations and associated didactic material. Experimental and control physicians were similar in baseline knowledge, patient mix and level of training. All feedback team physicians requested appointments for listed patients, and their patients made twice as many visits as control patients during the intervention period (p less than 0.05). Education team physicians showed significant gains on a content-specific post-intervention test: mean score 84 per cent compared with 74 per cent for the control group (p less than 0.005). All patient groups showed improvement in blood pressure over the study period. However, no differences between intervention teams could be detected (p greater than 0.20). The probability of missing a 10 mm interteam difference in outcome diastolic pressure was 1 per cent (power of 0.99). Strategies for further improvement in outpatient hypertension management may need to come from outside the traditional medical model.", "The effectiveness of two social support strategies designed to lower hypertensive patients' blood pressure were compared to each other and to a control group (N = 63) receiving routine care in a randomized clinical trial extending over a period of two years. Group 1 (N = 99) received visits and had family members actively participate in their care through home blood pressure monitoring; Group 2 (N = 56) received home visits from nurses and pharmacists. All groups were predominantly Black. After the first year of the trial, the proportion of patients with uncontrolled diastolic blood pressure (greater than or equal to 95mm Hg) had declined significantly for all three groups; no group showed a statistically significant advantage. However, during the last six months of the second year (after visiting had ended), both Groups 1 and 2 demonstrated clear superiority in DBP control over Group 3, achieving borderline statistical significance (p = .07) when multivariable analysis was performed to control for potential confounders. Supplementing routine care with periodic home visits produced an additional 21 per cent of patients with well-controlled DBP, while involving family members plus visits produced a 17 per cent improvement in the percentage of patients with DBP less than 95mm Hg. However, neither support strategy was clearly more effective than the other over time. The efficacy of the interventions is discussed with respect to cost and feasibility of implementation.", "To determine the effectiveness of specialist nurse delivered education in primary care to improve control of hypertension and hyperlipidaemia in patients with diabetes.\n Practice-level randomized controlled trial, Salford, England.\n From 44 practices, 10 303 subjects presenting in general practice with raised blood pressure (= 140/80 mmHg), raised total cholesterol (= 5.0 mmol/l) or both.\n Practices were randomized to receive either the intervention for hyperlipidaemia or for hypertension; practices acted as control for the intervention not received. Specialist nurses arranged a schedule of visits with general practitioners and general practice nurses, reminding them of diabetes protocols and clinical targets. They provided educational materials and protocols used in secondary care for nurse and doctor interventions including stepping up pharmacotherapy when necessary. Practices received a list of patients in their practice who were poorly controlled at their last annual review; new and recalled patients were targeted.\n At subsequent annual review, blood pressure and total cholesterol values were obtained from the Salford electronic diabetes register for patients from participating practices.\n Overall, specialist nurse-led educational outreach to primary care was associated with no improvement in patients achieving target after 1 year-odds ratio (OR): 1.03 (95% CI 0.95-1.11; P = 0.52). Similar results were achieved with hyperlipidaemia OR: 1.04 (95% CI 0.88-1.23; P = 0.62) and hypertension OR: 1.01 (95% CI 0.80-1.27; P = 0.93).\n This study provides evidence that the use of specialist nurses to perform educational outreach to improve target adherence to patients with diabetes in primary care is not effective.", "This study tested the feasibility of a low-technology office-based approach to weight reduction in obese hypertensive patients. Family practice residents were randomly assigned to either an experimental or a control group. Physicians in the experimental group were instructed in methods of weight reduction, which they then passed on to their patients. Patients of experimental physicians were seen monthly, their diets were discussed, and improvements were suggested. The control group patients received their usual care. After six months the experimental patients had lost significantly more weight than the controls and had significantly reduced the number of antihypertensive drugs while maintaining blood pressure control. After 12 months there was no significant difference between the two groups with respect to weight loss, blood pressure, or number of antihypertensive drugs. Experimental and control patients who lost weight had visited their physicians more frequently than those who did not and had reduced the number of antihypertensive medications they were taking. This educationally oriented intervention trial is an example of the type of research that is practical to perform in a family practice center and is applicable in family physicians' offices.", "The long-term management of patients with chronic conditions such as hypertension presents problems for the health services. Shared care addresses these by coordinating care and defining responsibilities.\n This study set out to investigate the feasibility, acceptability and cost effectiveness of shared general practitioner-hospital care for well-controlled hypertensive patients in an urban area by comparing three matched groups of patients.\n A total of 554 outpatient clinic attenders, considered suitable for shared care by their consultant, were randomly allocated to shared care or follow up in the outpatient clinic; a third group of 277 patients was selected from a nurse practitioner clinic. Main outcome measures were the proportion of patients in the second year of follow up who had undergone a complete review (blood pressure measurement, serum creatinine level result and electrocardiograph report), acceptability to patients and general practitioners as assessed by questionnaire, and cost per complete review in year two (National Health Service and patient costs).\n After two years 220 (82%) shared care patients had had a complete review compared with 146 (54%) outpatient clinic attenders and 202 (75%) nurse practitioner clinic attenders. Blood pressure control was similar in each group. Of 297 general practitioners invited, 85% wished to participate in the study; 61% of questionnaire respondents subsequently wanted shared care to continue while 25% were unsure. Half of the patients receiving shared care preferred this method of follow up. The rank order of cost-effectiveness ratios was shared care, nurse practitioner care and conventional outpatient care, relative differences being most marked when only patient costs were considered.\n Shared care for hypertension is feasible in an urban setting, acceptable to the majority of participants and is a cost-effective method of long-term follow up.", "In the Hypertension Detection and Follow-up Program, 7825 (71.5 per cent) of the 10,940 participants had diastolic blood pressures averaging between 90 and 104 mm Hg on entry into the study and were designated Stratum 1. Half were referred to their usual source of care in the community (the referred-care group), and half were treated intensively in special clinics (the stepped-care group). Five-year mortality in the Stratum 1 patients given stepped care was 20.3 per cent lower than in those given referred care (P less than 0.01). Particularly noteworthy was the beneficial effect of stepped-care treatment on persons with diastolic pressures of 90 to 104 mm Hg who had no evidence of end-organ damage and were not receiving antihypertensive medication when they entered the study. This subgroup had 28.6 per cent fewer deaths at five years among those treated with stepped care than among those treated with referred care (P less than 0.01). These findings support a recommendation that in patients with mild hypertension, treatment should be considered early, before damage to end organs occurs.", "The majority of hypertensive patients do not reach the target blood pressure (BP). We sought to clarify whether intermittent self-monitoring of BP leads to better BP control compared to ordinary treatment in general practice.\n Two hundred sixty-nine hypertensive patients participated in this multicenter, randomized, parallel-group study in primary health care. Home BP was measured in the self-monitoring (SM) group at 0, 2, 4, and 6 months, and in the control (C) group at 0 and 6 months. The participating physicians were instructed to intensify the antihypertensive therapy when needed.\n At the beginning, both groups had similar home BP levels (SM 143.1 +/- 17.4/85.3 +/- 7.4 mm Hg v C 143.9 +/- 18.3/85.4 +/- 7.5 mm Hg). After 6 months, there were significant decreases in systolic (P <or= .0001), diastolic (P <or= .0029), and pulse pressures (P <or= .021) in both groups. Systolic (-7.8 +/- 13.1 mm Hg v -4.5 +/- 12.2 mm Hg, P = .047) and pulse pressure (-4.7 +/- 9.0 mm Hg v -2.2 +/- 10.0 mm Hg, P = .042) decreased significantly more than in the self-monitoring group. The decrease in diastolic pressure was similar in both groups (SM -3.1 +/- 6.2 mm Hg v C -2.3 +/- 8.3 mm Hg, P = not significant). The patients in the SM group reached home BP target more often than those in the C group (29% v 16%, P = .016). There was a nonsignificant trend toward lower office BP values in the SM group.\n Self-monitoring decreased systolic and pulse pressure significantly more than ordinary treatment and promoted achievement of target BP. This was most likely due to improved patient compliance and more active treatment by the physicians. Our results suggest that home measurement is useful in the control of hypertension.", "To assess whether blood pressure control in primary care could be improved with the use of patient held targets and self monitoring in a practice setting, and to assess the impact of these on health behaviours, anxiety, prescribed antihypertensive drugs, patients' preferences, and costs.\n Randomised controlled trial.\n Eight general practices in south Birmingham.\n 441 people receiving treatment in primary care for hypertension but not controlled below the target of < 140/85 mm Hg.\n Patients in the intervention group received treatment targets along with facilities to measure their own blood pressure at their general practice; they were also asked to visit their general practitioner or practice nurse if their blood pressure was repeatedly above the target level. Patients in the control group received usual care (blood pressure monitoring by their practice).\n Primary outcome: change in systolic blood pressure at six months and one year in both intervention and control groups. Secondary outcomes: change in health behaviours, anxiety, prescribed antihypertensive drugs, patients' preferences of method of blood pressure monitoring, and costs.\n 400 (91%) patients attended follow up at one year. Systolic blood pressure in the intervention group had significantly reduced after six months (mean difference 4.3 mm Hg (95% confidence interval 0.8 mm Hg to 7.9 mm Hg)) but not after one year (mean difference 2.7 mm Hg (- 1.2 mm Hg to 6.6 mm Hg)). No overall difference was found in diastolic blood pressure, anxiety, health behaviours, or number of prescribed drugs. Patients who self monitored lost more weight than controls (as evidenced by a drop in body mass index), rated self monitoring above monitoring by a doctor or nurse, and consulted less often. Overall, self monitoring did not cost significantly more than usual care (251 pounds sterling (437 dollars; 364 euros) (95% confidence interval 233 pounds sterling to 275 pounds sterling) versus 240 pounds sterling (217 pounds sterling to 263 pounds sterling).\n Practice based self monitoring resulted in small but significant improvements of blood pressure at six months, which were not sustained after a year. Self monitoring was well received by patients, anxiety did not increase, and there was no appreciable additional cost. Practice based self monitoring is feasible and results in blood pressure control that is similar to that in usual care.", "Evaluation of a structured hypertension treatment and teaching programme in general practice.\n Prospective controlled trial; follow-up period 18 months.\n 10 primary health care practices. PRACTICES AND PATIENTS: From each practice 20 patients (30 to 60 years old, mean of the last two blood pressure measurements at or above 160 and/or 95 mmHg) were randomly selected; in 5 practices these patients were to participate in the treatment and teaching programme; in the remaining 5 practices hypertension care was continued without the availability of such a programme (controls).\n Structured treatment and teaching programme based upon four group sessions for patients mainly conducted by paramedical personnel.\n Blood pressure, body weight, prescription of antihypertensive drugs - as documented in the patient's records.\n Of the 100 control patients 26 and of the 100 intervention patients 14 were lost to observation; 46 patients had agreed to participate in the programme. The mean number of prescribed antihypertensive agents per patient decreased in the intervention group (1.8 +/- 1.3 at baseline, vs 1.2 +/- 1.2 at follow-up) compared to the control group (1.6 +/- 1.3 vs 1.8 +/- 1.6); difference 0.8 (95% CI 0.4 to 1.1), p < 0.0001. In the control group 9% and in the intervention group 33% of patients had documented reductions of body weight (p < 0.0001). Blood pressure decreased in the intervention group (162 +/- 14/100 +/- 7 mmHg at baseline, vs 154 +/- 16/95 +/- 9 mmHg at follow-up) compared to the control group (161 +/- 13/98 +/- 7 mmHg vs 158 +/- 18/96 +/- 11 mmHg); differences for systolic blood pressure 5 (95% CI 0 to 10) mmHg, p = 0.071; for diastolic blood pressure 4 (1 to 7) mmHg, p = 0.018.\n The introduction of a structured hypertension treatment and teaching programme in general practice may lead to significant improvements of hypertension care.", "An automated surveillance system utilizing a computer-based medical record system (COSTAR) was designed to improve the follow-up of patients with newly identified elevated diastolic blood pressure. A population of patients was selected where, in the 6-month period following the initial measurement of an elevated diastolic blood pressure, there were fewer than two visits during which blood pressure was recorded. In a randomized controlled clinical trial, this poor follow-up population was divided into two groups, with computer-generated reminders being automatically generated for only patients in the experimental group. Follow-up was significantly improved in the group receiving the reminders, both in terms of rate of follow-up attempted or achieved by the responsible physician and in the repeated recording of blood pressure. We conclude that a computer-based reminder system improves follow-up of newly discovered elevation in diastolic blood pressure.", "To develop a working model with which prescribing behaviour among general practitioners might be influenced.\n Intervention based on feedback on prescribing rates and problem-oriented educational outreach visits, using educational material and local opinion leaders. Randomised study with three parallel intervention groups of general practitioners, which also served as controls for each other. The pharmacotherapeutic fields chosen were hypertension, peptic ulcer/dyspepsia and depression. Prescription data were retrieved from the electronic patient records for periods of 1 year before and after the intervention.\n Six health care centres and three continuing medical education groups in Stockholm.\n Forty general practitioners.\n Drug prescribing rates and patterns before and after the intervention.\n In the hypertension field, desired trends in fractional prescribing (favouring diuretics and beta blocking agents) were recorded, with a significant (P < 0.05) effect on prescriptions for agents acting on the renin-angiotensin system, despite a pre-existing prescribing behaviour already much in line with the goals. In the peptic ulcer/dyspepsia field, desired trends were recorded for both types of therapies addressed. The fractional prescribing rates for proton-pump inhibitors decreased from 61.0% to 52.6% in the intervention arm and increased from 68.1% to 76.0% in the control arm (not significant due to low power). The depression group focused on better general attention to the disease and only minor changes were registered.\n Feedback of individual prescribing rates, combined with problem-oriented educational outreach visits, is a promising model for the improvement of prescribing behaviour. Data from the electronic patient record were feasible for feedback on prescribing rates.", "Pharmaceutical care programs may be an option to improve blood pressure (BP) control in patients with uncontrolled hypertension. The aim of this study was to evaluate the efficacy of pharmaceutical care programs in treating patients with resistant hypertension.\n In a double-blind randomized clinical trial, 71 patients with uncontrolled BP were enrolled in a pharmaceutical care program or in a control group and underwent a series of cognitive tests. The primary outcome was change in ambulatory BP (ABP) between the baseline evaluation and the final visit 6 months later. The secondary outcomes were the frequency of drug-related problems and adherence as determined by plasma levels of hydrochlorothiazide.\n The delta-values between the intervention and control groups for ABP in the different daily periods, with the corresponding 95% confidence limits, adjusted for age and baseline BP were: 3 (-1 to 5), 2 (-2 to 4), and 5 (-1 to 6) mm Hg for 24 h, daily and nightly systolic BP, respectively. The corresponding values for diastolic BP were 1 (-1 to 3), 0 (-2 to 2), and 3 (-1 to 4) mm Hg, respectively. Hydrochlorothiazide was detected in the plasma in 21 of 27 patients in the intervention group that attended to all appointments and 24 of 30 patients in the control group (P = .904).\n The pharmaceutical care program tested in this trial was feasible and showed a trend for better BP control in patients with uncontrolled hypertension.", "The ABCD (Appropriate Blood Pressure Control in Diabetes) Trial is a large, prospective, randomized clinical trial of 950 patients with non-insulin-dependent diabetes mellitus (NIDDM) designed to compare the effects of intensive blood pressure control with moderate control on the prevention and progression of diabetic nephropathy, retinopathy, cardiovascular disease, and neuropathy in NIDDM. The secondary objective is to determine equivalency of the effects of a calcium channel blocker (nisoldipine) and an angiotensin-converting-enzyme inhibitor (enalapril) as a first-line antihypertensive agent in the prevention and/or progression of these diabetic vascular complications. The study consists of two study populations aged 40-74 years, 470 hypertensive patients (diastolic blood pressure of > or = 90.0 mmHg at time of randomization) and 480 normotensive patients (diastolic blood pressure of 80.0 mmHg at time of randomization). The study duration is 5 years and is scheduled to end in May of 1998. Patients are randomized to receive either intensive antihypertensive drug therapy or moderate antihypertensive drug therapy. Patients are also randomized to nisoldipine or enalapril, with open-label medications added if further blood pressure control is necessary. The primary outcome measure is glomerular filtration rate as assessed by 24-h creatinine clearance. Secondary outcome measures are urinary albumin excretion, left ventricular hypertrophy, retinopathy, and neuropathy. Cardiovascular morbidity and mortality will also be evaluated. Given the data showing the impact of hypertension on complications in NIDDM, the ABCD Trial is designed to determine if intensive antihypertensive therapy will be more efficacious than moderate antihypertensive therapy on the outcome of diabetic complications in NIDDM.", "This prospective, randomized, controlled study evaluated the impact of pharmacist-initiated home blood pressure monitoring and intervention on blood pressure control, therapy compliance, and quality of life (QOL). Subjects were 36 patients with uncontrolled stage 1 or 2 hypertension. Eighteen subjects received home blood pressure monitors, a diary, and instructions to measure blood pressure twice every morning. Home measurements were evaluated by a clinical pharmacist by telephone, and the patient's family physician was contacted with recommendations if mean monthly values were 140/90 mm Hg or higher. Eighteen control patients did not receive home monitors or pharmacist intervention. Office blood pressure measurements and QOL surveys (SF-36) were obtained at baseline and after 6 months. Mean absolute reductions in systolic and diastolic pressures were significantly reduced from baseline in intervention subjects (17.0 and 10.5 mm Hg, both p < 0.0001) but not in controls (7.0 and 3.8 mm Hg, p = 0.12 and p = 0.09). More intervention subjects (8) had blood pressure values below 140/90 at 6 months compared with controls (4). During the study 83.3% (15) of intervention subjects had drug therapy changes versus 33% (6) of controls (p < 0.01). Compliance and QOL were not significantly affected. Our data suggest that the combination of pharmacist intervention with home monitoring can improve blood pressure control in patients with uncontrolled hypertension. This may be related to increased modifications of drug regimens.", "Despite widely publicized hypertension treatment guidelines for physicians and lifestyle recommendations for patients, blood pressure control rates remain low. In community-based primary care clinics, we performed a nested, 2 x 2 randomized, controlled trial of physician intervention versus control and/or patient intervention versus control. Physician intervention included internet-based training, self-monitoring, and quarterly feedback reports. Patient intervention included 20 weekly group sessions followed by 12 monthly telephone counseling contacts and focused on weight loss, Dietary Approaches to Stop Hypertension dietary pattern, exercise, and reduced sodium intake. The primary outcome was change in systolic blood pressure at 6 months. Eight primary care practices (32 physicians) were randomized to physician intervention or control groups. Within those practices, 574 patients were randomized to patient intervention or control groups. Patient mean age was 60 years, 61% were women, and 37% were black. Blood pressure data were available for 91% of patients at 6 months. The main effect of physician intervention on systolic blood pressure at 6 months, adjusted for baseline pressure, was 0.3 mm Hg (95% CI: 1.5 to 2.2; P=0.72). The main effect of the patient intervention was 2.6 mm Hg (95% CI: 4.4 to 0.7; P=0.01). The interaction of the 2 interventions was significant (P=0.03); the largest impact was observed with the combination of physician and patient intervention (9.7 +/- 12.7 mm Hg). Differences between treatment groups did not persist at 18 months. Combined physician and patient interventions lowers blood pressure; future research should focus on enhancing effectiveness and sustainability of these interventions.", "We wanted to examine whether integrating depression treatment into care for hypertension improved adherence to antidepressant and antihypertensive medications, depression outcomes, and blood pressure control among older primary care patients.\n Older adults prescribed pharmacotherapy for depression and hypertension from physicians at a large primary care practice in West Philadelphia were randomly assigned to an integrated care intervention or usual care. Outcomes were assessed at baseline, 2, 4, and 6 weeks using the Center for Epidemiologic Studies Depression Scale (CES-D) to assess depression, an electronic monitor to measure blood pressure, and the Medication Event Monitoring System to assess adherence.\n In all, 64 participants aged 50 to 80 years participated. Participants in the integrated care intervention had fewer depressive symptoms (CES-D mean scores, intervention 9.9 vs usual care 19.3; P <.01), lower systolic blood pressure (intervention 127.3 mm Hg vs usual care 141.3 mm Hg; P <.01), and lower diastolic blood pressure (intervention 75.8 mm Hg vs usual care 85.0 mm Hg; P <.01) compared with participants in the usual care group at 6 weeks. Compared with the usual care group, the proportion of participants in the intervention group who had 80% or greater adherence to an antidepressant medication (intervention 71.9% vs usual care 31.3%; P <.01) and to an antihypertensive medication (intervention 78.1% vs usual care 31.3%; P <.001) was greater at 6 weeks.\n A pilot, randomized controlled trial integrating depression and hypertension treatment was successful in improving patient outcomes. Integrated interventions may be more feasible and effective in real-world practices, where there are competing demands for limited resources.", "The prevalence of hypertension is high, but the overall control rate is low. Poor control of, hypertension is associated with a number of diseases, such as stroke, heart and renal failure, and high, mortality rates. Studies have shown the separate effects of nurse clinics and telephone follow-up on, blood pressure control, but the incremental effect of combining the two interventions is unknown.\n This study examines whether there is an incremental effect on blood pressure control when using a nurse clinic combined with telephone follow-up.\n This was a randomised controlled trial. The primary outcome measure was blood pressure reading. The secondary outcome measures included adherence to home blood pressure monitoring, exercise, diet, medication, and satisfaction with care.\n There were no significant differences in the baseline measures between the control and study groups. Significant differences were found at 8 weeks after intervention was initiated between groups in, systolic blood pressure (control -7.97 vs study -19.03, t=2.35, p=0.022, CI 1.66-20.47) and diastolic, blood pressure (control -3.72 vs study -11.68, t=3.02, p=0.004, CI 2.68-13.24). Other variables with a significant between-group differences (p<0.05) were blood pressure control rate, adherence, to home blood pressure monitoring, exercise and satisfaction with care. Further analysis using, regression showed that home blood pressure monitoring is the most significant predictor for improved, systolic blood pressure.\n This study showed that nurse clinics have positive effects on blood pressure control and adherence to healthy lifestyle, but telephone follow-up after such clinics augments the effects of the clinic consultation. This combined mode of services is worth considering for other chronic disease, management programmes.\n Copyright 2010 Elsevier Ltd. All rights reserved.", "This study assessed the effectiveness of enhanced tracking and follow-up services provided by community health workers in promoting medical follow-up of persons whose elevated blood pressures were detected during blood pressure measurement at urban community sites.\n In a randomized controlled trial, 421 participants received either enhanced or usual referrals to care. Participants were 18 years or older, were either Black or White, and had blood pressure greater than or equal to 140/90 mm Hg and income equal to or less than 200% of poverty. The primary outcome measure was completion of a medical follow-up visit within 90 days of referral.\n The enhanced intervention increased follow-up by 39.4% (95% confidence interval [CI] = 14%, 71%; P = .001) relative to usual care. Follow-up visits were completed by 65.1% of participants in the intervention group, compared with 46.7% of those in the usual-care group. The number needed to treat was 5 clients (95% CI = 3, 13) per additional follow-up visit realized.\n Enhanced tracking and outreach increased the proportion of persons with elevated blood pressure detected during community measurement who followed up with medical care.", "First Nations people with diabetes mellitus and hypertension are at greater risk of renal and cardiovascular complications than are non-native patients because of barriers to health care services. We conducted this randomized controlled trial to assess whether a community-based treatment strategy implemented by home care nurses would be effective in controlling hypertension in First Nations people with existing hypertension and type 2 diabetes.\n We compared 2 community-based strategies for controlling hypertension in First Nations people with existing hypertension and diabetes. In the intervention group, a home care nurse followed a predefined treatment algorithm of pharmacologic antihypertensive therapy. In the control group, treatment decisions were made by each subject's primary care physician. The primary outcome measure was the difference between the 2 groups in the change in systolic blood pressure after 12 months. Secondary outcome measures were the change in diastolic blood pressure over time, the change in urine albumin status and the incidence of adverse events.\n Both groups experienced a significant reduction in systolic blood pressure by the final visit (by 24.0 [standard deviation (SD) 13.5] mm Hg in the intervention group and by 17.0 [SD 18.6] mm Hg in the control group); p < 0.001 in each case). However, the difference between the 2 groups in this change was not significant. Patients in the intervention group had a larger decrease in diastolic blood pressure over time than did those in the control group (by 11.6 [SD 10.6] mm Hg v. 6.8 [SD 11.1] mm Hg respectively; p = 0.05). The groups did not differ significantly in terms of changes in urine albumin excretion or incidence of adverse events.\n High rates of blood pressure control in the community were achieved in both groups in the DREAM 3 study. The addition of a home care nurse to implement a treatment strategy for blood pressure control was more effective in lowering diastolic than systolic blood pressure compared with home care visits for blood pressure monitoring alone and follow-up treatment by a family physician.", "The hypothesis that general practitioners would obtain better outcomes for patients with hypertension using a computer than doctors not using a computer was tested. Sixty family physicians were randomised to two treatment strategies. \"Test\" physicians completed a data collection form after each visit from a patient with hypertension and mailed the forms to the test centre for processing. Computer feedback on management was mailed to the doctors. This encouraged doctors to apply the \"stepped care\" protocol, supplied charts of diastolic blood pressure v time, and ranked patients' diastolic blood pressures by percentile. Letters were mailed to patients to remind them of appointments. \"Control\" doctors filled out the same data collection forms as test physicians, but neither doctors nor patients received computer feedback. Physicians who used the computer saw more patients per practice than control doctors (test 50 patients, control 40). For all patients the length of follow up was significantly longer in test practices (test 199 days, control 167), and a smaller percentage dropped out of active treatment in test practices (test 37.5%, control 42.1%). For patients with \"moderate\" hypertension of a baseline diastolic pressure of greater than 104 mm Hg the mean score of the last recorded pressure was below the goal of 90 mm Hg in test practices (88.5 mm Hg), but it failed to reach this goal in control practices (93.3 mm Hg). A greater average reduction of diastolic pressure was achieved in test practices (test 21.7 mm Hg, control 16.7 mm Hg). Though patients with \"moderate\" hypertension were better controlled in test practices than in control practices, the patients in test practices visited their doctors less often (test 13.3 visits per patient-year, control 17.4 visits). Among patients with newly detected hypertension test practices achieved a greater reduction in diastolic pressure than control practices (test 15.1 mm Hg v control 11.3 mm Hg) and more sustained control of hypertension (test 323 days per patient-year with a diastolic pressure of 90 mm Hg or less v control 259 days).", "38 hypertensive Canadian steelworkers who were neither compliant with medications nor at goal diastolic blood-pressure six months after starting treatment were allocated either to a control group or to an experimental group who were taught how to measure their own blood-pressures, asked to chart their home blood-pressures and pill taking, and taught how to tailor pill taking to their daily habits and rituals; these men were also seen fortnightly by a highschool graduate with no formal health professional training who reinforced the experimental manoeuvres and rewarded improvements in compliance and blood-pressure. Six months later, average compliance had fallen by 1.5% in the control group but rose 21.3% in the experimental group. Blood-pressures fell in 17 of 20 experimental patients (to goal in 6) and in 10 of 18 control patients (to goal in 2).", "It is widely believed that patients' compliance can be increased by persuading them to participate in their own care. We tested whether patients with hypertension could manage their own clinical records and whether their doing so would affect the quality of their care. Two hundred patients were randomly assigned to an intervention or a control group. Those in the intervention group were asked to complete a 10-page booklet containing a personal standardized medical record. All patients were scheduled for a follow-up appointment at the end of one year and were referred to their general practitioners for interim care. At the end of the follow-up period, the proportion of patients seen was comparable in the two groups. More of the patients in the intervention group than in the control group filled out a questionnaire as requested, and more added comments. Within the intervention group, the proportion of patients seen and the fall in systolic blood pressure were significantly higher among the 44 patients who had completed the personal record as requested than among the 57 who had not. Patients who completed the personal record also had fewer compliance problems.", "Three educational interventions for the control of essential hypertension in ambulatory patients were based on analyses of the educational needs of patients and providers. The educational program increased reported compliance with medication, improved the proportion of patients losing weight, and improved appointment keeping. Most important, there was a favorable effect on blood pressure (BP) control. The proportion of patients with BP under control in the group assigned to all three interventions increased by 28% (from 38% to 66%), while the proportion in the control group receiving standard medical therapy with no educational interventions remained unchanged at 42%.", "Assessing the compliance of people over 60 years of age and older with an antihypertensive treatment regimen was a major objective of the Systolic Hypertension in the Elderly Program (SHEP) pilot study. The study randomized 551 men and women over the age of 60 (mean age = 72 years) to a stepped care treatment that included chlorthalidone or placebo in a double-blind trial. Three measures of compliance to treatment protocol--pill count, self-report, and a urine chlorthalidone assay--all indicated high levels of compliance in 80 to 90% of participants at 3 months and 1 year after randomization. Pill-taking compliance was similar in the active and placebo groups, although the rate of discontinuance from study medications at 1 year was higher in the placebo than in the active group. Compliance was high in all age categories, including those over age 80. These data suggest that elderly patients can achieve high levels of compliance with antihypertensive medications.", "A randomized controlled trial of an information and medical record booklet designed to improve patient understanding and participation in the management of hypertension was conducted in six inner London general practices. After one year there were no significant differences between the group who had received the booklets and the control group in mean systolic or diastolic blood pressure, but the study group scored significantly higher on knowledge about hypertension and its management. However, the difference between the two groups was small, possibly because both groups started with a high level of understanding about hypertension and its management. In addition, the mean diastolic blood pressure in the control group showed that the treatment provided was already satisfactory, and that there was little need for improvement. Nevertheless, the information booklet evaluated in this study provides health professionals with a highly acceptable method of informing the patient about hypertension and its management and could be used both in hospital and general practice.", "To see whether general practitioners could effectively carry out training in relaxation and management of stress to reduce mild hypertension a study was carried out with a subsample of phase 2 of the Medical Research Council's treatment of mild hypertension trial. In the main mild hypertension trial patients had been receiving either an active drug or placebo for six years. In phase 2 a subsample of these patients were randomly allocated either to continue or to stop receiving the active drug or placebo. In a further subsample patients were again randomised to receive or not to receive relaxation therapy. This factorial design presented an additional opportunity to assess whether patients controlled with active drugs might have their blood pressure maintained by this behavioural therapy once drug treatment was stopped and to assess whether blood pressure might be further reduced by this therapy in patients who had been under regular medical supervision for as long as six years and who had already received non-pharmacological advice. The therapy was conducted by general practitioners in group sessions once a week for eight weeks. The training in relaxation was accompanied by galvanic skin resistance biofeedback. At one year follow up blood pressure in the relaxation subgroups was either maintained (in the group who had stopped receiving drugs) or reduced further (in the group who had continued receiving drugs and in both placebo groups), while in the control group it had increased in all the subgroups, but particularly in those who had stopped receiving drugs. Differences in changes in blood pressure between the relaxation and control groups were significant. There were five new cardiovascular events, including evidence of myocardial ischaemia in blindly coded electrocardiograms in the control group, compared with one in the treatment group. General practitioners, if motivated, can successfully apply this technique of training those with mild hypertension in relaxation and management of stress.", "Three health education interventions for urban poor hypertensive patients were introduced sequentially in a randomized factorial design: 1) an exit interview to increase understanding of and compliance with the prescribed regimen; 2) a home visit to encourage a family member to provide support for the patient's regimen; and 3) invitations to small group sessions to increase the patient's confidence and ability to manage his/her problem. Previous evaluation of the initial two-year experience demonstrated a positive effect of the educational program on compliance with the medical treatment and blood pressure control. Data accumulated over an additional three years, including mortality analysis, are now presented. The study group consisted of the same cohort of 400 ambulatory hypertensive outpatients in the eight experimental and control groups. The five-year analysis shows a continuing positive effect on appointment keeping, weight control, and blood pressure control. All-cause life table mortality rate was 57.3 per cent less for the experimental group compared to the control group (12.9/100 vs 30.2/100, p less than .05), while the hypertension-related mortality rate was 53.2 per cent less (8.9/100 vs 19.0/100, p less than .01). The results from this longitudinal study provide evidence to encourage health practitioners to utilize such educational programs in the long-term management and control of high blood pressure.", "Standard office-based approaches to controlling hypertension show limited success. Such suboptimal hypertension control reflects in part the absence of both an infrastructure for patient education and frequent, regular blood pressure (BP) monitoring. We tested the efficacy of a physician-directed, nurse-managed, home-based system for hypertension management with standardized algorithms to modulate drug therapy, based on patients' reports of home BP.\n We randomized outpatients requiring drug therapy for hypertension according to the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) criteria to receive usual medical care only (UC, n = 76) or usual care plus nurse care management intervention (INT, n = 74) over a 6-month period.\n Patients receiving INT achieved greater reductions in office BP values at 6 months than those receiving UC: 14.2 +/- 18.1 versus 5.7 +/- 18.7 mm Hg systolic (P < .01) and 6.5 +/- 10.0 versus 3.4 +/- 7.9 mm Hg diastolic, respectively (P < .05). At 6 months, we observed one or more changes in drug therapy in 97% of INT patients versus 43% of UC patients, and 70% of INT patients received two or more drugs versus 46% of UC. Average daily adherence to medication, measured by electronic drug event monitors, was superior among INT subjects (mean +/- SD, 80.5% +/- 23.0%) than among UC subjects (69.2 +/- 31.1%; t(113) = 2.199, P = .03). There were no significant adverse drug reactions in either group.\n Telephone-mediated nurse management can successfully address many of the systems-related and patient-related issues that limit pharmacotherapeutic effectiveness for hypertension.", "The authors examined the effects of a comprehensive lifestyle modification intervention on blood pressure (BP) and other cardiovascular risk factors in hypertensive patients. A total of 70 participants were randomly placed into either a lifestyle intervention or a control group. Four education classes and individual counseling sessions were held for the intervention group. Participants in the control group were provided with routine outpatient services and were asked to maintain their usual lifestyle. Data were gathered at baseline and at the end of 6 months. At the end of 6 months, BP, body weight, body mass index, waist circumference, and fasting lipids, apart from high-density lipoprotein cholesterol, significantly declined in the intervention group. Healthpromoting lifestyle scores of the intervention group had increased significantly compared to those of the control group. In conclusion, the results demonstrate the feasibility of comprehensive lifestyle modification and show its beneficial effects.", "To evaluate the efficacy of a programme of home blood pressure measurement (HBPM) on therapeutic compliance in mild-to-moderate hypertension.\n A prospective controlled multicentre clinical trial.\n Forty primary care centres in Spain, with a duration of 6 months.\n A total of 250 patients with newly diagnosed or uncontrolled hypertension were included.\n The patients were randomly selected and distributed in two groups: (1) the control group (CG) who received standard health intervention; (2) the intervention group (IG): the patients in this group received an OMRON in their homes for a programme of HBPM.\n Four visits were scheduled, for the measurement of blood pressure (BP). They were provided with an electronic monitor for measuring compliance (monitoring events medication system; MEMS). Therapeutic compliance was defined as a drug consumption of 80-110%. A number of variables were calculated using the MEMS. The mean BP were calculated and the percentage of controlled patients.\n A total of 200 patients completed the study (100 in each group). Compliance was observed in 74 and 92%, respectively, in the CG and IG [95% confidence interval (CI) 63.9-84.1 and 86.7-97.3; P = 0.0001], the mean percentage compliances were 87.6 and 93.5% (95% CI 81.2-94 and 80.7-98.3; P = 0.0001), the percentages of correct days were 83.6 and 89.4%, the percentages of subjects who took the medication at the prescribed time were 79.89 and 88.06%, and the levels of therapeutic cover were 86.7 and 93.1%. The number needed to treat to avoid one case of non-compliance was 5.6 patients. The differences in the mean decreases in BP were significant for diastolic BP, with a greater decrease observed in the IG.\n An HBPM programme using electronic monitors is effective in improving compliance in arterial hypertension, measured using the MEMS.", "To compare group versus individual academic detailing to increase diuretic or beta-blocker use in hypertension.\n We conducted a cluster-randomized controlled trial in a large health maintenance organization. Subjects (N=9820) were patients with newly treated hypertension in the year preceding the intervention (N=3692), the 9 months following the intervention (N=3556), and the second year following intervention (N=2572). We randomly allocated 3 practice sites to group detailing (N=227 prescribers), 3 to individual detailing (N=235 prescribers), and 3 to usual care (N=319 prescribers). Individual detailing entailed a physician-educator meeting individually with clinicians to address barriers to prescribing guideline-recommended medications. The group detailing intervention incorporated the same social marketing principles in small groups of clinicians.\n In the first year following the intervention, the rates of diuretic or beta-blocker use increased by 13.2% in the group detailing practices, 12.5% in the individual detailing practices, and 6.2% in the usual care practices. As compared with usual care practices, diuretic or beta-blocker use was more likely in group detailing practices (adjusted odds ratio (OR), 1.40; 95% confidence interval (CI), 1.11 - 1.76) and individual detailing practices (adjusted OR, 1.30; 95% CI, 0.95 - 1.79). Neither intervention affected blood pressure control. Two years following this single-visit intervention, there was still a trend suggesting a persistent effect of individual (OR, 1.22; 95% CI, 0.92 - 1.62), but not group, detailing (OR, 1.06; 95% CI, 0.80 - 1.39), as compared with usual care.\n Both group and individual academic detailing improved antihypertensive prescribing over and above usual care but may require reinforcement to sustain improvements.", "This study was planned in the context of a regional high blood pressure programme, to compare the efficacy of two educative methods. The group of 722 hypertensive patients (58.8% women), mean age 61 years, was randomly selected from 19 primary care centres. Initial assessment was based on a patient interview including 22 questions on high blood pressure, its consequences and treatment. Patients agreeing to participate in an active education team programme were distributed into three groups: individual education, team education and a control group. Those who declined to participate formed two groups: individual education and controls. Team education consisted of two audiovisual sessions attended by groups of 8-12 patients and conducted by treating physicians and nurses. Individual education included comments related to the 22 questions. Follow-up assessment was made after two months. An increase in the level of hypertension control was observed only in the accepting group, in which educative action was followed by increased knowledge. Results were similarly favourable for both the individual and team education groups and suggested the need to consider educational factors together with those influencing patient attitude towards an active educational programme.", "To evaluate the implementation of clinical guidelines for hypertension in general practice by use of a computer-based clinical decision support system (CDSS) and a specific implementation strategy. Evaluation of patient outcome.\n Randomised study with health centres as units. The intervention group had the CDSS installed and made ready for use, doctors and assistants were trained and received a user-manual, the doctors were offered telephone repetitions, a seminar in risk intervention and, at the same seminar, further demonstration of the CDSS. The doctors received baseline registrations with information of how they treated their own hypertensive patients, and use of the CDSS was checked repeatedly.\n General practice in Sør- and Nord-Trøndelag counties in Norway, 380,000 inhabitants.\n Seventeen health centres with 24 doctors and 984 patients in the intervention group. Data from 879 patients used in the final analyses. Twelve health centres with 29 doctors and 1255 patients in the control group. Data from 1119 patients used in the final analyses.\n After an intervention period of 18 months, group differences in level of systolic and diastolic blood pressure, serum cholesterol, body mass index, and risk score for myocardial infarction were calculated, as well as group differences in fractions of smokers.\n Significant group difference in favour of intervention group: diastolic blood pressure 1 mmHg (95% CI -1.89, -0.17). However, a significant baseline difference in systolic blood pressure in favour of control group of 2.7 mmHg (95% CI 1.0, 4.5) had been reduced to 1.2 mmHg (95% CI -0.6, 3.0) after intervention.\n Implementation of clinical guidelines in the treatment of hypertensive patients in general practice by means of a CDSS and several other procedures for implementation did not affect patient outcome in any clinically significant way.", "A clinical trial of 204 untreated patients with mild hypertension was conducted to assess the effect of home blood pressure monitoring on blood pressure level, pharmacologic treatment, reduction of risk factors, and use of health services. After 1 year, no statistically significant differences were found between the treatment and control groups. The findings indicate that, while home blood pressure monitoring may be useful, it has no measurable short-term impact on these aspects of blood pressure management for patients with mild hypertension.", "To assess effects of multifactorial lifestyle modification on antihypertensive drug needs in treated hypertensive individuals.\n Randomized controlled trial.\n Research studies unit.\n Overweight hypertensive patients, receiving one or two antihypertensive drugs, were recruited by advertising, and allocated randomly to a usual care group (controls; n = 118) or a lifestyle modification group (programme group; n = 123).\n A 4-month programme of weight loss, a low-sodium 'Dietary Approaches to Stop Hypertension'-type diet with added fish, physical activity and moderation of alcohol intake. After 4 months, if mean 24-h ambulatory blood pressure (ABP) was less than 135/85 mmHg, antihypertensive drugs were withdrawn over 4 weeks and long-term home blood pressure monitoring was begun.\n Antihypertensive drug requirements, ABP, weight, waist girth at 4 months and 1-year follow-up.\n Ninety control group and 102 programme group participants completed the study. Mean 24-h ABP changed after 4 months by -1.0/-0.3 +/- 0.5/0.4 mmHg in controls and -4.1/-2.1 +/- 0.7/0.5 mmHg with the lifestyle programme (P < 0.01). At follow-up, changes in the two groups were not significantly different (4.1/1.3 +/- 1.1/1.0 mmHg in controls; 2.5/-0.1 +/- 1.1/0.8 mmHg in the programme group; P = 0.73). At 4 months, drug withdrawal differed significantly between the groups (P = 0.038) in men (control 44%; programme 66%) but not in women (65 and 64%, respectively; P = 0.964). At follow-up, sex-related differences were not significant, and 41% in the control group and 43% in the programme group maintained drug-withdrawal status. With the programme, net weight loss was 3.3 kg (P < 0.001) at 4 months and 3.0 kg (P < 0.001) at follow-up; respective net decreases in waist girth were 3.3 cm (P < 0.001) and 3.5 cm (P < 0.001).\n A 4-month multifactorial lifestyle modification in patients with treated hypertension reduced blood pressure in the short-term. Decreased central obesity persisted 1 year later and could reduce overall cardiovascular risk.", "The present study describes a 16-week trial of the use of a combination of biofeedback and relaxation techniques for the treatment of hypertension. Twenty-two hypertensive patients were randomly allocated to one of three groups: (1) diastolic blood pressure feedback, electromyographic feedback, and verbal relaxation; (2) sham blood pressure feedback; and (3) no treatment. For the 14 patients completing active treatment during an initial or crossover period, the average changes in blood pressure as measured outside the laboratory were minimal (0/-1 and +1/0 mm Hg, supine and standing, respectively). Average blood pressure reduction in the laboratory was no greater with active than with sham blood pressure feedback (-3/-2 vs. -5/-2 mm Hg). One subject, however, after showing no change in blood pressure during sham feedback, achieved pronounced and prolonged improvement following active treatment. Overall results do not support the usefulness of these techniques as primary therapy in most hypertensives.", "To measure clinical, economic, and humanistic outcomes associated with a pharmacist-managed hypertension clinic compared with physician-managed clinics.\n Prospective, randomized, comparative study.\n Managed care organization.\n A total of 330 patients with mild-to-moderate essential hypertension.\n Hypertension care provided by either the pharmacist-managed hypertension clinic or physician-managed general medical clinics.\n Baseline and 6-month evaluations consisted of systolic and diastolic blood pressure measurements, a short-form health survey, and collection of health care utilization information. After treatment, blood pressure measurements were significantly lower (p<0.001) in the pharmacist-managed hypertension clinic group than in the physician-managed clinic group. Patient satisfaction was significantly higher in the hypertension clinic group. Total costs for the hypertension clinic group were not different from those of the physician-managed clinic group ($242.46 vs $233.20, p=0.71), but cost:effectiveness ratios were lower in the hypertension clinic group ($27 vs $193/mm Hg for systolic blood pressure readings, and $48 vs $151/mm Hg for diastolic blood pressure readings).\n In a hypertension clinic, pharmacists can be a cost-effective alternative to physicians in management of patients, and they can improve clinical outcomes and patient satisfaction.", "To investigate the effect of a computer based clinical decision support system and a risk chart on absolute cardiovascular risk, blood pressure, and prescribing of cardiovascular drugs in hypertensive patients.\n Cluster randomised controlled trial.\n 27 general practices in Avon.\n 614 patients aged between 60 and 79 years with high blood pressure.\n Patients were randomised to computer based clinical decision support system plus cardiovascular risk chart; cardiovascular risk chart alone; or usual care.\n Percentage of patients in each group with a five year cardiovascular risk >/=10%, systolic blood pressure, diastolic blood pressure, prescribing of cardiovascular drugs.\n Patients in the computer based clinical decision support system and chart only groups were no more likely to have cardiovascular risk reduced to below 10% than patients receiving usual care. Patients in the computer based clinical decision support group were more likely to have a cardiovascular risk >/=10% than chart only patients, odds ratio 2.3 (95% confidence interval 1.1 to 4.8). The chart only group had significantly lower systolic blood pressure compared with the usual care group (difference in means -4.6 mm Hg (95% confidence interval -8.4 to -0.8)). Reduction of diastolic blood pressure did not differ between the three groups. The chart only group were twice as likely to be prescribed two classes of cardiovascular drugs and over three times as likely to be prescribed three or more classes of drugs compared with the other groups.\n The computer based clinical decision support system did not confer any benefit in absolute risk reduction or blood pressure control and requires further development and evaluation before use in clinical care can be recommended. Use of chart guidelines are associated with a potentially important reduction in systolic blood pressure.", "Although nonpharmacologic interventions are widely recommended in the therapy of high blood pressure in older adults, surprisingly little data exist to confirm the efficacy of these interventions in older persons.\n We conducted a randomized, controlled clinical trial in persons aged 60 to 85 years with a diastolic blood pressure of 85 to 100 mm Hg. The experimental arm was a nonpharmacologic intervention combining weight reduction, sodium restriction, and increased physical activity. The nonpharmacologic intervention consisted of eight weekly group and two individual sessions during the intensive phase, followed by four monthly group sessions during the maintenance phase. The control group received no treatment during the study. Blood pressure was assessed by certified technicians (blinded to group assignment) using random zero sphygmomanometers.\n Of 56 participants randomized, 47 completed the entire 6-month trial (21 in the intervention group and 26 in the control group). Attendance at the intervention sessions was excellent. The intervention group lost more weight (-2.1 kg) over 6 months than the control group (+0.3 kg). Trends for decreasing 24-hour urine sodium excretion in both the intervention and control groups, with greater trend in the intervention group, were not statistically significant. The intervention group experienced more reduction in systolic and diastolic blood pressure than did the control group (mean differences between groups at 6 months, 4.2/4.9 mm Hg, respectively).\n Our data indicate that a nonpharmacologic intervention will lower systolic and diastolic blood pressure levels in older people with borderline or mild elevations of diastolic blood pressure.", "Lifestyle factors like weight, alcohol consumption, salt intake and physical activity have shown to be important in treating hypertension. There have been made some randomised trials about the effects of lifestyle interventions, but the numbers of patients have been relatively small and the durations of follow-ups have been short. No controlled trials assessing the effects of lifestyle intervention in a rehabilitation setting have been reported. In this study, the effects of multidisciplinary lifestyle intervention in rehabilitation centres among middle-aged hypertensive employees were described. A total of 731 hypertensives from 45 worksites were randomised to lifestyle intervention in a rehabilitation centre or to usual care in an occupational or primary health-care centre for 12 months. Standard measurements were conducted before the intervention and 1-year later. Blood pressure (BP) levels were clearly reduced in the intervention group, while only minor changes were observed in the control group. The net changes between the two groups both for systolic and diastolic BPs were -2.1 mmHg (95% confidence intervals (CI) -4.0 to -0.1) and -1.5 mmHg (95% CI -2.6 to -0.4), respectively. The net changes were greater among men than women. The multidisciplinary lifestyle intervention in a rehabilitation centre setting produced significant reductions in BP among middle-aged employees with hypertension." ]	Family practices and community-based clinics need to have an organized system of regular follow-up and review of their hypertensive patients. Antihypertensive drug therapy should be implemented by means of a vigorous stepped care approach when patients do not reach target blood pressure levels. Self-monitoring and appointment reminders may be useful adjuncts to the above strategies to improve blood pressure control but require further evaluation.
CD006422	[ "11427243", "16139778", "14702229", "16084809", "11201312" ]	[ "Collaborative interventions for physically injured trauma survivors: a pilot randomized effectiveness trial.", "Individually tailored treatment targeting activity, motor behavior, and cognition reduces pain-related disability: a randomized controlled trial in patients with musculoskeletal pain.", "Early cognitive-behavioural therapy for post-traumatic stress symptoms after physical injury. Randomised controlled trial.", "A trial of neuropsychologic rehabilitation in mild-spectrum traumatic brain injury.", "Neuropsychological rehabilitation for traumatic brain injury: do carers benefit?" ]	[ "Posttraumatic behavioral and emotional disturbances occur frequently among physically injured hospitalized trauma survivors. This investigation was a pilot randomized effectiveness trial of a 4-month collaborative care intervention for injured motor vehicle crash and assault victims. As surgical inpatients, intervention subjects (N=16) were assigned to a trauma support specialist who provided counseling, consulted with surgical and primary care providers, and attempted postdischarge care coordination. Control subjects (N=18) received usual posttraumatic care. For all participants, posttraumatic stress disorder (PTSD) and depressive symptoms, episodic alcohol intoxication, and functional limitations were evaluated during the hospitalization and 1 and 4 months postinjury. Study logs and field notes revealed that over 75% of intervention activity occurred in the first month after the trauma. One-month post-trauma intervention subjects when compared to controls demonstrated statistically significant decreases in PTSD symptoms as well as a reduction in depressive symptoms. However, at the 4-month assessment, intervention subjects evidenced no significant improvements in PTSD and depressive symptoms, episodic alcohol intoxication, or functional limitations. Future larger scale trials of stepped collaborative care interventions for physically injured trauma survivors are recommended.", "This study compares the outcomes of an individually tailored behavioral medicine intervention (experimental) with physical exercise therapy (control). The experimental intervention was systematically individualized according to each participant's behavioral treatment goals and functional behavioral analyses. One hundred twenty-two patients seeking care at 3 primary health care clinics because of musculoskeletal pain were randomized. Ninety-seven completed the trial. Data were collected at baseline, immediately after treatment, and at a 3-month follow-up. Analyses of data from completers, as well as intention-to-treat analyses, showed that the experimental group experienced lower levels of disability (P = .01), lower maximum pain intensity (P = .02), higher levels of pain control (P = .001), and lower fear of movement (P = .022) as a result of treatment condition. Self-efficacy (P = .0001) and physical performance (P = .0001) increased over time for both groups. Participants in the experimental group generally reported more positive effects after treatment. Treatment fidelity was maintained during the course of the study. Activity can be resumed and pain might be managed by the patients themselves if treatment incorporates the biopsychosocial explanatory model of pain and strategies are tailored according to individual's priorities of everyday life activities and empirically derived determinants of pain-related disability.\n This study shows that the biomedical and the psychosocial perspectives of the experiences and consequences of pain complement rather than contradict each other. Primary health care patients with persistent musculoskeletal pain benefit more from a systematic tailoring of treatments according to biopsychosocial factors than from a physically based exercise intervention.", "Early single-session psychological interventions, including psychological debriefing following trauma, have not been shown to reduce psychological distress. Longer early psychological interventions have shown some promise.\n To examine the efficacy of a four-session cognitive-behavioural intervention following physical injury.\n A total of 152 patients attending an accident and emergency department displaying psychological distress following physical injury were randomised 1-3 weeks post-injury to a four-session cognitive-behavioural intervention that started 5-10 weeks after the injury or to no intervention and then followed up for 13 months.\n At 13 months, the total Impact of Event Scale score was significantly more reduced in the intervention group (adjusted mean difference=8.4,95% CI 2.4-14.36). Other differences were not statistically significant.\n A brief cognitive-behavioural intervention reduces symptoms of post-traumatic stress disorder in individuals with physical injury who display initial distress.", "To test the effectiveness of a neuropsychologic rehabilitation program consisting of psychotherapy and cognitive remediation in the treatment of the affective and neuropsychologic sequelae of mild-spectrum traumatic brain injury (TBI).\n Single-blind randomized, wait-listed controlled trial, with repeated measures and multiple baselines.\n Outpatient clinic in northern New Jersey.\n Twenty persons with persisting complaints after mild and moderate TBI (11 in treatment group, 9 controls).\n The experimental group received both 50 minutes of individual cognitive-behavioral psychotherapy and 50 minutes of individual cognitive remediation, 3 times a week for 11 weeks. The control group was wait-listed and received treatment after conclusion of follow-up.\n Symptom Check List-90R General Symptom Index, plus scales of depression, anxiety, coping, attention, and neuropsychologic functioning.\n Compared with the control group, the treatment group showed significantly improved emotional functioning, including lessened anxiety and depression. Most significant improvements in emotional distress were noted at 1 month and 3 months posttreatment. Performance on a measure of divided auditory attention also improved, but no changes were noted in community integration scores.\n Cognitive behavioral psychotherapy and cognitive remediation appear to diminish psychologic distress and improve cognitive functioning among community-living persons with mild and moderate TBI.", "This study evaluated the effectiveness of a new rehabilitation service, compared with existing services, for carers of people with traumatic brain injury (TBI). Subjects were 96 adult carers of people consecutively admitted to two local hospitals. They were assigned to one of three groups: Early new service (pre-discharge); Late new service (post-discharge); or a Control condition (existing services only). Individual randomization was not possible and randomization by hospital site was rejected because of demographic and clinical differences between sites. Group assignment was determined by a pre-specified timetable which alternated between hospitals. Two outcomes were compared at 6 months post-injury: carers' emotional distress and how well-informed they felt about TBI and available resources. Analyses adjusting for potential confounding factors confirmed a clinically plausible superior outcome for both intervention groups compared to the control group. However, these differences did not obtain statistical significance (p > or = 0.01). Several reasons for these findings are discussed, including the novelty of the new service and methodological issues such as statistical power. Longer term follow-up studies are required as psychological sequelae and, therefore, the need for intervention is known to increase with time and may not be most apparent during the first 6 months." ]	This review provides no convincing evidence of the effectiveness of psychosocial interventions for the prevention of disability following traumatic physical injury. Taken together, our findings cannot be considered as supporting the provision of psychosocial interventions to prevent aspects of disability arising from physical injury. However, these conclusions are based on a small number of disparate trials with small to moderate sample sizes and are therefore necessarily cautious. More research, using larger sample sizes, and similar interventions and patient populations to enable pooling of results, is needed before these findings can be confirmed.
CD005195	[ "8971064", "1702663", "3124081", "2332904", "6475911", "19064517", "11696701", "18444146", "14684401", "11588133", "15126606", "6134981", "17209198", "3366933", "11860943", "3788940", "3610461", "15361287", "7707436", "9829869", "18299496", "3474437", "19036851", "8423627", "19066370", "16123147", "4068802", "1834125", "18541571", "3594351", "9719083", "8000296", "1942470", "10453813", "20670733", "11121464", "17620655", "9698665", "1726411", "9152515", "19365873", "21990298", "23028897", "3046338", "2722382", "8360931", "9568790", "14679373", "10753245", "17174015" ]	[ "Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group.", "Intervention trial with selenium for the prevention of lung cancer among tin miners in Yunnan, China. A pilot study.", "Low plasma selenium as a risk factor for cancer death in middle-aged men.", "Serum selenium and subsequent risk of cancer among Finnish men and women.", "Association between serum selenium and the risk of cancer.", "Plasma selenium concentration and prostate cancer risk: results from the European Prospective Investigation into Cancer and Nutrition (EPIC).", "Plasma selenium level before diagnosis and the risk of prostate cancer development.", "The nutritional prevention of cancer: 400 mcg per day selenium treatment.", "Prospective study of serum selenium concentrations and esophageal and gastric cardia cancer, heart disease, stroke, and total death.", "Predictors of serum selenium in cigarette smokers and the lack of association with lung and prostate cancer risk.", "A prospective study of plasma selenium levels and prostate cancer risk.", "Prediagnostic serum selenium and risk of cancer.", "Serum selenium and risk of prostate cancer-a nested case-control study.", "Serum selenium concentration associated with risk of cancer.", "[The prevention of primary liver cancer by selenium in high risk populations].", "Is serum selenium a risk factor for cancer in men only?", "Selenium levels in nails of premenopausal breast cancer patients assessed prediagnostically in a cohort-nested case-referent study among women screened in the DOM project.", "An intervention study to prevent gastric cancer by micro-selenium and large dose of allitridum.", "Prospective study of toenail selenium levels and cancer among women.", "Is low selenium status a risk factor for lung cancer?", "Serum selenium levels and all-cause, cancer, and cardiovascular mortality among US adults.", "Serum selenium and the risk of cancer, by specific sites: case-control analysis of prospective data.", "Selenium supplementation does not improve vascular responsiveness in healthy North American men.", "A prospective cohort study on toenail selenium levels and risk of gastrointestinal cancer.", "Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT).", "Selenium and mortality in the elderly: results from the EVA study.", "Is serum selenium a risk factor for cancer?", "Selenium in human mammary carcinogenesis: a case-cohort study.", "Randomized, double-blind, placebo-controlled trial of selenium supplements among HIV-infected pregnant women in Tanzania: effects on maternal and child outcomes.", "Serum selenium and risk of cancer. A prospective follow-up of nine years.", "Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer.", "Prediagnostic serum selenium and zinc levels and subsequent risk of lung and stomach cancer in Japan.", "Selenium supplementation in low-birthweight premature infants: relationship to trace metals and antioxidant enzymes.", "Plasma selenium levels and risk of hepatocellular carcinoma among men with chronic hepatitis virus infection.", "No effect of selenium supplementation on serum glucose levels in men with prostate cancer.", "Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer.", "Effects of long-term selenium supplementation on the incidence of type 2 diabetes: a randomized trial.", "The effect of oral selenium supplementation on human sperm motility.", "A preliminary report on the intervention trials of primary liver cancer in high-risk populations with nutritional supplementation of selenium in China.", "Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong.", "Increased consumption of wheat biofortified with selenium does not modify biomarkers of cancer risk, oxidative stress, or immune function in healthy Australian males.", "Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT).", "A randomized trial of selenium supplementation and risk of type-2 diabetes, as assessed by plasma adiponectin.", "Serum levels of selenium and retinol and the subsequent risk of cancer.", "Prediagnostic serum selenium in a case-control study of thyroid cancer.", "Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population.", "The association between baseline vitamin E, selenium, and prostate cancer in the alpha-tocopherol, beta-carotene cancer prevention study.", "Serum selenium and cancer mortality: a nested case-control study within an age- and sex-stratified sample of the Belgian adult population.", "The effect of selenium supplementation on outcome in very low birth weight infants: a randomized controlled trial. The New Zealand Neonatal Study Group.", "Effect of selenium supplementation on biochemical markers and outcome in critically ill patients." ]	[ "To determine whether a nutritional supplement of selenium will decrease the incidence of cancer.\n A multicenter, double-blind, randomized, placebo-controlled cancer prevention trial.\n Seven dermatology clinics in the eastern United States.\n A total of 1312 patients (mean age, 63 years; range, 18-80 years) with a history of basal cell or squamous cell carcinomas of the skin were randomized from 1983 through 1991. Patients were treated for a mean (SD) of 4.5 (2.8) years and had a total follow-up of 6.4 (2.0) years.\n Oral administration of 200 microg of selenium per day or placebo.\n The primary end points for the trial were the incidences of basal and squamous cell carcinomas of the skin. The secondary end points, established in 1990, were all-cause mortality and total cancer mortality, total cancer incidence, and the incidences of lung, prostate, and colorectal cancers.\n After a total follow-up of 8271 person-years, selenium treatment did not significantly affect the incidence of basal cell or squamous cell skin cancer. There were 377 new cases of basal cell skin cancer among patients in the selenium group and 350 cases among the control group (relative risk [RR], 1.10; 95% confidence interval [CI], 0.95-1.28), and 218 new squamous cell skin cancers in the selenium group and 190 cases among the controls (RR, 1.14; 95% CI, 0.93-1.39). Analysis of secondary end points revealed that, compared with controls, patients treated with selenium had a nonsignificant reduction in all-cause mortality (108 deaths in the selenium group and 129 deaths in the control group [RR; 0.83; 95% CI, 0.63-1.08]) and significant reductions in total cancer mortality (29 deaths in the selenium treatment group and 57 deaths in controls [RR, 0.50; 95% CI, 0.31-0.80]), total cancer incidence (77 cancers in the selenium group and 119 in controls [RR, 0.63; 95% CI, 0.47-0.85]), and incidences of lung, colorectal, and prostate cancers. Primarily because of the apparent reductions in total cancer mortality and total cancer incidence in the selenium group, the blinded phase of the trial was stopped early. No cases of selenium toxicity occurred.\n Selenium treatment did not protect against development of basal or squamous cell carcinomas of the skin. However, results from secondary end-point analyses support the hypothesis that supplemental selenium may reduce the incidence of, and mortality from, carcinomas of several sites. These effects of selenium require confirmation in an independent trial of appropriate design before new public health recommendations regarding selenium supplementation can be made", "This pilot study evaluated the feasibility and effectiveness of conducting a double-blind clinical trial for the prevention of lung cancer with selenium (Se) in Yunnan Tin Corporation, the People's Republic of China, where the incidence rates of lung cancer are extraordinarily high among the miners. Forty healthy miners were randomized to either 300 micrograms of Se in high Se malt cakes or an identical placebo of malt cakes daily for one year. Subjects consumed their usual daily diet. The low Se concentrations in plasma (0.05 +/- 0.008 microgram/mL) and hair (0.442 +/- 0.085 microgram/g) reflected their low dietary Se intake in the control subjects. In Se-supplemented group, the Se status was increased by 178% for serum and 194.8% for hair. The serum GSHpx activity was increased by 155.7%, whereas the lipid peroxide level was reduced by 74.5% compared to the placebo. The results of UDS assay indicated that the lymphocyte DNA damage induced by ultraviolet irradiation and carcinogen 3,4-benzpyrene could be protected by Se supplementation. Se-supplementation did not affect the liver function test (SGPT), as well as the concentrations of hemoglobin, albumin, and cholesterol. Thus, daily intake of 300 micrograms Se in form of Se-malt as a chemopreventive measure is safe and effective to humans with low Se status.", "In a population study, 10,000 men (aged 46-48 years) were invited to a health screening program. At follow-up, which was up to eight years later, 61 subjects had died from cancer; from 35 of these subjects, plasma samples were available that were obtained at the initial screening. These samples, together with samples from two living controls for each case, were analyzed for selenium, retinol, cholesterol, triglyceride, and a number of plasma proteins. Plasma selenium was significantly lower (p less than 0.05) in cases than in controls (means: 1.06 vs. 1.12 mumol/l). The proportion of cases increased significantly from the highest to the lowest quintile of plasma selenium, and the relative risk for cancer death was 3.8 times higher in the lowest quintile compared with the highest. Mean plasma retinol was similar in cases (2.53 mumol/l) and controls (2.56 mumol/l). Cases and controls also had similar values for plasma cholesterol, triglyceride, uric acid, apolipoprotein B, orosomucoid, prealbumin, retinol-binding protein, and beta 2-microglobulin. Apolipoprotein AI in plasma was lower among cases (p less than 0.025). Cases smoked significantly more than controls did (p less than 0.05). Data indicate that low plasma selenium was a risk factor for cancer death in middle-aged men who lived in the same area. Further studies are necessary to establish whether differences in selenium intake, selenium metabolism, or other factors related to selenium are responsible for the relations observed. At present, the available data do not justify selenium supplementation programs in the whole population.", "The association between the serum selenium level and the subsequent incidence of cancer was investigated in a longitudinal study of 39,268 men and women participating in the Social Insurance Institution's Mobile Clinic Health Examination Survey in Finland. The baseline examinations, including the collection of blood samples, were performed in 1968-1972. During a median follow-up of 10 years, 1,096 new cancer cases were identified from the files of the Finnish Cancer Registry. Selenium concentrations were measured from the stored serum samples collected from these cancer cases and from two controls per case, matched for sex, municipality, and age. The mean serum selenium level was 59.1 micrograms/L among all male cancer cases and 62.5 micrograms/L among controls. The difference was statistically significant (P less than .001). Corresponding values among women were 63.6 and 63.9 micrograms/L, respectively. Low serum selenium levels were associated with an increased risk of developing cancer at several sites, especially cancers of the stomach and lung among men. The relative risk of lung cancer between the highest and lowest decile of serum selenium was 0.11, and it differed significantly from unity (P less than .001). These findings are in agreement with the hypothesis that low selenium intake may increase the risk of some cancers among men.", "A matched-pair analysis was conducted with data based on a prospective six-year follow-up of a random population sample to study the association between serum selenium and the risk of cancer. Case-control pairs were from a population, after exclusions, of 8,113 persons examined in 1972 from two counties in eastern Finland. Cases were 31- to 59-year-old men and women initially free of cancer. One control was matched to each case according to age, gender, daily tobacco consumption, and serum cholesterol concentration. The mean serum selenium of the 128 cases was 50.5 micrograms/liter and that of the controls was 54.3 micrograms/liter (p = 0.012 for difference). When the residual variation in tobacco consumption and serum cholesterol as well as that in four other possible confounders was allowed for in a multiple logistic model, serum selenium of less than 45 micrograms/liter was associated with a relative risk of cancer of 3.1 (95% confidence interval, 1.5-6.7, p less than 0.01). These data support the hypothesis that selenium deficiency increases the risk of certain cancers in middle-aged persons.", "Some evidence indicates that a low selenium intake may be associated with an increased risk of prostate cancer.\n The aim of this study was to investigate the association of plasma selenium concentration with subsequent prostate cancer risk and to examine this association by stage and grade of disease and other factors.\n A nested case-control study was performed among men in the European Prospective Investigation into Cancer and Nutrition (EPIC). The association between plasma selenium concentration and prostate cancer risk was assessed in 959 men with incident prostate cancer and 1059 matched controls.\n Overall, plasma selenium concentration was not associated with prostate cancer risk; the multivariate relative risk for men in the highest fifth of selenium concentration compared with the lowest fifth was 0.96 (95% CI: 0.70, 1.31; P for trend = 0.25). There were no significant differences in the association of plasma selenium with risk when analyzed by stage or grade of disease. Similarly, the association of selenium with risk did not differ by smoking status or by plasma alpha- or gamma-tocopherol concentration.\n Plasma selenium concentration was not associated with prostate cancer risk in this large cohort of European men.", "Epidemiological studies and a randomized intervention trial suggest that the risk of prostate cancer may be reduced by selenium intake. We investigated whether plasma selenium level before diagnosis correlated with the risk of later developing prostate cancer.\n A case control study was performed on men from the Baltimore Longitudinal Study of Aging registry, including 52 with known prostate cancer and 96 age matched controls with no detectable prostatic disease. Plasma selenium was measured at an average time plus or minus standard deviation of 3.83 +/- 1.85 years before the diagnosis of prostate cancer by graphite furnace atomic absorption spectrophotometry. Adjusted odds ratio and 95% confidence interval were computed with logistic regression.\n After correcting for years before diagnosis, body mass index, and smoking and alcohol use history, higher selenium was associated with a lower risk of prostate cancer. Compared with the lowest quartile of selenium (range 8.2 to 10.7 microg./dl.), the odds ratios of the second (10.8 to 11.8), third (11.9 to 13.2) and fourth (13.3 to 18.2) quartiles were 0.15 (95% confidence interval 0.05 to 0.50), 0.21 (0.07 to 0.68) and 0.24 (0.08 to 0.77, respectively, p =0.01). Furthermore, plasma selenium decreased significantly with patient age (p <0.001).\n Low plasma selenium is associated with a 4 to 5-fold increased risk of prostate cancer. These results support the hypothesis that supplemental selenium may reduce the risk of prostate cancer. Because plasma selenium decreases with patient age, supplementation may be particularly beneficial to older men.", "Nonexperimental studies suggest that individuals with higher selenium (Se) status are at decreased risk of cancer. The Nutritional Prevention of Cancer (NPC) study randomized 1,312 high-risk dermatology patients to 200-mcg/day of Se in selenized yeast or a matched placebo; selenium supplementation decreased the risk of lung, colon, prostate, and total cancers but increased the risk of nonmelanoma skin cancer. In this article, we report on a small substudy in Macon, GA, which began in 1989 and randomized 424 patients to 400-mcg/day of Se or to matched placebo. The subjects from both arms had similar baseline Se levels to those treated by 200 mcg, and those treated with 400-mcg attained plasma Se levels much higher than subjects treated with 200 mcg. The 200-mcg/day Se treatment decreased total cancer incidence by a statistically significant 25%; however, 400-mcg/day of Se had no effect on total cancer incidence.", "We previously reported an inverse association between prediagnostic serum selenium concentrations and the risk of esophageal squamous cell carcinoma (ESCC) and gastric cardia cancer (GCC) but not gastric noncardia cancer (GNCC) in a nested study from the Nutrition Intervention Trial in Linxian, China.\n We examined the relation between baseline serum selenium and the subsequent risk of death from ESCC, GCC, GNCC, heart disease (HD), stroke, and total death over 15 y of follow-up (1986-2001).\n We measured baseline serum selenium concentrations in 1103 subjects randomly selected from a larger trial cohort. We identified 516 deaths during the 15-y follow up, including 75 from ESCC, 36 from GCC, 116 from HD, and 167 from stroke. Relative risks (RRs) and 95% CIs were estimated by using Cox proportional hazards regression models. Reported RRs estimated the change in risk conferred by a 25% increase in serum selenium relative to the population distribution. All estimates were adjusted for sex, age, smoking, drinking, and serum cholesterol.\n We found significant inverse associations between baseline serum selenium and death from ESCC (RR: 0.83; 95% CI: 0.71, 0.98) and GCC (0.75; 0.59, 0.95). Trends toward inverse associations were noted for death from HD (0.89; 0.78, 1.01; P = 0.07), but no association was noted for total death (0.96; 0.90, 1.02) or stroke (0.99; 0.88, 1.11).\n Population-wide selenium supplementation in the region of China with low serum selenium and high incidences of ESCC and GCC merits serious consideration.", "Epidemiological studies have suggested that low levels of selenium are associated with a higher incidence of both lung and prostate cancer. We analyzed the selenium serum concentration in 356 Carotene and Retinol Efficacy Trial (CARET) participants who later developed lung cancer and 356 matched controls and in 235 prostate cancer cases and 456 matched controls. Serum samples were obtained a mean of 4.7 years before diagnosis for both tumor types. Controls were matched to cases by year of randomization, age, smoking status, treatment arm, exposure population (asbestos workers or cigarette smokers), and year of blood draw. In the control population (n = 820), significant predictors of low serum selenium concentration were current smoking status and East Coast locations of the study center. Overall, there was no significant difference in mean serum selenium in lung cancer cases versus controls (11.91 microg/dl versus 11.77 microg/dl) or prostate cancer cases versus controls (11.48 microg/dl versus 11.43 microg/dl). No statistically significant trend in odds ratio was seen across quartiles of serum selenium for lung cancer (P = 0.49) or prostate cancer (P = 0.69). In a subpopulation of 174 prostate cancer patients who had clinical and pathological staging material reviewed, there was no association between serum selenium and Gleason score or clinical or pathological stage. In the CARET population of current and former smokers consuming an ad libitum diet, the serum concentration of selenium was not a risk factor for either lung cancer or prostate cancer.", "Epidemiologic studies suggest that low selenium levels are associated with an increased incidence of prostate cancer, although results are conflicting. We examined the association between pre-diagnostic plasma selenium levels and risk of prostate cancer in men enrolled in the Physicians' Health Study.\n Using plasma samples obtained in 1982 from healthy men enrolled in the study, we conducted a nested case-control study among 586 men diagnosed with prostate cancer during 13 years of follow-up and 577 control subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of prostate cancer in pre- (before October 1990) and post- (after October 1990) prostate-specific antigen (PSA) screening eras were calculated using multivariable logistic regression.\n Pre-diagnostic plasma selenium levels were inversely associated with risk of advanced prostate cancer (5th versus 1st quintile OR = 0.52, 95% CI = 0.28 to 0.98; P(trend) =.05), even among men diagnosed after 1990 (5th versus 1st quintile OR = 0.39, 95% CI = 0.16 to 0.97). The inverse association with prostate cancer risk was observed only for case subjects with elevated baseline PSA levels (PSA >4 ng/mL, 5th versus 1st quintile OR = 0.49, 95% CI = 0.28 to 0.86; P(trend) =.002). These inverse associations were observed in both pre- and post-PSA eras.\n The inverse association between baseline plasma selenium levels and risk of advanced prostate cancer, even among men diagnosed during the post-PSA era, suggests that higher levels of selenium may slow prostate cancer tumor progression. Ongoing randomized trials of selenium supplements may help to further evaluate this issue.", "Selenium levels in serum samples collected in 1973 from 111 subjects in whom cancer developed during the subsequent 5 years were compared with those in serum samples from 210 cancer-free subjects matched for age, race, sex, and smoking history. The mean selenium level of cases (0.129 +/- SEM 0.002 micrograms/ml) was significantly lower than that of controls (0.136 +/- 0.002 micrograms/ml). The risk of cancer for subjects in the lowest quintile of serum selenium was twice that of subjects in the highest. Multivariate adjustment for geographical area and serum levels of lipids, vitamins A and E, and carotene, did not alter this relation. The association between low selenium level and cancer was strongest for gastrointestinal and prostatic cancers. Serum levels of vitamins A and E compounded the effect of low selenium; relative risks for the lowest tertile of selenium were 2.4 and 3.9 in the lowest tertiles of vitamins E and A, respectively.", "Selenium is a potential chemopreventive agent against prostate cancer, whose chemoprotective effects are possibly mediated through the antioxidative properties of selenoenzymes. Interrelations with other antioxidative agents and oxidative stressors, such as smoking, are poorly understood.\n The aims were to investigate the association between serum selenium and prostate cancer risk and to examine interactions with other antioxidants and tobacco use.\n A nested case-control study was performed within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Serum selenium in prospectively collected samples was compared between 724 incident prostate cancer case subjects and 879 control subjects, frequency-matched for age, time since initial screen, and year of blood draw. The men were followed for up to 8 y.\n Overall, serum selenium was not associated with prostate cancer risk (P for trend = 0.70); however, higher serum selenium was associated with lower risks in men reporting a high (more than the median: 28.0 IU/d) vitamin E intake [odds ratio (OR) for the highest compared with the lowest quartile of selenium: 0.58; 95% CI: 0.37, 0.91; P for trend = 0.05; P for interaction = 0.01] and in multivitamin users (OR for highest compared with the lowest quartile of selenium: 0.61; 95% CI: 0.36, 1.04; P for trend = 0.06; P for interaction = 0.05). Furthermore, among smokers, high serum selenium concentrations were related to reduced prostate cancer risk (OR for the highest compared with the lowest quartile of selenium: 0.65; 95% CI: 0.44, 0.97; P for trend = 0.09; P for interaction = 0.007).\n Greater prediagnostic serum selenium concentrations were not associated with prostate cancer risk in this large cohort, although greater concentrations were associated with reduced prostate cancer risks in men who reported a high intake of vitamin E, in multivitamin users, and in smokers.", "The association between serum selenium concentration and risk of cancer was studied in a nested case control study. Case control pairs came from a population of 9364 people examined in 1979. During the six year follow up, 60 men and women aged between 20-54 at the time of blood sampling, who had been free of malignant disease, developed cancer. The mean serum selenium concentration of 1.56 mumol/l (123.2 micrograms/l) in patients was not significantly different from that in controls (1.63 mumol/l (128.7 micrograms/l]. The difference in mean selenium concentration was largest and most significant for haematological malignancies alone. The difference in selenium concentrations in cases of fatal cancer compared with controls was significant (p less than 0.01). The risk of developing adenocarcinomas does not seem to be influenced by serum selenium concentration.", "To study the preventive effects of selenium on primary liver cancer.\n After screening of blood samples in 18,000 males from 20 to 65 years-old in Qidong, Jiangsu province (a high risk area for liver cancer), 2,065 cases of HBsAg positive, AFP negative and normal liver function (normal ALT values) were found. The subjects were randomly divided into two groups, based on their residence areas; 1,112 subjects (experimental group) received one tablet of sodium selenite (0.5 mg Se) every day and 953 subjects (control group) received one placebo tablet every day.\n During three years of intervention and follow up, the blood selenium concentration and glutathione peroxidase activity of the subjects in the experimental group were increased and had significant difference as compared with those of the control group (P < 0.01). At the same time, the prevalence rate of micronucleus cells in peripheral blood lymphocytes in the experimental group was significantly lower than that of the control group (P < 0.01), and the incidence of new liver cancer in the experimental group (3 057.55/10(6), 34 cases out of 1,112 subjects) was significantly lower than the control group (5 981.11/10(6); 57 cases out of 953 subjects) (P < 0.01).\n The results confirms that selenium supplementation in general populations lived in high risk is effective in the prevention of liver cancer and the using of selenium tablets is simple and feasible.", "The association of serum selenium with the subsequent risk of death from cancer was investigated in a case-control study that was nested in a prospective nine-year follow-up study in the Netherlands. In 1975-1978, 10,532 persons in the Dutch town of Zoetermeer who were aged five years or more participated in a medical survey. Serum samples were collected and stored at -20 C. For the 82 persons who died of cancer since the baseline examination, 164 cohort members still alive by the end of 1983 were selected as controls and matched for age, sex, and smoking. Cancer deaths that occurred in the first year of follow-up were excluded, leaving 69 cases for statistical analyses. The mean serum selenium level of 116.7 +/- 4.0 micrograms/liter among male cancer deaths (n = 40) was significantly different (p = 0.04) from that in the control subjects (126.4 +/- 3.1 micrograms/liter). In females, selenium levels were similar among cases and controls. The adjusted risk of death from cancer for men in the lowest quintile of serum selenium (below 100.8 micrograms/liter) was more than twice that of subjects with higher levels (relative risk = 2.7,90% confidence interval = 1.2-6.2). These data support recent findings of an increased cancer risk associated with low serum selenium levels in men but not in women.", "To determine the possible role of selenium in the pathogenesis of breast cancer, prediagnostic Se 77 m isotope levels in toenail clippings in premenopausal women were measured. The study was designed as a case-referent study nested in a cohort. Participants were recruited from the DOM-project breast-cancer screening cohorts. No decreased selenium levels were found up to two years prior to diagnosis, nor were Se levels different between prevalent and/or incident breast cancer cases, referents and women with benign breast disease. Se levels measured in nails could not detect women at higher risk for breast cancer. This study does not support the idea that Se supplementation could have a preventive potential for premenopausal breast cancer in women in the Netherlands.", "People have more and more concerned about allitridum as studies have shown that taking more raw garlic associated with a lower risk for cancers of the alimentary system. In the present study, we tried to examine whether a large dose of allitridum and a microdose of selenium prevent gastric cancer.\n A double-blind intervention study was performed on the participants aged (35 - 74) years, who had matched at least one of the following criteria: (1) a medical history of stomach disorder, (2) a family history of tumour, or (3) smoking and/or alcohol consumption. A total of 2,526 and 2,507 persons were randomly enrolled into intervention group and control group respectively from 288 natural villages of seven communities in Qixia County, Shandong Province, China. Each person of the intervention group orally took 200 mg synthetic allitridum every day and 100 microg selenium every other day for one month of each year during November 1989 to December 1991. At the same time, people in control group were given 2 placebo capsules containing corn oid with the identical appearance to that in the intervention group.\n For all subjects the large dose of allitridum was accepted and no harmful side effects were found during the study. In the first follow-up five years (1992 - 1997) after stopping the intervention, the morbidity rates of malignant tumours in the intervention group declined by 22%, in contrast to the control group, declined by 47.3%. After adjusting for age, gender, and other potential confounders, relative risks (RRs) for all tumours and gastric cancer of the whole population were 0.67 (95% CL: 0.43 - 1.03) and 0.48 (95% CL: 0.21 - 1.06), respectively, and for male group they were 0.51 (95% CL: 0.30 - 0.85) and 0.36 (95% CL: 0.14 - 0.92), respectively. No signigicantly protective effect was found for the female subgroup.\n The present study proves that large doses of allitridum and microdorse of selenium may effectively prevent gastric cancer, especially in men.", "Inverse associations between selenium status and cancer risk have been observed in animal studies, ecologic studies, and some case-control and prospective studies. Whereas results of some prospective studies have suggested an overall inverse relationship between selenium levels and cancer, other prospective studies have failed to confirm this finding. Prospective data on women are particularly limited because fewer women than men have been studied prospectively.\n The aim of this study was to prospectively examine the relationship between selenium levels in toenails (previously shown to reflect selenium intake) and incidence of cancer among women.\n The Nurses' Health Study cohort began in 1976 with 121,700 female nurses aged 30-55 years living in 11 U.S. states. In 1982, we requested toenail clippings from the members of the cohort, and 62,641 participants with no history of cancer returned these clippings. During 41 months of follow-up, 503 cases of cancer other than breast cancer (results previously reported) or nonmelanoma skin cancer were analyzed. For each case patient, a control subject was chosen from women who remained free of diagnosed cancer, matched by age and by date of nail return.\n No inverse association was observed between selenium levels in toenails and cancer risk. The age- and smoking-adjusted relative risk (RR), comparing the highest with the lowest quintile of toenail selenium level, was 1.44 (95% confidence interval [CI] = 0.97-2.13), and the trend across quintiles was marginally significant (two-sided P = .06). Comparing the highest with the lowest decile, the RR (age- and smoking-adjusted) was 1.77 (95% CI = 1.04-3.02). When these data were combined with the data from 434 breast cancer case patients and their matched control subjects identified in parallel from this same cohort, the RR comparing the highest with the lowest quintile was 1.24 (95% CI = 0.93-1.65). Toenail selenium level was not inversely associated with cancer at any major site, including uterine cancer, colorectal cancer, melanoma, ovarian cancer, or lung cancer (after adjusting for smoking); in fact, nonsignificant positive associations were observed at several sites.\n Toenail selenium levels were not inversely associated with cancer risk in this study.\n These data, in conjunction with previous findings of no association between toenail selenium status and breast cancer risk, strongly suggest that higher selenium intake within the range consumed by most U.S. women (as reflected by toenail selenium levels) is not protective against overall cancer incidence in women.", "The hypothesis that low selenium may in some circumstances be a risk factor for lung cancer was investigated in a case-control study nested within a longitudinal study. Serum samples from 9,101 cancer-free individuals were collected and stored at -20 degrees C by the Finnish Mobile Clinic in 1968-1971 and 1973-1976. During follow-up until the end of 1991, 95 cases of lung cancer were diagnosed. Selenium concentrations were determined from the serum samples of the cases and 190 controls, individually matched for sex, age, and place of residence. Mean levels of serum selenium in cases and controls were 53.2 microg/liter and 57.8 microg/liter, respectively. The relative risk of lung cancer between the highest and lowest tertiles of serum selenium, adjusted for smoking, serum alpha-tocopherol, serum cholesterol, serum copper, serum orosomucoid, and body mass index (kg/m2), was 0.41 (95% confidence interval (CI) 0.17-0.94). The association was stronger at lower levels (<5.9 mg/liter) of alpha-tocopherol (relative risk=0.24, 95% CI 0.07-0.85). The association was also pronounced among current smokers and at higher levels of serum orosomucoid and serum copper. The relative risk for smokers who were twice ranked in higher selenium tertiles, at an interval of 4-7 years, in comparison with smokers who remained in the lowest tertile was 0.16 (95% CI 0.04-0.74). In accordance with the hypothesis, the findings suggest that very low selenium status may contribute to the risk of lung cancer.", "Selenium, an essential trace element involved in defense against oxidative stress, may prevent cancer and cardiovascular disease. We evaluated the association between selenium levels and all-cause and cause-specific mortality in a representative sample of US adults.\n Serum selenium levels were measured in 13,887 adult participants in the Third National Health and Nutrition Examination Survey. Study participants were recruited from 1988 to 1994 and followed up for mortality for up to 12 years.\n The mean serum selenium level was 125.6 ng/mL. The multivariate adjusted hazard ratios comparing the highest (> or = 130.39 ng/mL) with the lowest (< 117.31 ng/mL) serum selenium level tertile were 0.83 (95% confidence interval [CI], 0.72-0.96) for all-cause mortality, 0.69 (95% CI, 0.53-0.90) for cancer mortality, and 0.94 (95% CI, 0.77-1.16) for cardiovascular mortality. However, based on spline regression models, the association between serum selenium levels and all-cause and cancer mortality was nonlinear, with an inverse association at low selenium levels (< 130 ng/mL) and a modest increase in mortality at high selenium levels (> 150 ng/mL). There was no association between serum selenium levels and cardiovascular mortality.\n In a representative sample of the US population, we found a nonlinear association between serum selenium levels and all-cause and cancer mortality. Increasing serum selenium levels were associated with decreased mortality up to 130 ng/mL. Our study, however, raises the concern that higher serum selenium levels may be associated with increased mortality.", "From 1971 to 1975, serum specimens were obtained from 6,860 men of Japanese ancestry in Hawaii. Since then, the following numbers of newly diagnosed cases with epithelial cancer have been identified: 82 colon, 71 lung, 66 stomach, 32 rectum, and 29 urinary bladder. The stored sera of the 280 cases and of 293 randomly selected controls were tested to determine their levels of selenium. There was no association of serum selenium with lung, stomach, or rectal cancer. An increase in relative risk (RR) was noted only for subjects in the lowest quintile of selenium values, as compared to the RR for subjects in the highest quintile, for colon (RR = 1.8) and urinary bladder cancer (RR = 3.1), but neither of these RR estimates was statistically significant (P = .09 and P = .07, respectively). Further work is needed to determine whether the antioxidant properties of selenium protect against specific types of cancer.", "Selenium is an essential trace nutrient required for the synthesis of selenoproteins such as glutathione peroxidase and thioredoxin reductase, the major forms of selenium in the endothelium that have important functions relevant to inflammation and cardiovascular disease. Selenium deficiency is associated with cardiomyopathy and sudden cardiac death in animals, and a low selenium status is associated with cardiovascular disease in humans. Endothelial dysfunction, measured as the impaired flow-mediated vasorelaxation of the brachial artery, is a reliable indicator of future cardiovascular disease risk in healthy individuals. To test whether selenium supplementation affects endothelial function, we conducted a randomized, placebo-controlled trial in healthy men who were administered 300 microg of selenium a day as high-selenium yeast for 48 wk. Brachial artery responsiveness to transient occlusion was assessed at baseline and after 24 and 48 wk of supplementation. The supplementation increased the selenium concentration by more than half in blood plasma and erythrocytes. However, there was no effect of selenium on arterial diameter or blood flow rate before or after transient occlusion or on the maximum dilated diameter after the administration of nitroglycerin. This study indicates that selenium supplementation is not likely to improve endothelial function or peripheral arterial responsiveness in healthy North American men receiving adequate selenium from their diets.", "Various animal studies and ecologic studies suggest an inverse association between low dietary selenium intake and risk of various types of cancer.\n The goal of this prospective cohort study was to investigate the association between toenail selenium levels and risks of stomach cancer and colorectal cancer.\n Our cohort study on diet and cancer started in The Netherlands in 1986 with enrollment of 120,852 subjects aged 55-69 years. Of this number, 58,279 were men and 62,573 were women. Following the case-cohort approach for analysis of the data, we randomly selected from the cohort a subcohort of 3500 subjects (1688 men and 1812 women). After 3.3 years of follow-up, 155 incident cases of microscopically confirmed stomach cancer, 313 cases of colon cancer, and 166 cases of rectal cancer had been detected in the cohort. Toenail selenium data were available for 104 patients with stomach cancer, 234 with colon cancer, and 113 with rectal cancer and for 2459 subjects from the subcohort.\n In a multivariate analysis, the relative rates (RRs) of stomach cancer for subjects in increasing quintiles of toenail selenium level were 1.00, 0.44, 0.59, 0.84, and 0.64 (trend, P = .491). For men, there was some evidence for an inverse association between toenail selenium levels and stomach cancer: The RR for those in the highest compared with the lowest quintile of toenail selenium was 0.40 (95% confidence interval = 0.17-0.96), but the trend was not statistically significant (P = .136). For stomach cancer in women, there was no negative association with toenail selenium levels. Toenail selenium level was not associated with the risk of colon or rectal cancer. After exclusion of cases diagnosed in the 1st year of follow-up, the RRs of colon cancer for increasing quintiles of toenail selenium were 1.00, 1.27, 1.17, 0.75, and 1.07 (trend, P = .544); for rectal cancer, RR estimates were 1.00, 1.73, 0.83, 1.58, and 1.12 (trend, P = .890).\n These data support a suggestive but inconsistent inverse association between selenium levels and risk of stomach cancer. Our findings, like those of other studies, do not suggest an inverse association with risk of colorectal cancer.", "Secondary analyses of 2 randomized controlled trials and supportive epidemiologic and preclinical data indicated the potential of selenium and vitamin E for preventing prostate cancer.\n To determine whether selenium, vitamin E, or both could prevent prostate cancer and other diseases with little or no toxicity in relatively healthy men.\n A randomized, placebo-controlled trial (Selenium and Vitamin E Cancer Prevention Trial [SELECT]) of 35,533 men from 427 participating sites in the United States, Canada, and Puerto Rico randomly assigned to 4 groups (selenium, vitamin E, selenium + vitamin E, and placebo) in a double-blind fashion between August 22, 2001, and June 24, 2004. Baseline eligibility included age 50 years or older (African American men) or 55 years or older (all other men), a serum prostate-specific antigen level of 4 ng/mL or less, and a digital rectal examination not suspicious for prostate cancer.\n Oral selenium (200 microg/d from L-selenomethionine) and matched vitamin E placebo, vitamin E (400 IU/d of all rac-alpha-tocopheryl acetate) and matched selenium placebo, selenium + vitamin E, or placebo + placebo for a planned follow-up of minimum of 7 years and a maximum of 12 years.\n Prostate cancer and prespecified secondary outcomes, including lung, colorectal, and overall primary cancer.\n As of October 23, 2008, median overall follow-up was 5.46 years (range, 4.17-7.33 years). Hazard ratios (99% confidence intervals [CIs]) for prostate cancer were 1.13 (99% CI, 0.95-1.35; n = 473) for vitamin E, 1.04 (99% CI, 0.87-1.24; n = 432) for selenium, and 1.05 (99% CI, 0.88-1.25; n = 437) for selenium + vitamin E vs 1.00 (n = 416) for placebo. There were no significant differences (all P>.15) in any other prespecified cancer end points. There were statistically nonsignificant increased risks of prostate cancer in the vitamin E group (P = .06) and type 2 diabetes mellitus in the selenium group (relative risk, 1.07; 99% CI, 0.94-1.22; P = .16) but not in the selenium + vitamin E group.\n Selenium or vitamin E, alone or in combination at the doses and formulations used, did not prevent prostate cancer in this population of relatively healthy men.\n clinicaltrials.gov identifier: NCT00006392.", "Inadequate plasma selenium can adversely affect the maintenance of optimal health; therefore, reported decreases in plasma selenium in an aging population are cause for concern. To further examine this hypothesis, we explored the relationships between plasma selenium and mortality in an elderly population: the EVA (Etude du Vieillissement Artériel) study.\n The EVA study was a 9-year longitudinal study with 6 periods of follow-up. During the 2-year period from 1991 to 1993 (EVA0), 1389 men and women born between 1922 and 1932 were recruited. The effects of plasma selenium at baseline on mortality were determined by Cox proportional hazards regression analysis, adjusting for the following variables: sociodemographic characteristics, dietary habits, health, and cognitive factors.\n During the 9-year follow-up, 101 study participants died. Baseline plasma selenium was higher in individuals who were alive at the end of follow-up [mean (SD), 1.10 (0.20) micromol/L] than in those who died during the follow-up [1.01 (0.20) micromol/L; P <10(-4)]. Mortality rates were significantly higher in individuals with low selenium [increments = 0.2 micromol/L; relative risk (RR) = 1.56 (95% confidence interval, 1.28-1.89)]. After we controlled for various potential confounding factors, this association remained significant [RR = 1.54 (1.25-1.88)]. When the underlying causes of death were considered, we found an association with cancer-related mortality [adjusted RR = 1.79 (1.32-2.44)].\n Even if it is premature to present selenium as a longevity indicator in an elderly population, our results are in accordance those of large, interventional, randomized trials with selenium, which suggest that this essential trace element plays a role in health maintenance in aging individuals.", "A narrow band of counties extending along the southeastern Atlantic coast from Jacksonville, Florida to Charleston, South Carolina were found to have excessively high incidence rates for esophageal cancer in non-white males. White males in the same areas have a 30% higher incidence rate for lung cancer but only average incidence rates were found for non-white males. Selenium is considered to decrease cancer risk in the animal model. In this coastal region, a study of 130 cancer patients who developed a malignancy 2-12 years after baseline examination showed no dose response relationship between baseline serum selenium levels and risk of subsequent cancer.", "In a prospective study conducted on the island of Guernsey a cohort of 5162 ostensibly healthy women was enrolled between 1967 and 1976. Blood samples were drawn from each participant, who also completed a questionnaire, which provided information on established risk indicators in human mammary carcinogenesis. Plasma selenium levels were measured in 46 breast cancer cases diagnosed a mean of 11 (S.D. 4) years after entry into the study cohort and in an age-stratified sample of 138 women drawn from the study base. Plasma selenium level in the cases was 109 (28) micrograms/l and in the base sample 103 (22) micrograms/l (95% confidence interval for the overall difference, -2 to 14 micrograms/l). The adjusted relative risk of developing breast cancer in the different quartiles of the selenium distribution was 0.80, 0.79, 0.72 and 1.00, respectively. Thus, in the present study selenium was not a strong indicator of human breast cancer risk.", "In observational studies, adequate selenium status has been associated with better pregnancy outcomes and slowed HIV disease progression.\n We investigated the effects of daily selenium supplements on CD4 cell counts, viral load, pregnancy outcomes, and maternal and infant mortality among 913 HIV-infected pregnant women.\n In this randomized, double-blind, placebo-controlled trial, eligible women between 12 and 27 wk of gestation were given daily selenium (200 mug as selenomethionine) or placebo as supplements from recruitment until 6 mo after delivery. All women received prenatal iron, folic acid, and multivitamin supplements irrespective of experimental assignment.\n The selenium regimen had no significant effect on maternal CD4 cell counts or viral load. Selenium was marginally associated with a reduced risk of low birth weight [relative risk (RR) = 0.71; 95% CI: 0.49, 1.05; P = 0.09] and increased risk of fetal death (RR = 1.58; 95% CI = 0.95, 2.63; P = 0.08), but had no effect on risk of prematurity or small-for-gestational age birth. The regimen had no significant effect on maternal mortality (RR = 1.02; 95% CI = 0.51, 2.04; P = 0.96). There was no significant effect on neonatal or overall child mortality, but selenium reduced the risk of child mortality after 6 wk (RR = 0.43; 95% CI = 0.19, 0.99; P = 0.048).\n Among HIV-infected women from Dar es Salaam, Tanzania, selenium supplements given during and after pregnancy did not improve HIV disease progression or pregnancy outcomes, but may improve child survival. This trial was registered at clinicaltrials.gov as NCT00197561.", "The association between serum selenium concentration and the risk of cancer was studied in 1110 men aged 55 to 74 years in two rural areas of Finland. The men were followed-up prospectively for 9 years and there were 109 new cases of cancer, with the cases of the first follow-up year excluded. The serum selenium concentrations were adjusted for age, area, smoking, serum cholesterol, and alcohol intake. The patients had a slightly lower adjusted mean serum selenium than the subjects without cancer at the end of the follow-up (+/- standard error of mean) 53.9 +/- 1.5 and 55.3 +/- 0.5 micrograms/l, respectively. The relative risks of cancer were essentially the same when these were calculated in the tertiles of the serum selenium distribution. Thirty-seven men had a history of cancer at baseline or had cancer diagnosed during the first follow-up year and their adjusted mean serum selenium was 49.4 +/- 2.6 micrograms/l, which was significantly lower (P less than 0.05) than that of the subjects without cancer during the follow-up.", "In a recent randomized intervention trial, the risk of prostate cancer for men receiving a daily supplement of 200 microg selenium was one third of that for men receiving placebo. By use of a nested case-control design within a prospective study, i.e., the Health Professionals Follow-Up Study, we investigated the association between risk of prostate cancer and prediagnostic level of selenium in toenails, a measure of long-term selenium intake.\n In 1986, 51,529 male health professionals aged 40-75 years responded to a mailed questionnaire to form the prospective study. In 1987, 33,737 cohort members provided toenail clippings. In 1988, 1990, 1992, and 1994, follow-up questionnaires were mailed. From 1989 through 1994, 181 new cases of advanced prostate cancer were reported. Case and control subjects were matched by age, smoking status, and month of toenail return. Selenium levels were determined by neutron activation. All P values are two-sided.\n The selenium level in toenails varied substantially among men, with quintile medians ranging from 0.66 to 1.14 microg/g for control subjects. When matched case-control data were analyzed, higher selenium levels were associated with a reduced risk of advanced prostate cancer (odds ratio [OR] for comparison of highest to lowest quintile = 0.49; 95% confidence interval [CI] = 0.25-0.96; P for trend = .11). After additionally controlling for family history of prostate cancer, body mass index, calcium intake, lycopene intake, saturated fat intake, vasectomy, and geographical region, the OR was 0.35 (95% CI = 0.16-0.78; P for trend = .03).\n Our results support earlier findings that higher selenium intakes may reduce the risk of prostate cancer. Further prospective studies and randomized trials of this relationship should be conducted.", "Serum samples were collected in Hiroshima and Nagasaki, Japan, from 1970 to 1972 for 208 persons who in 1973-1983 developed stomach cancer; for 77 who in 1973-1983 developed lung cancer; and for controls matched for age, sex, city, and season of blood collection. Average serum levels of selenium and zinc were slightly (< 5%) but not significantly lower among the cancer cases than among controls. Smoking-adjusted risks of lung cancer were elevated only among those in the lowest quartiles of serum selenium [odds ratio (OR) = 1.8] and zinc (OR = 1.3); the trends in risk of this cancer with decreasing serum levels were neither linear nor significant. Little or no excess risk of stomach cancer was observed among those with lowest levels of selenium (OR = 1.0) or zinc (OR = 1.2). These exploratory findings add to limited data available from other reports showing slightly increased risks of lung cancer associated with low blood levels of selenium, but suggest little association with either lung or stomach cancer across normal selenium or zinc ranges in this Japanese population.", "We attempted to study the effect of selenium supplementation upon trace metal metabolism in low-birthweight infants less than 1000 g birthweight. Serum levels of the trace metals copper, zinc, and selenium; and white blood cell glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities were measured in conjunction with the trace metals when parenteral nutrition (TPN) was begun (sample A), at the initiation of enteral nutrition (sample B), and when TPN was discontinued (sample C). Two randomly selected groups of infants were evaluated: group S received selenium supplementation (1.34 micrograms/kg per d) in their parenteral nutrition solutions; group C was a control which did not receive selenium supplementation. Selenium levels declined to equally low levels in both groups by sample C, but were significantly higher in group S at sample B. GSH-Px activities demonstrated a significant increase at sample B in group S and then tended to decrease. In group C, GSH-Px tended to increase, then decreased significantly by sample C. Both groups received 20 micrograms/kg per d of copper in TPN, however, serum copper declined significantly at sample B in group S whereas there were no significant changes in group C. There were no significant changes in zinc and SOD levels. There were no significant differences between groups in clinical characteristics or outcome. This study suggests that a dose of supplemental selenium of 1.34 micrograms/kg per d in TPN is inadequate for low-birthweight premature infants. Selenium supplementation may also affect copper metabolism.", "Both experimental and epidemiologic studies have linked a low dietary intake of selenium with an increased risk of cancer. The authors examined the association between plasma selenium levels and risk of hepatocellular carcinoma (HCC) among chronic carriers of hepatitis B and/or C virus in a cohort of 7,342 men in Taiwan who were recruited by personal interview and blood draw during 1988-1992. After these men were followed up for an average of 5.3 years, selenium levels in the stored plasma were measured by using hydride atomic absorption spectrometry for 69 incident HCC cases who were positive for hepatitis B surface antigen (HBsAg) and/or antibodies against hepatitis C virus (mostly HBsAg positive) and 139 matched, healthy controls who were HBsAg positive. Mean selenium levels were significantly lower in the HCC cases than in the HBsAg-positive controls (p = 0.01). Adjusted odds ratios of HCC for subjects in increasing quintiles of plasma selenium were 1.00, 0.52, 0.32, 0.19, and 0.62, respectively. The inverse association between plasma selenium levels and HCC was most striking among cigarette smokers and among subjects with low plasma levels of retinol or various carotenoids. There was no clear evidence for an interaction between selenium and alpha-tocopherol in relation to HCC risk.", "Literature indicates a relationship between selenium supplementation and risk of diabetes. However, because these data are inconclusive, we investigated the effect of selenium supplementation on serum glucose levels in men with prostate cancer enrolled in a clinical trial testing of the effect of selenium on prostate cancer progression.\n Subjects were randomized to receive placebo (n=46), selenium 200 microg/day (n=47), and selenium 800 microg/day (n=47). Serum glucose levels were obtained every 6 months for up to 5 years. Longitudinal analysis was carried out to assess whether rate of change of serum glucose levels was significantly different in the selenium-supplemented groups as compared with placebo. Sensitivity analyses were performed to assess the robustness of findings.\n Changes in serum glucose levels during the course of the trial were not statistically significantly different as compared with placebo for the selenium 200 microg/day (P=.56) or selenium 800 microg/day (P=.91) treatment groups.\n These results do not support a relationship between selenium supplementation and changes in serum glucose levels. Recommendations about selenium supplementation and risk of diabetes will require more definitive studies.\n Copyright 2010 Elsevier Inc. All rights reserved.", "Selenium and alpha-tocopherol, the major form of vitamin E in supplements, appear to have a protective effect against prostate cancer. However, little attention has been paid to the possible role of gamma-tocopherol, a major component of vitamin E in the U.S. diet and the second most common tocopherol in human serum. A nested case-control study was conducted to examine the associations of alpha-tocopherol, gamma-tocopherol, and selenium with incident prostate cancer.\n In 1989, a total of 10,456 male residents of Washington County, MD, donated blood for a specimen bank. A total of 117 of 145 men who developed prostate cancer and 233 matched control subjects had toenail and plasma samples available for assays of selenium, alpha-tocopherol, and gamma-tocopherol. The association between the micronutrient concentrations and the development of prostate cancer was assessed by conditional logistic regression analysis. All statistical tests were two-sided.\n The risk of prostate cancer declined, but not linearly, with increasing concentrations of alpha-tocopherol (odds ratio (highest versus lowest fifth) = 0.65; 95% confidence interval = 0.32--1.32; P(trend) =.28). For gamma-tocopherol, men in the highest fifth of the distribution had a fivefold reduction in the risk of developing prostate cancer than men in the lowest fifth (P:(trend) =.002). The association between selenium and prostate cancer risk was in the protective direction with individuals in the top four fifths of the distribution having a reduced risk of prostate cancer compared with individuals in the bottom fifth (P(trend) =.27). Statistically significant protective associations for high levels of selenium and alpha-tocopherol were observed only when gamma-tocopherol concentrations were high.\n The use of combined alpha- and gamma- tocopherol supplements should be considered in upcoming prostate cancer prevention trials, given the observed interaction between alpha-tocopherol, gamma-tocopherol, and selenium.", "Findings from animal models suggest that selenium supplementation improves glucose metabolism.\n To examine the effect of long-term selenium supplementation on the incidence of type 2 diabetes.\n Secondary analysis of a randomized, double-blind, placebo-controlled trial.\n Areas of low selenium consumption of the eastern United States.\n 1202 persons seen in dermatology clinics who did not have type 2 diabetes at baseline.\n Oral administration of selenium, 200 microg/d, or placebo.\n Incidence of type 2 diabetes.\n During an average follow-up of 7.7 years (SD, 2.7), type 2 diabetes developed in 58 selenium recipients and 39 placebo recipients (incidence, 12.6 cases per 1000 person-years vs. 8.4 cases per 1000 person-years, respectively; hazard ratio, 1.55 [95% CI, 1.03 to 2.33]). The lack of benefit of selenium supplementation on the incidence of type 2 diabetes persisted in analyses stratified by age, sex, body mass index, and smoking status. An exposure-response gradient was found across tertiles of baseline plasma selenium level, with a statistically significantly increased risk for type 2 diabetes in the highest tertile of baseline plasma selenium level (hazard ratio, 2.70 [CI, 1.30 to 5.61]).\n Diabetes was a secondary outcome in the parent trial. Diagnoses of diabetes were self-reported but were validated in most participants. The sample was mostly older and white.\n Selenium supplementation does not seem to prevent type 2 diabetes, and it may increase risk for the disease. Click here for related information on selenium.", "To determine whether the decline in selenium intake and selenium status in men in the West of Scotland might be a contributory factor to male subfertility.\n Two semen samples were collected from patients attending a subfertility clinic and those patients with samples showing reduced motility were invited to participate in an ethically approved double-blind clinically controlled trial with informed consent. Sixty-nine patients were recruited and received either placebo, selenium alone or selenium plus vitamins A, C and E daily for 3 months. A further semen sample was collected at the end of the trial. Plasma selenium status was determined at the beginning and end of the trial period, as was total sperm density and motility.\n Plasma selenium concentrations were significantly (P < 0.001) higher in both selenium-treated groups than in controls. No significant effect of treatment on sperm density was recorded. Sperm motility increased in both selenium-treated groups, in contrast to a slight decline in the placebo group, but the difference was not significant. However, as the provision of additional vitamins had no effect on any variable measured it was considered justified to combine the two selenium-treated groups and compare them with the placebo treatment. On this basis, selenium treatment significantly (P < 0.002) increased plasma selenium concentrations and sperm motility (P = 0.023) but sperm density was again unaffected. Five men (11%) achieved paternity in the treatment group, in contrast to none in the placebo group.\n This trial confirms the result of an earlier study, that selenium supplementation in subfertile men with low selenium status can improve sperm motility and the chance of successful conception. However, not all patients responded; 56% showed a positive response to treatment. The low selenium status of patients not supplemented again highlights the inadequate provision of this essential element in the Scottish diet.", "The purpose of this study was to evaluate the effect of selenium (Se) in the prevention of human primary liver cancer. Three intervention trials were conducted among the residents at high risk to primary liver cancer (PLC) in Qidong county, Jiang-su province, the People's Republic of China. This area has the second highest rate of PLC in China. One trial was undertaken among the general population in a township with supplement of table salt fortified with 15 ppm anhydrous sodium selenite (Se-salt) for 5 y and the other four townships with similar PLC incidence rate served as the controls using normal table salt. The second trial was undertaken among hepatitis B virus surface antigen carriers (HBVsAg+) receiving supplement of 200 micrograms Se in form of selenized yeast (Se-yeast) daily vs placebo for 4 y. The third trial was carried out in members of families with high PLC incidence using Se-yeast (200 micrograms of Se daily) vs placebo for 2 y. The results showed that nutritional supplement of Se could reduce the PLC incidence significantly.", "High rates of hepatitis B virus (HBV) infection and primary liver cancer (PLC) are present in Qidong county. Epidemiological surveys demonstrated an inverse association between selenium (Se) level and regional cancer incidence, as well as HBV infection. Four-year animal studies showed that dietary supplement of Se reduced the HBV infection by 77.2% and liver precancerous lesion by 75.8% of ducks, caused by exposure to natural environmental etiologic factors. An intervention trial was undertaken among the general population of 130,471. Individuals in five townships were involved for observation of the preventive effect of Se. The 8-yr follow-up data showed reduced PLC incidence by 35.1% in selenized table salt supplemented vs the nonsupplemented population. On withdrawal of Se from the treated group, PLC incidence rate began to increase. However, the inhibitory response to HBV was sustained during the 3-yr cessation of treatment. The clinical study among 226 Hepatitis B Surface Antigen (HBsAg)-positive persons provided either 200 micrograms of Se in the form of selenized yeast tablet or an identical placebo of yeast tablet daily for 4 yr showed that 7 of 113 subjects were diagnosed as having PLC in the placebo group, whereas no incidence of PLC was found in 113 subjects supplemented with Se. Again on cessation of treatment, PLC developed at a rate comparable to that in the control group, demonstrating that a continuous intake of Se is essential to sustain the chemopreventive effect.", "Increased intake of selenium (Se) may reduce the risk of degenerative diseases including cancer but excessive intake may be toxic. Wheat is a major source of dietary Se in humans. However, the effect of Se from wheat that is agronomically biofortified with Se on biomarkers of human health status is unknown. This study aimed to investigate whether improving Se status, by increased dietary intake of Se-biofortified wheat, affects biomarkers of cancer risk, cardiovascular disease risk, oxidative stress, and immune function in healthy South Australian men. A 24-week placebo-controlled double-blind intervention was performed in healthy older men (n = 62), with increased dose of Se intake every 8 weeks. Wheat was provided as 1, 2, and 3 puffed wheat biscuits, during weeks 1-8, 9-16, and 17-24, respectively. Blood was collected to measure a wide range of disease risk biomarkers. Consumption of Se-biofortified wheat was found to increase plasma Se concentration from a baseline level of 122 to 192 microg/L following intake of three biscuits/day, which provided 267 microg Se. Platelet glutathione peroxidase, chromosome aberrations, and DNA damage in lymphocytes measured using the cytokinesis-block micronucleus cytome assay and with the Comet assay, plasma F2-isoprostanes, protein carbonyls, plasma C-reactive protein, and leukocyte number were unaffected by the improved Se status. Improvement of Se status by consumption of Se-biofortified wheat did not substantially modify the selected biomarkers of degenerative disease risk and health status in this apparently selenium-replete cohort of healthy older men in South Australia.\n Copyright 2009 Wiley-Liss, Inc.", "The initial report of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) found no reduction in risk of prostate cancer with either selenium or vitamin E supplements but a statistically nonsignificant increase in prostate cancer risk with vitamin E. Longer follow-up and more prostate cancer events provide further insight into the relationship of vitamin E and prostate cancer.\n To determine the long-term effect of vitamin E and selenium on risk of prostate cancer in relatively healthy men.\n A total of 35,533 men from 427 study sites in the United States, Canada, and Puerto Rico were randomized between August 22, 2001, and June 24, 2004. Eligibility criteria included a prostate-specific antigen (PSA) of 4.0 ng/mL or less, a digital rectal examination not suspicious for prostate cancer, and age 50 years or older for black men and 55 years or older for all others. The primary analysis included 34,887 men who were randomly assigned to 1 of 4 treatment groups: 8752 to receive selenium; 8737, vitamin E; 8702, both agents, and 8696, placebo. Analysis reflect the final data collected by the study sites on their participants through July 5, 2011.\n Oral selenium (200 μg/d from L-selenomethionine) with matched vitamin E placebo, vitamin E (400 IU/d of all rac-α-tocopheryl acetate) with matched selenium placebo, both agents, or both matched placebos for a planned follow-up of a minimum of 7 and maximum of 12 years.\n Prostate cancer incidence.\n This report includes 54,464 additional person-years of follow-up and 521 additional cases of prostate cancer since the primary report. Compared with the placebo (referent group) in which 529 men developed prostate cancer, 620 men in the vitamin E group developed prostate cancer (hazard ratio [HR], 1.17; 99% CI, 1.004-1.36, P = .008); as did 575 in the selenium group (HR, 1.09; 99% CI, 0.93-1.27; P = .18), and 555 in the selenium plus vitamin E group (HR, 1.05; 99% CI, 0.89-1.22, P = .46). Compared with placebo, the absolute increase in risk of prostate cancer per 1000 person-years was 1.6 for vitamin E, 0.8 for selenium, and 0.4 for the combination.\n Dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men.\n Clinicaltrials.gov Identifier: NCT00006392.", "Evidence that selenium affects the risk of type-2 diabetes is conflicting, with observational studies and a few randomized trials showing both lower and higher risk linked to the level of selenium intake and status. We investigated the effect of selenium supplementation on the risk of type-2 diabetes in a population of relatively low selenium status as part of the UK PRECISE (PREvention of Cancer by Intervention with SElenium) pilot study. Plasma adiponectin concentration, a recognised independent predictor of type-2 diabetes risk and known to be correlated with circulating selenoprotein P, was the biomarker chosen.\n In a randomized, double-blind, placebo-controlled trial, five hundred and one elderly volunteers were randomly assigned to a six-month intervention with 100, 200 or 300 µg selenium/d as high-selenium or placebo yeast. Adiponectin concentration was measured by ELISA at baseline and after six months of treatment in 473 participants with one or both plasma samples available.\n Mean (SD) plasma selenium concentration was 88.5 ng/g (19.1) at baseline and increased significantly in the selenium-treatment groups. In baseline cross-sectional analyses, the fully adjusted geometric mean of plasma adiponectin was 14% lower (95% CI, 0-27%) in the highest than in the lowest quartile of plasma selenium (P for linear trend = 0.04). In analyses across randomized groups, however, selenium supplementation had no effect on adiponectin levels after six months of treatment (P = 0.96).\n These findings are reassuring as they did not show a diabetogenic effect of a six-month supplementation with selenium in this sample of elderly individuals of relatively low selenium status.", "A nested case-control study was conducted to assess the relation between serum levels of selenium and retinol and the subsequent risk of cancer. During the years 1972-1984, in northwest Washington State, 156 cases of cancer were identified among members of two employee cohorts from whom specimens had been previously obtained and stored. Two hundred eighty-seven controls were selected from these cohorts and matched to cases on the basis of employer, age, sex, race, and date of blood draw. Selenium and retinol levels were measured by neutron activation and high pressure liquid chromatography, respectively. Information on known cancer risk factors was collected by telephone interviews of subjects and next of kin. Levels of selenium and retinol were unassociated with the incidence of cancer of all sites combined, both overall and within subgroups defined by age, sex, levels of the other micronutrient, time between blood draw and diagnosis, smoking status, and family history of cancer. These findings suggest that neither serum levels of selenium nor those of retinol have an appreciable effect on the risk of cancer.", "Sera from 43 persons who developed thyroid cancer on an average 4.8 years after blood sampling were compared with sera from controls. Three controls per case matched for sex, age, place of residence and year of blood sampling, with regard to serum selenium and serum copper. Cases were significantly lower in serum selenium than controls, and the estimated odds ratio of thyroid cancer increased from 1 for levels greater than or equal to 1.65 mumol/l, to 6.1 for levels 1.26-1.64 mumol/l, to 7.7 for levels less than or equal to 1.25 mumol/l. When time from blood sampling to diagnosis of the case was considered, it could be shown that the protective effect of high serum selenium concentrations was restricted to the last (less than 7) years prior to the diagnosis of thyroid cancer. The serum selenium concentration of cases tended to decrease relative to controls the shorter time was from blood sampling to the diagnosis. There was no difference between cases and controls with regard to serum copper.", "Epidemiologic evidence indicates that diets high in fruits and vegetables are associated with a reduced risk of several cancers, including cancers of the esophagus and stomach. Vitamins and minerals in these foods may contribute to the reduced cancer risk. The people of Linxian County, China, have one of the world's highest rates of esophageal/gastric cardia cancer and a persistently low intake of several micronutrients.\n We sought to determine if dietary supplementation with specific vitamins and minerals can lower mortality from or incidence of cancer as well as mortality from other diseases in Linxian.\n Individuals of ages 40-69 were recruited in 1985 from four Linxian communes. Mortality and cancer incidence during March 1986-May 1991 were ascertained for 29,584 adults who received daily vitamin and mineral supplementation throughout this period. The subjects were randomly assigned to intervention groups according to a one-half replicate of a 2(4) factorial experimental design. This design enabled testing for the effects of four combinations of nutrients: (A) retinol and zinc; (B) riboflavin and niacin; (C) vitamin C and molybdenum; and (D) beta carotene, vitamin E, and selenium. Doses ranged from one to two times U.S. Recommended Daily Allowances.\n A total of 2127 deaths occurred among trial participants during the intervention period. Cancer was the leading cause of death, with 32% of all deaths due to esophageal or stomach cancer, followed by cerebrovascular disease (25%). Significantly (P = .03) lower total mortality (relative risk [RR] = 0.91; 95% confidence interval [CI] = 0.84-0.99) occurred among those receiving supplementation with beta carotene, vitamin E, and selenium. The reduction was mainly due to lower cancer rates (RR = 0.87; 95% CI = 0.75-1.00), especially stomach cancer (RR = 0.79; 95% CI = 0.64-0.99), with the reduced risk beginning to arise about 1-2 years after the start of supplementation with these vitamins and minerals. No significant effects on mortality rates from all causes were found for supplementation with retinol and zinc, riboflavin and niacin, or vitamin C and molybdenum. Patterns of cancer incidence, on the basis of 1298 cases, generally resembled those for cancer mortality.\n The findings indicate that vitamin and mineral supplementation of the diet of Linxian adults, particularly with the combination of beta carotene, vitamin E, and selenium, may effect a reduction in cancer risk in this population.\n The results on their own are not definitive, but the promising findings should stimulate further research to clarify the potential benefits of micronutrient supplements.", "The association between prostate cancer and baseline vitamin E and selenium was evaluated in the trial-based cohort of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (n = 29,133). During up to 9 years of follow-up, 317 men developed incident prostate cancer. Multivariate Cox proportional hazards models that adjusted for intervention group, benign prostatic hyperplasia, age, smoking, and urban residence were used to evaluate associations between prostate cancer and exposures of interest. There were no significant associations between baseline serum alpha-tocopherol, dietary vitamin E, or selenium and prostate cancer overall. The associations between prostate cancer and vitamin E and some of the baseline dietary tocopherols differed significantly by alpha-tocopherol intervention status, with the suggestion of a protective effect for total vitamin E among those who received the alpha-tocopherol intervention (relative risk was 1.00, 0.68, 0.80, and 0.52 for increasing quartiles; P = 0.07).", "To study the predictive power of serum selenium with regard to cancer mortality in a large sample of the Belgian population given the lack of coherence in the results of observational epidemiological studies in this domain.\n A prospective case-control study within a stratified sample of the Belgian male and female population.\n A total of 201 cases randomly selected from all cancer deaths (N=343) during a 10-y mortality follow-up of a large age- and sex-stratified sample of the total Belgian population aged 25-74 y were matched for age and gender with 603 controls.\n Conditional logistic regression for both univariate and multivariate analyses using tertile distribution of serum selenium in controls. Odds ratios (ORs) are adjusted for 10 baseline characteristics.\n Unadjusted ORs of cancer deaths taking the highest tertile of serum selenium as a reference: in male subjects T1/T3 is 2.2 (CI 1.3-3.7) (P for trend 0.011), whereas in female subjects a nonsignificant OR of 0.8 is observed. In multivariate analyses, no significant modifications of the ORs are observed for the predictive relation of serum selenium with cancer mortality. Besides serum selenium, beta-carotene intake and smoking are independent predictors in male subjects.\n In this nested case-control study of a stratified sample from the Belgian population, serum selenium is an independent predictor of cancer mortality in male subjects only, in a country with rather high serum selenium levels with respect to most other European countries.", "Low selenium (SE) status has been documented in preterm infants and has been suggested to be a risk factor for chronic lung disease.\n A total of 534 infants with birth weight <1500 g were enrolled in 8 New Zealand centers in a double-blind placebo-controlled randomized trial of SE supplementation from week 1 of life until 36 weeks' postmenstrual age or discharge home. Supplemented infants received 7 microg/kg/d of SE when fed parenterally and 5 microg/kg/d when fed orally. Plasma SE and glutathione peroxidase concentrations were measured in mothers after delivery and in infants before randomization and at 28 days and 36 weeks' postmenstrual age. Primary outcome measures were oxygen dependency at 28 days and total days oxygen dependency.\n No significant differences were seen between the groups with respect to primary or secondary outcome measures, with the exception that fewer supplemented infants had an episode of sepsis after the first week of life (P <.038). Mean plasma SE concentrations were 0.33 micromol/L before randomization in both groups and at 28 days had risen in the supplemented group (0.56 micromol/L) but fallen in the control group (0.29 micromol/L) (P <.0001). There was no association between outcome measures and SE concentrations at 28 days or 36 weeks' postmenstrual age. However, lower maternal and infant prerandomization SE concentrations were associated with increased respiratory morbidity.\n Postnatal SE supplementation in very low birth weight infants did not improve neonatal outcome. Further investigation of SE supplementation of mothers from the second half of pregnancy is warranted.", "This study aimed to assess the effect of high dose selenium (Se) supplementation on Se status in blood, oxidative stress, thyroid function and possible effects on requirement for renal replacement therapy (RRT) in severely septic patients admitted to the intensive care unit (ICU).\n This prospective single-centre study was carried out in 40 septic ICU patients who were randomized to high dose Se (Se+ group, N=18 (474, 316, 158 microg/day), each for 3 consecutive days followed by a standard dose of 31.6 microg/day of Se given as sodium selenite whereas the control group (Se-, N=22) received only the standard dose of Se. Plasma Se, glutathione peroxidase (GSH-Px), F2 isoprostanes, thyroid function tests (total T4 and total T3), C-reactive protein (CRP) and red blood cell (RBC) GSH-Px were estimated on day 0, 3, 7, 14.\n In the Se+ group, plasma Se increased by day 3 and 7 (P<0.0001) and day 14 (P=0.02), plasma GSH-Px increased by day 3 and 7 (P=0.01) as compared to Se- group. There was a significant negative correlation between plasma Se and SOFA (sepsis related organ failure assessment) (r=-0.36, P=0.03) along with low plasma Se and high CRP at the time of admission. Requirement for renal replacement therapy was not significantly different between the groups.\n Although high dose Se supplementation increased plasma Se and GSH-Px activity, it did not reduce oxidative damage or the requirement for RRT. Se levels in blood are influenced by redistribution and severity of illness and therefore should be interpreted with caution." ]	No reliable conclusions can be drawn regarding a causal relationship between low selenium exposure and an increased risk of cancer. Despite evidence for an inverse association between selenium exposure and the risk of some types of cancer, these results should be interpreted with care due to the potential limiting factors of heterogeneity and influences of unknown biases, confounding and effect modification. The effect of selenium supplementation from RCTs yielded inconsistent results. To date, there is no convincing evidence that selenium supplements can prevent cancer in men, women or children.
CD007325	[ "19365011", "20980427" ]	[ "Pegaptanib sodium for macular edema secondary to central retinal vein occlusion.", "Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study." ]	[ "To assess the safety and efficacy of intravitreous pegaptanib sodium for the treatment of macular edema following central retinal vein occlusion (CRVO).\n This dose-ranging, double-masked, multicenter, phase 2 trial included subjects with CRVO for 6 months' or less duration randomly assigned (1:1:1) to receive pegaptanib sodium or sham injections every 6 weeks for 24 weeks (0.3 mg and 1 mg, n=33; sham, n=32).\n Visual acuity at week 30.\n In the primary analysis at week 30, 12 of 33 (36%) subjects treated with 0.3 mg of pegaptanib sodium and 13 of 33 (39%) treated with 1 mg gained 15 or more letters from baseline vs 9 of 32 (28%) sham-treated subjects (P= .48 for 0.3 mg and P= .35 for 1 mg of pegaptanib sodium vs sham). In secondary analyses, subjects treated with pegaptanib sodium were less likely to lose 15 or more letters (9% and 6%; 0.3-mg and 1-mg pegaptanib sodium groups, respectively) compared with sham-treated eyes (31%; P= .03 for 0.3 mg and P= .01 for 1 mg of pegaptanib sodium vs sham) and showed greater improvement in mean visual acuity (+7.1 and +9.9, respectively, vs -3.2 letters with sham; P= .09 for 0.3 mg and P= .02 for 1 mg of pegaptanib sodium vs sham). By week 1, the mean central retinal thickness decreased in the 0.3-mg and 1-mg pegaptanib sodium groups by 269 microm and 210 microm, respectively, vs 5 microm with sham (P< .001).\n Based on this 30-week study, intravitreous pegaptanib sodium appears to provide visual and anatomical benefits in the treatment of macular edema following CRVO.\n Benefits accrued with intravitreous pegaptanib sodium treatment of macular edema following CRVO suggest a role for vascular endothelial growth factor in the pathogenesis of this condition.\n clinicaltrials.gov Identifier: NCT00088283.", "The expression of vascular endothelial growth factor (VEGF) is elevated in diabetic macular edema (DME). Ranibizumab binds to and inhibits multiple VEGF variants. We investigated the safety and efficacy of ranibizumab in DME involving the foveal center.\n This was a 12-month, multicenter, sham-controlled, double-masked study with eyes (age>18 years, type 1 or 2 diabetes, central retinal thickness [CRT]≥300 μm, and best corrected visual acuity [BCVA] of 73-39 ETDRS letters [Early Treatment Diabetic Retinopathy Study]) randomly assigned to intravitreal ranibizumab (0.3 or 0.5 mg; n=51 each) or sham (n=49). The treatment schedule comprised three monthly injections, after which treatment could be stopped/reinitiated with an opportunity for rescue laser photocoagulation (protocol-defined criteria). After month 1, dose-doubling was permitted (protocol-defined criteria, injection volume increased from 0.05 to 0.1 ml and remained at 0.1 ml thereafter). Efficacy (BCVA and CRT) and safety were compared between pooled ranibizumab and sham arms using the full analysis set (n=151, patients receiving≥1 injection).\n At month 12, mean±SD BCVA improved from baseline by 10.3±9.1 letters with ranibizumab and declined by 1.4±14.2 letters with sham (P<0.0001). Mean CRT reduction was 194.2±135.1 μm with ranibizumab and 48.4±153.4 μm with sham (P<0.0001). Gain of ≥10 letters BCVA from baseline occurred in 60.8% of ranibizumab and 18.4% of sham eyes (P<0.0001). Safety data were consistent with previous studies of intravitreal ranibizumab.\n Ranibizumab is effective in improving BCVA and is well tolerated in DME. Future clinical trials are required to confirm its long-term efficacy and safety." ]	Ranibizumab and pegaptanib sodium have shown promise in the short-term treatment of non-ischemic CRVO-ME. However, effectiveness and safety data from larger RCTs with follow up beyond six months are not yet available. There are no RCT data on anti-VEGF agents in ischemic CRVO-ME. The use of anti-VEGF agents to treat this condition therefore remains experimental.
CD006669	[ "18286501", "18239086", "19783136" ]	[ "Treatment of children with metastatic soft tissue sarcoma with oral maintenance compared to high dose chemotherapy: report of the HD CWS-96 trial.", "Prospective, multicenter randomized GITMO/IIL trial comparing intensive (R-HDS) versus conventional (CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at diagnosis: the superior disease control of R-HDS does not translate into an overall survival advantage.", "Sequential high-dose chemotherapy for children with metastatic rhabdomyosarcoma." ]	[ "We prospectively studied the efficacy of high dose therapy (HDT) versus an oral maintenance treatment (OMT) in patients with stage IV soft tissue sarcoma (STS).\n Both groups were pretreated with the CEVAIE combination consisting of carboplatin, etoposide, vincristine, actinomycin D, ifosfamide, and epirubicin. HDT consisted of a tandem cycle of thiotepa (600 mg/m(2)) plus cyclophosphamide (4,500 mg/m(2)) and melphalan (120 mg/m(2)) plus etoposide (1,800 mg/m(2)). This treatment was compared with OMT, consisting of four cycles trofosfamide (10 days 2 x 75 mg/m(2)/day) plus etoposide (10 days 2 x 25 mg/m(2)/day), and 4 cycles trofosfamide (10 days 2 x 75 mg/m(2)/day) plus idarubicin (10 days 4 x 5 mg/m(2)). Eligibility criteria were: diagnosis confirmed by reference pathology, primary stage IV, below 22 years of age, and having completed the study therapy.\n From 96 patients 45 were treated with HDT and 51 with OMT. The main risk parameters were equally distributed in both arms. After a median follow-up of 57.4 months, 11/45 (24.4%) patients in the HDT-arm and 26/51 (57.8%) patients in OMT-arm were alive. Kaplan-Meier analysis demonstrated an overall survival for the whole group of 0.27 (OMT group: 0.52, HDT group 0.27, log rank P = 0.03). The proportional hazard analysis for patients with rhabdomyosarcoma (RMS) or \"RMS-like\" tumors (77.1% of all patients) demonstrated an independent benefit of OMT on outcome.\n Oral maintenance therapy seems to be a promising option for patients with RMS-like stage IV tumors.\n (c) 2008 Wiley-Liss, Inc.", "In this randomized multicenter study of 136 patients, 6 courses of CHOP (cyclo-phosphamide/doxorubicin/vincristine/prednisone) followed by rituximab (CHOP-R) were compared with rituximab-supplemented high-dose sequential chemotherapy with autografting (R-HDS) to assess the value of intensified chemo-therapy as a first-line treatment for high-risk follicular lymphoma (FL) after the introduction of monoclonal antibodies. The analysis was intention to treat with event-free survival (EFS) as the primary endpoint. Complete remission (CR) was 62% with CHOP-R and 85% with R-HDS (P < .001). At a median follow-up (MFU) of 51 months, the 4-year EFS was 28% and 61%, respectively (P < .001), with no difference in overall survival (OS). Molecular remission (MR) was achieved in 44% of CHOP-R and 80% of R-HDS patients (P < .001), and was the strongest independent outcome predictor. Patients relapsing after CHOP-R underwent salvage R-HDS in 71% of cases. Salvage R-HDS had an 85% CR rate and a 68% 3-year EFS (MFU, 30 months). We conclude that (1) achieving MR is critical for effective disease control, regardless of which treatment is used; (2) R-HDS ensures superior disease control and molecular outcome than CHOP-R, but no OS improvement; and (3) CHOP-R failures have a good outcome after salvage R-HDS, suggesting that relapsed/refractory FL could be the most appropriate setting for R-HDS-like treatments. This trial was registered at www.clinicaltrials.gov as no. NCT00435955.", "The RMS4.99 study was designed to explore the role of multiple sequential high-dose chemotherapy cycles administered early in the treatment of children with metastatic rhabdomyosarcoma.\n Seventy patients were enrolled and received three cycles of initial standard chemotherapy, followed by a course of cyclophosphamide and etoposide to obtain peripheral blood stem cells (PBSC), then three consecutive high-dose combinations followed by PBSC rescue. This was followed by surgery and/or radiotherapy, after which a final maintenance treatment with six courses of vincristine, actinomycin D and cyclophosphamide was administered.\n Sixty-two patients underwent the high-dose chemotherapy phase. The 3-year overall survival (OS) and progression free survival (PFS) rates for the 70 patients were 42.3% (95% confidence interval [CI] 39.5-53.6) and 35.3% (95% CI, 24.3-46.5), respectively. By multivariate analysis survival correlated strongly with age > 10 years. In a subset of patients with only one or no unfavourable prognostic factors (age > 10 years, unfavourable site of primary tumour, bone or bone marrow involvement and number of metastatic sites >2) the PFS was significantly higher, i.e. 60.5% at 3 years.\n Our study confirms that patients with favourable prognostic characteristics have a better survival. The use of sequential cycles of high-dose chemotherapy did not appear of benefit for patients with metastatic rhabdomyosarcoma." ]	Overall, the results of this review do not justify the use of HDC with SCR as a standard therapy for children with metastatic rhabdomyosarcoma. However, all reported studies were possibly subject to significant bias, especially selection bias. This might have underestimated the measured effect of HDC. As a result, a clinically important excess of adverse risk patients in the HDC arms may explain the non-beneficial effect of HDC. Only a large prospective RCT will be able to answer the question of whether HDC with SCR adds to survival or not definitively.
CD009007	[ "8718912", "9559629", "11496075", "17803414", "9661685", "17940809", "8168414", "20973677" ]	[ "Use of red blood cell transfusions in terminally ill cancer patients admitted to a palliative care unit.", "Perioperative blood transfusions reduce long-term survival following surgery for colorectal cancer.", "Storage time of transfused blood and disease recurrence after colorectal cancer surgery.", "Survey of blood transfusion practice for palliative care patients in Yorkshire: implications for clinical care.", "A pilot randomized trial comparing symptomatic vs. hemoglobin-level-driven red blood cell transfusions following hip fracture.", "Prophylactic anti-coagulation in cancer palliative care: a prospective randomised study.", "Blood transfusion and survival in colorectal cancer.", "Assessment of fatigue after blood transfusion in palliative care patients: a feasibility study." ]	[ "Anemia is often associated with neoplastic disorders. Blood transfusions are used to alleviate the discomfort of anemic cancer patients. Of 246 terminally ill cancer patients admitted to our palliative care unit from October 1991 to December 1993 (128 women and 118 men), 31 patients (12.6%) (17 men and 14 women; age, 69.5 +/- 12 years) received on average 2.8 units of packed red blood cells (PRBCs) (range, 2-7 units/patient) in 35 separate admissions. PRBCs were transfused in the presence of low hemoglobin (Hb) levels ( < or = 8 g/dL) and/or severe fatigue or dyspnea. Pre-transfusion performance status, cognitive function, dyspnea, and fatigue at rest (evaluated by a four-point scale), complete blood count, serum albumin, and C-reactive protein were determined. The day after transfusion, subjective well-being was recorded as \"yes/no\" improvement in comparison with the pre-transfusion day. Improved subjective well-being after blood transfusion was reported in 51.4%, without significant relationship to pre-transfusion Hb levels or performance status. The influence of blood transfusion on subjective well-being was not related to the severity of dyspnea or fatigue. Twenty-one patients (60%), including seven with subjective improvement, died during the same hospitalization, a median of 49 days after transfusion. Pre-transfusion Hb level did not differ significantly in patients who benefited and did not benefit from transfusion, whereas time before death was significantly (P < 0.001) shorter in patients who did not benefit. In the discharged patients (40%), the median interval between transfusion and discharge was 13 days and the frequency of subjective improvement in well-being was 78.6%. Our data suggest that two main areas should be investigated, namely the relation between low Hb levels and symptoms and signs in terminally ill cancer patients, and the correct timing for effective blood transfusion. A combination of criteria is needed for effective transfusion; they must include not only Hb levels but also type and severity of anemic symptoms and signs. Furthermore, the identification of reliable prognostic indicators for survival would be useful.", "The aim of the study contained herein was to investigate the association between blood transfusion and long-term outcome for patients treated for colorectal cancer, controlling for the effect of other prognostic factors. We also wanted to study whether blood storage time influenced the prognosis.\n Cox's proportional hazards regression analysis was used to analyze data from 336 patients who survived resection with curative intent. Median follow-up was 5.8 (2-16.8) years or until death.\n Local recurrences and distant metastases were significantly more frequent when more than two units of blood had been transfused. In the multivariate Cox's analysis, with backward elimination of nonsignificant factors at the 10 percent level, the following risk factors were significantly related to death by colorectal cancer: tumor stage (T stage and N stage), perforation of tumor, age, and the need for a blood transfusion. Transfusions of more than two units of blood were independently and significantly associated with death from colorectal cancer (relative hazard, 2.7; 95 percent confidence intervals, 1.4-5.2). Time of blood storage had no effect on the prognoses. In patients dying from diseases unrelated to colorectal cancer, age and American Society of Anesthesiologists group were significantly related to death, whereas blood transfusion was not.\n We found an independent and significant association between perioperative blood transfusion and poor prognosis in colorectal cancer patients. Blood storage time was not a prognostic factor.", "Perioperative blood transfusion and subsequent development of postoperative infectious complications may lead to poor prognosis of patients with colorectal cancer. It has been suggested that the development of postoperative infectious complications may be related to the storage time of the transfused blood. Therefore, we studied the relationship between blood storage time and the development of disease recurrence and long-term survival after colorectal cancer surgery.\n Preoperative and postoperative data were prospectively recorded in 740 patients undergoing elective resection for primary colorectal cancer. None of the patients received preoperative or postoperative chemotherapy or radiation therapy. Endpoints were overall survival and disease recurrence in the subgroup of patients operated on with curative intention who also survived the first 30 days after operation. Storage of buffy-coat-depleted red cells suspended in saline, adenine, glucose, and mannitol blood for 21 days was used as cut-off point.\n Median follow-up was 6.8 years (range, 5.4 years to 7.9 years), and median overall survival was 4.6 years for 288 nontransfused patients and 3.0 years for 452 transfused patients (P = 0.004). The survival of patients receiving blood exclusively stored < 21 days was 2.5 years. For patients receiving any blood stored > or = 21 days, survival was 3.7 years (P = 0.12). Among patients with curative resection (n = 532), the hazard ratio of disease recurrence was 1.5 (95 percent CI; 1.1 to 2.2) and 1.0 (95 percent CI; 0.7 to 1.4) in the two transfused groups, respectively, compared with the nontransfused group after multivariable correction for patient age, gender, colonic/rectal tumor localization, Dukes classification, blood loss, and postoperative infectious complications.\n Transfusion of buffy-coat-depleted red cells suspended in saline, adenine, glucose, and mannitol blood stored for < 21 days may be an independent risk factor for development of recurrence after elective colorectal cancer surgery.", "Blood transfusions can be used to palliate the symptoms of fatigue or dyspnea in the presence of anemia. We studied the transfusion practices of 8 hospices in our cancer network over a 1-year period. We identified 164 patients who received 650 units of blood in 230 transfusions. The majority of patients received a single transfusion (71%), of 2 or 3 units of blood (76%), as an inpatient (83%). Blood transfusions occurred in 140 (5.7%) of 2460 hospice admissions. Median survival following first transfusion was 42 days and significantly longer for outpatients compared to inpatients (median of 104 days and 36 days, respectively, p = 0.006).", "The indications for transfusion have never been evaluated in an adequately sized clinical trial. A pilot study was conducted to plan larger clinical trials.\n Hip fracture patients undergoing surgical repair who had postoperative hemoglobin levels less than 10 g per dL were randomly assigned to receive 1) symptomatic transfusion: that is, transfusion for symptoms of anemia or for a hemoglobin level that dropped below 8 g per dL or 2) threshold transfusion: that is, patients receive 1 unit of packed RBCs at the time of random assignment and as much blood as necessary to keep the hemoglobin level above 10 g per dL. Outcomes were 60-day mortality, morbidity, functional status, and place of residence.\n Among 84 eligible patients enrolled, mean (+/- SD) prerandomization hemoglobin was 9.1 (+/- 0.6) g/ dL. The median number of units transfused in the threshold transfusion group was 2 (interquartile range, = 1-2), and that in the symptomatic transfusion group was 0 (6; interquartile range, = 0-2) (p < 0.001). Mean hemoglobin levels were approximately 1 g per dL higher in the threshold group than in the symptomatic group: for example, on Day 2, 10.3 (+/- 0.9) g per dL versus 9.3 (+/- 1.2) g per dL, respectively (p < 0.001). At 60 days, death or inability to walk across the room without assistance occurred in 16 (39.0%) of the symptomatic transfusion group and 19 (45.2%) of the threshold transfusion group. Death occurred by 60 days in 5 (11.9%) of the symptomatic transfusion group and 2 (4.8%) in the threshold transfusion group (relative risk = 2.5; 95% CI, 0.5-12.2). Other outcomes were similar for the two groups.\n Symptomatic transfusion may be an effective blood-sparing protocol associated with the transfusion of appreciably fewer units of RBCs and lower mean hemoglobin levels than are associated with the threshold transfusion policy. However, it is unknown whether these two clinical strategies have comparable mortality, morbidity, or functional status. A definitive trial is needed.", "The objective of this study was to determine utility of prophylactic anti-coagulation in cancer patients hospitalised for palliative care in a specialised centre.\n Prospective 1:1 open randomised study was designed. Twenty patients aged 55 to 88 years with advanced cancer and an estimated life expectancy of less than 6 months were assigned to either receive treatment with 2,850/3,800 U (<70/>70 kg) of daily subcutaneous nadroparin or no treatment. Suspicion of venous thrombo-embolism (deep vein thrombosis and pulmonary embolism) was confirmed by echo-Doppler examination of the lower limbs and/or by spiral computed tomography scan of the lungs. Bleeding episodes were recorded. Platelet count was measured on days 7 and 14. Survival time from study entry was determined.\n One venous thrombo-embolism and one major bleeding occurred in the group receiving nadroparin, whereas two minor bleedings occurred in the control group. At 3 months, nine of ten participants had died in the control group vs five of ten in the group receiving nadroparin (P = 0.141). Five participants could be discharged home (P = 0.141).\n Decision to administer prophylactic nadroparin in hospitalised cancer patients under palliative care remains a challenge. Better mobility score at admission and the likelihood to be discharged home may be useful for practical purposes. The observation of a potential influence of prophylactic nadroparin on survival deserves further studies.", "This study examined the effect of blood transfusion on the prognosis of patients undergoing surgery for colorectal cancer.\n Potentially curative resections for colorectal cancer were performed in 266 patients who were followed prospectively, with a minimum follow-up of 41 months. They were divided into transfused (n = 121) and nontransfused (n = 145) groups according to their perioperative blood transfusion requirements.\n There were significantly more rectal tumors (chi 2 = 9.5, df = 1, P = 0.002) and fixed tumors (chi 2 = 4.5, df = 1, P = 0.03) in the transfused group. There was no statistically significant difference between the two groups with regard to recurrence-free survival (chi 2 = 1.1, df = 1, P = 0.3) and overall survival (chi 2 = 2.8, df = 1, P = 0.09).\n In this study we have found no statistically significant effect of perioperative blood transfusion on the prognosis of colorectal cancer patients.", "Blood transfusions are often used as a potential treatment for cancer-related fatigue in anaemic palliative care patients. However, evidence of benefit using validated outcomes measures is lacking.\n The aim of this study was to test the feasibility of using two such tools; the Brief Fatigue Inventory and FACT F-fatigue subscale, to measure change in fatigue following a blood transfusion.\n Anemic cancer patients receiving specialist palliative care and undergoing transfusion for fatigue, completed the tools pre- and 3 days post-transfusion.\n Thirty patients with cancer-related fatigue who received a blood transfusion completed the study. Both measures were capable of detecting statistical and clinically significant change in fatigue following transfusion. Furthermore, the measures showed significant differences between patients that did, or did not, report an overall improvement in fatigue. Patients found the measures easy to complete with no preference for one over another. Future clinical trials of blood transfusion for the management of fatigue should incorporate these validated outcome measures." ]	Higher-quality studies are required to determine the effectiveness of blood transfusion at the end of life and, in particular, to determine which patients are most likely to respond and which are not, and the duration of any response. Potential harms of blood transfusion at the end of life (indicated by high 14-day mortality) need to be distinguished from inappropriate transfusion in patients who are dying from advanced cancer.
CD008244	[ "19132781", "20496365", "19108787", "15378666", "20156949" ]	[ "The efficacy and safety of milnacipran for treatment of fibromyalgia. a randomized, double-blind, placebo-controlled trial.", "Efficacy and safety of milnacipran 100 mg/day in patients with fibromyalgia: results of a randomized, double-blind, placebo-controlled trial.", "Milnacipran for the treatment of fibromyalgia in adults: a 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial.", "A double-blind placebo-controlled trial of milnacipran in the treatment of fibromyalgia.", "A European multicenter randomized double-blind placebo-controlled monotherapy clinical trial of milnacipran in treatment of fibromyalgia." ]	[ "To evaluate the safety and efficacy of milnacipran, a dual norepinephrine and serotonin reuptake inhibitor, in the treatment of fibromyalgia (FM).\n A 27-week, randomized, double-blind, multicenter study compared milnacipran 100 and 200 mg/day with placebo in the treatment of 888 patients with FM. Two composite responder definitions were used to classify each patient's individual response to therapy. \"FM responders\" concurrently satisfied response criteria for improvements in pain (visual analog scale 24-h morning recall), patient global impression of change (PGIC), and physical functioning (SF-36 Physical Component Summary); while \"FM pain responders\" concurrently satisfied response criteria for improvements in pain and PGIC.\n At the primary endpoint, after 3-month stable dose treatment, a significantly higher percentage of milnacipran-treated patients met criteria as FM responders versus placebo (milnacipran 200 mg/day, p = 0.017; milnacipran 100 mg/day, p = 0.028). A significantly higher percentage of patients treated with milnacipran 200 mg/day also met criteria as FM pain responders versus placebo (p = 0.032). Significant pain reductions were observed after Week 1 with both milnacipran doses. At 15 weeks, milnacipran 200 mg/day led to significant improvements over placebo in pain (realtime, daily and weekly recall; all measures, p < 0.05), PGIC (p < 0.001), fatigue (p = 0.016), cognition (p = 0.025), and multiple SF-36 domains. Milnacipran was safe and well tolerated by the majority of patients during 27 weeks of treatment; nausea and headache were the most common adverse events.\n Milnacipran is safe and effective for the treatment of multiple symptoms of FM.", "To assess the efficacy and safety of milnacipran at a dosage of 100 mg/day (50 mg twice daily) for monotherapy treatment of fibromyalgia.\n A double-blind, placebo-controlled trial was performed to assess 1,025 patients with fibromyalgia who were randomized to receive milnacipran 100 mg/day (n = 516) or placebo (n = 509). Patients underwent 4-6 weeks of flexible dose escalation followed by 12 weeks of stable-dose treatment. Two composite responder definitions were used as primary end points to classify the response to treatment. The 2-measure composite response required achievement of ≥30% improvement from baseline in the pain score and a rating of \"very much improved\" or \"much improved\" on the Patient's Global Impression of Change (PGIC) scale. The 3-measure composite response required satisfaction of these same 2 improvement criteria for pain and global status as well as improvement in physical function on the Short Form 36 (SF-36) physical component summary (PCS) score.\n After 12 weeks of stable-dose treatment, a significantly greater proportion of milnacipran-treated patients compared with placebo-treated patients showed clinically meaningful improvements, as evidenced by the proportion of patients meeting the 2-measure composite responder criteria (P < 0.001 in the baseline observation carried forward [BOCF] analysis) and 3-measure composite responder criteria (P < 0.001 in the BOCF). Milnacipran-treated patients also demonstrated significantly greater improvements from baseline on multiple secondary outcomes, including 24-hour and weekly recall pain score, PGIC score, SF-36 PCS and mental component summary scores, average pain severity score on the Brief Pain Inventory, Fibromyalgia Impact Questionnaire total score (all P < 0.001 versus placebo), and Multidimensional Fatigue Inventory total score (P = 0.036 versus placebo). Milnacipran was well tolerated by most patients, with nausea being the most commonly reported adverse event (placebo-adjusted rate of 15.8%).\n Milnacipran administered at a dosage of 100 mg/day improved pain, global status, fatigue, and physical and mental function in patients with fibromyalgia.", "Preclinical and clinical studies have suggested that milnacipran, a dual norepinephrine-serotonin reuptake inhibitor, may be efficacious in the treatment of fibromyalgia (FM).\n This study was conducted to evaluate the efficacy and tolerability of milnacipran in treating the multiple domains of FM.\n This was a multicenter, double-blind, placebo-controlled trial. Adult patients (age 18-70 years) who met 1990 American College of Rheumatology criteria for FM were randomized to receive milnacipran 100 mg/d, milnacipran 200 mg/d, or placebo for 15 weeks. Because this was a pivotal registration trial, the primary end points were chosen to investigate efficacy for 2 potential indications: the treatment of FM and the treatment of FM pain. Thus, the 2 primary efficacy end points were rates of FM composite responders and FM pain composite responders. FM composite responders were defined as patients concurrently experiencing clinically meaningful improvements in the following 3 domain criteria: pain (> or = 30% improvement, as recorded in an electronic diary); patients' global status (a rating of very much improved or much improved on the Patient Global Impression of Change [PGIC] scale); and physical function (a > or = 6-point improvement on the 36-item Short-Form Health Survey [SF-36] Physical Component Summary score). FM pain composite responders were defined as those who met the pain and PGIC criteria. Adverse events reported by patients or observed by investigators were recorded throughout the trial.\n Of 2270 patients screened, 1196 were randomized to receive milnacipran 100 mg/d (n = 399), milnacipran 200 mg/d (n = 396), or placebo (n = 401). The majority of patients were female (96.2%) and white (93.5%). The population had a mean age of 50.2 years, a mean baseline weight of 180.8 pounds, and a mean baseline body mass index of 30.6 kg/m(2). Compared with placebo, significantly greater proportions of milnacipran-treated patients were FM composite responders (100 mg/d: P = 0.01; 200 mg/d: P = 0.02) and FM pain composite responders (100 mg/d: P = 0.03; 200 mg/d: P = 0.004). Milnacipran was associated with significant improvements in pain after 1 week of treatment (100 mg/d: P = 0.004; 200 mg/d: P = 0.04), as well as significant improvements in multiple secondary efficacy end points, including global status (PGIC: P<0.001 for both doses), physical function (SF-36 physical functioning domain-100 mg/d: P < 0.001; 200 mg/d: P = 0.02), and fatigue (Multidimensional Fatigue Inventory- 100 mg/d: P = 0.04). The most commonly reported adverse events with milnacipran were nausea (100 mg/d, 34.3%; 200 mg/d, 37.6%), headache (18.0% and 17.7%, respectively), and constipation (14.3% and 17.9%). Adverse events resulted in premature study discontinuation in 19.5% and 23.7% of those who received milnacipran 100 and 200 mg/d, respectively, compared with 9.5% of placebo recipients.\n In these adult patients with FM, both doses of milnacipran (100 and 200 mg/d) were associated with significant improvements in pain and other symptoms. Clinical Trials Identification Number: NCT00098124.", "Fibromyalgia syndrome is a systemic disorder of widespread pain which is thought to result from abnormal pain processing within the central nervous system. There are no currently approved treatments for this indication. Antidepressants appear, however, to be effective, especially those with an action on noradrenergic neurotransmission. The objective of the present study was to test the efficacy of the dual action noradrenaline and serotonin reuptake inhibitor antidepressant, milnacipran, in the treatment of fibromyalgia. The 125 patients, who were enrolled in a double-blind, placebo-controlled, flexible dose escalation trial, were randomized to receive placebo or milnacipran for 4 weeks of dose escalation (up to 200 mg/day), followed by 8 weeks at a constant dose. The study evaluated the efficacy and safety of milnacipran for the treatment of pain and associated symptoms such as fatigue, depressed mood and sleep. 75% of milnacipran-treated patients reported overall improvement, compared with 38% in the placebo group (p < 0.01). Furthermore, 37% of twice daily milnacipran-treated patients reported at least 50% reduction in pain intensity, compared with 14% of placebo-treated patients (p < 0.05). 84% of all milnacipran patients escalated to the highest dose (200 mg/day) with no tolerability issues. Most adverse events were mild to moderate in intensity, and transient in duration. These results suggest that milnacipran may have the potential to relieve not only pain but several of the other symptoms associated with fibromyalgia.\n 2004 John Wiley & Sons, Ltd.", "This randomized, double-blind, placebo-controlled, multicenter study investigated the efficacy and safety of milnacipran in the treatment of fibromyalgia (FM) in a European population.\n Outpatients diagnosed with FM according to 1990 American College of Rheumatology criteria (N = 884) were randomized to placebo (n = 449) or milnacipran 200 mg/day (n = 435) for 17 weeks (4-week dose escalation, 12-week stable dose, 9-day down-titration), followed by a 2-week posttreatment period. The primary efficacy criterion was a 2-measure composite responder analysis requiring patients to achieve simultaneous improvements in pain (>or= 30% improvement from baseline in visual analog scale, 24-hour morning recall) and a rating of \"very much\" or \"much\" improved on the Patient Global Impression of Change scale. If responder analysis was positive, Fibromyalgia Impact Questionnaire (FIQ) was included as an additional key primary efficacy measure.\n At the end of the stable dose period (Week 16), milnacipran 200 mg/day showed significant improvements from baseline relative to placebo in the 2-measure composite responder criteria (p = 0.0003) and FIQ total score (p = 0.015). Significant improvements were also observed in multiple secondary efficacy endpoints, including Short-Form 36 Health Survey (SF-36) Physical Component Summary (p = 0.025), SF-36 Mental Component Summary (p = 0.007), Multidimensional Fatigue Inventory (p = 0.006), and Multiple Ability Self-Report Questionnaire (p = 0.041). Milnacipran was safe and well tolerated; nausea, hyperhidrosis, and headache were the most common adverse events.\n Milnacipran is an effective and safe treatment for pain and other predominant symptoms of FM. Registered as trial no. NCT00436033." ]	The evidence available indicates that milnacipran 100 mg or 200 mg is effective for a minority in the treatment of pain due to fibromyalgia, providing moderate levels of pain relief (at least 30%) to about 40% of participants, compared with about 30% with placebo. There were insufficient data to assess substantial levels of pain relief (at least 50%), and the use of last observation carried forward imputation may overestimate drug efficacy. Milnacipran is associated with increased adverse events and adverse event withdrawals, which were significantly greater for the higher dose. There were no data for the use of milnacipran for other chronic neuropathic pain conditions.
CD006090	[ "7913157", "8632216", "9846855", "7819847", "17298703", "8102720", "8436094", "10390287", "8116059", "12649946" ]	[ "Effect of vitamin A supplementation on diarrhoea and acute lower-respiratory-tract infections in young children in Brazil.", "Vitamin A supplementation fails to reduce incidence of acute respiratory illness and diarrhea in preschool-age Indonesian children.", "Randomized placebo-controlled clinical trial of the effect of a single high dose or daily low doses of vitamin A on the morbidity of hospitalized, malnourished children.", "Impact of massive dose of vitamin A given to preschool children with acute diarrhoea on subsequent respiratory and diarrhoeal morbidity.", "Supplementation with vitamin A reduces watery diarrhoea and respiratory infections in Mexican children.", "Vitamin A supplementation and increased prevalence of childhood diarrhoea and acute respiratory infections.", "Impact of large-dose vitamin A supplementation on childhood diarrhoea, respiratory disease and growth.", "The beneficial effects of weekly low-dose vitamin A supplementation on acute lower respiratory infections and diarrhea in Ecuadorian children.", "Effect of vitamin A on diarrhoeal and respiratory complications of measles.", "Effect of vitamin A supplementation on childhood morbidity and mortality." ]	[ "A beneficial effect of periodic vitamin A supplementation on childhood mortality has been demonstrated, but the effect on morbidity is less clear. We investigated the effect of vitamin A supplementation on diarrhoea and acute lower-respiratory-tract infections (ALRI) in children from northeastern Brazil in a randomised, double-blind, placebo-controlled community trial. 1240 children aged 6-48 months were assigned vitamin A or placebo every 4 months for 1 year. They were followed up at home three times a week, and data about the occurrence and severity of diarrhoea and ALRI were collected. Any child with cough and respiratory rate above 40 breaths per min was visited by a paediatrician. The overall incidence of diarrhoea episodes was significantly lower in the vitamin-A-supplemented group than in the placebo group (18.42 vs 19.58 x 10(-3) child-days; rate ratio 0.94 [95% Cl 0.90-0.98]). The benefit of supplementation was greater as regards severe episodes of diarrhoea; the incidence was 20% lower in the vitamin A group than in the placebo group (rate ratio 0.80 [0.65-0.98]). With the standard definition of diarrhoea (> or = 3 liquid or semi-liquid stools in 24 h) the effect of vitamin A on mean daily prevalence did not reach significance, but as the definition of diarrhoea was made more stringent (increasing number of stools per day), a significant benefit became apparent, reaching for diarrhoea with 6 or more liquid or semi-liquid stools in 24 h a 23% lower prevalence. We found no effect of vitamin A supplementation on the incidence of ALRI. The reduction in severity of diarrhoea may be the most important factor in the lowering of mortality by vitamin A supplementation.", "Vitamin A supplementation of populations of vitamin A-deficient preschool-age children has been shown to reduce childhood mortality, but the primary preventive effects of such supplements on childhood infectious diseases have not been carefully evaluated. We conducted an individually randomized, placebo-controlled, double-masked trial among 1,407 Indonesian preschool-age children, to measure the effects of high dose vitamin A on acute respiratory and diarrheal illnesses. Signs and symptoms of morbidity were monitored using every other day home surveillance by trained interviewers. High dose vitamin A supplements increased the incidence of acute respiratory illnesses (ARI) by 8%, and acute lower respiratory illnesses (ALRI) by 39%. These detrimental effects on acute lower respiratory illnesses were most marked in children with adequate nutritional status (rate ratio 1.83, 95% confidence interval 1.257-2.669). In contrast, vitamin A tended to be protective of ALRI in chronically malnourished children (rate ratio 0.71, 95% confidence interval 0.375-1.331). There was no overall effect of high-dose vitamin A supplements on the incidence of diarrheal disease (rate ratio 1.06, 95% confidence interval 0.920-1.225). However, we found a significant interaction between supplementation and age: vitamin A increased the incidence of diarrhea in children < 30 mo of age, but tended to reduce the incidence in older children. The finding of a significant adverse effect of vitamin A supplements in adequately nourished children highlights the need to review the criteria for selecting populations of preschool-age children for vitamin A supplementation.", "The effect of high-dose vitamin A supplementation on recovery from morbidity and on recovery from nosocomial morbidity of hospitalized children has been poorly studied and results are conflicting. The effect of daily, low doses has never been assessed. We investigated the effect of a single high dose and daily, low doses of vitamin A on diarrhea, acute lower respiratory tract infections (ALRIs), and all-cause fevers in 900 hospitalized preschool-age children in the Democratic Republic of Congo in a randomized, double-blind, placebo-controlled clinical trial. The high-dose treatment group received 200,000 IU vitamin A (100,000 IU if aged <12 mo) orally on the day of admission, the low-dose treatment group received 5000 IU vitamin A/d until discharge. Data on all-cause morbidity were collected daily. Mortality rates were not significantly different among the 3 groups. High-dose vitamin A supplementation had no significant effect on the duration of moderate or severe diarrhea nor on the duration and incidence of ALRIs and all-cause fevers. Children in the high-dose group with no edema had an increased risk of severe nosocomial diarrhea (relative risk: 2.42; 95% CI: 1.15, 5.11). Low-dose vitamin A supplementation significantly reduced the incidence of severe diarrhea in severely malnourished children (relative risk: 0.21; 95% CI: 0.07, 0.62) but showed no significant effect on the duration of moderate or severe diarrhea or on the duration and incidence of ALRIs and all-cause fevers. Supplementation with high doses of vitamin A did not reduce morbidity in this population of malnourished and subclinically vitamin A-deficient children; daily, low doses appeared more beneficial for severely malnourished children.", "To assess the impact of vitamin A supplementation on morbidity from acute respiratory tract infections and diarrhoea.\n Double blind randomised placebo controlled field trial.\n An urban slum area in New Delhi, India.\n 900 children aged 12-60 months attending a local health facility for acute diarrhoea of less than seven days' duration randomly allocated to receive vitamin A 200,000 IU or placebo.\n Incidence and prevalence of acute lower respiratory tract infections and diarrhoea during the 90 days after termination of the enrolment diarrhoeal episode measured by twice weekly household surveillance.\n The incidence (relative risk 1.07; 95% confidence interval 0.92 to 1.26) and average number of days spent with acute lower respiratory tract infections were similar in the vitamin A supplementation and placebo groups. Among children aged 23 months or less there was a significant reduction in the incidence of measles (relative risk 0.06; 95% confidence interval 0.01 to 0.48). The incidence of diarrhoea was also similar (relative risk 0.95; 0.86 to 1.05) in the two groups. There was a 36% reduction in the mean daily prevalence of diarrhoea associated with fever in the vitamin A supplemented children older than 23 months.\n Results were consistent with a lack of impact on acute lower respiratory tract related mortality after vitamin A supplementation noted in other trials and a possible reduction in the severity of diarrhoea.", "Previous clinical vitamin A trials have found no consistent effect on diarrhoeal disease and respiratory tract infection. These inconsistent results may be due to the distinct effects vitamin A supplementation has among children stratified by factors related to socio-economic status, nutritional status and season. We evaluated the effect of supplementation on the overall incidence of diarrhoeal disease and respiratory tract infections and on the incidence among children stratified by these factors. A total of 188 children, aged 6-15 months, from periurban, marginalized communities of Mexico City were assigned to receive vitamin A ( < 12 months of age, 20,000 IU retinol; >or= 12 months, 45,000 IU retinol) or a placebo every 2 months, and were followed for up to 15 months. Project personnel visited households twice a week to determine the onset and duration of diarrhoeal disease and respiratory tract infections. Vitamin A supplementation had no significant effect on risk of overall diarrhoeal disease but reduced mild watery diarrhoea (incidence rate ratio (RR) 0.69; 95 % CI 0.50, 0.93) and cough with fever (RR 0.69; 95 % CI 0.48, 0.98). Vitamin A supplementation decreased diarrhoeal disease during the summer (RR 0.74; 95 % CI 0.57, 0.94), among non-stunted children (RR 0.69; 95 % CI 0.52, 0.93) and among children from households with better socio-economic measures. Heterogeneity in the response to vitamin A supplementation may reflect heterogeneity in the aetiology and epidemiology of diarrhoeal disease and respiratory tract infections and the impact that supplementation has on the immune response.", "There is uncertainty over whether vitamin A supplementation reduces morbidity among children with subclinical deficiency of the vitamin. Hence a double-blind, placebo-controlled trial of the effect of vitamin A supplementation on childhood morbidity was conducted among 11,124 children aged 6-83 months in the northwest of Haiti. After a random start, children were sequentially assigned by household units to receive either megadose vitamin A or placebo in three distribution cycles 4 months apart. 2 to 8 weeks after each administration of the vitamin A and placebo capsules, indicators of childhood morbidity were reassessed through interviews conducted in the homes of participating families. The vitamin A group was found to have an increased 2-week prevalence of all symptoms and signs of childhood morbidity assessed, including diarrhoea (rate ratio [RR] = 1.09, 95% confidence interval 1.05-1.14), rhinitis (RR = 1.02, 95% confidence interval 1.00-1.04), cold/flu symptoms (RR = 1.04, 95% confidence interval 1.01-1.06), cough (RR = 1.07, 95% confidence interval 1.03-1.11), and rapid breathing (RR = 1.18, 95% confidence interval 1.09-1.27). The study shows an increased 2-week prevalence of diarrhoea and the symptoms of respiratory infections after vitamin A supplementation.", "One hundred and seventy-two 0.5-3.0-year-old children in a mountainous area of northern Hebei Province of China were randomly assigned to a vitamin A supplementation group (n = 98) or a control group (n = 74) for a 1 year double-blind study. Capsules containing 200,000 IU vitamin A and 40 IU vitamin E were given to the children in the experimental group 3 and 9 months after baseline examination. During the 12 month study period, there was a significant reduction in the incidence of diarrhoea (P < 0.01) and respiratory disease (P < 0.01) in the children of the experimental group compared to the control. Risk of diarrhoea and respiratory disease were respectively 2.5 and 3.4 times higher in the control children. Serum retinol and IgA levels of the treatment group were significantly higher than that of control group (P < 0.01) 7 weeks after first supplementation. There was no significant difference in saliva IgA level between groups. No significant differences in growth were observed. It was concluded that supplementation with large doses of vitamin A decreased the incidence and severity of diarrhoea and respiratory disease in these children, possibly through enhanced activity of the immune system, but had no effect on growth over 1 year.", "Previous studies of large-dose vitamin A supplementation on respiratory morbidity have produced conflicting results in a variety of populations. The influence of malnutrition has not been examined in the majority of these trials. We hypothesized that weekly low-dose vitamin A supplementation would prevent respiratory and diarrheal disease morbidity and that malnutrition might influence the efficacy of vitamin A supplementation.\n In a randomized, double-blind, placebo-controlled field trial of 400 children, 6 to 36 months of age in a high Andean urban slum, half of the children received 10 000 IU of vitamin A weekly and half received placebo for 40 weeks. Children were visited weekly at home by physicians and assessed for acute diarrheal disease and acute respiratory infections.\n Acute diarrheal disease and acute respiratory infection did not differ globally or by severity between supplement-treated and placebo groups. However, the incidence of acute lower respiratory infection (ALRI) was significantly lower in underweight (weight-for-age z score [WAZ] <-2 SD) supplement-treated children than in underweight children on placebo (8.5 vs 22.3 per 10(3) child-weeks; rate ratio: 0.38 [95% CI: 0.17-0.85]). ALRI incidence was significantly higher in normal-weight (WAZ >-2 SD) supplement-treated children than in normal-weight children on placebo (9.8 vs 4.4 per 10(3) child-weeks; rate ratio: 2.21 [95% CI: 1.24-3.93]). By logistic regression analysis the risk of ALRI was lower in underweight supplement-treated children than in underweight children on placebo (point estimate 0.148 [95% CI: 0.034-0.634]). In contrast, risk of ALRI was higher in normal-weight supplement-treated children (WAZ >-1 SD to mean) than in normal-weight children on placebo in the same WAZ stratum (point estimate: 2.51 [95% CI: 1.24-5.05]). The risk of severe diarrhea was lower in supplement-treated children 18 to 23 months of age than in children on placebo in this age group (point estimate: 0.26 [95% CI: 0.06-1.00]).\n Weekly low-dose (10 000 IU) vitamin A supplementation in a region of subclinical deficiency protected underweight children from ALRI and paradoxically increased ALRI in normal children with body weight over -1 SD. Protection from severe diarrhea was consistent with previous trials. Additional research is warranted to delineate potential beneficial and detrimental interactions between nutritional status and vitamin A supplementation regarding ALRI.", "A randomized placebo-controlled trial of high dose vitamin A in acute measles was performed in Nairobi, Kenya to determine if it reduced the incidence or severity of diarrhoeal and respiratory complications. On enrollment laryngotracheobronchitis (LTB) pneumonia, diarrhoea and otitis media were each found in 45-80% of children in the treatment and placebo groups. While 4 of 119 cases of LTB in the placebo group progressed to grade III (loud stridor, markedly diminished air entry, chest indrawing, cyanosis), none of 116 in the vitamin A group did. Episodes of diarrhoea, but not pneumonia, resolved faster and were less severe in the vitamin A group. There were no differences in the incidences of pneumonia, LTB or diarrhoea during hospitalization, but children treated with vitamin A had a lower rate of developing otitis media. The overall case fatality rate was 2.7% and did not differ by group. These findings, along with those from three other trials in Africa, suggest that high dose vitamin A reduces the severity of complications during measles.", "In a double blind design, 1520 children aged < 10 years were individually randomised in vitamin A and placebo group in slums of Chandigarh. Children > 12, 6-12 and < 6 months of age received 200,000, 100,000, 500,000 I.U. of vitamin A respectively every 4 to 6 months during 15 months trial period. The prevalence of vitamin A deficiency was significantly reduced in vitamin A compared to placebo group during the follow-up period. In vitamin A group, incidence of diarrhoea and measles was significantly reduced but incidence of acute respiratory infections was not significantly different compared to control group. Risk of death was also significantly less in vitamin A group. Therefore, promotion of vitamin A rich diet or supplementation with synthetic vitamin A at 4-6 month interval should be a priority in populations where risk of vitamin A deficiency is high." ]	This unexpected result is outside our current understanding of the use of vitamin A for preventing acute LRTIs. Accordingly, vitamin A should not be given to all children to prevent acute LRTIs. Despite its benefits in preventing diarrhoeal illnesses, vitamin A supplementation has only a limited effect in preventing acute LRTIs. Positive effects appear limited to populations with acute and chronic under nutrition. Low-dose vitamin A appears to have fewer side effects and at least equal benefit to a high dose of vitamin A.
CD000122	[ "9603794", "15655442", "9175946", "20237484" ]	[ "Lack of efficacy of light reduction in preventing retinopathy of prematurity. Light Reduction in Retinopathy of Prematurity (LIGHT-ROP) Cooperative Group.", "The effects of comfort care on the pain response in preterm infants undergoing screening for retinopathy of prematurity.", "Light reduction and the electroretinogram of preterm infants.", "Effect of topical anesthesia and age on pain scores during retinopathy of prematurity screening." ]	[ "Hospital-nursery lighting has been suggested as a factor in causing retinopathy of prematurity. Despite ongoing debate, a causal relation has not been established.\n We conducted a prospective, randomized, multicenter study of the effects of light reduction on 409 premature infants with birth weights of less than 1251 g and gestational ages of less than 31 weeks. Two hundred five infants were exposed to reduced light, and 204 to typical nursery lighting. The amount of light reaching the infants' eyes was reduced within 24 hours after birth by placing goggles on the infants that reduced visible-light exposure by 97 percent and ultraviolet-light exposure by 100 percent. The babies wore the goggles until 31 weeks' postconceptional age or 4 weeks after birth, whichever was longer. Once the goggles were removed, ophthalmologists masked to the treatment assignments assessed the infants for retinopathy of prematurity at least biweekly for up to 13 weeks.\n There were 188 infants in the group that wore goggles and 173 in the control group who survived and were available for follow-up. The mean birth weights were 906 g in the goggles group and 914 g in the control group; the mean gestational ages were 27.4 weeks and 27.2 weeks, respectively. The mean ambient-light level adjacent to the infants' faces was 399 lux for the goggles group and 447 lux for the control group. Retinopathy of prematurity was diagnosed in 102 infants (54 percent) in the goggles group and 100 (58 percent) in the control group (relative risk, 0.9; 95 percent confidence interval, 0.8 to 1.1; P=0.50).\n A reduction in ambient-light exposure does not alter the incidence of retinopathy of prematurity.", "The aim of the study was to determine if pain and distress during the retinopathy of prematurity (ROP) screening examination could be ameliorated by providing comfort care.\n This study was a prospective, randomized, controlled trial of 30 stable preterm infants who underwent initial ROP screening examinations. Fourteen study infants were swaddled, held, and given 24% sucrose solution during the examination. Sixteen controls were examined while lying in their cribs. Vital signs (i.e., pulse rate, respiratory rate, and oxygen saturation), crying time, and time for the vital signs to return to baseline values were recorded at different times during the examination.\n The vital signs did not vary significantly between the two groups. The participants in the control group had a trend of longer crying time, but this trend did not reach a level of statistical significance. In addition, The time required for the vital signs to return to their baseline values did not vary significantly.\n ROP screening is very distressful for preterm infants. The routine use of comfort care to reduce pain during the examination could not be supported by this study.", "To examine the effects of light on retinal development and function in preterm infants as measured by the electroretinogram (ERG). Secondary outcomes included visual acuity testing, the incidence of retinopathy of prematurity, and general wellbeing, reflected in feeding tolerance, rate of weight gain, and length of hospital stay.\n Eligibility criteria for enrollment were birthweight < or = 1250 g and gestational age < or = 31 weeks. Sixty one infants were randomly allocated by 6 hours after birth to a control or treatment group which wore 97% light filtering goggles for a minimum of four weeks or until the infant reached 31 weeks postmenstrual age.\n There were no significant differences between the two groups in the numbers of electroretinograms performed at 36 weeks of postmenstrual age. Although the sample size was not large enough to exclude clinically important differences in secondary outcomes, no significant differences were observed between the groups in visual acuity testing at 4-6 months corrected age, incidence of retinopathy of prematurity, weight gain, or length of stay.\n These data support the safety and feasibility of this intervention. A much larger study will be needed to determine whether light reduction to the eyes of very low birthweight infants will reduce the incidence of retinopathy of prematurity or enhance general well-being.", "The efficacy of topical anesthesia during retinopathy of prematurity (ROP) screening has been a controversial issue. To determine the efficacy of proparacaine eye drops (0.5%), we compared the Premature Infant Pain Profile (PIPP) scores in 40 preterm infants undergoing ROP screening.\n Prospective randomized double masked cross-over clinical trial. The study was conducted in the neonatal intensive units for infants undergoing routine ROP screening exams. Baseline PIPP scores and post-examination PIPP scores at 1 and 5 min were compared for: (1) those receiving saline vs proparacaine eye drops (2) first ROP screening vs second ROP screening, regardless of the type of eye drops used. Wilcoxon signed-ranks test was used to pair pain scores.\n Forty preterm infants were included in the study. Mean gestational age (GA) at first and second examinations was 33.3 and 35.3 weeks, respectively. Proparacaine use significantly lowered mean PIPP scores (P=0.027) and delta scores (P=0.013) at 1 min after examination, but there was no difference at 5 min after examination. Second examinations showed significantly lower mean PIPP scores after examination (1 min (P=0.003) and 5 min (P=0.025)), regardless of the type of drop used.\n Proparacaine eye drops offer significant relief of pain that is apparently short lived. Significantly lower PIPP scores at second ROP examinations suggested that infants of older GA may have a greater ability to tolerate ROP screening. We recommend the use of proparacaine eye drops for the short term, immediate relief of pain during ROP screening in preterm infants of lesser GA." ]	Decreasing retinal ambient light exposure in premature infants is very unlikely to reduce the incidence of ROP.
CD005288	[ "16784743", "9288368" ]	[ "Randomized controlled trial assessing a traditional Chinese medicine remedy in the treatment of primary dysmenorrhea.", "Analgesic effect of a herbal medicine for treatment of primary dysmenorrhea--a double-blind study." ]	[ "A proof-of-concept study to assess the safety and efficacy of a traditional Chinese medicine formula as treatment for primary dysmenorrhea showed no statistically significant benefit over placebo. However, some efficacy parameters suggested possible superiority of the active treatment and so a larger study needs to be performed to determine whether this remedy has a role in the treatment of dysmenorrhea.", "We evaluated the analgesic effect of Toki-shakuyaku-san (TSS) in women who had a combination of \"deficiency,\" of \"Yin,\" \"cold,\" and \"stagnated blood\" syndromes, and were suffering from dysmenorrhea. A diagnostic scoring system was used for determination of these conditions. We treated patients with either TSS or placebo during 2 menstrual cycles with a double-blind technique, and we followed them for 2 additional cycles. A significant alleviation of dysmenorrhea was observed in patients treated with TSS as compared to those treated with placebo. Our results suggest that TSS is effective for treatment of dysmenorrhea in patients with the above-mentioned conditions." ]	The review found promising evidence supporting the use of Chinese herbal medicine for primary dysmenorrhoea; however, results are limited by the poor methodological quality of the included trials.
CD008580	[ "11169347", "16318970", "17240233", "9690596" ]	[ "Does local anesthesia at mid-trimester amniocentesis decrease pain experience? A randomized trial in 220 patients.", "Reducing pain with genetic amniocentesis-A randomized trial of subfreezing versus room temperature needles.", "Does local anesthesia decrease pain perception in women undergoing amniocentesis?", "Thermoregulatory effects of spinal and epidural anesthesia during cesarean delivery." ]	[ "To evaluate whether local anesthesia decreases patients' pain experience during mid-trimester amniocentesis.\n In a randomized trial, one group did not receive local anesthesia while, in another group, lignocaine 1% was injected subcutaneously prior to amniocentesis. Five different scoring systems were used to evaluate patients' pain experience.\n Two hundred and twenty women entered the study: 114 received local anesthesia, while 106 did not. The mean (SD) Visual Analog Scale was 1.4 (1.5) on a 0-10 scale (range 0-7.6). Some 97% of patients described the procedure as not painful or bearable, 79% had expected the procedure to be more painful and 59% reported the amniocentesis to have a comparable discomfort as venous blood sampling; 98% of women declared they would undergo an amniocentesis again if indicated. There were no statistical differences between both randomization groups.\n Mid-trimester amniocentesis is not a painful procedure. Local anesthesia does not affect pain experience during amniocentesis.", "To determine whether pain associated with second trimester genetic amniocentesis is decreased by using subfreezing rather than room temperature needles.\n Subjects were randomized to a -14 degrees C or room temperature (20-22 degrees C) 22-gauge spinal needle. Patients, blinded to allocation, recorded anticipated and actual pain before and after the procedure, respectively, using a 0-10 visual analog scale with 0 = no pain and 10 = excruciating pain.\n Thirty-three subjects were randomized to room temperature and 29 subjects to subfreezing needles. Anticipated pain was similar in room temperature, 5.1 +/- 1.7, and subfreezing groups, 4.9 +/- 2.0, respectively (p = 0.6). Actual pain was also similar in the room temperature, 3.6 +/- 2.0, and subfreezing groups, 2.8 +/- 2.0, respectively (p = 0.14). Similar numbers of subjects in the room temperature and subfreezing groups reported less actual pain (20 vs. 18), greater actual pain (4 vs. 4) or no difference in pain (9 vs. 5) than anticipated (p = 0.6).\n A subfreezing 22-gauge spinal needle does not decrease perceived pain associated with second trimester genetic amniocentesis.", "The null hypothesis is that local anesthesia does not decrease pain perception during amniocentesis.\n We performed a prospective randomized study comparing local anesthesia (1% lidocaine) with no anesthesia before amniocentesis in a racially diverse population. Immediately after the procedure, subjects were asked to assess their pain using both a Visual Analogue Scale and a 101-point Numerical Rating Scale.\n Two hundred four women were enrolled; 101 women received local, 102 women received no local, and 1 woman declined the amniocentesis after randomization. There was no difference in pain perception between the 2 groups as measured by either the visual analogue scale or the numeric rating scale (P = .28 and .18 respectively). The correlation coefficient between the 2 pain scales was strong with 0.86 for the local group and 0.92 for the no local group, (P < .001).\n Administration of local anesthesia before amniocentesis does not decrease maternal pain perception.", "Hypothermia is likely to develop faster during spinal anesthesia than epidural anesthesia. A natural consequence of the rapid temperature decrease during spinal anesthesia is that the shivering threshold will be reached sooner and that more shivering will be required to prevent further hypothermia. We tested the hypotheses that the onset of hypothermia is more rapid and the onset and intensity of shivering earlier during spinal than epidural anesthesia.\n Patients undergoing cesarean delivery were randomly assigned to spinal anesthesia or epidural anesthesia. Spinal anesthesia was induced by injecting 2 mL 0.5% dibucaine into the L4-L5 interspace. Epidural anesthesia was induced with 20 mL 2% mepivacaine injected into the L2-L3 interspace. Thermal comfort and shivering were scored by a blinded observer.\n Fifteen patients given each type of anesthesia had upper sensory levels > or =T4 dermatome. Sensation was entirely absent from the leg during spinal anesthesia, but lower block levels were near S5 during epidural anesthesia. Tympanic membrane temperatures initially decreased faster during spinal anesthesia, but subsequently decreased at a rate of 0.5 degrees C/h in both groups. The onset and incidence of shivering (detected qualitatively) did not differ significantly between the two groups, but shivering intensity was significantly reduced during spinal anesthesia. Furthermore, the shivering thresholds were 36.4+/-0.3 degrees C (mean+/-SD) during spinal anesthesia versus 37.1+/-0.4 degrees C in those given epidural anesthesia (P=.006). There were no clinically important differences in thermal comfort with the two kinds of neuraxial anesthesia.\n We failed to confirm our hypothesis, but for an unexpected reason: Thermoregulation was impaired more by spinal anesthesia than epidural anesthesia. It seems likely that in our patients spinal anesthesia inhibited thermoregulatory control more than epidural anesthesia because it better blocked sensory input from the legs." ]	In general, women who undergo amniocentesis could be informed that pain during procedure is minor and that there is currently insufficient evidence to support the use of local anaesthetics, leg rubbing or subfreezing the needle for pain reduction during procedure.
CD001187	[ "9164365", "2021877", "17359604", "10359888", "3520626", "9298177", "8732235", "15080829", "14656350", "10412335", "15480319", "6342456", "10782522", "9260215", "7677828", "10520054", "8814042", "12079502", "16846450", "10697255", "2253088", "16136910", "10629456", "3353895", "1560167", "8596961", "7809773", "1789401", "8511730", "11149991", "9192919", "6821012", "10981523", "9284985", "7662102", "15480327", "12680861", "12002728", "9574889", "12867606", "1629503", "8454796", "10200009", "19650848", "7838620", "9042633", "54740" ]	[ "Continuous avoidance measures with or without acaricide in dust mite-allergic asthmatic children.", "Clinical evaluation of a double-blind dust-mite avoidance trial with mite-allergic rhinitic patients.", "House dust mite allergen avoidance and self-management in allergic patients with asthma: randomised controlled trial.", "House dust mite avoidance for children with asthma in homes of low-income families.", "Allergen avoidance in house dust mite sensitive adult asthma.", "Allergen-avoidance measures in homes of house-dust-mite-allergic asthmatic patients: effects of acaricides and mattress encasings.", "The respiratory effects of reduction of mite allergen in the bedrooms of asthmatic children--a double-blind controlled trial.", "Allergic rhinitis due to house dust mites: evaluation of the efficacy of specific sublingual immunotherapy.", "A randomized controlled trial of mite allergen-impermeable bed covers in adult mite-sensitized asthmatics.", "Environmental controls in reducing house dust mites and nasal symptoms in patients with allergic rhinitis.", "Three-year outcomes of dietary fatty acid modification and house dust mite reduction in the Childhood Asthma Prevention Study.", "Preventive measures in mite asthma. A controlled trial.", "House-dust-mite sublingual-swallow immunotherapy (SLIT) in perennial rhinitis: a double-blind, placebo-controlled study.", "Double-blind placebo-controlled study of sublingual immunotherapy with house dust mite extract (D.pt.) in children.", "House dust mite allergen avoidance: a randomized controlled trial of surface chemical treatment and encasement of bedding.", "Effects of house dust mite avoidance measures on Der p 1 concentrations and clinical condition of mild adult house dust mite-allergic asthmatic patients, using no inhaled steroids.", "Effect of application of benzyl benzoate on house dust mite allergen levels.", "House dust mite barrier bedding for childhood asthma: randomised placebo controlled trial in primary care [ISRCTN63308372].", "House dust mite allergen reduction and allergy at 4 yr: follow up of the PIAMA-study.", "An evaluation of mattress encasings and high efficiency particulate filters on asthma control in the tropics.", "House dust mite allergen levels and an anti-mite mattress spray (natamycin) in the treatment of childhood asthma.", "[The efficacy of controlling of house dusts in attacks of mite sensitive asthmatics].", "Mechanical ventilation and high-efficiency vacuum cleaning: A combined strategy of mite and mite allergen reduction in the control of mite-sensitive asthma.", "Effect of house dust mite avoidance measures on adult atopic asthma.", "Effective education of adults with asthma who are allergic to dust mites.", "Accumulation of house-dust mite (Der-p-1) levels on mattress covers.", "The effects of a single treatment of an acaricide, Acarosan, and a detergent, Metsan, on Der p 1 allergen levels in the carpets and mattresses of asthmatic children.", "Efficacy of an air-cleaning device equipped with a high efficiency particulate air filter in house dust mite respiratory allergy.", "Double blind trial of ionisers in children with asthma sensitive to the house dust mite.", "Eradication of house dust mite from homes of atopic asthmatic subjects: a double-blind trial.", "Allergen reduction measures in houses of allergic asthmatic patients: effects of air-cleaners and allergen-impermeable mattress covers.", "A double blind controlled trial of Bencard house dust mite (Migen) hyposensitisation in Zambian asthmatics.", "The effect of high-efficiency and standard vacuum-cleaners on mite, cat and dog allergen levels and clinical progress.", "A 1-year, placebo-controlled, double-blind house-dust-mite immunotherapy study in asthmatic adults.", "Efficacy of the acaricide: acardust for the prevention of asthma and rhinitis due to dust mite allergy, in children.", "Clinical effectiveness of a mite allergen-impermeable bed-covering system in asthmatic mite-sensitive patients.", "House-dust mite sublingual-swallow immunotherapy in perennial conjunctivitis: a double-blind, placebo-controlled study.", "The effect of anti-allergic mattress encasings on house dust mite-induced early- and late-airway reactions in asthmatic patients. A double-blind, placebo-controlled study.", "Clinical effects of benzyl benzoate in the prevention of house-dust-mite allergy. Results of a prospective, double-blind, multicenter study.", "Control of exposure to mite allergen and allergen-impermeable bed covers for adults with asthma.", "Reducing domestic exposure to dust mite allergen reduces bronchial hyperreactivity in sensitive children with asthma.", "A double-blind, placebo controlled trial of solidified benzyl benzoate applied in dwellings of asthmatic patients sensitive to mites: clinical efficacy and effect on mite allergens.", "Immunotherapy in children with allergic asthma: effect on bronchial hyperreactivity and pharmacotherapy.", "Effect of improved home ventilation on asthma control and house dust mite allergen levels.", "Benzyl-benzoate foam: effects on mite allergens in mattress, serum and nasal secretory IgE to Dermatophagoides pteronyssinus, and bronchial hyperreactivity in children with allergic asthma.", "Effect of a bed covering system in children with asthma and house dust mite hypersensitivity.", "Anti-mite measurements in mite-sensitive adult asthma. A controlled trial." ]	[ "Improvement in the quality of life in the Western world and increased time spent indoors by children have enhanced the spread of house dust mites and increased the exposure time for sensitive children. Also, exposure to house dust mites in infancy and subsequent development of childhood asthma have been clinically linked. Recently, new acaricides have been developed.\n To test the efficacy of the new acaricide (esdepallethin and piperonyl butoxide--\"Acardust\") combined with environmental control compared with continuous house dust mite avoidance measures.\n Forty-six house dust mite-allergic, asthmatic children were evaluated for 6 months in a prospective, randomized, double-blind, and placebo-controlled study. Patients were randomly allocated to active and placebo acaricide treatment combined with avoidance measures, whereas only continuous avoidance measures were taken in the third group. Symptom score, medication usage, and peak flow measurements were recorded daily. The amount of house dust mite allergen in the dust vacuumed from the bedrooms was also measured.\n Morning and evening peak expiratory flow rates and forced expiratory volume in one second remained unchanged throughout the study period. In all groups, the symptom scores improved significantly, whereas the amount of house dust mite allergen decreased significantly at the end of the trial.\n Continuous house dust mite avoidance measures have a significant positive effect on the symptomology of children with mild or moderate asthma. \"Acardust\" combined with continuous house dust mite avoidance measures is not more effective than continuous house dust mite avoidance measures alone in the treatment of house dust mite-allergic, asthmatic children.", "Inheritance and allergen exposure are key factors in the development and the course of atopic allergy, expressed as conjunctivitis, rhinitis, asthma or dermatitis. This study concerns the clinical significance of mite and mite-allergen avoidance measures based on intensive cleaning with acaricide (solidified benzylbenzoate) added (10 dwellings), and without biocidal activity (10 other homes) as a control in a double-blind trial with matched pairs. Twenty subjects with persisting rhinitic complaints were selected. They lived in 20 different dwellings and were all sensitized to pyroglyphid mites; 12 of them were also sensitized to stored product mites (Acari). Daily symptoms and medication score, guanine and dust exposure, total and mite-specific IgE in serum, eosinophilia in the blood and in the nasal smear, intracutaneous tests with house dust mite and storage mite extracts were compared in both pairs and groups. Acarological data, physiochemical aspects and exposure assessment are discussed in detail elsewhere. Symptom scores dropped significantly, as did the total IgE and exposure to dust and mite products in the acaricidal cleaner treatment group. After 1 year, the daily symptoms median was 47% (P = 0.025), total IgE was 38% (P = 0.0049), and exposure to dust and mite products (guanine exposure) was 53% (P = 0.0449) better or lower than in the controls. Intensive cleaning, without acaricidal treatment performed twice a year, resulted in clinical improvement in four out of 10 subjects, of whom none became free of complaints. In the Acarosan treatment group (cleaning + benzylbenzoate) eight out of 10 subjects improved, in three cases subjective symptoms disappeared.(ABSTRACT TRUNCATED AT 250 WORDS)", "The efficacy of bed covers that are impermeable to house dust mites has been disputed.\n The aim of the present study was to investigate whether the combination of 'house dust mite impermeable' covers and a self-management plan, based on peak flow values and symptoms, leads to reduced use of inhaled corticosteroids (ICS) than self-management alone.\n Prospective, randomised, double blind, placebo-controlled trial.\n Primary care in a south-eastern region of the Netherlands.\n Asthma patients aged between 16 and 60 years with a house dust mite allergy requiring ICS were randomised to intervention and placebo groups. They were trained to use a self-management plan based on peak flow and symptoms. After a 3-month training period, the intervention commenced using house dust mite impermeable and placebo bed covers. The follow-up period was 2 years. Primary outcome was the use of ICS; secondary outcomes were peak expiratory flow parameters, asthma control, and symptoms.\n One hundred and twenty-six patients started the intervention with house dust mite impermeable or placebo bed covers. After 1 and 2 years, significant differences in allergen exposure were found between the intervention and control groups (P<0.001). No significant difference between the intervention and control groups was found in the dose of ICS (P = 0.08), morning peak flow (P = 0.52), peak flow variability (P = 0.36), dyspnoea (P = 0.46), wheezing (P = 0.77), or coughing (P = 0.41). There was no difference in asthma control between the intervention and control groups.\n House dust mite impermeable bed covers combined with self-management do not lead to reduced use of ICS compared with self-management alone.", "Home exposure to high levels of house dust mite allergen has been shown to aggravate airways reactivity and asthma.\n The purpose of this study was to determine whether specific house dust mite control measures could reduce exposure levels and asthma severity.\n This double-blinded, randomized trial compared asthma progression over 1 year in children whose homes received standard environmental control intervention with those whose homes received aggressive intervention for dust mite elimination. The primary end point was doubling in PD20 methacholine.\n Symptom scores and quality-of-life scores were similar for the standard and aggressive intervention groups. PD20 methacholine doubling occurred in 9 members of the aggressive intervention group vs 4 control patients (P <.05). Dust mite levels decreased in the aggressive intervention homes compared with the standard intervention homes (P <.05).\n Aggressive dust mite intervention decreased dust mite levels and improved bronchial hyperresponsiveness.", "Fifty adult asthmatic patients with strongly positive skinprick tests to the house dust mite were admitted into a prospective randomised controlled trial of house dust mite avoidance in the community. Twenty-two of the experimental group completed one year of dust avoidance and 19 of these tolerated the use of plastic mattress and pillow covers. Twenty of the control group (who did not alter their housecleaning habits) also completed one year of study. A fall in mite and dust levels was noted in the homes of the experimental but not the control group. Fifteen of the experimental group who completed the study were strongly RAST positive (score 3 or more) to the house dust mite. These patients had a significant improvement in FEV1/FVC, PEFR, PC20, use of treatment, and symptom score at one year, whilst the seven experimental patients who were not strongly RAST positive (score 2 or less) did not, suggesting that the change noted in the former patients was not merely due to a placebo effect. Fifteen of the control group who completed the study were also strongly RAST positive for the house dust mite and these patients showed no change in any of the parameters. This study demonstrates that adult asthmatic patients can successfully carry out house dust eradication procedures in the community over a long period of time, and that those patients who are allergic to the house dust mite appear to have both subjective and objective improvement in their asthma.", "This double-blind, placebo-controlled study investigated whether the application of an acaricide (Acarosan) on mattresses and on textile floor coverings in living rooms and bedrooms can contribute to improvement in lung function and airway hyperresponsiveness in 40 adult asthmatic patients sensitized to house-dust mite. In a second group of 19 patients who refused chemical intervention, the clinical effects of application of allergen-impermeable mattress encasings were studied. In all three treatment groups, Der p 1 levels in mattress dust were statistically significantly decreased after 12 months. However, this decrease was much greater in the group who received mattress encasings (final mean level 430 ng/g) than in groups with acaricide- or placebo-treated mattresses (final mean levels 1730 and 2100 ng/g, respectively). Treatment of textile floors with either Acarosan or placebo chemical caused a statistically significant decrease in the level of the house-dust-mite allergen Der p1 in floor dust. In the group with mattress encasings, no significant changes of floor dust Der p 1 were found. Airway hyperresponsiveness (as measured by the PC20 histamine) improved significantly in the mattress cover group after 6 months. The Acarosan group also showed a small but statistically significant improvement after 12 months.", "Inhalation of house dust mite (HDM) allergen may provoke attacks of asthma.\n We investigated whether a double-blind placebo-controlled community-based study aimed at reducing the HDM allergens in the bedrooms of HDM sensitive asthmatic children using the best methods available would prove beneficial to the children's health.\n The children (mean age 9.9 years, 34 boys) were recruited by a questionnaire submitted to 7386 families in a geographically-defined area of the UK. Subjects were chosen to take part in the double-blind placebo-controlled trial if they were asthmatic, skin sensitive to mites, and had mite allergen in their mattresses. Seventy children were randomly allocated to groups. In the active group, the children's bedrooms were treated with an acaricide (Acarosan) and the mattresses, pillows and duvets were encased in exclusion covers. The control group received placebo treatments.\n Forty-nine complete data sets were obtained. Applying bedding covers and Acarosan led to a median reduction of 480 ng (100%) in mite allergen on the mattress vs 215 ng (53%) reduction in placebo-treated group by 6 weeks. No evidence was found that the acaricide reduced mite allergen level. A change in bronchial reactivity to histamine was observed in the children after 6 weeks. This was not associated with any change in thrice-daily records of peak expiratory flow rate. By 24 weeks, the actively-treated children had improved forced expiratory volume in 1s (FEV1) and fewer required bronchodilator therapy or reported asthmatic symptoms than did the controls.\n The results suggest that mite removal procedures may modestly improve mite-sensitive asthmatics and could perhaps be of value in exceptionally mite-sensitive and/or highly mite-exposed individuals whose response to the attempted removal should be measured.", "The efficacy and safety of sublingual immunotherapy (SLIT) in patients with chronic rhinitis related to sensitization to house dust mites are still controversial.\n After application of an anti-mite mattress cover, patients were only included in the study when the cumulative symptom score over a fortnight was greater than 70 out of a possible total of 168. Thirty-two of the 120 patients selected were randomized to receive SLIT for 2 years: 17 received placebo and 15 received the Dermatophagoides pteronyssinus and D. farinae 50/50 allergen extract.\n Significant between-group differences were observed after 1 year and persisted at the end of the second year for the rhinitis total score (P < 0.02), blocked nose score (P < 0.01) and nasal itching score (P < 0.01). Skin reactivity to house dust mites was significantly reduced in the group receiving house dust mite extract (P < 0.03). No statistical difference was observed between the two groups for medication scores, but a low medication consumption was observed in all patients. No serious and no systemic adverse reactions were reported.\n This study indicates the superiority of active treatment vs. placebo, evaluated on efficacy criteria (rhinitis score) or objective criteria (skin reactivity). The availability of a solid form (tablet) could represent a progress in terms of patient acceptability.", "Mite-allergic patients with allergic disease should benefit from avoiding mite allergens. Many physicians, however, are yet to be convinced that allergen avoidance can make a significant contribution to asthma management in these patients. Many allergen-avoidance regimes include multiple measures of allergen reduction, but as mite exposure in the home is most likely to be greatest in bed dust, bedding is usually the first target for intervention.\n This study selected adult patients considered to be most likely to benefit from avoiding mite allergens, namely diagnosed asthmatics, sensitized to house dust mites and exposed to mite allergen in their mattresses. Patients were randomized into a placebo-controlled trial of the use of allergen-impermeable bed covers for 12 months, without any other form of mite-reduction measures.\n Adults with asthma were selected from general practices and asthma clinics in south-east London. Their serum IgE to mite allergens and allergen content of mattress dust samples were measured. Those with >0.70 kU/L mite-specific IgE and >2 microg/g Der p 1 were randomized into active or placebo treatments. Information was collected on allergic symptoms and medication use and quarterly peak flow diaries were kept throughout the trial. Dog or cat allergic patients were excluded if they had a pet at home to which they were sensitized.\n The mean decrease in microg/g Der p 1 was 25.7 (95% CI 8.9, 74.1) in the active group and 4.5 (95% CI 1.8, 11.5) in the placebo group. Der p 1 concentrations in the active and placebo groups at the end of the trial were not significantly different. There was no effect on peak flow or asthma symptoms in a simple comparison of the treatment and placebo groups.\n In this group of patients, mite allergen avoidance in the bed by the use of allergen-impermeable bedding alone cannot be recommended as an effective way of relieving asthma symptoms.", "A randomized comparison group pretest-posttest experimental design was used to quantitatively determine the effects of environmental control measures on patients with allergic rhinitis. Environmental controls included wrapping the mattress with a vinyl cover, washing the top bedding cover with 55 degrees C hot water every two weeks, removal of soft furniture, and wet cleaning of the bedroom floor every day. Thirty subjects were randomly assigned to experimental and control groups. The amount of house dust mites in dust samples collected from the bedroom floor, bedding and mattress, as well as the nasal symptoms of patients, were measured twice at one-month intervals. A significant decrease in house dust mites in dust samples and relief in patients' nasal symptoms were observed in the experimental group who had environmental controls.", "Two factors thought to influence the risk of asthma are the promoting effect of sensitization to house dust mites and the preventive effect of increased omega-3 fatty acids. Although house dust mite allergen avoidance has been used as a preventive strategy in several trials, the effect of omega-3 fatty acid supplementation in the primary prevention of asthma and allergic disease is not known.\n To measure the effects of dietary supplementation with omega-3 fatty acids and house dust mite allergen avoidance in children with a family history of asthma.\n A total of 616 children at high risk of asthma were enrolled antenatally in a randomized controlled trial, and 526 children remained in the trial at age 3 years. The outcomes were symptoms of allergic disease and allergen sensitization.\n There was a significant 10.0% (95% CI, 3.7-16.4) reduction in the prevalence of cough in atopic children in the active diet group ( P=.003; number needed to treat, 10) but a negligible 1.1% (95% CI, -7.1 to 9.5) reduction cough among nonatopic children. There was a 7.2% (95% CI, 10.11-14.3) reduction in sensitization to house dust mite in the active allergen avoidance group ( P=.05; number needed to treat, 14). No significant differences in wheeze were found with either intervention.\n These results suggest that our interventions, designed to be used in simple public health campaigns, may have a role in preventing the development of allergic sensitization and airways disease in early childhood. This offers the prospect of reducing allergic disease in later life.", "To evaluate the effect of preventive measures 46 patients, all allergic to house-dust mites (Dermatophagoides spp.), were randomly allocated to a study and a control group. According to the patients' subjective recordings of symptom score and use of medicine, compared with the control group, the study group had improved. There was, however, no improvement when comparing the objective recordings of morning and evening peak flow and use of medicine, and it is concluded that the preventive measures in this programme are not very effective for patients allergic to house-dust mites. The reduction in indoor humidity in the study group was limited and, as a high indoor humidity is the cause of huge populations of house-dust mites in homes, it is emphasized that future programmes of preventive measures should focus more on damp problems, particularly those related to bad housing construction.", "The safety and efficacy of sublingual-swallow immunotherapy (SLIT) in rhinitis caused by house-dust mite were evaluated in a double-blind, placebo-controlled study including 75 patients for 24 months.\n Patients received either placebo or SLIT with a standardized Dermatophagoides pteronyssinus (D.pt.) - D. farinae (D.f) 50/50 extract. The mean cumulative dose was 90,000 IR, equivalent to 2.2 mg of Der p 1 and 1.7 mg of Der f I. Symptom and medication scores were assessed throughout the study. Exposure to house-dust mite, skin sensitivity, and serum specific IgE and IgG4 were assessed before starting treatment and after 12 and 24 months.\n Seventy-two patients (36 active-36 placebo) were eligible for intent-to-treat analysis. Thirty-six patients dropped out of the study. The number of patients who dropped out due to lack of efficacy was eight out of 37 (21.6%) in the active treatment group compared to 15 out of 38 (39.5%) in the placebo group (chi-square=2.81, P=0.09). Total symptom and medication scores decreased significantly after 12 and 24 months (P<0.05) of treatment in both groups, but no significant difference was observed between the active and placebo groups. After 24 months, the number of patients with high levels of indoor allergenic load decreased significantly in both groups compared to baseline data (P=0.01). Specific IgE (D.pt. and D.f.) increased significantly in the active treatment group after 12 and 24 months, while no change was observed in the placebo group. Specific IgG4 levels were not significantly modified in either group. Two patients in each group reported mild adverse effects. No severe adverse effects were reported.\n We conclude that SLIT in rhinitis caused by house-dust mite was safe, but there was a lack of consistent clinical benefit compared to placebo, probably due to the impact of the allergen avoidance measures that lowered the allergen burden.", "Safety and efficacy of sublingual (sublingual-swallow) immunotherapy (IT) with house dust mite extract were evaluated in 30 children (6-15 2/3 years of age) over the first 12 months of an ongoing study. The cumulative dose was 570 micrograms Der p I (five times that administered with subcutaneous therapy). Safety: One patient on active treatment dropped out after 8 weeks because of a subjective feeling of severe weakness, questionably induced by the therapy. Five patients on active therapy and one patient on placebo reported minor local side effects. Efficacy: Pulmonary symptoms were reduced after 12 months in actively treated asthmatics, but this was not consistent with the lack of improvement in bronchial reactivity, skin sensitivity and specific IgG and IgG4 against D.pt. in this group. In patients with rhinitis nasal sensitivity was reduced in the placebo group without concomitant improvement in the nasal symptom score. Specific IgE (D.pt. and D.f.) increased significantly more in the active treatment group after 3 and 12 months. We conclude that sublingual IT over 12 months with the fivefold Der p 1 dose of subcutaneous IT was well tolerated, but there was no consistent clinical or immunological benefit compared to placebo.", "To test the effectiveness of a house dust mite (HDM) allergen avoidance strategy we conducted a randomized controlled trial in 35 atopic subjects with asthma, aged 13 to 60 living in Sydney - a high HDM allergen environment. After a 3 month run-in period, subjects were randomized to active allergen avoidance treatment (n = 17) or placebo (n = 18) groups and followed for 6 months. The active treatment involved placing impermeable covers over the mattress, pillows and duvet and spraying the remaining bedding, as well as the carpets and furniture, with a tannic acid/acaricidal spray. Subjects kept a daily record of symptoms and peak expiratory flow rates and had 3 monthly assessments of lung function and airway hyperresponsiveness (AHR). Dust samples were collected from the bed, the bedroom floor and the living room floor at 3 monthly intervals and 2 weeks after the treatment. Mean HDM allergen levels at baseline at these sites were, in the active group, 15.5, 9.6 and 10.2 micrograms Der p I/g of fine dust, and, in the placebo group 25.7, 11.8 and 6.3 micrograms/g. Two weeks after the allergen avoidance treatment the HDM allergen level in the beds was reduced to 29% of baseline (95% CI 16-50%, P = 0.038 compared with placebo), but was not significantly different at 3 or 6 months. There was also no significant effect of the allergen avoidance treatment on symptom scores, peak flow variability, lung function or AHR P > 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)", "Exposure to house dust mite (HDM) allergens often results in worsening of asthma. Therefore, avoidance of exposure to HDM allergens is often proposed. Unfortunately, the most effective and feasible avoidance strategy is still not completely assessed. Consequently, we investigated the effects of a combined HDM avoidance strategy on HDM allergen concentrations and clinical condition of allergic, mild asthmatic, patients using no inhaled steroids.\n Asthmatic patients, allergic to HDM, using no inhaled corticosteroids, were randomly allocated to an active (n = 76) or a placebo allergen-avoidance group (n = 81). Avoidance measures consisted of applying Acarosan(R) (placebo: water) to the living room and bedroom floors, and the use of HDM-impermeable covers for mattresses and bedding (placebo: cotton covers for mattresses only). Effects on allergen concentrations (Der p 1), FEV1, bronchial hyperresponsiveness, peak flow parameters and asthma symptom scores were studied during 20 weeks and controlled for the allergic status of the patients.\n The active covers reduced Der p 1 concentrations to 9.4% (P = 0.0001), and were always significant lower than in the placebo group (P = 0.0002). Acarosan(R) resulted in slight but significant decreases (twofold, P = 0.0001), both on living room and bedroom floors, but concentrations were never significantly lower than the placebo group. Although the combined avoidance strategy resulted in a considerable reduction in allergen load in the active group, no differences were seen between the two groups in any of the clinical parameters during the follow-up period in this group of allergic asthmatics, using no inhaled corticosteroids. Corrections for the allergic status did not alter these results.\n The combined avoidance strategy was effective in reducing HDM allergen concentration. This was especially achieved by the allergen-impermeable covers, while the effects of Acarosan(R) were only marginal. However, this allergen reduction was not reflected in a convincing improvement in clinical condition in this group of mild allergic asthmatics, using no inhaled steroids. Perhaps, a longer follow-up period would have resulted in more pronounced effects.", "Several acaricides have become available for reducing house dust mite allergen levels.\n The purpose of this study was to assess whether the use of benzyl benzoate (Acarosan) provides additional benefit to the usual mite control measures including encasement of mattress and pillows with vinyl covers.\n A randomized controlled trial was carried out in 26 homes (14 control versus 12 treatment) of asthmatic patients in two cities (Vancouver and Winnipeg). The control group had the usual house dust mite control measures including the use of vinyl covers for mattresses and pillows while the treatment group had application of benzyl benzoate to mattresses and carpets in the bedroom and the most commonly used room, in addition to the above control measures. Mite allergen levels were measured 3 months and immediately before, 1 week, and 1 and 3 months after the application of house dust mite control measures. Patients kept diary cards on asthma symptoms and peak expiratory flow rates morning and evening one month before and three months after the onset of mite allergen control measures.\n A reduction of mite allergen level was found in mattress samples in both groups, statistically significant at all times in the treatment group and at one and three months in the control group. Mite allergen levels on floor carpets also showed progressive reduction in both groups, but were significantly different in the treatment group (compared with controls) at 1 week, and were lower compared with baseline in the treatment group up to 3 months. No significant changes in asthma symptoms, peak expiratory flow rates, spirometric measurements, or bronchial hyperresponsiveness were observed among treatment or control group subjects.\n The addition of benzyl benzoate to conventional house dust mite control measures resulted in a significant reduction in floor carpet dust mite levels that persisted for 3 months. The results of this study should be confirmed in a larger and longer study.", "The house dust mite is the most important environmental allergen implicated in the aetiology of childhood asthma in the UK. Dust mite barrier bedding is relatively inexpensive, convenient to use, and of proven effectiveness in reducing mattress house dust mite load, but no studies have evaluated its clinical effectiveness in the control of childhood asthma when dispensed in primary care. We therefore aimed to evaluate the effectiveness of house dust mite barrier bedding in children with asthma treated in primary care.\n Pragmatic, randomised, double-blind, placebo controlled trial conducted in eight family practices in England. Forty-seven children aged 5 to 14 years with confirmed house dust mite sensitive asthma were randomised to receive six months treatment with either house dust mite barrier or placebo bedding. Peak expiratory flow was the main outcome measure of interest; secondary outcome measures included asthma symptom scores and asthma medication usage.\n No difference was noted in mean monthly peak expiratory flow, asthma symptom score, medication usage or asthma consultations, between children who received active bedding and those who received placebo bedding.\n Treating house dust mite sensitive asthmatic children in primary care with house dust mite barrier bedding for six months failed to improve peak expiratory flow. Results strongly suggest that the intervention made no impact upon other clinical features of asthma.", "Exposure to high allergen levels in early life is a risk factor for the development of allergy. We previously reported limited effects of mite allergen impermeable mattress covers in the prevention and incidence of asthma and mite allergy (PIAMA) cohort at the age of 1 and 2 yr. We now present the results of follow-up at 4 yr objectives. To examine the effects of early reduction of house dust mite (HDM) allergen exposure by means of mattress covers on the incidence of allergy and asthma symptoms in the PIAMA birth cohort at the age of 4 yr. High-risk children (allergic mother) were prenatally recruited and randomly allocated to three groups; receiving mite allergen impermeable mattress covers (n = 416), placebo covers (n = 394) or no intervention (n = 472). At 4 yr of age, atopy was assessed by questionnaire; specific Immunoglobulin E (IgE) to inhalant and food allergens was measured in serum. Dust samples collected from the children's mattresses were analysed for mite allergens. Dermatophagoides farinae1 allergen (Der f 1) levels in dust were reduced in the active group. However, Dermatophagoides pteronissinus 1 (Der p 1) levels, sensitization and atopic symptoms were similar in all groups. We found no effect of mite allergen impermeable mattress covers on sensitization and atopy at 4 yr. Moreover, the allergen reducing effects of the covers had disappeared for one of the two mite allergens that were measured.", "The effect of two allergen avoidance modalities, Allergy Control Covers (ACC) and High Efficiency Particulate Filters (HEPA) on asthma control in children were evaluated. This was an open study involving 24 dust mite sensitive asthmatic children. Following a 4 week run-in period, the subjects were randomly allocated to use mattresses fitted with ACC (n = 6), HEPA filters in their bedrooms (n = 12) or act as controls (n = 6) for a study duration of 4 months. Measurements of the major Dermatophagoides spp. mite allergens, Der p 1 and Der f 1, levels in dust samples obtained from mattresses were made at baseline, 1, 2 and 4 months post implementation. Daily symptom scores including morning and evening peak flow readings, and monthly spirometry and exercise bronchoprovocation tests were carried out Our results showed that dust mite allergen levels in mattresses fell at 1 and 2 months post implementation in the ACC group (p<0.05). In contrast, no decrease in allergen levels was seen in the HEPA and control group. At the end of the 16 weeks, only the ACC group showed improvement in FEV1 and reduction in diurnal peak expiratory flow rate (p<0.05). Improvement in mean symptom scores was also observed for both the ACC and HEPA groups, but not the control groups (p<0.05). Although the numbers in this study were small, the results Indicate that the effectiveness on mite exposure barrier covers was short-lived, and the improvement in asthma control though documented was not obvious.", "Natamycin, a fungicide marketed as Tymasil, is claimed to reduce house dust mite numbers and would therefore be expected to improve asthma in children with mite sensitivity. We have tested this assertion by a double-blind, placebo-controlled trial. There was no significant effect on levels of Der p I in mattress dust between active and placebo groups at the end of the spraying period. Histamine inhalation challenge PC20, clinic visit symptom scores and lung function tests reflecting either large or small airways obstruction were also unchanged. Therefore this product is not a therapeutic option for mite-allergic patients using the manufacturer's recommended dose and method of administration. Other factors influencing the Der p I levels were also investigated. Of these, only month of measurement and bedroom wall humidity showed any association.", "To study the effect of controlling of house dusts in attacks of mite sensitive asthmatics (DMSA).\n Dust in mattresses, sofas, beddings and pillows were calculated for 43 cases of DMSA every season meanwhile the asthmatic symptoms, amount of drugs taken, PEF value in morning and evening were daily recorded by patients, then the patients were divided into two groups i.e. treatment group (A group, 22 cases) and no treatment group ( B group, 21 cases) randomly. The controlling measures included well-ventilation, washing clothes and bedclothes and catching dust frequently and exposing of clothing or bedclothes in the sun.\n Correlation was found between house dust density and asthmatic attacks. The number of dust mites was lower after treatment than before in A group [(N/g): spring 62 vs 103, summer 105 vs 132, autumn 163 vs 231, winter 9 vs 13]. Concomitant asthmatic symptoms and amount of drugs taken and total IgE reduced [(0.6 vs 1.6) mg/L] and PEF values or PEF difference improved.\n Control of dust mites growth could alleviate the asthmatic symptoms and decrease the attacks.", "The relationship between exposure to house dust mite (HDM) allergens and prevalence of sensitization to these allergens in patients with asthma has been confirmed in many studies. Mite population growth is regulated by humidity. Reducing humidity and removing allergen by efficient vacuuming should control mite allergen and reduce symptoms.\n We sought to investigate the effect of mechanical ventilation and high-efficiency vacuuming on HDM numbers and Der p 1 concentrations in the homes of mite-sensitive asthmatic subjects and to evaluate the effect of any reductions on symptoms.\n The homes of 40 HDM-sensitive asthmatic subjects were randomized to receive (1) mechanical ventilation and a high-efficiency vacuum cleaner (HEVC); (2) mechanical ventilation alone; (3) an HEVC alone; and (4) no intervention. Homes and patients were monitored for 12 months. Change in absolute humidity, mite numbers, Der p 1 concentrations, lung function, bronchial hyperresponsiveness, and symptom scores were analyzed.\n Homes with mechanical ventilation achieved significantly lower humidity levels than those without (P <.001), with an associated reduction of mite numbers (P <.05) and Der p 1 concentrations (P <.001 ¿in nanograms per gram, P =.006 ¿in milligrams per square meter) in bedroom carpets and some other mite sources in the ventilated areas of the homes. The addition of a vacuum cleaner enhanced this effect. There was a trend for an improvement in histamine PC(20) (P =.085) in the patients whose homes were ventilated.\n The use of a mechanical ventilation system in suitable homes resulted in some reduction in numbers of HDM and Der p 1 concentrations. The addition of an HEVC slightly enhanced the effect but not sufficiently to see an improvement in symptoms.", "Twenty one adult patients with asthma, with positive skin test responses to the European house dust mite, Dermatophagoides pteronyssinus, were randomly allocated to a control group or to a group applying house dust mite avoidance measures. These included an initial application of liquid nitrogen to mattresses and bedroom carpets to kill the live house dust mite population. Histamine airway responsiveness, symptom scores, peak expiratory flow rates (PEF), and house dust mite numbers were determined during the two week pretrial and eight week trial periods. Nine patients in each group completed the study. By the end of the study there was a significant reduction in live mites in the \"avoidance\" group but not in the control group. The avoidance group showed a significant improvement in symptom scores measured on a linear analogue scale, in the number of hours each day spent wheezing (mean reduced from 8.6 to 4.5 hours), and in PEF (l/min) both in the morning (from 364 to 388) and in the evening (from 368 to 392). These changes were not found in the control group. The provocative concentration (PC) of histamine causing a 20% fall in FEV1 (PC20FEV1) had increased significantly in the avoidance group at eight weeks (from 0.58 to 2.3 mg/ml), whereas no change was seen in the control group (from 0.93 to 1.21 mg/ml). These results show that house dust mite avoidance, combined with initial killing of the mite by liquid nitrogen, diminishes airway responsiveness and improves asthma symptom control over an eight week period in adult asthmatic patients with house dust mite allergy.", "The effects of supplementary computer instruction in house dust mite-avoidance measures on adherence to implementing measures, on home dust mite-allergen levels, and on symptomatology were investigated in 52 adult patients with mite-associated asthma. Twenty-six patients received conventional instruction (counseling and written instruction) and the other 26 patients received conventional plus 22 minutes of interactive computer-assisted instruction. Instructions were aimed at mite-avoidance measures. Pre- and postinstruction dust samples were collected, and adherence was monitored. All patients kept symptom diaries twice a day. Patients' progress was followed for 12 weeks, and all patients completed the study. Adherence, number of observed and self-reported mite-avoidance measures implemented after visit, was higher for the computer group (p = 0.023). The computer-instructed group achieved significantly lower levels of mite allergen in bedroom carpets (p = 0.004) with mean levels of mite allergen declining from 6.5 +/- 7.6 to 2.2 +/- 4.3 micrograms/gm of dust (two-site monoclonal antibody assays), whereas levels for the conventional-instructed group did not change. Moreover, by study weeks 9 and 10, the computer-instructed group was significantly less symptomatic (p = 0.033). Mean symptom scores for this group decreased from 12.4 to 7.7, compared with 16.4 to 14.3. Conventional instruction supplemented with computer instruction is suggested in mite education.", "Mattresses serve as a large reservoir for house-dust mite antigens and harbour the highest mite levels within the household. Mite reduction measures have previously been shown to be unsuccessful. The effect of mattress covers and acaracides on Der-p-1 levels in the mattresses of 60 patients with mite-allergic asthma was studied. Der-p-1 levels were measured using monoclonal antibodies (ELISA method). Baseline levels were recorded and re-assessed at 8-week intervals over a 6-month period. Patients were randomised into three equal groups. In group A mattresses were treated with Metsan (Snowchem) and benzylbenzoate only; group C had their mattresses covered with mattress covers (Allergy Control Products). Group B was the control group. We were unable to demonstrate any reduction of mite levels in the beds of all 3 groups. In fact all 3 groups demonstrated an increase in Der-p-1 levels over the study period, viz. group A (mean pre: 14.28, post: 34.18 micrograms/g dust); group C (mean pre: 8.26, post: 20.80 micrograms/g dust) and group B (mean pre: 18.21, post 38.47 micrograms/g dust). However, 12 patients in group C had their mattress covers washed in hot water at weekly intervals over a 5-week period at the end of the study. The results demonstrated a significant reduction in mite levels (mean pre: 41.95, post: 26.2 micrograms/g dust; P = 0.027). We therefore conclude that the use of mattress covers per se does not reduce Der-p-1 levels. The regular application of benzylbenzoate and Metsan does not prevent the accumulation of Der-p-1 on mattresses either.(ABSTRACT TRUNCATED AT 250 WORDS)", "Baseline levels of the house-dust mite allergen, Der p 1, were measured on the carpets and mattresses of 60 pure-mite-sensitive asthmatic children in the Cape Peninsula, by means of an enzyme-linked immunosorbent assay (ELISA). High levels of mite allergens were recorded (range 2-50 micrograms Der p 1/g dust). In order to investigate the efficacy of the application of acaricides to carpets and bedding, 3 groups of 20 children were studied. Carpets and mattresses in group A were treated with a detergent, Metsan (Snowchem), and in group B with Metsan combined with the acaricide, Acarosan (Noristan). Group C was a control group in which no treatment was applied. The level of airway hyperreactivity (PC20) to histamine was measured at the beginning of the study and again 3 months after acaricide treatment. Significant reductions in carpet Der p 1 levels were achieved in group A (22.83 v. 13.26 micrograms Der p 1/g dust; P = 0.04) and group B (21.76 v. 13.26 micrograms Der p 1/g dust; P = 0.01), but mite levels were not reduced in any of the mattresses treated. There was also no improvement in airway hyperreactivity in any of the groups. This study clearly demonstrates that at present it is not possible to reduce Der p 1 antigen levels in mattresses in the Cape Peninsula with the available acaricides, even when one of these is combined with a detergent solution. Until strategies are developed which will significantly reduce Der p 1 levels in the bedding of sensitive individuals, a reduction in ongoing airway inflammation and airway hyperreactivity cannot be expected.", "The efficacy of an air-cleaning device equipped with a high efficiency particulate air (HEPA) filter (without further avoidance measures) was studied in patients allergic to house dust mite. The effects of the air-cleaner on indoor Dermatophagoides sp. levels, symptom score and bronchial hyperresponsiveness in nine mite-allergic patients were assessed using a cross-over controlled study. No significant effect was demonstrated on indoor Dermatophagoides sp. levels when comparing the period of air-cleaner activity (2 months) with the control period (2 months). The Dermatophagoides sp. levels in the houses studied were lower than the risk level for asthmatic attacks, making it difficult to assess any effect on asthma; however, neither bronchial hyperresponsiveness nor rhinitis symptom score were changed by air-cleaner activity. During the trial period, however the mean level of Dermatophagoides sp. allergen in the houses changed spontaneously from 4.4 micrograms/g (mean level in the first 2 trial months) to 1.75 micrograms/g of dust (second 2 months) (P less than 0.05). Owing to this change, the mean rhinitis symptom score also decreased (P less than 0.05), even if no significant correlation was demonstrated (r = 0.4 P = 0.089). HEPA filter air-cleaners appear insufficient as substitutes for standard avoidance measures in mite allergic patients.", "Manufacturers of ionisers claim many benefits from the use of their devices, including the relief of asthma. Particles removed from the air are likely to include airborne allergens, so ionisers may achieve an effect by reducing the allergen load.\n The effect of ionisers on airborne concentrations of house dust mite allergen Der p I was investigated in a double blind, crossover, placebo controlled trial in the homes of 20 children with allergic asthma. Subjects recorded their peak expiratory flow rate (PEFR) twice daily and completed a daily symptom score and treatment schedule on a diary card for two six week periods, one with an active ioniser and the other with a placed ioniser (randomly allocated) used in the living room and the bedroom.\n Airborne Der p I concentrations fell significantly during the active period compared with the placebo period, but there was no significant change in PEFR, symptom scores, or treatment usage. There was an increase in night time cough which almost reached significance during the active period.\n This study indicates that the use of ionisers cannot be recommended in the homes of asthmatic subjects to improve their symptoms. The significant reduction of airborne allergen concentrations may be of use as part of a multidevice allergen avoidance regimen, but the increase in night time cough requires further study.", "House dust mite (HDM) allergens can accumulate to very high levels in homes. From the observed sensitivity of HDMs to heat and their allergens to steam, a novel treatment of furnishings has been developed.\n We sought to determine whether combined steam and heat treatment of home furnishings reduced asthmatic patients' bronchial hyperreactivity (BHR) and lowered HDM antigen loads.\n The homes of 30 asthmatic subjects aged 18 to 45 years were randomly allocated into 3 groups. In groups 1 and 2 mattresses and duvets were treated with hot air (110 degrees C), followed by steam and then heat again. All their carpets were steam cleaned. Group 2 also had a special ventilation system installed above each patient's bedroom. The homes of subjects in group 3 were sham treated. Neither patient nor laboratory staff was aware of the types of treatment. Der p 1 and 2 levels in the household dust from the lounge, bedroom carpet, and beds were determined before and after treatment and then at 6 and 12 months. BHR, measured by using histamine PD(20) values, was recorded during the 4-week run-in period and at 3, 6, 9, 12 months after treatment.\n Active heat-steam treatment of homes caused a sustained reduction of Der p 1 (P =.003) and Der p 2 (P =.001) compared with no change in sham-treated group 3 homes. Patients whose homes were treated showed a 4-fold reduction in BHR at 9 months in group 1 and throughout the posttreatment period in group 2. No change was observed in the asthmatic subjects whose homes were not treated. These improvements were sustained for 12 months in the homes with bedroom ventilation units.\n A single treatment of home furnishings reduced mite allergen load to below the risk level for sensitization and improved the asthmatic patients' BHR by 4-fold.", "Recommendations for allergen avoidance or allergen reduction measures play an important part in the treatment of allergic asthmatic patients. The purpose of this study was to test recently developed air-cleaners with respect to their capacity to capture airborne allergen particles and to improve clinical parameters of asthmatic patients sensitized to aeroallergens. Forty five allergic asthmatic patients were studied in a double-blind procedure for 6 months. The patients were divided into three groups of 15 patients. In Group 1, the intervention consisted of the application of active air-cleaners in living-rooms and bedrooms. In Group 2, placebo air-cleaners were used in combination with allergen-impermeable mattress covers. In Group 3, the same intervention was performed as in Group 2 but with active air-cleaners. Allergen levels in mattress and floor dust were measured before, and 3 and 6 months after the interventions. After 6 months, the air-cleaners were dismantled and the filters were analysed for the amount of dust collected and allergen content. Immunological and lung function parameters were measured before, and 3 and 6 months after the interventions. Considerable amounts of airborne dust and allergenic particles were captured in the filters of the air-cleaners. Up to the 18.9 g of dust, 4,513 ng of house dust mite allergen, Der p 1, and 50,000 mU of cat allergen, Fel d 1, (in houses with cats) were collected by air-cleaners in living-rooms. Only in Group 3 (in which both active air-cleaners and mattress covers were used) was a small (less than 1 doubling dose) but statistically significant improvement of provocative concentration of histamine causing a 20% fall in forced expiratory volume in one second (PC20) observed (from 5.96 to 9.02 mg x mL(-1)). The amount of dust and house dust mite allergen collected in the filters was significantly correlated with an improvement of peak flow variation. In combination with other allergen avoidance measures, the examined air-cleaners can contribute to diminished allergen exposure and improvement of airway hyperresponsiveness in asthmatic patients.", "A double blind controlled trial of Bencard HDM (Migen) for the prophylaxis of asthma in a group of Zambian asthmatics failed to show any benefit. The trial results suggest that asthmatics can benefit from regular supervision and the position of prophylactic and therapeutic medication.", "The major triggers for allergic asthma are exposure to allergens of the house dust mite, Dermatophagoides pteronyssinus, and of pets. Unfortunately studies of techniques designed to reduce house dust mite and pet allergens have had mixed results. However, new so-called 'improved' products continue to appear on the market and require subjective evaluation. The homes of 60 house dust mite-allergic patients were studied to compare the effects of high-efficiency and standard vacuum-cleaners on allergen concentration. Der p 1 (house dust mite), Fel d 1 (cat) and Can f 1 (dog) allergens were measured in four separate locations in each home. Clinical analysis was by lung function, bronchodilator usage and histamine challenge techniques. There was a significant reduction in Fel d 1 (ng/m2) in dust samples from the living-room carpet (p = 0.046), bedroom carpet (p = 0.003) and mattress (p = 0.013) and living-room sofa (p = 0.005) after 12 months of using the high-efficiency cleaners, but only in the mattress sample using the standard cleaners (p = 0.014). Can f 1 (ng/g dust) was reduced in the mattress sample after using the high-efficiency vacuum-cleaners (p = 0.028), but not at other sites. Der p 1 levels were not significantly changed over this period. Clinically, patients in the high-efficiency group showed improvements in peak expiratory flow rate (PEFR) (p = 0.004), FEV1 (p = 0.026) and bronchodilator usage (p = 0.005) after 12 months. When the cat-sensitive patients were analyzed separately, improvements in histamine PC20 (p = 0.039) were also seen. Reducing Fel d 1 concentrations, in the absence of any change in Der p 1 concentrations, can produce significant improvements in the lung function of atopic, asthmatic patients. This effect was primarily achieved in those patients with cat sensitivity, but who did not possess a cat themselves.", "Thirty-one adult patients with asthma caused by house-dust mites (HDM) were included in this placebo-controlled, double-blind study to evaluate the efficacy and safety of specific immunotherapy (SIT) with biologically standardized extracts of HDM. The specific diagnosis was confirmed by skin prick tests, specific IgE, and bronchial provocation tests with HDM allergens. The patients were randomized to receive active treatment with extracts of either Dermatophagoides pteronyssinus (Dpt) or D. farinae (Dfa) (Alutard SQ, ALK, Denmark) or placebo injections. Twenty-three patients completed the study. After 1 year of treatment, we found a clinically important and significant reduction in both asthma medicine consumption (inhaled steroids 38% and beta 2-agonists 46%) and symptom score (57%) in the actively treated group, but not the placebo group. These findings were confirmed by a significant decrease in skin and bronchial sensitivity to HDM in the active group. Additionally, there was a significant difference in the patients' scores for effect in favor of the actively treated group. Total IgE and specific IgE to HDM showed no significant changes before and after treatment for either group. Spirometric lung-function measurements showed a significant increase in forced expiratory volume in 1 s (FEV1) from 85% before to 89% of predicted values after treatment for the actively treated group. Peak-flow measurements at home showed no significant changes during the study. It is concluded that allergen SIT is an effective treatment in adult patients suffering from asthma due to HDM.", "A double blind, randomized, comparative study versus placebo, was done during 6 months in 32 children, aged 4-12 years, who suffer from either allergic asthma or rhinitis or both, slept in a bedroom rich in dust mite, have well documented allergy solely to house dust mite (H.D.M.), and a condition severe enough to require continuous medication. After thorough cleaning, their bedrooms were sprayed on day 0 and day 90 with the total content of a canister containing either Acardust or Placebo. Rooms were cleaned regularly throughout the study period. Each child completed an individual daily score card (scales from 0-3) for asthma, and rhinitis symptoms, medication taken, and any additional symptoms. Peak flow was recorded twice weekly. All the children were examined every month (at the clinic) when also PFF, FEVI, doctor's and patient's opinion of clinical symptoms were recorded according to the same scale (0-3) and dust samples from child's bedroom were examined for H.D.M. antigen content. At day 0, 90 and 180, total IgE and dust mite specific IgE determination was done. At the end of the study, patient's and doctor's opinion about the spray's efficacy were recorded on a scale from 0-3. The results were in favor of Acardust for asthma, according to patient's opinion (p = 0.001), doctor's opinion (p = 0.04) and individual score cards (p = 0.03), and for nasal secretion (p = 0.01), sneezing and lacrimation (p = 0.02); concurrent medication dropped significantly (p = 0.01) in the Acardust group. No side-effects were reported. We consider Acardust a safe and valuable preventive treatment in H.D.M. allergy.", "Exposure to allergens plays a role in the development of bronchial hyperresponsiveness and in the chronic inflammatory response seen in asthmatic patients. House dust mites (HDMs) are an important source of allergen. Reduction of these allergens might lead to better lung function and reduction of asthma symptoms.\n The effect of HDM-impermeable covers on HDM allergen levels, peak flow values, and asthma symptoms were measured. Therefore a randomized clinical trial was carried out.\n Fifty-two allergic asthmatic patients were randomly allocated to use the HDM-impermeable or placebo covers. During the study period, daily peak flow and asthma symptom scores were recorded. Dust samples were taken from the mattresses.\n We observed a significant reduction in HDM allergen levels on the mattresses after encasing them with HDM-impermeable covers (reduction of 87% of Der p 1 in micrograms per gram of dust; P <.001). Baseline symptoms were so low that no improvement could be established. Morning peak expiratory flow is significantly higher in the intervention group compared with that seen in the placebo group during the study period (beta=20.2; P <.01).\n HDM-impermeable covers significantly decreased the level of HDM allergens. Furthermore, morning peak flow was significantly increased during the intervention period. This study indicates that HDM allergen-avoidance measures might have beneficial effects on allergen reduction and asthma outcome.", "The safety and the efficacy of sublingual-swallow immunotherapy (SLIT) in perennial conjunctivitis caused by house dust mite were evaluated in a double-blind, placebo-controlled study including 60 patients for 24 months.\n Patients received either placebo or SLIT with standardized Dermatophagoides pteronyssinus (D.pt.) and D. farinae (D.f.) 50/50 extract. The evaluation of the efficacy of the SLIT was obtained by using standardized D. pteronyssinus (D.pt.) extracts on the antigen-specific conjunctival provocation test (CPT). Specific CPT, skin sensitivity and serum-specific IgE were performed before starting treatment and 6, 12, 18 and 24 months.\n Of the 60 patients included, only 45 completed the study (26 in the active group and 19 in the placebo group, P < 0.05). Two out of 30 (6.6%) patients dropped out because of insufficient efficacy in the active group compared to eight out of 30 (26.6%) in the placebo group (P < 0.05). There was a significant increase in the antigen threshold required to obtain a positive CPT from 8.2 IR [95% confidence interval (CI) 5.9-11.4] at baseline to 21.7 IR (95% CI 15.4-30.4) at 2 years (M24) in the active group, compared to 8.1 IR (95% CI 5.4-12.1) at baseline to 8.1 IR (95% CI 5.1-12.4) at M24 in the placebo group (P < 0.04 for overall treatment difference, P < 10-7 for the time-treatment interaction; repeated measures ANOVA). Differences between groups at individual time points were significant from 18 months on. Despite increased antigen concentrations, CPT scores were lower overall in the active than in the placebo group (P < 0.001). No serious adverse effects were reported.\n SLIT effectively increased the antigenic threshold required to obtain a positive CPT to house-dust mite antigen. Tolerance to and innocuity of SLIT were comparable to previous studies. This could justify recommending SLIT for the preventive treatment of perennial conjunctivitis caused by house dust mites.", "Anti-allergic mattress encasing may provide clinical benefit in asthmatic patients. However, the effect of mattress encasings on allergen-specific parameters, such as bronchial reactions to house dust mite (HDM) challenge, is not clear.\n To investigate the effect of anti-allergic mattress encasings on allergen sensitivity in patients with moderate to severe asthma.\n Twenty-seven patients with asthma and HDM allergy were studied in a double-blind, placebo-controlled study. Concentrations of Dermatophagoides pteronyssinus (Der p 1) were measured in mattress dust before and after 1 year of treatment; bronchial histamine challenge, bronchial challenge with HDM and intradermal skin challenges with HDM were performed. The number of eosinophils in peripheral blood was assessed.\n In the active group, but not in the placebo group, there was a significant reduction in Der p 1 concentration in the dust collected from the mattresses after 1 year of treatment compared to before. There was a significant difference between the groups with respect to HDM-induced early-reaction (ER) in the airways and the number of blood eosinophils, which reflected an increase in ER and eosinophils in the placebo group without significant change in the active group. No significant improvement in PC20 histamine, late-reaction (LR) and skin tests was found in either groups.\n Our data suggest that encasings protect against a further increase in allergen sensitivity in asthmatic patients, so their use should be recommended.", "The efficacy of the acaricide benzyl benzoate as an additive to a chemically and technically defined cleaning substance (Acarosan) was tested in a multicentric, prospective, randomized, controlled study on 118 outpatients with bronchial asthma due to house-dust-mite allergy. Subjective reports from patients and doctors revealed an improvement in clinical complaints in more than 50%, with only small differences between the verum and the placebo group. Objective parameters such as titrated skin tests, RAST, and bronchial challenge tests with histamine and Dermatophagoides pteronyssinus (D. pt.) did not reveal any significant changes either during the year of testing or between the two groups. A clinical improvement as observed in either group could not be assessed by objective parameters. Additional questions as to the merits of the possible prophylactic use of benzyl benzoate over more than 1 year remain unanswered.", "The effectiveness of avoidance of house-dust-mite allergen (Dermatophagoides pteronyssinus 1 [Der p1]) in the management of asthma is uncertain.\n We conducted a double-blind, randomized, placebo-controlled study of allergen-impermeable bed covers involving 1122 adults with asthma. The primary outcomes were the mean morning peak expiratory flow rate over a four-week period during the run-in phase and at six months and the proportion of patients who discontinued inhaled corticosteroid therapy as part of a phased-reduction program during months 7 through 12. Der p1 was measured in mattress dust in a 10 percent random subsample of homes at entry and at 6 and 12 months.\n The prevalence of sensitivity to dust-mite allergen was 65.4 percent in the group supplied with allergen-impermeable bed covers (active-intervention group) and 65.1 percent in the control group supplied with non-impermeable bed covers. The concentration of Der p1 in mattress dust was significantly lower in the active-intervention group at 6 months (geometric mean, 0.58 microg per gram vs. 1.71 microg per gram in the control group; P=0.01) but not at 12 months (1.05 microg per gram vs. 1.64 microg per gram; P=0.74). The mean morning peak expiratory flow rate improved significantly in both groups (from 410.7 to 419.1 liters per minute in the active-intervention group, P<0.001 for the change; and from 417.8 to 427.4 liters per minute in the control group, P<0.001 for the change). After adjustment for base-line differences (by analysis of covariance), there was no significant difference between the groups in the peak expiratory flow rate at six months (difference in means, active-intervention group vs. control group, -1.6 liters per minute [95 percent confidence interval, -5.9 to 2.7] among all patients [P=0.46] and -1.5 liters per minute [95 percent confidence interval, -6.9 to 3.9] among mite-sensitive patients [P=0.59]). There was no significant difference between the groups in the proportion in whom complete cessation of inhaled corticosteroid therapy was achieved (17.4 percent in the active-intervention group and 17.1 percent in the control group) or in the mean reduction in steroid dose, either among all patients or among mite-sensitive patients.\n Allergen-impermeable covers, as a single intervention for the avoidance of exposure to dust-mite allergen, seem clinically ineffective in adults with asthma.\n Copyright 2003 Massachusetts Medical Society", "nan", "The aim of this double-blind, randomized study was to investigate the effectiveness of an acaricidal cleaning product in modifying both clinical symptoms and mite allergen levels over a period of at least 1 year.\n Twenty-six asthmatic patients with proven Dermatophagoides pteronyssinus (Dp) asthma were selected; three were withdrawn from the trial. The patients' homes were divided into two groups; 11 homes were treated with solidified benzyl benzoate and tenside agents (A), and 12 were treated with a placebo (P). Two applications were performed at the beginning of the trial and at least 6 months later. Patients were examined 1 month before the trial, at the beginning of the trial, and every 3 months over a period of 1 year. Indoor mite exposure was evaluated by three methods: semiquantitative guanine determinations, quantitative guanine determinations, and the measurement of Der p I + Der f 1 (antigen P, of Dp + antigen F1 of D. farinae) levels.\n The symptom scores established at the beginning of the trial and 12 months later showed a statistically significant improvement only in the A group (p < 0.01). The visual analog scale also showed a statistically significant difference both in the A (p < 0.05) and P groups (p < 0.01). No statistical differences were found between medication scores in the A or P groups. A statistically significant increase was also observed for forced expiratory volume in 1 second and maximal expiratory flow rate 25/75 in the two groups (p < 0.05 for P group; p < 0.01 for A group). The mean decreases in Der p I + Der f 1 in patient mattresses between the beginning of the trial and after 12 months were 20% for the acaricide group and 17% for the placebo group, respectively (NS). For house dust samples with origins other than the patients' mattresses we found significant decreases in Der p I+Der f 1 in the A group (p < 0.01 for carpets and p < 0.05 for upholstery elements).", "Immunotherapy has been shown to reduce allergen sensitivity to allergens such as cat and dust mite. The aim of this study was to investigate the effect of cat or dust mite immunotherapy on bronchial hyperreactivity and the need for inhaled corticosteroids in children with asthma, cat or dust mite allergy, and hay fever.\n Twenty-nine children, 7 to 16 years old, completed the 3-year study. They were randomly allocated to receive cat/dust mite or placebo and birch/timothy immunotherapy.\n Before immunotherapy was begun and then once each year, bronchial histamine challenges were performed. Bronchial allergen challenge with the perennial allergen was done before and after the 3-year study. Pharmacotherapy was given according to a standardized protocol.\n PC20 allergen increased significantly in both the active immunotherapy group (P <.001) and in the placebo-pollen group (P <.05). PC20 histamine increased continuously in the active immunotherapy group (P <.05 and P =.002 after 1 and 3 years, respectively) and had also increased after 3 years in the placebo-pollen group (P <.05). The difference between the 2 groups was significant for PC20 allergen (P =.001) but not for PC20 histamine. There was no significant change in the dose of inhaled budesonide needed for symptom control in either of the groups.\n Pollen immunotherapy combined with inhaled corticosteroids results in improvement of both cat/dust mite bronchial sensitivity and hyperresponsiveness to histamine. The combination of cat or dust mite, pollen immunotherapy, and inhaled budesonide enhances this improvement. Cat immunotherapy also induces cat allergen tolerance.", "The warm, humid environment in modern homes favours the dust mite population, but the effect of improved home ventilation on asthma control has not been established. We tested the hypothesis that a domestic mechanical heat recovery ventilation system (MHRV), in addition to allergen avoidance measures, can improve asthma control by attenuating re-colonization rates.\n We conducted a randomized double-blind placebo-controlled parallel group trial of the installation of MHRV activated in half the homes of 120 adults with asthma, allergic to Dermatophagoides pteronyssinus. All homes had carpets steam cleaned and new bedding and mattress covers at baseline. The primary outcome was morning peak expiratory flow (PEF) at 12 months.\n At 12 months, the primary end-point; change in mean morning PEF as compared with baseline, did not differ between the MHRV group and the control group (mean difference 13.5 l/min, 95% CI: -2.6 to 29.8, P = 0.10). However, a secondary end-point; evening mean PEF, was significantly improved in the MHRV group (mean difference 24.5 l/min, 95% CI: 8.9-40.1, P = 0.002). Indoor relative humidity was reduced in MHRV homes, but there was no difference between the groups in Der p 1 levels, compared with baseline.\n The addition of MHRV to house dust mite eradication strategies did not achieve a reduction in mite allergen levels, but did improve evening PEF.", "Home mattresses of 24 asthmatic children with house dust mite allergy were sprayed with either benzyl-benzoate foam or placebo in a double blind fashion, 10 days before the children left the residential house for asthmatic children Istituto Pio XII (located in the Italian Alps in an environment free of mites) and went back to their own home for the Christmas and Easter holidays. A further group of 8 children, whose mattresses received no treatment, was kept as an absolute control. Two days after spraying, benzyl-benzoate or placebo were vacuumed from the mattresses. Acarex test was performed immediately before spraying and at the end of each holiday period of 20 and 10 days, respectively. Bronchial hyperreactivity as well as serum and nasal secretory specific IgE for Dermatophagoides pteronyssinus were assessed in all children immediately before leaving and within 48 hr after returning to the residential house. The results of the study show that sprayed benzyl-benzoate foam was no more effective than placebo in reducing the level of house dust mite recovered from patients' mattresses, or in reducing bronchial hyperreactivity and IgE concentration in serum and nasal secretions.", "Allergen avoidance is regarded as an important approach to management of atopic asthma. The effect of Intervent bed covering systems on house dust mite (HDM) allergen exposure, asthma symptoms and markers of inflammation was investigated in 31 HDM sensitive asthmatic children. Dust concentrations of Dermatophagoides pteronyssinus allergen 1 (Der p 1) were monitored before and after covering the mattress, duvet and pillow with active and placebo covers for 3 months, in a single-blind, cross-over trial. Twice daily peak expiratory flow rate (PEFR), daily symptom scores and treatment schedule were recorded. Bronchial hyperresponsiveness was monitored by histamine challenge (provocative concentration of histamine causing a 20% fall in forced expiratory volume in one second (PC20)), and inflammation by measuring eosinophil cationic protein (ECP), eosinophil protein X (EPX), eosinophil peroxidase (EPO), and soluble interleukin-2 receptor (sIL-2R) in serum. There was a significant reduction in Der p 1 when the mattress, duvet and pillow were covered with the active bedding. There was no significant improvement in symptoms of asthma, PEFR, bronchodilator usage of PC20. Also, ECP, EPX, sIL-2R concentrations did not change for either treatment. EPO concentrations were significantly lower in the active compared to the placebo period. The active bed covers reduced retrievable Dermatophagoides pteronyssinus allergen 1 (Der p 1) from the bedding, with short term clinical benefit.", "A cross-over controlled trial has been conducted among 32 adult patients with mite-sensitive asthma. The bedclothes and pillows of each subject were laundered and vacuum-cleaned and a plastic cover applied to the mattress for six weeks in an attempt to reduce exposure to mites. No improvement in daily peak-flow reading or drug usage was found in comparison with a control period." ]	Chemical and physical methods aimed at reducing exposure to house dust mite allergens cannot be recommended. It is doubtful whether further studies, similar to the ones in our review, are worthwhile. If other types of studies are considered, they should be methodologically rigorous and use other methods than those used so far, with careful monitoring of mite exposure and relevant clinical outcomes.
CD006207	[ "10969097", "19193267", "16153744", "16014825", "18519460", "10100548", "12737864", "15061941", "3033040", "10630654", "3039882", "21960187", "10742313", "3600729", "16231254", "20504841", "18498923", "19652172", "15297305", "1926024", "18823270", "2843040", "2225893", "12706704", "16708309", "3351266", "17177928", "16928714", "11642629", "1989570", "17018467", "10469764", "20528390", "21477089", "15006983", "16919803", "7426351", "10859037", "18461182", "17035445", "19811111", "3773177", "16918861", "4378136", "15249449", "15247610", "10645510", "19284644", "9269055", "9988287", "15236851", "18237352", "2348292", "14553868", "9279998", "10411194", "16569189", "20297744", "9616530", "1889273", "10493337" ]	[ "Nosocomial respiratory syncytial virus infections: the cost-effectiveness and cost-benefit of infection control.", "Face mask use and control of respiratory virus transmission in households.", "Using an integrated infection control strategy during outbreak control to minimize nosocomial infection of severe acute respiratory syndrome among healthcare workers.", "Rapid awareness and transmission of severe acute respiratory syndrome in Hanoi French Hospital, Vietnam.", "Reducing absenteeism from gastrointestinal and respiratory illness in elementary school students: a randomized, controlled trial of an infection-control intervention.", "Evaluation of a handwashing intervention to reduce respiratory illness rates in senior day-care centers.", "Effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome (SARS).", "[Effectiveness of personal protective measures in prevention of nosocomial transmission of severe acute respiratory syndrome].", "Prevention of colonization and respiratory infections in long-term ventilated patients by local antimicrobial prophylaxis.", "The effect of a respiratory home nurse intervention in patients with chronic obstructive pulmonary disease (COPD).", "Prevention of lower respiratory herpes simplex virus infection with acyclovir in patients with the adult respiratory distress syndrome.", "Cost-effectiveness of palivizumab for respiratory syncytial virus infection in high-risk children, based on long-term epidemiologic data from Austria.", "Effect of infection control measures on the frequency of upper respiratory infection in child care: a randomized, controlled trial.", "Prevention of nosocomial respiratory syncytial virus infections through compliance with glove and gown isolation precautions.", "Impact of rapid detection of viral and atypical bacterial pathogens by real-time polymerase chain reaction for patients with lower respiratory tract infection.", "Passive immunisation against respiratory syncytial virus: a cost-effectiveness analysis.", "Cost-effectiveness of palivizumab against respiratory syncytial viral infection in high-risk children in Austria.", "Facemasks and hand hygiene to prevent influenza transmission in households: a cluster randomized trial.", "Effectiveness of a multiple intervention to reduce antibiotic prescribing for respiratory tract symptoms in primary care: randomised controlled trial.", "Randomised controlled trial of the effectiveness of a respiratory health worker in reducing impairment, disability, and handicap due to chronic airflow limitation.", "Exploration of the effectiveness of social distancing on respiratory pathogen transmission implicates environmental contributions.", "Efficacy of virucidal nasal tissues in interrupting familial transmission of respiratory agents. A field trial in Tecumseh, Michigan.", "Prevention of nosocomial lung infection in ventilated patients: use of an antimicrobial pharyngeal nonabsorbable paste.", "Efficacy trial of live, cold-adapted and inactivated influenza virus vaccines in older adults with chronic obstructive pulmonary disease: a VA cooperative study.", "Communication training and antibiotic use in acute respiratory tract infections. A cluster randomised controlled trial in general practice.", "Prevention of nosocomial transmission of respiratory syncytial virus in a newborn nursery.", "Adoption of a ventilator-associated pneumonia clinical practice guideline.", "Reducing door-to-antibiotic time in community-acquired pneumonia: Controlled before-and-after evaluation and cost-effectiveness analysis.", "Effect of a conjugate pneumococcal vaccine on the occurrence of respiratory infections and antibiotic use in day-care center attendees.", "Effectiveness of psychoeducational interventions in reducing emotional distress after human immunodeficiency virus antibody testing.", "Cost-effectiveness analysis of palivizumab in premature infants without chronic lung disease.", "Cost-effectiveness of respiratory syncytial virus prophylaxis among preterm infants.", "Cost-effectiveness of palivizumab in infancy.", "Cost-effectiveness analysis of palivizumab as respiratory syncytial virus prophylaxis in preterm infants in Sweden.", "Dispersal of respiratory droplets with open vs closed oxygen delivery masks: implications for the transmission of severe acute respiratory syndrome.", "A brief individualized computer-delivered sexual risk reduction intervention increases HIV/AIDS preventive behavior.", "A study of live influenza virus vaccine in patients with chronic bronchitis. Report to Medical Research Council's Committee on Influenza and Other Respiratory Virus Vaccines. Advisory Group on pulmonary function tests in relation to live influenza virus vaccines.", "Early use of non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease on general respiratory wards: a multicentre randomised controlled trial.", "Preliminary findings of a randomized trial of non-pharmaceutical interventions to prevent influenza transmission in households.", "Impact of a winter respiratory virus season on patients with COPD and association with influenza vaccination.", "Cost effectiveness of palivizumab for RSV prevention in high-risk children in the Netherlands.", "The use of eye-nose goggles to control nosocomial respiratory syncytial virus infection.", "Using school staff to establish a preventive network of care to improve elementary school students' control of asthma.", "Live and inactivated adenovirus vaccines. Clinical evaluation of efficacy in prevention of acute respiratory disease.", "Limited impact of a multicenter intervention to improve the quality and efficiency of pneumonia care.", "Influence of school closure on the incidence of viral respiratory diseases among children and on health care utilization.", "An evaluation of statewide strategies to reduce antibiotic overuse.", "Which preventive measures might protect health care workers from SARS?", "Efficacy of repeated annual immunization with inactivated influenza virus vaccines over a five year period.", "Effectiveness of inactivated influenza vaccine among nursing home residents during an influenza type A (H3N2) epidemic.", "Reducing ventilator-associated pneumonia rates through a staff education programme.", "Strategies for improving the quality of health care in maternal and child health in low- and middle-income countries: an overview of systematic reviews.", "Screening for respiratory syncytial virus and assignment to a cohort at admission to reduce nosocomial transmission.", "Implementation of an evidence-based guideline to reduce duration of intravenous antibiotic therapy and length of stay for patients hospitalized with community-acquired pneumonia: a randomized controlled trial.", "Impacts of training of village health volunteers in reduction of morbidity from acute respiratory infections in childhood in southern Thailand.", "Effectiveness of live, attenuated intranasal influenza virus vaccine in healthy, working adults: a randomized controlled trial.", "Use of an 'evidence-based implementation' strategy to implement evidence-based care of asthma into rural district hospital emergency departments.", "Impact of non-pharmaceutical interventions on URIs and influenza in crowded, urban households.", "One-year economic evaluation of intensive vs conventional patient education and supervision for self-management of new asthmatic patients.", "Antibiotic prophylaxis of respiratory tract infection in mechanically ventilated patients. A prospective, blinded, randomized trial of the effect of a novel regimen.", "Randomized, placebo-controlled double blind study on the efficacy of influenza immunization on absenteeism of health care workers." ]	[ "To determine the cost-effectiveness and cost-benefit of an infection control program to reduce nosocomial respiratory syncytial virus (RSV) transmission in a large pediatric hospital.\n RSV nosocomial infection (NI) was studied for 8 years, before and after intervention with a targeted infection control program. The cost-effectiveness of the intervention was calculated, and cost-benefit was estimated by a case-control comparison.\n Children's Hospital of Philadelphia, a 304-bed pediatric hospital.\n All inpatients with RSV infection, both community- and hospital-acquired.\n Consisted of early recognition of patients with respiratory symptoms, confirmation of RSV infection by laboratory testing, establishing cohorts of patients and nursing staff, gown and glove barrier precautions, and monitoring and education of staff.\n The incidence density of RSV NI before and after the intervention was calculated as the rate per 1000 patient days-at-risk for infection. Intervention costs included laboratory testing, isolation, and administration of the program. The cost of RSV NI was estimated by comparing hospital charges for 30 cases and matched uninfected controls.\n A total of 148 patients acquired NI (88 before and 60 after the intervention). The Mantel-Haenszel stratified relative risk for NI in the period before the infection control program, compared with the postintervention period, was.61 (95% confidence interval:.53-.69). By applying the preintervention stratum-specific rates of infection to the days-at-risk in the postintervention period, an estimated 100 NIs would have been expected, which in comparison to the 60 NIs observed, yielded an estimated program effectiveness of 10 RSV NIs prevented per season. The total cost of the program per season was $15 627 or $1,563/NI prevented. In comparison, the mean cost to the hospital was $9,419/case of RSV NI, resulting in a cost-benefit ratio of 1:6.\n A targeted infection control intervention was cost-effective in reducing the rate of RSV NI. For every dollar spent on the program, approximately $6 was saved.", "Many countries are stockpiling face masks for use as a nonpharmaceutical intervention to control virus transmission during an influenza pandemic. We conducted a prospective cluster-randomized trial comparing surgical masks, non-fit-tested P2 masks, and no masks in prevention of influenza-like illness (ILI) in households. Mask use adherence was self-reported. During the 2006 and 2007 winter seasons, 286 exposed adults from 143 households who had been exposed to a child with clinical respiratory illness were recruited. We found that adherence to mask use significantly reduced the risk for ILI-associated infection, but <50% of participants wore masks most of the time. We concluded that household use of face masks is associated with low adherence and is ineffective for controlling seasonal respiratory disease. However, during a severe pandemic when use of face masks might be greater, pandemic transmission in households could be reduced.", "Healthcare workers (HCWs) are at risk of acquiring severe acute respiratory syndrome (SARS) while caring for SARS patients. Personal protective equipment and negative pressure isolation rooms (NPIRs) have not been completely successful in protecting HCWs. We introduced an innovative, integrated infection control strategy involving triaging patients using barriers, zones of risk, and extensive installation of alcohol dispensers for glove-on hand rubbing. This integrated infection control approach was implemented at a SARS designated hospital ('study hospital') where NPIRs were not available. The number of HCWs who contracted SARS in the study hospital was compared with the number of HCWs who contracted SARS in 86 Taiwan hospitals that did not use the integrated infection control strategy. Two HCWs contracted SARS in the study hospital (0.03 cases/bed) compared with 93 HCWs in the other hospitals (0.13 cases/bed) during the same three-week period. Our strategy appeared to be effective in reducing the incidence of HCWs contracting SARS. The advantages included rapid implementation without NPIRs, flexibility to transfer patients, and re-inforcement for HCWs to comply with infection control procedures, especially handwashing. The efficacy and low cost are major advantages, especially in countries with large populations at risk and fewer economic resources.", "A case-control study was conducted to examine the relationship between severe acute respiratory syndrome (SARS) and the time-dependent precautionary behaviors taken during an outbreak of SARS in Hanoi French Hospital (HFH), Vietnam. Masks (odds ratio [OR] = 0.3; 95% confidence interval [CI]: 0.1, 0.7) and gowns (OR = 0.2; 95% CI: 0.0, 0.8) appeared to prevent SARS transmission. The proportion of doctors and nurses who undertook each measure significantly improved (chi(2) = 9.8551, P = 0.043) after the onset of secondary cases. The impact of individual behaviors on an outbreak was investigated through mathematical approaches. The reproduction number decreased from 4.1 to 0.7 after notification. The basic reproduction number was estimated, and the use of masks alone was shown to be insufficient in containing an epidemic. Intuitive results obtained by means of stochastic individual-based simulations showed that rapid improvements in behavior and isolation would increase the probability of extinction.", "Students often miss school because of gastrointestinal and respiratory illnesses. We assessed the effectiveness of a multifactorial intervention, including alcohol-based hand-sanitizer and surface disinfection, in reducing absenteeism caused by gastrointestinal and respiratory illnesses in elementary school students.\n We performed a school-based cluster-randomized, controlled trial at a single elementary school. Eligible students in third to fifth grade were enrolled. Intervention classrooms received alcohol-based hand sanitizer to use at school and quaternary ammonium wipes to disinfect classroom surfaces daily for 8 weeks; control classrooms followed usual hand-washing and cleaning practices. Parents completed a preintervention demographic survey. Absences were recorded along with the reason for absence. Swabs of environmental surfaces were evaluated by bacterial culture and polymerase chain reaction for norovirus, respiratory syncytial virus, influenza, and parainfluenza 3. The primary outcomes were rates of absenteeism caused by gastrointestinal or respiratory illness. Days absent were modeled as correlated Poisson variables and compared between groups by using generalized estimating equations. Analyses were adjusted for family size, race, health status, and home sanitizer use. We also compared the presence of viruses and the total bacterial colony counts on several classroom surfaces.\n A total of 285 students were randomly assigned; baseline demographics were similar in the 2 groups. The adjusted absenteeism rate for gastrointestinal illness was significantly lower in the intervention-group subjects compared with control subjects. The adjusted absenteeism rate for respiratory illness was not significantly different between groups. Norovirus was the only virus detected and was found less frequently on surfaces in intervention classrooms compared with control classrooms (9% vs 29%).\n A multifactorial intervention including hand sanitizer and surface disinfection reduced absenteeism caused by gastrointestinal illness in elementary school students. Norovirus was found less often on classroom surfaces in the intervention group. Schools should consider adopting these practices to reduce days lost to common illnesses.", "To decrease respiratory infections in senior day care, staff were educated on viral transmission and the value of hand washing. Fanny packs with alcohol foam supplemented hand washing and were alternated monthly between centers. Infection rates were unchanged with alcohol foam use. The intervention year's infection rate was significantly lower than the previous 3 years, suggesting a benefit of education.", "We did a case-control study in five Hong Kong hospitals, with 241 non-infected and 13 infected staff with documented exposures to 11 index patients with severe acute respiratory syndrome (SARS) during patient care. All participants were surveyed about use of mask, gloves, gowns, and hand-washing, as recommended under droplets and contact precautions when caring for index patients with SARS. 69 staff who reported use of all four measures were not infected, whereas all infected staff had omitted at least one measure (p=0.0224). Fewer staff who wore masks (p=0.0001), gowns (p=0.006), and washed their hands (p=0.047) became infected compared with those who didn't, but stepwise logistic regression was significant only for masks (p=0.011). Practice of droplets precaution and contact precaution is adequate in significantly reducing the risk of infection after exposures to patients with SARS. The protective role of the mask suggests that in hospitals, infection is transmitted by droplets.", "To evaluate the effectiveness of personal protective measures of health care workers (HCWs) against severe acute respiratory syndrome (SARS).\n A case-control study from ten hospitals in Guangdong, with 180 non-infected and 77 infected staff members that accessed the isolation unit every day, and participated in direct first aid for severe SARS patients. All participants were surveyed about how they were using personal protective equipment (PPE), protective drugs and hygiene habits when caring for patients with SARS. Statistical analysis was done with either chi(2) or Fisher's exact test for univariate analysis, whereas we used forward stepwise selection (Waldesian) for logistic regression.\n Univariate analysis showed that mask, gown, gloves, goggles, footwear, \"hand-washing and disinfecting\", gargle, \"membrane protection\", \"taking shower and changing clothing after work\", \"avoid from eating and drinking in ward\", oseltamivir phospha tall had protective effects (P < 0.05), but stepwise logistic regression showed significant differences for mask (OR = 0.78, 95% CI: 0.60 - 0.99), goggles (OR = 0.20, 95% CI: 0.10 - 0.41) and footwear (OR = 0.58, 95% CI: 0.39 - 0.86). Analysis for linear trend in proportions showed that dose response relationship existed in mask, gown, gloves, goggles, footwear, gargle, \"membrane protection\" and \"taking shower and changing dree after work\" (P < 0.01). The attack rate of HCWs who were rescuing severe SARS patients without any PPE was 61.5% (16/26). It seemed that the more the protective measures were used, the higher the protective effect was (P < 0.001), and could reach 100% if mask, gown, gloves, goggles, footwear, \"hand-washing and disinfecting\" were all used at the same time.\n Nosocomial infection of SARS can be prevented effectively by precautions against droplets and personal contact. HCWs must take strict protection according to the guidance of WHO or Chinese MOH and pay attention to personal hygiene.", "In a randomized clinical trial the prophylactic effects of locally administered antimicrobials on quantitative colonization and respiratory infections were studied in intubated patients with an expected period of mechanical ventilation of greater than 6 days. Nineteen patients received 50 mg of polymyxin B and 80 mg of gentamicin distributed among nose, oropharynx and stomach at 6-h intervals, as well as 300 mg of amphotericin B in the oropharynx. Twenty untreated patients served as controls. In the control group colonization by respiratory pathogens was more common (oropharynx 19 vs 6 patients (p less than 0.001); trachea 19 vs 11 (p less than 0.01)), and the number as well as the count of the colonizing species was usually higher. Fourteen patients of the control group developed respiratory infections, including nine cases of pneumonia, as compared to four patients with prophylaxis, including one case of pneumonia (p less than 0.01). Pneumonia-associated deaths were prevented with prophylaxis; however, the overall mortality remained unchanged. Respiratory infections in the prophylaxis group were associated with organisms resistant to the agents used, but the overall occurrence of resistance was not increased, as compared to the control group. We conclude that unrestrained upper airway colonization by respiratory pathogens and respiratory tract infection were causally related. Local antimicrobial prophylaxis proved to be a highly effective strategy for the prevention of potentially life-threatening pneumonias in critically ill patients, but in the present study the host setting appeared to be the major determinant of outcome.", "Chronic obstructive pulmomary disease (COPD) is associated with substantial mortality, morbidity, and costs to the health care system. With the increasing interest in outreach care programmes it is important to evaluate their impact upon patients and health services, for conditions such as COPD.\n To determine the effectiveness of an outreach respiratory nurse in a shared care approach, with collaboration between general practitioners and hospital services, in the management of patients with severe COPD.\n Patients with severe COPD attending The Queen Elizabeth Hospital, Adelaide participated in a randomised controlled trial of a home based nursing intervention (HBNI) over 12 months with outcome measures including mortality rate, hospital service utilisation, FEV1 and health related quality of life (HRQL) using a modified Dartmouth Primary Care Co-operative Quality of Life questionnaire.\n There were 48 subjects in each study arm, with no differences in mortality rate (eight deaths in the HBNI group and seven in the control group), hospital admissions, length of stay, number of outpatient and Emergency Service visits. The study had inadequate follow-up of FEV1 and HRQL within the control group. Within the HBNI group, a small improvement in HRQL (in three of ten indices measured) was demonstrated, despite a deterioration in FEV1 (11% reduction, p=0.04) compared to baseline. Quality of life of HBNI subjects' carers did not change.\n An increased level of care given by an outreach respiratory nurse in a shared care approach for patients with severe COPD produced small improvements in HRQL but did not result in the prevention of deaths or reduced health care utilisation.", "Herpes simplex virus (HSV) type I commonly occurs in the lower respiratory tract (LRT) of seriously ill patients, particularly those with the adult respiratory distress syndrome (ARDS), but it is not known whether HSV is a benign mucosal colonizer or a pathogen. The aims of this study were to determine whether the antiviral agent acyclovir could prevent this occurrence, and if so, whether prevention improved the outcome. Forty-five patients with ARDS underwent double-blind randomization into a treatment group (22 subjects) who received prophylactic acyclovir intravenously, 5 mg/kg every 8 h, and a control group (23 subjects). Upper and lower respiratory secretions were examined for the presence of HSV before randomization and twice weekly thereafter. Seven patients were excluded because of HSV detection prior to treatment. There were no significant differences between the remaining 17 acyclovir and 21 control patients in age, sex, distribution of primary diagnostic categories, and severity of primary illness. Only 1 patient (6%) in the acyclovir group developed HSV after treatment compared with 15 (71%) in the control group (p less than 0.001), but there was no improvement in the acyclovir group in the severity of respiratory failure, the duration of ventilator support (acyclovir, 20 +/- 19 days; control, 14 +/- 11 days), or mortality (acyclovir, 8 of 17, 47%; control, 9 of 21, 43%). We conclude that acyclovir is effective in preventing the high incidence of HSV in patients with ARDS, but that this prevention does not improve outcome. Routine prophylaxis of HSV is not recommended.", "To assess the cost-effectiveness of palivizumab, a monoclonal antibody against respiratory syncytial virus (RSV), in infants at high risk for severe RSV lower respiratory tract infection, such as premature infants, infants with bronchopulmonary dysplasia, and those with congenital heart disease, based on long-term epidemiologic data from Austria.\n A decision-tree model was used, and the analysis was based on a lifetime follow-up investigating cost-effectiveness of palivizumab versus no RSV infection prevention. The primary perspective of the study was that of the healthcare system, the second that of society. Cost and effects were discounted by 5%. The base case analysis included only direct medical costs, and a scenario analysis included various indirect costs.\n Analyses were based on epidemiologic data on a total of 1579 children hospitalized because of RSV lower respiratory tract infection during 16 seasons. The incremental cost-effectiveness ratio for the first outcome measure (life years gained) amounted to discounted costs of €34,956 (for all preterm infants), €35,056 (for < 33 weeks' gestational age [wGA] infants), €35,233 (for 33-35 wGA infants), €35,611 (for infants with bronchopulmonary dysplasia), and €8956 (for infants with congenital heart disease). Use of palivizumab compared with no prophylaxis had an incremental cost-utility ratio of €26,212, €26,292, €24,392, €24,654, and €8484, respectively, per quality-adjusted life years. Results from the society perspective were more cost-effective in all study populations. An additional scenario analysis with 7 injections for the 33 to 35 wGA group revealed cost-effectiveness as well.\n Our results based on nationwide long-term epidemiologic data suggest that palivizumab is cost-effective in prevention of RSV disease in high-risk infants.", "Acute upper respiratory infections are common in children who attend child care, and preventing transmission of disease in this setting depends on actions by child care staff. We set out to discover whether transmission of respiratory infections in child care could be reduced by improved infection control procedures.\n We performed a cluster, randomized, controlled trial of an infection control intervention conducted in child care centers in 1 city in Australia. The intervention was training of child care staff about transmission of infection, handwashing, and aseptic nosewiping technique. Implementation of the intervention was recorded by an observer. Illness was measured by parent report in telephone interviews every 2 weeks.\n There were 311 child-years of surveillance for respiratory symptoms. By multivariable analysis, there was no significant reduction in colds in intervention center children across the full age range. However, a significant reduction in respiratory illness was present in children 24 months of age and younger. When compliance with infection control practices was high, colds in these children were reduced by 17%.\n This trial supports the role of direct transmission of colds in young children in child care. The ability of infection control techniques to reduce episodes of colds in children in child care was limited to children 24 months of age and under.", "To determine whether increased compliance with a policy of glove and gown isolation precautions could reduce the high rate of nosocomial respiratory syncytial virus (RSV) infection on an infant and toddler ward, we conducted a longitudinal intervention trial during three RSV seasons, from 1982 to 1985, with an intervention to increase compliance introduced midway through the second season. The risk of acquiring RSV infection in the hospital was adjusted for the intensity of nosocomial exposure to the virus by assigning each study week to one of five strata, defined by the proportion of hospital days on which virus was shed by children on the ward. Overall, 37 patients acquired nosocomial RSV infections during 7547 days at risk. The adjusted relative risk, comparing the infection rate in the period before the intervention (when compliance with isolation precautions was noted in only 38.5 percent of the observed patient contacts) with the infection rate in the postintervention period (when compliance more than doubled) was 2.9 (95 percent confidence interval, 1.5 to 5.7). Rates of nosocomial RSV infection increased linearly with increasing levels of exposure to patients shedding virus, but the rise in the infection rate with increasing exposure was less than one fourth as great (P less than 0.001) in the period after the intervention as it was before. We conclude that glove and gown precautions can substantially reduce the nosocomial transmission of RSV, particularly with increasing exposure to patients shedding the virus.", "Rapid diagnostic tests with a high sensitivity for lower respiratory tract infection (LRTI) could lead to improved patient care and reduce unnecessary antibiotic use and associated costs. Diagnostic yields, feasibility, and costs of real-time polymerase chain reaction (PCR) of nasopharyngeal and oropharyngeal swab specimens in the routine diagnostic work-up for LRTI were determined.\n In a randomized controlled trial, nasopharyngeal and oropharyngeal swab specimens from patients admitted for antibiotic treatment of LRTI were evaluated by means of real-time PCR for respiratory viruses and atypical pathogens, as well as by conventional diagnostic procedures. Real-time PCR results for patients in the intervention group were reported to the treating physician; results for patients in the control group were not made available.\n A total of 107 patients (mean age [+/- standard deviation], 63.6+/-16.3 years) were included, of whom 55 were allocated to the intervention group. The pathogens detected most frequently were influenza virus (14 patients), Streptococcus pneumoniae (8), coronavirus (6), Staphylococcus aureus (5), and rhinoviruses (5). Real-time PCR increased the diagnostic yield from 23 cases (21% of patients) to 47 cases (43% of patients), compared with conventional diagnostic tests. The detection of viral pathogens by PCR was associated with the winter season, less infiltrates on chest radiographs, lower C-reactive protein levels, and shorter duration of symptoms. Use of real-time PCR results resulted in partial or total cessation of antibiotic treatment for 6 patients (11%; 95% confidence interval, 2-19), but overall antibiotic use was comparable in the intervention group and the control group (median duration of treatment, 10.0 vs. 9.0 days; P=not significant). Use of real-time PCR increased treatment and diagnostic costs with 318.17 per patient.\n Implementation of real-time PCR for the etiological diagnosis of LRTI increased the diagnostic yield considerably, but it did not reduce antibiotic use or costs.", "The cost-effectiveness of passive immunisation against respiratory syncytial virus (RSV) in the Netherlands was studied by assessing incremental costs to prevent one hospitalisation in high-risk children using a novel individualised monthly approach.\n Cost-effectiveness analysis was performed by combining estimates of individual hospitalisation costs and monthly hospitalisation risks, with immunisation costs, parental costs and efficacy of passive immunisation for a reference case with the highest hospitalisation risks and costs of hospitalisation during the RSV season (male, gestational age < or =28 weeks, birth weight < or =2500 g, having bronchopulmonary dysplasia (BPD), aged 0 months at the beginning of the season (October)). Various sensitivity analyses and a cost-neutrality analysis were performed.\n Cost-effectiveness of passive immunisation varied widely by child characteristics and seasonal month. For the reference case it was most cost effective in December at euro13,190 per hospitalisation averted. Cost-effectiveness was most sensitive to changes in hospitalisation risk. For the reference case, cost neutrality was reached in December, if acquisition costs of passive immunisation decreased from euro 930 to euro 375, monthly hospitalisation risk increased from 7.6% to 17%, or hospitalisation costs increased from euro 10 250 to euro 23 250 per hospitalisation. Even if passive immunisation prevented all hospitalisations, costs per hospitalisation averted in December would still exceed euro 2645.\n Although cost-effectiveness of passive immunisation varied strongly by child characteristics and seasonal month, incremental costs per hospitalisation averted were always high. A restrictive immunisation policy only immunising children with BPD in high-risk months is therefore recommended. The costs of passive immunisation would have to be considerably reduced to achieve cost-effectiveness.", "The aim of this study was to estimate the cost-effectiveness of palivizumab, a monoclonal antibody against severe respiratory syncytial virus infection, in high-risk infants in Austria.\n A decision tree model was developed to determine cost-effectiveness in infants born prematurely (<or=35 weeks' gestational age), those with bronchopulmonary dysplasia (BPD), and children with congenital heart disease (CHD). The primary perspective of the analysis was that of the compulsory health insurance fund. The societal perspective was also considered.\n From the health insurance fund perspective, including the costs associated with asthma, the incremental cost-effectiveness ratio (cost per quality-adjusted life year [QALY] gained) without discounting was estimated to be euro 4484 (2006 euros) in preterm infants, euro 6719 in children with BPD, and euro 2668 in the CHD population. When discounted, these figures increased to euro 14,439, euro 21,672, and euro 9754, respectively. The results from the societal perspective were substantially more cost-effective in all populations. The undiscounted cost per QALY was euro 1435 in preterm infants, euro 4881 in children with BPD, and euro 251 in the CHD group. Discounted figures were euro 4623, euro 15,741, and euro 917, respectively. Sensitivity analyses confirmed the robustness of the model, and scenario analyses found that the inclusion of indirect costs led to further improvement in the cost-effectiveness outcomes for palivizumab.\n Use of palivizumab was cost-effective compared with no prophylaxis in high-risk infants and children in Austria.", "Few data are available about the effectiveness of nonpharmaceutical interventions for preventing influenza virus transmission.\n To investigate whether hand hygiene and use of facemasks prevents household transmission of influenza.\n Cluster randomized, controlled trial. Randomization was computer generated; allocation was concealed from treating physicians and clinics and implemented by study nurses at the time of the initial household visit. Participants and personnel administering the interventions were not blinded to group assignment. (ClinicalTrials.gov registration number: NCT00425893)\n Households in Hong Kong.\n 407 people presenting to outpatient clinics with influenza-like illness who were positive for influenza A or B virus by rapid testing (index patients) and 794 household members (contacts) in 259 households.\n Lifestyle education (control) (134 households), hand hygiene (136 households), or surgical facemasks plus hand hygiene (137 households) for all household members.\n Influenza virus infection in contacts, as confirmed by reverse-transcription polymerase chain reaction (RT-PCR) or diagnosed clinically after 7 days.\n Sixty (8%) contacts in the 259 households had RT-PCR-confirmed influenza virus infection in the 7 days after intervention. Hand hygiene with or without facemasks seemed to reduce influenza transmission, but the differences compared with the control group were not significant. In 154 households in which interventions were implemented within 36 hours of symptom onset in the index patient, transmission of RT-PCR-confirmed infection seemed reduced, an effect attributable to fewer infections among participants using facemasks plus hand hygiene (adjusted odds ratio, 0.33 [95% CI, 0.13 to 0.87]). Adherence to interventions varied.\n The delay from index patient symptom onset to intervention and variable adherence may have mitigated intervention effectiveness.\n Hand hygiene and facemasks seemed to prevent household transmission of influenza virus when implemented within 36 hours of index patient symptom onset. These findings suggest that nonpharmaceutical interventions are important for mitigation of pandemic and interpandemic influenza.\n Centers for Disease Control and Prevention.", "To assess the effectiveness of a multiple intervention aimed at reducing antibiotic prescription rates for symptoms of the respiratory tract in primary care.\n Randomised controlled trial.\n Twelve peer review groups including 100 general practitioners with their collaborating pharmacists in the region of Utrecht, Netherlands.\n The intervention consisted of group education meetings, with a consensus procedure on indication for and type of antibiotics and with training in communication skills; monitoring and feedback on prescribing behaviour; group education for assistants of general practitioners and pharmacists; and education material for patients. The control group did not receive any of these elements.\n Antibiotic prescription rates for acute symptoms of the respiratory tract and patients' satisfaction.\n 89 general practitioners completed the study (89%). At baseline, prescription rates for antibiotics for respiratory tract symptoms did not differ between intervention and control group (27% v 29%, respectively). After nine months, the prescription rates in the intervention group fell to 23%, whereas the control group's rose to 37% (mean difference in change -12%, 95% confidence interval -18.9% to -4.0%). Multilevel analysis confirmed the results of the unadjusted analysis (intervention effect -10.7%, -20.3% to -1.0%). Patients' satisfaction was high and did not differ in the two groups at baseline or after the intervention.\n A multiple intervention reduced prescribing rates of antibiotics for respiratory tract symptoms while maintaining a high degree of satisfaction among patients. Further research should focus on the sustainability and cost effectiveness of this intervention.", "A randomised controlled trial was undertaken to determine whether a respiratory health worker was effective in reducing the respiratory impairment, disability, and handicap experienced by patients with chronic airflow limitation attending a respiratory outpatient department. The 152 adults (aged 30-75 years) who participated had a prebronchodilator forced expiratory volume in one second (FEV1) below 60% predicted and no other disease. They were randomised to receive the care of a respiratory health worker or the normal services provided by the outpatient department. The respiratory health worker provided health education and symptom and treatment monitoring in liaison with primary care services. After one year there was little difference between the two groups in spirometric values (FEV1 and forced vital capacity before and after salbutamol 200 micrograms), disability (six minute walking distance and paced step test), and handicap (sickness impact profile, hospital anxiety and depression scale). Patients not looked after by the respiratory health worker were more likely to die (relative risk 2.9 (95% confidence limits 0.8, 10.2); when age and FEV1 were controlled for this risk increased to 5.5 (95% confidence limits 1.2, 24.5). Patients looked after by the respiratory health worker attended their general practitioner more frequently and were prescribed a greater range of drugs. This is the third study to have found limited measurable benefit in terms of morbidity from the intervention of a respiratory health worker. This may be due to the ability of such workers to keep frail patients alive.", "In both military and civilian settings, transmission of respiratory pathogens may be due to person-to-person and environmental contributions. This possibility was explored in a military training setting, where rates of febrile respiratory illness (FRI) often reach epidemic levels.\n Population size and FRI rates were monitored over 10 months in the units of 50-90 individuals. Some units were open to the influx of potentially infectious convalescents (hereafter referred to as \"open units,\" and some were closed to such an influx (hereafter referred to as \"closed units\"). Virologic testing and polymerase chain reaction analysis were used to detect adenovirus on surface structures.\n The odds ratio (OR) associated with FRI in closed units, compared with open units, was 1.13 (95% confidence interval [CI], 0.99-1.28). The OR in units with a population greater than the median size, compared with units with a population lower than the median size was 1.38 (95% CI, 1.23-1.55). Between 5% and 9% of surface samples obtained from selected units harbored viable adenovirus.\n FRI rates were not reduced in units that were closed to potentially contagious individuals. These findings imply that the primary source of the pathogen is likely environmental rather than human, and they underscore what is known about other virus types. Diligence in identifying the relative roles of different transmission routes is suggested for civilian settings similar to those described in the current study.", "A randomized field trial was conducted in Tecumseh, Michigan, to test the efficacy of virucidal nasal tissues in interrupting transmission of respiratory agents in the household. In the double-blinded trial, 296 households were stratified by household size and randomly assigned to the group using treated tissues and the group using placebo tissues. Households were recruited in late August to early September 1984, and the tissues were distributed in November 1984. A 10-week influenza A(H3N2) period was identified from January 13 to March 23, 1985, although there was also evidence of rhinovirus circulation during that period. A household-level infection transmission model was used to assess the effectiveness of the virucidal tissue in the household. The model was used to estimate the secondary attack rate for the placebo and treated tissue households during the influenza A(H3N2) period. The efficacy of the treated tissue in interrupting secondary transmission was found to vary from 30.1% to 36.9%, although it could be as high as 39.4% when historical comparisons are used. However, these differences were not statistically significant. In general, the use of virucidal nasal tissue in the household appears to result in the partial interruption of transmission of influenzavirus from an infected household member to another household member during an influenza epidemic.", "A comparative, prospective study was made of the incidence of infection in the lower airway (purulent tracheobronchitis and pneumonia) in long-term patients who were mechanically ventilated due to respiratory failure of noninfectious origin. Twenty-eight patients were randomly allocated into a study group (A, n = 13) in which a nonabsorbable paste containing 2% tobramycin, 2% amphotericin B, and 2% polymyxin E was administered locally to decontaminate the oropharynx, and a control group (B, n = 15) in which a paste without antibiotics was also applied to the oropharynx. We studied the effectiveness of the prophylactic technique in decontaminating the oropharynx and trachea of organisms potentially pathogenic for the respiratory system. Decontamination was successful in ten of 13 patients in group A vs. one of 15 patients in group B (p less than .001). The results demonstrated a lower rate of infection in the lower respiratory tract in the study group (three patients with tracheobronchitis and no pneumonias) than in the control group (three patients with tracheobronchitis and 11 with pneumonia), the difference between both being highly significant (p less than .001). Two (15%) patients in group B developed sepsis of pulmonary origin. None of the patients on prophylactic treatment developed this complication. Although the overall mortality was similar in both groups (group A, 30% vs. group B, 33%), we believe that infection contributed to a great extent to the death of two of five patients in group B. We conclude that nosocomial pneumonia, which is a frequent complication in critically ill patients on mechanical ventilation, could be prevented by local application of nonabsorbable antibiotics to the oropharynx.", "We assessed whether trivalent live, cold-adapted influenza virus (CAIV-T) vaccine provides added protection when co-administered with trivalent inactivated influenza virus vaccine (TVV) in patients with chronic obstructive pulmonary disease (COPD). Subjects (N=2215) were randomly assigned to receive either TVV intramuscularly (IM) and CAIV-T intranasally (TC), or TVV and placebo (TP). The vaccines were well-tolerated. Efficacy of TC compared to TP was not statistically significant and was 0.16 for any influenza virus strain (95% confidence limit (CL): -0.22, 0.43), 0.26 for A (H3N2) virus (95% CL: -0.17, 0.53), and -0.05 for type B virus (95% CL: -1.13, 0.48). However, there was a possible advantage for TC over TP in reducing respiratory consequences of an influenza season measured by pulmonary function and symptoms at end of study.", "A cluster-randomised controlled trial in general practice\n Physician-patient communication plays a key role in treatment decisions in primary care. We aimed to reduce the antibiotic prescription rate for acute respiratory tract infections using a short training programme in patient-centred communication.\n We conducted a cluster-randomised controlled trial in 45 general practices in Switzerland. Thirty physicians received evidence-based guidelines for the management of acute respiratory tract infections; 15 physicians randomised to the full intervention additionally received training in patient-centred communication. A further 15 physicians, not randomised, served as a control to blind the physicians in the other two groups to the true comparison. The primary outcome was the antibiotic prescription rate reported by pharmacists. Secondary outcomes were patient satisfaction and enablement, re-consultation rates, days with restrictions, and days off work. 1108 adults with acute respiratory infections were screened between January and May 2004. Outcomes were measured in 837 consultations; 624 patients had follow-up interviews at 7 and 14 days.\n The antibiotic prescription rate reported by pharmacists was low in both full and limited intervention groups (13.5% and 15.7% respectively) but only half of the antibiotics were prescribed according to guidelines (53.8% and 53.1%). No significant differences were seen between the two randomised groups in primary and secondary outcomes. In both groups patient satisfaction was high (median score for both 68 out of 70).\n In this trial, patient-centred communication training did not reduce the rate of antibiotic prescriptions below an already unusually low level. Even with this low prescription rate, patient satisfaction with received care was high.", "During three winter seasons prior to 1984-1985 the special care nursery at New England Medical Center experienced respiratory syncytial virus (RSV) epidemics that required closure of the unit. Prior to and during the 1984-1985 winter season, several measures were taken to prevent recurrent nosocomial RSV transmission. In the winters of 1984-1985 and 1985-1986 there were 26 introductions of community-acquired RSV with no transmission of nosocomial cases during 1,688 patient days at risk as compared with 1983-1984 when there were seven cases of nosocomial RSV following six introductions of RSV during 875 patient days at risk (rate = 8 per 1,000 patient days) (P = 0.0016). The institution of many infection control measures including active surveillance, cohorting infected patients, a strict winter visiting policy, and gowning, gloving, and applying mask on contact, was associated with the successful prevention of nosocomial transmission of RSV in this nursery setting.", "The Academic Center for Evidence-based Practice (ACE) Star Model was used to implement an evidence-based clinical practice guideline (CPG) in order to decrease ventilator-associated pneumonia (VAP) incidence rates and ventilator days. The goal was to interrupt person-to-person transmission of bacteria and bacterial colonization using low-cost, evidence-based strategies to prevent VAP. DISCOVERY: Two geographically proximate medical centers, inclusive of five intensive care units located in the southwestern region of the United States had significant variations in their VAP rates.\n Using the U.S. Preventive Services Task Force grading criteria, the results of 69 studies were used to establish a clinical practice guideline to prevent ventilator-associated pneumonia. TRANSLATION: A clinical practice guideline was developed for the prevention of VAP and included five nursing activities: (a) head-of-bed elevation; (b) oral care; (c) ventilator tubing condensate removal; (d) hand hygiene; and (e) glove use. The effect of the CPG, inclusive of an educational intervention, was measured using an observational, prospective, quasi-experimental design. INTEGRATION: A multidisciplinary education team developed a self-learning packet, educational materials, and storyboards for the staff as dissemination strategies. Strategies also included e-mail, one-on-one teaching with clinicians, and feedback on guideline adoption and VAP rate reports.\n Observation data were collected to evaluate adoption of the CPG while caring for 106 ventilated patients. VAP rates changed at both hospitals although the change was not statistically significant. Additionally, the ICU length of stay declined at both facilities, causing cost savings.\n These results support the idea that adoption of evidence-based practices contributes to decreased VAP rates. For a successful program, ICU leaders should emphasize strategies that routinize adoption of evidence-based CPGs.", "Practice guidelines suggest that all patients hospitalised with community-acquired pneumonia (CAP) should receive antibiotics within 4 h of admission. An audit at our hospital during 1999-2000 showed that this target was achieved in less than two thirds of patients with severe CAP.\n An experienced multidisciplinary steering group designed a management pathway to improve the early delivery of appropriate antibiotics to patients with CAP. This was implemented using a multifaceted strategy. The effect of implementation was evaluated using a controlled before-and-after study design over two winter seasons (November-April 2001-2 and 2002-3). Cost-effectiveness analyses were performed from the hospital's perspective.\n The proportion of patients receiving appropriate antibiotics within 4 h of admission to hospital increased from 33% to 56% at the intervention site, and from 32% to 36% at the control site (absolute change adjusted for differences in severity of illness 17%, p = 0.035). The cost per additional patient receiving appropriate antibiotics within 4 h was 132 pound with no post-implementation evaluation, and 456 pound for a limited post-implementation evaluation. Simple modelling from the results of a large observational study suggests that the cost per death prevented could be 3003 pound with no post-implementation evaluation, or 16,632 pound with a limited post-implementation evaluation.\n The intervention markedly improved door-to-antibiotic time, albeit at considerable cost. It might still be a cost-effective strategy, however, to reduce mortality in CAP. Uncertainty about the cost effectiveness of such interventions is likely to be resolved only by a well-designed, cluster randomised trial.", "Incidence and severity of respiratory infections are increased in day-care center attendees. Streptococcus pneumoniae is an important contributor to these infections.\n To examine whether the use of a pneumococcal conjugate vaccine could reduce the occurrence of respiratory infections and the ensuing antibiotic drug use in the day care.\n In this double blind, randomized, controlled study performed in 8 day-care centers located in Beer-Sheva, Israel, 264 toddlers ages 12 to 35 months at enrollment were randomized to receive either a 9-valent conjugate pneumococcal vaccine (conjugated to CRM197) or a control vaccine [conjugate meningococcus C vaccine (conjugated to CRM197)] and were followed for an average of 22 months. The main outcome measures were respiratory morbidity and antibiotic use.\n An overall reduction of 7% in child months with > or = 1 reported illness episodes was observed among vaccinees (P = 0.008), and 85% of all episodes were related to the respiratory tract. Reductions of 15, 16 and 17% were observed in upper respiratory infections, lower respiratory problems and otitis media, respectively. An overall reduction of 17% in antibiotic days was observed [10% for upper respiratory infections, 20% for otitis and 47% for lower respiratory problems (P < or = 0.005 for each entity)]. The reduction in episodes and antibiotic use was greater for those <36 months of age than for the older children.\n The reduction of respiratory problems, including those not traditionally considered of pneumococcal origin and the ensuing lowered antibiotic use in day-care center attendees by pneumococcal conjugate vaccination suggest a broader benefit from the vaccine than preventing invasive disease only.", "To examine the effectiveness of three psychoeducational interventions in reducing emotional distress after voluntary serologic testing for human immunodeficiency virus-1,307 physically asymptomatic adults were randomly assigned to standard counseling, counseling plus a three-session interactive video program, or counseling plus six individual sessions of stress prevention training. Subjects were evaluated using five standardized distress measures at entry and 3 months later. Among the 204 human immunodeficiency virus-seronegative subjects, mean distress measures decreased significantly after all three interventions without differential treatment effects. Among the 103 human immunodeficiency virus-seropositive subjects, mean distress measures decreased significantly after the stress prevention training and did not significantly increase in the other two interventions. We conclude that stress prevention training is particularly helpful after notification of human immunodeficiency virus seropositivity.", "To evaluate the cost-effectiveness of palivizumab as respiratory syncytial virus prophylaxis in premature infants without chronic lung disease and to evaluate the impact on cost-effectiveness of a potential reduction in risk of asthma following respiratory syncytial virus infection among infants receiving palivizumab.\n Two decision analytic models were designed, one with and the other without accounting for increased risk of asthma following respiratory syncytial virus infection.\n A hypothetical community or university hospital.\n Hypothetical cohorts of infants without chronic lung disease born at 26 to 32 weeks' gestation.\n Palivizumab prophylaxis vs no prophylaxis.\n Expected costs and incremental cost-effectiveness ratio expressed as cost per quality-adjusted life-year.\n The expected costs were higher for palivizumab prophylaxis as compared with no prophylaxis. The incremental cost-effectiveness ratios were high for all gestations and are not considered cost-effective by today's standards (<$200 000 per quality-adjusted life-year). Both models were sensitive to variation in the cost of palivizumab. The model that included asthma was sensitive to variation in quality of life for children with asthma. In instances where asthma was considered severe with profound worsening in quality of life compared with life without asthma, some infants had an incremental cost per quality-adjusted life-year that was less than $200 000.\n Our model supports implementing more restrictive guidelines for palivizumab prophylaxis. Palivizumab was cost-effective for some infants in an analysis that accounted for increased risk of severe asthma following respiratory syncytial virus infection.", "To evaluate the costs and benefits of two new agents, respiratory syncytial virus immune globulin (RSVIG) and palivizumab, to prevent respiratory syncytial virus (RSV) infection among premature infants discharged from the neonatal intensive care unit (NICU) before the start of the RSV season. Method. Decision analysis was used to compare the projected societal cost-effectiveness of three strategies-RSVIG, palivizumab, and no prophylaxis-among a hypothetical cohort of premature infants. Probabilities and costs of hospitalization were derived from a cohort of 1721 premature infants discharged from six Kaiser Permanente-Northern California NICUs. Efficacies of prophylaxis were based on published trials. Costs of prophylaxis were derived from published sources. Mortality among infants hospitalized for RSV was assumed to be 1.2%. Future benefits were discounted at 3%.\n Palivizumab was both more effective and less costly than RSVIG. Cost-effectiveness varied widely by subgroup. Palivizumab appeared most cost-effective for infants whose gestational age was </=32 weeks, who required >/=28 days of oxygen in the NICU, and who were discharged from the NICU from September through November. In this subgroup, palivizumab was predicted to cost $12,000 per hospitalization averted (after taking into account savings from prevention of RSV admissions) or $33,000 per life-year saved, and the number needed to treat to avoid one hospitalization was estimated at 7.4. However, for all other subgroups, ratios ranged from $39,000 to $420,000 per hospitalization averted or $110,000 to $1,200,000 per life-year saved, and the number needed to treat extended from 15 to 152. The results were sensitive to varying assumptions about the cost and efficacy of prophylaxis, as well as the probability of hospitalization, but were less sensitive to the cost of hospitalization.\n In our model, the cost of prophylaxis against RSV for most subgroups of preterm infants was high relative to the benefits realized. Lower costs might permit the benefits of prophylaxis to be extended to additional groups of preterm infants.", "Respiratory syncytial virus is the most common cause of bronchiolitis, a lower respiratory tract infection occurring in infancy. It is responsible for several rehospitalizations, substantial morbidity and occasional deaths in the UK every year. Palivizumab is a recombinant monoclonal antibody that has been shown to reduce hospitalizations in infected infants. It is licensed for high-risk infants, primarily those born pre-term or with chronic pulmonary or cardiac conditions. Palivizumab is expensive, but several economic analyses have determined highly discrepant costs. This article reviews the limitations of the available efficacy and economic data, and highlights problems in interpretation and extrapolation. We also present the results of a cost-effectiveness analysis relevant to populations of high-risk infants in the UK.", "To investigate the cost-effectiveness of palivizumab vs. no prophylaxis for respiratory syncytial virus (RSV) infection in preterm infants in Sweden.\n A probabilistic Markov model was populated using a nationwide register linkage and data from the literature. Cost-effectiveness was investigated from a societal perspective over a lifetime for infants born at <29 weeks of gestation. Palivizumab was modelled using assumptions for its direct effect on RSV hospitalization risk and an indirect effect (via decreased RSV hospitalization) on subsequent asthma and mortality during the epidemic. Costs and effects were discounted by 3%.\n In the base case, prophylaxis resulted in an additional 0.102 quality-adjusted life-year (QALY) at a cost of 20,000 SEK relative to no prophylaxis (incremental cost-effectiveness ratio [ICER] 195,000 SEK/QALY). The probability of prophylaxis being cost-effective was 99% at a willingness-to-pay of 500,000 SEK/QALY. Assumptions about a causal association between RSV infection and subsequent asthma had a moderate impact, while exclusion of the indirect prophylaxis effect on mortality increased the ICER to 492,000 SEK/QALY. When excluding both of these, prophylaxis was not cost-effective.\n Based on a willingness-to-pay of 500,000 SEK/QALY, palivizumab was found to be cost-effective compared with no prophylaxis for infants born at <29 weeks if severe RSV infection was assumed to increase subsequent asthma or mortality risk.\n © 2011 The Author(s)/Acta Paediatrica © 2011 Foundation Acta Paediatrica.", "Nosocomial transmission of droplet-borne respiratory infections such as severe acute respiratory syndrome (SARS) may be influenced by the choice of oxygen face mask. A subject inhaled saline mist and exhaled through three oxygen masks to illustrate the pattern of dispersal of pulmonary gas. In two commonly used masks, exhaled gas formed a plume emanating from the side vents, while a third mask with a valved manifold, which was modified by adding a respiratory filter, retained the droplets. Maintaining respiratory isolation during the administration of oxygen may reduce the risk of the nosocomial transmission of respiratory infections such as SARS.", "One objective of translational science is to identify elements of human immunodeficiency virus (HIV) risk-reduction interventions that have been shown to be effective and find new ways of delivering these interventions to the community to ensure that they reach the widest possible audience of at-risk individuals. The current study reports the development and evaluation of a computer-delivered, theory-based, individually tailored HIV risk-reduction intervention.\n This study evaluated the effectiveness of a custom computerized HIV/AIDS risk reduction intervention at increasing HIV/AIDS preventive behaviors in a randomized trial with 157 college students. The intervention content and delivery were based on the Information-Motivation-Behavioral Skills Model of Health Behavior Change and used Motivational Interviewing techniques. Participants completed a baseline assessment of HIV prevention information, motivation, behavioral skills and behavior, attended two brief computer-delivered intervention sessions, and completed a follow-up assessment.\n As compared to the control group (a nutrition education tutorial), participants who interacted with the computer-delivered HIV/AIDS risk reduction intervention exhibited a significant increase in risk reduction behavior. Specifically, participants reported a greater frequency of keeping condoms available and displayed greater condom-related knowledge at a four-week follow-up session; among sexually active participants, there was a significant increase in self-reported condom use.\n Delivery of brief individually tailored HIV/AIDS risk reduction interventions via computer may be an effective HIV/AIDS prevention approach for adolescents. More research is needed to further support the effectiveness of this type of intervention and determine the generalizability of these findings to economically and educationally disadvantaged adolescents.", "A multicentre study of the effects of influenza virus RIT 4050 (H3N2) in patients with chronic bronchitis was conducted by members of an MRC Committee. The results showed that RIT 4050 vaccine virus did not cause a deterioration in clinical or physiological status in these patients within the limitation of the relatively reproducible ventilatory tests which were employed. This conclusion applied equally to those who were inoculated and became infected and to those who failed to develop serological evidence of infection. The relatively high proportion of antibody-negative volunteers not infected by the inoculated virus raises doubts concerning the value of this method of immunization for patients at risk during influenza epidemics.", "Within the intensive-care unit, non-invasive ventilation (NIV) can prevent the need for intubation and the mortality associated with severe episodes of chronic obstructive pulmonary disease (COPD). The aim of this study was to find whether the introduction of NIV, early after the admission on a general respiratory ward, was effective at reducing the need for intubation and the mortality associated with acute exacerbations of COPD.\n We did a prospective multicentre randomised controlled study comparing NIV with standard therapy in patients with mild to moderate acidosis. NIV was administered on the ward with a simple non-invasive ventilator and a standardised predefined protocol. Patients were recruited from 14 UK hospitals over 22 months.\n 236 patients were recruited, 118 received standard therapy alone and 118 additional NIV. The two groups had similar characteristics at enrolment. The use of NIV significantly reduced the need for intubation as defined by the failure criteria. 32/118 (27%) of the standard group failed compared with 18/118 (15%) of the NIV group (p=0.02). In-hospital mortality was also reduced by NIV, 24/118 (20%) died in the standard group compared with 12/118 (10%) in the NIV group (p=0.05). In both groups pH, PaCO2, and respiratory rate improved at 4 h (p<0.01). However, NIV led to a more rapid improvement in pH in the first hour (p=0.02) and a greater fall in respiratory rate at 4 h (p=0.035). The duration of breathlessness was also reduced by NIV (p=0.025).\n The early use of NIV for mildly and moderately acidotic patients with COPD in the general ward setting leads to more rapid improvement of physiological variables, a reduction in the need for invasive mechanical ventilation (with objective criteria), and a reduction in in-hospital mortality.", "There are sparse data on whether non-pharmaceutical interventions can reduce the spread of influenza. We implemented a study of the feasibility and efficacy of face masks and hand hygiene to reduce influenza transmission among Hong Kong household members.\n We conducted a cluster randomized controlled trial of households (composed of at least 3 members) where an index subject presented with influenza-like-illness of <48 hours duration. After influenza was confirmed in an index case by the QuickVue Influenza A+B rapid test, the household of the index subject was randomized to 1) control or 2) surgical face masks or 3) hand hygiene. Households were visited within 36 hours, and 3, 6 and 9 days later. Nose and throat swabs were collected from index subjects and all household contacts at each home visit and tested by viral culture. The primary outcome measure was laboratory culture confirmed influenza in a household contact; the secondary outcome was clinically diagnosed influenza (by self-reported symptoms). We randomized 198 households and completed follow up home visits in 128; the index cases in 122 of those households had laboratory-confirmed influenza. There were 21 household contacts with laboratory confirmed influenza corresponding to a secondary attack ratio of 6%. Clinical secondary attack ratios varied from 5% to 18% depending on case definitions. The laboratory-based or clinical secondary attack ratios did not significantly differ across the intervention arms. Adherence to interventions was variable.\n The secondary attack ratios were lower than anticipated, and lower than reported in other countries, perhaps due to differing patterns of susceptibility, lack of significant antigenic drift in circulating influenza virus strains recently, and/or issues related to the symptomatic recruitment design. Lessons learnt from this pilot have informed changes for the main study in 2008.\n ClinicalTrials.gov NCT00425893 HKClinicalTrials.com HKCTR-365.", "We assessed the effects of an influenza season on patients with COPD. Data from 2,215 veterans in a multicenter, randomized, double-blind influenza vaccine efficacy study were analyzed for changes in spirometric and functional status, comparing patients with laboratory-documented influenza (LDI)-caused illness, non-LDI-caused respiratory illness, or no illness, and for association with influenza vaccination.\n Patients received either IM trivalent inactivated influenza virus vaccine (TIV) plus intranasal trivalent, live attenuated, cold-adapted influenza virus vaccine (TC) or TIV plus intranasal placebo (TP). We performed spirometry, measured the chronic lung disease severity index (CLDSI) score to assess functional status and well-being, and tested for influenza virus infection.\n Worsening in FEV(1), percentage of predicted FEV(1), and CLDSI score (p < 0.001) was associated with acute respiratory illness in 585 illnesses including 94 LDI-caused illnesses. LDI-caused illness was more likely to be associated with worsening in FEV(1) and CLDSI score acutely than non-LDI-caused illness (p < 0.01). Logistic regression showed acute respiratory illness (odds ratio [OR], 1.78; 95% confidence limit [CL], 1.40 to 2.26) to be associated with worsening in CLDSI score, and receipt of TC (OR, 1.39; 95% CL, 1.10 to 1.74) and no illness (OR, 0.70; 95% CL, 0.53 to 0.91 for acute respiratory illness) to be associated with better CLDSI score at the end of the study. Hospitalization was more frequent in patients with acute respiratory illness (p < 0.0001).\n Acute respiratory illness was associated with increased health-care utilization and obstruction to airflow, and worse functional status and well-being. At the end of the study, receipt of TC was associated with improvement and acute respiratory illness was associated with worsening in functional status and well-being.", "Respiratory syncytial virus (RSV) is a common pathogen that is the leading cause of lower respiratory tract infections in young children. High-risk children are at risk of severe infection, which may require hospitalisation. RSV is also associated with a high risk for respiratory morbidity and mortality, which may have long-term clinical and economic consequences.\n To assess the cost effectiveness of palivizumab, a humanised monoclonal antibody, used as prevention against severe respiratory syncytial virus (RSV) infection requiring hospitalisation, in the indication of preterm infants and infants with preterm/bronchopulmonary dysplasia and in the second indication of children with congenital heart disease in the Dutch healthcare setting.\n A decision-tree model was used to estimate the cost effectiveness of palivizumab, used as a preventative treatment against severe respiratory syncytial virus (RSV) infection, in high-risk groups of children in the Netherlands. The analysis was based on a lifetime follow-up period in order to capture the impact of palivizumab on long-term morbidity and mortality resulting from an RSV infection. Data sources included published literature, the palivizumab pivotal trials, official price/tariff lists and national population statistics. The study was conducted from the perspective of society in the Netherlands.\n The use of palivizumab results in undiscounted incremental cost-effectiveness ratios of €12,728/QALY and €4,256/QALY in preterm/bronchopulmonary dysplasia and congenital heart disease indications, respectively. Inclusion of indirect costs leads to even more favourable cost-effectiveness outcomes. The study is limited by a number of conservative assumptions. It was assumed that palivizumab only affects the occurrence of RSV hospitalisation and does not influence the severity of the RSV infection. Another assumption was that international clinical trial data and data on utilities could be applied to the Dutch healthcare setting.\n Palivizumab provides cost-effective prophylaxis against RSV in high-risk infants. The use of palivizumab in these children results in positive short- and long-term health-economic benefits.", "We evaluated an eye-nose goggle to determine its usefulness in reducing nosocomial RSV infection in patients and staff members on our infant ward. During a community outbreak of RSV in 1984, infection was assessed by biweekly routine viral cultures on all ward personnel and patients and also by seroconversion in personnel. For three weeks staff members wore the goggles; two (5%) adults and one (6%) child acquired nosocomial infection. During the subsequent three-week study period, goggles were not used and 34% of personnel and 43% of susceptible infants became infected. The use of the disposable eye-nose goggles was associated with a significant decrease in nosocomial RSV infections (P less than .003 for staff and P less than .05 for contact infants).", "School-based asthma interventions delivered by nonschool staff have been successful but are limited in their reach because of the cost and effort of bringing in outside educators and their inability to establish improved communication about asthma between schools, families, and primary care providers (PCPs). To address these problems, Columbia University and the New York City Department of Education and the New York City Department of Health and Mental Hygiene undertook a randomized controlled trial to test the efficacy of a comprehensive school-based asthma program. In this intervention, school nurses were trained to facilitate the establishment of a preventive network of care for children with asthma by coordinating communications and fostering relationships between families, PCPs, and school personnel. PCPs also received training regarding asthma management. There was limited support for this model. While case detection helped nurses identify additional students with asthma and nurses increased the amount of time spent on asthma-related tasks, PCPs did not change their medical management of asthma. Few improvements in health outcomes were achieved. Relative to controls, 12-months posttest intervention students had a reduction in activity limitations due to asthma (-35% vs -9%, p < .05) and days with symptoms (26% vs 39%, p = .06). The intervention had no impact on the use of urgent health care services, school attendance, or caregiver's quality of life. There were also no improvements at 24-months postintervention. We faced many challenges related to case detection, training, and implementing preventive care activities, which may have hindered our success. We present these challenges, describe how we coped with them, and discuss the lessons we learned.", "nan", "To evaluate the impact of a multifactorial intervention to improve the quality, efficiency, and patient understanding of care for community-acquired pneumonia.\n Times series cohort study.\n Four academic health centers in the New York City metropolitan area.\n All consecutive adults hospitalized for pneumonia during a 5-month period before (n = 1,013) and after (n = 1,081) implementation of an inpatient quality improvement (QI) initiative.\n A multidisciplinary team of opinion leaders developed evidence-based treatment guidelines and critical pathways, conducted educational sessions with physicians, distributed pocket reminder cards, promoted standardized orders, and developed bilingual patient education materials.\n The average age was 71.4 years, and 44.1% of cases were low risk, 36.8% were moderate risk, and 19.2% were high risk. The preintervention and postintervention groups were well matched on age, sex, race, nursing home residence, pneumonia severity, initial presentation, and most major comorbidities. The intervention increased the use of guideline-recommended antimicrobial therapy from 78.1 to 83.4% (p = 0.003). There was also a borderline decrease in the proportion of patients being discharged prior to becoming clinically stable, from 27.0 to 23.5% (p = 0.06). However, there were no improvements in the other targeted indicators, including time to first dose of antibiotics, proportion receiving antibiotics within 8 h, timely switch to oral antibiotics, timely discharge, length of stay, or patient education outcomes.\n This real-world QI program was able to improve modestly on some quality indicators, but not effect resource use or patient knowledge of their disease. Changing physician and organizational behavior in academic health centers will require the development and implementation of more intensive, system-oriented strategies.", "We evaluated the effect of school closure on the occurrence of respiratory infection among children ages 6-12 years and its impact on health care services. During this period, there were significant decreases in the diagnoses of respiratory infections (42%), visits to physician (28%) and emergency departments (28%) and medication purchases (35%). The present study provides quantitative data to support school closure during an influenza pandemic.", "The rapid increase of antibiotic resistance poses a significant threat to human health. Overuse of antibiotics has been linked to rates of antibiotic resistance. This study assessed the utility of two common interventions--1) practice profiling and feedback and 2) patient education materials--implemented to decrease antibiotic prescribing for pediatric upper respiratory infections (URIs).\n Based on Medicaid regions in Kentucky, primary care physicians managing pediatric respiratory infections in Medicaid were randomized into four groups. Groups received either 1) performance feedback only, 2) patient education materials only, 3) both feedback and education materials, or 4) no intervention. Participating physicians had their antibiotic prescribing assessed for the period of July 1, 1996, to November 30, 1997, with an intervention in June 1997. The study included 216 physicians and 124,092 episodes of care.\n All groups increased in proportion of episodes with antibiotics between the pre-intervention and post-intervention periods. Prescribing in the patient education group and the patient education and feedback group increased at a significantly lower rate than in the control group. Physicians did not change their coding of illness to justify antibiotics after the intervention, and there was no significant generalization of effect of the pediatric intervention on prescribing for adult URIs.\n These interventions demonstrate little if any impact on promoting appropriate antibiotic prescribing. Antibiotic prescribing for viral respiratory infections continues to increase, suggesting concomitant increases in antibiotic resistance.", "Despite the use of a series of preventive measures, a high incidence of severe acute respiratory syndrome (SARS) was observed among health care workers (HCWs) during the SARS epidemic. This study aimed to determine which preventive measures may have been effective in protecting HCWs from infection, and which were not effective.\n A retrospective study was performed among 758 'frontline' health care workers who cared for SARS patients at the Second Affiliated Hospital and the Third Affiliated Hospital of Sun Yat-sen University. The HCWs with IgG against SARS and those without IgG against SARS were respectively defined as the \"case group\" and the \"control group\", and logistic regression was conducted to explore the risk factors for SARS infection in HCWs.\n After adjusting for age, gender, marital status, educational level, professional title, and the department in which an individual worked, the results of a multivariate logistic regression analysis indicated that incidence of SARS among HCWs was significantly and positively associated with: performing tracheal intubations for SARS patients, methods used for air ventilation in wards, avoiding face-to-face interaction with SARS patients, the number of pairs of gloves worn by HCWs, and caring for serious SARS cases.\n Some measures, particularly good air ventilation in SARS wards, may be effective in minimizing or preventing SARS transmission among HCWs in hospitals.", "Some reports have suggested that influenza virus vaccine is less effective in persons that have received prior annual vaccination(s) than in those receiving it for the first time. This issue was addressed by evaluating the efficacy of annual influenza vaccinations over a 5 year period in healthy adults employing commercially-available, inactivated whole-virus vaccine. Influenza vaccination had minimal effects on overall respiratory illnesses during epidemic periods. However, it reduced influenza virus shedding by an average of 38.8% and conferred protection against influenza virus infection during each epidemic. Some variation in infection rates were noted between vaccine groups given one or more than one annual immunization, and between years, but no consistent pattern of differences was noted in relation to number of successive years of vaccination. These results suggest that the current recommendation for annual influenza vaccination of persons at special risk of serious disease and complications is appropriate, but that continued efforts to improve the effectiveness of our prophylactic measures against influenza are needed.", "To evaluate the use of influenza vaccine in nursing homes and its effectiveness in reducing the likelihood of influenza-like illness.\n A retrospective case-control study with active identification of influenza infection.\n All nursing homes in a seven-county study area in southern lower Michigan were eligible for participation. Analyses were based on data collected from 23 homes with documented influenza transmission.\n Persons aged 65 years or older who were residents of the nursing homes under study during the influenza type A(H3N2) outbreak in 1989-1990.\n Residents were identified as cases or controls based on occurrence of febrile respiratory illness meeting a case definition. Demographic and underlying illness information were gathered as were data on the use of influenza vaccine, antibiotics, and antivirals. Characteristics of the nursing homes were also recorded. Logistic regression analyses were carried out to determine vaccine effectiveness.\n Determinants of vaccine use were different from those observed in a parallel community-based study. In a multivariate model that considered the effects of resident and nursing home characteristics, vaccinated residents were significantly less likely than those who were not vaccinated to have an influenza-like illness (OR = .58 (95% CI, .43-.78), P < .001, imputed vaccine effectiveness estimate of 42%). Vaccination was more effective in younger residents (those aged 65 to 84) then in older residents (those older than 84 years).\n Influenza vaccination was effective in reducing the likelihood of influenza-like illness in nursing home residents. Effectiveness appeared to be related to age, which may function as a surrogate for related immunologic factors. Older nursing home residents should be targeted for newer vaccines and/or potential prophylactic use of antivirals.", "Ventilator-associated pneumonia (VAP) is the most common nosocomial infection in patients on mechanical ventilation and results in increases in mortality, prolonged hospitalization and costs. Preventive measures for VAP are well-documented and evidence-based, yet remain poorly implemented in most intensive care units. We undertook an observational pre and post-intervention study to assess whether an educational programme focusing on preventive practices for VAP could reduce the incidence. Six hundred and seventy-seven adult patients, mechanically ventilated for >48 h were included in the study population. An evidence-based guideline for preventive practices at the bedside was developed and disseminated to the intensive care unit staff. VAP incidence rates before and after implementation of the educational programme were compared. VAP infection rates reduced by 51%, from a mean of 13.2+/-1.2 in the pre-intervention period to 6.5+/-1.5/1000 device days in the post-intervention period (mean difference 6.7; 95% CI: 2.9-10.4, P =0.02). A multidisciplinary educational programme geared towards intensive care unit staff can successfully reduce the incidence rates of VAP. Further studies will be needed to assess the impact on broader outcome measures such as costs or mortality.", "There are many systematic reviews of continuing education programmes and educational strategies for quality improvement in health care. Most of the reviewed studies are one-off evaluations rather than impact evaluations with long-term follow-up. There are few systematic reviews of organisational, financial and regulatory interventions, and few high-quality studies. These interventions are probably as or more important than educational strategies, although they are less well evaluated. Few studies have been undertaken in low- and middle-income countries (LMIC) or that address maternal and child health (MCH). Thus, the results of the available studies and reviews need to be interpreted cautiously when applied to LMIC. Interactive workshops, reminders and multifaceted interventions can improve professional practice, and they generally have moderate effects. Educational outreach visits consistently improve prescribing but have variable effects on other behaviours. Audit and feedback interventions have variable effects on professional practice, but most often these are small to moderate effects. Mass-media and patient-mediated interventions may change professional practice. Multifaceted interventions that combine several quality-improvement strategies are also effective but may not be more so than single interventions. While all of these strategies are applicable to MCH in LMIC, the applicability of the results to rural settings, in particular, may be limited. Use of these strategies could exacerbate inequalities, and this should be taken into consideration when planning implementation. Scaling up and sustainability may be difficult to achieve in LMIC contexts and need careful consideration. The use of financial interventions has not been well studied; financial incentives and disincentives may be difficult to use effectively and efficiently, although their impact on practice needs to be considered. Organisational interventions are likely to be important, given that there are often underlying organisational or system problems. Regulatory interventions have not been well evaluated, but may sometimes be both inexpensive and effective. There are no 'magic bullets' or simple solutions for ensuring the quality of health care services. Interventions should be selected or tailored to address the underlying reasons for a failure to deliver effective services. Decision-makers should select the most appropriate interventions for specific problems. This requires a governance structure that clearly assigns responsibility for quality-improvement activities, priority setting, selection and design of interventions, and evaluation.", "To limit nosocomial spread of respiratory syncytial virus (RSV) infection, a longitudinal intervention trial was instituted. Nasal secretions or washes were screened for RSV antigen by enzyme-linked immunosorbent assay, and patients were assigned to an RSV-infected or an RSV-uninfected cohort. The baseline (preintervention) rate of 7.17 nosocomial cases of RSV per 1000 patient-days of care was used for comparison. Despite continued infections in the community after screening was initiated, there were no cases of RSV infection in 1880 patient-days of care for 3 months (p = 0.039). During the fourth month, an RSV-infected child was erroneously assigned to the RSV-uninfected cohort, and three nosocomial cases occurred--5.33/1000 patient-days of care (p = 0.286). Overall, there were three nosocomial RSV infections in 2443 patient-days of care in the 1987 season after screening was introduced--1.23/1000 patient-days of care (p = 0.026). In the subsequent RSV season, there was one nosocomial case--0.461/1000 patient-days of care for 3 months (p = 0.0074). During the same period, nosocomial cases of RSV were observed in the pediatric and neonatal intensive care units, where assignment to a cohort was not possible. We conclude that entry into a cohort at the time of admission, on the basis of prospective RSV screening by enzyme-linked immunosorbent assay, effectively reduces nosocomial transmission of RSV.", "Patients with pneumonia often remain hospitalized after they are stable clinically, and the duration of intravenous antibiotic therapy is a rate-limiting step for discharge. The purpose of this study was to determine whether implementation of an evidence-based guideline would reduce the duration of intravenous antibiotic therapy and length of stay for patients hospitalized with pneumonia.\n In a seven-site, cluster randomized clinical trial, we enrolled 325 control and 283 intervention patients who were admitted by one of 116 physician groups. Within site, physician groups were assigned randomly to receive a practice guideline alone (control arm) or a practice guideline that was implemented using a multifaceted strategy (intervention arm). The effectiveness of guideline implementation was measured by the duration of intravenous antibiotic therapy and length of stay; differences in the rates of discontinuation and hospital discharge were assessed with proportional hazards models. Medical outcomes were assessed at 30 days.\n Intravenous antibiotic therapy was discontinued somewhat more quickly in the intervention group (hazard ratio [HR] =1.23; 95% confidence interval [CI]: 1.00 to 1.52; P = 0.06) than in the control group. Intervention patients were discharged more quickly, but the difference was not statistically significant (HR = 1.16; 95% CI: 0.97 to 1.38; P = 0.11). Fewer intervention (55% [157/283]) than control (63% [206/325]) patients had medical complications during the index hospitalization (P = 0.04), with no differences in other medical outcomes, including mortality, rehospitalization, and return to usual activities, between treatment arms.\n The multifaceted guideline implementation strategy resulted in a slight reduction in the duration of intravenous antibiotic therapy and a nonsignificant reduction in length of stay, without affecting patient outcomes.", "In 1990, the Ministry of Public Health of Thailand started a five-year education program on management of cases with acute respiratory infection (ARI). The objective of this-study was to test whether such a program could reduce the average number of sick days of the target children. 30 villages in the study district were randomly allocated into 15 study and 15 control villages. A 2-day training workshop for village health volunteers from the study villages was conducted. The cohort of children age below 5 years in the two areas were followed-up for 19 week in the peak season of the disease. Among the 664 and 649 target children with 67,083 and 67,984 child-days observed in the study and the control villages, 71 and 41 children, respectively, were free from any episode. The preventive odds ratio of treatment adjusted for age and village effects = 0.88, 95% (CI 0.4-1.95). The median of the average sick periods in the individuals were 27 and 34 days, respectively. After adjusting for age, episodes/month and locality, the ratio of average sick days between children in the study and control villages was 0.89 (95% CI 0.76-1.05) or 11% shorter duration without statistical significance. The adjusted odds ratios of visiting the health center, private clinics, the community hospital and provincial hospital were 0.95 (95% CI 0.69-1.25), 1.43 (95% CI 0.98-2.11), 2.01 (95% CI 1.06-3.82) and 4.71 (95% CI 1.50-14.8), respectively. The training program thus had rather little impact on morbidity of the disease but tended to promote utilization of higher level of health services by the affected children.", "Influenza virus is a major cause of illness, disruption to daily life, and increased use of health care in all age groups.\n To assess the safety and effectiveness of intranasally administered trivalent, live, attenuated influenza virus (LAIV) vaccine for reducing illness, absenteeism, and health care use among healthy, working adults.\n Randomized, double-blind, placebo-controlled trial conducted from September 1997 through March 1998.\n Thirteen centers across the United States.\n A total of 4561 healthy, working adults aged 18 to 64 years recruited through health insurance plans, at work sites, and from the general population.\n Participants were randomized 2:1 to receive intranasally administered trivalent LAIV vaccine (n = 3041) or placebo (n = 1520) in the fall of 1997.\n Episodes of febrile illness, severe febrile illness, febrile upper respiratory tract illness, work loss, and health care use during the peak and total influenza outbreak periods, and adverse events.\n Recipients of LAIV vaccine were as likely to experience 1 or more febrile illnesses as placebo recipients during peak outbreak periods (13.2% for vaccine vs 14.6% for placebo; P=.19). However, vaccination significantly reduced the numbers of severe febrile illnesses (18.8% reduction; 95% confidence interval [CI], 7.4%-28.8%) and febrile upper respiratory tract illnesses (23.6% reduction; 95% CI, 12.7%-33.2%). Vaccination also led to fewer days of illness across all illness syndromes (22.9% reduction for febrile illnesses; 27.3% reduction for severe febrile illnesses), fewer days of work lost (17.9% reduction for severe febrile illnesses; 28.4% reduction for febrile upper respiratory tract illnesses), and fewer days with health care provider visits (24.8% reduction for severe febrile illnesses; 40.9% reduction for febrile upper respiratory tract illnesses). Use of prescription antibiotics and over-the-counter medications was also reduced across all illness syndromes. Vaccine recipients were more likely to experience runny nose or sore throat during the first 7 days after vaccination, but serious adverse events between the groups were not significantly different. The match between the type A(H3N2) vaccine strain and the predominant circulating virus strain (A/Sydney/05/97[H3N2]) for the 1997-1998 season was poor, suggesting that LAIV provided substantial cross-protection against this variant influenza A virus strain.\n Intranasal trivalent LAIV vaccine was safe and effective in healthy, working adults in a year in which a drifted influenza A virus predominated.", "To determine if an evidence-based implementation (EBI) could lead to the successful implementation of evidence based care for adult asthma in small rural district hospitals.\n A controlled trial involving eight small rural hospitals (four each in the study and control groups) was conducted. Retrospective pre-intervention audits were conducted at all eight hospitals for 7 months (1 January 2004 to 31 July 2004) and evidence-practice gaps identified. An EBI was then used to implement established guidelines for the management of asthma in the study hospitals. Post-intervention audits were then performed over a period of 7 months (1 October 2004 to 31 April 2005).\n There were 52 presentations of asthma in the study hospitals in the pre-implementation phase and 47 post-implementation. The corresponding numbers for the control hospitals were 46 and 42 respectively. There were no statistically significant differences in the severity between the groups. Following the EBI there were significant improvements at the study hospitals for the documentation of severity (8% to 62%, p <0.001), use of spirometry (12% to 62%, p <0.001) and the use of written short-term asthma plans (9% to 26%, p = 0.05). There was a decrease in use of ipratropium in mild asthma (44% to 30%, p = 0.228), an increase in the use of systemic steroids (61% to 72%, p = 0.255) and no change in prescribing antibiotics for afebrile patients with asthma (21% to 21% p = 0.956). There was no significant change in practice at the control hospitals except for a decrease in the use of systemic steroids (48% to 21%, p = 0.011). For the six clinical indicators aggregate there was a significant increase in compliance with guidelines at the study hospitals (36% to 62%, p < 0.001) but no change at the control hospitals (31% to 31%, p = 0.970).\n The pre-intervention audits demonstrated low levels of compliance with asthma guidelines across six clinical indicators. An EBI significantly improved compliance across these six indicators, and no improvement was noted in the control hospitals. This study demonstrates that an EBI can alter clinical practice in small rural district hospitals.", "We compared the impact of three household interventions-education, education with alcohol-based hand sanitizer, and education with hand sanitizer and face masks-on incidence and secondary transmission of upper respiratory infections (URIs) and influenza, knowledge of transmission of URIs, and vaccination rates.\n A total of 509 primarily Hispanic households participated. Participants reported symptoms twice weekly, and nasal swabs were collected from those with an influenza-like illness (ILI). Households were followed for up to 19 months and home visits were made at least every two months.\n We recorded 5034 URIs, of which 669 cases reported ILIs and 78 were laboratory-confirmed cases of influenza. Demographic factors significantly associated with infection rates included age, gender, birth location, education, and employment. The Hand Sanitizer group was significantly more likely to report that no household member had symptoms (p < 0.01), but there were no significant differences in rates of infection by intervention group in multivariate analyses. Knowledge improved significantly more in the Hand Sanitizer group (p < 0.0001). The proportion of households that reported > or = 50% of members receiving influenza vaccine increased during the study (p < 0.001). Despite the fact that compliance with mask wearing was poor, mask wearing as well as increased crowding, lower education levels of caretakers, and index cases 0-5 years of age (compared with adults) were associated with significantly lower secondary transmission rates (all p < 0.02).\n In this population, there was no detectable additional benefit of hand sanitizer or face masks over targeted education on overall rates of URIs, but mask wearing was associated with reduced secondary transmission and should be encouraged during outbreak situations. During the study period, community concern about methicillin-resistant Staphylococcus aureus was occurring, perhaps contributing to the use of hand sanitizer in the Education control group, and diluting the intervention's measurable impact.", "The purpose was to compare the short-term cost-effectiveness of intensive vs conventional education and supervision for the self-management of mild asthmatic patients. Consecutive newly diagnosed asthmatic patients (n = 162) were randomized into an intervention group (IG) and a control group (CG) with 1 yr of treatment and follow-up. Intensive education was given to 77 patients at visits every third month in the outpatient clinic. Eighty CG patients received conventional education and advice at the baseline visit only. All patients received similar inhaled anti-inflammatory treatment. At baseline and at 12 months standard clinical lung functions and health-related quality of life (HRQOL) were measured, the latter by the disease-specific St George's Respiratory Questionnaire and the generic 15D. Furthermore, the use of extra health care services, medication and sickness days were recorded. The IG experienced a significant improvement in all clinical and HRQOL outcome variables. The same applied to the CG except spirometric values. The groups differed significantly only in terms of FEV1 (P < 0.05) in favour of the IG. There was a significant difference between the groups in extra costs. The mean cost was FIM 2351 per patient (294 Pounds sterling) in the CG and FIM 2757 per patient (345 Pounds) in the IG, of which the intervention cost was FIM 1978 per patient (247 Pounds). In 1 yr follow-up the intensive education programme did not prove to be cost effective but was dominated by the conventional one regardless of what effectiveness measure was used. Also, a purely monetary cost-benefit calculation showed that the intervention resulted in a negative net benefit (loss) of FIM 406 per patient (51 Pounds). A longer follow-up may be needed before definitive conclusions about the cost-effectiveness of this kind of intervention can be drawn.", "The objective of this study was to assess the effect of a novel regimen of antibiotic prophylaxis on the incidence of lower respiratory tract infection in patients requiring prolonged (at least five days) mechanical ventilation. The design was a controlled, prospective, randomized trial, with blinded comparison of the groups regarding the incidence of respiratory tract infection in an intensive care unit of a university hospital. After determination of the APACHE II score for severity of disease, 88 patients were randomly divided in three groups. Twenty-four of these patients did not complete five days of mechanical ventilation, and eight were withdrawn for other reasons. Fifty-six patients (18 in group 1, 21 in group 2, 17 in group 3) completed the study. Patients in both control groups 1 and 2 did not receive antibiotic prophylaxis, but the two groups differed in the antibiotic policy in case of infection. Patients in group 3 received antibiotic prophylaxis consisting of norfloxacin, polymyxin E, and amphotericin B, applied topically in oropharynx and stomach from time of ICU admission until extubation, and intravenous cefotaxime 500 mg three times a day during the first five days of admission. In both control groups, about 90 percent of the patients acquired microbial colonization of oropharynx or stomach. In group 3, only 12 percent and 24 percent of the patients acquired colonization of oropharynx and stomach, respectively (p less than 0.001). This resulted in a reduction of the incidence of lower respiratory tract infection (78 percent in group 1, 62 percent in group 2, 6 percent in group 3 [p = 0.0001]). The regimen of antibiotic prophylaxis studied prevented respiratory tract infection in mechanically ventilated patients. Antibiotic prophylaxis should be considered in all patients expected to require prolonged mechanical ventilation.", "In healthy adults influenza immunization reduces absenteeism caused by respiratory infections, but data on its efficacy among health care workers are scarce.\n To determine the effect of the conventional inactivated influenza A vaccine on reducing absenteeism related to respiratory infections among pediatric health care providers.\n A randomized, placebo-controlled, double blind study on vaccine efficacy was conducted in two pediatric hospitals during the winter season 1996 to 1997. The primary endpoint was days of work lost from the hospital because of respiratory infections. The documentation of absenteeism was based on personal sickness logs.\n Of the 547 randomized vaccinees 427 (78%) persons completed the 4-month follow-up and returned the sickness logs. Immunization failed to reduce episodes of respiratory infections (1.8 episodes/study period among vaccinees vs. 2.0 among controls). Similarly the vaccine failed to affect the total number of days the vaccinees suffered from respiratory infections (13.5 days vs. 14.6 days, respectively). However, days of work lost because of respiratory infections (1.0 days vs. 1.4 days, respectively, P = 0.02) and especially total numbers of days the study persons felt themselves unable to work when either on or off duty (2.5 days vs. 3.5 days, P 0.02) were significantly decreased.\n Influenza vaccination reduced absenteeism related to respiratory infections by 28%. We therefore believe that routine annual influenza immunizations should be recommended to health care providers working in pediatric settings." ]	Simple and low-cost interventions would be useful for reducing transmission of epidemic respiratory viruses. Routine long-term implementation of some measures assessed might be difficult without the threat of an epidemic.
CD009163	[ "15684116", "9726683", "2248740", "3488978", "19434268", "1683673", "6389394", "3884218", "14769785", "11159657", "17846935", "2647105", "1693411", "10819344", "10657332", "3545844", "8970215", "9821420", "11158489", "2405348" ]	[ "A randomized, double-blind, placebo-controlled noninferiority trial of amoxicillin for clinically diagnosed acute otitis media in children 6 months to 5 years of age.", "Epidemiology and treatment of otitis media with effusion in children in the first year of primary school.", "The efficacy of oral steroids in the treatment of persistent otitis media with effusion.", "Efficacy of oral antibiotics for the treatment of persistent otitis media with effusion.", "Management for the children with otitis media with effusion in the tertiary hospital.", "Antimicrobial therapy for otitis media with effusion ('secretory' otitis media).", "Antimicrobial therapy of chronic otitis media with effusion.", "The long-term outcome of nonsuppurative otitis media with effusion.", "Adenoidectomy versus chemoprophylaxis and placebo for recurrent acute otitis media in children aged under 2 years: randomised controlled trial.", "Pragmatic randomised controlled trial of two prescribing strategies for childhood acute otitis media.", "Evaluation of phenoxymethylpenicillin treatment of acute otitis media in children aged 2-16.", "Antibiotic treatment of children with secretory otitis media. A randomized, double-blind, placebo-controlled study.", "Otitis media with effusion and chronic upper respiratory tract infection in children: a randomized, placebo-controlled clinical study.", "Five vs. ten days of antibiotic therapy for acute otitis media in young children.", "Primary care based randomised, double blind trial of amoxicillin versus placebo for acute otitis media in children aged under 2 years.", "Amoxicillin twice daily in the treatment of acute otitis media in infants and children.", "Efficacy of antimicrobial prophylaxis for recurrent middle ear effusion.", "A multicenter, randomized, double-blind trial of 5 versus 10 days of antibiotic therapy for acute otitis media in young children.", "A randomized controlled trial of point-of-care evidence to improve the antibiotic prescribing practices for otitis media in children.", "A controlled trial comparing three treatments for chronic otitis media with effusion." ]	[ "Debate continues with respect to a \"watch and wait\" approach versus immediate antibiotic treatment for the initial treatment of acute otitis media. In this double-blind noninferiority trial, we compared clinical improvement rates at 14 days for children (6 months to 5 years of age) with acute otitis media who were randomly assigned to receive amoxicillin or placebo.\n We enrolled healthy children who presented to clinics or the emergency department with a new episode of acute otitis media during the fall and winter months in Ottawa (from December 1999 to the end of March 2002). The children were randomly assigned to receive amoxicillin (60 mg/kg daily) or placebo for 10 days. Telephone follow-up was performed on each of days 1, 2 and 3 and once between day 10 and day 14. The primary outcome was clinical resolution of symptoms, defined as absence of receipt of an antimicrobial (other than the amoxicillin in the treatment group) at any time during the 14-day period. Secondary outcomes were the presence of pain and fever and the activity level in the first 3 days, recurrence rates, and the presence of middle ear effusion at 1 and 3 months.\n According to clinical scoring, 415 of the 512 children who could be evaluated had moderate disease. At 14 days 84.2% of the children receiving placebo and 92.8% of those receiving amoxicillin had clinical resolution of symptoms (absolute difference -8.6%, 95% confidence interval -14.4% to -3.0%). Children who received placebo had more pain and fever in the first 2 days. There were no statistical differences in adverse events between the 2 groups, nor were there any significant differences in recurrence rates or middle ear effusion at 1 and 3 months.\n Our results did not support the hypothesis that placebo was noninferior to amoxicillin (i.e., that the 14-day cure rates among children with clinically diagnosed acute otitis media would not be substantially worse in the placebo group than the treatment group). Nevertheless, delaying treatment was associated with resolution of clinical signs and symptoms in most of the children.", "In this multicentre study we evaluated the prevalence and risk factors of otitis media with effusion (OME) in Italian school-children and the effectiveness of medical treatment of chronic OME with a new cephalosporin, ceftibuten. During two winter periods, 3413 children, aged 5 to 7 years, were examined for the presence of OME by means of pneumotoscopy and a portable, hand-held tympanometer. The prevalence of asymptomatic OME was 14.2%, with no difference as regards sex, age, month of examination or geographic area. Younger children had significantly more bilateral than unilateral effusion. A recent episode of acute otitis media and previous tonsillectomy or adenoidectomy were associated with an increased risk of OME in multivariate logistic regression models. The presence of OME was unrelated to such factors as birthweight, prematurity, sibling or parental history of allergy, duration of daycare attendance, family history of ear infections. After 12 weeks, 26.6% of children with OME still had middle-ear fluid: 52 were randomized to ceftibuten (9 mg/kg q.d. for 14 days) and 59 to no treatment (nasal saline drops allowed). Children treated with ceftibuten had a significantly better resolution of middle-ear effusion after 4 and 8 weeks. As mass screening programmes for OME in the year of school entry are questioned, a focus only on children with known risk factors seems advisable. Ceftibuten can be useful in reducing the duration of middle-ear effusion.", "One hundred thirty-six children with otitis media with effusion of at least 2 months' duration were investigated in a strict, double-blind, randomized prospective study to evaluate the efficacy of oral steroids in the treatment of this disease. The results of our study showed a significant complete and partial recovery from otitis media with effusion in the group treated by a combination of antibiotics (amoxicillin) and oral steroids (prednisone), compared with an amoxicillin-treated group and a placebo-treated group. We believe that this treatment mostly benefits children aged 4 to 10 years without oversized adenoids. The findings of our study imply that a combined course of antibiotics and oral steroids deserves its place as a routine conservative trial before surgery.", "We followed 137 children who were found to have persistent otitis media with effusion (POME) one month after the diagnosis of acute otitis media. Subjects were randomly assigned to either treatment with erythromycin ethylsuccinate and sulfisoxizole or to no treatment. Follow-up utilizing pneumatic otoscopy and tympanometry showed that treated patients were more likely to have normal findings, and less likely to develop acute otitis media during the month following treatment. These data indicate that children with POME one month following acute otitis media may benefit from an additional course of antibiotics.", "Recently, new evidence-based recommendations have been introduced for diagnosing and managing otitis media with effusion (OME) in children. However, there are some difficulties to follow the general guidelines in the tertiary hospitals. The purpose is to evaluate the efficiency of antibiotics or antihistamines for treatment of children with OME in the tertiary hospital with a randomized prospective clinical study.\n Eighty-four children with OME who had been diagnosed in the tertiary hospital were randomized to receive 5 different medications for 2 weeks. We prescribed antibiotics (amoxicillin-clavulanate syrup) in Group I (n=16), antibiotics/steroids (prednisolone) in Group II (n=18), antibiotics/antihistamines (ebastine) in Group III (n=15), antibiotics/steroids/antihistamines in Group IV (n=17), and mucolytics (ivy leaf extract) in Group V (n=17) for control. We followed-up children every 2 weeks and evaluated the state of OME at 3 months.\n Thirty six (42.9%) of 84 children were resolved within average 6.9 weeks after the treatments. Thirty-six (42.9%) were treated with ventilation tube insertion and 12 patients (14.3%) were observed. There was no difference in the resolution rates of OME among the five different protocols (P>0.05). There was no difference in the resolution rates among groups who used steroids, antihistamines, steroids and antihistamines, or other medications to manage 42 children with allergies (P>0.05).\n In the tertiary hospital, the cure rate of children with OME was not as high as well-known, and antibiotics or anti-allergic medications were not more effective than control. We may, therefore, need any other guidelines which are different from the previous evidence-based recommendations, including early operation in the tertiary hospitals.", "To determine the effectiveness of antimicrobial treatment for otitis media with effusion (\"secretory\" otitis media) in children.\n We report the reexamination of a previously published study by Mandel et al that evaluated the efficacy of a 2-week course of antimicrobials (amoxicillin trihydrate) with and without a 4-week course of an oral decongestant-antihistamine combination in a double-blind, placebo-controlled, randomized trial involving 518 infants and children with otitis media with effusion.\n At 4 weeks, amoxicillin efficacy as determined by a tympanometric criterion (P = .121) or by a measure of improvement in hearing (P = .311) was insignificant. Only by otoscopic judgment, which is shown to contain a systematic bias as used in this clinical trial, could an argument be made for a marginal efficacy of amoxicillin at the 4-week end point. Logistic regression analyses of the combined effects of treatment and prognostic factors showed no significant differences between placebo- and antibiotic-treated groups for unilateral effusions and for bilateral effusions. When subjects with unilateral and bilateral effusions were combined, the estimated efficacy of antibiotic treatment was 12.3% by otoscopy (P = .014) and 4.8% by tympanometry (P = .171). We also demonstrate the sensitivity of outcome to diagnostic measures used and provide statistical evidence questioning the validity of otoscopic observations in this study. Six weeks after the termination of amoxicillin therapy, the recurrence of effusion was two to six times higher in the amoxicillin-treated children than in those treated with placebo (P = .001), and resolution of effusion was not significantly different among antibiotic and placebo groups (13.6% and 11.3%, respectively; P = .477).\n Amoxicillin with and without decongestant-antihistamine combination is not effective for the treatment of persistent asymptomatic middle-ear effusions in infants and children.", "Otitis media with effusion is the most common cause of hearing loss in children. Prior studies have indicated that viable bacteria may be present in this process. A controlled clinical trial was therefore undertaken to assess the efficacy of antimicrobial agents in the treatment of this disease entity over a four week period. It appears that the use of antibiotics significantly improves the outcome in patients treated for four weeks when compared with patients observed over the same time period.", "Seventy-four children were enrolled in a double-blind placebo-controlled study to define the outcome of nonsuppurative otitis media with effusion (OME) over a 12-week period. Participants were randomly assigned to one of three treatment groups: pseudoephedrine (4 mg/kg/day), chlorpheniramine (0.35 mg/kg/day), or placebo. The children were reexamined at 2, 4, 8, and 12 weeks after enrollment unless earlier dismissed from the study because OME resolved or acute suppurative otitis media developed. Of the 66 children completing the study protocol, 44 percent had resolved OME, 38 percent developed acute suppurative otitis media, 14 percent had unresolved OME, and 4 percent developed severe hearing loss or medication side effects by the end of 12 weeks. The greatest incidence of both suppurative otitis media and resolution of OME occurred by 2 weeks of follow-up. There was no significant difference in resolution of effusion between treatment groups. Children who were 18 months of age or older with unilateral effusion had the best likelihood of resolution.", "To evaluate the efficacy of adenoidectomy compared with long term chemoprophylaxis and placebo in the prevention of recurrent acute otitis media in children aged between 10 months and 2 years.\n Randomised, double blind, controlled trial.\n Oulu University Hospital, a tertiary centre in Finland.\n 180 children aged 10 months to 2 years with recurrent acute otitis media.\n Adenoidectomy, sulfafurazole (sulphisoxazole) 50 mg/kg body weight, given once a day for six months or placebo. Follow up lasted for two years, during which time all symptoms and episodes of acute otitis media were recorded.\n Intervention failure (two episodes in two months or three in six months or persistent effusion) during follow up, number of episodes of acute otitis media, number of visits to a doctor because of any infection, and antibiotic prescriptions Number of prescriptions, and days with symptoms of respiratory infection.\n Compared with placebo, interventions failed during both the first six months and the rest of the follow up period of 24 months similarly in the adenoidectomy and chemoprophylaxis groups (at six months the differences in risk were 10% (95% confidence interval -9% to 29%) and 18% (-2% to 38%), respectively). No significant differences were observed between the groups in the numbers of episodes of acute otitis media, visits to a doctor, antibiotic prescriptions, and days with symptoms of respiratory infection.\n Adenoidectomy, as the first surgical treatment of children aged 10 to 24 months with recurrent acute otitis media, is not effective in preventing further episodes. It cannot be recommended as the primary method of prophylaxis.", "To compare immediate with delayed prescribing of antibiotics for acute otitis media.\n Open randomised controlled trial. Setting: General practices in south west England.\n 315 children aged between 6 months and 10 years presenting with acute otitis media.\n Two treatment strategies, supported by standardised advice sheets-immediate antibiotics or delayed antibiotics (antibiotic prescription to be collected at parents' discretion after 72 hours if child still not improving).\n Symptom resolution, absence from school or nursery, paracetamol consumption.\n On average, symptoms resolved after 3 days. Children prescribed antibiotics immediately had shorter illness (-1.1 days (95% confidence interval -0.54 to -1.48)), fewer nights disturbed (-0.72 (-0.30 to -1.13)), and slightly less paracetamol consumption (-0.52 spoons/day (-0.26 to -0.79)). There was no difference in school absence or pain or distress scores since benefits of antibiotics occurred mainly after the first 24 hours-when distress was less severe. Parents of 36/150 of the children given delayed prescriptions used antibiotics, and 77% were very satisfied. Fewer children in the delayed group had diarrhoea (14/150 (9%) v 25/135 (19%), chi(2)=5.2, P=0.02). Fewer parents in the delayed group believed in the effectiveness of antibiotics and in the need to see the doctor with future episodes.\n Immediate antibiotic prescription provided symptomatic benefit mainly after first 24 hours, when symptoms were already resolving. For children who are not very unwell systemically, a wait and see approach seems feasible and acceptable to parents and should substantially reduce the use of antibiotics for acute otitis media.", "To study the clinical recovery from acute otitis media (AOM) in children, 2-16 years of age, managed with or without treatment with phenoxymethylpenicillin (PcV).\n An open, prospective randomized trial. Children aged between 2 and 16 years, presenting with one- or double-sided AOM (without perforation) with symptom duration of less than four days, were included. The children were randomized to PcV for five days or to no primary antibiotic treatment. A health score and compliance were registered on a daily basis for seven days.\n A total of 32 health centres and 72 GPs in south-east Sweden. Subjects. Children aged 2-16 presenting with earache.\n Recovery time, symptom duration, frequency of complications (up to three months) and consumption of healthcare services independent of treatment with or without antibiotics.\n A total of 179 patients carried out the trial; 92 were randomized to PcV, 87 to no primary antibiotic treatment. The median recovery time was four days in both groups. Patients who received PcV had less pain (p <0.001) and used fewer analgesics. There were no significant differences in the number of middle-ear effusions or perforations at the final control after three months. Children randomized to PcV treatment consulted less (p <0.001) during the first seven days.\n Our investigation supports that PcV treatment of AOM does not affect the recovery time or complication rates. PcV provided some symptomatic benefit in the treatment of AOM in otherwise healthy children, aged 2-16 years.", "A double-blind, randomized, placebo-controlled clinical trial was conducted to evaluate one month of amoxicillin-clavulanate potassium treatment of children with secretory otitis media. In total, 264 children, aged 1 to 10 years, were randomly assigned to either antibiotic or placebo treatment; 43 patients were excluded during treatment, equally distributed in both groups, leaving 221 patients completing the trial. The inclusion criterion was a type C2 and type B tympanometry result of at least three months' duration. Tympanometry was performed every month for 12 additional months. At the end of the treatment period, the disease was reversed in 61% in the antibiotic-treated group compared with 30% in the placebo-treated group (P less than .0001), and the improvement was persistently significant in favor of antibiotic for eight months. The effect was present in all age groups and independent of laterality of disease. The middle-ear status at the end of treatment was the determining factor for the outcome of tympanometry the year following treatment. From the end of treatment, there was no difference between tympanometry in a patient having been treated with the antibiotic and a patient having been treated with placebo. Antibiotic treatment shifts the individual patient from poor to better tympanometric conditions, so antibiotics can be recommended in the treatment of secretory otitis media before inserting ventilating tubes.", "This study was performed to investigate the course of spontaneous recovery from otitis media with effusion in children with chronic rhinosinusitis treated in various ways. One hundred forty-one children between 3 and 10 years of age were selected for the presence of chronic rhinosinusitis and unilateral or bilateral otitis media with effusion. The children were assigned at random to one of four treatment groups, i.e., placebo, amoxicillin combined with xylometazoline hydrochloride nose drops, maxillary sinus drainage, or a combination of the latter two forms of therapy. The follow-up period was 6 months. Drainage of the maxillary sinus had no effect on either the recovery of the chronic upper respiratory tract infection or otitis media with effusion. Amoxicillin combined with xylometazoline nose drops had no significant effect on recovery from the upper respiratory tract infection, but did have a small but significant effect on recovery from otitis media with effusion. However, the general tendency of the upper respiratory tract and ears to recover was poor. Persistence of the chronic upper respiratory tract infection during the follow-up period proved to be a negative prognostic factor with respect to cure of otitis media with effusion. Children with chronic rhinosinusitis as defined in this study appear to have a high risk of developing chronic otitis media with effusion. The results of the study are discussed.", "Many publications in recent years have argued in favor of shortened therapy for acute otitis media. However, doubt persists regarding children younger than 2 years, and some authors therefore restrict short course therapy to children older than 2 years.\n In a prospective, comparative, double blind, randomized, multicenter trial we compared cefpodoxime-proxetil, 8 mg/kg/day in two divided doses for 10 days, with an identical 5-day regimen followed by a 5-day placebo period.\n Between October, 1996, and April, 1997, 450 children (mean age, 14.3 months) were enrolled, 227 in the 5-day group and 223 in the 10-day group. In the per protocol analysis clinical success was obtained on Days 12 to 14 after the beginning of treatment (main analysis) in 175 (84.1%) of the 208 children receiving the 5-day regimen and 194 (92.4%) of the 210 children receiving the 10-day regimen (P = 0.009). The superiority of the standard regimen was more marked among children cared for outside their homes (92.5% vs. 81.5%). Clinical success persisted on Days 28 to 42 among 134 (85.4%) of the 157 assessable patients in the 5-day group and 144 (83.7%) of the 172 assessable patients in the 10-day group (P = 0.68).\n The 10-day regimen resulted in a higher success rate at the conclusion of therapy, but there were no differences between the two study groups 4 to 6 weeks after enrollment in the study protocol.", "To determine the effect of antibiotic treatment for acute otitis media in children between 6 months and 2 years of age.\n Practice based, double blind, randomised, placebo controlled trial.\n 53 general practices in the Netherlands.\n 240 children aged 6 months to 2 years with the diagnosis of acute otitis media.\n Amoxicillin 40 mg/kg/day in three doses.\n Persistent symptoms at day four and duration of fever and pain or crying, or both. Otoscopy at days four and 11, tympanometry at six weeks, and use of analgesic.\n Persistent symptoms at day four were less common in the amoxicillin group (risk difference 13%; 95% confidence interval 1% to 25%). The median duration of fever was two days in the amoxicillin group versus three in the placebo group (P=0.004). No significant difference was observed in duration of pain or crying, but analgesic consumption was higher in the placebo group during the first 10 days (4.1 v 2.3 doses, P=0.004). In addition, no otoscopic differences were observed at days four and 11, and tympanometric findings at six weeks were similar in both groups.\n Seven to eight children aged 6 to 24 months with acute otitis media needed to be treated with antibiotics to improve symptomatic outcome at day four in one child. This modest effect does not justify prescription of antibiotics at the first visit, provided close surveillance can be guaranteed.", "A total of 110 children with acute otitis media were assigned randomly to treatment with 60 mg/kg per day amoxicillin in a twice-daily (group A) or a thrice-daily (group B) regimen for 10 days. Patients were scheduled for follow-up examinations at mid-treatment, 5 days after the end of therapy and 30, 60, 90 days after starting therapy. At 15 days 6 out of 55 patients (10.9%) treated with amoxicillin twice daily were considered treatment failures compared to 4 children (7.2%) in the thrice daily group. Rates of cure, recurrent otitis media and persistent middle ear effusion were comparable in the two groups of patients at later time intervals. By 90 days the total cure rate was 42.3% (22/52) in children treated twice daily and 41.5% (22/53) in those who had received amoxicillin thrice daily. At the same time persistence of bilateral and unilateral effusion was noted in 12/52 (23.1%) and 8/52 (15.3%) children in group A and in 16/53 (30.1%) and in 10/53 (18.9%) in group B respectively. No significant difference was noted in the two treatment regimens with regard to adverse side effects. Because reduction in division of the amoxicillin dose caused no significant difference in the efficacy of antibiotic treatment of acute otitis media in infants and children, we think that this simplified scheme of therapy can routinely be used in clinical practice and thus improve compliance to antibiotic administration.", "This trial compared the efficacy of amoxicillin prophylaxis with that of placebo for the management of recurrent middle ear effusion (MEE) in children.\n Children between 7 months and 12 years of age who were effusion-free at entry but had histories of chronic or recurrent MEE were randomly assigned to receive either amoxicillin (20 mg/kg once daily) or placebo for 1 year. They were examined monthly and when there were symptoms of ear, nose or throat disease. Acute otitis media (AOM) and new episodes of otitis media with effusion (OME) were treated with amoxicillin-clavulanate; tympanocentesis was performed when possible for episodes of AOM. Throat cultures were obtained at entry; 4, 8 and 12 months after entry; and with new episodes of AOM and OME. Tympanometry was performed at each visit and audiometry was performed at entry and 4, 8 and 12 months after entry.\n One hundred eleven children were entered in this study. The rates per person year of new episodes of disease in the amoxicillin and placebo groups, respectively, were: MEE, 1.81 vs. 3.18 (P < 0.001); AOM, 0.28 vs. 1.04 (P < 0.001); and OME, 1.53 vs. 2.15 (P = 0.016). Subjects in the amoxicillin group had less time with MEE than the placebo group (19.7 and 33.2%, respectively; P = 0.002). Middle ear and throat cultures did not reveal any increase in beta-lactamase-producing organisms or in Streptococcus pneumoniae attributable to daily use of amoxicillin.\n Amoxicillin prophylaxis lowered the rates of occurrence of MEE, AOM and OME and decreased the percentage of time with MEE. However, because of present day concerns regarding antibiotic resistance, management should be individualized.", "All but 2 of the 15 published trials have failed to show a difference in efficacy between short (3 to 5 days) and standard (7 to 10 days) antibiotic regimens for acute otitis media (AOM). These studies involved relatively few patients under 2 years of age, who are at a higher risk for treatment failure.\n In a prospective, comparative, double-blind, randomized, multicenter trial, we compared amoxicillin/clavulanate in 3 divided doses for 10 days with an identical 5-day regimen, followed by a 5-day placebo period.\n Between February 1995 and May 1996, 385 children (mean age, 13.3 months) were enrolled, 194 in the 5-day treatment group and 191 in the 10-day treatment group. In the per protocol analysis, clinical success was obtained on days 12 to 14 after the beginning of treatment (main analysis) in 125 (76.7%) of the 163 children receiving the 5-day regimen and 148 (88.1%) of the 168 receiving the 10-day regimen (P = .006). Clinical success persisted on days 28 to 42 among 57 (40.4%) of the 141 assessable patients in the 5-day group and 64 (46%) of the 139 assessable patients in the 10-day group. (P = .34). Multivariate analysis showed that the 10-day course was statistically superior only among children cared for outside their homes (86.8% vs 70.8%; P = .008).\n When assessed on days 12 to 14 after the outset of treatment, a 5-day regimen is not equivalent to a 10-day regimen among young children with AOM.", "Prescribing practices for otitis media are not consistent with current evidence-based recommendations.\n To determine whether point-of-care evidence delivery regarding the use and duration of antibiotics for otitis media decreases the duration of therapy from 10 days and decreases the frequency of prescriptions written.\n Randomized, controlled trial.\n Primary care pediatric clinic affiliated with university training program. Intervention. A point-of-care evidence-based message system presenting real time evidence to providers based on their prescribing practice for otitis media.\n Proportion of prescriptions for otitis media that were for <10 days and frequency with which antibiotics were prescribed.\n Intervention providers had a 34% greater reduction in the proportion of time they prescribed antibiotics for <10 days. Intervention providers were less likely to prescribe antibiotics than were control providers.\n A point-of-care information system integrated into outpatient pediatric care can significantly influence provider behavior for a common condition.", "A randomized, controlled clinical trial was conducted in 76 children to evaluate the efficacy of trimethoprim-sulfamethoxazole for 4 weeks, prednisone for 2 weeks and aluminum ibuprofen suspension for 2 weeks in resolving chronic otitis media with effusion which had persisted for more than 8 weeks. After 2 weeks of treatment resolution rates of chronic otitis media with effusion in the prednisone and trimethoprim-sulfamethoxazole groups were significantly greater than those in the control (no treatment) and ibuprofen groups. After 4 weeks the differences in resolution rates between the control, trimethoprim-sulfamethoxazole and prednisone groups became smaller. After 12 months of follow-up, differences in hearing sensitivity among study groups were not statistically significant, although 83% of patients had a 15-dB or greater hearing loss. Therefore short term antimicrobial and antiinflammatory treatment did not appear to have a long lasting effect on chronic middle ear inflammation." ]	The results of our review do not support the routine use of antibiotics for children up to 18 years with otitis media with effusion. The largest effects of antibiotics were seen in children treated continuously for four weeks and three months. Even when clear and relevant benefits of antibiotics have been demonstrated, these must be balanced against the potential adverse effects when making treatment decisions. Immediate adverse effects of antibiotics are common and the emergence of bacterial resistance has been causally linked to the widespread use of antibiotics for common conditions such as otitis media.
CD004160	[ "12744577" ]	[ "A controlled trial of modified electroconvulsive therapy in schizophrenia in a Nigerian teaching hospital." ]	[ "The efficacy of ECT in the treatment of Schizophrenia was investigated in a double blind controlled trial. The ICD-10 criteria for Schizophrenia were fulfilled by the 20 patients who entered the trial. Consecutive individuals who satisfied the inclusion criteria were randomly allocated to a course of (bilateral) six real or simulated ECTs each as applicable. Sixteen patients completed the ECT treatment and 20 weeks follow up period. Analysis of measures of clinical change (BPRS and SANS Scores) showed that both groups of patients improved, but the improvement of patients receiving ECT was not significantly greater than that of the control group." ]	The studies in this field are few, small, poorly reported and outdated. Hypnosis could be helpful for people with schizophrenia. If we are to find this out, better designed, conducted and reported randomised studies are required. This current update has not revealed any new studies in this area since 2003.
CD003053	[ "18321486", "20435692", "15840746", "11994052", "11172832", "15921686", "15063963", "16579997", "11473953", "18505764", "20517830", "19463994", "19522426", "21114583", "19396538", "10634377", "16827766", "16501038", "9637806", "16199429", "20148739", "12093831", "10999803", "12734787", "12070543", "21193187", "19729161", "16352680", "15117902", "19892338", "11804430", "12857428", "12519844", "15302293", "15482765", "17766923", "11821265", "16543255", "11836287", "19268929" ]	[ "Comparison of clomiphene citrate, metformin, or the combination of both for first-line ovulation induction, achievement of pregnancy, and live birth in Asian women with polycystic ovary syndrome: a randomized controlled trial.", "PCOSMIC: a multi-centre randomized trial in women with PolyCystic Ovary Syndrome evaluating Metformin for Infertility with Clomiphene.", "Prospective parallel randomized, double-blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in nonobese anovulatory women with polycystic ovary syndrome.", "Metformin does not enhance ovulation induction in clomiphene resistant polycystic ovary syndrome in clinical practice.", "Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone.", "Ultra-short metformin pretreatment for clomiphene citrate-resistant polycystic ovary syndrome.", "The effects of metformin on insulin resistance, clomiphene-induced ovulation and pregnancy rates in women with polycystic ovary syndrome.", "Two weeks of metformin improves clomiphene citrate-induced ovulation and metabolic profiles in women with polycystic ovary syndrome.", "Effects of metformin on ovulation rate, hormonal and metabolic profiles in women with clomiphene-resistant polycystic ovaries: a randomized, double-blinded placebo-controlled trial.", "Extended-release metformin does not reduce the clomiphene citrate dose required to induce ovulation in polycystic ovary syndrome.", "[Indication of metformin in the management of hormonal dysfunction secondary to polycystic ovarian syndrome: prospective comparative study of 63 cases].", "An assessment of lifestyle modification versus medical treatment with clomiphene citrate, metformin, and clomiphene citrate-metformin in patients with polycystic ovary syndrome.", "Metformin effects on clomifene-induced ovulation in the polycystic ovary syndrome.", "Combined metformin and clomiphene citrate versus laparoscopic ovarian diathermy for ovulation induction in clomiphene-resistant women with polycystic ovary syndrome: a randomized controlled trial.", "Evaluating the equivalence of clomiphene citrate with and without metformin in ovulation induction in PCOS patients.", "Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation.", "The effect of metformin on fat distribution and the metabolic syndrome in women with polycystic ovary syndrome--a randomised, double-blind, placebo-controlled trial.", "The use of metformin for women with PCOS undergoing IVF treatment.", "Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome.", "Combined lifestyle modification and metformin in obese patients with polycystic ovary syndrome. A randomized, placebo-controlled, double-blind multicentre study.", "Clinical, metabolic, and endocrine parameters in response to metformin and lifestyle intervention in women with polycystic ovary syndrome: a randomized, double-blind, and placebo control trial.", "Clinical, endocrine and metabolic effects of metformin added to ethinyl estradiol-cyproterone acetate in non-obese women with polycystic ovarian syndrome: a randomized controlled study.", "Endocrine and metabolic effects of metformin versus ethinyl estradiol-cyproterone acetate in obese women with polycystic ovary syndrome: a randomized study.", "Clinical, metabolic and endocrine parameters in response to metformin in obese women with polycystic ovary syndrome: a randomized, double-blind and placebo-controlled trial.", "The effect of metformin plus clomiphene citrate on ovulation and pregnancy rates in clomiphene-resistant women with polycystic ovary syndrome.", "The effects of metformin with lifestyle therapy in polycystic ovary syndrome: a randomized double-blind study.", "Comparison of metformin treatment and laparoscopic ovarian diathermy in patients with polycystic ovary syndrome.", "Early effects of metformin in women with polycystic ovary syndrome: a prospective randomized, double-blind, placebo-controlled trial.", "Metformin treatment before IVF/ICSI in women with polycystic ovary syndrome; a prospective, randomized, double blind study.", "Metformin versus laparoscopic ovarian drilling in clomiphene- and insulin-resistant women with polycystic ovary syndrome.", "Improved responsiveness of PCOS patients to clomiphene after CYP17a inhibitor.", "The effect of metformin on ovarian stimulation and in vitro fertilization in insulin-resistant women with polycystic ovary syndrome: an open-label randomized cross-over trial.", "Metformin versus ethinyl estradiol-cyproterone acetate in the treatment of nonobese women with polycystic ovary syndrome: a randomized study.", "A randomized, 48-week, placebo-controlled trial of intensive lifestyle modification and/or metformin therapy in overweight women with polycystic ovary syndrome: a pilot study.", "Effects of metformin and rosiglitazone, alone and in combination, in nonobese women with polycystic ovary syndrome and normal indices of insulin sensitivity.", "Efficacy of metformin in obese and non-obese women with polycystic ovary syndrome: a randomized, double-blinded, placebo-controlled cross-over trial.", "Co-administration of metformin during rFSH treatment in patients with clomiphene citrate-resistant polycystic ovarian syndrome: a prospective randomized trial.", "Clomiphene citrate and dexamethazone in treatment of clomiphene citrate-resistant polycystic ovary syndrome: a prospective placebo-controlled study.", "Ovarian function and metabolic factors in women with oligomenorrhea treated with metformin in a randomized double blind placebo-controlled trial.", "Metformin effects on ovarian ultrasound appearance and steroidogenic function in normal-weight normoinsulinemic women with polycystic ovary syndrome: a randomized double-blind placebo-controlled clinical trial." ]	[ "To determine the first-line medication to be used in anovulatory patients with polycystic ovary syndrome (PCOS) for ovulation induction and pregnancy achievement.\n Randomized controlled trial.\n Infertility unit of a public hospital.\n One hundred fifteen newly diagnosed patients with PCOS based on ESHRE/ASRM criteria.\n These patients were assigned to three groups: group 1 (38 patients) received 500 mg of metformin three times a day; group 2 (39 patients) received clomiphene citrate (CC) at an incremental dose; group 3 (38 patients) received both medications.\n Rates of ovulation, pregnancy (PR), and live birth.\n The ovulation rate was 23.7% in the metformin group, 59% in the CC group, and 68.4% in the combination treatment group. This was translated into a similar PR and live birth rate, which were higher in the CC and combination groups compared to the metformin group (PR: 7.9%, 15.4%, and 21.1%; live birth rate: 7.9%, 15.4%, and 18.4% in metformin, CC, and combination treatment groups, respectively), although statistically the differences were not significant. There were no multiple pregnancies and the rate of spontaneous first trimester loss was similar to the general population.\n Clomiphene citrate should be the first-line treatment for ovulation induction in anovulatory patients with PCOS.", "Ovulation induction treatment with metformin, either alone or in combination with clomiphene citrate (CC), remains controversial even though previous randomized trials have examined this.\n A double blinded multi-centre randomized trial was undertaken including 171 women with anovulatory or oligo-ovulatory polycystic ovary syndrome. Women with high body mass index (BMI) > 32 kg/m(2) received placebo ('standard care') or metformin; women with BMI < or = 32 kg/m(2) received CC ('standard care'), metformin or both. Treatment continued for 6 months or until pregnancy was confirmed. Primary outcomes were clinical pregnancy and live birth.\n For women with BMI > 32 kg/m(2), clinical pregnancy and live birth rates were 22% (7/32) and 16% (5/32) with metformin, 15% (5/33) and 6% (2/33) with placebo. For women with BMI < or = 32 kg/m(2), clinical pregnancy and live birth rates were 40% (14/35) and 29% (10/35) with metformin, 39% (14/36) and 36% (13/36) with CC, 54% (19/35) and 43% (15/35) with combination metformin plus CC.\n There is no evidence that adding metformin to 'standard care' is beneficial. Pregnancy and live birth rates are low in women with BMI > 32 kg/m(2) whatever treatment is used, with no evidence of benefit of metformin over placebo. For women with BMI < or = 32 kg/m(2) there is no evidence of significant differences in outcomes whether treated with metformin, CC or both. ClinicalTrials.gov number NCT00795808; trial protocol accepted for publication November 2005: Johnson, Aust N Z Journal Obstet Gynaecol 2006;46:141-145.", "Although metformin has been shown to be effective in the treatment of anovulation in women with polycystic ovary syndrome (PCOS), clomiphene citrate (CC) is still considered to be the first-line drug to induce ovulation in these patients.\n The goal of this study was to compare the effectiveness of metformin and CC administration as a first-line treatment in anovulatory women with PCOS.\n We describe a prospective parallel randomized, double-blind, double-dummy controlled clinical trial.\n The study was conducted at the University \"Magna Graecia\" of Catanzaro, Catanzaro, Italy.\n One hundred nonobese primary infertile anovulatory women with PCOS participated.\n We administered metformin cloridrate (850 mg twice daily) plus placebo (group A) or placebo plus CC (150 mg for 5 d from the third day of a progesterone withdrawal bleeding) (group B) for 6 months each.\n The main outcome measures were ovulation, pregnancy, abortion, and live-birth rates.\n The subjects of groups A (n = 45) and B (n = 47) were studied for a total of 205 and 221 cycles, respectively. The ovulation rate was not statistically different between either treatment group (62.9 vs. 67.0%, P = 0.38), whereas the pregnancy rate was significantly higher in group A than group B (15.1 vs. 7.2%, P = 0.009). The difference found between groups A and B regarding the abortion rate was significant (9.7 vs. 37.5%, P = 0.045), whereas a positive trend was observed for the live-birth rate (83.9 vs. 56.3%, P = 0.07). The cumulative pregnancy rate was significantly higher in group A than group B (68.9 vs. 34.0%, P < 0.001).\n Six-month metformin administration is significantly more effective than six-cycle CC treatment in improving fertility in anovulatory nonobese PCOS women.", "To determine whether metformin pretreatment has beneficial effects in clomiphene resistant infertile women with polycystic ovary syndrome (PCOS) in an infertility clinic.\n This was a randomized placebo controlled double-blind crossover study of 3 months metformin (1500 mg day-1)/placebo, followed by 3 months metformin/placebo together with clomiphene (50-100 mg for 5 days) for three cycles in clomiphene resistant women with PCOS. The primary outcomes were restoration of spontaneous menses, ovulation induction (spontaneous or clomiphene induced) and pregnancy. Secondary endpoints were changes in biochemical parameters related to androgens and insulin.\n Twelve women completed the metformin arm and 14 the placebo arm. Spontaneous menstruation resumed in five metformin treated patients and in six placebo treated women, P=0.63. No women given metformin spontaneously ovulated, although one patient given placebo did, P=0.30. There was no difference in the efficacy of clomiphene between the two groups with ovulation being induced in five (out of 12) metformin treated women and four (out of 14) placebo treated women, P=0.63. Pregnancy occurred in three (out of 12) women given metformin and two (out of 14) women given placebo, P=0.59.\n Metformin is not always beneficial when given to clomiphene resistant infertile women with PCOS in clinical practice.", "To determine whether metformin treatment increases the ovulation and pregnancy rates in response to clomiphene citrate (CC) in women who are resistant to CC alone.\n Randomized, double-blind, placebo-controlled trial.\n Multicenter environment.\n Anovulatory women with the polycystic ovary syndrome (PCOS) who were resistant to CC.\n Participants received placebo or metformin, 500 mg three times daily, for 7 weeks. Information on reproductive steroids, gonadotropins, and oral glucose tolerance testing was obtained at baseline and after treatment. Metformin or placebo was continued and CC treatment was begun at 50 mg daily for 5 days. Serum P level > or =4 ng/mL was considered to indicate ovulation. With ovulation, the daily CC dose was not changed, but with anovulation it was increased by 50 mg for the next cycle. Patients completed the study when they had had six ovulatory cycles, became pregnant, or experienced anovulation while receiving 150 mg of CC.\n Ovulation and pregnancy rates.\n In the metformin and placebo groups, 9 of 12 participants (75%) and 4 of 15 participants (27%) ovulated, and 6 of 11 participants (55%) and 1 of 14 participants (7%) conceived, respectively. Comparisons between the groups were significant.\n In anovulatory women with PCOS who are resistant to CC, metformin use significantly increased the ovulation rate and pregnancy rate from CC treatment.", "To evaluate the effect of ultra-short (12 days) metformin pretreatment in clomiphene-citrate (CC) resistant polycystic ovary syndrome (PCOS).\n Eighty women with CC-resistant PCOS were randomly allocated to metformin pretreatment or usual treatment. Forty women received 1500 mg metformin daily for 12 days, followed by clomiphene 150 mg daily for 5 days along with metformin. Forty women (control group) received the same dose of clomiphene but no metformin pretreatment.\n In the metformin group, 17 (42.5%) women ovulated, and 6 (15%) conceived. In the control group, 5 (12.5%) women ovulated but none conceived. Compared with the control group, the metformin group had significantly higher ovulation (P = 0.03) and pregnancy rates (P = 0.026).\n Twelve days of metformin pretreatment improves ovulation and pregnancy rates in women with CC-resistant PCOS.", "To evaluate the effects of metformin on insulin resistance, ovarian androgen production, and clomiphene-induced ovulation and pregnancy rates in infertile women with polycystic ovary syndrome (PCOS).\n Twenty-one infertile women with PCOS were selected in this prospective randomized clinical study. Basal steroid and gonadotropin levels were measured, and oral glucose tolerance test (OGTT) was performed. The patients were divided randomly into group 1 (n = 11) and group 2 (n = 10). Group 1 patients were treated with 1700 mg per day of metformin for 3 months. The basal tests and OGTT were repeated after metformin therapy. Group 2 patients did not receive metformin. The patients in both groups received 100 mg of clomiphene citrate (CC) daily for 5 days until either a pregnancy occurred, or six CC cycles were reached. Metformin administration continued during CC therapy until the day of hCG in group 1. Serum progesterone (P) level >or=5 ng/ml was considered as confirmatory of ovulation. Ovulation and pregnancy rates after six cycles were determined.\n Serum androgens and insulin response to OGTT decreased significantly after metformin therapy. Midluteal serum P level was significantly higher in cycles treated with metformin plus CC (P < 0.05). The ovulation (38 of 51 cycles, 74.4% versus 34 of 55 cycles, 61.8%) and pregnancy rates (5 of 11 women, 45.5% versus 3 of 10 women, 30%) were higher, but not significantly, in the metformin plus CC group than in the CC alone group. All the patients who conceived had insulin resistance in group 1 whereas non-insulin resistance in group 2.\n Metformin improves insulin resistance and reduces androgen levels. Metformin did not increase significantly the ovulation and pregnancy rates.", "To determine if short courses of metformin (MET) administration in patients with polycystic ovary syndrome (PCOS) would reduce fasting insulin and improve the efficacy of clomiphene citrate (CC) to induce ovulation.\n A randomized prospective trial involving 31 subjects with PCOS and infertility.\n University-based medical center.\n Obese patients (body mass index > 29 kg/m2) with PCOS.\n Patients with PCOS were treated either with CC or CC+MET for 2 weeks.\n Ovulation as determined by serum P, serum insulin, and total and free T.\n In the CC/MET group, a significant increase in sex hormone-binding globulin (SHBG) levels, a decrease in fasting insulin, and an increase in fasting glucose/fasting insulin was detected on day 21 of the cycle. Of these parameters, only SHBG levels increased significantly in the CC group. In the CC/MET group, a significant increase in day 21 progesterone occurred, with 44% of subjects ovulating in the CC+MET group as compared with 6.7% in the CC group. Five subjects in the CC+MET group and none in the CC group conceived. Total and free testosterone levels did not change significantly for either group.\n In obese PCOS patients, 2 weeks of MET significantly reduces serum insulin and insulin resistance and increases SHBG levels, resulting in an improved response to CC. This regimen may be beneficial in noncompliant patients or those with intolerance to the side effects of MET.", "Metformin, an insulin-sensitizing agent, has been used successfully as the first-line drug to induce ovulation in women with polycystic ovary syndrome. There are, however, very few studies evaluating metformin treatment in women with clomiphene citrate (CC)-resistant polycystic ovaries (PCO).\n Twenty infertile Chinese women aged <40 years, who had ultrasound features of PCO and remained anovulatory on CC, were randomized by computer using the sealed envelope method to receive placebo or metformin 500 mg three times a day for 3 months. Hormonal and metabolic profiles were determined before the therapy and were repeated after 3 months for women who failed to become pregnant within this period. Clomiphene was then added for one cycle to those women who did not ovulate after taking placebo or metformin alone.\n The median ovulation rate in the placebo group was 0% (range: 0--50%) after placebo only and 6.9% (range: 0--50%) after placebo and CC, whereas the corresponding rates in the metformin group were 0% (range: 0--22%) and 0% (range: 0--22%) respectively. There was no improvement in the ovulation rate despite a significant reduction of body mass index, serum testosterone and fasting leptin concentrations in the metformin group.\n Metformin treatment may result in successful ovulation only in certain subgroups of these women.", "When used for ovulation induction, higher doses of clomiphene may lead to antiestrogenic side effects that reduce fecundity. It has been suggested that metformin in combination with clomiphene can restore ovulation to some clomiphene-resistant anovulators with polycystic ovary syndrome (PCOS).\n Our objective was to determine if cotreatment with extended-release metformin (metformin XR) can lower the threshold dose of clomiphene needed to induce ovulation in women with PCOS.\n A secondary analysis of data from the National Institute of Child Health and Human Development Cooperative Multicenter Reproductive Medicine Network prospective, double-blind, placebo-controlled multicenter clinical trial, Pregnancy in Polycystic Ovary Syndrome, was performed.\n Study volunteers at multiple academic medical centers were included.\n Women with PCOS and elevated serum testosterone who were randomized to clomiphene alone or with metformin (n = 209 in each group) were included in the study.\n Clomiphene citrate, 50 mg daily for 5 d, was increased to 100 and 150 mg in subsequent cycles if ovulation was not achieved; half also received metformin XR, 1000 mg twice daily. Treatment was for up to 30 wk or six cycles, or until first pregnancy.\n Ovulation was confirmed by a serum progesterone more than or equal to 5 ng/ml, drawn prospectively every 1-2 wk.\n The overall prevalence of at least one ovulation after clomiphene was 75 and 83% (P = 0.04) for the clomiphene-only and clomiphene plus metformin groups, respectively. Using available data from 314 ovulators, the frequency distribution of the lowest clomiphene dose (50, 100, or 150 mg daily) resulting in ovulation was indistinguishable between the two treatment groups.\n Metformin XR does not reduce the lowest dose of clomiphene that induces ovulation in women with PCOS.", "Polycystic ovarian syndrome (PCOS) is the most common hormonal dysfunction in women. It's a cause of female infertility by oligoanovulation, clinical and biochemical hyperandrogenism and polycystic ovaries. Weight loss, firstly proposed in overweight or obese patient suffering from PCOS, aims to reduce hyperinsulinism and hyperandrogenism. Recently, Metformin, an insulin sensitizer, has been proposed as an alternative first line treatment for polycystic ovarian syndrome by improving hyperinsulinemia and hyperandrogenism in these women.\n The aim of our study, and through a literature review, is to demonstrate if Metformin should be used as a first-line drug for infertile women with this syndrome or as an adjunction to Clomifene Citrate, the longest established treatment already used in this syndrome.\n A prospective comparative study including 63 patients with PCOS has been done during 2 years. Women were randomly allocated to clomifene + Metformin (Metformin group, Metformin took during 8 weeks, 850 mg twice a day, plus Clomifene 100 mg per day during five days) or Clomifene only (100 mg per day during five days). All patients underwent a two- month's diet.\n The middle age was about 30.63 years and the body mass index (BMI) was about 29.88 kg/ m(2). We noticed a 6.2% weight loss in both groups (a non significant difference in p=0.04). The median of infertility period was about 2.49 years. The ovulation rate in the Metformin group was 53.12% (significant difference for inducing ovulation p=0.02) and 32.25% in Clomifene group (non-significant difference 0.07). There was also a significant difference for ongoing pregnancies (p=0.04). In fact, 11 on 32 patients (34%) achieved a full-term pregnancy in Metformin group versus only 4 ones on 31 patients (12.9%) in Clomifene group.\n Our conclusion is that Metformin is an effective addition to Clomifene Citrate in term of reestablishment of ovulation and full-term pregnancies achievement, excluding ART cycles.", "To compare the effect of clomiphene citrate, metformin, and lifestyle modification on treatment of patients with polycystic ovary syndrome (PCOS).\n Prospective randomized double-blind study.\n University-based infertility clinic and research center.\n Three hundred forty-three overweight infertile women with PCOS.\n The participating women were assigned to four groups: clomiphene (n = 90), metformin (n = 90), clomiphene + metformin (n = 88), and lifestyle modification (n = 75). The patients in each group received standardized dietary and exercise advice from a dietitian.\n The primary outcome variables were change in menstrual cycle, waist circumference measurements, endocrine parameters, and lipid profile. The main secondary outcome variable was clinical pregnancy rate.\n The clinical pregnancy rate was 12.2% in clomiphene group, 14.4% in metformin group, 14.8% in clomiphene + metformin group, and 20% in lifestyle modification group. Lifestyle modification group achieved a significant reduction in waist circumference, total androgen, and lipid profile.\n Lifestyle modification improves the lipid profile in PCOS patients. Therefore, lifestyle modification may be used as the first line of ovulation induction in PCOS patients.\n Copyright (c) 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.", "Polycystic ovary syndrome (PCOS) is a common, complex endocrine disorder for women on reproductive age. A high incidence of ovulation failure is observed in PCO women and perhaps linked to insulin resistance related to metabolic features In the last few years some studies assessed hyperinsulinimea and insulin resistance attenuation effects, by insulin sensitizing agents such as metformin, in PCOS women suggesting potential scope for these drugs in CC ovulation induction quality improvement.\n Our prospective study aim is to compare the effectiveness of clomifene citrate plus metformin and clomifene citrate plus placebo in women with newly diagnosed polycystic ovary syndrome.\n From February 24 to September 29 (2007), PCOS was explored on women attending the Department of Obstetrics & Gynaecology sterility consultation unit (CHU Hedi Chaker-Sfax) according to the Rotterdam 2003 diagnostic criteria. PCOS patients were randomized to receive, in addition to clomifene citrate treatment, placebo or metformin 850 mg two times a day all ovulatory cycle for three trials maximum. Ovulation detection was done by the E2 serum measurements and ovarian transvaginal ultrasonography' evolution controlling on 7th, 11th and 13th day of the cycle.\n Within 7 months, 32 PCOS women were recruited in the study and equally allocated to the two groups. Baseline characteristics were similar in metformin group and placebo one. Ovulation was characterized by the presence of at least one mature follicle (> 16 mm), a circulating estradiol concentration in the edge of 150-250 pg and accessory an endometrial depth > 8 mm. The ovulation rate in the metformin group was 62.5% compared with 37.5% in the placebo group, a non-statistically significant (small study population) but important difference (1.66 times). Analyses show a higher mature follicle number and estradiol concentration in metformin group than in the placebo one. Metformin effect was, in our study, his only insulinosensitizer property consequence far away a 'making thinner' or Hyperandrogenism reducing ones.\n The ovulatory response to clomifene can be increased in polycystic ovary syndrome women by decreasing insulin secretion with metformin.", "To compare the effect of combined metformin and clomiphene citrate (CC) with laparoscopic ovarian diathermy (LOD) meant for ovulation induction in CC-resistant women with polycystic ovary syndrome (PCOS).\n Two-hundred and eighty-two anovulatory women with CC-resistant PCOS were selected in this randomized controlled trial. Patients (n = 138) received combined metformin-CC for up to six cycles or underwent LOD (n = 144) with six months follow up. The outcome measures were: ovulation rate, midcycle endometrial thickness, pregnancy and miscarriage rates.\n Ovulation occurred in 386/576 cycles (67%) in the combined metformin-CC group and 381/558 cycles (68.2%) in LOD group without a significant difference between the groups. Resumption of regular menstruation was similar in both groups. A significant increase in midcycle endometrial thickness was observed in the combined metformin-CC group (9.2 ± 1.2 mm vs 7.6 ± 1.1 mm) (P < 0.05). The pregnancy rate was similar in both groups (15.4% vs 17%), and there were no statistically significant differences regarding the miscarriage rate between both groups. Four twin pregnancies occurred in the metformin-CC group. No ovarian hyperstimulation occurred in either group.\n Combined metformin-CC and LOD are equally effective for inducing ovulation and achieving pregnancy in CC-resistant PCOS patients.\n © 2010 The Authors. Journal of Obstetrics and Gynaecology Research © 2010 Japan Society of Obstetrics and Gynecology.", "To evaluate the benefit of Metformin added to Clomiphene Citrate in a primary ovulation induction protocol in PCOS patients.\n Prospective randomised controlled study.\n Tygerberg Academic Hospital, Stellenbosch University and the Institute of Reproductive Medicine at Vincent Pallotti Hospital, Cape Town.\n 107 patients presenting with PCOS.\n Group A was pre-treated with metformin 850 mg twice a day for at least 6 weeks before clomiphene was added and the metformin was used throughout the study period. Group B received clomiphene without pre-treatment with metformin. In both groups clomiphene was given at a starting dose of 50 mg day 4-8 and increase with increments of 50 mg to a maximum of 150 mg if no response was achieved.\n The ovulation rate achieved in women in the M+C/C arm was 34/52 (65.4%) compared to 36/55 (65.5%) in the C/C arm. The treatment effect ((M+C/C) - C/C) is 0% with 95% confidence interval of -18.1% to 18%. The per protocol ovulation results were 34/42 (81%) in the M+C/C arm compared to 36/48 (75%) in the C/C arm. The ovulation rate difference was 6% with 95% confidence interval -11% to 22%. In a comparison of successful ovulating versus non-ovulating women from the trial the following were significant baseline determinants: lower median weight in the ovulating group (77 kg versus 86 kg, p = .021), lower median bmi (29.0 versus 32.9, p = .009), lower median DHEAS at baseline (4.6 compared to 7.0, p = .049), lower median 17OH-progesterone (2.2 versus 4.6, p = .027) and higher baseline median SHBG ( 37.8 compared to 28.5, p = .036).\n Although identical ovulation rates were observed in both arms equivalence could not be concluded with respect to the specified criteria.", "In the last few years some studies assessed the effects of attenuation of hyperinsulinemia and insulin resistance, obtained by insulin sensitizing agents, in women with polycystic ovary syndrome (PCOS), suggesting potential scope for these drugs in treating the whole spectrum of reproductive, endocrine, and metabolic abnormalities found in such subjects. However, the results of these studies, mostly uncontrolled and short-term, are still inconclusive, and there is no long-term follow-up. In the present study, 23 PCOS subjects [mean (+/- SE) body mass index 30.0+/-1.1 kg/m2] were randomly assigned to double-blind treatment with metformin (500 mg tid) or placebo for 6 months, while maintaining their usual eating habits. Before and after treatment, menstrual history, endocrine and metabolic profiles, serum 17-hydroxyprogesterone response to GnRH-agonist testing, and insulin sensitivity measured by the glucose clamp technique were assessed. Eighteen of these women, as well as 14 additional PCOS patients, were subsequently given metformin in an open trial for 11.0+/-1.3 months (range 4-26), to assess long-term effects of treatment and baseline predictors of metformin efficacy on reproductive abnormalities. After metformin treatment, mean frequency of menstruation improved (P = 0.002), due to striking amelioration of menstrual abnormalities in about 50% of subjects. Women given metformin showed reduced plasma insulin (at fasting: P = 0.057; during the clamp studies: P<0.01) and increased insulin sensitivity (P<0.05). Concurrently, ovarian hyperandrogenism was attenuated, as indicated by significant reductions in serum free testosterone (P<0.05) and in the 17-hydroxyprogesterone response to GnRH-agonist testing (P<0.05). No changes were found in the placebo group. Only comparable minor changes in body mass index were found both in the metformin group and in the placebo group. In the open, long-term trial 17 women (54.8%) showed striking improvements of their menstrual abnormalities and were considered as responders. Logistic regression analysis of baseline characteristics in responders and nonresponders showed that plasma insulin, serum androstenedione, and menstrual history were independent predictors of the treatment's clinical efficacy. In 10 subjects whose menses proved regular after treatment, the great majority of cycles became ovulatory (32 out of 39 assessed, 79%). In conclusion, in women with PCOS metformin treatment reduced hyperinsulinemia and hyperandrogenemia, independently of changes in body weight. In a large number of subjects these changes were associated with striking, sustained improvements in menstrual abnormalities and resumption of ovulation. Higher plasma insulin, lower serum androstenedione, and less severe menstrual abnormalities are baseline predictors of clinical response to metformin.", "To establish whether metformin has a significant action in reducing visceral fat and improving other metabolic parameters in women with polycystic ovary syndrome (PCOS).\n Randomised, double-blind, placebo-controlled trial.\n Reproductive medicine clinic.\n Forty women with anovulatory PCOS.\n Participants were randomised into receiving metformin 500 mg three times a day or placebo for 3 months.\n Fat distribution was measured by computed tomography scan. Secondary outcome measures included serum indices of the metabolic syndrome and evidence of ovulation.\n We found no significant differences in any of the measures of fat distribution between the placebo and metformin groups. The metformin group had significantly lower total cholesterol (P= 0.02), low-density lipoprotein cholesterol (P= 0.02) and cholesterol:high-density lipoprotein cholesterol ratio (P= 0.05), but there was no statistically significant treatment effect on androgens, insulin, insulin resistance, triglycerides, ovulation or pregnancy.\n Metformin has no clinically significant effect in reducing visceral fat mass, although it does have a beneficial effect on lipids. This trial lends support to the growing evidence that metformin is not a weight loss drug. Metformin might therefore be used as an adjunct to lifestyle modification in women with PCOS, but not as a substitute for it.", "Metformin appears to improve reproductive function in some women with polycystic ovary syndrome (PCOS). We wished to explore the effect of metformin in women with PCOS undergoing IVF.\n A randomized, placebo-controlled, double-blind study was carried out between 2001 and 2004. Patients with PCOS undergoing IVF/ICSI treatment using a long GnRH agonist protocol were randomized to receive metformin (MET), 850 mg, or placebo (PLA) tablets twice daily from the start of the down-regulation process until the day of oocyte collection. The primary outcome was to be an improvement in the overall fertilization rate.\n One-hundred and one IVF/ICSI cycles were randomized to receive metformin (52) or to receive placebo (49). There was no difference in the total dose of rFSH required per cycle (median dose: MET = 1200 U, PLA = 1300 U; P = 0.937). The median number of oocytes retrieved per cycle (MET = 17.2, PLA = 16.2; P = 0.459) and the overall fertilization rates (MET = 52.9%, PLA = 54.9%; P = 0.641) did not differ. However, both the clinical pregnancy rates beyond 12 weeks gestation per cycle (MET = 38.5%, PLA = 16.3%; P = 0.023) and per embryo transfer (MET = 44.4%, PLA = 19.1%; P = 0.022) were significantly higher in those treated with metformin. Furthermore, a significant decrease in the incidence of severe ovarian hyperstimulation syndrome (OHSS) was observed (MET = 3.8%, PLA = 20.4%; P = 0.023), and this was still significant after adjustment for BMI, total rFSH dose and age (OR = 0.15; 95% CI: 0.03, 0.76; P = 0.022).\n Short-term co-treatment with metformin for patients with PCOS undergoing IVF/ICSI cycles does not improve the response to stimulation but significantly improves the pregnancy outcome and reduces the risk of OHSS.", "Obese women with the polycystic ovary syndrome are relatively unresponsive to the induction of ovulation by clomiphene. We hypothesized that reducing insulin secretion by administering metformin would increase the ovulatory response to clomiphene.\n We performed oral glucose-tolerance tests before and after the administration of 500 mg of metformin or placebo three times daily for 35 days in 61 obese women with the polycystic ovary syndrome. Women who did not ovulate spontaneously were then given 50 mg of clomiphene daily for five days while continuing to take metformin or placebo. Serum progesterone was measured on days 14, 28, 35, 44, and 53, and ovulation was presumed to have occurred if the concentration exceeded 8 ng per milliliter (26 nmol per liter) on any of these days.\n Twenty-one women in the metformin group and 25 women in the placebo group were given clomiphene because they did not ovulate spontaneously during the first phase of the study. Among the 21 women given metformin plus clomiphene, the mean (+/-SE) area under the serum insulin curve after oral glucose administration decreased from 6745+/-2021 to 3479+/-455 microU per milliliter per minute (40.5+/-12.1 to 20.9+/-2.7 nmol per liter per minute, P=0.03), but it did not change significantly in the 25 women given placebo plus clomiphene. Nineteen of the 21 women (90 percent) who received metformin plus clomiphene ovulated (mean peak serum progesterone concentration, 23.8+/-3.4 ng per milliliter [7.6+/-10.9 nmol per liter]). Two of the 25 women (8 percent) who received placebo plus clomiphene ovulated (P<0.001). Overall, 31 of the 35 women (89 percent) treated with metformin ovulated spontaneously or in response to clomiphene, as compared with 3 of the 26 women (12 percent) treated with placebo.\n The ovulatory response to clomiphene can be increased in obese women with the polycystic ovary syndrome by decreasing insulin secretion with metformin.", "It has been reported that women with polycystic ovary syndrome (PCOS) benefit from metformin therapy.\n A randomized, placebo-controlled, double-blind study of obese (body mass index >30 kg/m2), oligo-/amenorrhoeic women with PCOS. Metformin (850 mg) twice daily was compared with placebo over 6 months. All received the same advice from a dietitian. The primary outcome measures were: (i) change in menstrual cycle; (ii) change in arthropometric measurements; and (iii) changes in the endocrine parameters, insulin sensitivity and lipid profile.\n A total of 143 subjects was randomized [metformin (MET) = 69; placebo (PL) = 74]. Both groups showed significant improvements in menstrual frequency [median increase (MET = 1, P < 0.001; PL = 1, P < 0.001)] and weight loss [mean (kg) (MET = 2.84; P < 0.001 and PL = 1.46; P = 0.011)]. However, there were no significant differences between the groups. Logistic regression analysis was used to analyse the independent variables (metformin, percentage of weight loss, initial BMI and age) in order to predict the improvement of menses. Only the percentage weight loss correlated with an improvement in menses (regression coefficient = 0.199, P = 0.047, odds ratio = 1.126, 95% CI 1.001, 1.266). There were no significant changes in insulin sensitivity or lipid profiles in either of the groups. Those who received metformin achieved a significant reduction in waist circumference and free androgen index.\n Metformin does not improve weight loss or menstrual frequency in obese patients with PCOS. Weight loss alone through lifestyle changes improves menstrual frequency.", "The aim of this study was to evaluate the effects of metformin in addition to diet and exercise on endocrine and metabolic disturbances in women with polycystic ovary syndrome (PCOS) in a prospective, double-blind, randomized, placebo (PBO) control trial. Thirty women with insulin resistance and PCOS received lifestyle modification and 1500 mg of metformin or placebo for 4 months. Before and after treatment, body mass index, waist/hip ratio, blood pressure, hirsutism, and menstrual patterns were evaluated. Serum concentrations of gonadotropins, androgens, progesterone, glucose, insulin, and lipids were measured. Lifestyle interventions resulted in similar weight and menstrual cycle's improvements in both groups. A significant reduction in serum fasting insulin, HOMA index, waist and testosterone levels was only observed with metformin. There were no significant changes in androstenedione, dehydroepiandrosterone sulfate, gonadotropins, and lipids levels. No other changes were observed in hirsutism or blood pressure. These findings suggest that metformin has an additive effect to diet and exercise to improve parameters of hyperandrogenism and insulin resistance. Although, a small decrease in body weight trough lifestyle changes could be enough to improve menstrual cycles in insulin-resistant women with PCOS.", "Oral contraceptive pills (OC) are usually the first choice of treatment for polycystic ovarian syndrome (PCOS), when fertility is not desired. However, they do not improve, or may even further induce impairment of insulin sensitivity, which is already impaired in women with PCOS. In this prospective, randomized study, we analysed the additional benefits of adding metformin to the OC treatment in non-obese women with PCOS.\n After a baseline work-up including body mass index (BMI), waist:hip ratio (WHR), Ferriman-Gallwey score, ovarian volume, serum gonadotrophin, androgen and sex hormone-binding globulin (SHBG) levels, and fasting lipid, glucose and insulin levels, 40 non-obese women with PCOS were assigned either to the OC or to the OC + metformin treatment by computer-assisted randomization. At the end of the 4 month follow-up period, subjects were re-evaluated.\n The two groups were similar at baseline. After treatment, women in the OC + metformin group had significant decreases in BMI and WHR, and a significant increase in insulin sensitivity, in contrast to those in the OC group, who had insignificant changes in these parameters. Adding metformin also caused significant improvements in serum androstenedione and SHBG levels compared with the OC treatment alone.\n Adding metformin to the OC treatment may improve the insulin sensitivity, and may further suppress the hyperandrogenaemia in non-obese women with PCOS.", "Metformin, a biguanide antihyperglycemic drug, has been shown to improve ovarian function and glucose metabolism in women with polycystic ovary syndrome (PCOS), but results concerning its effects on insulin sensitivity are controversial. Oral contraceptive pills are commonly used in the treatment of PCOS; but, like metformin, their influence on insulin sensitivity is not well known. We randomized 32 obese (body mass index > 27 kg/m2) women with PCOS, either to metformin (500 mg x 2 daily for 3 months, then 1,000 mg x 2 daily for 3 months) or to ethinyl estradiol (35 microg)-cyproterone acetate (2 mg) oral contraceptive pills (Diane Nova) for 6 months. Metformin significantly decreased the waist-to-hip ratio, serum testosterone, fasting free fatty acid, and insulin concentrations and improved oxidative glucose utilization and menstrual cyclicity, with slight (but nonsignificant) improvements in insulin hepatic extraction and insulin sensitivity. Diane Nova significantly decreased serum testosterone and increased serum sex hormone-binding globulin concentrations and glucose area under the curve during oral glucose tolerance test. It is concluded that metformin, probably by way of its effect on adipose tissue, leads to reduction of hyperinsulinemia and concomitant improvement in the menstrual pattern; and therefore, it offers a useful alternative treatment for obese, anovulatory women with PCOS. Despite slight worsening of glucose tolerance, Diane Nova is an efficient treatment for women with hyperandrogenism and hirsutism.", "There is still some controversy concerning the effects of metformin in the treatment of Polycystic Ovary Syndrome (PCOS). The aim of this study was to asses the effect of metformin on clinical, metabolic and hormone parameters in obese women with PCOS. Thirty obese, non-diabetic women with PCOS received 500 mg of metformin or placebo, TID, over 90 days. Assessed parameters included body mass index, waist-to-hip ratio, blood pressure, FSH, LH, total testosterone, SHBG, fasting insulinemia, insulin-to-glucose ratio, total, HDL and LDL cholesterol, triglycerides, and menstrual cycles before and after the use of the drugs. Before treatment, patients did not differ in the two groups. After 90 days of metformin use, PCOS women presented significantly lower levels of total testosterone (p = 0.030) and total cholesterol (p = 0.023) compared to the women that used placebo. The other parameters did not differ between the groups. In conclusion, obese women with PCOS may benefit from the use of metformin through the reduction of hyperandrogenemia, total cholesterol, and possibly by restoration of regular menstrual cycles. Further studies with longer follow-ups are necessary to determine cardiovascular and endometrial metformin benefits and insulin-resistance decrease in women with polycystic ovary syndrome.", "To study the effect of metformin in combination with clomiphene citrate, as compared with placebo plus clomiphene citrate, on the ovulation and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome.\n This study was carried out at King Hussein Medical Center, Amman, Jordan, during the period January 2001 through to July 2001. Twenty-eight clomiphene citrate-resistant polycystic ovary syndrome women were evaluated prospectively for 6 treatment cycles by receiving metformin, 850mg twice daily throughout the cycle along with 50 mg clomiphene citrate, starting on day 5-9 of the same cycle (N=16), or by taking placebo with clomiphene citrate (N=12). During cycles 2-6, clomiphene citrate was added with increments of 50mg (up to 200 mg/day) for both groups. Progesterone level on day 21 and 28 >5ng/dl was indicative of ovulation.\n A statistically significant increase in the rates of ovulation (68.6% versus 25%, p<0.05) and pregnancy (56.3% versus 16.6%, p<0.05) were observed in the metformin-clomiphene citrate group as compared with the placebo-clomiphene citrate controls. Insignificant increase in the rate of ovarian hyperstimulation was noted in the placebo-clomiphene citrate group.\n Metformin-clomiphene citrate regimen in resistant-clomiphene citrate polycystic ovary syndrome women significantly increases the ovulation and pregnancy rates, and decreases the occurrence of ovarian hyperstimulation syndrome.", "To determine if the combination of lifestyle (caloric restriction and exercise) and metformin (MET) would be superior to lifestyle and placebo (PBO) in improving the polycystic ovary syndrome (PCOS) phenotype.\n Double-blind randomized 6-month trial of MET versus PBO.\n Two academic medical centers.\n One hundred fourteen subjects with PCOS were randomized to MET (N = 55) or PBO (N = 59).\n Subjects collected urine daily for ovulation monitoring, had monthly monitoring of hormones and weight and determination of body composition by dual-energy x-ray absorptiometry, glucose tolerance, and were evaluated for quality of life at baseline and completion.\n Ovulation rates and testosterone levels.\n Dropout rates were high. There was no significant difference in ovulation rates. Testosterone levels were significantly lower compared with baseline in the MET group at 3 mos but not at 6 mos. There were no differences in weight loss between groups, but MET showed a significant decline at 6 months compared with baseline (-3.4 kg, 95% confidence interval -5.3 to -1.5 kg). We noted divergent effects of MET versus PBO on oral glucose tolerance test indices of insulin sensitivity (increased) and secretion (worsened). Total bone mineral density increased significantly in MET. There were no differences in quality of life measures between the groups. The MET group had increased diarrhea and headache, but fewer bladder infections and musculoskeletal complaints.\n The addition of metformin to lifestyle therapy produced little reproductive or glycemic benefit in women with PCOS, although our study had limited power owing to a high dropout rate. It is not possible at baseline to identify women likely to drop out.\n Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.", "To compare hormone levels and clinical outcomes in patients with polycystic ovary syndrome (PCOS) after metformin therapy or laparoscopic ovarian diathermy (LOD) at 6 months follow-up.\n A randomized trial was conducted in 126 patients with PCOS who had a history of infertility for at least 1 year and resistance to clomiphene citrate (CC). Patients (n=63) received metformin treatment or underwent LOD (n=63).\n Levels of follicle-stimulating hormone did not change in either group after the intervention (P>0.05). Serum levels of testosterone (P<0.001) and luteinizing hormone (P<0.001) were significantly lower after the treatment in both groups. The proportion of women with regular menstrual cycles increased significantly to 35% (P<0.001) in the LOD group and to 49% (P<0.001) in metformin group compared with before the intervention. Although proportion was higher in the metformin group compared with the LOD group, the difference was not significant (odds ratio 1.81; 95% CI, 0.88-3.69, P=0.1). Hirsutism decreased significantly from 100% to 79.37% (P<0.001) in both groups.\n CC-resistant patients with PCOS were treated effectively by both metformin and LOD.", "Metformin is successfully used in the treatment of cycle disorders and anovulation in women with polycystic ovary syndrome (PCOS). No data of the exact point and the impact of insulin resistance (IR) on metformin's efficacy exist.\n The objective of the study was to evaluate the early potential effects of metformin treatment, their time of onset, and the role of IR on metformin's efficacy.\n This was a prospective randomized, double-blind, placebo-controlled trial.\n The study was conducted at the University of Heidelberg, Heidelberg, Germany.\n The patient population was 45 oligo-/anovulatory PCOS women with typical ovaries.\n Women were stratified for IR (32 of 13) and then randomly allocated to receive either metformin (n = 22) or placebo (n = 23) and were assessed before and every 4 wk within a treatment period of 12 wk.\n Menstrual disturbance and markers of insulin metabolism were measured.\n The main outcome criterion menstrual disturbance was successfully improved in the metformin-treated group, depending on IR (12 of 15 vs. three of 17), whereas women without IR (four of seven vs. four of six) had no significant amelioration of their menstrual irregularities (P < 0.05). Estradiol levels increased continuously only in the treatment group (P < 0.005), indicating an improvement of ovulatory function. Sixty-seven percent of metformin-treated women had at least one ovulation, compared with only 45% in the placebo group, shown by biphasic body temperature curves. Insulin sensitivity improved within 4 wk after beginning of metformin as shown by an increased area under the curve glucose to insulin ratio, compared with baseline (P < 0.005).\n IR is a baseline predictor of clinical efficacy in metformin treatment in PCOS women measured by improved menstrual cyclicity and ovulatory function.", "Our aim was to investigate the effect of pre-treatment with metformin in women with polycystic ovary syndrome (PCOS) scheduled for IVF stimulation.\n Seventy-three oligo/amenorrhoeic women with polycystic ovaries and at least one of the following criteria: hyperandrogenaemia, elevated LH/FSH ratio, hyperinsulinism, decreased SHBG levels or hirsutism, were studied. Normal weight and overweight patients were randomized separately in a prospective, randomized, double blind study. All patients were treated for at least 16 weeks with metformin (1000 mg bid) or placebo ending on the day of HCG injection.\n No differences were found in the primary end-points: duration of FSH stimulation 14.4 (13.1-15.7) versus 14.2 (12.6-15.7) days or estradiol on the day of HCG injection 6.8 (5.3-8.2) versus 7.6 (5.6-9.6) nmol/l in the metformin and placebo groups, respectively. The secondary end-points number of oocytes, fertilization rates, embryo quality, pregnancy rates and clinical pregnancy rates were equal. However, in the normal weight subgroup (BMI <28 kg/m(2), n = 27), pregnancy rates following IVF were 0.71 (0.63-0.79) versus 0.23 (0.15-0.31) in the metformin and placebo groups, respectively (P = 0.04). Overall clinical pregnancy rates were equal: 0.51 (0.34-0.68) versus 0.44 (0.27-0.62) in the metformin and placebo groups, respectively. However, in the normal weight subgroup, clinical pregnancy rates were 0.67 (0.43-0.91) and 0.33 (0.06-0.60), respectively (P = 0.06).\n Pre-treatment with metformin prior to conventional IVF/ICSI in women with PCOS does not improve stimulation or clinical outcome. However, among normal weight PCOS women, pre-treatment with metformin tends to improve pregnancy rates. Further studies in subgroups of PCOS women are required.", "To compare the hormonal-metabolic profiles and reproductive outcomes in clomiphene-resistant patients with polycystic ovary syndrome and insulin resistance between women receiving metformin and those undergoing laparoscopic ovarian drilling.\n A total of 110 eligible participants were randomly allocated to diagnostic laparoscopy plus metformin therapy (group 1, n=55) or laparoscopic ovarian drilling (group 2, n=55). The t test was used for mean comparisons of hormonal-metabolic parameters and OGTT values before and after treatment. The chi(2) test was used for comparisons of ovulation, pregnancy, and abortion rates.\n Groups 1 and 2 showed a significant decline in testosterone, insulin-like growth factor-1 (P<0.001 vs P<0.001), and luteinizing hormone (P<0.05 vs P<0.001), while the glucose to insulin ratio was significantly increased (P<0.001 vs P<0.05) compared with baseline. Group 2 patients had more regular cycles and higher rates of ovulation and pregnancy compared with group 1: 76.4% [42/55] vs 58.2% [32/55], P<0.04; 50.8% [131/258] vs 33.5% [94/281], P<0.001; and 38.2% [21/55] vs 20.0% [11/55], P<0.03, respectively. The difference in the early abortion rate between the groups was not statistically significant.\n Although metformin results in a better attenuation of insulin resistance, laparoscopic ovarian drilling is associated with higher rates of ovulation and pregnancy.\n Copyright 2009 Elsevier Ireland Ltd. All rights reserved.", "To study the effect of CYP17a inhibitor, \"ketoconazole,\" on clomiphene responsiveness in PCOS patients.\n Prospective analysis was employed with the setup at Alexandria IVF/ICSI center. Ninety-seven insulin-resistant PCOS patients undergoing ovulation induction using clomiphene citrate were randomly divided, by random number table, into two groups. The first group (n = 49) received ketoconazole (400 mg daily) till correction of metabolic syndrome followed by clomiphene (100 mg/day); the second group (n = 48) receiving clomiphene without ketoconazole pretreatment. Main outcome measures were incidence of clomiphene resistance, monofollicular response, fasting insulin/glucose ratio, serum testosterone, and pregnancy rates.\n The ketoconazole group showed significantly (p < 0.05) higher incidence of monofollicular response (38%), higher pregnancy rates, and significantly less marked antiestrogenic manifestations than did the control group. They also had significantly lower incidence of clomiphene resistance (11.6%), lower serum testosterone levels, less hyperinsulinaemia, than did the control group.\n Ketoconazole improved clomiphene responsivenss in PCOS patients and attenuated its untoward biological effects.", "Metformin effectively restores insulin sensitivity in insulin-resistant women with polycystic ovary syndrome (PCOS). We examined whether metformin, given prior to and during ovarian stimulation for in vitro fertilization (IVF), altered follicle stimulating hormone (FSH) requirement and increased the number of collected oocytes in these women. Seventeen insulin-resistant women with PCOS were recruited to our IVF unit to receive two consecutive cycles of ovarian stimulation with or without metformin co-treatment, the order of treatments being randomized using a table of random numbers. Metformin treatment (1500 mg/day) started 3 weeks before downregulation with buserelin acetate and was continued throughout ovarian stimulation with human recombinant FSH. Nine women completed both cycles, the results of eight women being excluded because of pregnancy after the first cycle (n = 4) or because the protocol of the study was not followed (n = 4). Mean total FSH dose was 2301 IU (range 1500-6563 IU) in metformin cycles and 2174 IU (range 1200-3900 IU) in parallel control cycles, while the mean number of collected oocytes was 8.6 (range 2-28) and 4.6 (range 1-16), respectively. Bayesian analysis showed probabilities of 0.05 that metformin reduces FSH requirement by at least 10%, and of 0.61 that at least 10% more oocytes are collected after metformin co-treatment. Co-administration of metformin is therefore likely to increase the number of oocytes collected after ovarian stimulation in insulin-resistant women with PCOS but is unlikely to reduce the requirement for FSH.", "Metformin, an insulin-sensitizing drug, has been shown to improve ovarian function and glucose metabolism in obese women with polycystic ovary syndrome (PCOS), but its effects and possible benefits in nonobese PCOS subjects are not well known. Seventeen nonobese (body mass index < 25 kg/m(2)) women with PCOS were randomized to receive either metformin (500 mg twice daily for 3 months, then 1000 mg twice daily for 3 months; n = 8) or ethinyl estradiol (EE, 35 microg)-cyproterone acetate (CA, 2 mg) oral contraceptive pills (EE-CA; n = 9). Waist to hip ratio; serum concentrations of sex steroids, glucose, and insulin during a 75-g oral glucose tolerance test; early phase insulin and C-peptide secretion; and insulin sensitivity using a euglycemic hyperinsulinemic clamp were assessed at baseline and at 3 and 6 months of treatment. Metformin did not have any effect on glucose tolerance or insulin sensitivity, but fasting insulin concentrations decreased from 44.4 +/- 5.1 (SE) to 29.8 +/- 4.3 pmol/liter (P = 0.03), the waist to hip ratio decreased from 0.78 +/- 0.01 to 0.75 +/- 0.01 (P = 0.01), and hepatic insulin clearance increased during the treatment. Furthermore, metformin decreased serum testosterone levels from 2.7 +/- 0.3 to 2.0 +/- 0.2 nmol/liter (P = 0.01) and improved menstrual cyclicity. EE-CA did not have any significant effect on glucose tolerance, serum insulin levels, or insulin sensitivity, but it increased slightly the body mass index (P = 0.09) and significantly serum leptin concentrations (P < 0.001) and decreased serum testosterone levels from 2.1 +/- 0.2 to 1.4 +/- 0.2 nmol/liter (P = 0.03). In conclusion, EE-CA seems to be an efficient mode of therapy for hyperandrogenic symptoms associated with PCOS, but its possible negative effects on insulin and glucose metabolism also have to be taken into consideration in nonobese subjects. Metformin improved hyperandrogenism, hyperinsulinemia, and menstrual cyclicity, most likely through its positive effect on insulin clearance and abdominal adiposity. Thus, similarly to obese PCOS women, nonobese PCOS subjects with anovulation may also benefit from metformin treatment.", "To obtain data from a pilot randomized trial on the effect of metformin therapy and lifestyle modification on ovulation and androgen concentrations in women with polycystic ovary syndrome (PCOS).\n Prospective, randomized, placebo-controlled pilot trial.\n Academic medical center.\n Thirty-eight overweight or obese women with PCOS.\n All subjects were randomized to one of four 48-week interventions: metformin 850 mg two times per day, lifestyle modification plus metformin 850 mg two times per day, lifestyle modification plus placebo, or placebo alone.\n Recruitment, dropout, and compliance with a long-term lifestyle intervention in PCOS; preliminary estimates of treatment effect on ovulation, as measured by weekly urinary pregnanediol glucuronide, and on total T and free androgen index.\n It was necessary to screen seven women to have one subject randomized. The dropout rate was 39%, with the majority of dropouts occurring within the first 24 weeks. Mean body mass index was >39 mg/kg(2). Modest weight reduction was found in all treatment groups, with the most significant reduction occurring with the combination of metformin and lifestyle intervention. Significant androgen reduction occurred in the combination group only. Ovulation rates did not differ significantly between groups. However, when data were analyzed by presence or absence of weight reduction in subjects, independent of treatment group, the estimated odds ratio for weight loss was 9.0 (95% confidence interval 1.2-64.7) with respect to regular ovulation. If weight loss occurred during metformin therapy, the odds ratio for regular ovulation was 16.2 (95% confidence interval 4.4-60.2).\n Key methodologic issues for a large-scale, randomized trial of lifestyle intervention in PCOS include minimizing early dropout from the lifestyle intervention and including a range of body mass index that is not skewed toward severe obesity. Weight reduction might play the most significant role in restoration of ovulation in obese women with PCOS.", "To determine whether insulin-sensitizing drugs would improve ovulation and T levels in women with polycystic ovary syndrome (PCOS), without clinical or biochemical criteria indicating insulin resistance and whether the combination of two distinct insulin-sensitizing drugs would be of any benefit over either drug alone.\n Randomized controlled double-blind trial.\n A referral center in Caracas, Venezuela.\n One hundred twenty-eight nonobese PCOS women with normal indices of insulin sensitivity-that is, normal glucose tolerance, fasting insulin, peak insulin during an oral glucose tolerance test (OGTT), and fasting glucose-to-insulin ratio. Twenty-eight women were lost to follow-up initially and did not receive any intervention.\n One hundred women received twice daily one of the following for 6 months: metformin (850 mg), rosiglitazone (4 mg), combination of both drugs, or at least one placebo.\n Frequencies of ovulation and serum free T after 6 months.\n Frequencies of ovulation were higher after treatment with an insulin-sensitizing drug (ovulations per subject in 6 months: metformin, 3.3; rosiglitazone, 2.4; and combination, 3.4) than with placebo (0.4). Ovulatory frequencies increased significantly more with metformin than rosiglitazone, and the combination was not more potent. After treatment, serum free-T levels were comparable among all active treatment groups (metformin: 2.34 pg/mL, rosiglitazone: 3.06 pg/mL, and combination: 2.39 pg/mL) and were significantly lower than in the placebo group (7.26 pg/mL). Compared with placebo, fasting insulin levels, area under the insulin curve during OGTT, the homeostatic model assessment of insulin sensitivity, and OGTT-derived insulin sensitivity index improved significantly after metformin or combination therapies but not after rosiglitazone.\n These findings suggest that insulin-sensitizing drugs increase ovulatory frequency and ameliorate hyperandrogenemia, even in nonobese women with PCOS who appear to have normal insulin sensitivity.", "Our aim was to assess the effects of metformin on menstrual frequency, fasting plasma glucose (FPG), insulin resistance assessed as HOMA-index, weight, waist/hip ratio, blood pressure (BP), serum lipids, and testosterone levels in women with polycystic ovary syndrome (PCOS) METHODS: In a randomized, controlled, double-blinded setup, 56 women aged 18-45 with PCOS were treated with either metformin 850 mg or placebo twice daily for 6 months. After a wash-out period of 3 months participants received the alternate treatment for 6 months. The changes in the measured parameters were analysed by intention-to-treat and per protocol.\n There were no changes in menstrual frequency. In the intention-to-treat analysis, weight and systolic BP were reduced on metformin treatment (p=0.009 and 0.047, respectively), while high-density lipoprotein (HDL) increased (p=0.001). On placebo, weight and FPG increased (p<0.05). Post-hoc subgrouping according to BMI revealed reductions in testosterone (p=0.013), FPG (p=0.018), insulin (p=0.045) and HOMA-index (p=0.022) in obese women. Per protocol analysis showed the following differences between the changes on placebo and metformin (mean (5 - 95 % percentiles): weight (-4.2 (-7.0, -1.9) kg, p<0.001), FPG (-0.23 (-0.44, -0.01) mmol/l, p=0.041), insulin (-4.17 (-8.10, -0.23) mIU/l, p=0.039) and HOMA index (-1.50 (-2.53, -0.47) mIU/l*mmol/l, p=0.006). Weight, FPG and HOMA index were lower after metformin than after placebo.\n Metformin treatment lowered weight and systolic blood pressure and increased HDL in women with PCOS. In post-hoc analysis it increased insulin sensitivity and lowered testosterone in obese women. Non-obese women did not benefit from metformin.", "This study aims to evaluate the impact of metformin on ovarian response when co-administered during recombinant (r)FSH using the low-dose step-up protocol in clomiphene citrate-resistant polycystic ovarian syndrome (PCOS) patients with normal glucose tolerance.\n Thirty-two patients were randomized to metformin (n = 16) and placebo (n = 16) groups. Hormonal assessment, a 75 g oral glucose tolerance test (OGTT) and a frequently sampled i.v. glucose tolerance test (FSIGTT) were performed before and after oral administration of metformin (850 mg twice daily) or placebo for 6 weeks. Recombinant FSH treatment was undertaken, thereafter, in women who did not ovulate on metformin (n = 10) or placebo (n = 15). There was no significant change in all insulin sensitivity indices in both groups. The only change noted was a decline in mean serum free testosterone concentration in the metformin group (P = 0.049). One patient on placebo and six patients on metformin ovulated spontaneously (P < 0.05). All parameters of ovarian response were comparable between the two groups during rFSH treatment. Combining the 6 week placebo or metformin-only period with a single rFSH treatment cycle, the overall ovulation rates were 75 and 94% in the placebo and metformin groups respectively (P > 0.05). The respective figures for pregnancy were 6.3 and 31.3% (P > 0.05).\n Metformin may restore ovulation with no improvement on insulin resistance in clomiphene citrate-resistant PCOS patients with normal glucose tolerance, but has no significant effect on ovarian response during rFSH treatment.", "The aim of this work was to evaluate the efficacy of adding dexamethazone (DEX) (high dose, short course) to clomiphene citrate (CC) in CC-resistant polycystic ovary syndrome (PCOS) with normal dehydroepiandrosterone sulphate (DHEAS) in induction of ovulation.\n Eighty infertile women with CC-resistant PCOS were randomly assigned into two groups. Group I: Clomiphene citrate 100 mg/day was given from day 3 to day 7 of the cycle and DEX 2 mg/day from day 3 to day 12 of the cycle. Group II: Same protocol of CC combined with placebo (folic acid tablets) was given from day 3 to day 12 of the cycle. The main outcome was ovulation. Secondary measures included number of follicles >18 mm endometrial thickness and pregnancy rate. Ovarian follicular response was monitored by transvaginal ultrasound. HCG 10,000 U was given when at least one follicle measured 18 mm, and timed intercourse was advised.\n There were no statistically significant differences between groups as regards age, duration of infertility, BMI, waist-hip ratio (WHR), menstrual pattern, hirsutism, serum DHEAS or day of HCG administration. The mean number of follicles>18 mm at the time of HCG administration and the mean endometrial thickness were significantly higher in the DEX group than in the placebo group (P<0.05). Similarly, there were significantly higher rates of ovulation (75 versus 15%) (P<0.001) and pregnancy (40 versus 5%) (P<0.05) in the DEX group. Dexamethazone was very well tolerated as no patients complained of any side effect. There was a significant difference between the responders and non-responders in the presence of oligomenorrhea, amenorrhea or hirsutism.\n Induction of ovulation by adding DEX (high dose, short course) to CC in CC-resistant PCOS with normal DHEAS is associated with no adverse anti-estrogenic effect on the endometrium and higher ovulation and pregnancy rates in a significant number of patients. Induction with DEX appears to be independent on age, period of infertility, BMI or WHR.", "Women with oligomenorrhea and polycystic ovaries show a high incidence of ovulation failure perhaps linked to insulin resistance and related metabolic features. A number of reports show that the biguanide metformin improves ovarian function. However, in these trials the quality of evidence supporting ovulation is suboptimal, and few studies have been placebo-controlled. The aim of our study was to use a double-blind, placebo-controlled approach with detailed assessment of ovarian activity (two blood samples per week) to assess the validity of this therapeutic approach in this group of women. Of the 94 patients randomized, 2 withdrew before treatment commenced, 47 received placebo, and 45 received metformin (850 mg, twice a day). The numbers discontinuing the study prematurely were higher in the treatment group (n = 15) than the placebo group (n = 5; P < 0.05). The ovulation frequency assessed by the ratio of luteal phase weeks to observation weeks was significantly (P < 0.01) higher in the treated group (23%) compared with the placebo (13%), and the time to first ovulation was significantly (P < 0.05) shorter [23.6 d; 95% confidence interval (CI), 17, 30; compared with 41.8 d; 95% CI, 28, 56]. The proportion of patients failing to ovulate during the placebo-treatment period was higher (P < 0.05) in the placebo group, and the majority of ovulations were characterized by normal progesterone concentrations in both groups. The effect of metformin on follicular maturation was rapid, because the E2 circulating concentration increased over the first week of treatment only in the metformin group. Significant (P < 0.01) weight loss (and leptin reduction) was recorded in the metformin group, whereas the placebo group actually increased weight (P < 0.05). A significant increase in circulating high-density lipoprotein was observed only in the metformin-treated group. Metabolic risk factor benefits of metformin treatment were not observed in the morbidly obese subgroup of patients (body mass index > 37). No change in fasting glucose concentrations, fasting insulin, or insulin responses to glucose challenge was recorded after 14-wk metformin or placebo therapy. There was an inverse relationship between body mass and treatment efficacy. We show in a large randomized placebo-controlled trial that metformin treatment improves ovulation frequency in women with abnormal ovarian function and polycystic ovaries significantly but to a modest degree, and protracted treatment improves cardiovascular risk factors. These data support a beneficial effect of metformin in improving ovarian function in women with oligomenorrhea and polycystic ovaries.", "To investigate metformin effects on the endocrine-metabolic parameters and ovarian morphology in normoinsulinemic women with polycystic ovary syndrome (PCOS).\n Randomized double-blind study.\n Operative Division of Endocrinological Gynecology, Università Cattolica del Sacro Cuore.\n Twenty-eight normal-weight normoinsulinemic PCOS women.\n Patients were randomized to receive metformin 500 mg twice a day (group A, 15 subjects) or placebo (group B, 13 subjects) for 6 months. Ultrasonographic pelvic exams, hormonal and lipid features, and oral glucose tolerance test were performed at baseline and after 3 and 6 months of treatment.\n Hormonal and glycoinsulinemic assessment, ovarian ultrasound appearance.\n Glycoinsulinemic assessment remained unvaried in both groups. About 70% of patients in group A experienced a restoration of menstrual cyclicity. Metformin significantly decreased testosterone levels at 3 and 6 months) and 17-hydroxyprogesterone levels at 6 months, and improved hirsutism score at 6 months. No clinical or hormonal modifications occurred in group B. Metformin, but not placebo, reduced ovarian volume and stromal/total area ratio at 3 and 6 months.\n Metformin seems to improve the menstrual pattern and ultrasonographic ovarian features in normoinsulinemic PCOS women. These effects seem to be, at least in part, independent of the insulin-lowering properties of the drug.\n Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved." ]	In agreement with the previous review, metformin was associated with improved clinical pregnancy but there was no evidence that metformin improves live birth rates whether it is used alone or in combination with clomiphene, or when compared with clomiphene. Therefore, the role of metformin in improving reproductive outcomes in women with PCOS appears to be limited.
CD005086	[ "17198065", "12790954", "10982049" ]	[ "Anal plugs for the management of fecal incontinence in children and adults: a randomized control trial.", "Anal plug for faecal incontinence.", "A new polyurethane anal plug in the treatment of incontinence after anal atresia repair." ]	[ "To evaluate the contribution of the anal plug to the management of fecal incontinence in children and adults.\n Effective management of fecal incontinence remains problematic. Previous studies of an anal plug have yielded conflicting results.\n A randomized controlled trial was conducted. The intervention was the Conveen anal plug (Coloplast Limited) used for 12 months. Outcomes measures included: generic measures of child health [Functional Status II-R, Child Health Questionnaire (CHQ-PF50) and Dartmouth Primary Care Cooperative Information Project Charts]; generic measures of adult health for patients and carers (the SF-36, and Patient Generated and Carer Generated indices); condition-specific measures for adults and children; qualitative interviews, bowel charts, and diaries. The main outcome measure was a condition-specific score on a 0 to 100 scale, where 0 was the most severe and 100 was the least severe incontinence.\n Thirty-one intervention and 17 control patients were recruited. Fecal incontinence was due to 1 of 3 reasons: congenital, acquired, and neurogenic. At baseline, patients managed their condition preemptively or protectively. Intervention patients used the plug as a complete management substitute or as an adjunct to existing management. The majority of intervention respondents retained the plug most of the time. There was greater improvement from baseline in mean condition-specific score in intervention group compared with control group but this difference was not statistically significant (t test P=0.053). Complete data analysis using analysis of covariance showed the mean difference between the treatment groups in condition-specific score of 9.9 (95% confidence interval-1.4, 21.1). Intention to treat analyses using imputation showed similar results. There was generally greater improvement in intervention groups subjects using other measures for children, adults, and carers.\n The anal plug is of benefit to the majority of patients. It does not suit all eligible patients with in situ plug retention being a problem for some.", "Despite the availability of pharmacological, behavioural and surgical treatments for faecal incontinence, many patients remain symptomatic. There are few devices designed specifically to cope with this, and perineal pads are inefficient and unacceptable for many patients. This study aimed to evaluate a new device in patients with intractable faecal incontinence.\n Two sizes of a purpose-designed anal plug were evaluated in 20 patients with intractable faecal incontinence for solid or liquid stool. Each plug size was tested for 2 weeks, with patients completing a structured questionnaire after each size.\n The majority [14/20] could not tolerate a plug due to discomfort. Four patients (20%) wished to continue to use a plug on a regular basis after the study, and two others on an occasional basis. However, for this minority who could tolerate a plug, it was highly successful at controlling faecal incontinence. There was no clear preference for the smaller or larger plug. There was no association between comfort in using the plug and anorectal sensitivity as measured by electrophysiological tests. It was not possible to predict which patients would benefit from plug use.\n The anal plug is effective in controlling faecal incontinence and is well tolerated in a minority of patients. Evaluation quickly reveals whether the patient will find it an effective and acceptable option. This device therefore offers a further management option for patients with faecal incontinence.", "38 totally or partially incontinent patients following imperforate anus repair (age 6-15 years) tested a new polyurethane (PU) anal plug against another, widely used anal plug (PVA) in a randomized crossover trial. Plugs were tested 3 weeks each, data concerning bowel habits, handling and plug-related problems were collected by questionnaire before trial, at time of product change and after trial.\n 15 of 38 patients did not complete the protocol, among them 6 with anal canal diameters too small for the smallest plug. During plug use, patients experienced enhanced awareness of repletion and urge. Stool consistence did not change in 82% of patients. There were no changes in children constipated prior to study (n = 8/23). 12,123 children were absolutely clean during use of either plug. 15 patients (68%) using the PU plug and 10 (45%) using the PVA plug felt secure from soiling during plug use. 74% of patients preferred the PU plug. Painful plug insertion, a feeling of pressure inside the anal canal and painful plug removal were reported with both plugs, but were less frequent with the PU plug.\n Anal plugs, regardless of their make, offer absolute cleanliness for periods of several hours to 66% of our incontinent patients. The PU plug (Conveen, Coloplast) is preferred by the patients and offers greater security than the PVA plug." ]	The available data were limited and incomplete, and not all pre-specified outcomes could be evaluated. Consequently, only tentative conclusions are possible. The available data suggest that anal plugs can be difficult to tolerate. However, if they are tolerated they can be helpful in preventing incontinence. Plugs could then be useful in a selected group of people either as a substitute for other forms of management or as an adjuvant treatment option. Plugs come in different designs and sizes; the review showed that the selection of the type of plug can impact on its performance.
CD004815	[ "17350451", "11419424", "15080865", "11075740", "9768925" ]	[ "Long-term outcome after an early invasive versus selective invasive treatment strategy in patients with non-ST-elevation acute coronary syndrome and elevated cardiac troponin T (the ICTUS trial): a follow-up study.", "Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban.", "A multi-centre randomised controlled trial of minimally invasive direct coronary bypass grafting versus percutaneous transluminal coronary angioplasty with stenting for proximal stenosis of the left anterior descending coronary artery.", "A prospective randomized trial comparing stenting to internal mammary artery grafting for proximal, isolated de novo left anterior coronary artery stenosis: the SIMA trial. Stenting vs Internal Mammary Artery.", "Modifying risk for extracorporeal circulation: trial of four antiinflammatory strategies." ]	[ "The ICTUS trial was a study that compared an early invasive with a selective invasive treatment strategy in patients with non-ST-elevation acute coronary syndrome (nSTE-ACS). The study reported no difference between the strategies for frequency of death, myocardial infarction, or rehospitalisation after 1 year. We did a follow-up study to assess the effects of these treatment strategies after 4 years.\n 1200 patients with nSTE-ACS and an elevated cardiac troponin were enrolled from 42 hospitals in the Netherlands. Patients were randomly assigned either to an early invasive strategy, including early routine catheterisation and revascularisation where appropriate, or to a more selective invasive strategy, where catheterisation was done if the patient had refractory angina or recurrent ischaemia. The main endpoints for the current follow-up study were death, recurrent myocardial infarction, or rehospitalisation for anginal symptoms within 3 years after randomisation, and cardiovascular mortality and all-cause mortality within 4 years. Analysis was by intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN82153174.\n The in-hospital revascularisation rate was 76% in the early invasive group and 40% in the selective invasive group. After 3 years, the cumulative rate for the combined endpoint was 30.0% in the early invasive group compared with 26.0% in the selective invasive group (hazard ratio 1.21; 95% CI 0.97-1.50; p=0.09). Myocardial infarction was more frequent in the early invasive strategy group (106 [18.3%] vs 69 [12.3%]; HR 1.61; 1.19-2.18; p=0.002). Rates of death or spontaneous myocardial infarction were not different (76 [14.3%] patients in the early invasive and 63 [11.2%] patients in the selective invasive strategy [HR 1.19; 0.86-1.67; p=0.30]). No difference in all-cause mortality (7.9%vs 7.7%; p=0.62) or cardiovascular mortality (4.5%vs 5.0%; p=0.97) was seen within 4 years.\n Long-term follow-up of the ICTUS trial suggests that an early invasive strategy might not be better than a more selective invasive strategy in patients with nSTE-ACS and an elevated cardiac troponin, and implementation of either strategy might be acceptable in these patients.", "There is continued debate as to whether a routine, early invasive strategy is superior to a conservative strategy for the management of unstable angina and myocardial infarction without ST-segment elevation.\n We enrolled 2220 patients with unstable angina and myocardial infarction without ST-segment elevation who had electrocardiographic evidence of changes in the ST segment or T wave, elevated levels of cardiac markers, a history of coronary artery disease, or all three findings. All patients were treated with aspirin, heparin, and the glycoprotein IIb/IIIa inhibitor tirofiban. They were randomly assigned to an early invasive strategy, which included routine catheterization within 4 to 48 hours and revascularization as appropriate, or to a more conservative (selectively invasive) strategy, in which catheterization was performed only if the patient had objective evidence of recurrent ischemia or an abnormal stress test. The primary end point was a composite of death, nonfatal myocardial infarction, and rehospitalization for an acute coronary syndrome at six months.\n At six months, the rate of the primary end point was 15.9 percent with use of the early invasive strategy and 19.4 percent with use of the conservative strategy (odds ratio, 0.78; 95 percent confidence interval, 0.62 to 0.97; P=0.025). The rate of death or nonfatal myocardial infarction at six months was similarly reduced (7.3 percent vs. 9.5 percent; odds ratio, 0.74; 95 percent confidence interval, 0.54 to 1.00; P<0.05).\n In patients with unstable angina and myocardial infarction without ST-segment elevation who were treated with the glycoprotein IIb/IIIa inhibitor tirofiban, the use of an early invasive strategy significantly reduced the incidence of major cardiac events. These data support a policy involving broader use of the early inhibition of glycoprotein IIb/IIIa in combination with an early invasive strategy in such patients.", "To compare the clinical- and cost-effectiveness of minimally invasive direct coronary artery bypass grafting (MIDCAB) and percutaneous transluminal coronary angioplasty (PTCA) with or without stenting in patients with single-vessel disease of the left anterior descending coronary artery (LAD).\n Multi-centre randomised trial without blinding. The computer-generated sequence of randomised assignments was stratified by centre, allocated participants in blocks and was concealed using a centralised telephone facility.\n Four tertiary cardiothoracic surgery centres in England.\n Patients with ischaemic heart disease with at least 50% proximal stenosis of the LAD, suitable for either PTCA or MIDCAB, and with no significant disease in another vessel.\n Patients randomised to PTCA had local anaesthetic and underwent PTCA according to the method preferred by the operator carrying out the procedure. Patients randomised to MIDCAB had general anaesthetic. The chest was opened through an 8-10-cm left anterior thoracotomy. The ribs were retracted and the left internal thoracic artery (LITA) harvested. The pericardium was opened in the line of the LAD to confirm the feasibility of operation. The distal LITA was anastomosed end-to-side to an arteriotomy in the LAD. All operators were experienced in carrying out MIDCAB.\n The primary outcome measure was survival free from cardiac-related events. Relevant events were death, myocardial infarction, repeat coronary revascularisation and recurrence of symptomatic angina or clinical signs of ischaemia during an exercise tolerance test at annual follow-up. Secondary outcome measures were complications, functional outcome, disease-specific and generic quality of life, health and social services resource use and their costs.\n A total of 12,828 consecutive patients undergoing an angiogram were logged at participating centres from November 1999 to December 2001. Of the 1091 patients with proximal stenosis of the LAD, 127 were eligible and consented to take part; 100 were randomised and the remaining 27 consented to follow-up. All randomised participants were included in an intention-to-treat analysis of survival free from cardiac-related events, which found a non-significant benefit from MIDCAB. Cumulative hazard rates at 12 months were estimated to be 7.1 and 9.2% for MIDCAB and PTCA, respectively. There were no important differences between MIDCAB and PTCA with respect to angina symptoms or disease-specific or generic quality of life. The total NHS procedure costs were 1648 British pounds and 946 British pounds for MIDCAB and PTCA, respectively. The costs of resources used during 1 year of follow-up were 1033 British pounds and 843 British pounds, respectively.\n The study found no evidence that MIDCAB was more effective than PTCA. The procedure costs of MIDCAB were observed to be considerably higher than those of PTCA. Given these findings, it is unlikely that MIDCAB represents a cost-effective use of resources in the reference population. Recent advances in cardiac surgery mean that surgeons now tend to carry out off-pump bypass grafting via a sternotomy instead of MIDCAB. At the same time, cardiologists are treating more patients with multi-vessel disease by PTCA. Future primary research should focus on this comparison. Other small trials of PTCA versus MIDCAB have now finished and a more conclusive answer to the original objective could be provided by a systematic review.", "To compare coronary artery bypass grafting (CABG) with percutaneous transluminal coronary angioplasty (PTCA) in patients with proximal, isolated de novo left anterior descending coronary artery disease and left ventricular ejection fraction of 45%.\n In the multicenter Stenting vs Internal Mammary Artery (SIMA) study, patients were randomly assigned to PTCA and stent implantation or to CABG (using the internal mammary artery). The primary clinical composite end point was event-free survival, including death, myocardial infarction, and the need for additional revascularization. Secondary end points were functional class, antianginal treatment, and quality of life. Analyses were by intention to treat.\n Of 123 patients who accepted randomization, 59 underwent CABG, and 62 were treated with stent implantation (2 patients were excluded because of protocol violation). At a mean +/- SD follow-up of 2.4+/-0.9 years, a primary end point had occurred in 19 patients (31%) in the stent group and in 4 (7%) in the CABG group (P<.001). This significant difference in clinical outcome is due to a higher incidence of additional revascularization in the stent group, the incidence of death and myocardial infarction being similar (7% vs 7%, respectively; P=.90). The functional class, need for antianginal drug, and quality-of-life assessment showed no significant differences.\n Both stent implantation and CABG are safe and highly effective treatments to relieve symptoms in patients with isolated, proximal left anterior descending coronary artery stenosis. Both are associated with a low and comparable incidence of death and myocardial infarction. However, similar to PTCA alone, a percutaneous approach using elective stent placement remains hampered by a higher need for repeated intervention because of restenosis.", "Despite recent rediscovery of beating heart cardiac surgical techniques, extracorporeal circulation remains appropriate for most heart operations. To minimize deleterious effects of cardiopulmonary bypass, antiinflammatory strategies have evolved.\n Four state-of-the-art strategies were studied in a prospective, randomized, preoperatively risk stratified, 400-patient study comprising primary (n = 358), reoperative (n = 42), coronary (n = 307), valve (n = 27), ascending aortic (n = 9), and combined operations (n = 23). Groups were as follows: standard, roller pump, membrane oxygenator, methylprednisolone (n = 112); aprotinin, standard plus aprotinin (n = 109); leukocyte depletion, standard plus a leukocyte filtration strategy (n = 112); and heparin-bonded circuitry, centrifugal pumping with surface modification (n = 67).\n Analysis of variance, linear and logistic regression, and Pearson correlation were applied. Actual mortality (2.3%) was less than half the risk stratification predicted mortality (5.7%). The treatment strategies effectively attenuated markers of the inflammatory response to extracorporeal circulation. Compared with the other groups the heparin-bonded circuit had highly significantly decreased complement activation (p = 0.00001), leukocyte filtration blunted postpump leukocytosis (p = 0.043), and the aprotinin group had less fibrinolysis (p = 0.011). Primary end points, length of stay, and hospital charges, were positively correlated with operation type, age, pump time, body surface area, stroke, pulmonary sequelae, predicted risk for stroke, predicted risk for mortality, and risk strata/treatment group interaction (p = 0.0001). In low-risk patients, leukocyte filtration reduced length of stay by 1 day (p = 0.02) and mean charges by $2,000 to $6,000 (p = 0.05). For high-risk patients, aprotinin reduced mean length of stay up to 10 fewer days (p = 0.02) and mean charges by $6,000 to $48,000 (p = 0.0007).\n These pharmacologic and mechanical strategies significantly attenuated the inflammatory response to extracorporeal circulation. This translated variably into improved patient outcomes. The increased cost of treatment was offset for selected strategies through the added value of significantly reduced risk." ]	Compared to a conservative strategy for UA/NSTEMI, an invasive strategy is associated with reduced rates of refractory angina and rehospitalization in the shorter term and myocardial infarction in the longer term. However, the invasive strategy is associated with a doubled risk of procedure-related heart attack and increased risk of bleeding and procedural biomarker leaks. Available data suggest that an invasive strategy may be particularly useful in those at high risk for recurrent events.
CD005978	[ "12052800", "9651405", "20375190", "16168782", "15158629", "20882421" ]	[ "Effect of routine zinc supplementation on pneumonia in children aged 6 months to 3 years: randomised controlled trial in an urban slum.", "Zinc supplementation reduces the incidence of acute lower respiratory infections in infants and preschool children: a double-blind, controlled trial.", "A randomized controlled trial of the effect of zinc as adjuvant therapy in children 2-35 mo of age with severe or nonsevere pneumonia in Bhaktapur, Nepal.", "Effect of weekly zinc supplements on incidence of pneumonia and diarrhoea in children younger than 2 years in an urban, low-income population in Bangladesh: randomised controlled trial.", "Zinc for severe pneumonia in very young children: double-blind placebo-controlled trial.", "Zinc supplementation in severe acute lower respiratory tract infection in children: a triple-blind randomized placebo controlled trial." ]	[ "To evaluate the effect of daily zinc supplementation in children on the incidence of acute lower respiratory tract infections and pneumonia.\n Double masked, randomised placebo controlled trial.\n A slum community in New Delhi, India.\n 2482 children aged 6 to 30 months.\n Daily elemental zinc, 10 mg to infants and 20 mg to older children or placebo for four months. Both groups received single massive dose of vitamin A (100 000 IU for infants and 200 000 IU for older children) at enrollment.\n All households were visited weekly. Any children with cough and lower chest indrawing or respiratory rate 5 breaths per minute less than the World Health Organization criteria for fast breathing were brought to study physicians.\n At four months the mean plasma zinc concentration was higher in the zinc group (19.8 (SD 10.1) v 9.3 (2.1) micromol/l, P<0.001). The proportion of children who had acute lower respiratory tract infection during follow up was no different in the two groups (absolute risk reduction -0.2%, 95% confidence interval -3.9% to 3.6%). Zinc supplementation resulted in a lower incidence of pneumonia than placebo (absolute risk reduction 2.5%, 95% confidence interval 0.4% to 4.6%). After correction for multiple episodes in the same child by generalised estimating equations analysis the odds ratio was 0.74, 95% confidence interval 0.56 to 0.99.\n Zinc supplementation substantially reduced the incidence of pneumonia in children who had received vitamin A.", "Increased acute lower respiratory infection incidence, severity, and mortality are associated with malnutrition, and reduced immunological competence may be a mechanism for this association. Because zinc deficiency results in impaired immunocompetence and zinc supplementation improves immune status, we hypothesized that zinc deficiency is associated with increased incidence and severity of acute lower respiratory infection.\n We evaluated the effect of daily supplementation with 10 mg of elemental zinc on the incidence and prevalence of acute lower respiratory infection in a double-blind, randomized, controlled trial in 609 children (zinc, n = 298; control, n = 311) 6 to 35 months of age. Supplementation and morbidity surveillance were done for 6 months.\n After 120 days of supplementation, the percentage of children with plasma zinc concentrations <60 microg/dL decreased from 35.6% to 11.6% in the zinc group, whereas in the control group it increased from 36.8% to 43.6%. Zinc-supplemented children had 0.19 acute lower respiratory infection episodes/child/year compared with 0.35 episodes/child/year in the control children. After correction for correlation of data using generalized estimating equation regression methods, there was a reduction of 45% (95% confidence interval, 10% to 67%) in the incidence of acute lower respiratory infections in zinc-supplemented children.\n A dietary zinc supplement resulted in a significant reduction in respiratory morbidity in preschool children. These findings suggest that interventions to improve zinc intake will improve the health and survival of children in developing countries.", "Pneumonia is a leading cause of illness and death in young children. Interventions to improve case management of pneumonia are needed.\n Our objective was to measure the effect of zinc supplementation in children with pneumonia in a population in which zinc deficiency is common.\n In a double-blind, placebo-controlled clinical trial, children aged 2-35 mo with severe (n = 149) or nonsevere (n = 2479) pneumonia defined according to criteria established by the World Health Organization were randomly assigned to receive zinc (10 mg for children aged 2-11 mo, 20 mg for children aged > or =12 mo) or placebo daily for 14 d as an adjuvant to antibiotics. The primary outcomes were treatment failure, defined as a need for change in antibiotics or hospitalization, and time to recovery from pneumonia.\n One of 5 children did not respond adequately to antibiotic treatment; the odds ratios between zinc and placebo groups for treatment failure were 0.95 (95% CI: 0.78, 1.2) for nonsevere pneumonia and 0.97 (95% CI: 0.42, 2.2) for severe pneumonia. There was no difference in time to recovery between zinc and placebo groups for nonsevere (median: 2 d; hazard ratio: 1.0; 95% CI: 0.96, 1.1) or severe (median: 4 d; hazard ratio: 1.1; 95% CI: 0.79, 1.5) pneumonia. Regurgitation or vomiting < or =15 min after supplementation was observed more frequently among children in the zinc group than among those in the placebo group during the supplementation period (37% compared with 13%; odds ratio: 0.25; 95% CI: 0.20, 0.30).\n Adjuvant treatment with zinc neither reduced the risk of treatment failure nor accelerated recovery in episodes of nonsevere or severe pneumonia. This trial was registered at clinicaltrials.gov as NCT00148733.", "Pneumonia and diarrhoea cause much morbidity and mortality in children younger than 5 years. Most deaths occur during infancy and in developing countries. Daily regimens of zinc have been reported to prevent acute lower respiratory tract infection and diarrhoea, and to reduce child mortality. We aimed to examine whether giving zinc weekly could prevent clinical pneumonia and diarrhoea in children younger than 2 years.\n 1665 poor, urban children aged 60 days to 12 months were randomly assigned zinc (70 mg) or placebo orally once weekly for 12 months. Children were assessed every week by field research assistants. Our primary outcomes were the rate of pneumonia and diarrhoea. The rates of other respiratory tract infections were the secondary outcomes. Growth, final serum copper, and final haemoglobin were also measured. Analysis was by intention to treat.\n 34 children were excluded before random assignment to treatment group because they had tuberculosis. 809 children were assigned zinc, and 812 placebo. After treatment assignment, 103 children in the treatment group and 44 in the control group withdrew. There were significantly fewer incidents of pneumonia in the zinc group than the control group (199 vs 286; relative risk 0.83, 95% CI 0.73-0.95), and a small but significant effect on incidence of diarrhoea (1881 cases vs 2407; 0.94, 0.88-0.99). There were two deaths in the zinc group and 14 in the placebo group (p=0.013). There were no pneumonia-related deaths in the zinc group, but ten in the placebo group (p=0.013). The zinc group had a small gain in height, but not weight at 10 months compared with the placebo group. Serum copper and haemoglobin concentrations were not adversely affected after 10 months of zinc supplementation.\n 70 mg of zinc weekly reduces pneumonia and mortality in young children. However, compliance with weekly intake might be problematic outside a research programme.", "Pneumonia is a leading cause of morbidity and mortality in young children. Early reversal of severity signs--chest indrawing, hypoxia, and tachypnoea--improves outcome. We postulated that zinc, an acute phase reactant, would shorten duration of severe pneumonia and time in hospital.\n In a double-blind placebo-controlled clinical trial in Matlab Hospital, Bangladesh, 270 children aged 2-23 months were randomised to receive elemental zinc (20 mg per day) or placebo, plus the hospital's standard antimicrobial management, until discharge. The outcomes were time to cessation of severe pneumonia (no chest indrawing, respiratory rate 50 per min or less, oxygen saturation at least 95% on room air) and discharge from hospital. Discharge was allowed when respiratory rate was 40 per minute or less for 24 consecutive hours while patients were maintained only on oral antibiotics.\n The group receiving zinc had reduced duration of severe pneumonia (relative hazard [RH]=0.70, 95% CI 0.51-0.98), including duration of chest indrawing (0.80, 0.61-1.05), respiratory rate more than 50 per min (0.74, 0.57-0.98), and hypoxia (0.79, 0.61-1.04), and overall hospital duration (0.75, 0.57-0.99). The mean reduction is equivalent to 1 hospital day for both severe pneumonia and time in hospital. All effects were greater when children with wheezing were omitted from the analysis.\n Adjuvant treatment with 20 mg zinc per day accelerates recovery from severe pneumonia in children, and could help reduce antimicrobial resistance by decreasing multiple antibiotic exposures, and lessen complications and deaths where second line drugs are unavailable.", "To evaluate the efficacy of zinc supplementation on duration of illness in children with severe acute lower respiratory tract infection (ALRTI).\n This randomized triple-blind placebo-controlled trial was conducted in pediatric emergency of a teaching referral hospital. Children in the age group of 2-24 months presenting to pediatric emergency with severe ALRTI were included. Eligible children were randomly allocated to zinc (n=53) or control (n=53) groups. Zinc group received 20 mg of elemental zinc per day (5 ml syrup per day) as a single daily dose for 5 days. Control group received an equal amount of placebo which was appropriately modified to give the taste, smell, color and consistency similar to zinc mixture. Primary outcome was 'time to be asymptomatic', a composite outcome defined as resolution of all four of the following: danger signs, respiratory distress, tachypnea and hypoxia in room air.\n Age, gender, nutritional status, pretreatment zinc levels and other demographic and clinical variables were similar in the two groups. 'Time to be asymptomatic' was comparable in the two groups (h; median (IQR): 60 (24-78) vs. 54 (30-72), P=0.98]. At any time point a similar proportion of children were symptomatic in both the groups. Time to resolution of respiratory distress, tachypnea, dangers signs and hypoxia were also similar in two groups. Duration of hospital stay was shorter by 9 h in the zinc group but the difference was statistically insignificant.\n Zinc supplementation did not reduce recovery time and duration of hospital stay in children with ALRTI. Larger randomized controlled trials are needed to evaluate role of zinc in ALRTI." ]	Zinc supplementation in children is associated with a reduction in the incidence and prevalence of pneumonia, the leading cause of death in children.
CD003931	[ "9647153", "15511762", "17202604" ]	[ "Effective analgesia following perineal injury during childbirth: a placebo controlled trial of prophylactic rectal diclofenac.", "The prophylactic use of diclofenac (Voltarol) suppositories in perineal pain after episiotomy. A random allocation double-blind study.", "A comparative study of nonpharmacological methods to reduce pain in neonates." ]	[ "To determine if diclofenac suppositories administered prophylactically produce effective and lasting analgesia following perineal injury.\n A randomised double blind placebo controlled trial.\n York District Hospital.\n One hundred women sustaining objective perineal injury (second degree tear or episiotomy) during spontaneous vaginal delivery at term.\n Suppositories were administered at the time of repair and approximately 12 hours later. The suppositories were randomised prior to issue by the pharmacy department and contained either 100 mg diclofenac or placebo.\n Pain scores assessed at 12, 24, 48 and 72 hours after delivery using a six point numerical scoring system and the use of additional analgesia and local treatments to the perineum.\n The mean pain score was significantly reduced in the diclofenac group at 24, 48 and 72 hours after delivery (0.86, 0.7 and 0.59, respectively) compared with the control group (1.64, 1.31 and 1.5; P < 0.005). In addition there was less supplementary analgesia required (eight women only at 72 hours compared with 15 in the control group) and this was limited to paracetamol or topical treatments to the perineum.\n Prophylactic rectal diclofenac provides effective analgesia after perineal repair and its effect appears to be maintained into the second and third postpartum days.", "One hundred and ten patients who had episiotomies to aid normal vaginal delivery without epidural analgesia were = allocated at random to receive either diclofenac (n = 56) or = placebo (n = 54) suppositories. Pain after episiotomy was assessed at 24 and 48 hours using a combination of a visual analogue scale, a modified pain score and a review of additional analgesia required. All patients in both groups were allowed routine hospital analgesia on request. Our data suggests that very few patients suffered severe pain, even in the placebo group. However, the prophylactic use of diclofenac suppositories significantly reduced perineal pain in the first 24 hours, although the difference was less marked by 48 hours. Overall additional analgesia requirement was correspondingly less in the diclofenac group.", "A randomized study was done to compare non pharmacological methods to reduce the pain of heel pricks in 104 stable term neonates. Non-nutritive sucking (NNS), rocking, massage, sucrose (20 percent), distilled water (DW) and expressed breast milk (EBM) were used as pain reducing agents. Duration of cry and Douleur Aiguë du Nouveau né (DAN) score were used to assess pain. Physiological parameters were also recorded before and after the stimulus. At 30 seconds after the stimulus, the pain scores were lowest in the sucrose group but this was not sustained at 1, 2 and 4 minutes. At 2 and 4 minutes pain scores were lowest in the NNS and rocking groups as compared to sucrose, distilled water, expressed breast milk and massage. The total duration of crying was also lowest in the NNS and rocking groups. Physiological parameters were comparable in all groups. Babies who were in Prechtl State 1 and 2 (sleeping) at the time of stimulus showed significantly lesser response to pain compared to babies who were awake. This was seen in all the intervention groups. In conclusion, our study suggests that rocking or giving a baby a pacifier are more effective non-pharmacological analgesics than EBM, DW, sucrose or massage for the pain of heel pricks in neonates. A calm or sleeping state before a painful procedure also appears to decrease crying and pain scores." ]	NSAID rectal suppositories are associated with less pain up to 24 hours after birth, and less additional analgesia is required. More research is required regarding long-term effects and maternal satisfaction with the treatment.
CD004531	[ "8067808", "7930743", "1347854", "17054744", "8882193", "9561593", "8560531" ]	[ "Randomized trial of mefloquine alone and artesunate followed by mefloquine for the treatment of acute uncomplicated falciparum malaria.", "Treatment of multidrug-resistant Plasmodium falciparum malaria with 3-day artesunate-mefloquine combination.", "Randomised trial of artesunate and mefloquine alone and in sequence for acute uncomplicated falciparum malaria.", "An open label randomized comparison of mefloquine-artesunate as separate tablets vs. a new co-formulated combination for the treatment of uncomplicated multidrug-resistant falciparum malaria in Thailand.", "Artemether or artesunate followed by mefloquine as a possible treatment for multidrug resistant falciparum malaria.", "A comparative study of artesunate and artemether in combination with mefloquine on multidrug resistant falciparum malaria in eastern Thailand.", "Artesunate versus artemether in combination with mefloquine for the treatment of multidrug-resistant falciparum malaria." ]	[ "Mefloquine is the main antimalarial used for treatment of falciparum malaria patients at the malaria clinics in Thailand. However, the cure rate with mefloquine alone has declined seriously in recent years. The efficacy and tolerability of a sequential treatment of artesunate followed by mefloquine was therefore compared with those of mefloquine alone, in a randomized therapeutic trial involving 125 patients with acute uncomplicated falciparum malaria. Sixty-three patients received mefloquine alone (750 mg given immediately, followed by 500 mg 6 h later) and 62 each received 800 mg artesunate over 2 days (200 mg every 12 h) followed 6 h later by a single, 750-mg dose of mefloquine. All patients were admitted to the hospital in Bangkok for 28 days to exclude re-infection. Most patients (107) completed the study; 18 left the hospital prior to completion of follow-up for reasons unrelated to their treatment. Cure rates for the two groups were 74% (42/57) for mefloquine alone and 92% (46/50) for artesunate followed by mefloquine. The mean parasite clearance time was significantly shorter (P < 0.001) in the group treated with the sequential combination than in the group treated with mefloquine alone, but the mean fever clearance times were not significantly different (P = 0.26). Most patients responded well to the treatment regimens and none suffered from serious toxic adverse reactions. Only four patients who were treated with mefloquine alone had parasitaemia persisting to day 7 (RII), thus requiring alternative follow-up treatment.(ABSTRACT TRUNCATED AT 250 WORDS)", "Studies of 652 adults and children with acute uncomplicated falciparum malaria were done to determine the optimum treatment of multidrug-resistant Plasmodium falciparum malaria on the Thai-Burmese border. Single-dose artesunate (4 mg/kg) plus mefloquine (25 mg of base/kg) gave more rapid symptomatic and parasitologic responses than high-dose mefloquine alone but did not improve cure rates. Three days of artesunate (total dose, 10 mg/kg) plus mefloquine was 98% effective compared with a 28-day failure rate of 31% with high-dose mefloquine alone (relative risk [RR], 0.06; 95% confidence interval [CI], 0.02-0.2; P < .0001). By day 63, the reinfection adjusted failure rates were 2% and 44%, respectively (P < .0001). Artesunate also prevented high-grade failures. Both drugs were well tolerated. No adverse effects were attributable to artesunate. Vomiting was reduced significantly by giving mefloquine on day 2 of treatment (RR, 0.40; 95% CI, 0.20-0.79; P = .009. Artesunate (10 mg/kg over 3 days) plus mefloquine (25 mg/kg) is currently the most effective treatment for falciparum malaria in this area of increasing mefloquine resistance.", "The increasing frequency of therapeutic failures in falciparum malaria in Thailand shows an urgent need for effective drugs or drug combinations. Artesunate, a qinghaosu derivative, is effective in clearing parasitaemia rapidly, but the recrudescence rate can be as high as 50%. We have compared artesunate followed by mefloquine with each drug alone in acute, uncomplicated falciparum malaria. 127 patients were randomly assigned treatment with artesunate (600 mg over 5 days), mefloquine (750 mg then 500 mg 6 h later), or artesunate followed by mefloquine. All patients were admitted to hospital for 28 days to exclude reinfection. Cure was defined as no recrudescence during the 28 days' follow-up. The cure rates for mefloquine and artesunate alone were 81% (30/37 patients) and 88% (35/40); the combination was effective in all of 39 patients. Fever and parasite clearance times were significantly shorter in the groups that received artesunate than in the mefloquine-only group. The frequency of nausea and vomiting was slightly, but not significantly, higher among patients who received both drugs than in the other groups. The combination of artesunate followed by mefloquine is highly effective and well tolerated in patients with acute, uncomplicated falciparum malaria in Thailand.", "Delivering drugs in a fixed combination is essential to the success of the strategy of artemisinin-based combination therapy. This prevents one drug being taken without the protection of the other, reducing the chance of emergence and spread of drug resistant strains of Plasmodium falciparum. A lower tablet burden should also facilitate adherence to treatment. A new fixed combination of mefloquine plus artesunate has been developed. This was compared with the conventional regimen of separate tablets for the treatment of uncomplicated multidrug-resistant falciparum malaria.\n On the north-western border of Thailand 500 adults and children with uncomplicated falciparum malaria were randomized to receive either the new fixed combination or separate tablets. They were followed up weekly for 63 days.\n The day 63 polymerase chain reaction-adjusted cure rates were 91.9% (95% CI 88.2-95.6) in the fixed combination group and 89.2% (85.0-93.4) in the loose tablets group (P=0.3). There was a lower incidence of early vomiting in the group receiving the fixed combination.\n This new fixed combination of mefloquine and artesunate was efficacious, well tolerated and convenient to administer.", "Plasmodium falciparum in south-east Asia is highly resistant to chloroquine and sulfadoxine-pyrimethamine. Mefloquine used to be the chemosuppressant drug of choice in areas with chloroquine resistance. However, sensitivity to this drug has recently decreased in Thailand, Cambodia and Myanmar, and there is no suitable single alternative drug. We therefore investigated possible alternative combination therapies for multidrug resistant falciparum malaria. 120 male Thai patients at Makarm Malaria Clinic, Chantaburi, in eastern Thailand were allocated at random to receive either oral artemether (group A) or artesunate (group B) at a single dose of 300 mg on day 1, both followed by mefloquine, 750 and 500 mg at 24 and 30 h, respectively. Follow-up was on days 1, 2, 7, 14, 21, 28, 35 and 42. Patients in both groups had a rapid initial response to treatment; in most cases parasitaemia was cleared within 24 h, and fever was cleared within 24 h in 62% and 76.7% of the patients in groups A and B, respectively. 58 patients in group A and 57 in group B completed follow-up and cure rates were 98% and 97%, respectively. Reinfection could not be excluded for the 3 patients with recrudescences; all were cured with a repeated course of treatment. No serious adverse effect was observed in either group, only mild and transient nausea, vomiting and loss of appetite, with no significant difference between the 2 groups. These results suggest that a single oral dose of 300 mg of either artemether or artesunate followed by 1250 mg of mefloquine in 2 divided doses is effective against multiple drug resistant falciparum malaria. Either regimen can be considered as a suitable 'stand-by' in endemic areas of multiple drug resistant falciparum malaria.", "Plasmodium falciparum in Thailand is highly resistant to chloroquine, sulfadoxine-pyrimethamine and there is increasing resistance to quinine and mefloquine. The use of qinghaosu derivatives alone or in combination with mefloquine has been shown successfully effective against multidrug resistant P. falciparum in many clinical trials. However their applications with ambulatory treatment should be assessed. 394 uncomplicated falciparum malaria cases studied at Trat and Chanthaburi malaria clinics, eastern Thailand, were allocated at random to receive either one of the seven following regimens: A) artesunate 600 mg over 2 days and mefloquine 1,250 mg in divided doses. B) artemether 640 mg over 2 days and mefloquine 1,250 mg in divided doses. C) artesunate alone 700 mg over 5 days period. D) artemether alone 800 mg over 5 days period. E) quinine plus tetracycline for 7 days. F) mefloquine 1,250 mg in divided doses and G) artesunate 600 mg over 2 days period and mefloquine 750 mg. The follow-up was on Days 1, 2, 7, 14, 21 and 28. Patients tolerated all regimens very well and there was no serious side effects. The adverse effects did not differ among the seven regimens. The cure rates were 98.7, 97.1, 97.9, 96.7, 92.3, 100 and 95.2%, respectively. There was no significant difference of cure rates among various regimens. A total of 16 P. vivax and 1 P. malariae reinfections were reported among the study groups during the second half of the follow-up period, 14 of which were from the groups administered short action drugs (artesunate, artemether or quinine). The results suggested that either artesunate 600 mg or artemether 640 mg in combination with mefloquine 1,250 mg over a period of two days should be considered as alternative regimens for treating uncomplicated multi-drug resistant falciparum malaria.", "To compare the therapeutic efficacy of oral artesunate and artemether in combination with mefloquine for the treatment of multidrug resistant malaria, a trial was conducted in 540 adults and children on the Thai-Myanmar border. Three regimens were compared: artesunate (4 mg/kg/d for 3 d), artemether (4 mg/kg/d for 3 d), both in combination with mefloquine (25 mg/kg), and a single dose of mefloquine (25 mg/kg). The artesunate and artemether regimens gave very similar clinical and parasitological responses, and were both very well tolerated. There was no significant adverse effect attributable to the artemisinin derivatives. Fever and parasite clearance times with mefloquine alone were significantly longer (P < 0.001). After adjusting for reinfections the failure rates were 13.9% for the artesunate combination, 12.3% for the artemether combination and 49.2% for mefloquine alone (P < 0.0001; relative risk 3.8 [95% confidence interval 2.6-5.4]). Mefloquine should no longer be used alone for the treatment of multidrug resistant falciparum malaria in this area. Three-day combination regimens with artesunate or artemether are well tolerated and more effective." ]	Artesunate plus mefloquine performs better than mefloquine alone for treating uncomplicated falciparum malaria in areas with low malaria transmission. A total dose of 25 mg/kg mefloquine and at least 10 mg artesunate leads to higher cure rates. Better reporting of methods and standardisation of outcomes would help the interpretation of future trials. 2008: As monotherapy is no longer recommended by the World Health Organization for malaria treatment, the authors do not intend to update this review.
CD003583	[ "8564938", "9191523", "12910531", "10561942", "9654256", "11013363", "14665609", "14732656", "8002642", "9552047", "16159735", "7595738", "16832795", "18616780", "10071291", "15210457", "18281266" ]	[ "A psychoeducational nursing intervention to enhance coping and affective state in newly diagnosed malignant melanoma patients.", "Postsurgical adjuvant therapy for melanoma. Evaluation of a 3-year randomized trial with recombinant interferon-alpha after 3 and 5 years of follow-up.", "Cognitive-behavioral intervention for distress in patients with melanoma: comparison with standard medical care and impact on quality of life.", "Topical isotretinoin for melasma in Thai patients: a vehicle-controlled clinical trial.", "Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. French Cooperative Group on Melanoma.", "Long term results of a randomized study by the Swedish Melanoma Study Group on 2-cm versus 5-cm resection margins for patients with cutaneous melanoma with a tumor thickness of 0.8-2.0 mm.", "Adjuvant interferon in high-risk melanoma: the AIM HIGH Study--United Kingdom Coordinating Committee on Cancer Research randomized study of adjuvant low-dose extended-duration interferon Alfa-2a in high-risk resected malignant melanoma.", "Photodynamic therapy of multiple nonmelanoma skin cancers with verteporfin and red light-emitting diodes: two-year results evaluating tumor response and cosmetic outcomes.", "Topical retinoic acid (tretinoin) for melasma in black patients. A vehicle-controlled clinical trial.", "Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. Austrian Malignant Melanoma Cooperative Group.", "A randomized multicenter study to compare two treatment regimens of topical methyl aminolevulinate (Metvix)-PDT in actinic keratosis of the face and scalp.", "Randomized, surgical adjuvant clinical trial of recombinant interferon alfa-2a in selected patients with malignant melanoma.", "A randomized trial to improve early detection and prevention practices among siblings of melanoma patients.", "A randomized controlled trial of the efficacy and safety of a fixed triple combination (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) compared with hydroquinone 4% cream in Asian patients with moderate to severe melasma.", "Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b.", "Parametric modeling of narrowband UV-B phototherapy for vitiligo using a novel quantitative tool: the Vitiligo Area Scoring Index.", "Adjuvant low-dose interferon {alpha}2a with or without dacarbazine compared with surgery alone: a prospective-randomized phase III DeCOG trial in melanoma patients with regional lymph node metastasis." ]	[ "The primary purpose of this study was to determine if a psychoeducational nursing intervention including (a) health education, (b) stress management, and (c) the teaching of coping skills could enhance the coping behavior and affective state of newly diagnosed Stage I/II malignant melanoma patients. The secondary purpose was to determine if this intervention could be implemented by a nurse and integrated into the overall patient care program. Sixty-one patients were randomized to a control condition or an experimental condition that received and educational manual plus 3 h of individual nurse teaching. Despite randomization, experimental patients had significantly higher baseline distress. By 3 months there was a complete reversal of the baseline trend in Profile of Mood States (POMS) total mood disturbance (TMD), suggesting that the experimental subjects were experiencing less distress over time. Between-group analysis of change scores found significant decreases in experimental subjects for POMS TMD, fatigue, and Brief Symptom Index (BSI) somatization. Within-group analysis found significant experimental decreases for BSI somatization, anxiety, grand total, General Severity Index, and Positive Symptom Distress Index as well as for POMS anxiety, fatigue, confusion, vigor, and TMD. No significant changes were found for controls. Experimental patients were using significantly fewer ineffective passive resignation coping strategies than controls at 3 months.", "Early surgical intervention is still the most successful therapy for patients with melanoma. The results obtained with medical therapies are still quite disappointing, with better results observed in soft tissue and lymph node metastasis. There currently is no standardized adjuvant therapy for primary melanoma. On the basis of the activity demonstrated in vitro against melanoma cell lines and the results obtained in many clinical trials in patients with advanced melanoma, the authors chose to study the use of recombinant interferon-alpha (IFN-alpha) as adjuvant therapy for patients with Stage I and Stage II melanoma.\n A randomized multicenter trial based on the use of recombinant IFN-alpha-2b for 3 years at the dose of 3 MU given intramuscularly 3 times a week for a period of 6 months with a 1-month interval between cycles was conducted in Stage I and Stage II melanoma patients (using the American Joint Committee on Cancer classification). The efficacy of this treatment was evaluated calculating the incidence of recurrence after 3 and 5 years.\n Results were collected at the end of the treatment period and after 5 years of follow-up for a smaller number of patients. Statistical evaluation showed a significant difference between treated patients and untreated controls with regard to progression of the disease. In particular, IFN-alpha appears to be more effective in patients with worse prognosis lesions.\n IFN-alpha appears to be effective as adjuvant therapy for high risk melanoma patients and the risk/benefit ratio appears to be very favorable. The authors' next goal is to separate those patients who might benefit from adjuvant therapy from those who are cured after the surgical intervention only.", "Melanoma accounts for > 79% of skin cancer-related deaths, although it accounts for only 4% of skin cancer incidence. Given the potential for lethality, it is likely that patients with melanoma may experience significant emotional distress. The current study was designed to determine the effect of a cognitive-behavioral intervention on distress and health-related quality of life (HRQOL) in patients with melanoma who had medium-to-high distress.\n Forty-eight patients who had Global Severity Index scores >or= 60 2 months after their initial visit to the multidisciplinary melanoma clinic were randomized to receive either standard care or 4 sessions of a cognitive-behavioral intervention (CBI). Repeated assessments using the Brief Symptom Inventory, the Medical Outcomes Survey Short Form-36, and the State-Trait Anxiety Inventory occurred at baseline, at 2 months, and at 6 months after intervention for both groups.\n An intent-to-treat analysis did not reveal significantly lower distress in the CBI group at 2 months or 6 months of follow-up, although differences were noted in anxiety and HRQOL. An effect-of-intervention analysis did reveal lower levels of distress in the CBI group at 2 months, with differences approaching significance at 6 months.\n The four-session CBI significantly reduced distress and improved HRQOL for a period of 2 months in patients with melanoma who had medium-to-high distress, with improved general health evident 6 months after the intervention. Some variation in results was revealed in an intent-to-treat analysis. The initial evidence from the current study showed that a brief intervention may be effective for creating change in individuals with cancer who have increased distress, although further research is needed to identify the most optimal approach for delivering the intervention.\n Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11579", "Melasma is an acquired hyperpigmentary disorder commonly seen in Orientals. Recently it has been demonstrated that tretinoin (all-trans-retinoic acid) can produce significant clinical improvement of melasma. However, moderate cutaneous side effects (retinoid dermatitis) occurred in a number of patients.\n To investigate the efficacy of topical 0.05 per cent isotretinoin gel (Isotrex) in the treatment of melasma in Thai patients.\n Thirty patients with moderate to severe melasma entered a 40-week, randomized, vehicle-controlled clinical trial in which they applied either 0.05 per cent isotretinoin gel, or its vehicle base together with a broad spectrum sunscreen (SPF 28) daily to the entire face. They were evaluated clinically (using Melasma Area and Severity Index), and colorimetrically (using our Melasma Area and Melanin Index).\n After 40 weeks, the average MASI and MAMI scores of the isotretinoin-treated group decreased by 68.2 per cent and 47 per cent respectively, while the corresponding control scores declined 60 per cent and 34 per cent. There was no statistically significant difference between the isotretinoin and vehicle groups. When the MASI and MAMI scores of each visit were compared to their baseline data, a statistically significant reduction of the score was first noted at weeks 4 and 12 respectively. Lightening of melasma, as determined clinically (MASI score), correlated well with pigmentation measurements (MAMI score). Side effects were limited to a mild transient \"retinoid dermatitis\" occurring in 27 per cent of isotretinoin-treated patients.\n Daily use of broad spectrum sunscreen has a significant lightening effect on melasma in Thai patients. However, there was no statistically significant difference between the isotretinoin and vehicle-treated group.", "Owing to the limited efficacy of therapy on melanoma at the stage of distant metastases, a well-tolerated adjuvant therapy is needed for patients with high-risk primary melanoma. Our hypothesis was that an adjuvant treatment with low doses of interferon alpha could be effective in patients with localised melanoma.\n After resection of a primary cutaneous melanoma thicker than 1.5 mm, patients without clinically detectable node metastases were randomly assigned to receive either 3x10(6) IU interferon alpha-2a, three-times weekly for 18 months, or no treatment. The primary endpoint was the relapse-free interval.\n 499 patients were enrolled, of whom 489 were eligible. When used as part of a sequential procedure, interferon alpha-2a was of significant benefit for relapse-free interval (p=0.038). A long-term analysis, after a median follow-up of 5 years, showed a significant extension of relapse-free interval (p=0.035) and a clear trend towards an increase in overall survival (p=0.059) in interferon alpha-2a-treated patients compared with controls. There were 100 relapses and 59 deaths among the 244 interferon alpha-2a-treated patients compared with 119 relapses and 76 deaths among the 245 controls. The estimated 3-year-relapse rates were 32% in the interferon alpha-2a group and 44% in controls; the 3-year death rates were 15% and 21%, respectively. Only 10% of patients experienced WHO grade 3 or 4 adverse events. Treatment was compatible with normal daily life.\n Adjuvant therapy of high-risk melanoma with low doses of interferon alpha-2a for 18 months is safe and is beneficial when started before clinically detectable node metastases develop.", "Large, prospective, randomized trials with long term follow-up are required to obtain an unbiased evaluation of the significance of resection margins in patients with cutaneous melanoma.\n The Swedish Melanoma Study Group performed a prospective, randomized, multicenter study of patients with primary melanoma located on trunk or extremities and with a tumor thickness > 0.8 mm and </= 2 mm. Patients were allocated randomly to a 2-cm excision margin or a 5-cm excision margin. In total, 989 patients were recruited during the period 1982-1991. The median follow-up was 11 years (range, 7-17 years) for estimation of survival and 8 years (range, 0-17 years) for evaluation of recurrent disease.\n The crude rate of local recurrence, defined as a recurrence in the scar or transplant, was < 1% (8 of 989 patients). Twenty percent of the patients (194 of 989 patients) experienced any disease recurrence, and 15% (146 of 989 patients) died of melanoma. There were no statistically significant differences between the two treatment arms. In a multivariate Cox analysis with patients allocated to wide excision as the reference group, the estimated relative hazards for overall survival and recurrence free survival among those allocated to a 2-cm resection margin were 0.96 (95% confidence interval, 0.75-1.24), and 1.02 (95% confidence interval, 0.80-1.30), respectively.\n In this long term follow-up study, local recurrences were found to be rare among patients with tumors > 0.8 mm thick and </= 2.0 mm thick. No difference in recurrence rate or survival between the two treatment groups was found. Patients in this category can be treated with a resection margin of 2 cm as safely as with a resection margin of 5 cm.", "To evaluate low-dose extended duration interferon alfa-2a as adjuvant therapy in patients with thick (> or = 4 mm) primary cutaneous melanoma and/or locoregional metastases.\n In this randomized controlled trial involving 674 patients, the effect of interferon alfa-2a (3 megaunits three times per week for 2 years or until recurrence) on overall survival (OS) and recurrence-free survival (RFS) was compared with that of no further treatment in radically resected stage IIB and stage III cutaneous malignant melanoma.\n The OS and RFS rates at 5 years were 44% (SE, 2.6) and 32% (SE, 2.1), respectively. There was no significant difference in OS or RFS between the interferon-treated and control arms (odds ratio [OR], 0.94; 95% CI, 0.75 to 1.18; P =.6; and OR, 0.91; 95% CI, 0.75 to 1.10; P =.3; respectively). Male sex (P =.003) and regional lymph node involvement (P =.0009), but not age (P =.7), were statistically significant adverse features for OS. Subgroup analysis by disease stage, age, and sex did not show any clear differences between interferon-treated and control groups in either OS or RFS. Interferon-related toxicities were modest: grade 3 (and in only one case, grade 4) fatigue or mood disturbance was seen in 7% and 4% respectively, of patients. However, there were 50 withdrawals (15%) from interferon treatment due to toxicity.\n The results from this study, taken in isolation, do not indicate that extended-duration low-dose interferon is significantly better than observation alone in the initial treatment of completely resected high-risk malignant melanoma.", "Efficient treatment of patients with multiple synchronous nonmelanoma skin cancers represents a therapeutic challenge.\n To study the safety and efficacy of photodynamic therapy (PDT) with verteporfin and red light in the treatment of multiple nonmelanoma skin cancers.\n Open-label, randomized, multicenter, dose-ranging phase 2 study conducted at 4 North American university-based dermatology clinics.\n Fifty-four patients with 421 multiple nonmelanoma skin cancers including superficial and nodular basal cell carcinoma and squamous cell carcinoma in situ (Bowen disease).\n A single intravenous infusion of 14 mg/m(2) of verteporfin followed 1 to 3 hours later by exposure of tumors to 60, 120, or 180 J/cm(2) of red light (688 +/- 10 nm) from a light-emitting diode panel.\n Pathologic response of treated sites was assessed at 6 months. Clinical and cosmetic responses were assessed and graded at 6 weeks, 3 months, and 6 months after verteporfin PDT, with optional follow-up visits at 12, 18, and 24 months.\n The histopathologic response, defined as absence of tumor on biopsy specimens 6 months after verteporfin PDT, ranged from 69% at 60 J/cm(2) to 93% at 180 J/cm(2). At 24 months of follow-up (276 tumors in 31 patients), the clinical complete response rate ranged from 51% at 60 J/cm(2) to 95% at 180 J/cm(2). No significant systemic adverse events were observed; most events occurred at the treated tumor sites and included events such as pain. Overall, 65% (95% confidence interval, 58%-71%) of tumors were judged to have good to excellent cosmesis at 24 months.\n A single course of verteporfin PDT showed treatment benefit for patients with multiple nonmelanoma skin cancers.", "Melasma is an acquired, masklike, facial hyperpigmentation. The pathogenesis and treatment of melasma in black (African-American) patients is poorly understood. We investigated the efficacy of topical 0.1% all-trans-retinoic acid (tretinoin) in the treatment of melasma in black patients. Twenty-eight of 30 black patients with melasma completed a 10-month, randomized, vehicle-controlled clinical trial in which they applied either 0.1% tretinoin or vehicle cream daily to the entire face. They were evaluated clinically (using our Melasma Area and Severity Index), colorimetrically, and histologically.\n After 40 weeks, there was a 32% improvement in the Melasma Area and Severity Index score in the tretinoin treatment group compared with a 10% improvement in the vehicle group. Colorimetric measurements showed lightening of melasma after 40 weeks of tretinoin treatment vs vehicle. Lightening of melasma, as determined clinically, correlated well with colorimetric measurements. Histologic examination of involved skin revealed a significant decrease in epidermal pigmentation in the tretinoin group compared with the vehicle group. Side effects were limited to a mild \"retinoid dermatitis\" occurring in 67% of tretinoin-treated patients. Among the patients in this study in comparison with comparably recruited white patients, melasma was reported to have begun at a later age and was more likely to be in a malar distribution.\n This controlled study demonstrates that topical 0.1% tretinoin lightens melasma in black patients, with only mild side effects.", "Patients with primary cutaneous melanoma with a Breslow thickness > or = 1.5 mm have only a 30% to 70% probability of survival after surgery, and no adjuvant therapy has so far improved this outcome. Since interferon alfa-2a (IFNalpha2a) exhibits antitumor activity in metastatic melanoma, we investigated whether adjuvant IFNalpha2a diminishes the occurrence of metastases and thus prolongs disease-free survival in melanoma patients after excision of the primary tumor.\n In a prospective randomized study, 311 melanoma patients with a Breslow thickness > or = 1.5 mm were assigned to either adjuvant IFNalpha2a treatment (n = 154) or observation (n = 157) after excision of the primary tumor. IFNalpha2a was given daily at a dose of 3 mIU subcutaneously (s.c.) for 3 weeks (induction phase), after which a dose of 3 mIU s.c. three times per week was given over 1 year (maintenance phase).\n Prolonged disease-free survival was observed in patients treated with IFNalpha2a versus those who underwent surgery alone. This difference was significant (P = .02) for all patients enrolled onto the study (intention-to-treat analysis) at a mean observation time of 41 months. Subgroup analysis showed that Breslow tumor thickness had no influence on treatment results in the groups of patients investigated.\n Adjuvant IFNalpha2a treatment diminishes the occurrence of metastases and thus prolongs disease-free survival in resected primary stage II cutaneous melanoma patients.", "Photodynamic therapy (PDT) with topical methyl aminolevulinate (MAL) administered in two treatment sessions separated by 1 week is an effective treatment for actinic keratoses. This open prospective study compared the efficacy and safety of MAL-PDT given as a single treatment with two treatments of MAL-PDT 1 week apart. Two hundred and eleven patients with 413 thin to moderately thick actinic keratoses were randomized to either a single treatment with PDT using topical MAL (regimen I; n=105) or two treatments 1 week apart (regimen II; n=106). Each treatment involved surface debridement, application of Metvix cream (160 mg/g) for 3 h, followed by illumination with red light using a light-emitting diode system (peak wavelength 634+/-3 nm, light dose 37 J/cm2). Thirty-seven lesions (19%) with a non-complete response 3 months after a single treatment were re-treated. All patients were followed up 3 months after the last treatment. A total of 400 lesions, 198 initially treated once and 202 treated twice, were evaluable. Complete response rate for thin lesions after a single treatment was 93% (95% CI=87-97%), which was similar to 89% (82-96%) after repeated treatment. Response rates were lower after single treatment of thicker lesions (70% (60-78%) vs 84% (77-91%)), but improved after repeated treatment (88% (82-94%)). The conclusion of this study is that single treatment with topical MAL-PDT is effective for thin actinic keratosis lesions; however, repeated treatment is recommended for thicker or non-responding lesions.", "We conducted a randomized prospective trial in selected patients with fully resected high-risk stage I and II malignant melanoma.\n Interferon alfa-2a (IFN-alpha 2a) 20 x 10(6) U/m2 was administered three times each week for 12 weeks by the intramuscular route. Both the treatment group (n = 131) and the control group (n = 131) were evenly balanced with regard to relevant prognostic discriminants.\n The median disease-free survival (DFS) time was 2.4 years for the IFN-alpha 2a group and 2.0 years for the observation group (log-rank P = 0.19). The median survival times were 6.6 years for IFN-alpha 2a and 5.0 years for observation (log-rank P = .40). For stage I patients (n = 102), there was no apparent therapeutic advantage from IFN-alpha 2a therapy. The DFS for stage II patients was a median of 10.8 months in the control group versus 17 months in the treatment group. The overall survival time was 4.1 years for the treatment group versus 2.7 years for the control group. The differences in DFS for stage II patient were significant in a Cox model. These results must be interpreted cautiously because of subset analysis. A severe flu-like toxicity occurred in 44% of patients, 13% lost at least 10% of their baseline weight, and 45% experienced a worsening of Eastern Cooperative Oncology Group (ECOG) performance score.\n Our findings indicate trends that suggest a possible benefit for selected patients with high-risk malignant melanoma. The results will require further study in a larger patient population for confirmation.", "Identifying high-risk individuals for melanoma education and risk reduction may be a viable strategy to curb the incidence of melanoma, which has risen precipitously in the past 50 years. The first-degree relatives of melanoma patients represent a risk group who may experience a 'teachable moment' for enhanced education and risk reduction.\n We report a randomized trial testing an intervention that provided personalized telephone counseling and individually tailored materials to siblings of recently-diagnosed melanoma patients. The purpose of this study was to test whether an intervention could lead to improvements in siblings' skin cancer risk reduction practices. Intervention condition participants received the following: (1) an initial motivational and goal-setting telephone intervention session delivered by the health educator; (2) three sets of computer-generated materials specifically tailored to individual responses from the baseline survey; (3) three telephone counseling sessions with the health educator, timed to follow receipt of the mailed materials; and (4) linkages to free screening programs. Families in the usual care arm received the suggestion from the physician that patients diagnosed with melanoma notify the family members about their diagnosis and encourage the family members to be screened.\n 494 siblings were recruited to the study and 403 siblings remained in the study through at least 6 months. At 12 months, intervention siblings were more likely to examine all moles, including those on the back (OR, 1.76; 95% CI, 1.06-2.91). Compared with baseline, the number of participants in both groups that had received a skin cancer examination more than doubled, with no differences between groups. At 12 months, two-thirds of siblings in both groups reported routine use of sunscreen, but there were no differences in change over baseline between the two groups.\n This study is the one of the first, to our knowledge, to address skin cancer risk-reduction strategies in a sample of individuals who have a recent family diagnosis of melanoma. Diagnosis of melanoma in a family member provides an important opportunity to intervene with others in that family. The components of the intervention may provide a useful foundation for future efforts to target the more than half million siblings at risk for melanoma, a lethal but preventable disease.", "Melasma is an acquired, chronic hypermelanosis for which therapy remains a challenge.\n To compare the efficacy and safety of a triple combination [TC: fluocinolone acetonide 0.01%, hydroquinone (HQ) 4%, tretinoin 0.05%] vs. HQ 4% after 8 weeks of treatment of moderate to severe facial melasma in Asian patients.\n This was a multicentre, randomized, controlled, investigator-blinded, parallel comparison study. East and South-East Asian patients aged 18 years or older, with a clinical diagnosis of moderate to severe melasma, were enrolled in this study. Patients were enrolled at baseline and treated daily for 8 weeks with TC cream (one application at bedtime) or HQ cream (twice daily). There were four study visits: at baseline and weeks 2, 4 and 8. The primary efficacy variable was the melasma global severity score (GSS). Other outcome measures included Melasma Area and Severity Index, global improvement and patient satisfaction. Safety was assessed through the reporting of adverse events.\n TC had superior efficacy to HQ for the primary variable: 77/120 patients (64.2%) on TC had GSS 'none' or 'mild' at week 8 vs. 48/122 patients (39.4%) on HQ (P < 0.001). The secondary efficacy variables confirmed these results. Patient satisfaction was in favour of TC (90/127, 70.8%, vs. 64/129, 49.6%; P = 0.005). More patients had related adverse events on TC (63/129, 48.8%) than on HQ (18/131, 13.7%) but most were mild and none was severe.\n Efficacy in Asians and patient satisfaction were superior with the fixed TC than with HQ 4%.", "The combination of chemotherapy with immunotherapeutic agents such as interleukin-2 and interferon alfa-2b has been reported to provide improved treatment results in patients with metastatic melanoma, compared with the use of chemotherapy alone. We have performed a prospective randomized trial in patients with metastatic melanoma, comparing treatment with chemotherapy to treatment with chemoimmunotherapy.\n One hundred two patients with metastatic melanoma were prospectively randomized to receive chemotherapy composed of tamoxifen, cisplatin, and dacarbazine or this same chemotherapy followed by interferon alfa-2b and interleukin-2. Objective responses, survival, and toxicity in the two groups were evaluated at a median potential follow-up of 42 months.\n In 52 patients randomized to receive chemotherapy, there were 14 objective responses (27%), including four complete responses. In 50 patients randomized to receive chemoimmunotherapy, there were 22 objective responses (44%) (P2 = .071), including three complete responses. In both treatment groups, the duration of partial responses was often short, and there was a trend toward a survival advantage for patients receiving chemotherapy alone (P2 = .052; median survival of 15.8 months compared with 10.7 months). Treatment-related toxicities were greater in patients receiving chemoimmunotherapy.\n With the treatment regimens used in this study, the addition of immunotherapy to combination chemotherapy increased toxicity but did not increase survival. The use of combination chemoimmunotherapy regimens is not recommended in the absence of well-designed, prospective, randomized protocols showing the benefit of this treatment strategy.", "There is currently no quantitative tool for evaluating vitiligo treatment response using parametric methods.\n To develop and apply a simple clinical tool, the Vitiligo Area Scoring Index (VASI), to model the response of vitiligo to narrowband UV-B (NB-UV-B) phototherapy using parametric tests.\n Prospective, randomized, controlled, bilateral left-right comparison trial.\n North American tertiary care, university-affiliated phototherapy center.\n Patients older than 18 years with stable vitiligo involving at least 5% of their total body surface in a symmetric distribution.\n Treatment with NB-UV-B was given 3 times a week to half of the body on all patients for either 60 treatments or 6 months. The contralateral side served as a no-treatment control.\n Repigmentation was assessed using the VASI, which was based on a composite estimate of the overall area of vitiligo patches at baseline and the degree of macular repigmentation within these patches over time. The VASI was validated separately against physician and patient global assessments. The overall reductions in VASI for NB-UV-B and control groups were modeled by multilevel regression with random effects and compared parametrically.\n The VASI scoring correlated well with both patient and physician global assessments (P =.05 and P<.001, respectively, using ordinal logistic regression). The extent of repigmentation after 6 months on the treated side was 42.9% (95% confidence interval, 26.7%-59.0%) vs 3.3% (95% confidence interval -19.3% to 30.0%) on the untreated side (P<.001). A significant difference between control and NB-UV-B groups was apparent within the first 2 months of therapy. The legs, trunk, and arms were much more likely to repigment than the feet and hands.\n The VASI is a quantitative clinical tool that can be used to evaluate vitiligo parametrically. Patients treated with NB-UV-B can be expected to achieve approximately 42.9% repigmentation of their vitiligo after 6 months of treatment, with the greatest response being achieved over the trunk and nonacral portions of the extremities.", "More than half of patients with melanoma that has spread to regional lymph nodes develop recurrent disease within the first 3 years after surgery. The aim of the study was to improve disease-free survival (DFS) and overall survival (OS) with interferon (IFN) alpha2a with or without dacarbazine (DTIC) compared with observation alone.\n A total of 444 patients from 42 centers of the German Dermatologic Cooperative Oncology Group who had received a complete lymph node dissection for pathologically proven regional node involvement were randomized to receive either 3 MU s.c. of IFNalpha2a three times a week for 2 years (Arm A) or combined treatment with same doses of IFNalpha2a plus DTIC 850 mg/m(2) every 4-8 weeks for 2 years (Arm B) or to observation alone (Arm C). Treatment was discontinued at first sign of relapse.\n A total of 441 patients were eligible for intention-to-treat analysis. Kaplan-Meier 4-year OS rate of those who had received IFNalpha2a was 59%. For those with surgery alone, survival was 42% (A versus C, P = 0.0045). No improvement of survival was found for the combined treatment Arm B with 45% survival rate (B versus C, P = 0.76). Similarly, DFS rates showed significant benefit for Arm A, and not for Arm B. Multivariate Cox model confirmed that Arm A has an impact on OS (P = 0.005) but not Arm B (P = 0.34).\n 3 MU interferon alpha2a given s.c. three times a week for 2 years significantly improved OS and DFS in patients with melanoma that had spread to the regional lymph nodes. Interestingly, the addition of DTIC reversed the beneficial effect of adjuvant interferon alpha2a therapy." ]	The quality of studies evaluating melasma treatments was generally poor and available treatments inadequate. High-quality randomised controlled trials on well-defined participants with long-term outcomes to determine the duration of response are needed.
CD006849	[ "9849452", "10470844", "11697833", "15454647", "8410110", "11720426", "2833577", "12506176", "20619634", "9363869", "16325695", "9716055", "8117604", "7539873", "8777169", "19016015", "12243809", "9060525", "3683485", "7844608", "2185340", "8648358", "16077990", "10655439", "8938220" ]	[ "Quality of life and survival in patients with advanced non-small cell lung cancer receiving supportive care plus chemotherapy with carboplatin and etoposide or supportive care only. A multicentre randomised phase III trial. Joint Lung Cancer Study Group.", "Standard combination versus alternating chemotherapy in small cell lung cancer: a randomised clinical trial including 394 patients. 'Petites Cellules' Group.", "Randomized comparison of early versus late hyperfractionated thoracic irradiation concurrently with chemotherapy in limited disease small-cell lung cancer: a randomized phase II study of the Hellenic Cooperative Oncology Group (HeCOG).", "Chemotherapy versus supportive care in advanced non-small cell lung cancer: improved survival without detriment to quality of life.", "Multiple-drug weekly chemotherapy versus standard combination regimen in small-cell lung cancer: a phase III randomized study conducted by the European Lung Cancer Working Party.", "A three-arm phase III randomised trial assessing, in patients with extensive-disease small-cell lung cancer, accelerated chemotherapy with support of haematological growth factor or oral antibiotics.", "Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer--report of a Canadian multicenter randomized trial.", "An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer.", "Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer--results from two randomised studies.", "Randomized trial of chemotherapy and radiation therapy with or without warfarin for limited-stage small-cell lung cancer: a Cancer and Leukemia Group B study.", "Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheral-blood stem-cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: results of a multicentre phase III trial.", "Randomised trial of high-dose chemotherapy and haemopoietic progenitor-cell support in operable breast cancer with extensive axillary lymph-node involvement.", "Induction chemotherapy plus high-dose radiotherapy versus radiotherapy alone in locally advanced unresectable non-small-cell lung cancer.", "Combination chemotherapy as induction therapy for advanced resectable head and neck cancer.", "A randomized study of high-dose split course radiotherapy preceded by high-dose chemotherapy versus high-dose radiotherapy only in locally advanced non-small-cell lung cancer. An EORTC Lung Cancer Cooperative Group trial.", "Randomized study of postoperative radiotherapy and simultaneous temozolomide without adjuvant chemotherapy for glioblastoma.", "Phase III study comparing chemotherapy and radiotherapy with preoperative chemotherapy and surgical resection in patients with non-small-cell lung cancer with spread to mediastinal lymph nodes (N2); final report of RTOG 89-01. Radiation Therapy Oncology Group.", "Initial versus delayed accelerated hyperfractionated radiation therapy and concurrent chemotherapy in limited small-cell lung cancer: a randomized study.", "Improving the quality of life during chemotherapy for advanced breast cancer. A comparison of intermittent and continuous treatment strategies.", "Randomized trial of hyperfractionated radiation therapy with or without concurrent chemotherapy for stage III non-small-cell lung cancer.", "Efficacy of adjuvant chemotherapy for patients with resectable head and neck cancer: a subset analysis of the Head and Neck Contracts Program.", "Hyperfractionated radiation therapy with or without concurrent low-dose daily carboplatin/etoposide for stage III non-small-cell lung cancer: a randomized study.", "A randomized trial between two neoadjuvant chemotherapy protocols: CDDP + 5-FU versus CDDP + VP16 in advanced cancer of the head and neck.", "Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma.", "Feasibility of non-cisplatin-based induction chemotherapy and concurrent chemoradiotherapy in advanced head and neck cancer." ]	[ "The aim of the present trial was to evaluate the effects of chemotherapy on the quality of life and survival of patients with advanced non-small cell lung cancer (NSCLC) (stage IIIB or IV). In a controlled multicentre trial, patients were randomised to receive supportive care only or supportive care plus chemotherapy. Chemotherapy consisted of intravenous (i.v.) carboplatin 300 mg/m2 on day 1 and etoposide 120 mg/m2 orally on days 1-5 every 4 weeks for a maximum of eight courses. Quality of life was measured at randomisation and prior to each treatment course and at corresponding 4-week intervals in the control arm, using the EORTC QLQ-C30 + LC13 questionnaire. 48 patients were randomised (supportive care 26, chemotherapy 22), being eligible for comparative analyses. Another 102 patients, 97 of which received chemotherapy, were subsequently included in the study on an individual treatment preference basis. Data from these patients were used for confirmative purposes. Patients in the chemotherapy group reported better overall physical functioning and symptom control compared with the supportive care group. Group differences were smaller within the psychosocial domain, although trends were seen in favour of the chemotherapy group. No significant differences were seen in favour of the supportive care group, except for hair loss. Median survival times were 29 weeks in the chemotherapy group versus 11 weeks in the supportive care group, and 1-year survival rates were 28% versus 8%. Quality of life and survival outcomes were similar in the randomised and non-randomised patients receiving chemotherapy. No treatment-related deaths occurred. In conclusion, treatment with carboplatin and etoposide can improve both the quality of life and the survival of patients with advanced NSCLC.", "to compare standard and alternating administration of chemotherapy combinations in small cell lung cancer (SCLC) patients.\n in a multicenter clinical trial, 394 previously untreated SCLC patients were randomised to receive, every 4 weeks, eight courses of either a standard regimen with CCNU, cyclophosphamide, adriamycin (CCA) and VP16 or an alternating regimen (CCA regimen alternating with cisplatin-vindesine-VP16).\n overall response rate was higher in the standard group (78%) than in the alternating group (64%) (P = 0.0001). Complete response rate was also higher in the standard group (32%) than in the alternating group (18%) (P = 0.004). The median survival in the overall SCLC population was 306 days in the standard group and 272 days in the alternating group (P = 0.08). In limited SCLC patients, median survival was higher in the standard group (421 days) than in the alternating group (328 days) (P = 0.01). Grade III/IV haematological toxicity was lower in patients in the alternating group (25 versus 47%) (P < 0.001).\n the standard regimen was better than the alternating regimen for patients with limited forms of SCLC. The alternating regimen, associated with better haematological safety and ensuring a fairly similar survival, may be considered in patients with extensive SCLC. Pleiomorphic resistance mechanisms to chemotherapy make it difficult to define a non-cross-resistant chemotherapy regimen.", "Concurrent platinum etoposide chemotherapy given in combination with hyperfractionated thoracic radiation therapy (HTRT) in limited disease (LD) small cell lung cancer (SCLC) is associated with a high response rate and significant prolongation of survival. Given these results, the Hellenic Cooperative Oncology Group (HeCOG) performed a multicenter randomized phase II study in patients with LD SCLC to evaluate the timing of HTRT (early vs. late) when given concurrently with chemotherapy.\n To be eligible for the study, patients were required to have histologically or cytologically proven LD SCLC, confined to one hemithorax and/or ipsilateral mediastinal or supraclavicular lymphnodes and absence of pleural effusion or controlateral supraclavicular lymphnode involvement. Moreover, patients had to have a good performance status and adequate haematological, liver and renal function. Patients with LD SCLC were randomized to receive HTRT either concurrently with the first (Group A) or with the fourth (Group B) cycle of chemotherapy. Chemotherapy consisted of carboplatin administered at an AUC of six given as an i.v. 1-hour-infusion immediately followed by etoposide at a dose of 100 mg/m2 i.v. as a two-hour infusion for three consecutive days every three weeks up to a total of six cycles. Prophylactic cranial irradiation was also given to patients achieving a complete response.\n 42 and 39 patients, were eligible for efficacy evaluation in group A and B respectively. The overall response rate was 76% in group A and 92.5% in group B (P = 0.07) with a complete response rate of 40.5% and 56.5%, respectively. After a median follow-up of 35 months, time to progression was 9.5 months in group A and 10.5 in group B (NS) while overall median survival was 17.5 and 17 months respectively (NS). The 2-year survival was 36% in group A and 29% in group B (NS) and the 3-year survival 22% and 13%, respectively (NS). The distant relapse rate was 38% in group A and 61% in group B (P = 0.046). Severe grade 3 4 anemia was recorded in 19% of group A and 12.5% of group B (NS), while severe leucopenia was recorded in 35.5% and 20.5% (P = 0.09) and neutropenic fever in 5% and 2.5% (NS), respectively. Severe thrombocytopenia did not differ significantly between the two treatment groups being 21.5% and 23%, respectively. Severe grade 2-3 esophageal toxicity was 19% in group A and 23% in group B (NS), while grade 3 lung toxicity was 5% and 7.5% (NS), respectively. No toxicity-related deaths were recorded.\n Concurrent administration of HTRT with carboplatin etoposide is associated with a high response and survival rate. Although a trend for higher response rate was recorded in the group of patients who received late HTRT, the overall median, 2-year and 3-year survival rates did not differ significantly between the two treatment groups. The toxicity of this promising therapeutic approach was acceptable. Comparative phase III studies with an adequate number of patients are recommended in order to answer this question.", "In 1995 a meta-analysis of randomised trials investigating the value of adding chemotherapy to primary treatment for non-small cell lung cancer (NSCLC) suggested a small survival benefit for cisplatin-based chemotherapy in each of the primary treatment settings. However, the meta-analysis included many small trials and trials with differing eligibility criteria and chemotherapy regimens.\n The aim of the Big Lung Trial was to confirm the survival benefits seen in the meta-analysis and to assess quality of life and cost in the supportive care setting. A total of 725 patients were randomised to receive supportive care alone (n = 361) or supportive care plus cisplatin-based chemotherapy (n = 364).\n 65% of patients allocated chemotherapy (C) received all three cycles of treatment and a further 27% received one or two cycles. 74% of patients allocated no chemotherapy (NoC) received thoracic radiotherapy compared with 47% of the C group. Patients allocated C had a significantly better survival than those allocated NoC: HR 0.77 (95% CI 0.66 to 0.89, p = 0.0006), median survival 8.0 months for the C group v 5.7 months for the NoC group, a difference of 9 weeks. There were 19 (5%) treatment related deaths in the C group. There was no evidence that any subgroup benefited more or less from chemotherapy. No significant differences were observed between the two groups in terms of the pre-defined primary and secondary quality of life end points, although large negative effects of chemotherapy were ruled out. The regimens used proved to be cost effective, the extra cost of chemotherapy being offset by longer survival.\n The survival benefit seen in this trial was entirely consistent with the NSCLC meta-analysis and subsequent similarly designed large trials. The information on quality of life and cost should enable patients and their clinicians to make more informed treatment choices.", "A randomized trial was conducted in patients with small-cell lung cancer (SCLC) to determine if survival can be improved by a weekly chemotherapy regimen combining various drugs.\n Two hundred twenty-three patients were randomized to receive either six courses of a multiple-drug combination (MDC) regimen (Adriamycin [ADR; doxorubicin; Farmitalia Carlo Erba, Milan, Italy] 25 mg/m2 intravenously [i.v.] on day 1; etoposide [VP16] 120 mg/m2 i.v. on day 1; cyclophosphamide [CPA] 500 mg/m2 i.v. on day 1; cisplatin 60 mg/m2 i.v. on day 8; vindesine [VDS] 3 mg/m2 i.v. on day 8; vincristine [VCR] 2 mg i.v. on day 15; methotrexate [MTX] 100 mg/m2 i.v. on day 15), or a standard chemotherapy (SC) regimen (ADR 50 mg/m2 i.v. on day 1; CPA 1 g/m2 i.v. on day 1; VP16 80 mg/m2 i.v. on days 1 to 3).\n In 98 MDC-treated and 101 SC-treated assessable patients, we observed 69% and 62% objective responses rates, respectively. There was no significant difference in survival, with median durations and 2-year overall survival rates of 49 and 43 weeks and 8.5% and 7.9%, respectively. There was a significant increase in response rate in favor of MDC patients with limited disease (84% v 62%). Toxicity was tolerable, although SC was more hematotoxic, with 76% (v 59%) experiencing leukopenia and 17% (v 7%) experiencing thrombocytopenia (grades III and IV). If the cumulative doses received were nearly equal to the scheduled cumulative doses in both arms, the total relative dose-intensity (RDI) was significantly higher in the SC arm. The difference was due to increased treatment delays in the MDC arm.\n Weekly MDC failed to improve survival rates in patients with SCLC.", "The European Lung Cancer Working Party (ELCWP) designed a 3-arm phase III randomised trial to determine the role of accelerated chemotherapy in extensive-disease (ED) small-cell lung cancer (SCLC). Eligible patients were randomised between the 3 following arms: (A) Standard chemotherapy with 6 courses of EVI (epirubicin 60 mg m(-2), vindesine 3 mg m(-2), ifosfamide 5 g m(-2); all drugs given on day 1 repeated every three weeks. (B) Accelerated chemotherapy with EVI administered every 2 weeks and GM-CSF support. (C) Accelerated chemotherapy with EVI and oral antibiotics (cotrimoxazole). Primary endpoint was survival. 233 eligible patients were randomised. Chemotherapy could be significantly accelerated in arm B with increased absolute dose-intensity. Best response rates, in the population of evaluable patients, were, respectively for arm A, B and C, 59%, 76% and 70%. The response rate was significantly higher in arm B in comparison to arm A (P = 0.04). There was, however, no survival difference with respective median duration and 2-year rate of 286 days and 5% for arm A, 264 days and 6% for arm B and 264 days and 6% for arm C. Severe thrombopenia occurred more frequently in arm B but without an increased rate of bleeding. Non-severe infections were more frequent in arm B and severe infections were less frequent in arm C. Our trial failed to demonstrate, in ED-SCLC, a survival benefit of chemotherapy acceleration by using GM-CSF support.", "The survival benefit of combination chemotherapy to patients with advanced non-small-cell carcinoma of the lung (NSCLC) is controversial. To study this question, the National Cancer Institute of Canada (NCIC) Clinical Trials Group conducted a prospective randomized trial comparing best supportive care (BSC) to two chemotherapy regimens, vindesine and cisplatin (VP), and cyclophosphamide, doxorubicin, and cisplatin (CAP). Between February 1983 and January 1986, 23 centers across Canada entered 251 patients on study. Eighteen centers participated in the three-arm schema (150 patients); centers choosing not to participate in a study with a no-chemotherapy arm followed a two-arm schema comparing VP with CAP (101 additional patients). Altogether, 233 patients were eligible. Patients had measurable or evaluable disease, with either distant metastases (82.5%) or bulky limited disease considered inoperable or unsuitable for radical radiotherapy. The treatment groups were comparable in terms of age, sex, performance status, histology, disease extent, and weight loss. The overall response rates (complete response [CR] plus partial response [PR]) on the chemotherapy arms were CAP, 15.3%, and VP, 25.3% (P = .06). Patients on the three-arm portion of the trial had a median survival of 32.6 weeks when treated with VP, 24.7 weeks with CAP, and 17 weeks with BSC. The significance of the differences in survival, adjusted for prognostic factors, is as follows: chemotherapy v BSC, P = .02; VP v BSC, P = .01; and CAP v BSC, P = .05. Toxicity on the chemotherapy arms was significant, with leukopenia of severe or greater degree occurring in 37.8% (CAP) and 40.0% (VP), severe vomiting in 12.2% (CAP) and 23.3% (VP), and severe neurotoxicity in 15.6% (VP).", "The Head and Neck Intergroup conducted a phase III randomized trial to test the benefit of adding chemotherapy to radiation in patients with unresectable squamous cell head and neck cancer.\n Eligible patients were randomly assigned between arm A (the control), single daily fractionated radiation (70 Gy at 2 Gy/d); arm B, identical radiation therapy with concurrent bolus cisplatin, given on days 1, 22, and 43; and arm C, a split course of single daily fractionated radiation and three cycles of concurrent infusional fluorouracil and bolus cisplatin chemotherapy, 30 Gy given with the first cycle and 30 to 40 Gy given with the third cycle. Surgical resection was encouraged if possible after the second chemotherapy cycle on arm C and, if necessary, as salvage therapy on all three treatment arms. Survival data were compared between each experimental arm and the control arm using a one-sided log-rank test.\n Between 1992 and 1999, 295 patients were entered on this trial. This did not meet the accrual goal of 362 patients and resulted in premature study closure. Grade 3 or worse toxicity occurred in 52% of patients enrolled in arm A, compared with 89% enrolled in arm B (P <.0001) and 77% enrolled in arm C (P <.001). With a median follow-up of 41 months, the 3-year projected overall survival for patients enrolled in arm A is 23%, compared with 37% for arm B (P =.014) and 27% for arm C (P = not significant).\n The addition of concurrent high-dose, single-agent cisplatin to conventional single daily fractionated radiation significantly improves survival, although it also increases toxicity. The loss of efficacy resulting from split-course radiation was not offset by either multiagent chemotherapy or the possibility of midcourse surgery.", "Endometrial cancer patients with high grade tumours, deep myometrial invasion or advanced stage disease have a poor prognosis. Randomised studies have demonstrated the prevention of loco-regional relapses with radiotherapy (RT) with no effect on overall survival (OS). The possible additive effect of chemotherapy (CT) remains unclear. Two randomised clinical trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) were undertaken to clarify if sequential combination of chemotherapy and radiotherapy improves progression-free survival (PFS) in high-risk endometrial cancer. The two studies were pooled.\n Patients (n=540; 534 evaluable) with operated endometrial cancer International Federation of Obstetrics and Gynaecology (FIGO) stage I-III with no residual tumour and prognostic factors implying high-risk were randomly allocated to adjuvant radiotherapy with or without sequential chemotherapy.\n In the NSGO/EORTC study, the combined modality treatment was associated with 36% reduction in the risk for relapse or death (hazard ratio (HR) 0.64, 95%confidence interval (CI) 0.41-0.99; P=0.04); two-sided tests were used. The result from the Gynaecologic Oncology group at the Mario Negri Institute (MaNGO)-study pointed in the same direction (HR 0.61), but was not significant. In the combined analysis, the estimate of risk for relapse or death was similar but with narrower confidence limits (HR 0.63, CI 0.44-0.89; P=0.009). Neither study showed significant differences in the overall survival. In the combined analysis, overall survival approached statistical significance (HR 0.69, CI 0.46-1.03; P=0.07) and cancer-specific survival (CSS) was significant (HR 0.55, CI 0.35-0.88; P=0.01).\n Addition of adjuvant chemotherapy to radiation improves progression-free survival in operated endometrial cancer patients with no residual tumour and a high-risk profile. A remaining question for future studies is if addition of radiotherapy to chemotherapy improves the results.\n Copyright 2010 Elsevier Ltd. All rights reserved.", "Studies by the Veterans Administration Cooperative Studies Program and Cancer and Leukemia Group B (CALGB) suggested that the addition of warfarin to chemotherapy might enhance response and/or survival in small-cell lung cancer (SCLC). This randomized study evaluated the effect of warfarin with chemotherapy and radiation therapy in limited-stage SCLC.\n Patients were randomized to receive warfarin or no warfarin. All patients received three cycles of doxorubicin, cyclophosphamide, and etoposide (ACE). Cycles 4 and 5 (cisplatin, cyclophosphamide, and etoposide [PCE]) were given concurrently with radiation therapy. Three cycles of ACE were given after chemoradiation therapy, but were discontinued due to a high rate of pulmonary toxicity.\n There were no significant differences in response rates, survival, failure-free survival, disease-free survival, or patterns of relapse between the warfarin-treated and control groups. In patients treated according to the initial design, an increase in failure-free survival seen with warfarin treatment approached significance (P = .07). Preamendment results, while not significant, did not have superimposable treatment survival curves. A landmark analysis at 8 months showed a median survival time after the landmark for complete responders of 33 months with warfarin treatment compared with < or = 13.75 months for complete or partial responders not treated with warfarin (P = .05). Differences between the complete responders in this preamendment population were not significant (P = .103).\n Warfarin does not appear to improve outcome significantly in limited-stage SCLC. However, the differences in some variables between populations before the protocol amendment correspond to the favorable effects of anticoagulants observed in previous studies.", "Breast cancer with extensive axillary-lymph-node involvement has a poor prognosis after conventional treatment. In trials with historical controls, high-dose chemotherapy produced improved outcomes. We compared an intensive double-cycle high-dose chemotherapy regimen with an accelerated conventionally dosed regimen in high-risk breast cancer in a multicentre trial.\n Patients with at least nine positive nodes were randomly assigned either two courses of accelerated (2-week intervals, with filgrastim support), conventionally dosed epirubicin and cyclophosphamide followed by two courses of high-dose chemotherapy (epirubicin, cyclophosphamide, and thiotepa supported by peripheral-blood progenitors) or four identical cycles of epirubicin and cyclophosphamide followed by three cycles of accelerated cyclophosphamide, methotrexate, and fluorouracil. The primary endpoint was event-free survival. Analyses were done both by intention to treat and per protocol.\n 403 patients were enrolled; 201 were assigned high-dose chemotherapy and 202 conventional treatment. The mean number of positive nodes was 17.6, and median follow-up was 48.6 months. 4-year event-free survival (intention-to-treat analysis) was 60% (95% CI 53-67) in the high-dose chemotherapy group and 44% (37-52) in the control group (p=0.00069). The corresponding overall survival was 75% (69-82) versus 70% (64-77; p=0.02). There were no treatment-related deaths.\n Our finding of significant improvements in both event-free and overall survival for high-dose chemotherapy compared with a dose-dense conventional regimen contrasts with the results of other studies. The discrepancy might be due partly to design differences (tandem, brief induction) between our regimen and those studied in other trials. This approach merits further study.", "Uncontrolled studies suggest that high-dose chemotherapy is beneficial in patients with breast cancer and multiple metastases to the axillary lymph nodes. Many physicians accept this treatment as standard care. We aimed to assess adjuvant high-dose chemotherapy in breast cancer in a phase II randomised trial.\n 97 women aged younger than 60 years, who had breast cancer with extensive axillary-node metastases (confirmed by a tumour-positive infraclavicular lymph-node biopsy), received three courses of up-front chemotherapy (FE120C). This regimen consisted of cyclophosphamide 500 mg/m2, epirubicin 120 mg/m2, and 5-fluorouracil 500 mg/m2 once weekly for 3 weeks. After surgery, stable patients or those who responded to chemotherapy were randomly assigned conventional therapy (fourth course of FE120C, followed by radiation therapy and 2 years of tamoxifen [40 patients]) or high-dose therapy (identical treatment but an additional high-dose regimen and peripheral-blood progenitor-cell [PBPC] support after the fourth FE120C course [41 patients]). This high-dose regimen comprised cyclophosphamide 6 g/m2, thiotepa 480 mg/m2, and carboplatin 1600 mg/m2. The primary endpoint was overall and disease-free survival. All analyses were by intention to treat.\n No patients died from toxic effects of chemotherapy. With a median follow-up of 49 (range 21-76) months, the 4-year overall and relapse-free survivals for all 97 patients were 75% and 54%, respectively. There was no significant difference in survival between the patients on conventional therapy and those on high-dose therapy.\n High-dose therapy is associated with substantial cost and acute toxic effects, but also has potentially irreversible long-term effects. Until the benefit of this therapy is substantiated by large-scale phase III trials, high-dose chemotherapy should not be used in the adjuvant treatment of breast cancer, apart from in randomised studies.", "High-dose radiation therapy is generally recommended as standard treatment in regionally advanced unresectable non-small-cell lung cancer (NSCLC), but median- and long-term survival remain poor. Some reports have recently shown an improvement of results in advanced NSCLC when cisplatin was included in the chemotherapy regimens. Therefore, we designed a randomized trial to determine whether induction chemotherapy before high-dose radiotherapy improves response rate and survival in stage III NSCLC over that achieved with radiotherapy alone.\n From March, 1984 to December, 1988, 66 consecutive patients with stage III unresectable NSCLC were randomized to one of two treatment arms; 61 were evaluable for survival and 58 for response and toxicity. Patients randomly assigned to arm A received cisplatin (CDDP 100 mg/m2 on day 1) and etoposide (VP 16 120 mg/m2 on days 1, 2, 3) every 3 wks for 3 courses followed by radiotherapy 56 Gy on pre-treatment tumor volume and 40 Gy on mediastinum and bilateral supraclavicular nodes. Patients assigned to arm B received only the same radiotherapy. The 61 eligible patients were comparable in terms of age, performance status, histology and treatment.\n Response rate was 53% in arm A and 32% in arm B. The median survival was 52 wks for the combined treatment arm and 36 wks for the radiation therapy arm. At six years of follow-up all the patients were dead. Toxicity was mild and no treatment-related deaths were recorded.\n Induction chemotherapy produced a better response rate and a trend of improved survival (4 months) but a significant survival advantage was not achieved (p < 0.11), probably because of the small number of patients enrolled in the trial.", "Fifty-four previously untreated patients with locally advanced resectable squamous cell carcinoma of the head and neck (SCCHN) were enrolled into a prospective randomized controlled trial to evaluate whether induction chemotherapy improves the disease-free survival compared to the standard treatment (surgery + radiation). Thirty patients received chemotherapy, which consisted of cisplatin 20 mg/m2 day 1-5, bleomycin 10 mg/m2, continuous infusion from day 3-7, and methotrexate 40 mg/m2 given on day 15 and day 22. The cycle was repeated on day 29 for two cycles. Twenty patients completed chemotherapy courses. Overall response rate was 77% (23 of 30). No survival improvement was observed. Kaplan-Meier analysis indicated survival (and 95% confidence interval) at 3 years was 57% (29%-84%) for the control group and 60% (34%-87%) for the chemotherapy group, and 57% (29%-84%) and 45% (12%-78%) at 4 years (P = 0.736). However, patients who had a complete response were significantly better in terms of long-term survivors (5 of 7 patients were still alive), in contrast to patients who had partial responses among whom only 4 of 16 were alive. Toxicities of this induction protocol are tolerable; one chemotherapy-related death occurred from profound thrombocytopenia. If efforts in determining a chemotherapy-sensitive patient were successfully established, along with a better sequence and the discovery of new and safer drugs, survival of SCCHN should be much improved.", "The treatment results of radiotherapy in stage III non-small-cell lung cancer are very poor. Several phase II studies showed that neoadjuvant chemotherapy followed by radiotherapy was feasible in this patient group and suggested that treatment outcome might improve. A randomized phase II study was performed addressing the response rate and morbidity of high-dose split course radiotherapy (RT) versus the same radiotherapy preceded by high-dose chemotherapy (CT) in patients with stage III non-small-cell lung cancer.\n Seventy eligible patients were randomized in this study. CT consisted of cisplatin 100 mg/m2 days 1 and 22, and vindesine 3 mg/m2 on days 1, 8, 22 and 29. Radiotherapy started on day 43 in the combined arm and immediately in the RT-only arm. The primary tumour and the regional nodes were treated by 30 Gy/10 fractions/2 weeks and after the split by a second course of 25 Gy/10 fractions/2 weeks. In the combined arm a third CT cycle was planned during the split between RT courses.\n In the CT + RT arm 34 patients were evaluable for response and toxicity and 30 patients in the RT only arm. After completion of treatment 7 patients had a complete response (2 in the CT plus RT arm, 5 in the RT alone arm) and 26 patients a partial response (13 in the CT plus RT arm, 13 in the RT alone arm) for an overall response rate of 52% (95% CI 39%-65%). Acute toxicity was worse in the combined treatment arm with grade 4 leucocytopenia in 8 patients and thrombocytopenia grade 4 in one patient. Three patients had reversible renal toxicity grade 2. There was one toxic death in the RT plus CT arm. There was no enhancement of acute or late radiation pulmonary or oesophageal toxicity. Time to progressive disease (median 30 vs. 35 weeks) and overall survival time (median 12 months) were equal in both treatment arms.\n High-dose radiotherapy preceded by high-dose chemotherapy was more toxic than radiotherapy alone and did not result in this study in any benefit in terms of response rate, time to progressive disease and overall survival.", "To evaluate the efficacy of simultaneous postoperative temozolomide radiochemotherapy in glioblastoma patients.\n From February 2002 to July 2004, n = 65 patients from 11 German centers with macroscopic complete tumor resection were randomized to receive either postoperative radiotherapy alone (RT, n = 35) or postoperative radiotherapy with simultaneous temozolomide (RT + TMZ, n = 30). Patients were stratified according to age (< or =/>50 years) and WHO performance score (0-1 vs. 2). RT consisted of 60 Gy in 30 fractions. In the RT + TMZ arm, oral TMZ was administered daily at a dose of 75 mg/m(2) including weekends (40-42 doses). Adjuvant treatment was not given, but in both arms, patients with recurrent tumors and in good condition (WHO 0-2) were scheduled for salvage chemotherapy with TMZ.\n The trial was stopped early due to the results of EORTC-study 26981-22981 that showed a survival benefit for the combination of concomitant and adjuvant TMZ compared to radiotherapy alone. In total, 62/65 patients were evaluable. Stratification variables were well balanced (< or = 50 years 26% vs. 20%, WHO 0-1 91% vs. 100%). Neither overall survival (median 17 vs. 15 months) nor progression-free survival (median 7 vs. 6 months) differed significantly between the two arms. In the RT (RT + TMZ) arm, 76% (62%) of the progressing patients received salvage chemotherapy with TMZ, 36% (50%) had a second resection. There was a time-constant trend for increased general quality of life (EORTC questionnaire QLQ C30) and brain-specific quality of life (EORTC questionnaire B20) in the combined arm. Lymphopenia G3-4 was more frequent (33 vs. 6%) in the RT + TMZ arm.\n After early closure of this trial, a benefit for progression-free survival for simultaneous TMZ radiochemotherapy alone could not be demonstrated. In both arms, salvage therapies were frequently used and probably had a major effect on overall survival.", "To compare the outcome of treatment of mediastinoscopy-verified N2 non-small-cell lung cancer treated with induction chemotherapy followed by either surgery or radiotherapy (RT), with both options followed by consolidation chemotherapy.\n A randomized Phase III trial for Stage IIIA (T1-T3N2M0) non-small cell lung cancer was conducted by the Radiation Therapy Oncology Group (RTOG) and Eastern Cooperative Oncology Group between April 1990 and April 1994. After documentation of N2 disease by mediastinoscopy or anterior mediastinotomy, patients received induction chemotherapy with cisplatin, vinblastine, and mitomycin-C. Mitomycin-C was later dropped from the induction regimen. Patients were then randomized to surgery or RT (64 Gy in 7 weeks) followed by cisplatin and vinblastine.\n RTOG 89-01 accrued 75 patients, of whom 73 were eligible and analyzable. Twelve patients received induction chemotherapy but were not randomized to RT or surgery thereafter. Forty-five patients were randomized to postinduction RT or surgery. Of the analyzable patients, 90% had a Karnofsky performance score of 90-100, 18% had weight loss >5%, 37% had squamous cell histologic features, and 54% had bulky N2 disease. The distribution of bulky N2 disease was uniform among the treatment arms. The incidence of Grade 4 toxicity was 56% in patients receiving mitomycin-C and 29% in those who did not. Only 1 patient in each group had acute nonhematologic toxicity greater than Grade 3 (nausea and vomiting). No acute Grade 4 radiation toxicity developed. The incidences of long-term toxicity were equivalent across the arms. Three treatment-related deaths occurred: 2 patients in the surgical arms (one late pulmonary toxicity and one pulmonary embolus), and 1 patient in the radiation arm (radiation pneumonitis). Induction chemotherapy was completed in 78% of the patients. Complete resection was performed in 73% of 26 patients undergoing thoracotomy. Consolidation chemotherapy was completed in 75% of the patients. No statistically significant difference was found among the treatment arms. The overall progression-free survival rate was 53% at 1 year and 17% at 3 years. The median progression-free survival was 14 months. No difference in the 1-year survival rate (70% vs. 66%) or median survival time (19.4 vs. 17.4 months) between the surgery and RT arms. The median survival in the patients receiving induction chemotherapy only was 8.9 months. Mitomycin-C had no impact on survival (p = 0.75). No statistically significant difference was noted in the time to local failure between the surgical and RT arms.\n The patient accrual to this trial made its results inconclusive, but several observations are notable. In this trial, histologic confirmation of N2 disease in the surgical and nonsurgical arms eliminated the usual biases from clinical staging. In this setting, local control and survival were essentially equal between the surgical and RT arms. The 3- and 5-year survival rates of nonsurgical therapy were comparable to published surgical trials of N2 disease.", "To perform a randomized study of the optimal timing of thoracic radiation (RT) as accelerated hyperfractionated radiation therapy (ACC HFX RT) in combination with concurrent chemotherapy (CHT) in limited-stage small-cell lung cancer (SCLC).\n Between 1988 and 1992, 107 patients were enrolled and 103 were assessable. All patients received ACC HFX RT with 1.5 Gy twice daily to 54 Gy plus concurrent daily carboplatin/etoposide (C/E) (30 mg each) and four sequential cycles of cisplatin/etoposide (PE) (30 mg/m2 and 120 mg/m2, respectively, on days 1 to 3). Group I patients (n = 52) received concurrent chemoradiation at weeks 1 to 4, and group II (n = 51) at weeks 6 to 9. Patients who showed a complete response (CR) or partial response (PR) underwent prophylactic cranial irradiation (PCI) at weeks 16 to 17.\n The median survival time was 34 months in group I and 26 months in group II, and the Kaplan-Meier 5-year survival rates were 30% and 15%, respectively. The difference was almost significant on univariate analysis (P = .052) and was significant on multivariate analysis (P = .027). Group I patients had a significantly higher local control rate than group II patients, but there was no difference between the two groups in distant metastasis rate. There was no difference in the incidence of acute or late grade 3 to 4 toxicity.\n Initial administration of thoracic ACC HFX RT with concurrent C/E seems to produce better local control and survival rates than delayed administration.", "Since chemotherapy for metastatic breast cancer is not curative, consideration of the quality of life is important in selecting a treatment regimen. We conducted a randomized trial comparing continuous chemotherapy, administered until disease progression was evident, with intermittent therapy, whereby treatment was stopped after three cycles and then repeated for three more cycles only when there was evidence of disease progression. Each approach was tested with doxorubicin combined with cyclophosphamide or with cyclophosphamide combined with methotrexate, fluorouracil, and prednisone. Intermittent therapy resulted in a significantly worse response (P = 0.02 by Mann-Whitney test), a significantly shorter time to disease progression (relative risk based on proportional-hazards model, 1.8; 95 percent confidence interval, 1.4 to 2.4), and a trend toward shorter survival (relative risk, 1.3; confidence interval, 0.99 to 1.6). The quality of life was expressed as linear-analogue self-assessment scores for physical well-being, mood, pain, and appetite and as a quality-of-life index. It improved significantly during the first three cycles, when all patients received treatment. Thereafter, intermittent therapy was associated with worse scores for physical well-being (by 23 percent of scale; 95 percent confidence interval, 11 to 35 percent), mood (25 percent; 13 to 37 percent), and appetite (12 percent; 0 to 24 percent) and for the quality-of-life index as indicated by the patient (14 percent; 5 to 23 percent) and the physician (16 percent; 7 to 26 percent). Changes in the quality of life were independent prognostic factors in proportional-hazards models of subsequent survival. We conclude that, as tested, continuous chemotherapy is better than intermittent chemotherapy for advanced breast cancer.", "To investigate the efficacy of combined hyperfractionated radiation therapy (HFX RT) and concurrent chemotherapy (CHT) in stage IIIA or IIIB non-small-cell lung cancer (NSCLC) compared with that of HFX RT alone.\n Between January 1988 and December 1989, 169 patients were divided randomly into the following groups: group I, HFX RT with 1.2 Gy twice daily to a total dose of 64.8 Gy (n = 61); group II, same HFX RT with CHT consisting of 100 mg of carboplatin (CBDCA) on days 1 and 2 and 100 mg of etoposide (VP-16) on days 1 to 3 of each week during the RT course (n = 52); and group III, same HFX RT with CHT consisting of 200 mg of CBDCA on days 1 and 2 and 100 mg of VP-16 on days 1 to 5 of the first, third, and fifth weeks of the RT course (n = 56).\n The median survival time (MST) was 8 months for group I, 18 months for group II, and 13 months for group III. The 3-year survival rates were 6.6%, 23%, and 16%, respectively. There was a significant difference in the survival rate between groups I and II (P = .0027, log-rank test), but not between groups I and III (P = .17) or between groups II and III (P = .14). The relapse-free survival rate in group II was also higher than that in group I (P = .0024), which was largely due to improved local control in group II patients. Patients in groups II and III showed a higher incidence of acute and/or late high-grade toxicity compared with group I patients, but no patient died of treatment-related toxicity.\n The combination of HFX RT and continuous CBDCA/VP-16 CHT was tolerable and substantially increased the survival rate.", "To evaluate the efficacy of adjuvant chemotherapy for patients with advanced head and neck squamous cancer, the Head and Neck Contracts Program conducted a three-arm study comparing standard surgery and radiation, induction chemotherapy (cisplatin and bleomycin) plus standard therapy, and induction chemotherapy plus standard therapy followed by maintenance cisplatin for 6 months. As previously reported, this trial of 462 patients demonstrated no significant difference in disease-free survival or survival, but a significantly lower metastatic rate in the maintenance arm. To determine whether particular subgroups may have benefited from adjuvant therapy, we evaluated results based on primary site, and tumor (T) and node (N) stage. Of the 192 patients with oral cavity cancer, those on the maintenance arm had a significantly improved 3-year disease-free survival (67%) compared with the standard arm (49%) or induction arm (44%) (overall P = .05). For hypopharyngeal and laryngeal cancers there was no marked overall benefit. For the 106 patients with T1 plus T2 disease, there was marginal improvement in disease-free survival for the maintenance group (72%) compared with the standard group (47%) or induction group (43%) (overall P = .09). There was no advantage for patients with T3 and T4 disease. There was superior disease-free survival for patients with N1 disease on the maintenance arm (70%) compared with the standard arm (42%) (P = .024). The same was true for disease-free survival in 109 patients with N2 disease: standard (52%), induction (30%), maintenance (84%) (overall P less than .001). There was no benefit for N3 disease. A significant survival advantage with maintenance chemotherapy was only seen for N2 disease (overall P = .04). Since head and neck cancer patients are a heterogeneous group, there may be particular sites and stages for which adjuvant chemotherapy would be advantageous, and subset analysis can help indicate directions for new trials.", "To investigate the efficacy of concurrent hyperfractionated radiation therapy (HFX RT) and low-dose daily chemotherapy (CHT) in stage III non-small-cell lung cancer (NSCLC).\n Between January 1990 and December 1991, 131 patients with histologically or cytologically confirmed stage III NSCLC, Karnofsky performance status (KPS) > or = 50, and no previous therapy were randomly treated as follows: group I, HFX RT with 1.2 Gy twice daily to a total dose of 69.6 Gy (n = 66); and group II, same HFX RT with CHT consisting of 50 mg of carboplatin (CBDCA) and 50 mg of etoposide (VP-16) given on each RT day (n = 65).\n Group II patients had a significantly longer survival time than group I patients, with a median survival of 22 versus 14 months and 4-year survival rates of 23% versus 9% (P = .021). The median time to local recurrence and 4-year local recurrence-free survival rate were also significantly higher in group II than in group I (25 v 20 months and 42% v 19% respectively, P = .015). In contrast, the distant metastasis-free survival rate did not significantly differ in the two groups (P = .33). The two groups showed similar incidence of acute and late high-grade toxicity (P = .44 and .75, respectively). No treatment-related toxicity was observed.\n The combination of HFX RT and low-dose daily CBDCA plus VP-16 was tolerable and improved the survival of patients with stage III NSCLC as a result of improved local control.", "We investigated a phase III randomized trial to compare efficacy and tolerance of CDDP + 5-FU to CDDP + VP16, both given intravenously in patients with unresectable advanced head and neck cancer. The 197 eligible patients were paired off successively on the basis of tumor sites and UICC stage. Comparisons were made through sequential closed plans. In 179 patients, tumor beds and cervical lymph nodes were irradiated, and 20 patients underwent salvage surgical procedures. Cisplatin plus 5-fluorouracil showed a response (CR + PR) rate of 15% greater than that observed with cisplatin plus etoposide (alpha=0.05, power 70%). Complete responses played a major role in the CDDP + 5-FU regimen. Furthermore, we noted a higher cervical node regression with this chemotherapy combination. Because radiotherapy was administered after chemotherapy, we could not analyze the mean duration response for each protocol. No significant difference in survival existed between the two groups. Myelosuppression was the most frequent sign of toxicity observed, especially with the CDDP + VP16 regimen. Mucositis was rare with allopurinol protection. In the CDDP + 5-FU group, one patient had grade 4 cardiac dysfunction, and 3 patients exhibited unconsciousness that may be related to cerebral vascular damage. Thirteen patients died, with 8 cases related to septic shock (5 CPPP + VP16 and 3 CDDP + 5-FU). Cisplatin plus 5-FU chemotherapy showed a satisfactory efficacy and acceptable toxicity profile compared with CDDP + VP16, with caution to patients with a cardiac or vascular history. Although we could not show a benefit in survival with the CDDP + 5-FU protocol, this trial supports literature data and confirms that this regimen may be proposed as a first-line therapy in advanced cancer of the head and neck.", "Uncontrolled studies have reported encouraging outcomes for patients with high-risk primary breast cancer treated with high-dose chemotherapy and autologous hematopoietic stem cell support. We conducted a prospective randomized trial to compare standard-dose chemotherapy with the same therapy followed by high-dose chemotherapy. PATIENTS and\n Patients with 10 or more positive axillary lymph nodes after primary breast surgery or patients with four or more positive lymph nodes after four cycles of primary (neoadjuvant) chemotherapy were eligible. All patients were to receive eight cycles of 5-fluorouracil, doxorubicin (Adriamycin), and cyclophosphamide (FAC). Patients were stratified by stage and randomly assigned to receive two cycles of high-dose cyclophosphamide, etoposide, and cisplatin with autologous hematopoietic stem cell support or no additional chemotherapy. Tamoxifen was planned for postmenopausal patients with estrogen receptor-positive tumors and chest wall radiotherapy was planned for all. All P values are from two-sided tests.\n Seventy-eight patients (48 after primary surgery and 30 after primary chemotherapy) were registered. Thirty-nine patients were randomly assigned to FAC and 39 to FAC followed by high-dose chemotherapy. After a median follow-up of 6.5 years, there have been 41 relapses. In intention-to-treat analyses, estimated 3-year relapse-free survival rates were 62% and 48% for FAC and FAC/high-dose chemotherapy, respectively (P =.35), and 3-year survival rates were 77% and 58%, respectively (P =.23). Overall, there was greater and more frequent morbidity associated with high-dose chemotherapy than with FAC; there was one septic death associated with high-dose chemotherapy.\n No relapse-free or overall survival advantage was associated with the use of high-dose chemotherapy, and morbidity was increased with its use. Thus, high-dose chemotherapy is not indicated outside a clinical trial.", "The purpose of the present study was to determine the safety and efficacy of induction chemotherapy followed by concomitant chemoradiotherapy. Thirty-eight patients were randomised to receive induction chemotherapy, consisting of cyclophosphamide and methotrexate followed by concomitant 5-fluorouracil and irradiation (study group) or irradiation alone (control group). There were non-significant differences in the initial tumor clearance rates in the two groups. Median disease-free survival (in complete responders) was 17 months (6-60+) vs 11 months (5-60+) (p = 0.407) and overall survival 11 months (1-60+) vs 14 months (2-60+) (p = 0.428) in the study and control groups respectively. Acute morbidity and deaths during intervention were higher in the study group (p = 0.007). This study suggests that induction along with concomitant chemoradiotherapy is too toxic for routine use and also fails to provide a survival benefit." ]	Platinum-based chemotherapy regimens did not offer a statistically significant benefit in survival or overall tumour response compared with non-platinum-based regimens. However, platinum-based chemotherapy regimens did increase complete response rates, at the cost of higher adverse events including nausea and vomiting, anaemia and thrombocytopenia toxicity. These data suggest non-platinum chemotherapy regimens have a more advantageous risk-benefit profile. This systematic review highlights the lack of quality of life data in trials involving chemotherapy treatment for SCLC. With poor long-term survival associated with both treatment groups, the issue of the quality of the survival period takes on even more significance. It would be beneficial for future trials in this area to include a quality of life assessment.
CD005147	[ "11479066", "16816304", "12701663", "15259827", "10422481", "18515890", "16055807", "3074860", "11016522", "10711914", "18005494", "18606949", "10396167", "12402370", "8770428", "16603748", "12873325", "12365879", "10945081", "10665619", "15240438", "19876673", "16579323", "18519821", "9545998", "16917681", "9373419", "15534017" ]	[ "Early intervention and a five year follow up in young adults with a short duration of untreated psychosis: ethical implications.", "Outcomes of an effectiveness trial of cognitive-behavioural intervention by mental health nurses in schizophrenia.", "Early intervention for relapse in schizophrenia: results of a 12-month randomized controlled trial of cognitive behavioural therapy.", "A randomized controlled trial of a brief intervention for families of patients with a first episode of psychosis.", "Patient and relative education in community psychiatry: a randomized controlled trial regarding its effectiveness.", "Cognitive--behavioural therapy and family intervention for relapse prevention and symptom reduction in psychosis: randomised controlled trial.", "Interventions in the initial prodromal states of psychosis in Germany: concept and recruitment.", "The community management of schizophrenia. A controlled trial of a behavioural intervention with families to reduce relapse.", "Early detection and assertive community treatment of young psychotics: the Opus Study Rationale and design of the trial.", "A program for relapse prevention in schizophrenia: a controlled study.", "Acute-phase and 1-year follow-up results of a randomized controlled trial of CBT versus Befriending for first-episode psychosis: the ACE project.", "Five-year follow-up of a randomized multicenter trial of intensive early intervention vs standard treatment for patients with a first episode of psychotic illness: the OPUS trial.", "A pilot study evaluating the effectiveness of individual inpatient cognitive-behavioural therapy in early psychosis.", "Medication and symptom management education program for the rehabilitation of psychiatric patients in Korea: the effects of promoting schedule on self-efficacy theory.", "A one year prospective study of the effect of life events and medication in the aetiology of schizophrenic relapse.", "Multiple-family group treatment for English- and Vietnamese-speaking families living with schizophrenia.", "Suicide prevention in first episode psychosis: the development of a randomised controlled trial of cognitive therapy for acutely suicidal patients with early psychosis.", "Randomized controlled trial of interventions designed to reduce the risk of progression to first-episode psychosis in a clinical sample with subthreshold symptoms.", "Cognitive therapy and recovery from acute psychosis: a controlled trial. 3. Five-year follow-up.", "A randomized controlled trial of cognitive-behavioral therapy for persistent symptoms in schizophrenia resistant to medication.", "Effect of joint crisis plans on use of compulsory treatment in psychiatry: single blind randomised controlled trial.", "Cognitive behavioural treatment of negative symptoms in schizophrenia patients: study design of the TONES study, feasibility and safety of treatment.", "An intervention study to prevent relapse in patients with schizophrenia.", "Prevention of negative symptom psychopathologies in first-episode schizophrenia: two-year effects of reducing the duration of untreated psychosis.", "Randomized trial of general hospital and residential alternative care for patients with severe and persistent mental illness.", "Family interventions for schizophrenia in Italy: randomized controlled trial.", "London-East Anglia randomised controlled trial of cognitive-behavioural therapy for psychosis. I: effects of the treatment phase.", "One-year follow-up of a multiple-family-group intervention for Chinese families of patients with schizophrenia." ]	[ "In a Dutch treatment intervention study of patients (n=76) with first psychotic episodes of schizophrenia the hypothesis tested was whether early differential treatment after an acute psychotic break improved outcome as compared with other studies. Patients had a relatively short duration of untreated psychosis. No significant effect between two treatment conditions on relapse rate was found. The 15-month intervention program kept the psychotic relapse rate as low as 15%; lower than comparable studies. Thus, the initial results were in support of the hypothesis. After completion of the 15 months study, patients were referred to other agencies and followed for five years. Results of the follow up study showed that the low relapse rate could not be maintained. Of the remaining 71 patients of the initial sample, 52% had one or more psychotic relapses, 25% developed chronic positive symptoms and 23% did not have another psychotic episode. In addition, the level of social functioning turned out to be low: the majority of patients were dependent upon their parents, few held down a skilled or paid job and also their quality of life seemed low, results indicate that early intervention may improve short term but not long term outcome in schizophrenia. Our results also suggest that referral to other mental health agencies after intervention is not sufficient. Continuity of outpatient care, including continuity of a professional relationship, continuity of support for the family, and the continuity in management of illness, medication and stress may be a key issue in the first five years after the onset of psychosis in schizophrenia. Early recognition and intervention may not nearly be as important for outcome as continuity in care and caregivers. At present, however, it remains questionable whether early intervention programs in first-episode patients with a short duration of untreated psychosis can offer the prospect of altering the course of schizophrenia without a sustained comprehensive treatment program.", "Little is known about the medium-term durability of cognitive-behavioural therapy (CBT) in a community sample of people with schizophrenia.\n To investigate whether brief CBT produces clinically important outcomes in relation to recovery, symptom burden and readmission to hospital in people with schizophrenia at 1-year follow-up.\n Participants (336 of 422 randomised at baseline) were followed up at a mean of 388 days (s.d. = 53) by raters masked to treatment allocation (CBT or usual care).\n At 1-year follow-up, participants who received CBT had significantly more insight (P = 0.021) and significantly fewer negative symptoms (P = 0.002). Brief therapy protected against depression with improving insight and against relapse; significantly reduced time spent in hospital for those who did relapse and delayed time to admission. It did not improve psychotic symptoms or occupational recovery, nor have a lasting effect on overall symptoms or depression at follow-up.\n Mental health nurses should be trained in brief CBT for schizophrenia to supplement case management, family interventions and expert therapy for treatment resistance.", "The paper describes a randomized controlled trial of targeting cognitive behavioural therapy (CBT) during prodromal or early signs of relapse in schizophrenia. We hypothesized that CBT would result in reduced admission and relapse, reduced positive and negative symptoms, and improved social functioning.\n A total of 144 participants with schizophrenia or a related disorder were randomized to receive either treatment as usual (TAU) (N = 72) or CBT+TAU (N = 72). Participants were prospectively followed up between entry and 12 months.\n At 12 months, 11 (15.3%) participants in the CBT group were admitted to hospital compared to 19 (26.4%) of the TAU group (hazard ratio = 0.53, P = 0.10, 95% CI 0.25, 1.10). A total of 13 (18.1%) participants in CBT relapsed compared to 25 (34.7%) in TAU (hazard ratio = 0.47, P < 0O05, 95% CI 0.24, 0.92). In addition, the CBT group showed significantly greater improvement in positive symptoms, negative symptoms, global psychopathology, performance of independent functions and prosocial activities.\n The study provides evidence for the feasibility and effectiveness for targeting CBT on the appearance of early signs of relapse in schizophrenia. The results are discussed in context of the study's methodological limitations.", "Carers' satisfaction with psychiatric services related to information and advice is generally poor. This may be particularly true for services trying to meet the needs of ethnically diverse communities. It is important that services attempt to ameliorate carers' concerns as early as possible. The authors aimed to assess the impact of a brief educational and advice support service on carers of patients with a first episode of psychotic illness.\n Carers of all patients identified with a first episode of psychosis in a defined psychiatric catchment area of North London were invited to participate. Following consent from patients and relatives, relatives were randomly allocated to receive (in addition to usual services) a brief intervention comprising education and advice about the disorder from a support team or to usual care from community psychiatric services.\n One hundred and six carers were recruited to the study. Take-up of the intervention was less than expected and the intervention had little impact. The authors found no differences over time between the randomized arms for relatives' satisfaction (F = 23, p = 0 .4, df = 1) or number of days spent by patients in hospital over nine months from entry to the trial (F= 1.7, p= 0.18, df = 1).\n It was found that the support and advice intervention for families had little impact on their satisfaction or on patients' outcomes. However, failure to take up the intervention threatens the conclusions as the power to show an effect was reduced. Although family interventions, in general, are considered an important adjunct to the treatment of patients with chronic psychosis, there may be difficulties in providing an educational and support intervention shortly after first onset. How and when psychiatric services provide information and advice to carers of people newly diagnosed with a psychosis requires further study.", "Family psychoeducation has a well-documented effect on the short-term prognosis in schizophrenia. Less is known about the effectiveness of shorter programmes with the main focus on information for patients (patient education) or for patients and relatives (family education).\n A randomized study of the effectiveness of an eight-session psychoeducational programme for patients with schizophrenia and for their relatives was conducted in two community mental health centres, in Arhus and Viborg (Denmark). Patient outcome measures were knowledge, relapse, compliance, insight and satisfaction, and relative outcome measures were knowledge and satisfaction. Post-intervention outcome and follow-up evaluation 1 year after the start of the intervention are presented.\n A statistically significant increase in knowledge of schizophrenia in both relatives and patients was demonstrated at postintervention and a non-significant trend at 1-year follow-up. Statistically significant changes in the Verona Service Satisfaction Scale Scores in the subdimension of satisfaction with Relatives involvement were demonstrated both for patients and relatives postintervention and for patients at 1-year follow-up. There was a tendency that time-to-relapse increased in the intervention group at postintervention and that the schizophrenia subscore of the Brief Psychiatric Rating Scale was reduced in the intervention group at 1-year follow-up. No differences were found between the groups regarding compliance, insight into psychosis, psychosocial function (General Assessment of Function) or in relatives' expressed emotion scores postintervention or at 1-year follow-up.\n A short patient and relative education programme seems to be able to influence knowledge and some aspects of satisfaction, but does not seem to be sufficient to influence important variables such as relapse, compliance, psychopathology, insight or psychosocial functioning.", "Family intervention reduces relapse rates in psychosis. Cognitive-behavioural therapy (CBT) improves positive symptoms but effects on relapse rates are not established.\n To test the effectiveness of CBT and family intervention in reducing relapse, and in improving symptoms and functioning in patients who had recently relapsed with non-affective psychosis.\n A multicentre randomised controlled trial (ISRCTN83557988) with two pathways: those without carers were allocated to treatment as usual or CBT plus treatment as usual, those with carers to treatment as usual, CBT plus treatment as usual or family intervention plus treatment as usual. The CBT and family intervention were focused on relapse prevention for 20 sessions over 9 months.\n A total of 301 patients and 83 carers participated. Primary outcome data were available on 96% of the total sample. The CBT and family intervention had no effects on rates of remission and relapse or on days in hospital at 12 or 24 months. For secondary outcomes, CBT showed a beneficial effect on depression at 24 months and there were no effects for family intervention. In people with carers, CBT significantly improved delusional distress and social functioning. Therapy did not change key psychological processes.\n Generic CBT for psychosis is not indicated for routine relapse prevention in people recovering from a recent relapse of psychosis and should currently be reserved for those with distressing medication-unresponsive positive symptoms. Any CBT targeted at this acute population requires development. The lack of effect of family intervention on relapse may be attributable to the low overall relapse rate in those with carers.", "The Early Detection and Intervention Programme of the German Research Network on Schizophrenia (GRNS) investigates the initial prodromal phase of psychosis in a multidimensional approach. Two intervention strategies are being studied by two large-scale multicentre projects.\n To present the concept of the intervention studies, and to provide an interim report of the recruitment procedure.\n Comprehensive cognitive-behavioural therapy has been developed for patients in the \"early initial prodromal state\". For patients in the \"late initial prodromal state\" the atypical neuroleptic amisulpride is explored. Both interventions are evaluated in randomised controlled trials using clinical management as the control condition.\n Between January 2001 and March 2003, 1212 individuals seeking help for mental health problems were screened for putative prodromal symptoms at four university centres. More than 388 individuals fulfilled criteria for both interventions and 188 (48.5%) gave informed consent to participate in the trials.\n The screening procedure appears to be feasible and trial participation seems to be acceptable to a relevant proportion of people at increased risk of developing psychosis.", "Schizophrenic patients were recruited into a trial of a prophylactic behavioural intervention with families. Families with at least one high Expressed Emotion (EE) relative were randomly allocated to one of four intervention groups: Behavioural Intervention Enactive; Behavioural Intervention Symbolic; Education Only; Routine Treatment. Patients from low-EE families were randomly allocated to two groups: Education Only or Routine Treatment. Relapse rates over nine months after discharge were significantly lower for patients in the two Behavioural Intervention, compared with Education Only and Routine Treatment groups. There was little difference between the two low-EE groups. Patients returning to high-EE relatives showed significantly higher relapse rates than those returning to low-EE relatives, in groups not receiving active intervention. Changes from high to low EE occurred in the Behavioural Intervention groups, and similar although less extensive changes occurred in the Education Only and Routine Treatment groups. Changes in criticism and marked emotional over-involvement (EOI) occurred generally in high-EE groups but were larger in magnitude in the Enactive and Symbolic groups. Reduction of hostility only occurred in the Behavioural Intervention groups. These results give partial support for the causal role of EE in relapse. There were no significant differences between the groups with respect to contact with the psychiatric services or medication.", "Recent research indicates that early detection of young persons suffering from psychosis and subsequent intensive intervention enhances treatment response and prognosis, but the data are only preliminary and suggestive.\n We present the rationale and design of the largest study to date to evaluate two major issues in the field of secondary prevention: (1) Does education and intensified collaboration with general practice, social services etc. reduce the duration of untreated psychosis? and (2) Can modified assertive community treatment improve the course and outcome in young persons suffering from psychosis as compared to treatment in community mental health centres? The article aims additionally to put the study in context and assist in designing future studies.\n Preliminary experiences are described. The findings of the first 312 patients show that modified assertive community treatment results in patients adhering to treatment significantly better than standard treatment in community mental health centres.\n The surge of interest in preventively oriented detection and treatment models for untreated psychosis in young people calls for research programmes and evidence. The obstacles to this are manifold. The initial findings of the OPUS study suggest, however, that better adherence to treatment is possible.", "This study examined whether a program for relapse prevention (PRP) is more effective than treatment as usual (TAU) in reducing relapse and rehospitalization rates among outpatients with schizophrenia.\n Eighty-two outpatients with DSM-III-R schizophrenia or schizoaffective disorder were randomly assigned to receive either PRP (experimental group, n = 41) or TAU (control group, n = 41) and were followed up for an 18-month prospective controlled study. Patients in both groups were prescribed standard doses of maintenance antipsychotic medication. Treatment with PRP consisted of a combination of psychoeducation, active monitoring for prodromal symptoms with clinical intervention when such symptoms occurred, weekly group therapy for patients, and multifamily groups. The TAU consisted of biweekly individual supportive therapy and medication management.\n Outcome rates over 18 months were 17% for relapse (7 patients) and 22% for rehospitalization (9 patients) in the PRP group, compared with 34% for relapse (14 patients) and 39% for rehospitalization (16 patients) in the TAU group (P = .01 and P = .03, respectively). Addition of age, sex, baseline Global Assessment Scale score, Positive and Negative Syndrome Scale scores (3 measures), and substance abuse to the proportional hazards regression models all yielded nonsignificant effects. The PRP teams were much more likely than the TAU psychiatrists to identify prodromal episodes before patients met objective relapse criteria or needed hospitalization.\n The PRP was effective in detecting prodromal symptoms of relapse early in an episode. Crisis intervention including increased antipsychotic medication use during the prodromal phase reduced relapse and rehospitalization rates.", "The ACE project involved 62 participants with a first episode of psychosis randomly assigned to either a cognitive behaviour therapy (CBT) intervention known as Active Cognitive Therapy for Early Psychosis (ACE) or a control condition known as Befriending. The study hypotheses were that: (1) treating participants with ACE in the acute phase would lead to faster reductions in positive and negative symptoms and more rapid improvement in functioning than Befriending; (2) these improvements in symptoms and functioning would be sustained at a 1-year follow-up; and (3) ACE would lead to fewer hospitalizations than Befriending as assessed at the 1-year follow-up.\n Two therapists treated the participants across both conditions. Participants could not receive any more than 20 sessions within 14 weeks. Participants were assessed by independent raters on four primary outcome measures of symptoms and functioning: at pretreatment, the middle of treatment, the end of treatment and at 1-year follow-up. An independent pair of raters assessed treatment integrity.\n Both groups improved significantly over time. ACE significantly outperformed Befriending by improving functioning at mid-treatment, but it did not improve positive or negative symptoms. Past the mid-treatment assessment, Befriending caught up with the ACE group and there were no significant differences in any outcome measure and in hospital admissions at follow-up.\n There is some preliminary evidence that ACE promotes better early recovery in functioning and this finding needs to be replicated in other independent research centres with larger samples.", "Intensive early treatment for first-episode psychosis has been shown to be effective. It is unknown if the positive effects are sustained for 5 years.\n To determine the long-term effects of an intensive early-intervention program (OPUS) for first-episode psychotic patients.\n Single-blinded, randomized, controlled clinical trial of 2 years of an intensive early-intervention program vs standard treatment. Follow-up periods were 2 and 5 years.\n Copenhagen Hospital Corporation and Psychiatric Hospital, Aarhus, Denmark. Patients A total of 547 patients with a first episode of psychosis. Of these, 369 patients were participating in a 2-year follow-up, and 301 were participating in a 5-year follow-up. A total of 547 patients were followed for 5 years.\n Two years of an intensive early-intervention program vs standard treatment. The intensive early-intervention treatment consisted of assertive community treatment, family involvement, and social skills training. Standard treatment offered contact with a community mental health center.\n Psychotic and negative symptoms were recorded. Secondary outcome measures were use of services and social functioning.\n Analysis was based on the principles of intention-to-treat. Assessment was blinded for previous treatment allocation. At the 5-year follow-up, the effect of treatment seen after 2 years (psychotic dimension odds ratio [OR], -0.32; 95% confidence interval [CI], -0.58 to -0.06; P = .02; negative dimension OR, -0.45; 95% CI, -0.67 to -0.22; P = .001) had equalized between the treatment groups. A significantly smaller percentage of patients from the experimental group were living in supported housing (4% vs 10%, respectively; OR, 2.3; 95% CI, 1.1-4.8; P = .02) and were hospitalized fewer days (mean, 149 vs 193 days; mean difference, 44 days; 95% CI, 0.15-88.12; P = .05) during the 5-year period.\n The intensive early-intervention program improved clinical outcome after 2 years, but the effects were not sustainable up to 5 years later. Secondary outcome measures showed differences in the proportion of patients living in supported housing and days in hospital at the 5-year follow-up in favor of the intensive early-intervention program.", "Recent research indicates that cognitive-behaviour therapy (CBT) can be effective in ameliorating persistent positive symptoms in chronic psychotic patients. The effectiveness of CBT in acute and recent-onset psychosis has been little explored, although a recent pilot study indicated that CBT could significantly improve recovery in acutely psychotic inpatients.\n Short-term individual CBT was compared to supportive counselling/psychoeducation (SC) as an adjunct to standard inpatient hospital care and medication in 21 inpatients experiencing a recent-onset acute schizophrenic episode.\n Both groups showed significant reductions in Brief Psychiatric Rating Scale (BPRS) scores following treatment, although there were no group differences. Time to discharge did not differ significantly between the groups, although there was a greater variance for the SC patients. Two-year follow-up showed no significant differences between the groups, although the number of patients who relapsed, the number of relapses and the time to recurrence of psychotic symptoms was lower in the CBT group than the SC group. Interestingly, the time to readmission was shorter in the CBT group.\n CBT and SC are acceptable treatments for recent-onset acutely psychotic inpatients. A larger randomised controlled trial over multiple hospital sites is warranted.", "An effective rehabilitation program was developed for psychiatric patients' self-management of medication and symptoms. The rehabilitation program was designed to allow the patients to understand their illness, cope with their medical regimen, and prevent a relapse by recognizing any of the symptoms when they recur. This study consisted of three phases. The first phase was to explore the extent and the specific mental health needs of psychiatric patients. Data was obtained from 82 subjects who had symptoms of a mental illness including schizophrenia, bipolar disorders, and delusional disorder. They had received medication instruction during their hospitalization. The subjects were at the time outpatients in a psychiatric hospital. In the second phase, the researchers developed an educational program focused on coping with the residual and relapse warning signs, managing the drug side effects, medication compliance, and daily routines, according to the information acquired in the first step. The developed program includes the self-efficacy method reported by Bandura, including manuals and videotapes focusing on real life situations, small group discussions, and telephone coaching. Finally, the researchers investigated the effects of this program. Thirty-eight patients were selected for this study, 18 in the experimental program and 20 as controls. The diagnoses were same as those with the first step. The results showed that the subjects who attended this educational program reported significantly more improvement in self-efficacy (p=0.014) and medication compliance (p= 0.005), and significantly less relapse warning symptom scores (p=0.000) than the controls. In conclusion, these instructional materials will be beneficial for medication and symptom management in rehabilitating psychiatric patients in Korea. In addition, the materials may be a useful psychoeducational resource for professionals in the field of clinical psychiatry.", "We set out to determine whether and to what degree life events independent of illness increase the risk of relapse in schizophrenia following withdrawal from medication in the previous 6 months, either by triggering a relapse in the following 4 weeks or by acting cumulatively over time.\n Seventy-one patients fulfilling DSM-III-R criteria for schizophrenia with chronic illness were followed for 48 weeks and assessed on the LEDS scale. Half were treated with regular neuroleptic medication and half had been recently withdrawn from medication. A subgroup was randomised double-blind to treatment or placebo.\n A proportional hazards regression model showed that life events made a significant cumulative contribution over time (P < 0.05) to the risks of relapse and that ceasing medication made an independent contribution. The risk of relapse increased in proportion to the number of life events but no interaction between medication status and events could be detected, i.e. life events were not more closely associated with relapse on medication than off medication. For those of the sample exposed to the mean rate of life events during the study period, it was estimated that 23% of the relapse risk could be attributed to life events, and for those with twice the mean rate of events, 41%. In contrast, patients who continued on regular medication had 80% less risk of relapse than those who had been withdrawn from medication either by choice or under double-blind controlled conditions.\n A contribution of life events to the risk of relapse in schizophrenia was confirmed by this study but the hypothesis that life events trigger relapse was not supported, nor was the hypothesis that life events are more relevant to relapse in patients on maintenance medication than in patients off medication.", "This study, which was the first evaluation in Australia of multiple-family group treatment, explored the effectiveness of this approach for a newly arrived non-English speaking migrant group, first-generation Vietnamese families, and for English-speaking families.\n Thirty-four pairs of English-speaking consumers and family members and 25 Vietnamese-speaking pairs were randomly assigned to a multiple-family group or a control group. All consumers had a diagnosis of schizophrenia. The multiple-family group intervention (26 sessions over 12 months) was delivered as an adjunct to case management services, which all consumers received. Outcomes, which were measured immediately after treatment and 18 months later, included the number of relapse episodes; the presence and severity of symptoms, as measured by the Brief Psychiatric Rating Scale (BPRS) and the Scale for the Assessment of Negative Symptoms; and social functioning, as measured by the Family Burden Scale, the Health of the Nation Outcome Scale, and the Quality of Life Scale.\n Relapse rates immediately after treatment were significantly lower for the multiple-family group than for the control group (12 and 36 percent), and relapse rates were also lower during the follow-up period (25 and 63 percent). BPRS ratings were significantly lower for participants in the multiple-family group, and vocational outcomes also improved. The reductions in relapse and symptoms were similar for the English-speaking and the Vietnamese-speaking family groups; sample size precluded statistical analysis of differences.\n Multiple-family group treatment is an effective cognitive-behavioral intervention in the treatment of schizophrenia. The findings suggest continued application of and research on family interventions for non-English speaking migrant populations.", "Young people with early psychosis are at particularly high risk of suicide. However, there is evidence that early intervention can reduce this risk. Despite these advances, first episode psychosis patients attending these new services still remain at risk. To address this concern, a program called LifeSPAN was established within the Early Psychosis Prevention and Intervention Centre (EPPIC). The program developed and evaluated a number of suicide prevention strategies within EPPIC and included a cognitively oriented therapy (LifeSPAN therapy) for acutely suicidal patients with psychosis. We describe the development of these interventions in this paper.\n Clinical audit and surveys provided an indication of the prevalence of suicidality among first episode psychosis patients attending EPPIC. Second, staff focus groups and surveys identified gaps in service provision for suicidal young people attending the service. Third, a suicide risk monitoring system was introduced to identify those at highest risk. Finally, patients so identified were referred to and offered LifeSPAN therapy whose effectiveness was evaluated in a randomised controlled trial.\n Fifty-six suicidal patients with first episode psychosis were randomly assigned to standard clinical care or standard care plus LifeSPAN therapy. Forty-two patients completed the intervention. Clinical ratings and measures of suicidality and risk were assessed before, immediately after the intervention, and 6 months later. Benefits were noted in the treatment group on indirect measures of suicidality, e.g., hopelessness. The treatment group showed a greater average improvement (though not significant) on a measure of suicide ideation.\n Early intervention in psychosis for young people reduces the risk of suicide. Augmenting early intervention with a suicide preventative therapy may further reduce this risk.", "Most disability produced by psychotic illnesses, especially schizophrenia, develops during the prepsychotic period, creating a case for intervention during this period. However, only recently has it been possible to engage people in treatment during this phase.\n A randomized controlled trial compared 2 interventions in 59 patients at incipient risk of progression to first-episode psychosis. We termed this group ultra-high risk to emphasize the enhanced risk vs conventional genetic high-risk studies. Needs-based intervention was compared with specific preventive intervention comprising low-dose risperidone therapy (mean dosage, 1.3 mg/d) and cognitive behavior therapy. Treatment was provided for 6 months, after which all patients were offered ongoing needs-based intervention. Assessments were performed at baseline, 6 months, and 12 months.\n By the end of treatment, 10 of 28 people who received needs-based intervention progressed to first-episode psychosis vs 3 of 31 from the specific preventive intervention group (P=.03). After 6-month follow-up, another 3 people in the specific preventive intervention group became psychotic, and with intention-to-treat analysis, the difference was no longer significant (P=.24). However, for risperidone therapy-adherent patients in the specific preventive intervention group, protection against progression extended for 6 months after cessation of risperidone use.\n More specific pharmacotherapy and psychotherapy reduces the risk of early transition to psychosis in young people at ultra-high risk, although their relative contributions could not be determined. This represents at least delay in onset (prevalence reduction), and possibly some reduction in incidence.", "This paper describes the 5-year outcome of a cohort of patients who had received a cognitive therapy intervention during an acute episode of non-affective psychosis.\n Thirty-four out of the original 40 patients who had taken part in a randomised controlled trial of a cognitive intervention were assessed, using standardised instruments completed at entry into the study. In the original trial, half the patients received a cognitive therapy programme (CT group) and the other half received recreational activities and support (ATY group).\n At follow-up no significant differences in relapse rate, positive symptoms or insight between the groups were found, although the CT group did show significantly greater perceived 'Control over illness' than the ATY group. For individuals who had experienced a maximum of one relapse in the follow-up period, self-reported residual delusional beliefs and observer-rated hallucinations and delusions were significantly less in the CT than in the ATY group.\n Cognitive therapy applied in the acute phase of a psychotic disorder can produce enduring and significant clinical benefits if experience of relapse can be minimised.", "Research evidence supports the efficacy of cognitive-behavioral therapy in the treatment of drug-refractory positive symptoms of schizophrenia. Although the cumulative evidence is strong, early controlled trials showed methodological limitations.\n A randomized controlled design was used to compare the efficacy of manualized cognitive-behavioral therapy developed particularly for schizophrenia with that of a nonspecific befriending control intervention. Both interventions were delivered by 2 experienced nurses who received regular supervision. Patients were assessed by blind raters at baseline, after treatment (lasting up to 9 months), and at a 9-month follow-up evaluation. Patients continued to receive routine care throughout the study. An assessor blind to the patients' treatment groups rated the technical quality of audiotaped sessions chosen at random. Analysis was by intention to treat.\n Ninety patients received a mean of 19 individual treatment sessions over 9 months, with no significant between-group differences in treatment duration. Both interventions resulted in significant reductions in positive and negative symptoms and depression. At the 9-month follow-up evaluation, patients who had received cognitive therapy continued to improve, while those in the befriending group did not. These results were not attributable to changes in prescribed medication.\n Cognitive-behavioral therapy is effective in treating negative as well as positive symptoms in schizophrenia resistant to standard antipsychotic drugs, with its efficacy sustained over 9 months of follow-up.", "To investigate whether a form of advance agreement for people with severe mental illness can reduce the use of inpatient services and compulsory admission or treatment.\n Single blind randomised controlled trial, with randomisation of individual patients. The investigator was blind to allocation.\n Eight community mental health teams in southern England.\n 160 people with an operational diagnosis of psychotic illness or non-psychotic bipolar disorder who had experienced a hospital admission within the previous two years.\n The joint crisis plan was formulated by the patient, care coordinator, psychiatrist, and project worker and contained contact information, details of mental and physical illnesses, treatments, indicators for relapse, and advance statements of preferences for care in the event of future relapse.\n Admission to hospital, bed days, and use of the Mental Health Act over 15 month follow up.\n Use of the Mental Health Act was significantly reduced for the intervention group, 13% (10/80) of whom experienced compulsory admission or treatment compared with 27% (21/80) of the control group (risk ratio 0.48, 95% confidence interval 0.24 to 0.95, P = 0.028). As a consequence, the mean number of days of detention (days spent as an inpatient while under a section of the Mental Health Act) for the whole intervention group was 14 compared with 31 for the control group (difference 16, 0 to 36, P = 0.04). For those admitted under a section of the Mental Health Act, the number of days of detention was similar in the two groups (means 114 and 117, difference 3, -61 to 67, P = 0.98). The intervention group had fewer admissions (risk ratio 0.69, 0.45 to 1.04, P = 0.07). There was no evidence for differences in bed days (total number of days spent as an inpatient) (means 32 and 36, difference 4, -18 to 26, P = 0.15 for the whole sample; means 107 and 83, difference -24, -72 to 24, P = 0.39 for those admitted).\n Use of joint crisis plans reduced compulsory admissions and treatment in patients with severe mental illness. The reduction in overall admission was less. This is the first structured clinical intervention that seems to reduce compulsory admission and treatment in mental health services.", "Currently, there are no convincing treatment strategies for negative symptoms of schizophrenia. On this background, we are conducting the treatment of negative symptoms (TONES) study which addresses the question whether cognitive behavioural therapy (CBT) is efficacious for the reduction of negative symptoms in schizophrenia. The present paper aims at presenting the design of the clinical trial of the study as well as the treatment concept. Further, we investigate the feasibility and the safety of our study treatment. The TONES study is a multicentric, prospective, single-blind, randomised, and controlled trial (RCT). The clinical trial compares CBT (test condition) and cognitive remediation (CR; control condition) with respect to the efficacy in reducing negative symptoms. In order to systematically assess aspects of adherence and feasibility therapists filled in session reports after each session. The safety analysis is performed using the sequential method of Whitehead (The design and analysis of sequential clinical trials, Ellis Horwood, Chichester, 1983). We were able to conduct a systematic recruitment and to include a sample of N = 198 patients which is characterised by negative symptoms of medium severity. The majority of patients accepted the format of a 50-min treatment session. The manualised treatment content seemed to be adequate and the cooperation between patients and therapists was excellent or adequate in approximately 80% of the treatment sessions. Of the 15 severe adverse events 10 occurred in the CBT and 5 in the CR. This difference between the groups was not significant. The study presented here is presumably the first high quality RCT which evaluates CBT with negative symptoms as primary endpoint. On the background of the data presented we conclude that CBT for the reduction of negative symptoms is feasible and can be conducted safely.", "To determine whether the use of relapse prevention plans (RPPs) in nursing practice is an effective intervention in reducing relapse rates among patients with schizophrenia.\n Experimental design. Patients with schizophrenia (or a related psychotic disorder) and nurses from three mental health organizations were randomly assigned to either an experimental (RPP) or control condition (care as usual). The primary outcome measure was the psychotic relapses in the research groups.\n The relapse rates in the experimental and control groups after 1-year follow-up were 12.5% and 26.2%, respectively (p=. 12, ns). The relative risk of a relapse in the experimental versus the control group was 0.48 (ns).\n In this study no statistically significant effects of the intervention were found. Effectiveness research in this area should be continued with larger sample sizes and longer follow-up periods.", "The duration of untreated psychosis (DUP)-the time from onset of psychotic symptoms to the start of adequate treatment--is consistently correlated with better course and outcome, but the mechanisms are poorly understood.\n To report the effects of reducing DUP on 2-year course and outcome.\n A total of 281 patients with a DSM-IV diagnosis of nonorganic, nonaffective psychosis coming to their first treatment during 4 consecutive years were recruited, of which 231 participated in the 2-year follow-up. A comprehensive early detection (ED) system, based on public information campaigns and low-threshold-psychosis-detecting teams, was introduced in 1 health care area (ED area), but not in a comparable area (no-ED area). Both areas ran equivalent 2-year treatment programs.\n First-episode patients from the ED area had a significantly lower DUP, better clinical status, and milder negative symptoms at the start of treatment. There were no differences in treatment received for the first 2 years between the groups. The difference in negative symptoms was maintained at the 1-year follow-up. There was a statistically significant difference in the Positive and Negative Syndrome Scale negative component, cognitive component, and depressive component in favor of the ED group at the 2-year follow-up. Multiple linear regression analyses gave no indication that these differences were due to confounders.\n Reducing the DUP has effects on the course of symptoms and functioning, including negative symptoms, suggesting secondary prevention of the negative psychopathologies in first-episode schizophrenia.", "Severe and persistent mental illnesses are often lifelong and characterized by intermittent exacerbations requiring hospitalization. Providing needed care within budgetary constraints to this largely publicly subsidized population requires technologies that reduce costly inpatient episodes. The authors report a prospective randomized trial to test the clinical effectiveness of a model of acute residential alternative treatment for patients with persistent mental illness requiring hospital-level care.\n Patients enrolled in the Montgomery County, Md., public mental health system who experienced an illness exacerbation and were willing to accept voluntary treatment were randomly assigned to the acute psychiatric ward of a general hospital or a community residential alternative. There were no psychopathology-based exclusion criteria. Treatment episode symptom improvement, satisfaction, discharge status, and 6-month pre- and postepisode acute care utilization, psychosocial functioning, and patient satisfaction were assessed.\n Of 185 patients, 119 (64%) were successfully placed at their assigned treatment site. Case mix data indicated that patients treated in the hospital (N = 50) and the alternative (N = 69) were comparably ill. Treatment episode symptom reduction and patient satisfaction were comparable for the two settings. Nine (13%) of 69 patients randomly assigned to the alternative required transfer to a hospital unit; two (4%) of 50 patients randomly assigned to the hospital could not be stabilized and required transfer to another facility. Psychosocial functioning, satisfaction, and acute care use in the 6 months following admission were comparable for patients treated in the two settings and did not differ significantly from functioning before the acute episode.\n Hospitalization is a frequent and high-cost consequence of severe mental illness. For patients who do not require intensive general medical intervention and are willing to accept voluntary treatment, the alternative program model studied provides outcomes comparable to those of hospital care.", "To evaluate the effectiveness of multiple group family treatment for Schizophrenia.\n Relatives were randomly provided with an informative programme (n = 50), or allocated to receive an additional support programme (n = 26). Patients did not attend the programme to overcome cultural and organizational implementation barriers. The 12 and 24 months clinical and family outcomes were assessed.\n Patients' compliance with standard care was greater at 12 months in the more intensive behavioural management group over a control group receiving treatment as usual (TAU) (n = 25). A reduction in levels of expressed emotion (EE), significantly more frequent in those receiving the additional support programme than just the informative, occurred after treatment completion. Other clinical and family outcomes did not differ. However, treatment benefits declined at 24 months, when baseline high EE was again predictive of patient's admission and relatives were more vulnerable to objective burden. Baseline illness severity variables predicted a number of medium and long-term poor clinical outcomes.\n Although family psychoeducation has been tested in a wide range of Anglo-Saxon settings, there remains need to assess outcomes more internationally. Effective family interventions for people with schizophrenia probably require continued administration of key-elements or ongoing informal support to deal with the vicissitudes of illnesses.", "A series of small, mainly uncontrolled, studies have suggested that techniques adapted from cognitive-behavioural therapy (CBT) for depression can improve outcome in psychosis, but no large randomised controlled trial of intensive treatment for medication-resistant symptoms of psychosis has previously been published.\n Sixty participants who each had at least one positive and distressing symptom of psychosis that was medication-resistant were randomly allocated between a CBT and standard care condition (n = 28) and a standard care only control condition (n = 32). Therapy was individualised, and lasted for nine months. Multiple assessments of outcome were used.\n Over nine months, improvement was significant only in the treatment group, who showed a 25% reduction on the BPRS. No other clinical, symptomatic or functioning measure changed significantly. Participants had a low drop-out rate from therapy (11%), and expressed high levels of satisfaction with treatment (80%). Fifty per cent of the CBT group were treatment responders (one person became worse), compared with 31% of the control group (three people became worse and another committed suicide).\n CBT for psychosis can improve overall symptomatology. The findings provide evidence that even a refractory group of clients with a long history of psychosis can engage in talking about psychotic symptoms and their meaning, and this can improve outcome.", "This study tested the effectiveness of a mutual support multiple-family-group intervention for schizophrenia in terms of improvements in patients' psychosocial functioning, use of mental health services, and rehospitalization compared with a psychoeducation intervention and standard care.\n A controlled trial was conducted in a sample of 96 Chinese families who were caring for a relative with schizophrenia in Hong Kong. The families were randomly assigned to one of three groups: mutual support (N=32), psychoeducation (N=33), and standard care (N=31). The interventions were delivered at two psychiatric outpatient clinics over a six-month period. The mutual support and psychoeducation interventions consisted of 12 group sessions every two weeks, each lasting about two hours. The mutual support group was a peer-led group designed to provide information, emotional support, and coping skills for caregiving in stages. The psychoeducation group was a professional-led group designed to educate families about the biological basis of schizophrenia and treatment and to improve illness management and coping skills. The standard care group and the other two groups received routine psychiatric outpatient care during the intervention. Data analyses of multiple outcomes over one-year follow-up were conducted on an intention-to-treat basis.\n Multivariate analyses of variance showed that the mutual support intervention was associated with consistently greater improvements in patients' functioning and rehospitalization and stable use of mental health services over the follow-up period compared with the other two interventions.\n The study provides evidence that mutual support groups can be an effective family intervention for Chinese persons with mental illness in terms of improving patients' functioning and hospitalization without increasing their use of mental health services." ]	This review indicates that early warning signs interventions may have a positive effect on the proportions of people re-hospitalised and on rates of relapse, but not on time to recurrence. However, the overall quality of the evidence was very low, indicating that we do not know if early warning signs interventions will have similar effects outside trials and that it is very likely that further research will alter these estimates. Moreover, the early warning signs interventions were used along side other psychological interventions, and we do not know if they would be effective on their own. They may be cost-effective due to reduced hospitalisation and relapse rates, but before mental health services consider routinely providing psychological interventions involving the early recognition and prompt management of early warning signs to adults with schizophrenia, further research is required to provide evidence of high or moderate quality regarding the efficacy of early warning signs interventions added to usual care without additional psychological interventions, or to clarify the kinds of additional psychological interventions that might aid its efficacy. Future RCTs should be adequately-powered, and designed to minimise the risk of bias and be transparently reported. They should also systematically evaluate resource costs and resource use, alongside efficacy outcomes and other outcomes that are important to people with serious mental illness and their carers.
CD003368	[ "6685644", "667798", "7074523", "2731120", "20619634", "1260337", "2208013", "991103", "9215817", "10334524", "16226397", "17308269", "2649221", "16421418", "10655439", "8293400" ]	[ "Randomized trial of 3 different regimens of combination chemotherapy in patients receiving simultaneously a hormonal treatment for advanced breast cancer.", "Combination chemotherapy for advanced breast cancer: two regimens containing adriamycin.", "Comparison of four-combination chemotherapy programs in metastatic breast cancer: comparison of multiple drug therapy with cytoxan, 5-FU and prednisone versus cytoxan and adriamycin, versus cytoxan, 5-FU and adriamycin, versus cytoxan, 5-FU and prednisone alternating with cytoxan and adriamycin.", "Differential response to chemotherapy in metastatic breast cancer in relation to estrogen receptor level. Results of a prospective randomized study.", "Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer--results from two randomised studies.", "Response and survival in advanced breast cancer after two non-cross-resistant combinations.", "Survival of premenopausal women with metastatic breast cancer. Long-term follow-up of Eastern Cooperative Group and Cancer and Leukemia Group B studies.", "Combination chemotherapy for metastatic breast carcinoma. Prospective comparison of multiple drug therapy with L-phenylalanine mustard.", "Megestrol acetate and aminoglutethimide/hydrocortisone in sequence or in combination as second-line endocrine therapy of estrogen receptor-positive metastatic breast cancer: a Southwest Oncology Group phase III trial.", "Safety and efficacy of using a single agent or a phase II agent before instituting standard combination chemotherapy in previously untreated metastatic breast cancer patients: report of a randomized study--Cancer and Leukemia Group B 8642.", "A phase III randomized study on the sequencing of radiotherapy and chemotherapy in the conservative management of early-stage breast cancer.", "Sequenced compared with simultaneous anthracycline and cyclophosphamide in high-risk stage I and II breast cancer: final analysis from INT-0137 (S9313).", "Randomized clinical trial of CFP versus CMFP in women with metastatic breast cancer.", "Multicycle dose-intensive chemotherapy for women with high-risk primary breast cancer: results of International Breast Cancer Study Group Trial 15-95.", "Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma.", "Hormonal treatment for metastatic breast cancer. An Eastern Cooperative Oncology Group Phase III trial comparing aminoglutethimide to tamoxifen." ]	[ "We report the results of a randomized trial carried out by the Swiss Group for Clinical Cancer Research (SAKK) and in which 230 patients with advanced breast cancer receiving concurrently a hormonal treatment (oophorectomy for pre- and tamoxifen for postmenopausal women) were randomly allocated to three different regimens of combination chemotherapy. The therapeutic results registered with the two more intensive combinations (LMP/FVP and LMFP/ADM) were similar with regard to response rates, time to progression and survival. The patients receiving the low-dose chemotherapy lmfp showed a statistically significant lower response rate (32%, P less than 0.001) and a shorter survival (P = 0.03) than the results observed in patients treated with the two other regimens. This difference was particularly pronounced, at least regarding survival, in the following subgroups: postmenopausal women, patients with a poor performance status, dominant visceral lesions, two sites of disease and a disease-free interval longer than 12 months. Patients with bony metastases as dominant lesion fared similarly with all three regimens of chemotherapy. This latter subset of advanced breast cancer patients should probably be spared too intensive cytotoxic treatment. This is, to our knowledge, the first report of a randomized trial showing an evident correlation between response rate and survival in various subgroups of patients with advanced breast cancer treated with different chemotherapeutic regimens.", "Forty-eight women with advanced metastatic carcinoma of the breast were treated with one of two combination chemotherapy regimens: 1) adriamycin and cyclophosphamide or 2) adriamycin, cyclophosphamide, methotrexate and 5-fluorouracil. The response rate in the two-drug treatment group was 50% and in the four-drug treatment group, 55%. The median duration of response was ten months in both treatment groups. Dramatic responses were seen in patients with visceral metastases. Patients who responded to chemotherapy had a significantly longer survival than nonresponders (p less than 0.01). The long interval between adriamycin doses (six weeks) in the four drug regimen did not adversely effect the response rate--an important finding in view of the dose-related cardiac toxicity of this agent.", "In 126 postmenopausal women with metastatic breast cancer, four chemotherapeutic combination programs were tested. Patients were stratified and randomized to one of the four programs: (1) fluorouracil, cytoxan and prednisone (CFP): (2) fluorouracil, cytoxan and Adriamycin (CAF); (3) cytoxan and Adriamycin (CA); or (4) alternating combinations of CFP-CA. Objective response rates were 17% for 18 patients on CFP, 25% for 40 patients on CAF, 42% for 41 patients on CA and 63% for 19 patients on CFP-CA. CFP-CA provided a significantly higher response rate than either CFP or CAF. The response rate of CA was intermediate. The duration of remission and survival were similar for all four groups. When progression or relapse following remission was demonstrated, patients were rerandomized to either adrenalectomy or tamoxifen. There were no responders either in the 15 patients undergoing adrenalectomy or the 11 patients receiving tamoxifen. In a crossover study, nine adrenalectomized patients received tamoxifen and four tamoxifen-treated patients underwent adrenalectomy. None responded. It appears that response rates to hormonal modalities are reduced in patients previously treated by combination chemotherapy.", "The predictive value of estrogen receptor (ER) level for response to chemotherapy was studied in 182 patients with metastatic breast cancer in a prospective study. Patients were stratified according to ER status and dominant site of disease and randomized to one of three regimens: cyclophosphamide, 5-Fluorouracil, and prednisone (CFP) versus CFP, methotrexate, and vincristine (CFPMV) versus doxorubicin and cyclophosphamide (AC). There was no significant differences in all response categories (P = 0.21), was taken as a predictor for response to chemotherapy, there was no significant difference in overall response (P = 0.61) between ER+ (62/108, 57%) and ER- patients (31/49, 63%). However, there was a significant trend toward a higher degree of response in ER- patients (more complete response [CR] nine of 49, 18%, and fewer failures six of 49, 12%) than in ER+ (less CR seven of 108, 7%, and more failures 37/108, 34%) (P = 0.006). Patients with higher measured levels of ER showed worse response (Kendall's tau C, P = 0.026). This trend for ER- patients to have better response than ER+ patients was generally consistent, regardless of the predominant site of metastases or chemotherapy regimen (P = 0.04 for CFP; P = 0.08 for CFPMV; and P = 0.20 for AC). The advantage of a better response for ER- patients was nullified by an earlier relapse which was reflected in longer duration of remission, time to treatment failure, and survival in favor of ER+ patients (12.3 months versus 7.3 months remission duration, 18.7 months versus 13.6 months survival in partial responders). These data suggest that ER- patients respond to a higher extent to chemotherapy but relapse sooner than ER+ patients, suggesting a more rapid growth for ER- tumors. In patients with ER- tumors and poorer prognosis on conventional chemotherapy, new trials of intensive consolidation after response should be considered.", "Endometrial cancer patients with high grade tumours, deep myometrial invasion or advanced stage disease have a poor prognosis. Randomised studies have demonstrated the prevention of loco-regional relapses with radiotherapy (RT) with no effect on overall survival (OS). The possible additive effect of chemotherapy (CT) remains unclear. Two randomised clinical trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) were undertaken to clarify if sequential combination of chemotherapy and radiotherapy improves progression-free survival (PFS) in high-risk endometrial cancer. The two studies were pooled.\n Patients (n=540; 534 evaluable) with operated endometrial cancer International Federation of Obstetrics and Gynaecology (FIGO) stage I-III with no residual tumour and prognostic factors implying high-risk were randomly allocated to adjuvant radiotherapy with or without sequential chemotherapy.\n In the NSGO/EORTC study, the combined modality treatment was associated with 36% reduction in the risk for relapse or death (hazard ratio (HR) 0.64, 95%confidence interval (CI) 0.41-0.99; P=0.04); two-sided tests were used. The result from the Gynaecologic Oncology group at the Mario Negri Institute (MaNGO)-study pointed in the same direction (HR 0.61), but was not significant. In the combined analysis, the estimate of risk for relapse or death was similar but with narrower confidence limits (HR 0.63, CI 0.44-0.89; P=0.009). Neither study showed significant differences in the overall survival. In the combined analysis, overall survival approached statistical significance (HR 0.69, CI 0.46-1.03; P=0.07) and cancer-specific survival (CSS) was significant (HR 0.55, CI 0.35-0.88; P=0.01).\n Addition of adjuvant chemotherapy to radiation improves progression-free survival in operated endometrial cancer patients with no residual tumour and a high-risk profile. A remaining question for future studies is if addition of radiotherapy to chemotherapy improves the results.\n Copyright 2010 Elsevier Ltd. All rights reserved.", "A prospective study with two cytotoxic combinations (cyclophosphamide, methotrexate, and fluorouracil (CMF), and adriamycin plus vincristine (AV)) was carried out in 110 patients with advanced breast cancer. There was no significant difference between the treatment groups in the response rate after primary treatment, the median duration of response, and the median survival. In both groups responders survived for longer than non-responders. Secondary treatment after crossover for progression or relapse resulted in response rates of 35% for AV and 20% for CMF. Toxicity was mainly represented by reversible haemosuppression. These results are comparable with those obtained with other multiple-drug regimens, and combination chemotherapy alone seems to have reached a plateau in its capacity to control disseminated breast cancer.", "In premenopausal women with metastatic breast cancer, differences in survival curves early during follow-up can be misleading. The authors therefore analyzed long-term survival in 378 patients, entered in three randomized trials, started between 1973 and 1978. Combined data from the three trials were used to increase the power for identifying prognostic variables. Cancer and Leukemia Group B (CALGB) trial 7382 randomized patients to oophorectomy plus either cyclophosphamide or combination chemotherapy or observation. Eastern Cooperative Oncology Group (ECOG) 2174 randomized patients who had not progressed 3 months after oophorectomy to combination chemotherapy or combination chemotherapy or observation. Trial ECOG 2177 randomized estrogen receptor (ER) positive or ER-unknown patients to oophorectomy plus combination chemotherapy or immediate combination chemotherapy, and ER-negative patients were directly assigned to combination chemotherapy. Hence ER-negative patients need not have been healthy enough to be randomized to oophorectomy. With only 14% of the patients still alive, median survival on the three studies was 30, 24, and 28 months. The median survival of individual treatments changed noticeably in ECOG 2174 and ECOG 2177 with long-term follow-up. At this time there are no differences in survival between randomized regimens in any of the three trials. In a multivariate model, factors associated with significantly poorer survival were visceral-dominant disease, nodal metastases, breast metastases, age younger than 45 years, ER negativity, and not receiving chemotherapy immediately after oophorectomy. This treatment difference was thus not due to imbalances in the prognostic variables used in the model, but it may be due to imbalances of unknown prognostic factors or differences in patient selection.", "A prospective randomized clinical trial was undertaken in 184 patients with metastatic breast carcinoma to compare single drug chemotherapy with L-phenylalanine mustard (L-PAM) and intermittent combination chemotherapy with cyclophosphamide, methotrexate, and 5-fluourouracil (CMF). All patients had not been previously treated with cytotoxic drugs and all had objectively measurable visceral of soft tissue disease. Of the 93 patients who received CMF, 49 (53%) achieved a complete (14 patients) or partial (35 patients) regression of measurable tumor, for a median duration of 25 weeks. Eighteen of the 91 patients (20%) treated with L-PAM responded, for a median duration of 13 weeks. The toxicity was primarily hematologic, and greater in the CMF group, which also received more cycles of therapy because of the higher rate and duration of response. The overall survival of CMF-treated patients was superior to that of the single drug group. The differences were even greater when the patients were subclassified according to the presence of liver involvement or nonambulatory performance status. The superior antitumor effect of CMF over L-PAM suggests that it may be a more effective drug regimen to be used as an adjuvant to primary therapy.", "A phase III randomized trial was performed to determine whether combination hormonal therapy with aminoglutethimide (AG) and hydrocortisone (HC) plus megestrol acetate (MA) improved response rates, response duration, or increased survival over the sequential use of each hormone in women with estrogen receptor-positive metastatic breast cancer (MBC) who had maintained stable disease for at least 6 months or responded to tamoxifen.\n Two hundred eighty-eight postmenopausal women with progressive estrogen receptor-positive MBC were randomly selected to receive MA 40 mg four times daily (arm I), AG 250 mg four times daily with HC 40 mg daily in divided doses (arm II), versus the combination of MA plus AG given at the same dosages (arm III). Patients on arms I and II who progressed after an adequate trial were crossed over to the other treatment arm.\n Two hundred thirty-five eligible patients were evaluated for response, time to treatment failure, and survival. Response was only reported for patients with measurable disease and was not statistically different among the three arms. There were two partial responses (PRs) on MA (6%), four complete responses (CRs) and six PRs on AG (24%), and eight PRs and three CRs on MA plus AG (23%) in 32, 42, and 48 measurable patients, respectively. Median times to treatment failure were also similar at 5, 4, and 7 months. Survival was also not statistically different among the three arms at 26, 27, and 26 months for arms I, II, and III, respectively. Toxicity was greater in the two AG arms with respect to fatigue, nausea and vomiting, and rash.\n With the exception of toxicity, there is no response, time to treatment failure, or survival benefit for any one group when comparing MA, AG, or the combination at their stated doses in women with estrogen receptor-positive MBC who had previously responded to or stabilized with tamoxifen.", "We undertook a prospective, randomized phase III trial to evaluate the safety and efficacy of using a phase II agent before initiating therapy with standard combination chemotherapy in metastatic breast cancer patients.\n A total of 365 women with measurable metastatic breast cancer, previously untreated with chemotherapy for their metastatic disease, were randomized to receive either immediate chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) or up to four cycles of one of five sequential cohorts of single-agent drugs: trimetrexate, melphalan, amonafide, carboplatin, or elsamitrucin, followed by CAF.\n The toxicity of each single agent followed by CAF was comparable to that of CAF alone. The cumulative response rates for the single agent followed by CAF were not statistically different from those of CAF alone (44% v 52%; P = .24). However, in the multivariate analysis, patients with visceral disease had a trend toward lower response rates on the phase II agent plus CAF arm (P = .078). Although survival and response duration also were not statistically significantly different between the two study arms (P = .074 and P = .069, respectively), there was a suggestion of benefit for the CAF-only arm.\n The brief use of a phase II agent, regardless of its efficacy, followed by CAF resulted in response rates, toxicities, durations of response, and survival statistically equivalent to those seen with the use of CAF alone. These findings support the use of a new paradigm for the evaluation of phase II agents in the treatment of patients with metastatic breast cancer.", "To compare two different timings of radiation treatment in patients with breast cancer who underwent conservative surgery and were candidates to receive adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy.\n A total of 206 patients who had quadrantectomy and axillary dissection for breast cancer and were planned to receive adjuvant CMF chemotherapy were randomized to concurrent or sequential radiotherapy. Radiotherapy was delivered only to the whole breast through tangential fields to a dose of 50 Gy in 20 fractions over 4 weeks, followed by an electron boost of 10-15 Gy in 4-6 fractions to the tumor bed.\n No differences in 5-year breast recurrence-free, metastasis-free, disease-free, and overall survival were observed in the two treatment groups. All patients completed the planned radiotherapy. No evidence of an increased risk of toxicity was observed between the two arms. No difference in radiotherapy and in the chemotherapy dose intensity was observed in the two groups.\n In patients with negative surgical margins receiving adjuvant chemotherapy, radiotherapy can be delayed to up to 7 months. Concurrent administration of CMF chemotherapy and radiotherapy is safe and might be reserved for patients at high risk of local recurrence, such as those with positive surgical margins or larger tumor diameters.", "We conducted a phase III randomized study of two adjuvant treatment schedules of doxorubicin (A) and cyclophosphamide (C) in early-stage breast cancer to determine if administration of sequential single agents (A --> C) results in superior disease-free survival (DFS) and overall survival (OS) versus the same total dose given in combination (AC).\n High-risk node-negative or low-risk node-positive breast cancer patients received AC given: (arm I) concurrently (AC) doxorubicin 54 mg/m2 and cyclophosphamide 1.2 g/m2 intravenously (IV) every 3 weeks for six cycles; or (arm II) in sequence (A C) doxorubicin 40.5 mg/m2 IV days 1 and 2 every 3 weeks for four cycles followed by cyclophosphamide 2.4 gm/m2 IV every 2 weeks for three cycles. Total dose and duration were identical, but the intensity of each drug was increased on A C. Both arms included granulocyte colony-stimulating factor support and prophylactic antibiotics. All but premenopausal women with receptor negative tumors received tamoxifen after chemotherapy.\n Between 1994 and 1997, 3,176 patients were randomly assigned. Arms were well balanced; 48% of eligible patients were node-negative and 48% were estrogen receptor-positive. No significant differences in OS or DFS were observed; 5-year estimates of OS (95% CI) were 88% (87% to 90%) on AC and 89% (87% to 91%) on A --> C. Grade 4 hematologic toxicity was greater on A --> C, but nonhematological grade 4 was similar.\n The overall result does not support superiority of dose-intense sequenced single agents. The greater toxicity of higher doses of single agents does not support their sequential use.", "A randomized trial was performed to determine relative efficacy and toxicity of two first-line combination chemotherapy regimens in women with metastatic breast cancer: CFP (cyclophosphamide, 5-fluorouracil, prednisone) and CMFP (cyclophosphamide, 5-fluorouracil, methotrexate, prednisone). Both regimens have reported efficacy in this setting but differ in dosages and scheduling of the agents they have in common. Three hundred thirty-six women with no prior chemotherapy for metastatic disease were eligible and evaluable, and 309 had either measurable or evaluable disease and were assessable for objective response. Responses were seen in 65 of 153 (42%) on CFP and 83 of 156 (53%) on CMFP (two-sided P = 0.06). Median durations of response were 7.1 months for CFP and 8.5 months for CMFP (log-rank, two-sided P = 0.67). Considering all 336 patients, the median times to disease progression were 4.7 months for CFP and 6.2 months for CMFP (log-rank P = 0.31) and median survivals were 15.2 and 14.9 months, respectively (log-rank P = 0.88). Covariate analysis did not alter these findings. Median leukocyte nadirs were 1800 for CFP and 1500 for CMFP, with 22% and 21%, respectively, having nadirs less than 1000/microliters. Emesis was more frequent on CFP (49%) than on CMFP (26%) but was severe in only 7% and 5%, respectively. It is concluded that despite a higher response rate on CMFP and some differences in toxicities including a higher reported incidence of emesis on CFP, there was no substantial difference in efficacy or tolerability between the two regimens.", "To compare adjuvant dose-intensive epirubicin and cyclophosphamide chemotherapy administered with filgrastim and progenitor cell support (DI-EC) with standard-dose anthracycline-based chemotherapy (SD-CT) for patients with early-stage breast cancer and a high risk of relapse, defined as stage II disease with 10 or more positive axillary nodes; or an estrogen receptor-negative or stage III tumor with five or more positive axillary nodes.\n Three hundred forty-four patients were randomized after surgery to receive seven cycles of SD-CT over 22 weeks, or three cycles of DI-EC (epirubicin 200 mg/m2 plus cyclophosphamide 4 gm/m2 with filgrastim and progenitor cell support) over 6 weeks. All patients were assigned tamoxifen at the completion of chemotherapy. The primary end point was disease-free survival (DFS).\n After a median follow-up of 5.8 years (range, 3 to 8.4 years), 188 DFS events had occurred (DI-EC, 86 events; SD-CT, 102 events). The 5-year DFS was 52% for DI-EC and 43% for SD-CT, with hazard ratio of DI-EC compared with SD-CT of 0.77 (95% CI, 0.58 to 1.02; P = .07). The 5-year overall survival was 70% for DI-EC and 61% for SD-CT, with a hazard ratio of 0.79 (95% CI, 0.56 to 1.11; P = .17). There were eight cases (5%) of anthracycline-induced cardiomyopathy (two fatal) among those who received DI-EC. Women with hormone receptor-positive tumors benefited significantly from DI-EC.\n There was a trend in favor of DI-EC with respect to disease-free survival. A larger trial or meta-analysis will be required to reveal the true effect of dose-intensive therapy.", "Uncontrolled studies have reported encouraging outcomes for patients with high-risk primary breast cancer treated with high-dose chemotherapy and autologous hematopoietic stem cell support. We conducted a prospective randomized trial to compare standard-dose chemotherapy with the same therapy followed by high-dose chemotherapy. PATIENTS and\n Patients with 10 or more positive axillary lymph nodes after primary breast surgery or patients with four or more positive lymph nodes after four cycles of primary (neoadjuvant) chemotherapy were eligible. All patients were to receive eight cycles of 5-fluorouracil, doxorubicin (Adriamycin), and cyclophosphamide (FAC). Patients were stratified by stage and randomly assigned to receive two cycles of high-dose cyclophosphamide, etoposide, and cisplatin with autologous hematopoietic stem cell support or no additional chemotherapy. Tamoxifen was planned for postmenopausal patients with estrogen receptor-positive tumors and chest wall radiotherapy was planned for all. All P values are from two-sided tests.\n Seventy-eight patients (48 after primary surgery and 30 after primary chemotherapy) were registered. Thirty-nine patients were randomly assigned to FAC and 39 to FAC followed by high-dose chemotherapy. After a median follow-up of 6.5 years, there have been 41 relapses. In intention-to-treat analyses, estimated 3-year relapse-free survival rates were 62% and 48% for FAC and FAC/high-dose chemotherapy, respectively (P =.35), and 3-year survival rates were 77% and 58%, respectively (P =.23). Overall, there was greater and more frequent morbidity associated with high-dose chemotherapy than with FAC; there was one septic death associated with high-dose chemotherapy.\n No relapse-free or overall survival advantage was associated with the use of high-dose chemotherapy, and morbidity was increased with its use. Thus, high-dose chemotherapy is not indicated outside a clinical trial.", "Tamoxifen and aminoglutethimide are two hormone therapies reported to be effective palliative approaches for patients with metastatic breast cancer. The current trial was designed to evaluate their relative therapeutic effectiveness.\n Two hundred forty-nine postmenopausal women with advanced breast cancer were randomized in an Eastern Cooperative Oncology Group (ECOG) Phase III study to treatment with adrenalectomy, aminoglutethimide, or tamoxifen with crossover to alternate therapy if disease progressed. Adrenalectomy was dropped as a treatment after 2 years because of low patient accrual.\n There were 216 evaluable patients entered in the study with 108 initially randomized to aminoglutethimide and 108 to receive tamoxifen therapy. The overall response rate for aminoglutethimide was 45%, and for tamoxifen it was 27%. One institution had a response rate of 60% with aminoglutethimide and only 4% with tamoxifen, whereas all of the other institutions combined had a response rate of 41% with aminoglutethimide and 34% with tamoxifen. Eighty-seven evaluable patients crossed over to the other drug (44 to aminoglutethimide and 43 to tamoxifen). There was a 36% response rate to aminoglutethimide and 19% to tamoxifen, with stable disease in 36% of both groups. The overall survival rates were identical. Toxicity was greater with aminoglutethimide (dermatitis) but was not life-threatening. Glucocorticoid support with either dexamethasone or hydrocortisone was acceptable.\n Both aminoglutethimide and tamoxifen produced responses in postmenopausal patients with breast cancer, and a significant number of crossover responses were observed. Of interest in this randomized study was the observation that one institution had a markedly different response rate on induction, reinforcing the need for multi-institution trials in Phase III studies." ]	The addition of one or more drugs to the regimen shows a statistically significant advantage for tumour response in women with metastatic breast cancer but the results suggest no difference in survival time or time to progression. The positive effect on tumour response was also associated with increased toxicity.
CD008675	[ "19410397", "16549410", "16702565", "16446892", "15235364", "15011204", "21859055", "11799859", "16878246", "11353937", "16178407" ]	[ "Are postural restrictions after an Epley maneuver unnecessary? First results of a controlled study and review of the literature.", "Short-term efficacy of Epley's manoeuvre: a double-blind randomised trial.", "Efficacy of postural restriction in treating benign paroxysmal positional vertigo.", "Posture restrictions do not interfere in the results of canalith repositioning maneuver.", "Effect of mastoid oscillation on the outcome of the canalith repositioning procedure.", "Treatment variations on the Epley maneuver for benign paroxysmal positional vertigo.", "Are postural restrictions necessary for management of posterior canal benign paroxysmal positional vertigo?", "Benign paroxysmal vertigo: a comparative prospective study of the efficacy of Brandt and Daroff exercises, Semont and Epley maneuver.", "Is it important to restrict head movement after Epley maneuver?", "A pilot randomized clinical trial on the relative effect of instrumental (MFMA) versus manual (HVLA) manipulation in the treatment of cervical spine dysfunction.", "Treatment of benign paroxysmal positional vertigo: necessity of postmaneuver patient restrictions." ]	[ "Postural restrictions after canalith repositioning maneuvers (CRM) for benign paroxysmal positional vertigo of the posterior semicircular canal (p-BPPV) have no proven value and therefore most physicians regard them as unnecessary. The aim of this study was to assess the short-term efficacy of head and body movement limitations after a single Epley maneuver. A review of the literature was performed to assess the current level of evidence for the efficacy of postural restrictions.\n Sixty-four patients, median age 59 years (range 37-82 years), with p-BPPV, were allocated either to instructions for movement restrictions or free movements for 48 h after a single Epley maneuver. The minimization method was used for allocation to treatment. This procedure 'minimizes' the differences in the distribution of pre-specified prognostic factors (e.g. sex and age) between the two groups of treatment. Minimization was preferred over randomization which is not as effective in balancing baseline characteristics when the number of participants is small. Outcome was assessed by physician and patient reported measures (Dix-Hallpike test, subjective vertigo intensity in a 10-point scale, patient's assessment of improvement) within 1 week after treatment by an independent investigator. The level of statistical significance was 0.05.\n More patients with movement restrictions reported a subjective improvement after treatment (p=0.007). Ninety percent of patients with movement restrictions and 74.2% of patients with free movements had a negative follow up Dix-Hallpike test but the difference was not significant (p=0.108). The mean pre-treatment vertigo intensity was reduced from 6.07 and 5.97 to 1.18 and 2.86, respectively but the difference was not significant (p=0.122).\n Postural restrictions do not increase the efficacy of the canal-repositioning maneuver despite the fact that patients report a subjective improvement after post-procedural instructions. In the review of the literature, all studies except one conclude that postural restrictions are unnecessary. However, a number of methodological issues such as inadequate sample size are not addressed and more conclusive evidence is required. Based on current evidence, the use of postural restrictions after the canal-repositioning maneuver is unjustified.", "Benign paroxysmal positional vertigo of the posterior canal (PC-BPPV) is a common vestibular disorder and can be easily treated with Epley's manoeuvre. Thus far, the short-term efficacy of Epley's manoeuvre for treatment of PC-BPPV is unknown.\n To evaluate the efficacy of Epley's manoeuvre for treatment of PC-BPPV 24 h after applying the manoeuvre.\n The short-term efficacy of Epley's manoeuvre was compared with a sham procedure in 66 patients with PC-BPPV by using a double-blind randomised study design.\n 24 h after treatment, 28 of 35 (80%) patients in the Epley's manoeuvre group had neither vertigo nor nystagmus on positional testing compared with 3 of 31 (10%) patients in the sham group (p<0.001).\n Epley's manoeuvre is shown to resolve PC-BPPV both effectively and rapidly.", "To investigate the efficacy of postural restriction after canalith repositioning in treating benign paroxysmal positional vertigo (BPPV).\n Prospective trial of patients with postural restriction vs those without postural restriction after treatment.\n Patients with classic BPPV and with BPPV without nystagmus were treated using the modified Epley canalith repositioning procedure. Patients were randomly separated into 2 groups. The first group was instructed to wear a cervical collar and to maintain an upright head position for 2 days. The second group had no motion restriction. After 5 days, the patients were followed up and evaluated using the Dix-Hallpike test.\n In the first group, 56 of 62 ears healed after the first maneuver, and the remaining ears healed after the second. In the second group, 45 of 57 ears healed after the first maneuver, 6 after the second, and 5 (with subsequent postural restriction) after the third (1 ear did not improve). Five patients in the first group and 3 patients in the second group had BPPV without nystagmus; all of these patients healed after a single maneuver. The difference between the 2 groups in the number of maneuvers required for treatment was statistically significant (P<.05). The number of patients who required a third maneuver was significantly higher in the second group (P<.05).\n Postural restriction enhances the therapeutic effect of canalith repositioning in the treatment of posterior semicircular canal BPPV. The long-term efficacy of postural restriction in preventing BPPV recurrence has not been demonstrated.", "Benign Paroxysmal Positional Vertigo (BPPV) is a frequent cause of dizziness and despite of the excellent results with its treatment, there is some controversy about management.\n To assess the efficacy of Epley Maneuver with and without post-maneuver restrictions.\n Prospective randomized.\n Fifty patients presenting BPPV of the posterior semicircular canal, treated with Epley Maneuver and divided into two groups: study group--23 patients--with post-maneuver restrictions, and control group--27 patients--without post-maneuver restrictions.\n No significant difference was found between the studied and the control group.\n Post-maneuver restrictions do not influence the efficacy of Epley Maneuver for BPPV management.", "The canalith repositioning procedure (CRP), as described by Epley, is a well-established method of treatment for benign paroxysmal positional vertigo (BPPV). Debate exists as to whether simultaneous application of a mastoid oscillator confers any added benefit. The aim of this study was to examine this question.\n Prospective randomized study.\n Eighty-four subjects with unilateral posterior canal BPPV were randomized into two groups. The oscillator group was treated by CRP with mastoid oscillation and the nonoscillator group was treated by CRP alone. Positive outcome was regarded as complete resolution of symptoms and a negative Dix-Hallpike's test after a 4 to 6 week follow-up period.\n Five patients were lost to follow-up. Twenty-eight (72%) patients from the oscillator group and 26 (65%) patients from the nonoscillator group had a positive outcome. This difference was not significant (chi = 0.17, P =.68)\n For the treatment of posterior canal BPPV, concurrent mastoid oscillation with CRP does not significantly alter the short-term outcome.", "To determine if using more head rotation during the Epley maneuver or specific posttreatment instructions for sleeping position would affect treatment effectiveness, compared with the usual maneuver without extra instructions.\n Patients with unilateral benign paroxysmal positional vertigo of the posterior semicircular canal were randomized to a standard Epley maneuver group, a group that received an additional 45 degrees head rotation during the maneuver (Augmented Epley), and a group that received instructions about sleeping position after treatment.\n Posttests from 1 week to 6 months showed no differences in vertigo intensity or frequency or responses to the Dix-Hallpike maneuver. All groups showed significant decreases in vertigo and Dix-Hallpike responses. Some subjects in each group had abnormal pretreatment scores on computerized dynamic posturography. Those subjects in the Augmented Epley group who had abnormal pretreatment posturography scores had significantly better posttreatment scores than those subjects in the Home Instruction group who had abnormal pretreatment scores. All subjects with abnormal responses, however, showed improvement.\n Although clinicians continue to give patients home instructions and to use additional head rotation during the maneuver, these variations are not essential for achieving improvement in symptoms.", "An important component of management of benign paroxysmal positional vertigo (BPPV) has been the application of postural restrictions after use of a canalith repositioning maneuver (CRM) to prevent the return of otolithic debris into the posterior semicircular canal (PSC). This study was designed to explore the effectiveness of postural restrictions in patients with BPPV caused by otolithic debris in the PSC.\n Seventy-four adult patients with unilateral PSC BPPV were enrolled into this study. All patients were managed with a CRM--either the modified Epley maneuver or the Semont maneuver. The patients were divided randomly into 2 groups: group A, with postural restrictions, and group B, without postural restrictions. The statistical analysis was performed with X2 tests and t-tests.\n No patients in either group showed positional nystagmus in the posttreatment evaluation under infrared videonystagmoscopy. No patients had symptoms of vertigo after the therapy. The results of follow-up vestibular tests were normal in both groups.\n In our experience, postural restrictions do not enhance the beneficial effect of the CRMs. They do not seem to have any protective role and therefore should not be recommended as an adjunct to the treatment of PSC BPPV.", "We performed a prospective study to evaluate the efficacy of three physical treatments for benign paroxysmal positional vertigo: Brandt & Daroff habituation exercises, the Semont manoevre (intended as a statoconia-detachment maneuver), and the Epley maneuver (intended as a statoconia-repositioning maneuver). A total of 106 BPPV patients were randomly assigned to one of the three treatment groups, and responses were evaluated one week, one month and three months after the initial treatment. At the one-week follow-up, similar cure rates were obtained with the Semont and Epley maneuver (74% and 71% respectively), both cure rates being significantly higher than that obtained with Brandt & Daroff exercises (24%). By the three-month follow-up, the cure rate obtained with the Epley maneuver was higher (93%) than that obtained with the Semont maneuver (77%), though both remained higher than that obtained with the Brandt & Daroff maneuver (62%). However, the proportion of initially responding patients showing subsequent relapse was lower among patients treated by the Semont maneuver than among patients treated by the Epley maneuver. In view of these findings, we propose a treatment algorithm for patients with BPPV.", "The effectiveness of postmaneuver postural restrictions is controversial in patients with benign paroxysmal positional vertigo.\n To verify the role of postural restrictions in patients with benign paroxysmal positional vertigo of posterior canal, submitted to a single Epley maneuver.\n clinical prospective.\n Fifty eight patients with benign paroxysmal positional vertigo of posterior canal were randomly divided in two groups following the application of a unique Epley maneuver. The patients from group 1 were informed to restrict their head movements and to use a cervical collar and group 2 patients were not informed about these postmaneuver restrictions. The patients from both groups were reevaluated one week after Epley maneuver, regarding the presence of symptoms and positional nystagmus.\n One week after Epley maneuver 82.1% of the patients from group 1 and 73.3% from group 2 didn't present positional nystagmus (p=0.421). There was a clinical improvement in 96.0% of the patients from group 1 and in 94.0% from group 2 (p=0.781).\n The use of postural restrictions in patients with benign paroxysmal positional vertigo of posterior canal didn't interfere in their clinical evaluation, one week after a unique Epley maneuver.", "To determine the relative effect of instrument-delivered thrust cervical manipulations in comparison with traditional manual-delivered thrust cervical manipulations in the treatment of cervical spine dysfunction.\n Prospective, randomized, comparative clinical trial.\n Outpatient chiropractic clinic, Technikon Natal, South Africa.\n Thirty patients diagnosed with neck pain and restricted cervical spine range of motion without complicating pathosis for at least 1 month were included in the study.\n The patients were randomized into 2 groups. Those in one group received mechanical force, manually assisted (MFMA) manipulation to the cervical spine, delivered by means of a hand-held instrument (Activator II Adjusting Instrument). Those in the other group received specific contact high-velocity, low-amplitude (HVLA) manipulation consisting of standard Diversified rotary/lateral break techniques to the cervical spine. Each group received only the specific therapeutic intervention, no other treatment modalities or interventions (including medication) being used, until asymptomatic status was achieved or a maximum of 8 treatments had been received. Main Outcome Measures: Both treatment groups were assessed through use of subjective (Numerical Pain Rating Scale 101, McGill Short-Form Pain Questionnaire, and Neck Disability Index) and objective (goniometer cervical range of motion) measurement parameters at specific intervals during the treatment period and at 1-month follow-up. The data were assessed through use of 2-tailed nonparametric paired and unpaired analysis, descriptive statistics, and power analysis of the data.\n The results indicate that both treatment methods had a positive effect on the subjective and objective clinical outcome measures, no significant difference being observed between the 2 groups (P < .025). The subjective data from all 3 questionnaires showed statistically significant changes from initial to final consultations as well as from initial consultation to 1-month follow-up (P < .025). The objective range of motion measures showed statistically significant changes in the MFMA group for left and right rotation and left and right lateral flexion from initial consultation to final consultations and for right rotation and right lateral flexion from initial consultation to 1-month follow-up. The HVLA group showed only the change in left rotation from initial to final consultations and from initial consultation to 1-month follow-up to be statistically significant.\n The results of this clinical trial indicate that both instrumental (MFMA) manipulation and manual (HVLA) manipulation have beneficial effects associated with reducing pain and disability and improving cervical range of motion in this patient population. A randomized, controlled clinical trial in a similar patient base with a larger sample size is necessary to verify the clinical relevance of these findings.", "Benign paroxysmal positional vertigo (BPPV) is the most common cause of vertigo, resulting from migration of otoconia into the semicircular canals. Several treatment methods involving positioning maneuvers that return the otoconia to the utricle have been described. Following treatment, most patients are provided with a variety of activity restrictions. Previous studies suggest that, overall, BPPV treatment may be successful without these restrictions. The purpose of this study was to determine the necessity of postmaneuver restrictions using an experimental and control group with participants matched for age, gender, involved ear, and symptoms. A canalith repositioning maneuver was used to treat the BPPV. During postmaneuver instruction, the 21 participants assigned to the restricted group were provided with typical activity restrictions. Twenty-one participants assigned to the nonrestricted group were given no postmaneuver restrictions. Only one participant in the restricted group and two participants in the nonrestricted group were not clear at the one-week follow-up appointment. Results indicated that postmaneuver restrictions do not improve treatment efficacy." ]	There is evidence supporting a statistically significant effect of post-Epley postural restrictions in comparison to the Epley manoeuvre alone. However, it important to note that this statistically significant effect only highlights a small improvement in treatment efficacy. An Epley manoeuvre alone is effective in just under 80% of patients with typical BPPV. The additional intervention of postural restrictions has a number needed to treat (NNT) of 10. The addition of postural restrictions does not expose the majority of patients to risk of harm, does not pose a major inconvenience, and can be routinely discussed and advised. Specific patients who experience discomfort due to wearing a cervical collar and inconvenience in sleeping upright may be treated with the Epley manoeuvre alone and still expect to be cured in most instances. There is insufficient evidence to support the routine application of mastoid oscillation during the Epley manoeuvre, or additional steps in an 'augmented' Epley manoeuvre. Neither treatment is associated with adverse outcomes. Further studies should employ a rigorous randomisation technique, blinded outcome assessment, a post-treatment Dix-Hallpike test as an outcome measure and longer-term follow-up of patients.
CD006851	[ "17202945" ]	[ "Reactivation of herpes simplex virus type 1 and varicella-zoster virus and therapeutic effects of combination therapy with prednisolone and valacyclovir in patients with Bell's palsy." ]	[ "To determine whether reactivation of herpes simplex virus (HSV) type 1 or varicella-zoster virus (VZV) is the main cause of Bell's palsy and whether antiviral drugs bring about recovery from Bell's palsy.\n Randomized, multicenter, controlled study.\n One hundred fifty patients with Bell's palsy were enrolled in this study. The patients were randomly assigned to a prednisolone group or a prednisolone-valacyclovir group, in whom virologic examinations for HSV-1 and VZV were performed by simple randomization scheme in sealed envelopes. The recovery rates among various groups were analyzed using the Kaplan-Meier method and the Cox proportional hazards model.\n Reactivation of HSV-1, VZV, and both viruses was detected in 15.3%, 14.7%, and 4.0% of patients, respectively. There was no significant difference in recovery rates between the prednisolone group and the prednisolone-valacyclovir group, although recovery in the patients with HSV-1 reactivation tended to be higher in the prednisolone-valacyclovir group than in the prednisolone group. There was a significant difference in recovery among age groups and between individuals with complete and incomplete paralysis.\n Reactivation of HSV-1 or VZV was observed in 34% of the patients with Bell's palsy. The effect of combination therapy with prednisolone and valacyclovir on recovery was not significantly higher than that with prednisolone alone." ]	We found no evidence that anti-viral agents have a beneficial effect on outcomes in Ramsay Hunt syndrome, despite their widespread use in this condition. The use of these drugs in patients with herpes zoster infections in other parts of the body might suggest that they have a role in herpes zoster oticus. As usual, the absence of positive evidence of benefit (or, in this case, the 'negative' result of one small, statistically under-powered study) does not necessarily indicate that antivirals are ineffective. However, these drugs are associated with a number of adverse effects and this must be taken into consideration when undertaking the requisite risk-benefit analysis before instigating treatment.
CD009183	[ "19208440", "14702509", "15625351" ]	[ "Management of diabetic neuropathy by sodium valproate and glyceryl trinitrate spray: a prospective double-blind randomized placebo-controlled study.", "Sodium valproate for painful diabetic neuropathy: a randomized double-blind placebo-controlled study.", "Divalproex sodium in the management of post-herpetic neuralgia: a randomized double-blind placebo-controlled study." ]	[ "Combination of drugs with different mechanisms of action helps in achieving synergistic analgesic effect in neuropathic pain. Keeping this point in view, the effect and safety aspects of sodium valproate and GTN were assessed alone as well as in combination in this study.\n Prospective double-blind randomized placebo-controlled study.\n Eighty-seven type 2 diabetics with painful neuropathy were enrolled. Four were excluded: three with HbA1c>11 while one withdrew consent. The remaining 83 were given either sodium valproate and GTN spray (group A) or placebo drug and GTN spray (group B) or sodium valproate and placebo spray (group C) or placebo drug and placebo spray (group D). Quantitative assessment of pain was done by McGill pain questionnaire, visual analogue score (VAS) and present pain intensity (PPI) at the beginning of the study and after 3 months along with motor and sensory nerve conduction velocities measurements.\n All the three treatment groups experienced significant improvement in pain score in their drug phase of trial (p<0.001/<0.05) along with some of the electrophysiological parameters. The assessment of the magnitude of therapeutic effect of sodium valproate, GTN and their combination gave numbers needed to treat (NNT) of 7, 5 and 4, respectively.\n Sodium valproate and GTN are well tolerated and provide significant improvement in pain scores as well as in electrophysiological parameters.", "Various drugs are effective in the management of painful diabetic neuropathy, but none is completely satisfactory. We previously found sodium valproate to be effective and safe in a short-term study.\n To test the effectiveness and safety of sodium valproate in the management of painful diabetic neuropathy over 3 months.\n Randomized double-blind placebo-controlled study.\n Consecutive attending patients with type 2 diabetes mellitus with painful neuropathy were asked to participate in the trial: 48 agreed. Five were excluded: three with HbA(1c) > 11, one with too low a pain level and one who withdrew consent. The remaining 43 were given either drug (group A) or placebo (group B). Each patient was assessed clinically. Quantitative assessment of pain was done by McGill Pain Questionnaire, Visual Analogue Score and Present Pain Intensity, at the beginning of the study, after 1 month and after 3 months. Motor and sensory nerve conduction velocities were measured initially and after 3 months. Liver function tests and other adverse drug-related effects were assessed periodically.\n Of the 43 patients, four dropped out: one in group A and three in group B. There was significant improvement in pain score in group A, compared to group B, at 3 months (p < 0.001). Changes in electrophysiological data were not significant. The drug was well-tolerated by all patients, except one, who had raised serum AST and ALT levels after 1 month of treatment, and whose treatment was discontinued.\n Sodium valproate is well-tolerated, and provides significant subjective improvement in painful diabetic neuropathy.", "Post-herpetic neuralgia is difficult to treat. Divalproex sodium (valproic acid and sodium valproate in molar ratio 1:1) has been used successfully in the management of various painful neuropathies.\n To study the effectiveness and safety of divalproex sodium in the management of post-herpetic neuralgia.\n Randomized double-blind placebo-controlled trial.\n We enrolled 48 consecutively attending out-patients with post-herpetic neuralgia, out of whom three were excluded (two had insufficient pain, one withdrew consent). Quantification of pain was by Short Form-McGill pain questionnaire (SF-MPQ), visual analogue scale (VAS), present pain intensity score (PPI) and 11 point Likert scale (11 PLS) at the beginning of the study, after 2 weeks, 4 weeks and at the end of the study (8 weeks). We also assessed patients' global impression of change by questionnaire at the end of the study.\n After 8 weeks treatment with 1000 mg/day divalproex sodium, there was significant reduction in pain: SF-MPQ, 20.47 +/- 2.29 to 11.90 +/- 6.52 (p < 0.0001); PPI 4.0 +/- 0.52 to 1.95 +/- 1.29 (p < 0.0001); VAS 70.17 +/- 9.21 to 31.27 +/- 29.74 (p < 0.0001) and 11 PLS 6.97 +/- 0.73 to 3.63 +/- 2.34 (p < 0.0001) in comparison to placebo (means +/- SEM). The 'global impression of change' questionnaire showed much or moderate improvement in pain in 58.2% of patients receiving divalproex vs. 14.8% of those receiving placebo. The drug was well tolerated by all patients, except one who developed severe vertigo after 10 days of treatment.\n Divalproex sodium provides significant pain relief in patients of post-herpetic neuralgia, with very little incidence of adverse reactions. These data provide a basis for longer trials in a larger group of patients." ]	These three studies no more than hint that sodium valproate may reduce pain in diabetic neuropathy, and divalproex sodium in post-herpetic neuralgia, but the use of 'completer' analysis may overestimate efficacy, and there were too few data for pooled analysis of efficacy or harm, or to have confidence in the results of the individual studies. There is insufficient evidence to support the use of valproic acid or sodium valproate as a first-line treatment for neuropathic pain. There is more robust evidence of greater efficacy for a small number of other drugs.
CD007585	[ "9445122", "19070889" ]	[ "Effectiveness of radical systematic mediastinal lymphadenectomy in patients with resectable non-small cell lung cancer: results of a prospective randomized trial.", "Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study." ]	[ "To evaluate the effectiveness of lymphadenectomy in the treatment of non-small cell lung cancer (NSCLC).\n The extent of lymphadenectomy in the treatment of NSCLC is still a matter of controversy. Although some centers perform mediastinal lymph node sampling (LS) with resection of only suspicious lymph nodes, others recommend a radical, systematic mediastinal lymphadenectomy (LA) to improve survival and to achieve a better staging.\n In a controlled, prospective, randomized clinical trial, the effects of LA on recurrence rates and survival were analyzed, comparing LS and LA in 169 patients with operable NSCLC.\n After a median follow-up of 47 months, LA did not improve survival in the overall group of patients (hazard ratio: 0.78; 95% confidence interval: 0.47-1.24). Although recurrences rates tended to be reduced among patients who underwent LA, these decreases were not statistically significant (hazard ratio: 0.82; 95% confidence interval: 0.54-1.27). However, analysis of subgroups of patients according to histopathologic lymph node staging revealed that LA appears to prolong relapse-free survival (p = 0.037) with a borderline effect on overall survival (p = 0.058) in patients with limited lymph node involvement (pN1 disease or pN2 disease with involvement of only one lymph node level); in patients with pN0 disease, no survival benefit was observed.\n Radical systematic mediastinal lymphadenectomy does not influence disease-free or overall survival in patients with NSCLC and without overt lymph node involvement. However, a small subgroup of patients with limited mediastinal lymph node metastases might benefit from a systematic lymphadenectomy.", "Hysterectomy and bilateral salpingo-oophorectomy (BSO) is the standard surgery for stage I endometrial cancer. Systematic pelvic lymphadenectomy has been used to establish whether there is extra-uterine disease and as a therapeutic procedure; however, randomised trials need to be done to assess therapeutic efficacy. The ASTEC surgical trial investigated whether pelvic lymphadenectomy could improve survival of women with endometrial cancer.\n From 85 centres in four countries, 1408 women with histologically proven endometrial carcinoma thought preoperatively to be confined to the corpus were randomly allocated by a minimisation method to standard surgery (hysterectomy and BSO, peritoneal washings, and palpation of para-aortic nodes; n=704) or standard surgery plus lymphadenectomy (n=704). The primary outcome measure was overall survival. To control for postsurgical treatment, women with early-stage disease at intermediate or high risk of recurrence were randomised (independent of lymph-node status) into the ASTEC radiotherapy trial. Analysis was by intention to treat. This study is registered, number ISRCTN 16571884.\n After a median follow-up of 37 months (IQR 24-58), 191 women (88 standard surgery group, 103 lymphadenectomy group) had died, with a hazard ratio (HR) of 1.16 (95% CI 0.87-1.54; p=0.31) in favour of standard surgery and an absolute difference in 5-year overall survival of 1% (95% CI -4 to 6). 251 women died or had recurrent disease (107 standard surgery group, 144 lymphadenectomy group), with an HR of 1.35 (1.06-1.73; p=0.017) in favour of standard surgery and an absolute difference in 5-year recurrence-free survival of 6% (1-12). With adjustment for baseline characteristics and pathology details, the HR for overall survival was 1.04 (0.74-1.45; p=0.83) and for recurrence-free survival was 1.25 (0.93-1.66; p=0.14).\n Our results show no evidence of benefit in terms of overall or recurrence-free survival for pelvic lymphadenectomy in women with early endometrial cancer. Pelvic lymphadenectomy cannot be recommended as routine procedure for therapeutic purposes outside of clinical trials." ]	We found no evidence that lymphadenectomy decreases the risk of death or disease recurrence compared with no lymphadenectomy in women with presumed stage I disease. The evidence on serious adverse events suggests that women who receive lymphadenectomy are more likely to experience surgically related systemic morbidity or lymphoedema/lymphocyst formation.
CD003807	[ "6304203", "3548626", "2184513", "2191444", "3056555", "15177489", "9462438", "17912104", "2200826", "1567268", "7543781", "3664330", "8097273", "10397206", "8070443", "14752071", "7636666", "18485252", "18627504", "2919059", "8645677", "12447512", "2037541", "12072669", "2564563" ]	[ "Ketoconazole and candidiasis: a controlled study.", "Ketoconazole in the prevention of candidiasis in patients with cancer. A prospective, randomized, controlled, double-blind study.", "Therapy for oropharyngeal candidiasis in the immunocompromised host: a randomized double-blind study of fluconazole vs. ketoconazole.", "Prophylaxis of candidiasis in cancer patients.", "Control of oral mucositis and candidiasis in marrow transplantation: a prospective, double-blind trial of chlorhexidine digluconate oral rinse.", "An open multicentre comparative study of the efficacy, safety and tolerance of fluconazole and itraconazole in the treatment of cancer patients with oropharyngeal candidiasis.", "Fluconazole versus nystatin in the prevention of candida infections in children and adolescents undergoing remission induction or consolidation chemotherapy for cancer.", "Controlled study of lactoperoxidase gel on oral flora and saliva in irradiated patients with oral cancer.", "Once-weekly fluconazole to prevent recurrence of oropharyngeal candidiasis in patients with AIDS and AIDS-related complex: a double-blind placebo-controlled study.", "Gentian violet, ketoconazole and nystatin in oropharyngeal and esophageal candidiasis in Zairian AIDS patients.", "Effect of granulocyte colony-stimulating factor (G-CSF) on chemotherapy-induced oral mucositis.", "A randomized trial comparing ketoconazole and nystatin prophylactic therapy in neutropenic patients.", "Fluconazole once a week as secondary prophylaxis against oropharyngeal candidiasis in HIV-infected patients. A double-blind placebo-controlled study.", "Fluconazole prophylaxis prevents intra-abdominal candidiasis in high-risk surgical patients.", "Fluconazole versus ketoconazole in the treatment of oropharyngeal candidiasis in HIV-infected children. Multicentre Study Group.", "Efficacy of oral adjuvant therapy after resection of colorectal cancer: 5-year results from three randomized trials.", "Oropharyngeal candidiasis in immunocompromised children: a randomized, multicenter study of orally administered fluconazole suspension versus nystatin. The Multicenter Fluconazole Study Group.", "Honey as topical prophylaxis against radiochemotherapy-induced mucositis in head and neck cancer.", "A randomized clinical trial of chlorhexidine in the maintenance of oral candidiasis-free period in HIV infection.", "Effect of chlorhexidine rinsing on the oropharyngeal ecology in patients with head and neck cancer who have irradiation mucositis.", "A comparative study of the efficacy of fluconazole and amphotericin B in the treatment of oropharyngeal candidosis in patients undergoing radiotherapy for head and neck tumours.", "Prevention of severe Candida infections in nonneutropenic, high-risk, critically ill patients: a randomized, double-blind, placebo-controlled trial in patients treated by selective digestive decontamination.", "A randomized study to compare oral fluconazole to amphotericin B in the prevention of fungal infections in patients with acute leukaemia.", "Selective decontamination of the digestive tract to prevent postoperative infection: a randomized placebo-controlled trial in liver transplant patients.", "Comparison of fluconazole and ketoconazole for oropharyngeal candidiasis in AIDS." ]	[ "A double-blind, placebo-controlled study was undertaken to determine the efficacy of ketoconazole in the treatment of candidiasis. The drug was administered orally in the dosage of 200 mg/m2 of body surface per day for two weeks to cancer patients with oral candidiasis. Randomization in a 2:1 ratio provided 36 patients treated with ketoconazole and 20 managed with a placebo. Regression of visible lesions was achieved in 26 (72%) of 36 ketoconazole-treated and four (20%) of 20 untreated patients; eradication of culturable organisms occurred in 12 (36%) of 33 ketoconazole-treated and one (7%) of 14 untreated patients; and resolution of lesions plus eradication of Candida albicans occurred in nine (25%) of 36 ketoconazole-treated and one (5%) of 20 untreated patients. Although the therapeutic efficacy of ketoconazole was demonstrated for oropharyngeal candidiasis, the magnitude of its efficacy was less than that desired.", "A prospective, randomized, controlled, double-blind study was performed between 1982 and 1985 to assess the ability of ketoconazole to prevent fungal infections in selected patients with cancer. Fifty-six patients receiving induction chemotherapy for acute leukemia, autologous bone marrow transplant for refractory nonhematopoietic malignant neoplasms, multidrug chemotherapy for malignant lymphoma, or corticosteroids for brain metastases were randomized to receive either oral ketoconazole, 400 mg/d, or placebo and observed until leukopenia resolved or corticosteroid therapy was stopped. Oral candidiasis developed in eight (28%) of 29 patients receiving placebo compared with none of 27 receiving ketoconazole. However, ketoconazole failed to prevent Candida esophagitis and vulvovaginitis in two patients and one patient, respectively. Furthermore, prophylactic use of ketoconazole did not significantly alter the total number of hospital days, febrile days, or antibiotic days or the requirement for amphotericin B in patients with acute leukemia and autologous bone marrow transplant. Since oral candidiasis can be successfully managed by several different treatment modalities when it does occur, we do not think that the routine prophylactic use of ketoconazole is justified.", "Optimal therapy for oropharyngeal candidiasis, a common infection in immunocompromised patients, has yet to be clearly defined. Topical therapy is usually poorly tolerated; ketoconazole is effective but absorption is highly variable. New antifungal agents have been developed to increase the therapeutic options. Fluconazole is active against yeasts, is available in both oral and intravenous formulations, and has a pharmacokinetic profile different from that of ketoconazole. This randomized double-blind study evaluates systemic antifungal therapy with fluconazole (100 mg daily) or ketoconazole (400-mg daily) for oropharyngeal candidiasis in patients with cancer. Clinical cure was observed in 15 of 19 and 14 of 18 patients treated with fluconazole and ketoconazole, respectively. Eradication of pathogenic yeasts ws documented for 10 patients in both groups. The rates of relapse were similar, but relapse occurred earlier in patients in the ketoconazole group. Overall, this study demonstrates the value of a dosage of 100 mg of fluconazole or of 400 mg of ketoconazole daily for the management of oropharyngeal candidiasis in patients with cancer.", "Patients undergoing therapy for metastatic malignancies were randomly assigned to receive fluconazole or placebo as antifungal prophylaxis. Oropharyngeal candidiasis developed in 28% of 54 evaluable patients receiving placebo but in only 2% of 58 evaluable patients receiving fluconazole (P = .0003). Among patients receiving placebo, oropharyngeal candidiasis (thrush) occurred in 30% of those receiving antibiotic therapy and in 44% of those receiving adrenal corticosteroid therapy. Oropharyngeal candidiasis developed in 54% of the placebo patients who were colonized by Candida sp at the onset of prophylaxis. Fluconazole proved to be effective for prophylaxis of oropharyngeal candidiasis in susceptible patients and was well tolerated.", "Conditioning chemoradiotherapy damages the mucosal barrier of the mouth and throat and often produces severe oral inflammation and infection. In a prospective, double-blind, randomized study, we examined the use of a chlorhexidine digluconate mouthrinse for prophylaxis against oral mucosal complications in 51 bone marrow transplant patients. Use of chlorhexidine mouthrinse produced significant reductions in the incidence and severity of oral mucositis. Mucositis also resolved more quickly in patients receiving chlorhexidine. Concomitant reductions in total oral streptococci (p less than 0.02-p less than 0.001) and oral candida (p less than 0.004) were seen in patients using chlorhexidine. Persistent clinical oral candidiasis (thrush) was observed in 15 to 27 control group patients (56%), but only transiently in two (8%) of 24 patients who used chlorhexidine rinse (p less than 0.001). Five of 27 control group patients (19%) had candidemia, while no candidemia was observed in the chlorhexidine group (p less than 0.03). Three deaths from disseminated candidiasis occurred in the placebo group; none occurred in patients who received chlorhexidine. Prophylactic use of chlorhexidine mouthrinse produces reductions in oral soft tissue disease and oral microbial burden in patients undergoing bone marrow transplantation. The reductions in mucositis and in oral candida infections observed with prophylactic chlorhexidine mouthrinse represent a significant advantage for patients undergoing marrow transplantation.", "Oropharyngeal candidiasis is a frequent infection in cancer patients who receive cytotoxic drugs. In this study, the efficacy, safety and tolerance of fluconazole and itraconazole were compared in non-neutropenic cancer patients with oropharyngeal candidiasis. Of 279 patients who were randomised between the two treatment groups, 252 patients were considered to be eligible (126 in each group). The clinical cure rate was 74% for fluconazole and 62% for itraconazole (P=0.04, 95% Confidence Interval (CI): 0.5-23.3%). The mycological cure rate was 80% for fluconazole and 68% for itraconazole (P=0.03, 95% CI: 1.2-22.6%). The safety and tolerance profile of both drugs were comparable. This study has shown that in patients with cancer and oropharyngeal candidiasis, fluconazole has a significantly better clinical and mycological cure rate compared with itraconazole.", "An open, prospective, randomized pilot study was performed to assess the efficacy and safety of oral fluconazole 3 mg/kg once daily compared with oral nystatin 50,000 units/kg/day in four divided doses in preventing candida infections in 50 children undergoing remission induction or consolidation therapy for cancer. In 21 of 25 fluconazole-treated and 20 of 25 nystatin-treated patients the overall outcome of prophylaxis was clearly successful. Mild and transient oropharyngeal candidosis was observed in two and three patients in the fluconazole and nystatin groups respectively. One patient randomized to fluconazole and two patients randomized to nystatin required empirical treatment with amphotericin B and one patient assigned to fluconazole developed tissue-proven candida colitis. Initially non-colonized patients remained yeast-free throughout treatment with no differences between the two study arms. Initially colonized patients stayed colonized throughout treatment although at the end of the study, more patients randomized to nystatin were still harbouring yeasts (P = 0.05). Almost exclusively, Candida albicans (95%) was isolated. A change in species was observed in one patient in each arm of the study. Candida krusei or Candida glabrata were not encountered. Transient elevations of hepatic transaminases were more common in the fluconazole group, although not statistically significant (28% vs 12%, P = 0.15). Reversible grade I gastrointestinal and skin symptoms were observed in four patients randomized to fluconazole (16 vs 0%, P < 0.05). Fluconazole was as safe and effective as nystatin in controlling yeast colonization and in preventing superficial and invasive candida infections and the empirical use of amphotericin B in children and adolescents undergoing intensive chemotherapy for cancer.", "The aim of this study was to determine if radiotherapy induces hyposalivation altering oral microbial flora. The purpose of this placebo-controlled, single-blind study was to determine beneficial effects of a saliva substitute and an oral hygiene product on irradiated patients with oropharyngeal cancer. Eighteen patients were assigned to the test group (Biotène Oral Balance gel [Lacléde Incorporated Healthcare Products, Gardena, CA] and toothpaste used daily), and another 18 were put on a conventional daily regimen (carboxymethylcellulose gel and Oral-B toothpaste [Laclede Pharmaceuticals, Gardena, CA]). Cultures for identifying and quantitating microorganisms, whole unstimulated saliva, and visual analog measurements for comfort were obtained before mucositis occurred and after treatment. Daily use of Biotène products enhanced control of microbial flora, improved salivary flow, and increased oral comfort as compared with control subjects. Four weeks after mucositis, some aerobic isolates disappeared in the test group; periodontal-associated bacteria were markedly decreased in the test group; and candidal species were significantly lowered in the test group. Although baseline saliva was lower in the test group (P = 0.001), after 4 weeks, no difference between groups existed; comfort was greater in the test group (P = 0.007). Use of enzyme-engineered Biotène products that assist in control of the oral microbial flora as well as supporting oral comfort through lubrication appear to be useful aids for irradiated patients with oropharyngeal cancer.", "Fluconazole 50 mg daily for 14-28 days was effective in the treatment of patients with AIDS and AIDS-related complex with severe oropharyngeal and oesophageal candidiasis. Of 24 patients entered, 17 (81%), including seven with oesophageal candidiasis, were clinically cured and two (9.5%) improved at the end of treatment. Following clinical cure, 14 patients were entered into the double-blind phase of the study, where fluconazole (150 mg) or placebo capsules were given once weekly. Treatment was double blind. Fluconazole 150 mg once weekly was found to be effective in maintaining patients both clinically and mycologically free of oropharyngeal candidiasis.", "A randomized un-blinded study on the treatment of oropharyngeal and esophageal candidiasis was conducted in Kinshasa (Zaire), among 141 inpatients with AIDS and oropharyngeal candidiasis, of whom 136 also had esophageal candidiasis. The study compared the efficacy of gentian violet mouth washes (1.5 ml 0.5% aqueous solution b.i.d.), oral ketoconazole (200 mg/day, after a meal) and nystatin mouth washes (200.000 U oral suspension q.i.d.). Patients treated with mouth washes swallowed their medication after mouth washing. Patients enrolled in this study had a very high mortality (probability of death: 41.6% after 14 days). After 14 days, 72 patients could be evaluated. At that time, oropharyngeal lesions had disappeared in similar proportions of patients treated with gentian violet (11/26, 42%) and ketoconazole (10/23, 43%), and in a lower proportion of patients treated with nystatin (2/23, 9%; p less than 0.05). In esophageal candidiasis, ketoconazole seemed more efficient than both other treatments: esophageal lesions had disappeared in 5 (24%) of the 21 patients on ketoconazole, compared to less than 10% of patients on both other treatments (p = 0.07). The suboptimal results observed with all 3 treatments could be explained by the profound immunosuppression of patients enrolled in the study. This study suggests that gentian violet is effective treatment for oropharyngeal candidiasis. As it is very cheap (0.5 US$/treatment course in Kinshasa), we suggest that its use should be assessed in larger studies.", "In this study, the ability of granulocyte colony-stimulating factor (G-CSF) to treat or prevent chemotherapy-induced oral mucositis in patients with advanced breast cancer was evaluated. A total of 14 patients who received intraarterial (i.a.) adriamycin (ADM) preoperatively were divided into two groups according to whether or not G-CSF was given. Thus, group A (n = 7) was given G-CSF and group B (n = 7) was not. G-CSF therapy reduced both the incidence and duration of ADM-induced oral mucositis, and a positive correlation was also seen between the incidence of mucositis and ADM-induced leukopenia (< 2,000/mm3). Group A was further divided into two subgroups according to whether G-CSF was given after or before the leukopenia had dropped below 2,000/mm3: group A-1 (n = 3) and group A-2 (n = 4), respectively. ADM-induced mucositis was observed in two of the three patients in group A-1, but in none of the four patients in group A-2. These results strongly support the idea that G-CSF can effectively treat and prevent ADM-induced oral mucositis.", "A randomized trial was conducted comparing ketoconazole and nystatin in the prevention of oral candidiasis and appearance of invasive fungal infections in 51 neutropenic leukemic patients undergoing induction chemotherapy. Ketoconazole was administered in a 200 mg dose twice daily. Nystatin oral suspension was given in doses of 500,000 units four times daily. Surveillance cultures of the throat and urine were obtained prior to treatment and conducted weekly. Patients were enrolled in the study if the absolute granulocyte count was less than 1500/microliter, if physical examination revealed no evidence of oral candidiasis, no evidence of urinary tract infection, and there was no pulmonary infiltrate on chest x-ray. Patients were continued on study until the absolute granulocyte count reached 1500/microliter, evidence of oral candidiasis appeared, or presumed or proven invasive fungal infections appeared. Of the 46 evaluable patients, 22 received ketoconazole, 3 (14%) developed oral candidiasis, and 5 developed suspected systemic fungal infections (23%). Of 24 patients who received nystatin, 4 (17%) developed oral candidiasis and 8 (33%) developed systemic fungal infections, 4 proven and 4 suspected. Significantly more patients on the nystatin arm progressed to invasive fungal infections. Ketoconazole was not superior to nystatin in reducing the frequency of oral candidiasis but possibly reduced the frequency of invasive fungal infections.", "To assess the efficacy and tolerance of fluconazole (150 mg oral dose, once a week) in the prevention of recurrent oropharyngeal candidiasis in patients with moderate to severe human immunodeficiency virus (HIV) infection.\n A randomised, double-blind, placebo-controlled trial.\n Eighty-four patients with moderate to severe HIV infection who had successfully completed two to four weeks treatment with fluconazole for oropharyngeal candidiasis were randomly allocated to receive either placebo or fluconazole. Pre-treatment clinical and laboratory characteristics were similar in the two groups.\n Success was classified as absence throughout the course of treatment of clinical evidence of oropharyngeal candidiasis, and failure as recurrence or relapse of symptomatic oropharyngeal candidiasis.\n Of 73 evaluable patients the median time to relapse was > or = 168 days in the fluconazole group and 37 days in the placebo group (P < 0.0001). One patient in the placebo group and 18 patients in the fluconazole group completed six months' treatment without clinical relapse (P < 0.001).\n Fluconazole was well tolerated and prevented clinical relapse of oropharyngeal candidiasis in 71% of patients who completed three months of treatment (95% confidence interval [CI], 55-86) and 58% (95% CI, 41-75) who completed six months of treatment.", "To evaluate the efficacy and safety of intravenous fluconazole for the prevention of intra-abdominal Candida infections in high-risk surgical patients.\n Randomized, prospective, double-blind, placebo-controlled study.\n Two university-affiliated hospitals in Switzerland.\n Forty-nine surgical patients with recurrent gastrointestinal perforations or anastomotic leakages.\n Prophylaxis with intravenous fluconazole (400 mg per day) or placebo continued until resolution of the underlying surgical condition.\n Patients were evaluated daily, and specimens for culture were obtained three times per week during prophylaxis. The primary study end points were the frequency of and the time to intra-abdominal Candida infections. Secondary end points were the frequency of candidiasis (intra-abdominal and extra-abdominal) and the emergence or persistence of Candida colonization. Among patients who were not colonized at study entry, Candida was isolated from surveillance cultures during prophylaxis in 15% of the patients in the fluconazole group and in 62% of the patients in the placebo group (relative risk, 0.25; 95% confidence interval, 0.07 to 0.96; p = .04). Candida peritonitis occurred in one of 23 patients (4%) who received fluconazole and in seven of 20 patients (35%) who received placebo (relative risk, 0.12; 95% confidence interval, 0.02 to 0.93; p = .02). In addition, one catheter-related Candida albicans sepsis occurred in a fluconazole-treated patient. Thus, overall, candidiasis developed in two fluconazole patients and seven placebo patients (relative risk, 0.25; 95% confidence interval, 0.06 to 1.06; p = .06). C. albicans accounted for 87% of the Candida species isolated before or during prophylaxis, and all C. albicans strains were susceptible to fluconazole. Fluconazole was well tolerated, and adverse events occurred at similar frequencies in both treatment groups.\n Fluconazole prophylaxis prevents colonization and invasive intra-abdominal Candida infections in high-risk surgical patients.", "In an open multicentre study the efficacy and safety of fluconazole versus ketoconazole were evaluated in the treatment of 46 pediatric patients with oropharyngeal candidiasis and AIDS or HIV infection. Twenty-four subjects received oral fluconazole in a dosage of 3 mg/kg/day and 22 subjects received oral ketoconazole in a dosage of 7 mg/kg/day. The treatment duration ranged from 5 to 49 days. Results showed that fluconazole and ketoconazole have comparable efficacy and safety in the treatment of oropharyngeal candidiasis in HIV-infected children. Patients treated with fluconazole had higher clinical and mycological cure rates at the end of therapy (88% and 71% respectively) than those treated with ketoconazole (81% and 57% respectively). One case of drug-related side effects (diarrhea and abdominal pain) in a patient receiving ketoconazole resulted in discontinuation of treatment. Follow-up examinations 2 and 4 weeks post-treatment showed a comparably high rate of relapse in both patient groups.", "Adjuvant therapy of colorectal cancer with oral fluorinated pyrimidines is attractive because of its ease of administration and good tolerability. The purpose of this meta-analysis is to assess the survival and disease-free survival benefits of treating patients after surgical resection of a primary colorectal tumor with oral fluoropyrimidines for 1 year.\n This meta-analysis was performed on individual data from three randomized trials conducted by the Japanese Foundation for Multidisciplinary Treatment for Cancer involving a total of 5,233 patients with stages I to III colorectal cancer.\n The overall hazard ratio in favor of oral therapy was 0.89 for survival (95% CI, 0.80 to 0.99; P =.04), and 0.85 for disease-free survival (95% CI, 0.77 to 0.93; P <.001). Thus oral therapy reduced the risk of death by 11% and the risk of recurrence or death by 15%. There was no significant heterogeneity between trials, nor did the benefit of oral therapy depend on tumor stage (I, II, or III), tumor site (rectum or colon), patient age, or patient sex.\n Oral fluoropyrimidines improve disease-free survival and survival of patients after resection of early-stage colorectal cancer. These observations support the use of these agents alone after resection of early-stage disease, as well as further testing of oral agents in combination with new drugs that have recently shown antitumor activity in advanced colorectal cancer.", "To compare the efficacy, safety, and tolerance of fluconazole suspension versus nystatin in the treatment of oropharyngeal thrush in immunocompromised children.\n Multicenter, randomized, observer-masked trial.\n Thirty-two centers participated, including hospitals and ambulatory care clinics.\n We enrolled 182 immunocompromised infants and children, ages 5 months to 14 years, with signs of oral thrush and presence of yeasts on potassium hydroxide- or gram-stained preparations. Subjects were randomly assigned to receive a single daily dose of fluconazole suspension, 2 to 3 mg/kg per day, or nystatin, 400,000 units four times daily for 14 days; 159 patients, who had culture confirmation of thrush and received at least 7 days of study drug, were evaluated for efficacy; all patients were evaluated for safety.\n Clinical cure was demonstrated in 91% of the subjects in the fluconazole group and 51% of the subjects in the nystatin group (p < 0.001), and eradication of the organism cultured at entry occurred in 76% and 11% (p < 0.001), respectively. Gastrointestinal conditions developed in six patients who received fluconazole and in three who received nystatin; two fluconazole recipients were subsequently withdrawn from the study. Laboratory abnormalities occurred with equal frequency in both groups. Clinical relapse rates were similar in both groups at 2 weeks (18% and 24% for fluconazole and nystatin, respectively) and 1 month (28% and 27%, respectively) after the completion of study drug.\n Fluconazole suspension is more effective than nystatin in the treatment of thrush in immunocompromised children. Both regimens were well tolerated.", "To evaluate the efficacy of pure natural honey as prophylaxis against radiochemotherapy-induced mucositis, through clinical scoring of oral and oropharyngeal mucositis, and culturing of pathogenic oral and oropharyngeal microbes.\n The study was done in Assiut University Hospital, Egypt, between January 2005 and July 2006. Forty patients diagnosed with head and neck cancer were entered into the trial. Enrolled patients were randomised to either the treatment group, receiving concomitant chemotherapy and radiotherapy (with a significant area of directly visible oral and/or oropharyngeal mucosa included in the radiation fields) plus prior topical application of pure natural honey, or the control group, receiving concomitant chemotherapy and radiotherapy without honey. Patients were evaluated clinically every week to assess development of radiation mucositis. Aerobic cultures and candida colonisation assessment were undertaken, via oral and oropharyngeal swabs, prior to and at the completion of irradiation, and when infection was evident.\n In the treatment group, no patients developed grade four mucositis and only three patients (15 per cent) developed grade three mucositis. In the control group, 13 patients (65 per cent) developed grade three or four mucositis (p < 0.05). Candida colonisation was found in 15 per cent of the treatment group and 60 per cent of the control group, either during or after radiotherapy (p = 0.003). Positive cultures for aerobic pathogenic bacteria were observed in 15 per cent of the treatment group and 65 per cent of the control group, during or after radiotherapy (p = 0.007).\n This study shows that prophylactic use of pure natural honey was effective in reducing mucositis resulting from radiochemotherapy in patients with head and neck cancer.", "To determine if chlorhexidine can be used as an intervention to prolong the time to relapse of oral candidiasis.\n A double-blinded randomized clinical trial was performed in 75 HIV/AIDS subjects with oral candidiasis. Clotrimazole troche was prescribed, and the subjects were re-examined every 2 weeks until the lesions were completely eradicated. The subjects were then randomly divided into two groups; 0.12% chlorhexidine (n = 37, aged 22-52 years, mean 34 years) and 0.9% normal saline (n = 38, aged 22-55 years, mean 38 years). They were re-examined every 2 weeks until the next episode was observed.\n The time to recurrence of oral candidiasis between the chlorhexidine and the saline group was not statistically significant (P > 0.05). The following variables were significantly associated with the time of recurrence; frequency of antifungal therapy (P = 0.011), total lymphocyte (P = 0.017), alcohol consumption (P = 0.043), and candidiasis on gingiva (P = 0.048). The subjects with lower lymphocyte showed shorter oral candidiasis-free periods (P = 0.034).\n Chlorhexidine showed a small but not statistically significant effect in maintenance of oral candidiasis-free period. This lack of significance may be due to the small sample size. Further study should be performed to better assess the size of the effect, or to confirm our findings.", "Oral flora is thought to contribute to irradiation mucositis in patients with head and neck cancer. Neglect of oral hygienic care may also contribute to mucositis. The purpose of this prospective, randomized, placebo-controlled, double-blind study was to evaluate the effect of chlorhexidine 0.1% mouthrinses on oral flora and irradiation mucositis. This study included 30 patients with head and neck cancer who had comparable irradiation portals. One group (N = 15) rinsed four times daily with chlorhexidine 0.1%, the other group (N = 15) with a placebo. The oral flora was cultured (oral washing technique) twice before and three times per week during the period of radiotherapy. On the same days, the severity of mucositis was determined. The colonization index of viridans streptococci was significantly reduced only after 5 weeks of chlorhexidine 0.1% treatment. The colonization patterns of Candida species, Streptococcus faecalis, staphylococci, and Enterobacteriaceae, Pseudomonadaceae, and Acinetobacter species were not influenced by 5 weeks of use of chlorhexidine rinses when compared with the placebo. No differences were seen between the two study groups in the development and severity of mucositis. In conclusion, suppression of oral flora and a lowering of the severity of mucositis by means of disinfecting mouthrinses were not successful.", "Radiotherapy given during treatment of oral and pharyngeal malignancy is frequently associated with colonization of the oral mucosa by Candida species. Treatment of these infections has included topical and systemic agents. In the present study 73 patients with oropharyngeal candidosis were treated with either amphotericin B (10 mg lozenges, four times daily for 14 days, 36 patients) or fluconazole (50 mg daily for 7 days, 37 patients). The yeasts most frequently isolated were C albicans and C glabrata. Clinical signs and symptoms showed improvement at end of treatment in 72% of patients who received amphotericin B compared with 92% of patients who received fluconazole. Mycological cure at end of treatment was achieved in 31% of the amphotericin B group and 46% of patients who received fluconazole. For both treatments the cure rate was less in denture wearers than in non denture wearers.", "Infections caused by Candida spp. are a major cause of morbidity and mortality in critically ill patients and usually develop from endogenous colonization. We assessed the effectiveness of adding fluconazole to a selective digestive decontamination regimen to prevent candidal infections.\n We performed a prospective, randomized, double-blind, placebo-controlled trial among medical and surgical intensive care unit patients at a large university hospital.\n All adult patients mechanically ventilated for at least 48 h with an expectation to remain so for at least an additional 72 h, and receiving selective decontamination of the digestive tract.\n Patients were randomly assigned fluconazole 100 mg daily (n=103) or placebo (n=101).\n Candida infections occurred less frequently in the fluconazole group (5.8%) than in the placebo group (16%; rate ratio 0.35; Cl(95) 0.11-0.94). Some 90% of candidemia episodes occurred in the placebo group (rate ratio for fluconazole use 0.10; Cl(95) 0.02-0.74). The rate of treatment failure, development of candidal infection, or increased colonization, was 32% in the fluconazole group and 67% in the placebo group (P<0.001). Crude in-hospital mortality was similar in the two groups (39% fluconazole vs. 41% placebo).\n Prophylactic use of fluconazole in a selected group of mechanically ventilated patients at high risk for infection reduces the incidence of Candida infections, in particular candidemia.", "In a prospective randomized study the efficacy of fluconazole (50 mg in one single daily dose) was compared with oral amphotericin B in suspension and tablets (each 200 mg four times daily) for prevention of colonization and subsequent infection by yeasts in 50 patients undergoing remission induction treatment for acute leukaemia. All patients received ciprofloxacin for prevention of bacterial infections. Fluconazole was as effective as amphotericin B in preventing severe local and disseminated fungal disease (one documented and one highly suspected infection in each group of patients). Fluconazole effectively prevented yeast colonization of the oropharynx but was less effective than amphotericin B in preventing colonization of the lower alimentary tract. Fifty-two percent of patients receiving fluconazole had persistent positive stool cultures as compared to 4% in the amphotericin B group (P less than 0.01). Fluconazole was better tolerated than amphotericin B. One patient developed an extended rash leading to the termination of fluconazole.", "To determine the efficacy of selective decontamination of the digestive tract (SDD) in patients undergoing elective transplantation of the liver.\n Randomized, double-blind, placebo-controlled study.\n Two academic teaching hospitals.\n Adult patients undergoing elective liver transplantation: 26 patients receiving SDD and 29 patients receiving a placebo.\n Patients undergoing SDD were administered 400 mg of norfloxacin once daily as soon as they were accepted for transplantation. Postoperative treatment for this group consisted of 2 mg of colistin, 1.8 mg of tobramycin, and 10 mg of amphotericin B, four times daily, combined with an oral paste containing a 2% solution of the same drugs until postoperative day 30. Prophylactic intravenous administration of antibiotics was not part of the SDD regimen in this study. Control patients were given a similar regimen with placebo drugs.\n The mean number of postoperative bacterial and fungal infections in the first 30 days after transplantation was the primary efficacy end point. Days on a ventilator, days spent in the intensive care unit, and medical costs were registered as secondary outcome variables.\n Of the 26 patients undergoing SDD, 22 (84.5%) developed an infection in the postoperative study period; in the placebo group (n = 29), these numbers were not significantly different (25 patients, 86%). The mean number of postoperative infectious episodes per patient was also not significantly different: 1.77 (SDD) vs. 1.93 (placebo). Infections involving Gram-negative aerobic bacteria and Candida species were significantly less frequent in patients receiving SDD (p <.001 and p <.05). Total costs were higher in the group receiving SDD.\n Selective decontamination of the digestive tract does not prevent infection in patients undergoing elective liver transplantation and increases the cost of their care. It does, however, affect the type of infection. Infections with Gram-negative bacilli and with Candida species are replaced by infections with Gram-positive cocci.", "In a randomised, double-blind study the efficacy and toxicity of oral fluconazole 50 mg daily and ketoconazole 200 mg daily were compared for the treatment of oropharyngeal candidiasis in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex (ARC). 20 episodes (18 patients) were treated with fluconazole and 20 episodes (19 patients) with ketoconazole. Pretreatment clinical features and laboratory test results were similar in both groups. 17 episodes (85%) in the fluconazole group and 16 (80%) in the ketoconazole group could be evaluated. There was clinical cure at the end of therapy in all fluconazole-treated and 12 of 16 (75%) ketoconazole-treated episodes. Cultures were negative at the end of therapy in 87% of the fluconazole group and 69% of the ketoconazole group. 1 patients stopped taking fluconazole because of severe nausea. 1 of 18 fluconazole-treated and 4 of 19 ketoconazole-treated patients had transient rises in alanine or aspartate aminotransferase. Fluconazole seemed more effective than ketoconazole in the treatment of oral thrush among AIDS and ARC patients." ]	There is strong evidence, from randomised controlled trials, that drugs absorbed or partially absorbed from the GI tract prevent oral candidiasis in patients receiving treatment for cancer. There is also evidence that these drugs are significantly better at preventing oral candidiasis than drugs not absorbed from the GI tract.
CD007571	[ "17234558" ]	[ "Effect of once- or twice-daily MMX mesalamine (SPD476) for the induction of remission of mild to moderately active ulcerative colitis." ]	[ "SPD476 (MMX mesalamine), a novel, once-daily mesalamine formulation, uses MMX Multi Matrix System (MMX) technology to delay and extend delivery of active drug throughout the colon. We performed a randomized, double-blind, parallel-group, placebo-controlled, multicenter phase III study in patients with mild to moderately active ulcerative colitis.\n Two hundred eighty patients with mild to moderately active ulcerative colitis received MMX mesalamine 2.4 g/day given twice daily (n = 93), 4.8 g/day given once daily (n = 94), or placebo (n = 93) for 8 weeks. The primary end point was the percentage of patients in clinical and endoscopic remission (modified ulcerative colitis disease activity index score of < or =1, with a score of 0 for rectal bleeding and stool frequency, and at least a 1-point reduction in sigmoidoscopy score) at week 8. Patients with mucosal friability were not considered to have achieved this end point.\n Clinical and endoscopic remission at week 8 was achieved by 34.1% and 29.2% of patients receiving MMX mesalamine 2.4 g/day given twice daily and MMX mesalamine 4.8 g/day given once daily, respectively, versus 12.9% receiving placebo (P < .01). MMX mesalamine was generally well-tolerated.\n MMX mesalamine given once or twice daily is well-tolerated and, compared with placebo, demonstrated efficacy for the induction of clinical and endoscopic remission in mild to moderately active ulcerative colitis." ]	Data from one trial suggests that MLN-02 may be effective for induction of clinical response and remission in patients with moderately severe ulcerative colitis. Adverse events appear to be similar to placebo, although immunogenicity may be an issue. Further trials are needed to confirm the results of this study and to define the optimal dose and frequency of administration of MLN-02.
CD003430	[ "9162305", "7730878", "7473832", "9162304", "11522565" ]	[ "The polyp prevention trial II: dietary intervention program and participant baseline dietary characteristics.", "A randomized trial of a low fat high fibre diet in the recurrence of colorectal polyps. Toronto Polyp Prevention Group.", "Randomized trial of intake of fat, fiber, and beta carotene to prevent colorectal adenomas.", "The polyp prevention trial I: rationale, design, recruitment, and baseline participant characteristics.", "Implementation of a 4-y, high-fiber, high-fruit-and-vegetable, low-fat dietary intervention: results of dietary changes in the Polyp Prevention Trial." ]	[ "The Polyp Prevention Trial (PPT) is a multicenter randomized controlled trial to evaluate whether a low-fat, high-dietary fiber, high-fruit and -vegetable eating pattern will reduce the recurrence of adenomatous polyps of the large bowel. Men and women who had one or more adenomas removed recently were randomized into either the intervention (n = 1037) or control (n = 1042) arms. Food frequency questionnaire data indicate that PPT participants at the beginning of the trial consumed 36.8% of total energy from fat, 9.7 g of dietary fiber/1000 kcal, and 3.8 daily servings of fruits and vegetables. Baseline dietary characteristics, including intake of fat, fiber, and fruits and vegetables, as well as other macro- and micronutrients, were similar in the two study groups. The intervention participants receive extensive dietary and behavioral counseling to achieve the PPT dietary goals of 20% of total energy from fat, 18 g/1000 kcal of dietary fiber, and 5-8 daily servings (depending on total caloric intake) of fruits and vegetables. Control participants do not receive such counseling and are expected to continue their usual intake. Dietary intake in both groups is mentioned annually using a 4-day food record (also completed at 6 months by intervention participants only) and a food frequency questionnaire, with a 10% random sample of participants completing an annual unscheduled 24-h telephone recall. Blood specimens are drawn and analyzed annually for lipids and carotenoids. This article provides details on the rationale and design of the PPT dietary intervention program and describes the participant baseline dietary intake data characteristics.", "After polypectomy for adenomatous colorectal polyps, 201 persons were randomized to receive counselling on a diet low in fat (the lesser of 50 g/day or 20% of energy) and high in fibre (50 g/day) (LFHF), or to follow a normal western diet (ND), high in fat and low in fibre. After 12 months of counselling, fat consumption was about 25% of energy in the LFHF group and 33% in the ND group; fibre consumption was 35 g and 16 g respectively. After an average of two years of follow-up, an intention to treat analysis led to a ratio of cumulative incidence rates of 1.2 (95% CL 0.6-2.2) for recurrence of neoplastic polyps, a finding which suggests no significant difference between dietary groups over the period of observation. An exploratory analysis conducted among 142 persons with substantial diet counselling indicated a reduced risk of neoplastic polyp recurrence in women (RR = 0.5), associated with reduced concentrations of faecal bile acids while on the LFHF diet, but indicated an increased risk of recurrence in men (RR = 2.1), associated with increased faecal bile acids. Although a larger study would be needed to rule out the role of chance, these findings of gender-specific associations between diet counselling and both faecal bile acid concentrations and recurrence of colorectal neoplasia are consistent with recently published evidence of differences between genders.", "Epidemiologic evidence of associations between the high intake of fat and low intake of dietary fiber, beta carotene, and other dietary constituents and the risk of colorectal neoplasia has been inconsistent and has not provided a sufficient basis for recommendations concerning the dietary prevention of large-bowel cancer in humans.\n We conducted a clinical trial to assess the effects on the incidence of adenomas of reducing dietary fat to 25% of total calories and supplementing the diet with 25 g of wheat bran daily and a capsule of beta carotene (20 mg daily).\n We performed a randomized, partially double-blinded, placebo-controlled factorial trial in which half the patients were assigned to each intervention, resulting in seven intervention groups and one control group. Eligibility criteria included histologic confirmation of at least one colorectal adenoma and confidence expressed by the colonoscopist that all polyps had been removed. Dietary changes were individually initiated and monitored by dietitians and research nurses. At surveillance colonoscopy, the size and location of all polyps were recorded, and their histology was later centrally reviewed. Among 424 patients who were randomly assigned in the trial, 13 were found to be ineligible upon histologic review. Among the remaining 411, complete outcome data were collected from 390 at 24 months and from 306 at 48 months. All P values are from two-sided tests of statistical significance.\n There was no statistically significant prevention of total new adenomas with any of the interventions. We found a statistically non-significant reduced risk of large adenomas (> or = 10 mm) with the low-fat intervention: At 24 months, the odds ratio (OR) adjusted for potential confounders = 0.4 and 95% confidence interval (CI) = 0.1-1.1; at 48 months, OR = 0.3 and 95% CI = 0.1-1.0. Less and statistically nonsignificant reductions in the risk of large adenomas were found with wheat bran: At 24 months, OR = 0.8 and 95% CI = 0.3-2.2; at 48 months, OR = 0.8 and 95% CI = 0.3-2.5. Patients on the combined intervention of low fat and added wheat bran had zero large adenomas at both 24 and 48 months, a statistically significant finding (P = .03).\n Because only small numbers of patients were studied, our finding that the combination of fat reduction and a supplement of wheat bran reduced the incidence of large adenomas in this randomized, controlled trial must be treated with caution. The results do suggest, however, that these interventions may reduce the transition from smaller to larger adenomas, a step that may critically define those adenomas most likely to progress to malignancy.", "The Polyp Prevention Trial (PPT) is a multicenter randomized controlled trial examining the effect of a low-fat (20% of total energy intake), high-fiber (18 g/1000 kcal), high-vegetable and -fruit (5-8 daily servings) dietary pattern on the recurrence of adenomatous polyps of the large bowel, precursors of most colorectal malignancies. Eligibility criteria include one or more adenomas removed within 6 months of randomization; complete nonsurgical polyp removal and complete colonic examination to the cecum at the qualifying colonoscopy: age 35 years of more; no history of colorectal cancer, inflammatory bowel disease, or large bowel resection; and satisfactory completion of a food frequency questionnaire and 4-day food record. Of approximately 38,277 potential participants with one or more polyps recently resected, investigators at eight clinical centers randomized 2,079 (5.4%; 1,037 in the intervention and 1,042 in the control arm) between June 1991 and January 1994, making the PPT the largest adenoma recurrence trial ever conducted. Of PPT participants, 35% are women and 10% are minorities. At study entry, participants averaged 61.4 years of age; 14% of them smoked, and 22% used aspirin. At the baseline colonoscopy, 35% of participants had two or more adenomas, and 29% had at least one large (> of = 1 cm) adenoma. Demographic, behavioral, dietary, and clinical characteristics are comparable across the two study arms. Participants have repeat colonoscopies after 1 (T(1)) and 4 (T(4)) years of follow-up. The primary end point is adenoma recurrence; secondary end points include number, size, location, and histology of adenomas. All resected lesions are reviewed centrally by gastrointestinal pathologists. The trial provides 90% power to detect a reduction of 24% in the annual adenoma recurrence rate. The primary analytic period, on which sample size calculations were based is 3 years (T(1) to T(4)), which permits a 1-year lag time for the intervention to work and allows a more definitive clearing of lesions at T(1), given that at least 10-15% of polyps may be missed at baseline. The final (T(4)) colonoscopies are expected to be completed in early 1998.", "The Polyp Prevention Trial (PPT) was a multicenter randomized clinical trial designed to determine the effects of a high-fiber (4.30 g/MJ), high-fruit-and-vegetable (0.84 servings/MJ), low-fat (20% of energy from fat) diet on the recurrence of adenomatous polyps in the large bowel.\n Our goal was to determine whether the PPT intervention plan could effect change in 3 dietary goals and to examine the intervention's effect on the intake of other food groups and nutrients.\n Participants with large-bowel adenomatous polyps diagnosed in the past 6 mo were randomly assigned to either the intervention (n = 1037) or the control (n = 1042) group and remained in the trial for 4 y. Three dietary assessment instruments were used to measure dietary change: food-frequency questionnaires (in 100% of the sample), 4-d food records (in a 20% random cohort), and 24-h dietary recalls (in a 10% random sample).\n Intervention participants made and sustained significant changes in all PPT goals as measured by the dietary assessment instruments; the control participants' intakes remained essentially the same throughout the trial. The absolute differences between the intervention and control groups over the 4-y period were 9.7% of energy from fat (95% CI: 9.0%, 10.3%), 1.65 g dietary fiber/MJ (95% CI: 1.53, 1.74), and 0.27 servings of fruit and vegetables/MJ (95% CI: 0.25, 0.29). Intervention participants also reported significant changes in the intake of other nutrients and food groups. The intervention group also had significantly higher serum carotenoid concentrations and lower body weights than did the control group.\n Motivated, free-living individuals, given appropriate support, can make and sustain major dietary changes over a 4-y period." ]	There is currently no evidence from RCTs to suggest that increased dietary fibre intake will reduce the incidence or recurrence of adenomatous polyps within a two to four year period.
CD003748	[ "9715861", "9510281", "10510990", "11951094", "9848888", "17210383" ]	[ "Cilostazol has beneficial effects in treatment of intermittent claudication: results from a multicenter, randomized, prospective, double-blind trial.", "Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease.", "A new pharmacological treatment for intermittent claudication: results of a randomized, multicenter trial.", "Effect of cilostazol in patients with intermittent claudication: a randomized, double-blind, placebo-controlled study.", "Effect of the novel antiplatelet agent cilostazol on plasma lipoproteins in patients with intermittent claudication.", "The effect of supervised exercise and cilostazol on coagulation and fibrinolysis in intermittent claudication: a randomized controlled trial." ]	[ "Cilostazol is a new phosphodiesterase inhibitor that suppresses platelet aggregation and also acts as a direct arterial vasodilator. This prospective, randomized, placebo-controlled, parallel-group clinical trial evaluated the efficacy of cilostazol for treatment of stable, moderately severe intermittent claudication.\n Study inclusion criteria included age > or =40 years, initial claudication distance (ICD) on treadmill (12.5% incline, 3.2 km/h) between 30 and 200 m, and confirmation of diagnosis of chronic lower-extremity arterial occlusive disease. After stabilization and single-blind placebo lead-in, 81 subjects (62 male, 19 female) from 3 centers were randomized unequally (2:1) to 12 weeks of treatment with cilostazol 100 mg PO BID or placebo. Primary outcome measures included ICD and maximum distance walked (absolute claudication distance, or ACD). Secondary outcome measures included ankle pressures, subjective assessments of benefit by patients and physicians, and safety. Treatment and control groups were similar with respect to age, severity of symptoms, ankle pressures, and smoking status. Statistical analyses used intention-to-treat analyses for each of 77 subjects who had > or =1 treadmill test after initiation of therapy. Comparisons between groups were based on logarithms of ratios of ICD and ACD changes from baseline using ANOVA test at last treatment visit. The estimated treatment effect showed a 35% increase in ICD (P<0.01) and a 41% increase in ACD (P<0.01). There was no significant change in resting or postexercise ankle/brachial indexes. Patients' and physicians' subjective assessments corroborated the measured improvements in walking performance observed in the cilostazol-treated group.\n Cilostazol improved walking distances, significantly increasing ICD and ACD. The data suggest cilostazol is safe and well tolerated for the treatment of intermittent claudication.", "This study evaluated the effects of cilostazol on walking distances in patients with intermittent claudication (IC) caused by peripheral arterial occlusive disease.\n The study was a multicenter, randomized, double-blind, placebo-controlled trial. Two hundred thirty-nine patients with IC were randomly assigned to receive cilostazol (100 mg b.i.d.) or a placebo for 16 weeks. All patients underwent serial, variable-grade, constant-speed treadmill testing. Absolute claudication distance (ACD), assessed at the end of the 12-hour dosing interval (trough), was the primary end point. Secondary end points included ACD assessed 3 to 4 hours after dosing (peak) and initial claudication distances (trough and peak). Functional status measures, including the Medical Outcomes Scale (SF-36) and Walking Impairment Questionnaire, were used to assess subjective changes over the 16-week treatment period. Ankle-brachial indexes were calculated from Doppler-measured systolic pressures at every visit with treadmill testing.\n Patients treated with cilostazol demonstrated significant improvements over the placebo patients in ACD at all three time points tested after baseline (weeks 8, 12, and 16). Peak treadmill testing at weeks 8 and 12 also showed significant improvement in walking distances for cilostazol-treated patients over placebo-treated patients. At week 16, patients in the cilostazol group had a 96.4-meter (47%) increase in ACD compared with 31.4 meters (12.9%) for the placebo group (p < 0.001). In the SF-36, significant improvement was observed in the physical component subscale and the composite physical component score. In the Walking Impairment Questionnaire, improvements were significant in patient reports of walking speed and specific measures of walking difficulty. Ankle-brachial indexes improved in the cilostazol group (0.64 +/- 0.02 to 0.70 +/- 0.02) compared with the placebo group (0.68 +/- 0.02 to 0.69 +/- 0.02) (p < 0.0125). The most frequent adverse events were headache, abnormal stools (e.g. loose stools), diarrhea, and dizziness.\n Cilostazol significantly increased ACD at all measured time points and initial claudication distances at most time points. This agent may represent a new treatment option for patients with intermittent claudication.", "Effective medication is limited for the relief of intermittent claudication, a common manifestation of arterial occlusive disease. Cilostazol is a potent inhibitor of platelet aggregation with vasodilation effects.\n To evaluate the safety and efficacy of cilostazol for the treatment of intermittent claudication.\n Thirty-seven outpatient vascular medicine clinics at regional tertiary and university hospitals in the United States participated in this multicenter, randomized, double-blind, placebo-controlled, parallel trial. Of the 663 screened volunteer patients with leg discomfort, a total of 516 men and women 40 years or older with a diagnosis of moderately severe chronic, stable, symptomatic intermittent claudication were randomized to receive cilostazol, 100 mg, cilostazol, 50 mg, or placebo twice a day orally for 24 weeks. Outcome measures included pain-free and maximal walking distances via treadmill testing, patient-based quality-of-life measures, global assessments by patient and physician, and cardiovascular morbidity and all-cause mortality survival analysis.\n The clinical and statistical superiority of active treatment over placebo was evident as early as week 4, with continued improvement at all subsequent time points. After 24 weeks, patients who received cilostazol, 100 mg, twice a day had a 51% geometric mean improvement in maximal walking distance (P<.001 vs placebo); those who received cilostazol, 50 mg, twice a day had a 38% geometric mean improvement in maximal walking distance (P<.001 vs placebo). These percentages translate into an arithmetic mean increase in distance walked, from 129.7 m at baseline to 258.8 m at week 24 for the cilostazol, 100 mg, group, and from 131.5 to 198.8 m for the cilostazol, 50 mg, group. Geometric mean change for pain-free walking distance increased by 59% (P<.001) and 48% (P<.001), respectively, in the cilostazol, 100 mg, and cilostazol, 50 mg, groups. These results were corroborated by the results of subjective quality-of-life assessments, functional status, and global evaluations. Headache, abnormal stool samples or diarrhea, dizziness, and palpitations were the most commonly reported potentially drug-related adverse events and were self-limited. A total of 75 patients (14.5%) withdrew because of any adverse event, which was equally distributed between all 3 treatment groups. Similarly, there were no differences between groups in the incidence of combined cardiovascular morbidity or all-cause mortality.\n Compared with placebo, long-term use of cilostazol, 100 mg or 50 mg, twice a day significantly improves walking distances in patients with intermittent claudication.", "A multicenter, double-blind, randomized, placebo-controlled, parallel study was conducted to compare the efficacy and safety of cilostazol 100 mg and 50 mg, both administered twice daily, with that of placebo in patients with moderately severe intermittent claudication (IC) secondary to peripheral arterial disease.A total of 394 subjects 40 years of age or older with chronic, stable, symptomatic IC received cilostazol 100 mg twice daily, 50 mg twice daily, or placebo for 24 weeks. Subjects receiving cilostazol 100 mg twice daily experienced a 21% net improvement in maximal walking distance (MWD)compared with placebo subjects (p = 0.0003) and a 22% net improvement in distance walked to the onset of symptoms (PFWD) (p = 0.0015). Subjects who received cilostazol 50 mg twice daily also benefited from therapy, but not to a statistically significant degree (7% and 11% improvement in MWD and PFWD, respectively). Quality-of-life and functional status assessments corroborated these objective results. Cilostazol, in particular 100 mg twice daily, significantly improves symptoms in patients with IC.", "Cilostazol is an antiplatelet agent and vasodilator marketed in Japan for treatment of ischemic symptoms of peripheral vascular disease. It is currently being evaluated in the United States for treatment of symptomatic intermittent claudication (IC). Cilostazol has been shown to improve walking distance in patients with IC. In addition to its reported vasodilator and antiplatelet effects, cilostazol has been proposed to have beneficial effects on plasma lipoproteins. We examined the effect of cilostazol versus placebo on plasma lipoproteins in 189 patients with IC. After 12 weeks of therapy with 100 mg cilostazol BID, plasma triglycerides decreased 15% (P<0.001). Cilostazol also increased plasma high density lipoprotein cholesterol (HDL-C) (10%) and apolipoprotein (apo) A1 (5.7%) significantly (P<0.001 and P<0.01, respectively). Both HDL3 and HDL2 subfractions were increased by cilostazol; however, the greatest percentage increase was observed in HDL2. Individuals with baseline hypertriglyceridemia (>140 mg/dL) experienced the greatest changes in both HDL-C and triglycerides with cilostazol treatment. In that subset of patients, HDL-C was increased 12.2% and triglycerides were decreased 23%. With cilostazol, there was a trend (3%) toward decreased apoB as well as increased apoA1, resulting in a significant (9.8%, P<0.002) increase in the apoA1 to apoB ratio. Low density lipoprotein cholesterol and lipoprotein(a) concentrations were unaffected. Cilostazol treatment resulted in a 35% increase in treadmill walking time (P=0.0015) and a 9.03% increase in ankle-brachial index (P<0.001). These results indicate that in addition to improving the symptoms of IC, cilostazol also favorably modifies plasma lipoproteins in patients with peripheral arterial disease. The mechanism of this effect is currently unknown.", "The prothrombotic, hypofibrinolytic state that develops in patients with intermittent claudication (IC) upon walking due to ischemia-reperfusion injury (IRI) of the leg muscles may contribute to the high incidence of life- and limb-threatening thrombotic events observed in this patient group. Treatments, such as angioplasty, that obtund the IRI also ameliorate the procoagulant diathesis. The effect on this diathesis of supervised exercise and cilostazol, both of which provide symptomatic benefit in IC, but without significantly obtunding IRI, is unknown.\n Thirty-four patients (27 men and 7 women; median age, 67 years; range, 63-72 years) were randomized to receive best medical therapy (BMT) plus supervised exercise (n = 9), BMT plus cilostazol (n = 9), BMT plus supervised exercise plus cilostazol (n = 7), or BMT alone (n = 9) in a 2 x 2 factorial design. Thrombin-antithrombin complex and prothrombin fragments 1 and 2, both markers of thrombin generation; plasminogen activator inhibitor antigen and tissue plasminogen activator antigen, both markers of fibrinolysis; ankle-brachial pressure index (ABPI); and initial and absolute claudication distance (ACD) were measured at baseline and then 3 and 6 months after randomization.\n At 6 months, when compared with receiving BMT only, supervised exercise and cilostazol resulted in improvements in ABPI of 18% and 13% and in ACD of 40% and 64%, respectively. The effects on ABPI and ACD of combining supervised exercise and cilostazol were additive. Supervised exercise, cilostazol, and supervised exercise combined with cilostazol had no significant effect on any of the four hemostatic markers.\n Treatment of IC by supervised exercise or cilostazol results in significant improvements in ABPI and ACD but has no demonstrable effect on the prothrombotic diathesis. This suggests that supervised exercise and cilostazol, unlike angioplasty, are unlikely to have a long-term beneficial effect on the thrombotic risks faced by these patients." ]	Patients with IC should receive secondary prevention for cardiovascular disease. Cilostazol has been shown to be of benefit in improving walking distance in people with IC. There are no data on whether it results in a reduction of adverse cardiovascular events.
CD002813	[ "3688150" ]	[ "The benefits of group occupational therapy for patients with Parkinson's disease." ]	[ "The medical treatment of idiopathic Parkinson's disease has improved the quality of life and increased survival of patients with Parkinson's disease. However, as the illness progresses, impairments in daily living activities occur. A clinical trial for a group rehabilitation program was initiated to maintain the functional status of these patients. The research protocol consisted of a pretreatment evaluation, random assignment to experimental or control groups, and posttreatment evaluations after therapy, at 6 months and at 1 year. The results showed that the subjects of the treated experimental group maintained their functional status after 1 year, demonstrated a significant decrease of bradykinesia, and perceived a significant improvement in their psychological well-being. This study confirms the value of an occupational therapy group approach and its benefits to the functional independence, to the improvement of physical and motor symptoms, and to the quality of life of persons with Parkinson's disease." ]	Considering the significant methodological flaws in the studies, the small number of patients examined, and the possibility of publication bias, there is insufficient evidence to support or refute the efficacy of occupational therapy in Parkinson's disease. There is now a consensus as to UK current and best practice in occupational therapy when treating people with Parkinson's disease. We now require large well designed placebo-controlled RCTs to demonstrate occupational therapy's effectiveness in Parkinson's disease. Outcome measures with particular relevance to patients, carers, occupational therapists and physicians should be chosen and the patients monitored for at least six months to determine the duration of benefit. The trials should be reported using CONSORT guidelines.
CD008476	[ "3052065", "3513567", "3513569", "3513568", "1481832" ]	[ "Folic acid treatment of fragile X males: a further study.", "Oral folic acid versus placebo in the treatment of males with the fragile X syndrome.", "Folic acid treatment in males and females with fragile-(X)-syndrome.", "High dose folic acid treatment of fragile (X) males.", "Double-blind, placebo-controlled crossover study of folinic acid (Leucovorin for the treatment of fragile X syndrome." ]	[ "Investigations of the effect of high dose folic acid treatment of fragile X syndrome in males has produced mixed results. However, no study had examined the possible drug effects of folic acid on non-fragile X control males. Therefore, we examined the effect of folic acid on fragile X males using non-fragile X control males. Subjects were assigned randomly to an ABA or BAB design. Duration of either folic acid or placebo condition was 4 months. Folic acid or placebo was given in a double-blind fashion. At the end of each condition, the subjects' behavior was assessed. At the end of the study, parents were asked to complete a questionnaire. Using parents' responses, we examined 22 items on the Autistic Descriptors Checklist and two subscales from the Vineland Adaptive Behavior Scale which corresponded to areas of behavior parents' noted to have shown improvement. We did not find significant differences between fragile X males and control males, within subjects, nor across folic acid and placebo conditions. Thus, our follow-up study confirms and extends our original findings, as well as those of other researchers: namely, that no dramatic changes in behavior result from high dose folic acid. Moreover, subtle improvements observed in earlier investigations were not confirmed.", "A double-blind, crossover study of a 10 mg folic acid per day (vs. placebo) treatment was carried out in 25 fra(X) males (ages 1-31 years). Each treatment period lasted 6 months. Before, during and after the study, the patients were assessed blindly with psychological, language and behavioral evaluations, and parent or caretaker reports were collected. Standardized testing did not show statistically significant changes in the group as a whole; psychological testing demonstrated a statistically significant improvement on folic acid in the prepubertal males. After uncoding, caretaker or parent reports also demonstrated behavioral improvements in the prepubertal males while being treated with folic acid.", "Ten males with the fragile X (fra(X] syndrome were treated with folic acid (10 mg/day) for 4 months in a double-blind design study. To eight heterozygotes with mental impairment and fra(X), folic acid was given for 4 months (10 mg/day) in an effort to study possible beneficial effects of folic acid. Psychological and cytogenetic testing were carried out during the trial. There was no improvement in concentration, fine motor co-ordination, or comprehension in the adult male and female patients of the study. One patient showed improvement under a control medications. In the females, improvement was seen only in the youngest patient, a 5-year-old girl. Folate treatment does not seem to be effective in fra(X) adults, but may have some effect in children of both sexes with the disorder. Cytogenetic studies using peripheral lymphocytes showed that the fra(X) frequency decreased significantly (t = 0.00856; 1% level) only in cells cultured in a folic acid-free medium but not in cells cultured in a medium with added antifolate (methotrexate). This shows a \"contamination effect\" of folate-free culture medium after oral folic acid treatment of these patients. The decrease of fra(X) involves primarily the early-replicating X when culturing with folic acid-free medium. A synergistic suppression effect of \"external folate\" and BrdU is the most likely explanation of this phenomenon.", "We conducted an experimental trial of high-dose folic acid given to five males, ages 8 to 26 years, with the fra(X) syndrome. In this double blind study, each subject received 250 mg per day of folic acid for 3 months, followed by placebo for 3 months, and folic acid again for an additional three months. Based on IQ tests, behavior ratings, the Autistic Descriptors Checklist, and parental ratings, there was little evidence to suggest any positive effects seen during the administration of high-dose folic acid. Therefore, this study has provided little support for a hypothesis of benefit of high-dose folic acid in the treatment of the fra(X) syndrome.", "We conducted a randomized, double-blind, placebo-controlled crossover study of folinic acid therapy (dl-Leucovorin, 15 mg/day) or placebo for males with Fragile X (fra(x)) syndrome. Twenty-one patients were enrolled in the study. The treatment periods were 3 months in length. Patients were followed with chemistry panels and complete blood counts. No differences between placebo and treatment phases were noted in any laboratory parameter. Instruments to measure functioning were the Vineland Adaptive Behavioral Scales, Peabody Picture Vocabulary Test-Revised, Conners Parent and Teaching Rating Scales, the ADD-H: Comprehensive Teacher's Rating Scales (ACTeRS), and a questionnaire designed by the investigators. At the crossover point, 2 parents requested to withdraw from the study because they felt their children had made dramatic gains during the first half of the study and had lost those gains after the crossover point. Both parents had accurately predicted that their sons were receiving folinic acid during the first half of the study. However, no statistically significant differences could be demonstrated between the treatment and placebo phases of the study with any instrument when the results were averaged over the entire cohort. After the conclusion of the study, approximately one-half of the parents believed that their children had benefitted from the folinic acid therapy and elected to continue treatment. Thus far, no significant side effects have been noted from long-term folinic acid therapy so we are offering all Fragile X patients a 3-month trial of medication." ]	The quality of available evidence is low and not suitable for drawing conclusions about the effect of folic acid on fragile X syndrome patients. It consists of few studies with small samples of patients, all of them male, with little statistical power to detect anything other than huge effects.
CD004096	[ "11837755", "15863798", "12684359", "12941710", "11220553", "7648804", "11220522", "11191537", "10230747", "15531005", "15127325", "11407998", "11840224", "10028216", "11874427", "7491877", "1852793", "15613431", "10440592", "1317828", "8181239", "9918478", "14770192", "12502668", "10678259", "16847290", "16861099", "12681025", "12629532", "15724802", "11887193", "14693982", "7620754" ]	[ "Clinical evaluation of sibutramine in obese type 2 diabetic patients refractory to dietary management.", "A double-blind, placebo-controlled trial of sibutramine for olanzapine-associated weight gain.", "Behavior therapy and sibutramine for the treatment of adolescent obesity: a randomized controlled trial.", "One-year outcome of a combination of weight loss therapies for subjects with type 2 diabetes: a randomized trial.", "Weight loss with sibutramine improves glycaemic control and other metabolic parameters in obese patients with type 2 diabetes mellitus.", "A study of fluoxetine in obese elderly patients with type 2 diabetes.", "Sibutramine is effective for weight loss and diabetic control in obesity with type 2 diabetes: a randomised, double-blind, placebo-controlled study.", "Effect of sibutramine on weight maintenance after weight loss: a randomised trial. STORM Study Group. Sibutramine Trial of Obesity Reduction and Maintenance.", "Long-term maintenance of weight loss after a very-low-calorie diet: a randomized blinded trial of the efficacy and tolerability of sibutramine.", "Use of sibutramine in overweight adult hispanic patients with type 2 diabetes mellitus: a 12-month, randomized, double-blind, placebo-controlled clinical trial.", "Weight reduction by sibutramine in obese subjects in primary care medicine: the SAT Study.", "Randomized placebo-controlled trial of long-term treatment with sibutramine in mild to moderate obesity.", "Sibutramine is safe and effective for weight loss in obese patients whose hypertension is well controlled with angiotensin-converting enzyme inhibitors.", "Weight suppression and weight rebound in ex-smokers treated with fluoxetine.", "Role of sibutramine in the treatment of obese Type 2 diabetic patients receiving sulphonylurea therapy.", "Efficacies of dexfenfluramine and fluoxetine in preventing weight gain after smoking cessation.", "A randomized, double-blind study of fluoxetine and maprotiline in the treatment of major depression.", "Treatment of obese adolescents with sibutramine: a randomized, double-blind, controlled study.", "Absence of cardiac valve dysfunction in obese patients treated with sibutramine.", "Fluoxetine treatment of the obese diabetic.", "Fluoxetine in the treatment of obese type 2 diabetic patients.", "Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial.", "Health-related quality of life in a randomised placebo-controlled trial of sibutramine in obese patients with type II diabetes.", "A randomized trial of sibutramine in the management of obese type 2 diabetic patients treated with metformin.", "Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with orlistat for obesity. European Orlistat Obesity Study Group.", "Effects of sibutramine treatment in obese adolescents: a randomized trial.", "Use of sibutramine in obese mexican adolescents: a 6-month, randomized, double-blind, placebo-controlled, parallel-group trial.", "Latin-American trial of orlistat for weight loss and improvement in glycaemic profile in obese diabetic patients.", "Treatment of weight gain with fluoxetine in olanzapine-treated schizophrenic outpatients.", "Treatment effect of sibutramine compared to fluoxetine on leptin levels in polycystic ovary disease.", "Effects of sibutramine on the treatment of obesity in patients with arterial hypertension.", "XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients.", "Long-term fluoxetine treatment of bulimia nervosa. Fluoxetine Bulimia Nervosa Research Group." ]	[ "An open, non-comparative study was carried out to assess the efficacy and toleration profile of sibutramine, a new antiobesity drug, in promoting weight loss in obese type 2 diabetes mellitus subject who failed to reduce weight after strict dietary control. Twenty seven patients completed the study. Sibutramine was started as a single morning dose of 10 mg and was subsequently increased to 15 mg daily if weight loss was not satisfactory. The total duration of the study was twelve weeks with followup at every four weeks. Effect of drug was monitored in terms of weight reduction, changes in body mass index, waist circumference, hip circumference, waist/hip ratio and other metabolic parameters. A fixed dietary prescription and concomitant therapy with drugs, if required and not likely to interfere with the trial therapy, was permitted but was not changed during the study period.\n At the end of 12 week, mean weight reduction in study subjects was 4.16 kg (p < 0.001), the corresponding BMI decreased by 1.6 (p < 0.0001) and hip circumference by 3.68 (p < 0.001). However, there was no significant change in fasting blood glucose and Hb(A1c) values.\n The study indicates sibutramine to be an effective and well tolerated agent leading to significant reduction in parameter of obesity in obese type 2 diabetic subjects.", "Weight gain is commonly observed with olanzapine treatment and can increase the risk for obesity, cardiovascular disease, hypertension, and diabetes mellitus. This study examined the effectiveness of sibutramine, an approved weight loss agent, in overweight and obese subjects taking olanzapine for schizophrenia or schizoaffective disorder.\n Each subject had a DSM-IV diagnosis of schizophrenia or schizoaffective disorder, had been taking a stable dose of olanzapine for at least 4 months, and had a body mass index of >/=30 kg/m(2) or >/=27 kg/m(2) plus at least one cardiovascular risk factor. In a 12-week double-blind, randomized, placebo-controlled study, 37 subjects received placebo or sibutramine (up to 15 mg/day). For the first 8 weeks all subjects participated in weekly group sessions focused on nutrition and behavioral modification.\n The sibutramine and placebo groups had no significant baseline differences on age, gender, education, ethnicity, diagnosis, weight, body mass index, and blood pressure. At week 12 the sibutramine group had significantly greater losses than the placebo group in weight (mean=8.3 lb, SD=2.4, versus mean=1.8 lb, SD=1.6), waist circumference, body mass index, and hemoglobin A(1c). There were no significant differences on most side effects, although the sibutramine group exhibited a mean increase in systolic blood pressure of 2.1 mm Hg (SD=8.5), and anticholinergic side effects and sleep disturbances were at least twice as common in the sibutramine group.\n Sibutramine was an effective and well-tolerated adjunct to behavior modification for weight loss in patients with schizophrenia and schizoaffective disorder being treated with olanzapine.", "Adolescent obesity is becoming a national public health problem. Weight-loss medications including sibutramine facilitate weight control in adults and could be used with obese adolescents in combination with behavior therapy (BT).\n To examine whether increased weight loss in obese adolescents is induced when sibutramine is added to a family-based, behavioral weight control program.\n Randomized, double-blind, placebo-controlled trial consisting of 82 adolescents aged 13 to 17 years with a body mass index (BMI) of 32 to 44 conducted from March 1999 to August 2002 at a university-based clinic for 6 months, followed by open-label treatment during months 7 to 12.\n For the first 6 months, participants received either BT and sibutramine or BT and placebo. From months 7 to 12, all participants received sibutramine in open-label treatment.\n Percentage change in BMI; systolic and diastolic blood pressure and pulse; and hunger.\n In intention-to-treat analysis at month 6, participants in the BT and sibutramine group lost a mean (SD) of 7.8 kg (6.3 kg) and had an 8.5% (6.8%) reduction in BMI, which was significantly more than weight loss of 3.2 kg (6.1 kg) and reduction in BMI of 4.0% (5.4%) in the BT and placebo group. Significantly greater reductions in hunger (P =.002) also were reported by participants who received BT and sibutramine. From months 7 to 12, adolescents initially treated with sibutramine gained 0.8 kg (10.5 kg) with continued use of the medication, whereas those who switched from placebo to sibutramine lost an additional 1.3 kg (5.4 kg). Medication dose was reduced (n = 23) or discontinued (n = 10) to manage increases in blood pressure, pulse rate, or other symptoms.\n The addition of sibutramine to a comprehensive behavioral program induced significantly more weight loss than did BT and placebo. Until more extensive safety and efficacy data are available, medications for weight loss should be used only on an experimental basis in adolescents and children.", "The purpose of this study was to evaluate the effects of a combination weight loss program using intermittent low-calorie diets, energy-controlled meal replacement products, and sibutramine on weight loss, diabetes control, and cardiovascular risk factors in overweight or obese subjects with type 2 diabetes.\n Overweight or obese individuals with type 2 diabetes treated with diet or oral medication were randomly assigned to either a standard therapy or combination therapy group. Both groups received a standardized program to facilitate weight loss. The combination therapy group also received 10-15 mg sibutramine daily, low-calorie diets using meal replacement products for 1 week every 2 months, and between low-calorie diet weeks, once daily use of meal replacement product and snack bars to replace one usual meal and snack. Primary outcome measures were changes in body weight, glycemic control, plasma lipids, blood pressure, pulse, and body composition at 1 year.\n At 1 year, combination therapy, compared with standard therapy, resulted in significantly more weight loss (-7.3 +/- 1.3 kg vs. -0.8 +/- 0.9 kg, P < 0.001) and reduction in HbA(1c) (-0.6 +/- 0.3 vs. 0.0 +/- 0.2%, P = 0.05). Combination therapy resulted in reduced requirement for diabetes medications and decreased fat mass and lean body mass. A 5-kg decrease in weight at 1 year was associated with a decrease of 0.4% in HbA(1c) (P = 0.006). Changes in fasting glucose, lipids, pulse, and blood pressure did not differ between groups.\n This combination weight loss program resulted in greater weight loss and improved diabetes control compared with a standard weight loss program in overweight or obese subjects with type 2 diabetes.", "To determine the efficacy and tolerability of sibutramine hydrochloride in obese patients whose type 2 diabetes was poorly controlled on diet alone or with an oral antidiabetic agent.\n This study was a 24-week, double-blind, multicentre trial following a 5-week placebo run-in period. One hundred and seventy-five obese (body mass index (b.m.i.) > or =27 kg/m2) patients with poorly controlled type 2 diabetes mellitus were randomized either to sibutramine (n = 89; mean age 53.5 years; mean weight 99.3 kg) or placebo (n = 86; mean age 55 years; mean weight 98.2 kg) at 16 participating centres. To achieve moderate calorie restriction (deficit > or = 250-500 kcal/day), individual dietary counselling was accompanied by either placebo or sibutramine (initial dosage of 5 mg/day titrated up by 5 mg biweekly through week 6, and maintained at 20 mg through week 24). The main outcome measures included changes in weight, b.m.i., waist and hip circumference, glycaemic control, lipid profile, and quality of life, and evaluation of reported adverse events.\n Sixty-seven per cent of sibutramine patients and 71% of placebo patients completed the study. At week 24 when comparing those who completed the course, sibutramine compared with placebo patients showed significantly greater (p < 0.001) absolute (-4.3 vs. -0.4 kg) and percentage (-4.5% vs. -0.5%) weight loss. Weight loss > or =5% or 10% was achieved by 33% and 8% of sibutramine patients, respectively, but no placebo patients (p < 0.03 or better). Improvement in glycaemic control was correlated with weight loss (p < 0.001). In 5% and 10% weight-loss responders, mean treatment differences were -0.53% and -1.65% (p < or = 0.05), respectively, for HbA1c, and -1.4 mmol/l (p < or =0.05) and -3.8 (p < or =0.05) mmol/l for fasting plasma glucose. Sibutramine patients also showed improvements in fasting insulin, triglycerides, HDL cholesterol, and quality-of-life assessments. Overall, sibutramine was well tolerated compared with the placebo. Sibutramine treatment was associated with small mean increases in blood pressure (BP) and pulse, although an increase in BP was not seen in sibutramine-treated patients who lost > or = 5% of their weight.\n Sibutramine produced statistically and clinically significant weight loss when used in combination with recommendations for moderate caloric restriction. This weight loss was associated with improvements in metabolic control and quality of life, and sibutramine was generally well tolerated in obese patients with type 2 diabetes.", "In order to establish the safety and efficacy of fluoxetine in subjects over 60 years of age with Type 2 diabetes, a randomized, double-blind, parallel study of 30 obese subjects was undertaken, comparing the use of fluoxetine 60 mg daily with placebo. Subjects were diet controlled with an HbA1 < 14% (reference range 6-9%) and BMI > 29 kg m2. Those taking fluoxetine had a median weight loss of 2.6 kg at 3 months (p < 0.001) and 3.9 kg at 6 months (p < 0.02), compared with weight loss in the placebo group of 0.1 kg and 0.0 kg at 3 and 6 months, respectively. Improved glycaemic control was also demonstrated in the fluoxetine group compared with placebo, initial HbA1 levels of 8.0% vs 8.7% (NS) falling at 4 months by 0.9% (p < 0.02) and at six months by 0.9% (p < 0.02). No sustained improvement in fasting blood glucose levels was demonstrated. Reporting of adverse events was similar in both groups. Fluoxetine in the short term aids weight loss and improves glycaemic control without a significant increase in adverse events in elderly Type 2 diabetic subjects.", "To assess the efficacy and tolerability of sibutramine 15 mg once daily as a weight reduction agent in overweight and obese patients (body mass index (b.m.i.) > 26 kg/m2) with type 2 diabetes when given with a customised, reduced-calorie diet, and to evaluate the influence of weight loss on diabetic control.\n Randomised, placebo-controlled, double-blind, parallel-group, 12-week study conducted at two hospital-based obesity/diabetes clinics. Patients were men and women aged 30-65 years, with b.m.i. > 26 kg/m2 and < or = 35 kg/m2 and treated or untreated type 2 diabetes diagnosed > or = 6 months previously. Each patient was given sibutramine 15 mg or placebo once daily and advised to follow a customised diet of 500 kcal/day less than the individual's energy needs. The principal measure of efficacy was change in body weight (b.w.). Additional efficacy measurements were changes in b.m.i., body composition as measured by dual-energy X-ray absorptiometry, and change in waist and hip measurements. Changes in diabetic control were assessed by blood glucose levels fasting and after a standard test meal, fasting insulin level, and glycosylated haemoglobin level. Adverse events (AEs) were monitored at each visit, and routine laboratory safety tests were done at 4-week intervals.\n Ninety-one patients were randomised into the study, 44 to placebo and 47 to sibutramine 15 mg once daily. Eighty-three patients (91%) completed the study, 40 (91%) on placebo and 43 (91%) on sibutramine. Mean weight reduction from baseline was statistically significantly greater with sibutramine than with placebo at every measurement and at the end of the study (2.4 vs. 0.1 kg at week 12; p < 0.001; intent-to-treat). The proportion of patients who lost > 5% of their baseline b.w. was 19% in the sibutramine group and 0% in the placebo group (p < 0.001; 95% confidence interval: 9, 30). Patients receiving sibutramine lost significantly more fat mass compared with those receiving placebo, as a percentage (1.0% vs. 0.1%; p < 0.05) and in absolute terms (1.8 vs. 0.2 kg, p < 0.001). Loss of lean mass was not significantly different between the groups. Mean peak blood glucose concentration after a standard test meal decreased by 1.1 mmol/l in the sibutramine treatment group but increased by 0.5 mmol/l in the placebo group (p = 0.04; difference in means, 1.6, 95% confidence interval: -3.3, -0.1). Mean fasting blood glucose decreased by 0.3 mmol/l with sibutramine and increased by 1.4 mmol/l with placebo. Mean glycosylated haemoglobin levels decreased by 0.3% units with sibutramine treatment, and were unchanged with placebo. However, more sibutramine-treated patients (33%) than placebo-treated patients (5%) achieved decreases in glycosylated haemoglobin of 1% unit or more (p < 0.05). Sibutramine 15 mg was safe and well tolerated, and AEs were mostly mild or moderate in severity. No significant differences were found between treatment groups in blood pressure. No clinically significant conduction or rhythm abnormalities were observed on ECG.\n Sibutramine 15 mg once daily with a customised, reduced-calorie diet significantly reduced weight compared with placebo in overweight and obese patients (b.m.i. > 26 kg/m2) with type 2 diabetes. Sibutramine was well tolerated, and significant improvement in diabetic control was seen in conjunction with weight reduction on sibutramine treatment.", "Sibutramine is a tertiary amine that has been shown to induce dose-dependent weight loss and to enhance the effects of a low-calorie diet for up to a year. We did a randomised, double-blind trial to assess the usefulness of sibutramine in maintaining substantial weight loss over 2 years.\n Eight European centres recruited 605 obese patients (body-mass index 30-45 kg/m2) for a 6-month period of weight loss with sibutramine (10 mg/day) and an individualised 600 kcal/day deficit programme based on measured resting metabolic rates. 467 (77%) patients with more than 5% weight loss were then randomly assigned 10 mg/day sibutramine (n=352) or placebo (n=115) for a further 18 months. Sibutramine was increased up to 20 mg/day if weight regain occurred. The primary outcome measure was the number of patients at year 2 maintaining at least 80% of the weight lost between baseline and month 6. Secondary outcomes included changes in uric acid concentrations and glycaemic and lipid variables. Analysis was by intention to treat.\n 148 (42%) individuals in the sibutramine group and 58 (50%) in the placebo group dropped out. Of the 204 sibutramine-treated individuals who completed the trial, 89 (43%) maintained 80% or more of their original weight loss, compared with nine (16%) of the 57 individuals in the placebo group (odds ratio 4.64, p<0.001). Patients had substantial decreases over the first 6 months with respect to triglycerides, VLDL cholesterol, insulin, C peptide, and uric acid; these changes were sustained in the sibutramine group but not the placebo group. HDL cholesterol concentrations rose substantially in the second year: overall increases were 20.7% (sibutramine) and 11.7% (placebo, p<0.001). 20 (3%) patients were withdrawn because of increases in blood pressure; in the sibutramine group, systolic blood pressure rose from baseline to 2 years by 0.1 mm Hg (SD 12.9), diastolic blood pressure by 2.3 mm Hg (9.4), and pulse rate by 4.1 beats/min (11.9).\n This individualised management programme achieved weight loss in 77% of obese patients and sustained weight loss in most patients continuing therapy for 2 years. Changes in concentrations of HDL cholesterol, VLDL cholesterol, and triglyceride, but not LDL cholesterol, exceed those expected either from weight loss alone or when induced by other selective therapies for low concentrations of HDL cholesterol relating to coronary heart disease.", "Very-low-calorie diets are a well established method to achieve substantial short-term weight loss in obese patients, but long-term maintenance of the weight loss is very disappointing. A combined very-low-calorie diet and pharmacologic approach could be an effective means of prolonging its benefits.\n Eligible patients had a body-mass index greater than 30 kg/m2; those who lost 6 kg or more during a 4-week treatment with a very-low-calorie diet were randomly assigned to 1 year of treatment with sibutramine (10 mg) or identical placebo.\n In an intention-to-treat analysis, mean (+/-SD) absolute weight change at 1 year (or study endpoint) was -5.2 (+/-7.5) kg in the 81 patients in the sibutramine group and +0.5 (+/-5.7) kg in the 78 patients in the placebo group (P = 0.004). When compared with their weight at study entry (before the very-low-calorie diet), 86% of patients in the sibutramine group had lost at least 5% of their weight, compared with only 55% of those in the placebo group (P <0.001) at the study endpoint. Similarly, at month 12, 75% of subjects in the sibutramine group maintained at least 100% of the weight loss achieved with a very-low-calorie diet, compared with 42% in the placebo group (P <0.01).\n Following a very-low-calorie diet, sibutramine is effective in maintaining and improving weight loss for up to 1 year.", "The management of type 2 diabetes mellitus is complicated by the presence of risk factors related to overweight and obesity, particularly visceral adiposity. However, weight loss and weight maintenance are difficult for patients with diabetes, and the benefits of dietary modifications are typically modest. Sibutramine is a serotonin- and norepinephrine-reuptake inhibitor that reduces food intake by inducing early satiety and attenuates the decrease in basal energy expenditure associated with weight loss. Previous trials of sibutramine in overweight and obese patients with type 2 diabetes have shown significant weight loss accompanied by better glycemic control.\n The goal of this study was to assess the effect on body weight and glycemic control of sibutramine in combination with glibenclamide in obese Hispanic patients with type 2 diabetes.\n This was a 12-month, randomized, double-blind, placebo-controlled clinical trial conducted at the Endocrinology Service, General Hospital of Mexico, Mexico City. Included were overweight or obese (body mass index [BMI] >27 kg/M2) patients with type 2 diabetes between the ages of 24 and 65 years who had been receiving glibenclamide monotherapy for at least 2 weeks and whose glucose concentrations were stable. Patients were randomized to receive sibutramine 10 mg or placebo once daily. The primary efficacy measures were change in body weight, waist circumference, and glycosylated hemoglobin (HbA1c). Anthropometrics and fasting glucose concentrations were measured monthly. HbA1c was determined at baseline and at 6 and 12 months. Laboratory parameters were measured at baseline and at the end of the study.\n Forty-four patients were randomized to receive sibutramine (28 women, 16 men; mean [SD] age, 47.6 [9.0] years), and 42 were randomized to receive placebo (31 women, 11 men; mean age, 45.8 [8.1] years). Twenty-four patients in the sibutramine group and 23 in the placebo group completed the trial. In the sibutramine group, body weight was reduced from a mean (SD) of 73.9 (10.3) kg at baseline to 69.8 (10.6) kg at month 12; BMI decreased from 29.9 (2.6) to 28.2 (2.9) kg/M2; waist circumference was reduced from 94.9 (8.4) to 90.8 (8.4) cm; the plasma fasting glucose concentration decreased from 140.4 (29.4) to 114.2 (32.0) mg/dL; and the HbA1c value was reduced from 8.9% (1.2) to 8.3% (1.2) (all, P < 0.001). In the placebo group, the corresponding changes were from 74.5 (10.3) kg at baseline to 73.1 (11.2) kg at month 12; from 30.1 (2.5) to 29.5 (2.9) kg/M2; from 94.4 (7.3) to 93.1 (8.3) cm (P < 0.05); from 140.7 (25.2) to 123.9 (38.3) mg/dL (P < 0.05); and from 9.0% (1.2) to 9.1% (1.3). In the sibutramine group, weight loss continued for up to 12 months.\n In this population of obese Hispanic patients with type 2 diabetes, sibutramine combined with glibenclamide therapy achieved weight loss for up to 12 months and was associated with better glycemic control than placebo.", "Sibutramine is a selective serotonin and noradrenaline reuptake inhibitor that is known to reduce body weight. The efficacy of this drug in primary care medicine is currently unknown.\n To study, in a primary healthcare setting, the effect of a standardized non-pharmacological treatment program and 15 mg sibutramine or placebo on long-term weight reduction in obese subjects with a body mass index >or= 30 and < 40 kg/m(2).\n A multicentre, double-blind, placebo-controlled, randomized, parallel group comparison over 54 weeks of continuous therapy.\n 33 general practitioners in Germany.\n 389 obese patients were recruited of whom 362 were randomized.\n Primary measure was weight reduction at week 54; others included reduction in BMI, waist circumference, waist-hip ratio, blood pressure and blood lipids.\n 348 obese subjects were analyzed using an intention-to-treat analysis. Mean weight loss in the sibutramine (S) group was 8.1 +/- 8.2 kg vs. 5.1 +/- 6.5 kg in the placebo (P) group (p < 0.001; Intent-to-treat analysis). More subjects lost more than 5 % and 10 % of initial weight with sibutramine than with placebo (5 %, S: 62.6 %, P: 41.4 %, p < 0.001; 10 %, S: 40.8, P: 19.0 %, p < 0.001). Weight loss was accompanied by an improvement in the lipid profile, in particular, an increase in HDL-cholesterol and a decrease in fasting triglycerides. In both groups, systolic and diastolic blood pressure decreased in those with moderate hypertension and remained unchanged in those with normal blood pressure at baseline. There was a modest increase in heart rate in S (1.9 beats/min) vs. P (- 0.9 beats/min) (p < 0.05).\n Under primary care conditions, sibutramine 15 mg daily proved to be a safe and effective drug for additional weight loss in obese subjects undergoing a comprehensive weight reduction program.", "The researchers assessed the long-term weight reduction efficacy, tolerability, and safety of sibutramine used once daily in conjunction with behavior modification to treat mild to moderate obesity.\n This was a double-blind randomized placebo-controlled parallel-group comparative study of sibutramine 10 mg or 15 mg (or placebo) once daily for 1 year, given with dietary advice.\n A total of 485 obese men and women with uncomplicated obesity were included (mean age=42 years, mean body mass index=32.7 kg/m2).\n The outcomes were mean weight loss, percentage losing more than 5% or 10% of their body weight, and adverse drug effects.\n Among patients completing the study, those taking sibutramine 10 mg or 15 mg had greater mean weight loss compared with placebo at 12-month assessment (P < or = .001). Changes in body weight from baseline to end point were -1.6 kg for those taking placebo, -4.4 kg for those taking sibutramine 10 mg (P < or =.01, last observation carried forward [LOCF]), and -6.4 kg for those taking sibutramine 15 mg (P < or =.001, LOCF). For placebo patients, 20% lost 5% or more of their body weight compared with 39% of patients taking sibutramine 10 mg and 57% taking sibutramine 15 mg. Only 7% of the patients taking placebo lost 10% or more of their body weight, compared with 19% taking sibutramine 10 mg and 34% taking sibutramine 15 mg (P <.001 for both 10 mg and 15 mg vs placebo, and for both > or =5% and > or =10%).\n Sibutramine 10 mg or 15 mg once daily given with dietary advice produces and maintains statistically and clinically significantly greater weight loss than dietary advice alone (placebo) throughout a 12-month treatment period, and is safe and well tolerated.", "Sibutramine treatment in obesity results in significantly greater weight reduction compared with placebo, although weight loss with sibutramine may be accompanied by small but statistically significant mean increases in blood pressure (BP). This 52-week, placebo-controlled, double-blind, randomised study investigated the effects of sibutramine 20 mg once daily or placebo on body weight in 220 obese (body mass index (BMI) 27-40 kg/m2), hypertensive patients. At randomisation, hypertension was well controlled (< or = 95 mm Hg diastolic blood pressure (DBP)) with an angiotensin-converting enzyme (ACE) inhibitor, with or without concomitant thiazide diuretic therapy. Therapy for hypertension continued for the 52 weeks of the study. Sibutramine 20 mg produced significantly greater weight loss compared with placebo: 4.5 kg with sibutramine compared with 0.4 kg with placebo (last observation carried forward (LOCF); P < or = 0.05). A total of 62 patients (42.8%) treated with sibutramine lost < or = 5% of their body weight compared with six patients (8.3%) treated with placebo; 19 patients (13.1%) treated with sibutramine lost > or = 10% of their body weight compared with two patients (2.8%) treated with placebo (LOCF; P < or = 0.05 for both comparisons). Hypertension remained well controlled for the 52 weeks of the study with both sibutramine and placebo treatment. After 52 weeks, the differences between placebo treatment and sibutramine treatment for both mean supine systolic blood pressure (SBP) and DBP were approximately 3 mm Hg: mean DBP was 82.8 mm Hg with placebo treatment compared with 85.5 mm Hg with sibutramine treatment (LOCF; P = 0.004) and mean SBP was 130.4 mm Hg with placebo compared with 133.1 mm Hg with sibutramine (LOCF; P = 0.0497; both comparisons, sibutramine vs placebo). The mean increases in SBP and DBP did not appear to change the overall risk category for coronary heart disease end points. Changes in pulse rate at week 52 were a decrease of 0.3 beats per minute (bpm) for placebo treatment compared with an increase of 5.7 bpm for sibutramine treatment (P < 0.001). Mandated withdrawals from the study due to protocol-defined changes in BP were not statistically different between the two treatment groups. Greater favourable changes in lipid profile, serum glucose, and uric acid could be accounted for by greater weight losses occurring in the sibutramine treatment group. Sibutramine was well tolerated. This study indicates that in obese patients whose hypertension is well controlled at the outset with an ACE inhibitor, with or without concomitant thiazide diuretic therapy, sibutramine safely and effectively achieves weight loss without compromising good BP control.", "Fluoxetine's effect (30 mg, 60 mg, and placebo) on postcessation weight gain was studied among participants from a randomized, double-blind 10-week smoking cessation trial who met strict criteria for abstinence and drug levels. It was hypothesized that (a) fluoxetine would dose-dependently suppress postcessation weight gain and (b) drug discontinuation would produce dose-dependent weight rebound. During the on-drug phase, placebo participants gained weight linearly (M = 2.61 kg). exceeding both fluoxetine groups (30-mg group M = 1.33 kg, 60-mg group M = 1.25 kg). Weight suppression was initially greater for 60 mg than 30 mg, but both were followed by weight gain. Six months off drug produced greater dose-dependent weight rebound for 60 mg than 30 mg or placebo. Considering both on- and off-drug phases, weight gain for 60 mg of fluoxetine (M = 6.5 kg) was comparable with that for placebo (M = 4.7 kg) but greater than that for 30 mg (M = 3.6 kg). Fluoxetine appears to forestall postcessation weight gain, allowing time for the weight-conscious smoker to focus on quitting smoking rather than on preventing weight gain.", "To investigate whether the satiety-inducing agent sibutramine affected body weight and associated anthropometry in overweight and obese (body mass index (BMI) > 27) Type 2 diabetic patients on sulphonylurea therapy.\n A randomized, placebo-controlled trial was undertaken in 134 patients with stable metabolic control on chronic sulphonylurea therapy. Patients were placed on moderate caloric restriction and received treatment with either sibutramine (15 mg/day) or placebo for 6 months.\n Fifty-three of 69 sibutramine-treated and 57/65 placebo-treated patients completed the study. Both groups showed progressive weight loss. At the end of the trial weight loss was two times greater in the sibutramine group (mean +/- SEM; -4.5 +/- 0.5 kg) than placebo (-1.7 plus minus 0.5 kg, P < 0.001 vs. sibutramine). There was a trend for more patients to lose > 5% of initial body weight in the sibutramine group than placebo. BMI (P < 0.001) and waist circumference (P < 0.001) were also decreased to a greater extent by sibutramine. Mean reductions in HbA(1c) were commensurate with weight loss in both the sibutramine and placebo (- 0.78 +/- 0.17% and -0.73 +/- 0.23%; P = 0.84). Sibutramine was well tolerated with only two patients withdrawn due to potentially drug-related serious adverse events (palpitations).\n Sibutramine, in conjunction with moderate caloric restriction, enhances weight loss and reduces waist circumference in overweight and obese Type 2 diabetic patients receiving sulphonylurea therapy. This is associated with additional improvements in glycaemic control in a limited number of patients losing > or = 10% of their baseline body weight.", "We tested whether 14 wk of dexfenfluramine (30 mg) or fluoxetine (40 mg) treatment would prevent weight gain after subjects quit smoking. Normal-weight women (n = 144) were randomly assigned to drug or placebo on a double-blind basis for 2 wk before quitting smoking and 12 wk thereafter. The fluoxetine group had more dropouts (28/49, 57.1%) than the dexfenfluramine group (17/47, 36.2%), with an intermediate number of dropouts from the placebo group (21/48, 43.8%). All groups gained weight during treatment, but their amount and pattern of weight gain differed. In the first month after quitting smoking, the placebo group gained more weight than either the dexfenfluramine or fluoxetine group (P < 0.05). By 2 mo postcessation, dexfenfluramine still suppressed weight gain in comparison with placebo (P < 0.05); weight gain with fluoxetine was not differentiable from either dexfenfluramine or placebo. By 3 mo postcessation, the dexfenfluramine group had gained 1.0 +/- 0.7 kg, significantly less than either the placebo (3.5 +/- 0.7 kg) or fluoxetine (2.7 +/- 0.5 kg) groups. Three months after drug discontinuation, formerly medicated, but not placebo patients, showed additional weight gain, eliminating differences between groups. Results indicate that weight gain, an adverse accompaniment of smoking cessation, can be minimized to some degree by serotoninergic drugs, although only for the duration of drug treatment.", "In a six-week double-blind randomized trial, preceded by a one-week single-blind placebo treatment, the efficacy and the side-effects of fluoxetine (40-80 mg/d) (n = 30) and maprotiline (50-150 mg/d) (n = 35) were compared in hospitalized patients with DSM-III Major Depression without psychotic features. Efficacy was measured by means of the Hamilton Depression Rating Scale, the Raskin Depression Scale, the Covi Anxiety Scale, and a Clinical Global Impression. Side-effects were evaluated by an Adverse Events Scale. A statistically significant improvement was achieved in both treatment groups but success rates were modest. No differences in efficacy were found between the two groups. In addition, no statistically significant differences were found between the two groups either in frequency or in severity of adverse events. In fact, the only statistically significant difference found was in weight change: weight loss in the fluoxetine group and weight gain in the maprotiline group.", "Adolescent obesity is becoming a health problem in both developed and developing countries. Antiobesity drug therapy is not currently indicated for the treatment of adolescent obesity and remains investigational at this time. The aim of this study was to determine the efficacy and safety of sibutramine in obese adolescents. A randomized, double-blind, placebo-controlled trial, enrolling 60 adolescents, aged 14-17 yr, for 6 months was conducted. In the first month, all patients received placebo and a hypocaloric diet plus exercise orientation. For the next 6 months, participants received either sibutramine or placebo. Patients assigned to sibutramine group lost an average of 10.3 +/- 6.6 kg, and patients in placebo group lost 2.4 +/- 2.5 kg (P < 0.001). The mean body mass index reduction was significantly greater in the sibutramine group (3.6 +/- 2.5 kg/m(2)) than in the placebo group (0.9 +/- 0.9 kg/m(2); P < 0.001). No participant withdrew because of adverse events, and no difference in blood pressure or heart rate was noted between groups. There were no changes in echocardiographic parameters. In conclusion, sibutramine plus diet and exercise induced significantly more weight loss in obese adolescents.", "Serotonin-releasing agents prescribed as weight-loss medications have been implicated as a cause of acquired aortic and mitral valve abnormalities. Sibutramine hydrochloride (MERIDIA) is a serotonin and norepinephrine reuptake inhibitor with proven efficacy of weight reduction. The purpose of this study was to determine the incidence of cardiac valve disease in sibutraminetreated patients.\n Obese patients with type 2 diabetes mellitus enrolled in an ongoing double-blind, placebo-controlled, parallel-arm, 12-month study of sibutramine (followed by a 12-month open label extension) underwent transthoracic echocardiographic imaging and color Doppler interrogation for assessment of cardiac valve anatomy and function.\n A total of 210 patients were evaluated. Of these, 133 were receiving sibutramine (72 in the double-blind period), and 77 were receiving placebo. The mean+/-Standard Deviation age was 54+/-9 years, and the mean duration of treatment was 229+/-117 days (approximately 7.6 months). The prevalence of left-sided cardiac valve dysfunction was low and similar for the two treatment groups (sibutramine 3/133, or 2.3%; placebo 2/77, or 2.6%). All five cases were cases of aortic insufficiency; four were mild, one was severe (in a placebo patient). All three sibutramine cases were patients over age 50; two had a history of systemic hypertension.\n The prevalence of left-sided cardiac valve dysfunction was not higher than background in obese patients treated with sibutramine for an average of 7.6 months.", "Fluoxetine, an inhibitor of serotonin re-uptake, has been shown to cause weight loss in humans and animals. In order to determine the effects in diabetic subjects, 48 male and female, obese, type 2 non-insulin dependent diabetics being treated with insulin were randomized to receive fluoxetine 60 mg or placebo once daily in double blind fashion for 24 weeks. In all subjects, this treatment was preceded by four weeks and followed by six weeks of single blind placebo washout treatment. Subjects performed daily home glucose monitoring and were given instruction in a 1200 kcal American Diabetes Association diet. Fluoxetine treated subjects who completed the trial (n = 16) lost more weight than placebo treated subjects (n = 20) (9.3 +/- 2.4 vs. 1.9 +/- 2.9 kg +/- s.e.m, P less than 0.05). Subjects in the fluoxetine group also showed a greater percentage decrease in insulin dose than those in the placebo group (46.9 +/- 7.6% vs. 19.3 +/- 7.6%, P less than 0.01). During active treatment, the change in serum glucose levels did not differ between the two groups, while glycohemoglobin fell more in fluoxetine treated subjects than in placebo treated subjects at two of four follow-up visits. These results suggest that fluoxetine may be of benefit in the treatment of obese patients with type 2 non-insulin dependent diabetes mellitus.", "In a 12-month randomly allocated double-blind trial in 19 obese Type 2 diabetic patients, fluoxetine 60 mg daily compared to placebo produced a significant fall in median body weight after 3 months (3.8 kg), 6 months (6.5 kg), 9 months (7.1 kg) and at 1 year (5.8 kg). Median fasting blood glucose and HbA1c levels fell significantly after 3 months (1.9 mmol l-1) and 1.7%, respectively) and 6 months (1.8 mmol l-1 and 1.7%) but neither showed a significant difference to placebo after 9 or 12 months therapy with fluoxetine. There were no significant changes in serum cholesterol levels in the year but patients on fluoxetine showed a significant fall in serum triglyceride level (0.5 mmol l-1) after 3 months therapy but not thereafter. Compared to placebo there was a significant fall in median energy intake on fluoxetine after 3 months (257 kcal day-1) and 6 months (199 kcal day-1) but this difference was not significant at 9 or 12 months. There was also a significant fall in carbohydrate intake after 3 months (30 g day-1) and 6 months (23 g day-1) on fluoxetine as well as a significant fall in carbohydrate intake expressed as a percentage of the total daily energy intake; 5.9% at 3 months, 6.1% at 6 months, and 4.0% at 9 months. There were no significant effects on protein or fat intake except a significant increase in the intake of fat expressed as a percentage of daily energy intake, 5.9% after 6 months. Two of the nine patients on fluoxetine dropped out of the study due to gastrointestinal side-effects. Fluoxetine might prove to be a useful adjunct therapy in obese Type 2 diabetic patients where short-term weight loss and fall in carbohydrate intake and an improvement in glycaemia are indicated.", "Orlistat, a gastrointestinal lipase inhibitor that reduces dietary fat absorption by approximately 30%, may promote weight loss and reduce cardiovascular risk factors.\n To test the hypothesis that orlistat combined with dietary intervention is more effective than placebo plus diet for weight loss and maintenance over 2 years.\n Randomized, double-blind, placebo-controlled study conducted from October 1992 to October 1995.\n Obese adults (body mass index [weight in kilograms divided by the square of height in meters], 30-43 kg/m2) evaluated at 18 US research centers.\n Subjects received placebo plus a controlled-energy diet during a 4-week lead-in. On study day 1, the diet was continued and subjects were randomized to receive placebo 3 times a day or orlistat, 120 mg 3 times a day, for 52 weeks. After 52 weeks, subjects began a weight-maintenance diet, and the placebo group (n = 133) continued to receive placebo and orlistat-treated subjects were rerandomized to receive placebo 3 times a day (n = 138), orlistat, 60 mg (n = 152) or 120 mg (n = 153) 3 times a day, for an additional 52 weeks.\n Body weight change and changes in blood pressure and serum lipid, glucose, and insulin levels.\n A total of 1187 subjects entered the protocol, and 892 were randomly assigned on day 1 to double-blind treatment. For intent-to-treat analysis, 223 placebo-treated subjects and 657 orlistat-treated subjects were evaluated. During the first year orlistat-treated subjects lost more weight (mean +/- SEM, 8.76+/-0.37 kg) than placebo-treated subjects (5.81+/-0.67 kg) (P<.001). Subjects treated with orlistat, 120 mg 3 times a day, during year 1 and year 2 regained less weight during year 2 (3.2+/-0.45 kg; 35.2% regain) than those who received orlistat, 60 mg (4.26+/-0.57 kg; 51.3% regain), or placebo (5.63+/-0.42 kg; 63.4% regain) in year 2 (P<.001). Treatment with orlistat, 120 mg 3 times a day, was associated with improvements in fasting low-density lipoprotein cholesterol and insulin levels.\n Two-year treatment with orlistat plus diet significantly promotes weight loss, lessens weight regain, and improves some obesity-related disease risk factors.", "We evaluated the effects of 12-month treatment with sibutramine 15 mg daily compared with placebo on health-related quality of life (HRQL) in obese type II diabetes patients. We examined the associations between the changes in HRQL and in weight, glycaemic control, and haemodynamic variables. We also explored the predictive value of HRQL and its changes early during treatment.\n A randomised clinical trial. The subjects were enrolled in a 2-week single-blind run-in period with a modestly hypocaloric diet (700 kcal daily deficit) and then randomised to receive either sibutramine 15 mg (n=114, 60% female) or placebo (n=122, 58% female) once daily with the hypocaloric diet for 12 months.\n Obese (mean BMI 36 kg/m(2) and age 54 y) type II diabetes patients untreated with antidiabetic medications.\n The main outcome measures included body weight and HRQL (the RAND 36-Item Health Survey 1.0).\n The mean weight loss was greater in the sibutramine group (-7.1 kg) than in the placebo group (-2.6 kg, P<0.001). The baseline HRQL was relatively high. There were no significant differences between the treatment groups in glycaemic control or in any of the RAND-36 scales during the study. The scores on physical functioning (PF) and health change (HC) since last year improved in both groups and this improvement was related to weight loss. When HRQL changes were examined in categories of weight loss, the scores on PF and HC increased with >/=5% weight loss, but the scores on vitality (V) and general health (GH) increased only after >/=15% weight loss. Decrease in HbA1c was associated with increases in the scores of PF, GH, V, mental health, and HC. In the sibutramine group, the increase in diastolic blood pressure was associated with the decrease in the scores of PF, physical role functioning, emotional role functioning (ERF), social functioning (SF), and bodily pain. High baseline scores on ERF and SF, and low scores on V predicted weight loss at 12 months. Also, increasing scores on PF and V during the first 3 months predicted weight loss at 12 months. The sum of four dichotomised HRQL variables (baseline ERF >/=75=1 and <75=0; baseline SF>/=80=1 and <80=0; 3-month change in PF>0=1 and </=0=0; 3-month change in V>0=1 and </=0=0) predicted weight loss: In the group with sum 0, the mean(s.d.) weight change at 12 months was 0.0(2.6)% and with sum 4 it was -9.0(8.1)% of baseline weight.\n Despite the superior weight loss, sibutramine 15 mg daily did not produce HRQL benefits over placebo when measured with the generic RAND-36 in obese type II diabetes patients. PF and HC since last year improved with >/=5% weight loss, but >/=15% weight loss was needed to achieve a cluster of HRQL improvements. The decrease in HbA1c was associated with many HRQL benefits. Poor baseline HRQL and the improvement observed in the first months of treatment may prove to be useful in predicting success in long-term weight loss.", "To evaluate the effects of sibutramine (15 and 20 mg/day) on weight, metabolic control, and blood pressure in metformin-treated obese subjects with type 2 diabetes.\n A 12-month randomized prospective placebo-controlled double-blind study was performed. It included 21 primary and secondary care centers in England, Canada, France, and Belgium. A total of 195 subjects (44% male) with type 2 diabetes and a BMI >27 kg/m(2) were studied. Changes were assessed in weight, blood pressure and resting heart rate, HbA(1c), fasting glucose, and lipids.\n Sibutramine induced significant weight loss (P < 0.001) with both 15 mg/day (5.5 +/- 0.6 kg at 12 months) and 20 mg/day (8.0 +/- 0.9 kg), whereas placebo did not (0.2 +/- 0.5 kg). Weight loss > or = 10% was achieved by 14 and 27% of subjects receiving 15 and 20 mg, respectively, but by none given placebo. Glycemic control improved in parallel with weight loss, and subjects who lost > or = 10% weight showed significant decreases in both HbA(1c) (1.2 +/- 0.4%, P < 0.0001) and fasting plasma glucose (1.8 mmol/l, P < 0.001). HDL cholesterol increased slightly with the higher dose, whereas plasma triglycerides fell with both doses, especially in subjects with weight loss of > or = 10% (a 29% decrease, P < 0.01). Treatment was generally well tolerated. Sibutramine treatment raised sitting diastolic blood pressure by > or = 5 mmHg in a higher proportion of patients than did placebo (43% with 15 mg/day vs. 25% with placebo, P < 0.05), but this effect was less evident in subjects who had a weight loss of > or = 10% weight. Pulse rate increased significantly more with sibutramine, being > or = 10 bpm higher in 42% of treated patients versus 17% with placebo (P < 0.01).\n Sibutramine can be an effective adjunct to metformin treatment in selected obese type 2 diabetic subjects and improves metabolic control in individuals who lose weight.", "To determine the effect of orlistat, a new lipase inhibitor, on long-term weight loss, to determine the extent to which orlistat treatment minimizes weight regain in a second year of treatment, and to assess the effects of orlistat on obesity-related risk factors.\n This was a 2-year, multicenter, randomized, double-blind, placebo-controlled study. Obese patients (body mass index 28 to 43 kg/m2) were randomized to placebo or orlistat (60 or 120 mg) three times a day, combined with a hypocaloric diet during the first year and a weight maintenance diet in the second year of treatment to prevent weight regain. Changes in body weight, lipid profile, glycemic control, blood pressure, quality of life, safety, and tolerability were measured.\n Orlistat-treated patients lost significantly more weight (p<0.001) than placebo-treated patients after Year 1 (6.6%, 8.6%, and 9.7% for the placebo, and orlistat 60 mg and 120 mg groups, respectively). During the second year, orlistat therapy produced less weight regain than placebo (p = 0.005 for orlistat 60 mg; p<0.001 for orlistat 120 mg). Several obesity-related risk factors improved significantly more with orlistat treatment than with placebo. Orlistat was generally well tolerated and only 6% of orlistat-treated patients withdrew because of adverse events. Orlistat leads to predictable gastrointestinal effects related to its mode of action, which were generally mild, transient, and self-limiting and usually occurred early during treatment.\n Orlistat administered for 2 years promotes weight loss and minimizes weight regain. Additionally, orlistat therapy improves lipid profile, blood pressure, and quality of life.", "Increased prevalence of adolescent obesity requires effective treatment options beyond behavior therapy.\n To see whether sibutramine reduced weight more than placebo in obese adolescents who were receiving a behavior therapy program.\n 12-month, 3:1 randomized, double-blind trial conducted from July 2000 to February 2002.\n 33 U.S. outpatient clinics.\n 498 participants 12 to 16 years of age with a body mass index (BMI) that was at least 2 units more than the U.S. weighted mean of the 95th percentile based on age and sex, to the upper limit of 44 kg/m2. Interventions: Site-specific behavior therapy plus 10 mg of sibutramine or placebo. Blinded study medication dose was uptitrated to 15 mg or placebo at month 6 if initial BMI was not reduced by 10%.\n Body mass index, waist circumference, body weight, fasting lipid and glycemic variables, safety, and tolerability.\n Seventy-six percent of patients in the sibutramine group and 62% of patients in the placebo group completed the study. The estimated mean treatment group difference at month 12 (linear mixed-effects model) favored sibutramine for change from baseline in BMI (-2.9 kg/m2 [95% CI, -3.5 to -2.2 kg/m2]) and body weight (-8.4 kg [CI, -9.7 to -7.2 kg]) (P < 0.001 for both). The sibutramine group had greater improvements in triglyceride levels, high-density lipoprotein cholesterol levels, insulin levels, and insulin sensitivity (P < or = 0.001 for all). The rate of tachycardia was greater with sibutramine vs. placebo (12.5% vs. 6.2%; difference, 6.3 percentage points [CI, 1.0 to 11.7 percentage points]) but did not lead to increased withdrawal (2.4% vs. 1.5%; difference, 0.9 percentage point [CI, -1.7 to 3.5 percentage points]).\n The 1-year study duration precluded assessment of long-term weight maintenance and putative health benefits and harms, and 24% and 38% of the sibutramine and placebo groups, respectively, did not complete follow-up.\n Sibutramine added to a behavior therapy program reduced BMI and body weight more than placebo and improved the profile of several metabolic risk factors in obese adolescents.", "The prevalence of overweight and obesity in children and adolescents is increasing in both the United States and Mexico.\n The goal of this article was to assess the efficacy and safety of sibutramine in obese Mexican adolescents.\n This was a 6-month, randomized, double-blind, placebo-controlled, prospective clinical trial of sibutramine QD. Male and female patients aged 14 to 18 years with sex-specific body mass index (BMI) for age and sex >85th percentile were eligible. The primary end points for the trial were the baseline versus end point absolute values for body weight, BMI, and percentage of the initial BMI (%BMI); secondary end points were waist circumference and percentage of the initial waist circumference (%waist). These were measured at days -15, 0, 30, 60, 90, 120, 150, and 180 of the study. Quality of life was assessed at the study start and end using the 36-Item Short-Form Health Survey (SF-36) questionnaire. Blood pressure and heart rate were assessed, and adverse events (AEs) were recorded. Both groups received individually tailored diet and exercise programs.\n Forty-six patients (age range, 14-18 years) with a BMI >95th percentile for age were included (sibutramine group, n = 23 [14 females, 9 males]; placebo group, n = 23 [12 females, 11 males]). Twenty-one patients in the sibutramine group and 19 patients in the placebo group completed the 6-month trial. Using the intent-to-treat data, weight (mean [SD]) in the sibutramine group changed from 92.5 (14.6) kg to 85.7 (14.4) kg, for a net weight loss of 7.3 kg (95% CI 4.6-9.9), a waist circumference loss of 8.0 cm (95% CI, 4.7-11.3), and a % BMI loss of 9.2% (95% CI, 6.9-11.6). In the placebo group, weight changed from 98.9 (22.7) kg to 94.6 (22.5) kg, a weight loss of 4.3 kg (95% CI, 1.7-6.9), a waist circumference loss of 3.8 cm (95% CI, 0.7-7.0), and a %BMI loss of 5.2% (95% CI, 2.4-7.9) (P < 0.05 for all intragroup comparisons; P > 0.05 for the intergroup comparisons). Mean (SD) scores on the SF-36 scale in the sibutramine group changed from 78.0 (13.3) at baseline to 84.8 (7.4) at study end (P < 0.05); the respective values in the placebo group were 82.8 (10.3) and 87.3 (7.6) (P < 0.05). At base-line, systolic blood pressure (SBP) was 116.7 (5.9) mm Hg in the sibutramine group and 118.3 (7.6) mm Hg in the placebo group; at end point, the respective SBPs were 112.4 (9.6) mm Hg and 112.6 (6.5) mm Hg. At baseline, diastolic blood pressure (DBP) was 78.9 (4.5) mm Hg in the sibutramine group and 79.5 (5.2) mm Hg in the placebo group; at end point, the respective DBPs were 73.5 (6.3) mm Hg and 76.6 (6.2) mm Hg. At baseline, heart rate was 76.3 (6.4) beats/min in the sibutramine group and 81.1 (9.5) beats/min in the placebo group; at end point, the respective findings were 79.8 (8.8) beats/min and 77.6 (8.6) beats/min (P > 0.05 for all preceding intergroup comparisons). One patient in the sibutramine group had increased blood pressure (at month 3) and 3 had increased heart rate (at months 1, 2, and 4); 2 patients receiving placebo had increased blood pressure (month 3) and 2 had increased heart rate (at months 1 and 3). These changes disappeared in 1 week and did not require treatment or trial suspension. Additionally, in the sibutramine group, 3 patients experienced 4 mild AEs: headache, dry mouth, headache with nausea, and headache with weakness and paleness (P > 0.05). In the placebo group, 3 patients experienced 4 mild AEs: 2 cases of headache, as well as 1 case of headache with somnolence and 1 case of headache with dry mouth (P > 0.05).\n Sibutramine 10 mg QD in addition to diet and exercise was effective and generally well tolerated in this population of obese Mexican adolescents.", "To determine if obese non-insulin-dependent diabetic patients lose more weight when treated for 24 weeks (6 months) with orlistat (120 mg t.i.d.), in conjunction with a hypocaloric diet plus behavioural counselling, than when treated by placebo (t.i.d.) plus similar instructions. The secondary objectives were to evaluate the effects on glucose profile and to determine the tolerability and safety of orlistat.\n Double-blind, parallel, randomized, placebo-controlled, multicentre study.\n Obese, non-insulin-dependent diabetic patients, aged 18-70 years old, with BMI > 27 kg/m2, evaluated at 10 Latin-American centres, in five countries. EFFICACY AND TOLERABILITY MEASUREMENTS: After screened, eligible patients passed by a 2-week placebo run-in period receiving a hypocaloric diet. On day 0, patients were randomized to orlistat or placebo for 24 weeks. At each visit, body weight, blood pressure and waist circumference were measured. At the screening visit, baseline visit (week 0), and at weeks 8, 16 and 24, a central laboratory was in charge of measuring fasting glucose and insulin, HbA1c, postprandial glucose and insulin, fasting total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and postprandial triglycerides. Other safety laboratory assessments were measured locally at the screening visit, baseline visit and at the end of the study. Adverse events were assessed at each visit from baseline.\n After 24 weeks of treatment, the orlistat group lost an average of 4.7% of initial body weight vs. 3.0% in the placebo group (p = 0.0003). A greater weight loss was achieved in the orlistat compared with the placebo group (4.24 +/- 0.23 vs. 2.58 +/- 1.46 kg, p = 0.0003). Almost twice as many patients receiving orlistat (30% vs. 17%) lost > or = 5% of initial body weight (p = 0.003). Orlistat treatment plus diet compared to placebo plus diet was associated with significant improvement in glycaemic control, as reflected in decreases in HbA1c (p = 0.04), fasting plasma glucose (p = 0.036) and postprandial glucose (p = 0.05). Orlistat-treated patients had a mean decrease in glucose levels of 1.00 +/- 0.34 mmol/l [3.7%] vs. 0.01 +/- 0.30 mmol/l for placebo group, at week 24 and an absolute decrease of HbA1c of 0.61 +/- 0.15 vs. a decrease of 0.22 +/- 0.14% in the placebo group. Orlistat therapy also resulted in significantly greater improvements than placebo in lipid profile, with reductions in total cholesterol (p = 0.0001) and LDL-cholesterol (p = 0.002). Mild to moderate transient gastrointestinal events were reported, mainly with orlistat treatment, but their association with withdrawal from the study was low.\n Orlistat is a useful and an effective therapy in obese diabetic patients, promoting clinically significant weight loss and improved glycaemic control and lipid profile.", "Significant weight gain is a side effect associated with olanzapine treatment in some patients. We investigated the efficacy of high-dose fluoxetine as a weight-reducing agent for patients who develop early weight gain with olanzapine treatment. Patients that gained >/=3% of their baseline weight in the initial 8 weeks of olanzapine treatment (n=31) were randomized to double-blind treatment with placebo or fluoxetine (60 mg/day). Clinical, weight, and weight-related measures were assessed. Fluoxetine failed to demonstrate weight-reducing effects (fluoxetine group: baseline mean 80.5 kg, SD=19.1, last mean=83.5 kg, SD=19.8; placebo group: baseline mean=77.1 kg, SD=12.1, last mean=78.8 kg, SD=10.6; F=1.3; df=1, 18; p=0.3). There were no differential effects in psychopathology, extrapyramidal side effects or weight-related measures between the placebo and fluoxetine groups. Serotonin reuptake inhibitors are probably not a practical option to counteract weight gain induced by atypical antipsychotics. Atypical-induced weight gain may result from mechanisms other than 5HT reuptake blockade.", "Weight reduction on its own is observed to cause improvement in some of the abnormalities seen in patients with polycystic ovary syndrome (PCOS). With respect to this observation, we studied the possible effects of different serotonin reuptake inhibitors (fluoxetine and sibutramine) on serum leptin levels that might play a role in the obesity component seen in patients with PCOS. In a random design, sixteen patients were assigned to fluoxetine and sibutramine for a period of 10 days. In both treatment groups, no significant differences were observed between pre-treatment and post-treatment values in insulin levels (p > 0.05). There was no significant difference between pretreatment and post-treatment serum leptin levels in the fluoxetine treatment group (p > 0.05). However, a significant reduction was observed in the serum leptin levels at the end of treatment in the sibutramine group (p < 0.05). The observed difference in the serum leptin response to the treatment effect of sibutramine compared to fluoxetine seems to be due to a mechanism independent of serotonin reuptake inhibition, possibly to the thermogenic effect of the sibutramine itself. Further studies with larger groups are warranted, to examine the mechanism of the weight-reducing effect of sibutramine. Detailed analyses of basal metabolic activity and change in serum leptin levels should be carried out.", "To assess the effects of weight reduction with 10mg of sibutramine or placebo on blood pressure during 24 hours (ambulatory blood pressure monitoring), on left ventricular mass, and on antihypertensive therapy in 86 obese and hypertensive patients for 6 months.\n The patients underwent echocardiography, ambulatory blood pressure monitoring, and measurement of the levels of hepatic enzymes prior to and after treatment with sibutramine or placebo.\n The group using sibutramine had a greater weight loss than that using placebo (6.7% versus 2.5%; p<0.001), an increase in heart rate (78.3 +/- 7.3 to 82 +/- 7.9 bpm; p=0.02), and a reduction in the left ventricular mass/height index (105 +/- 29.3 versus 96.6 +/- 28.58 g/m; p=0.002). Both groups showed similar increases in the levels of alkaline phosphatase and comparable adjustments in antihypertensive therapy; blood pressure, however, did not change.\n The use of sibutramine caused weight loss and a reduction in left ventricular mass in obese and hypertensive patients with no interference with blood pressure or with antihypertensive therapy.", "It is well established that the risk of developing type 2 diabetes is closely linked to the presence and duration of overweight and obesity. A reduction in the incidence of type 2 diabetes with lifestyle changes has previously been demonstrated. We hypothesized that adding a weight-reducing agent to lifestyle changes may lead to an even greater decrease in body weight, and thus the incidence of type 2 diabetes, in obese patients.\n In a 4-year, double-blind, prospective study, we randomized 3,305 patients to lifestyle changes plus either orlistat 120 mg or placebo, three times daily. Participants had a BMI >/=30 kg/m2 and normal (79%) or impaired (21%) glucose tolerance (IGT). Primary endpoints were time to onset of type 2 diabetes and change in body weight. Analyses were by intention to treat.\n Of orlistat-treated patients, 52% completed treatment compared with 34% of placebo recipients (P < 0.0001). After 4 years' treatment, the cumulative incidence of diabetes was 9.0% with placebo and 6.2% with orlistat, corresponding to a risk reduction of 37.3% (P = 0.0032). Exploratory analyses indicated that the preventive effect was explained by the difference in subjects with IGT. Mean weight loss after 4 years was significantly greater with orlistat (5.8 vs. 3.0 kg with placebo; P < 0.001) and similar between orlistat recipients with impaired (5.7 kg) or normal glucose tolerance (NGT) (5.8 kg) at baseline. A second analysis in which the baseline weights of subjects who dropped out of the study was carried forward also demonstrated greater weight loss in the orlistat group (3.6 vs. 1.4 kg; P < 0.001).\n Compared with lifestyle changes alone, orlistat plus lifestyle changes resulted in a greater reduction in the incidence of type 2 diabetes over 4 years and produced greater weight loss in a clinically representative obese population. Difference in diabetes incidence was detectable only in the IGT subgroup; weight loss was similar in subjects with IGT or NGT [correction].", "A large collaborative 8-week study has shown fluoxetine to be effective and safe in treating patients with bulimia nervosa. The present study evaluated fluoxetine over 16 weeks.\n Fifteen US out-patient psychiatry clinics conducted a double-blind parallel study in men and women with DSM-III-R bulimia nervosa (483 patients entered, 398 randomised [3:1 ratio, fluoxetine 60 mg/day or placebo], 225 completed). Outcome measures included change in vomiting and binge-eating episodes per week. Eating Disorder Inventory, Clinical Global Impressions and Patient's Global Impression.\n Compared with placebo, fluoxetine treatment resulted in significantly greater reductions in vomiting (F[1,360] = 14.73, P < 0.0001) and binge-eating (F[1,360] = 14.39, P = 0.0002) episodes per week at endpoint and improvement in other outcome measures. Adverse event, vital sign and laboratory analyses indicated that fluoxetine was safe.\n Fluoxetine appeared to be safe and effective in patients with bulimia nervosa for up to 16 weeks." ]	Fluoxetine, orlistat, and sibutramine can achieve statistically significant weight loss over 12 to 57 weeks. The magnitude of weight loss is modest, however, and the long-term health benefits remain unclear. The safety of sibutramine is uncertain. There is a paucity of data on other drugs for weight loss or control in persons with type 2 diabetes.
CD003826	[ "11442615", "9810992", "8198723", "8113473", "16837136", "7591421", "11493295", "1448534", "2009067", "2529659", "8905040", "10490109", "16711171", "11207693" ]	[ "Prevention of hypertrophic scars and keloids by the prophylactic use of topical silicone gel sheets following a surgical procedure in an office setting.", "The use of silicone occlusive sheeting (Sil-K) and silicone occlusive gel (Epiderm) in the prevention of hypertrophic scar formation.", "Cica-Care gel sheeting in the management of hypertrophic scarring.", "A controlled clinical trial of topical silicone gel sheeting in the treatment of hypertrophic scars and keloids.", "A prospective randomized clinical trial to investigate the effect of silicone gel sheeting (Cica-Care) on post-traumatic hypertrophic scar among the Chinese population.", "Vitamin E added silicone gel sheets for treatment of hypertrophic scars and keloids.", "Silicone versus nonsilicone gel dressings: a controlled trial.", "Hypertrophic sternal scars: silicone gel sheet versus Kenalog injection treatment.", "Topical silicone gel for the prevention and treatment of hypertrophic scar.", "Topical silicone gel: a new treatment for hypertrophic scars.", "Effectiveness of silicone sheets in the prevention of hypertrophic breast scars.", "Prospective, single-blind, randomized, controlled study to assess the efficacy of the 585-nm flashlamp-pumped pulsed-dye laser and silicone gel sheeting in hypertrophic scar treatment.", "Evaluation of a self-adherent soft silicone dressing for the treatment of hypertrophic postoperative scars.", "Effect of the 585 nm flashlamp-pumped pulsed dye laser for the treatment of keloids." ]	[ "Topical silicone gel sheeting has been used for more than 20 years to help reduce the size of hypertrophic scars and keloids. Its clinical efficacy and safety is well established.\n To determine whether topical silicone gel sheeting can be used to prevent hypertrophic scars and keloids from forming following dermatologic skin surgery.\n Patients undergoing skin surgery were stratified into two groups: those with no history of abnormal scarring (low-risk group) and those with a history of abnormal scarring (high-risk group). Following the procedure, patients within each group were randomized to receive either routine postoperative care or topical silicone gel sheeting (48 hours after surgery). Patients were followed for 6 months.\n In the low-risk group, there were no statistical differences between individuals using routine postoperative care or using topical silicone gel sheets. In the high-risk group, there was a statistical difference (39% versus 71%) between patients who did not develop abnormal scars and used topical silicone gel sheeting and patients who developed abnormal scars after routine postoperative treatment. Those individuals having a scar revision procedure also showed a statistical difference if topical silicone gel sheeting was used following surgery.\n Topical silicone gel sheeting, with a 20-year history of satisfaction in dermatology, now appears to be useful in the prevention of hypertrophic scars and keloids in patients undergoing scar revision.", "The development of hypertrophic scars and keloids is an unsolved problem in the process of wound healing. For this reason, a successful treatment to prevent excessive scar formation still has not been found. Over the last decade, however, a promising new treatment has been introduced. Silicone materials have proved to reduce the amount of scar tissue and are believed even to prevent hypertrophic scar and keloid formation. In this study, the prophylactic effect of a silicone occlusive sheeting (Sil-K, Degania, Israel) and a silicone occlusive gel (Epiderm, Inamed B.V., The Netherlands) was investigated in a bilateral breast-reduction scar model in which the nontreated scars were supported by nonocclusive Micropore (3M, The Netherlands). The inframammary scars of 129 female patients with a mean age of 31 years ( 14 to 69 years) were studied up to 1 year after the operation. The width and height were measured, and B-scan ultrasound, laser-Doppler flowmetry, and color measurements were used as objective indicators to distinguish between normal and exuberant scars. Three months following the operation, 64.3 percent of the patients developed a hypertrophic scar, which was reduced to 56.6 percent after 6 months and down to 35.3 percent after 1 year. No keloids were seen. Patients with an easily tanning skin, nonsmokers, and patients with an allergy showed more hypertrophic scar formation. Neither Sil-K, used in 68 patients, nor Epiderm, used in 61 patients, could prevent the formation of hypertrophic scars. If both groups were taken together, the scars treated with silicone materials even developed significantly more hypertrophy compared with the Micropore-applicated scars.", "A prospective, controlled clinical trial was undertaken to assess the efficacy and safety of two types of silicone gel, Silastic Gel Sheeting (SGS) and Cica-Care (CC), in the management of hypertrophic scars. Forty-two patients were randomly assigned to SGS and CC groups and their hypertrophic scars were divided into treated and control areas. Extensometric measurements were made at monthly intervals for 6 months and significant improvement of the treated areas relative to the control areas was observed. The two gels were not significantly different in efficacy or safety, but CC, being more adhesive and more comfortable than SGS, has advantages in ease of use and patient acceptability.", "nan", "This study aimed to determine the efficacy of silicone gel (Cica-Care) on severe post-traumatic hypertophic scars among the Chinese population.\n A randomized clinical trial (RCT) was conducted on 45 Chinese patients with post-traumatic hypertrophic scars. Twenty-two subjects were placed in the experimental group with silicone gel sheeting (SGS) applied 24h per day for 6 months while all subjects were taught to massage the scar daily for 15 min serving as the control intervention. Scar assessments were conducted regularly to measure the changes in thickness, pigmentation, vascularity, pliability, itchiness and pain.\n Two-way repeated ANOVA showed a significant difference between MT group and SGS group on scar thickness. The post hoc comparison analysis showed that the difference was significant at the post-2-month (p=0.008) and post-6-month (p<0.001) intervention. The SGS group also showed changes in pigmentation which resembled normal skin but no statistical significance was found. Pain, itchiness and pliability were also improved after intervention.\n This study indicated that silicone gel sheeting (Cica-Care) was effective to reduce thickness, pain, itchiness and pliability of the severe hypertrophic scar among the Chinese population. The moisturization effect of the tough and hard scar might contribute to the reduction of the skin thickness after 6 month's intervention.", "Trauma of various origins can induce a connective tissue disorder that leads to keloids. This condition has yet not been clearly distinguished from scars and hypertrophic scars. Only electronmicroscopic and biochemical data can help to do this. Among some more or less therapeutic approaches, the use of silicon (polydimethylsiloxane) plates, wrapped on the keloid surface, has been reported effective by some authors. These authors also demonstrated that it is not the mechanical pressure that is the mechanism of action, but a direct action on fibroblasts and a hyperhydration of subcutaneous tissue. The authors of this study conceived that the silicon plate may be able to improve the transdermal penetration of a compound such as vitamin E. This vitamin is capable of preserving some important morphologic and functional features of biological membranes by means of its phytilside chain of the molecule acting as a stabilizer of lysosomal membranes.\n Eighty patients of both sexes, aged between 18 and 63 years, who had hypertrophic scars and keloids, were admitted to the trial. The patients were randomized to two groups in a simple-blinded study. Group A: Forty patients whose scars have been covered with silicon plates with added vitamin E. Group B: Forty patients treated with simple silicone gel sheets. No pressure bandages were used, only tape fixing the sheet for 10 hours overnight. The trial lasted for 2 months. The results were recorded at 4 and 8 weeks, evaluating the improvement according to a Scott-Husskinson scale. For objective assessment photos were taken. The results were analyzed by the chi-square test.\n At the end of the first month, group A had improved by more than 50% in 85% of cases, whereas the improvement in group B was 55% (P < 0.01). At the end of the second month, 95% of patients in group A had improved by 50%, whereas 75% had improved by 50% in group B (P < 0.05).\n Vitamin E added to the silicon plate scored better than the simple silicon plate at the end of both periods. We have reported the successful combined action of vitamin E and silicone gel sheets in scar treatment, especially in the short-term prophylaxis of hypertrophic scars or keloids.", "Silicone gel dressings decrease scar volume and soften hypertrophic tissue, allowing it to be more easily controlled by other methods. Although silicone does not appear to be an essential component of the treatment, nonsilicone dressings have been reported to cause no change in physical parameters during a 2-month treatment period.\n To compare silicone and nonsilicone gel dressings in the treatment of keloids and hypertrophic scars, including a control group, and to evaluate the effectiveness of these treatments using two new assessment techniques.\n Patients were randomly chosen to receive silicone or nonsilicone gel dressings in a 4.5-month controlled prospective study. Scar size, induration, and symptoms were evaluated before and after the treatment. Scar color was visually measured using a color palette catalog, and a new device was developed to measure intracicatricial pressure.\n All of the measured parameters were significantly reduced in both silicone- and nonsilicone-treated groups, as compared to the control, with no significant differences between them.\n Silicone and nonsilicone gel dressings are equally effective in the treatment of keloids and hypertrophic scars.", "A prospective, randomized trial was designed to compare the standard Kenalog injection of established hypertrophic sternal scars with topical silicone gel sheets (Spenco). Fourteen poststernotomy cardiac patients with symptomatic scars were randomized to treatment in one-half of the scar with Kenalog injection. Simultaneously, the other half of the scar received the silicone gel sheet. The standard Kenalog injection used was 40 mg/ml x 1 cc, mixed with 1 cc of 1% Xylocaine with epinephrine. The gel sheets were worn continuously for 12 hours for 12 weeks. Pretreatment and posttreatment photographs were compared for color and appearance by blindfolded observers. Scar measurements (length, width, and height) were taken weekly in each area, and the patients were asked to rank their symptoms within each half as worse, the same, or better. The primary outcome of patient preference was analyzed sequentially, and the recruitment was terminated after 11 patients had completed the study, 10 of whom favored the silicone gel treatment (p < 0.05). Three patients remained in the treatment phase at the time of termination and completed the study subsequently. For the total sample of 14 subjects, 11 preferred the silicone gel, 1 expressed no preference, and 2 preferred the injection. The average time to improvement was 3.9 +/- 0.62 days (gel) versus 6.8 +/- 1.86 days (Kenalog). This study demonstrates that silicone gel sheets provide earlier symptomatic relief and a more aesthetic scar and are the preferred treatment of patients with symptomatic hypertrophic sternal scars.", "We studied the effects of a silicone gel bandage that was worn for at least 12 hours daily on the resolution of hypertrophic burn scar. In a second cohort, the prevention of hypertrophic scar formation in fresh surgical incisions by this bandage was also evaluated. In 19 patients with hypertrophic burn scars, elasticity of the scars was quantitated serially with the use of an elastometer. An adjacent or mirror-image hypertrophic burn scar served as a control. Scar elasticity was increased after both 1 and 2 months compared with that in controls. There was corresponding improvement clinically that persisted for at least 6 months. In the other cohort, scar volume changes in 21 surgical incisions were measured before and after 1 and 2 months. Gel-treated incisions gained less volume than control incisions after both intervals. Clinical assessment corroborated this quantitative demonstration of a decrement in scar volume. We concluded that topical silicone gel is efficacious, both in the prevention and in the treatment of hypertrophic scar.", "A prospective, controlled clinical trial was designed to assess the efficacy of a new treatment of hypertrophic scars. Silicone gel sheeting was applied to 14 hypertrophic scars in 10 adults for 8 weeks. The treated scars and untreated, mirror-image or adjacent control scars were photographed, biopsy specimens were taken, and they were measured elastometrically before and after treatment. Photography and elastometry were repeated 4 weeks after treatment was discontinued. All the scars that had been treated for at least 12 hours a day were improved clinically after 4 weeks. There was further clinical improvement during the second 4 weeks of treatment. Elastometrically, the treated scars were improved significantly at 4, 8, and 12 weeks, compared with both their own treatment value and the control scars (p less than 0.05). Control scars were unchanged elastometrically. Clinical improvement persisted for at least 4 weeks after treatment was discontinued. The silicone gel sheeting was well tolerated, except for occasional transient rashes or superficial maceration--both of which resolved promptly when treatment was withdrawn. There was no histologic evidence of inflammation or foreign body reaction suggesting that silicone had entered the treated tissues. We conclude that this simple method of treating hypertrophic scar is efficacious, even in relatively chronic cases. The mechanism of action of silicone gel, which is apparently not related to compression, remains to be determined.", "A clinical study was designed in which 20 women who were to undergo bilateral McKissock reduction mammaplasties were requested to use a precut silicone elastomer sheet over the scars of one breast, starting at the time of suture removal. The patients were instructed to use the silicone sheet for 12 hours each day for 2 months. Evaluation of the scars at 2 months revealed that 60% of the nontreated scars were hypertrophic and only 25% of the treated scars were hypertrophic. The difference was found to be statistically significant (p < 0.05). The use of the sheets was discontinued after 2 months and the beneficial effect remained at the 6-month evaluation.", "To determine the efficacy of the 585-nm flashlamp-pumped pulsed-dye laser and silicone gel sheeting in the treatment of hypertrophic scars in lighter- and darker-skinned patients.\n Prospective, single-blind, randomized, internally controlled, comparison investigation.\n Large academic dermatology department.\n Twenty patients with hypertrophic scars (19 completed the laser treatments and 18 completed the silicone gel sheeting treatments).\n Clinical measurements included hypertrophic scar blood flow, elasticity, and volume. Patients' subjective complaints of pruritus, pain, and burning were also monitored. Histological assessment of fibrosis, number of telangiectasias, and number of mast cells was performed. Statistically significant improvements in clinical measurements and patients' subjective complaints determined treatment success.\n Mean scar duration was 32 months (range, 4 months to 20 years). There was an overall reduction in blood flow, volume, and pruritus over time (P = .001, .02, and .005, respectively). However, no differences were detected among treatment and control groups. There was no reduction in pain or burning (0-40 weeks), elasticity (8-40 weeks), or fibrosis (0-40 weeks, n = 5 biopsies) in the treated or control sections of the scars. Unlike in a previous study, the number of mast cells in the scars was similar to the number of mast cells in healthy skin.\n Clinical results demonstrate that the improvements in scar sections treated with silicone gel sheeting and pulsed-dye laser were no different than in control sections.", "The primary objective was to compare the efficacy of a self-adherent soft silicone dressing (Mepiform) with 'left-alone' management of hypertrophic scars using theVancouver Scar Scale. Secondary objectives were to follow photographs of the scars, patients' opinions of the scars, and doctors' and patients' assessments of the overall dressing performance, safety and tolerance.\n An exploratory open randomised controlled clinical investigation was undertaken on 11 female patients aged 21-43 years with postoperative scars (nine following breast surgery, two following lower abdominal-glutealplasty). Treatment was initiated between two weeks and two months (mean 4.7 weeks) after surgery. Ten patients completed the 12-month investigation; one patient in the treatment group discontinued for personal reasons.\n All parameters in the Vancouver Scar Scale improved in both groups, although patients treated with the soft silicone dressing showed greater and more rapid improvements compared with the non-treated patients, while their assessments of the condition of the scar were more favourable. Medical staff rated the overall dressing performance as 'very good' or'good'. One adverse event was reported--local skin irritation at the site of the scar.\n The results suggest that patients treated with the soft silicone dressing experienced greater and more rapid improvements compared with non-treated patients. These results concur with those of previous studies. The fact that Mepiform is self-adhesive and causes limited damage to the stratum corneum on removal gives it an added value compared with non-adhesive silicone gel dressings.", "Due to its potential effects on skin microcirculation and collagen metabolism, the 585 nm flashlamp-pumped pulsed dye laser has been proposed for treating abnormal scars. Indeed, one of the main problems with keloidal scars is their disfiguring erythematous color.\n To assess the efficacy of the 585 nm pulsed dye laser on the appearance of keloids.\n Eleven patients with skin phototypes II-IV and keloids were treated with the 585 nm pulsed dye laser. After one to three treatment sessions, clinical assessments of the scars were performed in combination with remittance spectroscopy measurements of the redness and melanin pigmentation. A group of nine keloids covered by silicone gel sheeting served as controls. Data were compared statistically.\n During laser treatments, a discrete decrease in redness of the scars was clinically reported. However, this improvement was not confirmed by the objective spectrophotometric data. No side effects, especially hyperpigmentation, were disclosed. The keloids redness was not improved in the control group.\n The 585 nm pulsed dye laser yields only minimal effects, if any, on the erythema of keloids. Similarly silicone gel sheeting does not modify the keloids redness." ]	Trials evaluating silicon gel sheeting as a treatment for hypertrophic and keloid scarring are of poor quality and highly susceptible to bias. There is weak evidence of a benefit of silicon gel sheeting as a prevention for abnormal scarring in high risk individuals but the poor quality of research means a great deal of uncertainty prevails.
CD006389	[ "16495014", "21262413", "11240079", "12488121", "22099722", "20363809", "16816304", "7673536" ]	[ "Short- and long-term efficacy of brief cognitive-behavioral therapy for patients with chronic temporomandibular disorder pain: a randomized, controlled trial.", "Short-term cognitive behavioral therapy for non-cardiac chest pain and benign palpitations: a randomized controlled trial.", "A randomized controlled component analysis of a behavioral medicine rehabilitation program for chronic spinal pain: are the effects dependent on gender?", "A controlled evaluation of cognitive behavioural therapy for posttraumatic stress in motor vehicle accident survivors.", "Cognitive behaviour therapy and supportive therapy for bipolar disorders: relapse rates for treatment period and 2-year follow-up.", "A workplace intervention for sick-listed employees with distress: results of a randomised controlled trial.", "Outcomes of an effectiveness trial of cognitive-behavioural intervention by mental health nurses in schizophrenia.", "A randomized controlled outcome and follow-up study of Mann's time-limited psychotherapy." ]	[ "We evaluated the short- and long-term efficacy of a brief cognitive-behavioral therapy (CBT) for chronic temporomandibular disorder (TMD) pain in a randomized controlled trial. TMD clinic patients were assigned randomly to four sessions of either CBT (n=79) or an education/attention control condition (n=79). Participants completed outcome (pain, activity interference, jaw function, and depression) and process (pain beliefs, catastrophizing, and coping) measures before randomization, and 3 (post-treatment), 6, and 12 months later. As compared with the control group, the CBT group showed significantly greater improvement across the follow-ups on each outcome, belief, and catastrophizing measure (intent-to-treat analyses). The CBT group also showed a greater increase in use of relaxation techniques to cope with pain, but not in use of other coping strategies assessed. On the primary outcome measure, activity interference, the proportion of patients who reported no interference at 12 months was nearly three times higher in the CBT group (35%) than in the control group (13%) (P=0.004). In addition, more CBT than control group patients had clinically meaningful improvement in pain intensity (50% versus 29% showed > or =50% decrease, P=0.01), masticatory jaw function (P<0.001), and depression (P=0.016) at 12 months (intent-to-treat analyses). The two groups improved equivalently on a measure of TMD knowledge. A brief CBT intervention improves one-year clinical outcomes of TMD clinic patients and these effects appear to result from specific ingredients of the CBT.", "Many patients with noncardiac chest pain or benign palpitations have poor prognosis in terms of symptom persistence, limitations in everyday activities, and reduced health-related quality of life (HRQOL). The aim of the study was to compare a three-session manualized cognitive behavioral therapy (CBT) intervention with normal care for patients with noncardiac chest pain or benign palpitations in a randomized controlled trial.\n Patients with persistent complaints six months after a negative evaluation at a cardiological outpatient clinic were invited to participate. Of the 94 eligible patients, 40 agreed to participate and were randomly assigned to either an intervention or control group. Patients in the intervention group received three manualized sessions with CBT, including one physical activity exposure session. The control group received usual care from their general practitioner.\n There were significantly larger improvements in the treatment group regarding fear of bodily sensations, avoidance of physical activity, depression and some domains of HRQOL at the end of treatment, and at three- and 12-month follow-up. A substantial proportion (about three-quarters) of the intervention effects on depression and avoidance of physical activity could be attributed to (was mediated by) the large reduction in catastrophic interpretations of bodily sensations.\n A three-session program of manualized CBT, including exposure to physical activity, was effective treatment for patients with noncardiac chest pain and benign palpitations up to the 12-month follow-up.\n Copyright © 2011 Elsevier Inc. All rights reserved.", "The aim of the present study was to evaluate the outcome of a behavioral medicine (BM) rehabilitation program and the outcome of its two main components, compared to a 'treatment-as-usual' control group (CG). The study employed a 4x4 repeated-measures design with four groups and four assessment periods (pre-treatment, post-treatment, 6-month follow-up, and 18-month follow-up). The group studied consisted of subjects on sick leave identified in a nationwide health insurance scheme in Sweden. After inclusion, the subjects were randomized to one of four conditions, which were: (1) behavior-oriented physical therapy (PT); (2) cognitive behavioral therapy (CBT); (3) BM rehabilitation consisting of PT+CBT (BM); (4) a 'treatment-as-usual' CG. The treatments were given over a period of 4 weeks, PT and CBT on a part-time basis and BM on a full-time basis. Outcome variables were sick leave, early retirement, and health-related quality of life (measured using the Short Form Health Survey, SF-36). The results showed that the risk of being granted full-time early retirement was significantly lower for females in PT and CBT compared to the CG during the 18-month follow-up period. However, the total absence from work (sick listing plus early retirement) in days over the 18-month follow-up period was not significantly different in the CG compared to the treatments. On the SF-36, women in CBT and BM reported a significantly better health-related quality of life than women in the CG at the 18-month follow-up. No significant differences for men were found on the SF-36 scales. In conclusion, the results revealed gender differences in the outcome of the treatments and that the components of this BM program yielded as good results as the whole program.", "Seventy-eight motor vehicle accident survivors with chronic (greater than 6 months) PTSD, or severe sub-syndromal PTSD, completed a randomized controlled comparison of cognitive behavioral therapy (CBT), supportive psychotherapy (SUPPORT), or a Wait List control condition with two detailed assessments. Scores on the CAPS showed significantly greater improvement for those in CBT in comparison to the Wait List and to the SUPPORT conditions. The SUPPORT condition in turn was superior (p=0.012) to the Wait List. Categorical diagnostic data showed the same results. An analysis of CAPS scores including drop-outs (n=98) also showed CBT to be superior to Wait List and to SUPPORT with a trend for SUPPORT to be superior to Wait List. The CBT condition led to significantly greater reductions in co-morbid major depression and GAD than the other two conditions. Results held up well at a 3-month follow-up on the two active treatment conditions.", "The efficacy of adjunctive psychosocial interventions such as cognitive behaviour therapy (CBT) for bipolar disorder (BD) has been demonstrated in several uncontrolled and controlled studies. However, these studies compared CBT to either a waiting list control group, brief psycho-education or treatment as usual (TAU). Our primary aim was to determine whether CBT is superior to supportive therapy (ST) of equal intensity and frequency in preventing relapse and improving outcome at post-treatment. A secondary aim was to look at predictors of survival time.\n We conducted a randomized controlled trial (RCT) at the Department of Psychology, University of Tübingen, Germany (n=76 patients with BD). Both CBT and ST consisted of 20 sessions over 9 months. Patients were followed up for a further 24 months.\n Although changes over time were observed in some variables, they were not differentially associated with CBT or ST. CBT showed a non-significant trend for preventing any affective, specifically depressive episode during the time of therapy. Kaplan-Meier survival analyses revealed that 64.5% of patients experienced a relapse during the 33 months. The number of prior episodes, the number of therapy sessions and the type of BD predicted survival time.\n No differences in relapse rates between treatment conditions were observed, suggesting that certain shared characteristics (e.g. information, systematic mood monitoring) might explain the effects of psychosocial treatment for BD. Our results also suggest that a higher number of prior episodes, a lower number of therapy sessions and a diagnosis of bipolar II disorder are associated with a shorter time before relapse.", "To evaluate the effectiveness of a participatory workplace intervention compared with usual care for sick-listed employees with distress, with regard to return to work (RTW) within the 12-month follow-up.\n Employees with distress and sick-listed for 2-8 weeks were randomised to a workplace intervention (n=73) or to usual care (n=72). The participatory workplace intervention is a stepwise process involving the sick-listed employee and their supervisor, aimed at reducing obstacles for RTW by reaching consensus about an action plan for RTW. Outcome variables were lasting RTW, cumulative sickness absence and stress-related symptoms.\n Overall, an HR of 0.99 (95% CI 0.70 to 1.39) indicated no effect of the workplace intervention on lasting RTW. However, the workplace intervention significantly reduced the time until lasting RTW for employees who at baseline intended to return to work despite symptoms with an HR of 2.05 (95% CI 1.22 to 3.45). Employees who intended to return to work despite symptoms returned to work after 55 days in the workplace intervention group and 120 days in the usual care group. No such effect of the intervention was found for employees without baseline intentions to return to work despite symptoms (HR=0.78, 95% CI 0.47 to 1.28).\n No overall effect of the participatory workplace intervention on lasting RTW was found. The workplace intervention appeared effective on lasting RTW for employees who at baseline intended to return to work despite symptoms. For employees who showed no baseline intention to return to work, the intervention did not have any effect. Other approaches are needed for this subgroup. This trial has been registered at the Dutch National Trial Register ISRCTN92307123.", "Little is known about the medium-term durability of cognitive-behavioural therapy (CBT) in a community sample of people with schizophrenia.\n To investigate whether brief CBT produces clinically important outcomes in relation to recovery, symptom burden and readmission to hospital in people with schizophrenia at 1-year follow-up.\n Participants (336 of 422 randomised at baseline) were followed up at a mean of 388 days (s.d. = 53) by raters masked to treatment allocation (CBT or usual care).\n At 1-year follow-up, participants who received CBT had significantly more insight (P = 0.021) and significantly fewer negative symptoms (P = 0.002). Brief therapy protected against depression with improving insight and against relapse; significantly reduced time spent in hospital for those who did relapse and delayed time to admission. It did not improve psychotic symptoms or occupational recovery, nor have a lasting effect on overall symptoms or depression at follow-up.\n Mental health nurses should be trained in brief CBT for schizophrenia to supplement case management, family interventions and expert therapy for treatment resistance.", "Thirty-three patients were assessed for suitability for time-limited psychotherapy (TLP). A battery of outcome measures was composed of patient self-report measurements and objective judgments by external (\"masked\") raters. Patients were randomly assigned to either the experimental group, which received TLP immediately, or the control group, whose TLP was delayed for 3 months. Patients were evaluated on outcome measures at TLP termination and again at 6 and 12 months after termination. Significant improvement was observed in the experimental group after TLP, but the control patients did not show any systemic changes after waiting. However, after TLP, the control patients improved significantly. The average effect size measured by the differences between gain scores of the experimental patients (before vs. after treatment) and those of the control patients (before vs. after waiting) was 0.986 SD. The gains achieved after therapy were stable in both groups after 6- and 12-month follow-ups." ]	We found moderate-quality evidence that CBT did not significantly reduce time until partial RTW and low-quality evidence that it did not significantly reduce time to full RTW compared with no treatment. Moderate-quality evidence showed that PST significantly enhanced partial RTW at one-year follow-up compared to non-guideline based care but did not significantly enhance time to full RTW at one-year follow-up. An important limitation was the small number of studies included in the meta-analyses and the small number of participants, which lowered the power of the analyses.
CD005015	[ "15714177", "8633378", "14569109", "14514747", "12826169", "12039990", "14717945", "9808483", "10988110", "10652047", "12631097", "15265162", "6368958", "80633", "8998681", "15860827", "21479913" ]	[ "A controlled study of vitamin D3 to prevent bone loss in renal-transplant patients receiving low doses of steroids.", "Prevention of bone loss in cardiac transplant recipients. A comparison of biphosphonates and vitamin D.", "Preventing bone loss in renal transplant recipients with vitamin D.", "Prevention of bone loss in renal transplant recipients: a prospective, randomized trial of intravenous pamidronate.", "Alendronate for treatment of renal transplant patients with osteoporosis.", "Treatment with vitamin D and calcium reduces bone loss after renal transplantation: a randomized study.", "Treatment with intermittent calcitriol and calcium reduces bone loss after renal transplantation.", "Treatment of osteopenia and osteoporosis after kidney transplantation.", "Efficacy of pamidronate for osteoporosis in patients with cystic fibrosis following lung transplantation.", "Pamidronate therapy as prevention of bone loss following renal transplantation.", "Zoledronic acid to prevent bone loss in the first 6 months after renal transplantation.", "Treatment of osteopenia and osteoporosis in renal transplant children and adolescents.", "Bone mineral content after renal transplantation. Placebo-controlled prospective study with 1,25-dihydroxy vitamin D3.", "Deterioration of renal function during treatment of chronic renal failure with 1,25-dihydroxycholecalciferol.", "A randomized controlled trial of salmon calcitonin to prevent bone loss in corticosteroid-treated temporal arteritis and polymyalgia rheumatica.", "Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care.", "Randomized trial of alendronate plus vitamin D3 versus standard care in osteoporotic postmenopausal women with vitamin D insufficiency." ]	[ "New and potent immunosuppressive regimens allow for reduced doses of corticosteroids after renal transplantation. The aims of our study were to investigate whether the use of low-dose corticosteroids is associated with a reduction in posttransplant bone loss and to assess the ability of cholecalciferol supplementation to further decrease bone loss in this setting.\n Ninety patients admitted for renal transplantation and scheduled to be treated per protocol with low doses of prednisolone were randomized to receive either 400 mg daily oral calcium (Ca group, n=44) or the same dose of calcium in association with a monthly dose of 25,000 IU of vitamin D3 (CaVitD group, n=46). Bone mineral density (BMD) was measured by dual energy absorptiometry at baseline and at 1 year.\n The overall population experienced a moderate but significant -2.3+/-0.9% loss of lumbar spine BMD (P<0.01) but no bone loss at the femoral neck and shaft during the first posttransplant year. Bone loss tended to be slightly higher in the CaVitD group, but the difference did not reach statistical significance. Patients in the CaVitD group had significantly higher 25(OH) but not 1,25(OH)2 vitamin D levels. We observed a highly significant negative correlation between 25(OH) vitamin D and intact parathyroid hormone (iPTH) serum levels.\n Kidney-transplant recipients receiving modern immunosuppressive regimens with low doses of corticosteroids experience only minimal loss of BMD during the first posttransplant year. Cholecalciferol supplementation did not prevent posttransplant bone loss but contributed to the normalization of iPTH levels after renal transplantation.", "Bone mineral density is already abnormally reduced at the moment of cardiac transplantation and bone loss occurs at an impressive rate in the first postoperative year. The aim of the study was to compare two prophylactic medical regimens as to their efficacy in mitigating bone loss after transplantation. Forty-eight consecutive recipients were randomized to receive either alternating calcium carbonate and disodium etidronate (group A) or a daily supplement of calcium carbonate and alphacalcidol (group B). Bone mineral density measurements were performed immediately before hospital discharge and 6, 12, and 24 months after surgery using dual energy X-ray absorptiometry. Clinical events were recorded and roentgenograms of the spine were performed postoperatively and 1 and 2 years later. In both treatment groups bone loss remained significant at the level of the lumbar spine in the first postoperative year (P<0.005) and at the level of the femoral neck in the first (P<0.005) and the second (P<0.06) year after transplantation. Six months after transplantation, however, patients receiving alphacalcidol had a significant reduction in bone loss at the level of the lumbar spine (P=0.047) and at the level of the femoral neck (P=0.043). At the level of the femoral neck this decrease in bone loss was even more pronounced in the second postoperative year (P<0.001). In the group of patients treated with disodium etidronate, 4 recipients needed additional hospitalizations for treatment of symptomatic fractures at the level of the lumbar spine or the femoral neck. No such events happened in recipients receiving vitamin D supplements. Prophylactic administration of calcium carbonate and alphacalcidol after cardiac transplantation reduces bone loss and seems to decrease osteoporotic complications.", "Very rapid bone loss, osteopenia, and osteoporosis have been documented in the first 6 to 12 mo after renal transplantation. Investigated was the effect of treatment with active vitamin D on the prevention of posttransplantation bone loss. Forty adult men who were recent renal transplant recipients were enrolled onto the study. Patients were randomized into two groups: group 1 received daily alfacalcidol 0.5 micro g by mouth, and group 2 (control) received placebo. Every patient in both groups received daily 500-mg calcium carbonate supplements. Parameters of bone metabolism and bone mineral density measured at three sites were assessed before and after the study period. Bone mineral density was increased by 2.1%, 1.8%, and 3.2% at lumbar spine, femoral neck, and forearm, respectively, in group 1, whereas it decreased by 3.2%, 3.8%, and 1.8% at the same sites in the control group (P < 0.05). Serum intact parathyroid hormone level decreased significantly in group 1 compared with the control group (P = 0.003). Early bone loss that occurs during the first 1 yr after renal transplantation could be prevented by alfacalcidol. Use of alfacalcidol early after transplantation is safe and well tolerated.", "Renal transplant recipients are at risk of developing bone abnormalities that result in bone loss and bone fractures. These are related to underlying renal osteodystrophy, hypophosphatemia, and immunosuppressive treatment regimen. Although bisphosphonates are useful in ameliorating bone mineral loss after transplantation, it is not known whether their use in renal transplant patients leads to excessive suppression of bone turnover and increased incidence of adynamic bone disease. A randomized, prospective, controlled, clinical trial was conducted using the bisphosphonate pamidronate intravenously in patients with new renal transplants. Treatment subjects (PAM) received pamidronate with vitamin D and calcium at baseline and at months 1, 2, 3, and 6. Control (CON) subjects received vitamin D and calcium only. During months 6 to 12, the subjects were observed without pamidronate treatment. Biochemical parameters of bone turnover were obtained monthly and, bone mineral density (BMD) was obtained at baseline and months 6 and 12. Bone biopsies for mineralized bone histology were obtained at baseline and at 6 mo in a subgroup of subjects who underwent scheduled living donor transplantation. PAM preserved bone mass at 6 and 12 mo as measured by bone densitometry and histomorphometry. CON had decreased vertebral BMD at 6 and 12 mo (4.8 +/- 0.08 and 6.1 +/- 0.09%, respectively). Biochemical parameters of bone turnover were similar in both groups at 6 and 12 mo. Bone histology revealed low turnover bone disease in 50% of the patients at baseline. At 6 mo, all of PAM had adynamic bone disease, whereas 50% of CON continued to have or developed decreased bone turnover. Pamidronate preserved vertebral BMD during treatment and 6 mo after cessation of treatment. Pamidronate treatment was associated with development of adynamic bone histology. Whether an improved BMD with adynamic bone histology is useful in maintaining long-term bone health in renal transplant recipients requires further study.", "Osteoporosis is a frequent complication after renal transplantation. Some workers have shown that bisphosphonates may be effective to prevent and treat corticosteroid-induced osteoporosis in these patients. In this study we report our experience with administration of the biphosphonate alendronate to treat renal transplanted patients with established osteoporosis.\n Twelve to 24 months after transplantation (9 women, 5 men) 14 renal transplant patient were treated with alendronate and 12 patients (7 women, 5 men) were untreated. All patients displayed an iPTH <240 pg/mL and a bone mineral density (BMD) t-score <-2.5. All patients received cyclosporine and prednisone therapy. Biochemical measurements, BMD, and X-rays of the lumbar spine were measured during study. Patients in the treatment group received alendronate 10 mg/d (po) and vitamin D plus calcium (800 UI cholecalciferol and 2.5 g of CaCO(3)) per day while those in the control group only received vitamin D plus calcium, at the same dose.\n There was no difference in mean age, weight, time after transplantation, or immunosuppression between the treatment and control groups. There were no significant differences in the biochemical parameters during the study period. Over the 1-year study period, patients receiving alendronate displayed a greater increase in BMD. Lumbar spine BMD increased 4.3 +/- 6.1% in the treatment group versus 0.55 +/- 5.30% in controls. Femoral neck BMD increased 10.3 +/- 11.9% and 2.2 +/- 5.7%, respectively, in the treatment and control groups. Patients receiving alendronate frequently experienced intestinal disconfort.\n The bisphosphonate alendronate is effective to treat renal transplant patients suffering from established osteporosis.", "A decrease in bone mineral density (BMD) is a major complication of renal transplantation (RTx), predominantly occurring within the first 6 mo after RTx. The most important causative factor is the use of corticosteroids, but persisting hyperparathyroidism and abnormalities in vitamin D metabolism play a role too. This study examines the effect of treatment with calcium and active vitamin D on the loss of BMD in the first 6 mo after RTx. A total of 111 renal transplant recipients (65 men, 46 women; age, 47 +/- 13 yr) were randomized to either treatment with active vitamin D (0.25 microg/d) plus calcium (1000 mg/d) (CaD group), or to no treatment (NoT group). Immunosuppressive therapy consisted of cyclosporine, prednisone, and mycophenolate mofetil. Laboratory parameters and BMD (lumbar spine and hip) were measured at 0, 1 (laboratory only), 3, and 6 mo after RTx. Lumbar BMD was nearly normal at the time of RTx. In both groups, a significant decrease in lumbar BMD was observed during the first 3 mo (CaD, -3.3 +/- 4.3%; P < 0.0001; NoT, -4.1 +/- 4.8%; P < 0.0001). Between the third day and sixth month, lumbar BMD slightly recovered in the CaD group, but it decreased further in the NoT group (total loss 0 to 6 mo: CaD, -2.6 +/- 5.0% [P < 0.001]; NoT, -5.0 +/- 4.7% [P < 0.0001]). As a result, the amount of bone loss at 6 mo was significantly lower in the CaD group (P = 0.02). Loss of BMD at the different femoral sites was also significantly reduced in the CaD group. Apart from a trend toward more frequent hypercalcemia in the CaD group, no clinical or biochemical differences existed between the groups. Treatment with a low dose of active vitamin D and calcium partially prevents bone loss at the lumbar spine and proximal femur during the first 6 mo after RTx.", "Bone loss occurs during the first 6 months after renal transplantation (RT), and corticosteroid therapy plays an important role. Although calcium plus vitamin D administration prevents corticosteroid-induced osteoporosis, its use in RT recipients is limited by the risk of hypercalcemia.\n This double-blind, randomized, and controlled prospective intervention trial examined the effect of intermittent calcitriol (0.5 microg/48 h) during the first 3 months after RT, plus oral calcium supplementation (0.5 g/day) during 1 year with calcium supplementation alone. The primary outcome measure was the change in bone mineral density (BMD) at 3 and 12 months after RT; we also explored whether the effect of calcitriol on BMD was different among vitamin D receptor (VDR) genotypes (BsmI). Forty-five recipients were randomized to calcitriol therapy (CT) and 41 were randomized to placebo (PL).\n Both groups had a similar degree of pre-existing hyperparathyroidism (197 +/- 229 vs. 191 +/- 183 pg/mL), but a more pronounced decrease of parathyroid hormone (PTH) levels after RT was observed in CT patients (at 3 months: 61.4 +/- 42.2 vs. 85.7 +/- 53.1 pg/mL, P= 0.02; at 12 months: 67.3 +/- 33.7 vs. 82.6 +/- 37 pg/mL; P= 0.08). CT patients preserved their BMD at the total hip significantly better than those on PL (3 months: 0.04 +/- 3.3 vs. -1.93 +/- 3.2%, P= 0.01; 12 months: 0.32 +/- 4.8 vs. -2.17 +/- 4.4%, P= 0.03); significant differences were noted at the intertrochanter, trochanter, and Ward's triangle. Differences did not reach significance at the femoral neck. Two CT patients (4.4%) and 4 PL patients (9.8%) developed a hypercalcemic episode during the first 3 months after RT. The effect of CT on BMD at 3 months was more prominent in recipients with the at-risk allele of the VDR gene (P= 0.03).\n Therapy with low-dose calcium supplements during 1 year, plus intermittent calcitriol for 3 months after RT, is safe, decreases PTH levels more rapidly, and prevents bone loss at the proximal femur; a more pronounced effect is seen in recipients with at least one at-risk allele of the VDR genotype.", "Osteopenia and osteoporosis are frequent complications after kidney transplantation. Data for the treatment of low bone mass after kidney transplantation are not available.\n To test the efficacy of antiresorptive treatment, 46 patients with osteopenia or osteoporosis after kidney transplantation (bone mineral density < or =1.5 SD below normal) were randomly assigned to three groups cyclically treated as follows: group 1 with daily oral clodronate (800 mg) and group 2 with daily intranasal calcitonin (200 IU) for 2 weeks every 3 months. These two groups were compared with a control group (group 3). Every patient was supplemented with 500 mg of calcium per day. Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry (DEXA) at the lumbar spine and femoral neck before and after the 12-month treatment period.\n BMD at the lumbar spine was increased by 4.6% in the clodronate group (n=15, P=0.005), by 3.2% in the calcitonin group (n=16, P=0.034), and by 1.8% in the control group (n=15, P=0.265). However, the differences in BMD changes among the groups were not statistically significant. During therapy, serum calcium decreased slightly in all groups by 4.6%; however, parathyroid hormone values increased significantly in the treatment groups by 116%. Therapy was well tolerated without impact on graft function.\n Cyclical therapy with clodronate or calcitonin appears to induce a gain in BMD at the lumbar spine in patients with low bone mass after kidney transplantation. This treatment had no adverse impact on graft function but may aggravate preexisting secondary hyperparathyroidism.", "Lung transplantation with its attendant life-long immunosuppression contributes to bone loss and its sequelae, fractures and kyphosis, in patients with lung disease, many of whom already suffer from severe osteoporosis. Patients with cystic fibrosis (CF) are one of the most severely affected groups. We conducted a controlled, randomized, nonblinded trial of pamidronate (30 mg intravenously every 3 mo) with vitamin D (800 IU/d) and calcium (1 g/d) (n = 16) compared with vitamin D and calcium alone (n = 18, the control subjects) for 2 yr in 34 patients after lung transplant to improve bone mineral density (BMD). The treatment groups were similar in age, sex, baseline T-scores, renal function, hospitalization rates, immunosuppressant levels, change in lung function, and body mass index (BMI) over the study period. The patients treated with pamidronate gained 8.8 +/- 2.5% and 8.2 +/- 3.8% in spine and femur BMD after 2 yr in comparison to control subjects, who gained, on average (+/- SD), 2.6 +/- 3.2 and 0.3 +/- 2.2%, respectively (p </= 0.015 for both). Seven and six fractures occurred in the control and pamidronate groups, respectively (p > 0.2). Measures of bone resorption were highest immediately after lung transplant and improved with both pamidronate and time. Measures of bone formation were very poor after lung transplant, but recovered in the first post-lung transplant year irrespective of therapy. We conclude that pamidronate was more effective than control in improving bone mineral density after lung transplantation in patients with CF and appears to be one of the most promising agents studied to date for posttransplant osteoporosis.", "Very rapid bone loss, osteopenia and skeletal morbidity after renal transplantation have been well documented and found to occur in a sex dependent fashion. Glucocorticoids, cyclosporine and pre-existing uremic osteodystrophy have been implicated in the pathogenesis of the skeletal lesions. Glucocorticoid induced osteopenia is also a serious clinical problem in patients with various nonrenal diseases and can be prevented, or at least attenuated, by pamidronate and other bisphosphonates.\n We prospectively studied 26 male patients undergoing renal transplantation, and randomized them to receive either placebo or intravenous pamidronate (0.5 mg/kg) at the time of transplantation and again one month later. All patients received immunosuppression comprising prednisolone, cyclosporine and azathioprine. The bone mineral density (BMD) of the second, third and fourth lumbar vertebrae and of the femoral neck was measured at the time of transplantation and at three months and 12 months after transplantation using dual energy X-ray absorptiometry (DXA).\n Twelve months after transplantation, the mean (+/- SEM) BMD of the lumbar vertebrae in patients who received placebo had decreased 6.4% (P < 0.05). In contrast, patients who received pamidronate experienced no significant reduction of BMD at the lumbar vertebrae. At the femoral neck, placebo-treated patients showed a reduction of BMD of 9% (P < 0.005), whereas there was no significant change in the pamidronate treated group. The two study groups had similar patient profiles, serum parathyroid hormone (PTH) and aluminium concentrations. After transplantation, comparable falls in the serum creatinine and PTH concentration were found in the two groups. Apart from transient hypocalcemia in two patients, no significant adverse effects of pamidronate were noted.\n This study has shown that the early rapid bone loss that occurs in men during the first 12 months after renal transplantation can be prevented by two intravenous doses of pamidronate given at transplantation and one month later. The regimen was simple to administer, well tolerated and potentially applicable to other clinical groups of glucocorticoid treatment patients.", "Bisphosphonates can prevent bone mineral density loss after renal transplantation, but their effect on trabecular mineralization and bone morphology, two key factors of bone stability, remains unknown.\n In a 6-month, randomized, placebo-controlled study, 20 kidney transplant recipients received either 4 mg zoledronic acid or placebo twice within 3 months after engraftment. At transplantation and after 6 months, mean trabecular calcium concentration and trabecular morphometry were measured in bone biopsies. Bone mineral density (BMD) of the femoral neck and the lumbar spine were evaluated by dual-energy x-ray absorptiometry, and serum biochemical markers of bone metabolism were determined monthly.\n Trabecular calcium content increased significantly in the zoledronic acid group, but remained unchanged in the placebo group. BMD at femoral neck showed no change in the zoledronic acid group, but decreased in the placebo group. BMD of the lumbar spine was increased in the zoledronic acid group without change in the placebo group. High-turnover bone disease resolved similarly in both groups, as evidenced by a significant decrease of eroded bone surface, osteoclast and osteoblast surface. Serologic markers of bone formation and resorption were significantly lower in zoledronic acid-treated patients throughout the study. Kidney transplant function was stable after zoledronic acid therapy.\n Our results show that administration of zoledronic acid improves the calcium content of cancellous bone after kidney transplantation. The beneficial effect of bisphosphonate therapy is further evidenced by an increase of lumbar spine BMD, and stabilization of femur BMD.", "Successful renal transplantation corrects many of the metabolic abnormalities associated with the development of renal osteodystrophy, but despite a well-functioning graft osteopenia, growth failure, spontaneous fractures, and avascular necrosis remain prevalent in adult and pediatric kidney recipients. A paucity of information exists regarding the effects of different therapies to prevent and treat bone loss in the renal transplant recipients. We constructed a design to study the effect of different modalities of treatment on bone mass in our renal transplant children. Among 93 patients who underwent renal transplantation at the age of 17 yr or less and were subjected to dual-energy X-ray absorptiometry (DEXA), we blindly randomized 60 patients who had osteopenia or osteoporosis (T-score = -1 by DEXA) in a prospective study. Their mean age at time of transplantation was 13.4 +/- 4.3 yr. The mean duration after transplantation was 48 +/- 34 months. The patients were classified randomly into four groups. Each group consisted of 15 patients: group 1 was the control group, group 2 received oral alfacalcidol 0.25 microg daily, group 3 received oral alendronate 5 mg daily, and group 4 received 200 IU/day nasal spray calcitonin. Parameters of bone turnover, calcium metabolism, and DEXA were measured before and after 12 months of treatment duration. The characteristics of all groups were comparable at the beginning of the study. At the lumber spine, bone mass density decreased from -2.4 to -2.8 in group 1, increased from -2.3 to -0.5 in group 2, from -2.3 to -1.9 in group 3, and from -2.3 to -1.0 in group 4. The four groups had similar patient profiles, serum creatinine, intact parathyroid hormone, osteocalcin, and deoxypyridinoline. This study confirmed the value of alfacalcidol and antiresorptive agents in the treatment of osteopenia and osteoporosis in young renal transplant recipients.These therapies were safe, tolerable, simple to administer and potentially applicable to other renal transplant patients.\n Copyright 2004 Blackwell Munksgaard", "Forearm bone mineral content (BMC), as evaluated by photonabsorption densitometry, was measured in 28 cadaver kidney donor recipients who entered the study 8 weeks postoperatively and were followed up for 18 months. BMC decreased significantly (p less than 0.05) but marginally in placebo-treated patients (n = 14) (initial BMC 1.09 +/- 0.25 g/cm; final BMC 1.05 +/- 0.24). Fourteen patients were prophylactically given 1,25(OH)2 vitamin D3 in a dose which avoided hypercalcemia and hypercalciuria (approximately 0.25 microgram/day); under 1,25(OH)2 vitamin D3 prophylaxis a significant decrease of forearm BMC was observed no longer (initial BMC 0.94 +/- 0.21 g/cm; final BMC 0.95 +/- 0.21), but the difference between placebo and 1,25(OH)2 vitamin D3 narrowly missed statistical significance (p = 0.066). It is concluded that the decrease of forearm BMC is negligible in transplant recipients with low steroid regimens. The data suggest a trend for prophylaxis with 1,25(OH)2 vitamin D3 to slightly ameliorate forearm (cortical) BMC loss.", "A controlled study of the effects of the potent vitamin-D metabolite, 1, 25-dihydroxycholecalciferol (1,25[OH]2D3), and vitamin D3 was done in 18 non-dialysed patients with chronic renal failure (C.R.F.). Patients with a creatinine clearance below 35 ml/min and mild renal osteodystrophy were selected. After 6 months' observation of the spontaneous course the patients were randomly allocated to 6 months' oral treatment with either 1, 25 (OH)2D3 or vitamin D3 in initial daily doses of 1microgram and 4000 I.U., respectively, combined with 0.5 g calcium. 1,25(OH)2D3 quickly corrected hypocalcaemia, reduced serum-alkaline-phosphatases and serum-immunoreactive-parathyroid-hormone, and more than doubled the urinary excretion rate of calcium. D3 had similar, but less pronounced effects. 7 out of 8 patients on 1,25(OH)2D3, developed hypercalcaemia which necessitated a reduction in dosage. None of the patients on D3 treatment developed hypercalcaemia. The percentage fall in creatinine clearance was greater during treatment than before treatment in all patients on 1, 25 (OH)2D3 (P less than 0.01) and in 7 of 9 patients on vitamin D3 treatment (though the group change here was not significant). Deterioration of renal function is a major limitation of the clinical use of 1, 25(OH)2D3 and D3 in non-dialysed patients with C.R.F. In fact, the decrased formation of 1, 25(OH)2D3 seen in C.R.F. might protect renal function at the expense of abnormalities in mineral metabolism.", "Patients treated with high-dose or long-term corticosteroids are at risk of accelerated osteoporosis and spontaneous vertebral and traumatic fractures. To assess the efficacy of salmon calcitonin in preventing corticosteroid- induced osteoporosis, 48 patients with newly diagnosed polymyalgia rheumatica, temporal arteritis, and other vasculitides were enrolled in a 2-year, double-blind, randomized, controlled trial. Patients were randomized to receive subcutaneous injections t.i.w. of either 100 IU of salmon calcitonin (25 patients) or placebo (23 patients). After 2 years, 19 and 21 patients, respectively, were evaluable. All patients also received supplemental calcium carbonate (1500 mg daily in divided doses) and vitamin D3 (400 IU daily). Baseline and serial radiologic assessments included dual-energy X-ray absorptiometry (DXA) of the lumbar spine and hip, and spine radiographs to detect vertebral fractures. There were no significant baseline differences between the two study groups. The mean within-subject percentage change in DXA lumbar spine density in the two groups over the 2-year period of the study was only -0.1% (calcitonin plus calcium) versus -0.2% (placebo plus calcium) a nonsignificant difference despite the high mean cumulative corticosteroid doses of 5371 mg and 4680 mg, respectively (NS). The incidence of vertebral fracture was 12.5% (calcitonin plus calcium: 11%, versus placebo plus calcium: 14%, NS), with four fractures in the first year and one fracture in the second year. Higher cumulative cortico-steroid dose was associated with a greater loss in bone density. In rheumatic disease patients starting high-dose, long-term corticosteroids, salmon calcitonin with calcium and vitamin D3 provided no greater bone preservation than that observed with calcium and vitamin D3 alone.", "To assess whether supplementation with calcium and cholecaliferol (vitamin D3) reduces the risk of fracture in women with one or more risk factors for fracture of the hip.\n Pragmatic open randomised controlled trial.\n Practice nurse led clinics in primary care.\n 3314 women aged 70 and over with one or more risk factors for hip fracture: any previous fracture, low body weight (< 58 kg), smoker, family history of hip fracture, or fair or poor self reported health.\n Daily oral supplementation using 1000 mg calcium with 800 IU cholecaliferol and information leaflet on dietary calcium intake and prevention of falls, or leaflet only (control group).\n Primary outcome measure was all clinical fractures and secondary outcome measures were adherence to treatment, falls, and quality of life (measured with the SF-12).\n 69% of the women who completed the follow-up questionnaire at 24 months were still taking supplements (55% with inclusion of randomised participants known to be alive). After a median follow-up of 25 months (range 18 to 42 months), clinical fracture rates were lower than expected in both groups but did not significantly differ for all clinical fractures (odds ratio for fracture in supplemented group 1.01, 95% confidence interval 0.71 to 1.43). The odds ratio for hip fracture was 0.75 (0.31 to 1.78). The odds of a woman having a fall at six and 12 months was 0.99 and 0.98, respectively. Quality of life did not significantly differ between the groups.\n We found no evidence that calcium and vitamin D supplementation reduces the risk of clinical fractures in women with one or more risk factors for hip fracture. Registration ISRCTN26118436, controlled trials registry.", "Vitamin D insufficiency is common in patients with osteoporosis. We conducted a randomized trial comparing alendronate 70 mg combined with vitamin D(3) 5,600 IU in a single tablet (ALN/D5600, n = 257) with standard care chosen by the patients' personal physicians (n = 258) in patients with postmenopausal osteoporosis (BMD T score ≤2.5 or ≤1.5 and a prior fragility fracture) who had vitamin D insufficiency (serum 25[OH]D values 8-20 ng/ml) and who were at risk of falls. Virtually all patients randomized to standard care received bisphosphonate therapy, and in approximately 70% of cases this was combined with vitamin D supplements. However, only 24% took ≥800 IU/day of supplemental vitamin D. At 6 months the proportion of patients with vitamin D insufficiency was 8.6% in the ALN/D5600 group compared with 31.0% in the standard care group (P < 0.001). Those in the ALN/D5600 group also had a greater reduction in urinary NTX/creatinine ratio (-57% vs. -46%, P < 0.001) and bone-specific alkaline phosphatase (-47% vs. -40%, P < 0.001). In the ALN/5600 group, by 12 months the increase in BMD was greater at the lumbar spine (4.9% vs. 3.9%, P = 0.047) and the total hip (2.2% vs. 1.4%, P = 0.035), significantly fewer patients were vitamin D-insufficient (11.3% vs. 36.9%, P < 0.001), and bone turnover marker (BTM) results were similar to those at 6 months. There was no difference between groups in those who experienced falls or fractures, and adverse events were similar. Based on the finding that ALN/D5600 was more effective than standard care at correcting vitamin D insufficiency, increasing BMD, and reducing BTMs in this patient group, greater attention needs to be directed toward optimizing the treatment of osteoporosis and correcting vitamin D deficiency in postmenopausal women." ]	Treatment with a bisphosphonate, vitamin D sterol or calcitonin after kidney transplantation may protect against immunosuppression-induced reductions in bone mineral density and prevent fracture. Adequately powered trials are required to determine whether bisphosphonates are better than vitamin D sterols for fracture prevention in this population. The optimal route, timing, and duration of administration of these interventions remains unknown.
CD006982	[ "11865270", "12162601", "10591428", "12673261", "15060235", "19578227" ]	[ "Preterm infants born at less than 31 weeks' gestation have improved growth in cycled light compared with continuous near darkness.", "Randomized controlled study of the effects of different durations of light exposure on weight gain by preterm infants in a neonatal intensive care unit.", "Comparison of the efficacy of conventional special blue light phototherapy and fiberoptic phototherapy in the management of neonatal hyperbilirubinaemia.", "A prospective randomized controlled study of phototherapy using blue and blue-green light-emitting devices, and conventional halogen-quartz phototherapy.", "Rest-activity patterns of premature infants are regulated by cycled lighting.", "Light emitting diodes versus compact fluorescent tubes for phototherapy in neonatal jaundice: a multi center randomized controlled trial." ]	[ "Our purpose was to evaluate the benefits of cycled light (CL) versus near darkness (ND) on health in preterm infants born at <31 weeks' gestational age.\n Randomized, interventional study comparing infants receiving (1) CL from birth, (2) CL at 32 weeks' postconceptional age (PCA), and (3) CL at 36 weeks' PCA in transition for discharge home. Statistical significance was assessed with segmented mixed general linear models, analysis of covariance, general estimating equations, chi(2), and Fisher's exact procedure.\n Infants receiving CL at birth and 32 weeks' PCA gained weight faster than infants not receiving CL until 36 weeks' PCA. There were no differences among the groups in length of hospitalization stay or number of ventilator days, but the power was low for these variables.\n These findings suggest that CL has significant weight gain benefits over ND, and there are no short-term advantages of ND over cycled light for health in preterm infants.", "A randomized controlled study was carried out on 96 preterm infants (< 37 wk) with birthweight less than 2000 g admitted to a neonatal intensive care unit. The aim was to compare the weight gain between preterm infants exposed to 12 h cyclical lighting (intensity of light: 78.4 +/- 24.7 lux, mean +/- SD) and those exposed to a continuously dim environment (5.9 +/- 1.9 lux). The exclusion criteria were infants with major congenital malformations or who needed continuous lighting for treatment procedure and care. From day 7 of life until discharge, 50 infants were randomized to receive 12 h cyclical lighting and 46 infants to a continuously dim environment. There was no significant difference in the mean birthweight (12 h lighting vs continuously dim: 1482 vs 1465 g, p = 0.8), mean gestational age (31.6 vs 31.4 wk, p = 0.6), median duration of hospital stay (28.5 vs 28.5 d, p = 0.8), mean age to regain birthweight (13.0 vs 12.9 d, p = 0.3), mean weight gained by day 14 (27.6 vs 36.2 g, p = 1.0), median weight gain per day (11.9 vs 12.2 g, p = 0.9) or median body weight on discharge (1800 vs 1800 g, p = 0.4) between the two groups of infants.\n Exposing preterm infants to either 12 h cyglical lighting or continuously dim environment did not have any significant effect on their weight gain during the neonatal period.", "The efficacy and usefulness of two types of phototherapy differing in the source, wavelength and irradiance of the light, conventional phototherapy consisting of special blue light and fiberoptic phototherapy, were compared in a relatively larger series of term newborns with non-haemolytic and more significant hyperbilirubinaemia than those in previous studies. In total, 108 newborns were allocated sequentially to receive either conventional phototherapy consisting of five special blue lamps or fiberoptic phototherapy. The average spectral irradiance measured at the skin surface level of newborns during the study period was significantly greater in the conventional phototherapy group. The special blue lamp of the conventional phototherapy unit had an emission spectrum almost identical to the bilirubin absorption spectrum, whereas the tungsten-halogen lamp of the fiberoptic phototherapy had a broad emission through the blue and green wavelengths (mainly in the green spectrum). Phototherapy was more effective in the conventional phototherapy group; the duration of exposure to phototherapy (h) was significantly shorter, and the overall bilirubin decline rate (as micromol/l/h and %/h) was significantly greater in the conventional phototherapy group. According to the nursing personnel, fiberoptic phototherapy was more comfortable than the conventional phototherapy frame because of the easier accessibility and handling of the infants during phototherapy. They complained of giddiness, nausea, glare, temporary blurring of vision and difficulty in detecting the skin colour changes of newborns with the blue light of the conventional phototherapy unit. Conventional phototherapy consisting of special blue fluorescent lamps with approximately twofold higher irradiance and an emission spectrum almost identical to the bilirubin absorption spectrum is preferable to fiberoptic phototherapy in the standard treatment of term newborns with non-haemolytic hyperbilirubinaemia.", "To determine the efficacy of blue versus blue-green phototherapy using new light sources with narrow luminous spectra. The devices made of high-intensity gallium nitride light-emitting diodes (LEDs) were also compared to conventional halogen-quartz bulbs phototherapy.\n Prospective open randomized study.\n A total of 114 jaundiced, but otherwise healthy term infants who met the entry criteria for phototherapy set by the American Academy of Pediatrics' Practice Parameter.\n The duration of phototherapy and the rate of decrease in total serum bilirubin (TSB).\n The mean TSB concentrations at initiation and termination of treatment, as well as the duration of phototherapy and the rate of decrease in TSB, were not statistically different in newborns receiving blue LED, blue-green LED or conventional phototherapy. The average rate of decrease in TSB (slope), after adjustment by a linear regression analysis for confounding factors, was -3.61 micromol/hour (95% confidence limits -5.47, -1.75) in the 25 newborns receiving blue LED phototherapy compared with -2.57 micromol/hour (-4.32, -0.82) in the 22 newborns treated with blue-green LED phototherapy and -3.42 micromol/hour (-5.02, -1.81) in the 57 newborns who received conventional phototherapy.\n When using low light irradiance, there was no statistically significant difference in the effectiveness of phototherapy using blue-green LEDs, blue LEDs or conventional halogen-quartz bulbs.", "Many hospitalized premature infants are exposed to continuous dim lighting rather than to cycled lighting. However, we do not know whether dim lighting or low-intensity cycled lighting is more conducive to the development of rest-activity patterns that are in phase with the solar light-dark cycle. Thus, we examined the effects of nursery lighting conditions on the development of activity patterns in premature infants.\n Premature infants who were born at <32 weeks' postmenstrual age and were medically stable in neonatal intensive care unit rooms were randomly assigned between 32 and 34 weeks' postmenstrual age to either continuous dim lighting (<25 lux; duration 24 days; control group; n = 29) or cycled lighting (239 +/- 29 lux, 7:00 AM to 7:00 PM; <25 lux, 7:00 PM to 7:00 AM; duration: 25 days; experimental group; n = 33). Activity was continuously monitored from enrollment until approximately 1 month after discharge from the hospital. Weight and head circumference were also assessed up to 6 months after discharge from the hospital.\n Over the first 10 days at home, distinct day-night differences in activity were not seen in control subjects (D day-night: N 1.07 +/- 0.02), but experimental group infants were more active during the day than at night (day-night: 1.25 +/- 0.03). It was not until 21 to 30 days after discharge that day-night activity ratios in control infants matched those seen in experimental group infants shortly after discharge, yet even at this age, experimental group infants (day-night: 2.13 +/- 0.19) were considerably more active during the day than at night as compared with control subjects (day-night: 1.43 +/- 0.09).\n Exposure of premature infants to low-intensity cycled lighting in the hospital nursery induces distinct patterns of rest-activity that are apparent within 1 week after discharge. In comparison, the appearance of distinct patterns of rest and activity are delayed in infants who are exposed to continuous dim lighting in the hospital. These observations show that day-night rhythms in activity patterns can be detected shortly after discharge to home in premature infants and that the circadian clock of developing infants is entrained by cycled lighting.", "To evaluate whether light-emitting diode (LED) phototherapy is as efficacious as compact fluorescent tube (CFT) phototherapy for the treatment of non-hemolytic jaundice in healthy term and late preterm neonates.\n Multi centre open label randomized controlled trial.\n Four tertiary care neonatal units.\n Healthy term and late preterm neonates with non-hemolytic jaundice.\n Single-surface LED or CFT phototherapy. PRIMARY OUTCOME VARIABLE: Duration of phototherapy.\n A total of 272 neonates were randomized to receive LED (n=142) or CFT (n=130) phototherapy. The baseline demographic and biochemical variables were similar in the two groups. The median duration of phototherapy (IQR) in the two groups was comparable (26 (22-36) h vs. 25(22-36) h; P=0.44). At any time point, a similar proportion of neonates were under phototherapy in the two groups (log-rank test, P=0.38). The rate of fall of serum total bilirubin (STB) during phototherapy and the incidence of failure of phototherapy were also not different. An equal proportion of neonates had a rebound increase in STB needing restarting of phototherapy. Side effects were rare, comparable in the two groups and included hypothermia, hyperthermia, rash, skin darkening and dehydration.\n LED and CFT phototherapy units were equally efficacious in the management of non-hemolytic hyperbilirubinemia in healthy term and late preterm neonates." ]	Trials assessing the effect of CL have enrolled 469 infants. Trends for many outcomes favoured cycled light (CL) compared to near darkness (ND) and CL compared to continuous bright light (CBL) The studies may have lacked significance due to a lack of statistical power. Future research should focus on comparing CL to ND.
CD009395	[ "12057549" ]	[ "Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial." ]	[ "Anticonvulsants are used for pre-eclampsia in the belief they prevent eclamptic convulsions, and so improve outcome. Evidence supported magnesium sulphate as the drug to evaluate.\n Eligible women (n=10141) had not given birth or were 24 h or less postpartum; blood pressure of 140/90 mm Hg or more, and proteinuria of 1+ (30 mg/dL) or more; and there was clinical uncertainty about magnesium sulphate. Women were randomised in 33 countries to either magnesium sulphate (n=5071) or placebo (n=5070). Primary outcomes were eclampsia and, for women randomised before delivery, death of the baby. Follow up was until discharge from hospital after delivery. Analyses were by intention to treat.\n Follow-up data were available for 10,110 (99.7%) women, 9992 (99%) of whom received the allocated treatment. 1201 of 4999 (24%) women given magnesium sulphate reported side-effects versus 228 of 4993 (5%) given placebo. Women allocated magnesium sulphate had a 58% lower risk of eclampsia (95% CI 40-71) than those allocated placebo (40, 0.8%, vs 96, 1.9%; 11 fewer women with eclampsia per 1000 women). Maternal mortality was also lower among women allocated magnesium sulphate (relative risk 0.55, 0.26-1.14). For women randomised before delivery, there was no clear difference in the risk of the baby dying (576, 12.7%, vs 558, 12.4%; relative risk 1.02, 99% CI 0.92-1.14). The only notable difference in maternal or neonatal morbidity was for placental abruption (relative risk 0.67, 99% CI 0.45-0.89).\n Magnesium sulphate halves the risk of eclampsia, and probably reduces the risk of maternal death. There do not appear to be substantive harmful effects to mother or baby in the short term." ]	There is currently insufficient evidence to assess the efficacy and safety of magnesium sulphate when administered to women for neuroprotection of the term fetus. As there has been recent evidence for the use of magnesium sulphate for neuroprotection of the preterm fetus, high-quality randomised controlled trials are needed to determine the safety profile and neurological outcomes for the term fetus. Strategies to reduce maternal side effects during treatment also require evaluation.
CD001904	[ "7823066", "8601999", "3098555", "7710545", "1298221", "3925335", "10406359", "8006647" ]	[ "Phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed adult epilepsy: a randomised comparative monotherapy trial.", "Randomised comparative monotherapy trial of phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed childhood epilepsy.", "Carbamazepine versus phenobarbital for partial onset seizures in children.", "Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. UK Lamotrigine/Carbamazepine Monotherapy Trial Group.", "A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. The Department of Veterans Affairs Epilepsy Cooperative Study No. 264 Group.", "Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures.", "Safety and efficacy of vigabatrin and carbamazepine in newly diagnosed epilepsy: a multicentre randomised double-blind study. Vigabatrin European Monotherapy Study Group.", "A multicentre comparative trial of sodium valproate and carbamazepine in adult onset epilepsy. Adult EPITEG Collaborative Group." ]	[ "Recent studies have shown that most newly diagnosed epileptic patients can be satisfactorily treated with a single antiepileptic drug. We therefore undertook a prospective randomised pragmatic trial of the comparative efficacy and toxicity of four major antiepileptic drugs, utilised as monotherapy in newly diagnosed epileptic patients. Between 1981 and 1987 243 adult patients aged 16 years or over, newly referred to two district general hospitals with a minimum of two previously untreated tonic-clonic or partial with or without secondary generalised seizures were randomly allocated to treatment with phenobarbitone, phenytoin, carbamazepine, or sodium valproate. The protocol was designed to conform with standard clinical practice. Efficacy was assessed by time to first seizure after the start of treatment and time to enter one year remission. The overall outcome with all of the four drugs was good with 27% remaining seizure free and 75% entering one year of remission by three years of follow up. No significant differences between the four drugs were found for either measure of efficacy at one, two, or three years of follow up. The overall incidence of unacceptable side effects, necessitating withdrawal of the randomised drug, was 10%. For the individual drugs phenobarbitone (22%) was more likely to be withdrawn than phenytoin (3%), carbamazepine (11%), and sodium valproate (5%). In patients with newly diagnosed tonic-clonic or partial with or without secondary generalised seizures, the choice of drug will be more influenced by considerations of toxicity and costs.", "The medical treatment of childhood epilepsy is largely influenced by clinical trials in adult patients. We know of only one randomised comparative trial (of two drugs) in newly diagnosed childhood epilepsy. We have undertaken a long-term, prospective, randomised, unmasked, pragmatic trial of the comparative efficacy and toxicity of four standard antiepileptic drugs used as monotherapy in children with newly diagnosed epilepsy.\n Between 1981 and 1987, 167 children aged 3-16 years, who had had at least two previously untreated tonic-clonic or partial seizures, with or without secondary generalisation, were randomly allocated treatment with phenobarbitone, phenytoin, carbamazepine, or sodium valproate. The protocol was designed to conform to standard clinical practice. Efficacy was assessed by time to first seizure after the start of treatment and time to achieving 1-year remission.\n The overall outcome with all four drugs was good. 20% of children remained free of seizures and 73% had achieved 1-year remission by 3 years of follow-up. We found no significant differences between the drugs for either measure of efficacy at 1, 2, or 3 years of follow-up. The overall frequency of unacceptable side-effects necessitating withdrawal of the randomised drug was 9%. This total included six of the first ten children assigned phenobarbitone; no further children were allocated this drug. Of the other three drugs, phenytoin (9%) was more likely to be withdrawn than carbamazepine (4%) or sodium valproate (4%). INTERPRETATION Our data will inform choice of drug and outcome with four of the standard drugs available for newly diagnosed tonic-clonic or partial seizures with or without secondary generalisation in children.", "Thirty-nine children were treated with either phenobarbital (PB) or carbamazepine (CBZ) for newly diagnosed partial onset seizures. Drug selection was randomized in 33 subjects. Parents and the psychologist evaluating the child were blind to drug identity. Psychometric and behavioral evaluations were done at intake and at 6- and 12-month follow-ups. There were no significant differences between drugs in effect on behavior or cognitive function. CBZ caused more systemic problems. There was a trend toward better seizure control with CBZ, but this was not statistically significant. Although individual children in each group had changes in behavior or cognitive status, neither group changed significantly, in either acute or chronic follow-up.", "Lamotrigine has been licensed widely as adjunctive therapy for partial and secondary generalised seizures. Use of the drug as monotherapy was investigated in a double-blind, randomised, parallel-group comparison with carbamazepine in newly diagnosed epilepsy. After 4 weeks of planned, fixed dose escalation, doses were adjusted according to efficacy, adverse events, and plasma concentrations. 151 of 260 patients (131 lamotrigine, 129 carbamazepine) in eight UK centres completed the 48-week trial. No differences in efficacy between the drugs were found for partial seizures with or without secondary generalisation or for primary generalised tonic-clonic seizures. The proportion of patients maintained seizure-free during the last 24 weeks of treatment was almost the same in both groups (39% lamotrigine, 38% carbamazepine). More patients with primary generalised tonic-clonic seizures (47% both groups) than those presenting with a focal onset (35%, 37%) were fully controlled. Overall, fewer patients on lamotrigine than on carbamazepine withdrew because of adverse events (15 vs 27%). The commonest side-effect leading to withdrawal with either drug was rash (9%, 13%). Sleepiness was less common in lamotrigine than in carbamazepine recipients (12 vs 22%, p < 0.05). More lamotrigine than carbamazepine recipients (65 vs 51%, p = 0.018) completed the study (hazard ratio 1.57 [95% CI 1.07-2.31]). Lamotrigine and carbamazepine showed similar efficacy against partial onset seizures and primary generalised tonic-clonic seizures in newly diagnosed epilepsy. Lamotrigine, however, was better tolerated.", "Valproate is approved for use primarily in patients with absence seizures, but the drug has a broad spectrum of activity against seizures of all types. Partial or secondarily generalized tonic-clonic seizures are often difficult to control adequately with standard treatment, usually carbamazepine or phenytoin.\n We conducted a multicenter, double-blind trial that compared valproate with carbamazepine in the treatment of 480 adults with complex partial seizures (206 patients) or secondarily generalized tonic-clonic seizures (274 patients). The patients were randomly assigned to treatment with carbamazepine or divalproex sodium (valproate) at doses adjusted to achieve blood levels in the middle of the therapeutic range. Patients were followed for one to five years or until seizures became uncontrollable, treatment had unacceptable adverse effects, or both these events occurred.\n For the control of secondarily generalized tonic-clonic seizures, carbamazepine and valproate were comparably effective (in 136 patients and 138 patients, respectively). For complex partial seizures, four of five outcome measures favored carbamazepine (100 patients) over valproate (106 patients): the total number of seizures (2.7 vs. 7.6, P = 0.05), the number of seizures per month (0.9 vs. 2.2, P = 0.01), the time to the first seizure (P less than 0.02), and the seizure-rating score (P = 0.04). Carbamazepine was also superior according to a composite score that combined scores for the control of seizures and for adverse effects (P less than 0.001). Valproate was associated more frequently than carbamazepine with a weight gain of more than 5.5 kg (12 lb) (20 percent vs. 8 percent, P less than 0.001), with hair loss or change in texture (12 percent vs. 6 percent, P = 0.02), and with tremor (45 percent vs. 22 percent, P less than 0.001). Rash was more often associated with carbamazepine (11 percent vs. 1 percent, P less than 0.001).\n Valproate is as effective as carbamazepine for the treatment of generalized tonic-clonic seizures, but carbamazepine provides better control of complex partial seizures and has fewer long-term adverse effects.", "We conducted a 10-center, double-blind trial to compare the efficacy and toxicity of four antiepileptic drugs in the treatment of partial and secondarily generalized tonic-clonic seizures in 622 adults. Patients were randomly assigned to treatment with carbamazepine, phenobarbital, phenytoin, or primidone and were followed for two years or until the drug failed to control seizures or caused unacceptable side effects. Overall treatment success was highest with carbamazepine or phenytoin, intermediate with phenobarbital, and lowest with primidone (P less than 0.002). Differences in failure rates of the drugs were explained primarily by the fact that primidone caused more intolerable acute toxic effects, such as nausea, vomiting, dizziness, and sedation. Decreased libido and impotence were more common in patients given primidone. Phenytoin caused more dysmorphic effects and hypersensitivity. Control of tonic-clonic seizures did not differ significantly with the various drugs. Carbamazepine provided complete control of partial seizures more often than primidone or phenobarbital (P less than 0.03). Overall, carbamazepine and phenytoin are recommended drugs of first choice for single-drug therapy of adults with partial or generalized tonic-clonic seizures or with both.", "Vigabatrin is a newly licensed drug for use in patients with epilepsy. We investigated whether this drug was comparable to standard first-line monotherapy in efficacy and incidence of adverse events.\n We enrolled 459 patients with newly diagnosed, previously untreated partial epileptic seizures from 44 European centres and randomly assigned them carbamazepine 600 mg daily (n=230) or vigabatrin 2 g daily (n=229). After initial maintenance doses were reached, doses were adjusted downwards (in the case of adverse events) or upwards (in the case of seizures) by the clinician. The primary outcome was time to withdrawal because of lack of efficacy or adverse events. Secondary outcomes included efficacy (time to 6-month remission of seizures, time to first seizure after initial dose stabilisation), and adverse events (incidence and severity). Analysis was by intention to treat.\n Time to withdrawal for lack of efficacy or adverse events did not differ between groups (p=0.318). Vigabatrin was better tolerated than carbamazepine with fewer withdrawals, but was more frequently associated with psychiatric symptoms (58 [25%] vs 34 [15%]) and weight gain (25 [11%] vs 12 [5%]). Carbamazepine was associated with rash (22 [10%] vs seven [3%]). All efficacy outcomes favoured carbamazepine and failed to show equivalence between the two drugs. No significant difference was found for time to achieve 6 months of remission from seizures (p=0.058), but the most powerful outcome, time to first seizure after the first 6 weeks from randomisation, showed carbamazepine to be significantly more effective than vigabatrin (p=0.0001).\n Vigabatrin seems less effective but better tolerated than carbamazepine, which is the first-choice drug for the treatment of partial epilepsies. Vigabatrin cannot therefore be recommended as a first-line drug for monotherapy in this group of patients.", "The long-term efficacy and safety of sodium valproate and carbamazepine in adult outpatients with newly diagnosed primary generalised or partial and secondarily generalised seizures were compared in a randomised, open, multicentre study at 22 neurology outpatient clinics. Patients were randomised to oral sodium valproate (Epilim EC enteric coated 200 mg tablets twice daily, n = 149) or oral carbamazepine (100 mg twice daily increasing to 200 mg twice daily in week 2, n = 151) and followed up for three years. If clinically necessary, dosages were regularly increased until seizures were controlled or toxicity developed. Sodium valproate and carbamazepine controlled both primary generalised and partial seizures equally effectively overall. Significantly more patients on sodium valproate than carbamazepine (126/140 (90%) v 105/141 (75%), p = 0.001) remained on randomised treatment for at least six months. Skin rashes occurred significantly more often in carbamazepine recipients than in sodium valproate recipients (11.2% v 1.7%, p < 0.05) and carbamazepine was associated with a higher withdrawal rate because of adverse events (15% v 5% on sodium valproate) in the first six months of treatment. There was no difference between the drugs in the rate of withdrawal because of poor seizure control at any stage, regardless of seizure type. At the end of the three year trial period, over 70% of the available patients were still on randomised treatment or had recently stopped treatment after achieving full seizure control. Sodium valproate and carbamazepine were both associated with a high degree of overall seizure control regardless of seizure type and both have good long-term tolerability in adult patients with newly diagnosed epilepsy. Recommendations are made for a higher initial dosage regime for sodium valproate in partial seizures." ]	We found no overall difference between carbamazepine and phenobarbitone for time to 12-month remission or time to first seizure, however, subgroup analyses for time to first seizure suggest an advantage with phenobarbitone for partial onset seizures and a clinical advantage with carbamazepine for generalized onset tonic-clonic seizures. Phenobarbitone is significantly more likely to be withdrawn, indicating that it is less well tolerated than carbamazepine.
CD008806	[ "7603807", "21334262", "17968821", "17921553" ]	[ "Oral glycerol and intravenous dexamethasone in preventing neurologic and audiologic sequelae of childhood bacterial meningitis. The Finnish Study Group.", "Glycerol adjuvant therapy in adults with bacterial meningitis in a high HIV seroprevalence setting in Malawi: a double-blind, randomised controlled trial.", "Adjuvant glycerol and/or dexamethasone to improve the outcomes of childhood bacterial meningitis: a prospective, randomized, double-blind, placebo-controlled trial.", "Role of dexamethasone and oral glycerol in reducing hearing and neurological sequelae in children with bacterial meningitis." ]	[ "To assess the value of adjunctive intravenous dexamethasone (DXM) and oral glycerol (GLY) for the treatment of bacteriologically proved bacterial meningitis, 122 infants and children with bacterial meningitis were randomly assigned to receive DXM intravenously (n = 32), GLY orally (n = 30), DXM plus GLY (n = 34) or neither (n = 26) of these drugs. All patients were treated with the same antimicrobial agent, ceftriaxone. The patients were followed neurologically for as long as 6 months. A thorough hearing evaluation was performed routinely 2 months or more after discharge from hospital. Overall 4 (7%) of the GLY-treated patients, compared with 11 (19%) of those not given GLY, developed audiologic or neurologic sequelae (P = 0.052), the relative risk of sequelae being 2.94 (95% confidence interval, 0.99 to 8.72). The patients who had received GLY showed less severe or profound bilateral hearing impairment than those not given GLY (0 vs. 7%, P = 0.049), and none of them had other neurologic abnormalities 3 or 6 months after discharge, compared with 5 (9%) of those not treated with GLY (P = 0.024). The DXM recipients showed only a tendency to less severe hearing impairment than those not given DXM. In conclusion oral GLY prevented neurologic sequelae in infants and children with bacterial meningitis more effectively than intravenous DXM.", "Southern Africa has a high incidence of bacterial meningitis in adults, often associated with HIV co-infection. Mortality exceeds 50%, even with appropriate antibiotic therapy, and is not improved with corticosteroids. Glycerol adjuvant therapy reduces long-term morbidity in bacterial meningitis in children, and its use is being promoted. We aimed to assess the effectiveness of glycerol as an adjuvant therapy for adults with bacterial meningitis in Africa.\n The study was done in two phases. First, in an open-label dose-finding study, 45 adult patients with symptoms, signs, and cerebrospinal fluid findings consistent with bacterial meningitis received either 50 mL, 75 mL, or 100 mL of glycerol four times a day for 4 days. We then did a randomised, double-blind, placebo-controlled trial of oral glycerol in adults with bacterial meningitis. Patients with clinical and cerebrospinal fluid findings suggestive of bacterial meningitis were randomly assigned in blocks of 12 by use of a random number list produced by an independent statistician to receive either glycerol or an equivalent volume of sugar solution. Glycerol and placebo were indistinguishable by colour or taste. The primary outcome was mortality at 40 days, with secondary outcomes including disability and mortality restricted to pneumococcal disease. All patients were analysed for the primary outcome excluding those who were lost to follow-up. This trial is registered at controlled-trials.com, number ISRCTN70121840.\n 75 mL glycerol four times a day was the highest tolerated dose, and was used for the main study. 265 patients were assigned treatment: 137 glycerol and 128 placebo. The trial was stopped early on the advice of the data and safety monitoring board after a planned interim analysis. By day 40, 61 (49%) of 125 patients in the placebo group and 86 (63%) of 136 in the glycerol group had died (adjusted odds ratio 2.4, 95% CI 1.3-4.2, p=0.003). There was no benefit from glycerol for death and disability by day 40, and glycerol did not improve death and disability by day 40 or death at day 40 in patients with proven bacterial disease or pneumococcal disease. Two serious adverse events occurred that were possibly due to the study drug.\n Oral glycerol therapy cannot be recommended as an adjuvant therapy in adults with bacterial meningitis in resource-poor settings with a high HIV prevalence.\n Meningitis Research Foundation.\n Copyright © 2011 Elsevier Ltd. All rights reserved.", "Despite favorable meta-analyses, no study involving third-generation cephalosporins for the treatment of childhood bacterial meningitis has documented a benefit of adjuvant dexamethasone therapy if the outcomes are examined individually.\n We conducted a prospective, randomized, double-blind trial comparing adjuvant dexamethasone or glycerol with placebo in children aged from 2 months through 16 years in Latin America. Ceftriaxone was administered to all children; children were randomized to also receive dexamethasone intravenously, glycerol orally, both agents, or neither agent. Primary end points were death, severe neurological sequelae, or deafness, with the first 2 end points forming a composite end point. A subgroup analysis for Haemophilus influenzae type b meningitis was undertaken. Intention-to-treat analysis was performed using binary logistic regression models.\n H. influenzae type b, pneumococci, and meningococci were the main agents found among 654 patients; dexamethasone was given to 166, dexamethasone and glycerol were given to 159, glycerol was given to 166, and placebo was given to 163. No adjuvant therapy significantly affected death or deafness. In contrast, glycerol and dexamethasone plus glycerol reduced severe neurological sequelae, compared with placebo; the odds ratios were 0.31 (95% confidence interval [95% CI], 0.13-0.76; P=.010) and 0.39 (95% CI, 0.17-0.93; P=.033), respectively. For neurological sequelae and death, the odds ratios were 0.44 (95% CI, 0.25-0.76; P=.003) and 0.55 (95% CI, 0.32-0.93; P=.027), respectively. Dexamethasone therapy prevented deafness in patients with H. influenzae type b meningitis only if patients were divided grossly into dexamethasone recipients and nonrecipients and if timing between dexamethasone and ceftriaxone administration was not taken into account (odds ratio, 0.27; 95% CI, 0.09-0.77; P=.014).\n Oral glycerol therapy prevents severe neurological sequelae in patients with childhood meningitis. Safety, availability, low cost, and oral administration also add to its usefulness, especially in resource-limited settings.", "To investigate the efficacy of dexamethasone and oral glycerol in reducing hearing and neurological sequelae in children with acute bacterial meningitis (ABM).\n Prospective double blind, placebo controlled randomized study.\n Pediatric services of a tertiary care teaching and referral hospital.\n Children 2 months to 12 years with a diagnosis of acute bacterial meningitis admitted between June 2002 to September 2003.\n Subjects were assigned randomly to receive dexamethasone, glycerol, dexamethasone+glycerol or placebo. Neurological and hearing impairment was assessed at discharge and after 1 month.\n 58 children (48 boys, 10 girls), mean age 50.2 +/- 41.0 months, were studied. Twelve patients received dexamethasone, 13 glycerol, 20 dexamethasone + glycerol and 13 placebo. Bacterial etiology was ascertained in 24 patients: Streptococcus pneumoniae-10, H influenzae b-7, Staph. aureus-5 and others-2. Three (5.2%) children died during hospital stay and 55 survived. Seven (12%) patients had neurological sequelae (3 in glycerol, 3 in dexamethasone+glycerol, 1 in placebo group, P = 0.29), and 10 patients (17%) had hearing sequelae (2 in glycerol, 3 in dexamethasone, 2 dexamethasone + glycerol and 3 in placebo group, P = 0.68).\n No significant difference was seen in neurological or hearing outcome with use of either glycerol or dexamethasone in children with acute bacterial meningitis." ]	The only osmotic diuretic to have undergone randomised evaluation is glycerol. Data from trials to date have not demonstrated benefit on death, but it may reduce deafness. Osmotic diuretics, including glycerol, should not be given to adults and children with bacterial meningitis unless as part of carefully conducted randomised controlled trial.
CD006322	[ "18245143", "18399862" ]	[ "Short term improvement in exercise capacity and symptoms following exercise training in interstitial lung disease.", "Effects of pulmonary rehabilitation in patients with idiopathic pulmonary fibrosis." ]	[ "Interstitial lung disease (ILD) is characterised by exertional dyspnoea, exercise limitation and reduced quality of life. The role of exercise training in this diverse patient group is unclear. The aims of this study were to establish the safety of exercise training in ILD; its effects on exercise capacity, dyspnoea and quality of life; and whether patients with idiopathic pulmonary fibrosis (IPF) had similar responses to those with other types of ILD.\n 57 subjects with ILD (34 IPF) were randomised to receive 8 weeks of supervised exercise training or weekly telephone support. The 6 min walk distance (6MWD), incremental exercise test, modified Medical Research Council (MRC) dyspnoea score and Chronic Respiratory Disease Questionnaire (CRDQ) were performed at baseline, following intervention and at 6 months.\n 80% of subjects completed the exercise programme and no adverse events were recorded. The 6MWD increased following training (mean difference to control 35 m, 95% CI 6 to 64 m). A significant reduction in MRC score was observed (0.7 points, 95% CI 0.1 to 1.3) along with improvements in dyspnoea (p = 0.04) and fatigue (p<0.01) on the CRDQ. There was no change in peak oxygen uptake; however, exercise training reduced heart rate at maximum isoworkload (p = 0.01). There were no significant differences in response between those with and without IPF. After 6 months there were no differences between the training and control group for any outcome variable.\n Exercise training improves exercise capacity and symptoms in patients with ILD, but these benefits are not sustained 6 months following intervention.", "Although pulmonary rehabilitation is effective for patients with COPD, its efficacy in patients with IPF is unknown. The purpose of this study was to evaluate the effects of pulmonary rehabilitation in IPF.\n Thirty patients diagnosed with IPF, according to the consensus statement, were randomly assigned to the rehabilitation group or the control group. The pulmonary rehabilitation mainly consisted of a 10-week programme of exercise training. Pulmonary function, blood gas analysis, 6MWD, dyspnoea rating with the baseline dyspnoea index and health-related quality of life score on the St George's Respiratory Questionnaire were evaluated at baseline and after the programme.\n Assessment of efficacy was carried out on 13 patients who completed the programme and 15 patients in the control group. There were no significant effects of the programme on measures of pulmonary function, values of arterial blood gas analysis or dyspnoea rating. Although there were some differences in the baseline 6MWD and total health-related quality of life score which were not statistically significant, marked improvements were observed in the 6MWD (mean difference 46.3 m (95% CI: 8.3-84.4), P < 0.05) and the total health-related quality of life score (-6.1 (95% CI: -11.7 to -0.5), P < 0.05).\n Pulmonary rehabilitation improves both exercise capacity and health-related quality of life in patients with IPF." ]	Physical training is safe for people with ILD. Improvements in functional exercise capacity, dyspnoea and quality of life are seen immediately following training, with benefits also evident in IPF. There is little evidence regarding longer-term effects of physical training.
CD008900	[ "18048059" ]	[ "A pilot study to evaluate the effects of Cerebrolysin on cognition and qEEG in vascular dementia: cognitive improvement correlates with qEEG acceleration." ]	[ "The effects of the neurotrophic compound Cerebrolysin (Cere) on cognitive performance, evaluated with the ADAS-cog, and on qEEG activity were investigated in forty one patients with mild to moderate severe probable vascular dementia (VaD) according to NINDS-AIREN criteria, included in a placebo-controlled pilot study. Patients received i.v. infusions of Cere (10 or 30 ml) or placebo (normal saline) 5 days/week for 4 weeks. Mean score of change from baseline in the ADAS-cog and percent change from baseline in slow to fast EEG power ratio (PR) scores were the two primary endpoints. Correlations between cognition and qEEG were also evaluated for both baseline scores and for scores of change from baseline in ADAS-cog and in qEEG parameters, including EEG power ratio (PR) as an index of EEG slowing. Baseline ADAS-cog scores showed significant positive correlations with delta power, theta power and PR scores, and correlated negatively with alpha activity. These correlations indicating that an increased EEG slowing is associated with a worst cognitive performance in VaD patients. Cere treatment improved cognitive performance significantly at the 10 ml dose and reduced EEG slowing with both 10 and 30 ml dosages. A significant positive correlation between PR and ADAS-cog scores of change from baseline was observed in Cere-treated patients. According to results of this pilot study, it is concluded that Cere improves cognitive performance and reduces EEG slowing in patients with VaD, and that there is a positive relationship between changes in cognition and qEEG activity induced by Cere. The conduction of further regular clinical trials is required to confirm the potential utility of Cere in the treatment of VaD suggested by the present results." ]	Cerebrolysin may have positive effects on cognitive function and global function in elderly patients with vascular dementia of mild to moderate severity, but there is still insufficient evidence to recommend Cerebrolysin as a routine treatment for vascular dementia due to the limited number of included trials, wide variety of treatment durations and short-term follow-up in most of the trials.
CD007281	[ "17034536", "18341663", "8977678", "12775317", "16159735", "19222455", "17223873", "12140473" ]	[ "Intraindividual, right-left comparison of topical methyl aminolaevulinate-photodynamic therapy and cryotherapy in subjects with actinic keratoses: a multicentre, randomized controlled study.", "Multicentre intraindividual randomized trial of topical methyl aminolaevulinate-photodynamic therapy vs. cryotherapy for multiple actinic keratoses on the extremities.", "Comparison of photodynamic therapy with cryotherapy in the treatment of Bowen's disease.", "A comparison of photodynamic therapy using topical methyl aminolevulinate (Metvix) with single cycle cryotherapy in patients with actinic keratosis: a prospective, randomized study.", "A randomized multicenter study to compare two treatment regimens of topical methyl aminolevulinate (Metvix)-PDT in actinic keratosis of the face and scalp.", "Optimization of photodynamic therapy with a novel self-adhesive 5-aminolaevulinic acid patch: results of two randomized controlled phase III studies.", "Treatment of post-transplant premalignant skin disease: a randomized intrapatient comparative study of 5-fluorouracil cream and topical photodynamic therapy.", "Photodynamic therapy using topical methyl 5-aminolevulinate compared with cryotherapy for actinic keratosis: A prospective, randomized study." ]	[ "Actinic keratosis (AK), the most common premalignant skin condition, can represent a management challenge. Treatment should not only be effective, but also well tolerated and allow for good cosmesis on typical sun-exposed highly visible body sites.\n The primary objective was to compare the lesion response and subject preference for topical methyl aminolaevulinate (MAL)-photodynamic therapy (PDT) vs. cryotherapy for the treatment of AK.\n In this 24-week, multicentre, randomized, intraindividual (right-left) study, subjects received both one treatment session of MAL-PDT and a double freeze-thaw cryotherapy; the treatments were randomly allocated to either side of the face/scalp. Lesions with a noncomplete response were retreated after 12 weeks. The primary assessments were the subject's overall preference and lesion response at week 24. Secondary assessments included lesion response at week 12, cosmetic outcome, subject and investigator cosmetic outcome preference at week 24, and investigator overall preference at week 24. Skin discomfort and adverse events were also evaluated.\n In total, 119 subjects with 1,501 lesions were included in the study. At week 12, treatment with MAL-PDT resulted in a significantly larger rate of cured lesions relative to cryotherapy (percentage lesion reduction from baseline: 86.9% vs. 76.2%; P < 0.001). At week 24, both treatment groups showed a high rate of cured lesions (89.1% for MAL-PDT vs. 86.1% for cryotherapy; P = 0.20; 95% confidence interval: -1.62 to 7.67). Results for subject and investigator preferences as well as cosmetic outcome favoured MAL-PDT. Both treatment regimens were safe and well tolerated.\n The present study shows that, when treated with both MAL-PDT and cryotherapy, subjects significantly prefer MAL-PDT treatment for AK. MAL-PDT is an attractive treatment option for AK, with comparable efficacy and superior cosmetic outcomes compared with double freeze-thaw cryotherapy.", "Methyl aminolaevulinate-photodynamic therapy (MAL-PDT) is an effective treatment in facial/scalp actinic keratosis (AK).\n The aims of this study were to compare efficacy, safety, cosmetic outcome and patient preference of MAL-PDT vs. cryotherapy in patients with AK at other locations.\n A multicentre, controlled, randomized, open, intraindividual, right-left comparison was performed. Patients with nonhyperkeratotic AK were treated once with MAL-PDT and cryotherapy on either side of the body. At week 12, lesions showing noncomplete response were retreated. The primary efficacy variable was the lesion response at week 24. Investigator's assessment of cosmetic outcome, patient's preference in terms of cosmetic outcome and a patient preference questionnaire were also analysed at week 24.\n In total, of 121 patients with 1343 lesions (98% located on the extremities and the remainder on the trunk and neck) were included. Both treatments provided a high mean percentage reduction in lesion count at week 24 with significantly higher efficacy for cryotherapy: 78% for MAL-PDT and 88% for cryotherapy (P=0.002, per protocol population). Investigator's assessment of cosmetic outcome was significantly better for MAL-PDT than cryotherapy (P<0.001), 79% of lesions having an excellent cosmetic outcome with MAL-PDT vs. 56% with cryotherapy at week 24. The cosmetic outcome achieved by MAL-PDT compared with cryotherapy was also preferred by patients (50% vs. 22%, respectively, P<0.001), and 59% of patients would prefer to have any new lesions treated with MAL-PDT compared with 25% with cryotherapy (P<0.001). Both treatment regimens were safe and well tolerated.\n MAL-PDT showed inferior efficacy for treatment of non-face/scalp AK compared with cryotherapy. However, both treatments showed high efficacy, and MAL-PDT conveyed the advantages of better cosmesis and higher patient preference.", "The efficacy and suitability of photodynamic therapy (PDT) was compared with that of cryotherapy in the treatment of 40 lesions of Bowen's disease. Lesions were randomized to receive either cryotherapy with liquid nitrogen, or PDT using a portable desktop lamp incorporating a 300 W xenon short arc discharge source. A porphyrin precursor, 5-aminolaevulinic acid (5-ALA), was applied topically 4 h before irradiation in the PDT group. Each lesion received 125 J/cm2 at a fluence rate of 70 mW/cm2. All patients were reviewed at 2-monthly intervals and treatments repeated if required. Cryotherapy produced clearance in 10 of 20 lesions after one treatment, the remaining 10 lesions requiring two or three treatment applications. PDT resulted in clearance of 15 of 20 lesions after one treatment and of the remaining five lesions after a second treatment. The probability that a lesion cleared after one treatment was greater with PDT than cryotherapy (P < 0.01). Cryotherapy was associated with ulceration (five of 20), infection (two of 20) and recurrent disease (two of 20); no such complications occurred following PDT. PDT using a non-laser light source and topical 5-ALA appears to be at least as effective as cryotherapy in the treatment of Bowen's disease with fewer adverse effects.", "Actinic keratosis (AK) is a very common condition, which has the potential of progressing to squamous cell carcinoma. The present study is a prospective, randomized study comparing the lesion response, cosmetic outcome, patient satisfaction and tolerability of a new treatment modality, photodynamic therapy (PDT), using topical methyl aminolevulinate (Metvix), with the most commonly used standard therapy for AK, cryotherapy.\n A total of 204 patients with clinically diagnosed AK were randomized to either cryotherapy or PDT. The PDT patients were further assigned to an active or placebo group in a random, double-blind manner. Cryotherapy was performed using liquid nitrogen spray in a single freeze-thaw cycle. PDT was performed using 160 mg/g methyl aminolevulinate cream or placebo, a 3-hour application time, red light (570-670 nm) and a total light dose of 75 J/cm(2). PDT was repeated after 7 days. Two sessions of PDT were undertaken, as a previous study had shown a single session had similar efficacy to cryotherapy. Lesion response was assessed clinically after 3 months (complete response or non-complete response).\n The lesion response rate was 91% in the methyl aminolevulinate PDT group, 68% in the cryotherapy group and 30% in the placebo PDT group. Methyl aminolevulinate PDT was statistically significantly better than both cryotherapy and placebo PDT in terms of response rates and cosmetic outcome. Most patients preferred PDT to other treatments.\n PDT with methyl aminolevulinate is an excellent treatment option, particularly for patients with widespread damage or AK lesions in cosmetically sensitive areas.", "Photodynamic therapy (PDT) with topical methyl aminolevulinate (MAL) administered in two treatment sessions separated by 1 week is an effective treatment for actinic keratoses. This open prospective study compared the efficacy and safety of MAL-PDT given as a single treatment with two treatments of MAL-PDT 1 week apart. Two hundred and eleven patients with 413 thin to moderately thick actinic keratoses were randomized to either a single treatment with PDT using topical MAL (regimen I; n=105) or two treatments 1 week apart (regimen II; n=106). Each treatment involved surface debridement, application of Metvix cream (160 mg/g) for 3 h, followed by illumination with red light using a light-emitting diode system (peak wavelength 634+/-3 nm, light dose 37 J/cm2). Thirty-seven lesions (19%) with a non-complete response 3 months after a single treatment were re-treated. All patients were followed up 3 months after the last treatment. A total of 400 lesions, 198 initially treated once and 202 treated twice, were evaluable. Complete response rate for thin lesions after a single treatment was 93% (95% CI=87-97%), which was similar to 89% (82-96%) after repeated treatment. Response rates were lower after single treatment of thicker lesions (70% (60-78%) vs 84% (77-91%)), but improved after repeated treatment (88% (82-94%)). The conclusion of this study is that single treatment with topical MAL-PDT is effective for thin actinic keratosis lesions; however, repeated treatment is recommended for thicker or non-responding lesions.", "Photodynamic therapy (PDT) is increasingly used for treatment of actinic keratoses (AKs) but is a cumbersome procedure. A thin self-adhesive patch (PD P 506 A) containing 5-aminolaevulinic acid (5-ALA) was developed to facilitate PDT.\n To investigate efficacy and safety of the patch in comparison with placebo-PDT (superiority design, observer-blinded; study AK 03) and standard therapy, cryosurgery (noninferiority design, open; study AK 04).\n Two separate confirmatory randomized parallel-group phase III studies were set up. In total, 449 patients with up to eight mild to moderate AK study lesions located on the head were treated in 29 German study centres (study AK 03: 103 patients; study AK 04: 346 patients).\n Twelve weeks after treatment, 5-ALA patch-PDT proved to be superior to placebo-PDT (P < 0.001) and cryosurgery (P = 0.007). Efficacy rates on a lesion basis were 82% (AK 03) and 89% (AK 04) for PDT, 77% for cryosurgery and 19% (AK 03) and 29% (AK 04) for placebo-PDT. Local reactions at the treatment site occurred in almost all patients treated with 5-ALA patch-PDT or cryosurgery. Headache was the only side-effect not related to the treatment site which occurred in more than one patient.\n PD P 506 A is an innovative, easy-to-handle 5-ALA patch for PDT of mild to moderate AK lesions. Compared with current PDT procedures, pretreatment (e.g. curettage) is not needed and handling is considerably facilitated. A single PDT treatment results in efficacy rates being statistically significantly superior to placebo and cryosurgery.", "Organ transplant recipients (OTR) are at high risk of developing nonmelanoma skin cancer and premalignant epidermal dysplasia (carcinoma in situ/ Bowen's disease and actinic keratoses). Epidermal dysplasia is often widespread and there are few comparative studies of available treatments.\n To compare topical methylaminolaevulinate (MAL) photodynamic therapy (PDT) with topical 5% fluorouracil (5-FU) cream in the treatment of post-transplant epidermal dysplasia.\n Eight OTRs with epidermal dysplasia were recruited to an open-label, single-centre, randomized, intrapatient comparative study. Treatment with two cycles of topical MAL PDT 1 week apart was randomly assigned to one area of epidermal dysplasia, and 5-FU cream was applied twice daily for 3 weeks to a clinically and histologically comparable area. Patients were reviewed at 1, 3 and 6 months after treatment. The main outcome measures were complete resolution rate (CRR), overall reduction in lesional area, treatment-associated pain and erythema, cosmetic outcome and global patient preference.\n At all time points evaluated after completion of treatment, PDT was more effective than 5-FU in achieving complete resolution: eight of nine lesional areas cleared with PDT (CRR 89%, 95% CI: 0.52-0.99), compared with one of nine lesional areas treated with 5-FU (CRR 11%, 95% CI: 0.003-0.48) (P = 0.02). The mean lesional area reduction was also proportionately greater with PDT than with 5-FU (100% vs. 79% respectively). Cosmetic outcome and patient preference were also superior in the PDT-treated group.\n Compared with topical 5-FU, MAL PDT was a more effective and cosmetically acceptable treatment for epidermal dysplasia in OTRs and was preferred by patients. Further studies are now required to confirm these results and to examine the effect of treating epidermal dysplasia with PDT on subsequent development of squamous cell carcinoma in this high risk population.", "Actinic keratoses (AKs) are the most common premalignant tumors. Without treatment, a significant number of patients with AK will experience squamous cell carcinoma. Photodynamic therapy (PDT) using the new highly selective photosensitizer methyl 5-aminolevulinate is a promising new treatment modality for AK.\n We investigated the complete response rates, cosmetic outcome, and patient satisfaction after photodynamic therapy (PDT) using methyl 5-aminolevulinate (Metvix) versus cryotherapy in the treatment of AKs.\n Patients were randomized to receive either cryotherapy with liquid nitrogen spray or PDT using methyl 5-aminolevulinate cream 160 mg/g, 3 hours application time, and red light (75 J/cm(2)).\n Efficacy results from 193 patients with 699 lesions (92% face/scalp and 93% thin/moderately thick) were analyzed. Overall complete response rates after 3 months were 69% for PDT and 75% for cryotherapy. Both treatments gave higher response rates in thin lesions (PDT 75%, cryotherapy 80%). PDT gave better cosmetic results and higher patient satisfaction than cryotherapy.\n PDT using methyl 5-aminolevulinate is an attractive treatment option for patients with AK, with a response rate similar to that of cryotherapy, but with superior cosmetic results and high patient satisfaction." ]	Overall, there has been very little good-quality research on treatments for Bowen's disease. There is limited evidence from single studies to suggest MAL-PDT is an effective treatment. Although cosmetic outcomes appear favourable with PDT, five-year follow-up data are needed. Significantly more lesions cleared with MAL-PDT compared to cryotherapy. No significant difference in clearance was seen when MAL-PDT was compared with 5-FU, but one study found a significant difference in clearance in favour of ALA-PDT when compared to 5-FU. There was no significant difference in clearance when cryotherapy was compared to 5-FU. The lack of quality data for surgery and topical cream therapies has limited the scope of this review to one largely about PDT studies. The age group, number, and size of lesions and site(s) affected may all influence therapeutic choice; however, there was not enough evidence available to provide guidance on this. More studies are required in the immunosuppressed populations as different therapeutic options may be preferable. Specific recommendations cannot be made from the data in this review, so we cannot give firm conclusions about the comparative effectiveness of treatments.
CD007411	[ "17065044", "17982752", "17550489", "10221237", "20104528", "15557412", "12623744", "8825017", "19020919", "18287793", "12435256", "21596735", "10485722", "15668500", "9197872", "7979565", "19687417", "11779098", "22009916", "16894312", "17999276", "12600905", "7672157", "17532088", "17888202", "16616557", "17199068" ]	[ "Lower rate of preeclampsia after antioxidant supplementation in pregnant women with low antioxidant status.", "May antioxidant therapy improve sperm parameters of men with persistent oligospermia after retrograde embolization for varicocele?", "A randomised control trial examining the effect of an antioxidant (Menevit) on pregnancy outcome during IVF-ICSI treatment.", "Antioxidant treatment of patients with asthenozoospermia or moderate oligoasthenozoospermia with high-dose vitamin C and vitamin E: a randomized, placebo-controlled, double-blind study.", "Incidence of cancers, ischemic cardiovascular diseases and mortality during 5-year follow-up after stopping antioxidant vitamins and minerals supplements: a postintervention follow-up in the SU.VI.MAX Study.", "The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals.", "Sperm oxidative stress and the effect of an oral vitamin E and selenium supplement on semen quality in infertile men.", "Multicenter ophthalmic and nutritional age-related macular degeneration study--part 2: antioxidant intervention and conclusions.", "Effect of antioxidants combined to resistance training on BMD in elderly women: a pilot study.", "Indications of the mechanisms involved in improved sperm parameters by zinc therapy.", "Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial.", "Effect of supplementation during pregnancy with L-arginine and antioxidant vitamins in medical food on pre-eclampsia in high risk population: randomised controlled trial.", "Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial.", "Antioxidant vitamin supplementation reduces benzo(a)pyrene-DNA adducts and potential cancer risk in female smokers.", "Antioxidants in the treatment of severe pre-eclampsia: an explanatory randomised controlled trial.", "Pregnancy outcomes in a randomised controlled trial of periconceptional multivitamin supplementation. Final report.", "Antioxidant supplementation and risk of incident melanomas: results of a large prospective cohort study.", "Effect of recombinant human erythropoietin administration on lipid peroxidation and antioxidant enzyme(s) activities in preterm infants.", "Carotenoids in Age-related Maculopathy Italian Study (CARMIS): two-year results of a randomized study.", "The effect of antioxidant supplementation on hepatitis C viral load, transaminases and oxidative status: a randomized trial among chronic hepatitis C virus-infected patients.", "Luteal estrogen supplementation in stimulated cycles may improve the pregnancy rate in patients undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer.", "Six-year effect of combined vitamin C and E supplementation on atherosclerotic progression: the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study.", "A double-blind randomized placebo cross-over controlled trial using the antioxidant vitamin E to treat reactive oxygen species associated male infertility.", "A randomized trial of antioxidant therapy alone or with corticosteroids in acute alcoholic hepatitis.", "A short-term intervention trial with selenate, selenium-enriched yeast and selenium-enriched milk: effects on oxidative defence regulation.", "Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial.", "Multimicronutrient supplementation for undernourished pregnant women and the birth size of their offspring: a double-blind, randomized, placebo-controlled trial." ]	[ "To investigate maternal and neonatal outcomes after antioxidant supplementation relatively early in pregnancy (8 to 12 weeks) for pregnant women with low antioxidant status.\n A randomized, double-blind, placebo-controlled trial of daily antioxidant supplementation was performed on pregnant women screening positive for low antioxidant status at 8 to 12 weeks of gestation. Low antioxidant status was defined as a superoxidedismutase (SOD) level below 1102 U/g Hb or 164 U/mL. The supplementation group received the following antioxidants daily: vitamins A (1000 IU), B6 (2.2 mg), B12 (2.2 microg), C (200 mg), and E (400 IU), folic acid (400 microg), N-acetylcysteine (200 mg), Cu (2 mg), Zn (15 mg), Mn (0.5 mg), Fe (30 mg), calcium (800 mg), and selenium (100 microg). The control group received Fe (30 mg) and folic acid (400 microg). Maternal (preeclampsia, abortion, and hypertension) and perinatal outcomes were assessed.\n In the supplementation group (29 subjects), we observed 2 cases of preeclampsia (6.8%, 1 mild and 1 severe), 1 of IUGR (birth weight 2300 g at 38 weeks), and 1 preterm delivery. In the control group (31 subjects), there were 8 abortions, 9 cases of preeclampsia (29%, 6 mild and 3 severe) with perinatal outcome: 3 preterm delivery cases and 1 IUGR (birth weight 2030 g at 39 weeks). Preeclampsia was significantly less frequent in the supplementation group when compared to the control group (2 vs. 9 cases, p = 0.043, OR = 0.18 [95% CI: 0.03, 0.92]). Finally we focused on the prediction of preeclampsia at 8 to 12 weeks. Combined sensitivity of markers of antioxidant status (SOD slutathione peroxidase, [GPx], and total anti-oxidant status [TAS]) was 33% (false-positive rate of 4.5%).\n Antioxidant supplementation was associated with better maternal and perinatal outcome in pregnant women with low antioxidant status than control supplementation with iron and folate alone. In a selected population already screened positive for low SOD, preeclampsia can be detected in 33% of asymptomatic cases in the first trimester using SOD, GPx, and TAS. It seems feasible that panels of both biochemical and molecular markers may be clinically useful in the prediction of this disease.", "We performed a randomized, prospective, controlled, intention to treat study in order to determine the effectiveness of an antioxidant therapy in improve the quality of seminal fluid parameters and the natural pregnancies in men with persistent oligospermia (5-20 million/ml) 6 months after retrograde embolization. Forty-two subjects were enrolled and randomized in the study. Treated group (20 subjects) was assigned to receive antioxidant therapy (NAC 600 mg and vitamins-minerals). Untreated group (22 subjects) received no adjunctive medical therapy and was used as controls. Our data were analyzed with an intention to treat strategy. A statistically significant increase in sperm count after antioxidant therapy was recorded (P=0.009). After this therapy, no statistical differences in percentage of WHO class A motile sperm (P=0.752) and typical forms (P=0.926) were found. The univariate logistic regression analysis showed that a man treated with antioxidant therapy presented a probability to have a normal sperm count 20-fold (OR=20.1; CI 95%=1.05-43.2; P=0.014) higher than a man who was untreated. No significant impact on spontaneous pregnancies was found after antioxidant therapy. Despite this preliminary data, we show that antioxidant therapy based on a combination of NAC and micronutrient supplementation can be helpful in improve the sperm count at least in a subset of oligospermic males. However, this improving in sperm count is not associated with a significant increase in spontaneous pregnancies after 12 months.", "Evidence has accumulated supporting the role of reactive oxygen species (ROS) in the pathogenesis of sperm dysfunction among men with infertility. Damage to sperm DNA by ROS can lead to failure of conception, miscarriage or potentially even childhood cancer. The objective of this study was to examine the effect of male antioxidant treatment on embryo quality and pregnancy outcome during in vitro fertilisation-intracytoplasmic sperm injection (IVF-ICSI) treatment.\n Sixty couples with severe male factor infertility were enrolled in a prospective randomised double-blind placebo-controlled trial. Male participants were randomly assigned to take either one capsule per day of the Menevit antioxidant or an identical in appearance placebo for three months prior to their partner's IVF cycle. The primary outcome was cleavage stage embryo quality and the secondary outcomes were oocyte fertilisation rate, pregnancy rates and treatment side-effects. Approval by the local Human Research Ethics Committee was obtained prior to the commencement of this study.\n The antioxidant group recorded a statistically significant improvement in viable pregnancy rate (38.5% of transferred embryos resulting in a viable fetus at 13 weeks gestation) compared to the control group (16% viable pregnancy). No significant changes in oocyte fertilisation rate or embryo quality were detected between the antioxidant and the placebo groups. Side-effects on the Menevit antioxidant were rare (8%) and mild in nature.\n The Menevit antioxidant appears to be a useful ancillary treatment that significantly improves pregnancy rates in couples undergoing IVF-ICSI treatment for severe male factor infertility.", "In a randomized, placebo-controlled, double-blind study we investigated whether high-dose oral treatment with vitamins C and E for 56 days was able to improve semen parameters of infertile men. Ejaculate parameters included semen volume, sperm concentration and motility, and sperm count and viability. Thirty-one patients without genital infection but with asthenozoospermia (< 50% motile spermatozoa) and normal or only moderately reduced sperm concentration (> 7 x 10(6) spermatozoa/ml) (according to WHO criteria) were examined. To investigate the influence of the epididymal storage period on semen parameters, the patients were asked to deliver two semen samples with abstinence times of 2 and 7 days both before and at the end of vitamin treatment. After randomization, the patients received either 1000 mg vitamin C and 800 mg vitamin E (n = 15) or identical placebo capsules (n = 16). No changes in semen parameters were observed during treatment, and no pregnancies were initiated during the treatment period. Combined high-dose antioxidative treatment with vitamins C and E did not improve conventional semen parameters or the 24-h sperm survival rate. Prolonged abstinence time increased ejaculate volume (P < 0.05), sperm count (P < 0.05), sperm concentration (P < 0.05) and the total number of motile spermatozoa (P < 0.05).", "The Supplementation in Vitamins and Mineral Antioxidants Study was a double-blind, placebo-controlled, randomized trial, in which 12,741 French adults (7,713 women aged 35-60 years and 5,028 men aged 45-60 years) received a combination of ascorbic acid (120 mg), vitamin E (30 mg), beta-carotene (6 mg), selenium (100 microg) and zinc (20 mg), or placebo daily for a median follow-up time of 7.5 years [October 1994 to September 2002]. Antioxidant supplementation decreased total cancer incidence and total mortality in men. Postintervention follow-up assessment of total cancer incidence, ischemic cardiovascular disease incidence and total mortality was carried out for 5 years [September 1, 2002, to September 1, 2007]. No late effect of antioxidant supplementation was revealed 5 years after ending the intervention neither on ischemic cardiovascular disease incidence and mortality in both genders nor on cancer incidence in women. Regarding duration of intervention effects in men, the reduced risk of total cancer incidence and total mortality was no longer evident after the 5-year postintervention follow-up. During the postsupplementation period, the relative risk (RR) for total cancer incidence (n = 126) was 0.98 (95% confidence interval [CI], 0.75-1.27) among antioxidant recipients compared to nonrecipients. For total mortality (n = 90), the RR was 0.98 (95% CI, 0.75-1.26) for men receiving antioxidants compared to nonrecipients. In conclusion, beneficial effects of antioxidant supplementation in men disappeared during postintervention follow-up.", "It has been suggested that a low dietary intake of antioxidant vitamins and minerals increases the incidence rate of cardiovascular disease and cancer. To date, however, the published results of randomized, placebo-controlled trials of supplements containing antioxidant nutrients have not provided clear evidence of a beneficial effect. We tested the efficacy of nutritional doses of supplementation with a combination of antioxidant vitamins and minerals in reducing the incidence of cancer and ischemic cardiovascular disease in the general population.\n The Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) study is a randomized, double-blind, placebo-controlled primary prevention trial. A total of 13 017 French adults (7876 women aged 35-60 years and 5141 men aged 45-60 years) were included. All participants took a single daily capsule of a combination of 120 mg of ascorbic acid, 30 mg of vitamin E, 6 mg of beta carotene, 100 mug of selenium, and 20 mg of zinc, or a placebo. Median follow-up time was 7.5 years.\n No major differences were detected between the groups in total cancer incidence (267 [4.1%] for the study group vs 295 [4.5%] for the placebo group), ischemic cardiovascular disease incidence (134 [2.1%] vs 137[2.1%]), or all-cause mortality (76 [1.2%] vs 98 [1.5%]). However, a significant interaction between sex and group effects on cancer incidence was found (P = .004). Sex-stratified analysis showed a protective effect of antioxidants in men (relative risk, 0.69 [95% confidence interval [CI], 0.53-0.91]) but not in women (relative risk, 1.04 [95% CI, 0.85-1.29]). A similar trend was observed for all-cause mortality (relative risk, 0.63 [95% CI, 0.42-0.93] in men vs 1.03 [95% CI, 0.64-1.63] in women; P = .11 for interaction).\n After 7.5 years, low-dose antioxidant supplementation lowered total cancer incidence and all-cause mortality in men but not in women. Supplementation may be effective in men only because of their lower baseline status of certain antioxidants, especially of beta carotene.", "Numerous studies have reported beneficial effects of antioxidant drugs on semen quality, but there is no well-defined therapeutical protocol in male infertility. This study aimed to test the effects of vitamin E and selenium supplementation on lipid peroxidation and on sperm parameters. The study included 54 voluntary and infertile men who produced semen samples for spermiogram and for spectrophotometric measurement of a lipid peroxidation marker, the malondialdehyde (MDA), and produced blood samples for high-performance liquid chromatography assessment of serum vitamin E level. The trial was randomized and open. Twenty-eight men were supplemented daily by vitamin E (400 mg) and selenium (225 microg), during 3 months. The remaining 26 patients received vitamin B (4,5 g/day) for the same duration. Only 20 patients achieved their treatment and returned for control analysis. MDA concentrations in sperm were much less than in seminal plasma and motility and viability were inversely correlated with semen MDA levels. In contrast to vitamin B supplementation, vitamin E and selenium supplementation produced a significant decrease in MDA concentrations and an improvement of sperm motility. The results confirm the protective and beneficial effects of vitamin E and selenium on semen quality and advocate their use in male infertility treatment.", "The experimental design, subjects, procedures and baseline data for the prospective double blind dry ARMD-antioxidant intervention study have been described in Part 1.\n At eight DVA medical centers, 32 patients (group one) were assigned a placebo and 39 patients (group two) a \"broad spectrum\" antioxidant capsule. Data was collected in five areas: demographic; ophthalmic; dietary analysis of daily food intake; serum analysis; and adverse gastrointestinal symptoms. Data was serially acquired at baseline, 6 months, 12 months and 18 months, and was analyzed by univariate repeated factors ANOVA, p = 0.05.\n Group two (antioxidant po BID) maintained their distance LogMAR visual acuity (p = 0.03), while there was a trend toward both stabilized near M print (p = 0.07) and 6 cycle/degree contrast sensitivity (p approximately 0.10), in left eyes. However, group two (antioxidant) also had increased cortical opacification of the right lens (p = 0.04), compared to group one (placebo). Self perceived stabilization of vision was reported by subjects in group two and supported the objective data (Pearson chi square; p = 0.05).\n A specific 14 component antioxidant capsule taken twice daily stabilized but did not improve dry ARMD over the study period of 1.5 years. The ARMD stabilized eyes had less advanced disease functionally but not by fundus appearance. Decreased intake of cardioprotective nutrients (vitamin E, zinc, magnesium, B6 and folate) in ARMD patients remained constant over the course of the trial.", "We determined the effect of antioxidants and resistance training on bone mineral density of postmenopausal women. After 6 months, we observed a significant decrease in the lumbar spine BMD of the placebo group while other groups remained stable. Antioxidants may offer protection against bone loss such as resistance training.\n The purpose of this pilot study was to determine the effects of antioxidant supplements combined to resistance training on bone mineral density (BMD) in healthy elderly women.\n Thirty-four postmenopausal women (66.1 +/- 3.3 years) were randomized in four groups (placebo, n = 7; antioxidants, n = 8; exercise and placebo, n = 11; and exercise and antioxidants, n = 8). The 6-month intervention consisted in antioxidant supplements (600 mg vitamin E and 1,000 mg vitamin C daily) or resistance exercise (3x/week). Femoral neck and lumbar spine BMD (DXA) and dietary intakes (3-day food record) were measured before and after the intervention. A repeated measure ANOVA and non-parametric Mann-Whitney U tests were used.\n We observed a significant decrease in the placebo group for lumbar spine BMD (pre, 1.01 +/- 0.17 g/cm(2); post, 1.00 +/- 0.16 g/cm(2); P < 0.05 respectively) while it remained stable in all other groups. No changes were observed for femoral neck BMD.\n Antioxidant vitamins may offer some protection against bone loss in the same extent as resistance exercise although combining both does not seem to produce additional effects. Our results suggest to further investigate the impact of antioxidant supplements on the prevention of osteoporosis.", "To determine possible indications of the mechanisms involved in improved sperm parameters by zinc therapy in asthenozoospermic men.\n Forty-five men with asthenozoospermia (>or=40% immotile sperm) were randomized into four therapy groups: zinc only: n = 11; zinc + vitamin E: n = 12 and zinc + vitamins E + C: n = 14 for 3 months, and non-therapy control group: n = 8. Semen analysis was done according to WHO guidelines. Malone dialdehyde, tumour necrosis factor-alpha (TNF-alpha), total antioxidant capacity, superoxide dismutase (SOD) and glutathione peroxidase were determined in the semen and serum. Antisperm antibodies IgG, IgM and IgA were evaluated by immunobeads. Sperm chromatin integrity was determined by acid denaturation by acridine orange and sperm apoptosis by light and electron microscopy. The effect of zinc on in vitro induced sperm oxidative stress by NADH was evaluated.\n Asthenozoospermia was significantly associated with oxidative stress with higher seminal malone dialdehyde (8.8 vs. 1.8 mmol/l, p < 0.001) and TNF-alpha (60 vs. 12 pg/l, p < 0.001), and low total antioxidant capacity (1.8 vs. 8.4, p < 0.01), SOD (0.8 vs. 3.1, p < 0.01) and glutathione peroxidase (1.6 vs. 4.2, p < 0.05), compared to normozoospermia. Zinc therapy alone, in combination with vitamin E or with vitamin E + C were associated with comparably improved sperm parameters with less oxidative stress, sperm apoptosis and sperm DNA fragmentation index (DFI). On the whole, there was no difference in the outcome measures between zinc only and zinc with vitamin E and combination of vitamins E + C. In the in vitro experiment zinc supplementation resulted in significantly lower DFI (14-29%, p < 0.05) compared to zinc deficiency.\n Zinc therapy reduces asthenozoospermia through several mechanisms such as prevention of oxidative stress, apoptosis and sperm DNA fragmentation.\n (c) 2008 S. Karger AG, Basel.", "Hormone replacement therapy (HRT) and antioxidant vitamins are widely used for secondary prevention in postmenopausal women with coronary disease, but no clinical trials have demonstrated benefit to support their use.\n To determine whether HRT or antioxidant vitamin supplements, alone or in combination, influence the progression of coronary artery disease in postmenopausal women, as measured by serial quantitative coronary angiography.\n The Women's Angiographic Vitamin and Estrogen (WAVE) Trial, a randomized, double-blind trial of 423 postmenopausal women with at least one 15% to 75% coronary stenosis at baseline coronary angiography. The trial was conducted from July 1997 to January 2002 in 7 clinical centers in the United States and Canada.\n Patients were randomly assigned in a 2 x 2 factorial design to receive either 0.625 mg/d of conjugated equine estrogen (plus 2.5 mg/d of medroxyprogesterone acetate for women who had not had a hysterectomy), or matching placebo, and 400 IU of vitamin E twice daily plus 500 mg of vitamin C twice daily, or placebo.\n Annualized mean (SD) change in minimum lumen diameter (MLD) from baseline to concluding angiogram of all qualifying coronary lesions averaged for each patient. Patients with intercurrent death or myocardial infarction (MI) were imputed the worst rank of angiographic outcome.\n The mean (SD) interval between angiograms was 2.8 (0.9) years. Coronary progression, measured in mean (SD) change, worsened with HRT by 0.047 (0.15) mm/y and by 0.024 (0.15) mm/y with HRT placebo (P =.17); and for antioxidant vitamins by 0.044 (0.15) mm/y and with vitamin placebo by 0.028 (0.15) mm/y (P =.32). When patients with intercurrent death or MI were included, the primary outcome showed an increased risk for women in the active HRT group (P =.045), and suggested an increased risk in the active vitamin group (P =.09). Fourteen patients died in the HRT group and 8 in the HRT placebo group (hazard ratio [HR], 1.8; 95% confidence interval [CI], 0.75-4.3), and 16 in the vitamin group and 6 in the vitamin placebo group (HR, 2.8; 95% CI, 1.1-7.2). Death, nonfatal MI, or stroke occurred in 26 HRT patients vs 15 HRT controls (HR, 1.9; 95% CI, 0.97-3.6) and in 26 vitamin patients and 18 vitamin controls (HR, 1.5; 95% CI, 0.80-2.9). There was no interaction between the 2 treatment interventions.\n In postmenopausal women with coronary disease, neither HRT nor antioxidant vitamin supplements provide cardiovascular benefit. Instead, a potential for harm was suggested with each treatment.", "To test the hypothesis that a relative deficiency in L-arginine, the substrate for synthesis of the vasodilatory gas nitric oxide, may be associated with the development of pre-eclampsia in a population at high risk.\n Randomised, blinded, placebo controlled clinical trial.\n Tertiary public hospital in Mexico City.\n Pregnant women with a history of a previous pregnancy complicated by pre-eclampsia, or pre-eclampsia in a first degree relative, and deemed to be at increased risk of recurrence of the disease were studied from week 14-32 of gestation and followed until delivery.\n Supplementation with a medical food-bars containing L-arginine plus antioxidant vitamins, antioxidant vitamins alone, or placebo-during pregnancy.\n Development of pre-eclampsia/eclampsia.\n 222 women were allocated to the placebo group, 228 received L-arginine plus antioxidant vitamins, and 222 received antioxidant vitamins alone. Women had 4-8 prenatal visits while receiving the bars. The incidence of pre-eclampsia was reduced significantly (χ(2) = 19.41; P < 0.001) in women randomised to L-arginine plus antioxidant vitamins compared with placebo (absolute risk reduction 0.17 (95% confidence interval 0.12 to 0.21). Antioxidant vitamins alone showed an observed benefit, but this effect was not statistically significant compared with placebo (χ(2) = 3.76; P = 0.052; absolute risk reduction 0.07, 0.005 to 0.15). L-arginine plus antioxidant vitamins compared with antioxidant vitamins alone resulted in a significant effect (P = 0.004; absolute risk reduction 0.09, 0.05 to 0.14).\n Supplementation during pregnancy with a medical food containing L-arginine and antioxidant vitamins reduced the incidence of pre-eclampsia in a population at high risk of the condition. Antioxidant vitamins alone did not have a protective effect for prevention of pre-eclampsia. Supplementation with L-arginine plus antioxidant vitamins needs to be evaluated in a low risk population to determine the generalisability of the protective effect, and the relative contributions of L-arginine and antioxidant vitamins to the observed effects of the combined treatment need to be determined. Trial registration Clinical trials NCT00469846.", "Oxidative stress has been implicated in the pathophysiology of pre-eclampsia. This randomised controlled trial investigated the effect of supplementation with vitamins C and E in women at increased risk of the disorder on plasma markers of vascular endothelial activation and placental insufficiency and the occurrence of pre-eclampsia.\n 283 women were identified as being at increased risk of pre-eclampsia by abnormal two-stage uterine-artery doppler analysis or a previous history of the disorder and were randomly assigned vitamin C (1000 mg/day) and vitamin E (400 IU/day) or placebo at 16-22 weeks' gestation. Plasma markers of endothelial activation (plasminogen-activator inhibitor 1 [PAI-1]) and placental dysfunction (PAI-2) were measured every month until delivery. Pre-eclampsia was assessed by the development of proteinuric hypertension. Analyses were done by intention to treat, and in the cohort who completed the study.\n Supplementation with vitamins C and E was associated with a 21% decrease in the PAI-1/PAI-2 ratio during gestation (95% CI 4-35, p=0.015). In the intention-to-treat cohort, pre-eclampsia occurred in 24 (17%) of 142 women in the placebo group and 11 (8%) of 141 in the vitamin group (adjusted odds ratio 0.39 [0.17-0.90], p=0.02). In the cohort who completed the study (81 placebo group, 79 vitamin group), the odds ratio for pre-eclampsia was 0.24 (0.08-0.70, p=0.002).\n Supplementation with vitamins C and E may be beneficial in the prevention of pre-eclampsia in women at increased risk of the disease. Multicentre trials are needed to show whether vitamin supplementation affects the occurrence of pre-eclampsia in low-risk women and to confirm our results in larger groups of high-risk women from different populations.", "Elevated benzo(a)pyrene [B(a)P]-DNA adducts have been associated with 3-fold increased risk of lung cancer in current smokers. We assessed the chemopreventive effects of antioxidant supplementation using B(a)P-DNA adducts in leukocytes as an intermediate cancer risk marker.\n Subjects were randomized to a double-blinded placebo-controlled clinical trial of antioxidant vitamin supplementation [500 mg vitamin C and 400 IU vitamin E (dl-alpha-tocopherol) daily] or placebo. Smokers with > or =10 cigarettes per day and serum cotinine > or =25 ng/mL were eligible for the study. B(a)P-DNA adduct level was the outcome. The randomization was stratified by gender and cigarettes per day (< or =20 or >20). Smoking habits and blood samples were collected every 3 months during the 15-month treatment period. Samples were analyzed for B(a)P-DNA adducts (high-performance liquid chromatography), plasma cotinine, vitamin levels, and GSTM1 genotype. The intent-to-treat model adjusted for B(a)P-DNA and cotinine at randomization.\n Overall and among men, there was no effect of treatment on B(a)P-DNA adduct levels. Among treated women, B(a)P-DNA adducts decreased by 31% compared with women on placebo (P = 0.03). Among treated women with the GSTM1 genotype, there was a 43% decrease in adducts (P = 0.04).\n Our primary hypothesis that the mean level of smoking-related B(a)P-DNA adducts would be lower in all subjects in the vitamin treatment group compared with all placebo-treated subjects was not substantiated. However, oursecondary gender-specific analysis found a significant reduction in B(a)P-DNA adducts in women with vitamin treatment, suggesting that antioxidant supplementation maymitigate some of the procarcinogenic effects of exposuretoB(a)P. The effect in GSTM1-null women suggeststhat certain subgroups may derive more benefit fromsupplementation. Although the results of this trial showthe potential chemopreventive role of antioxidants, thebest way for smokers to reduce their cancer risk remains smoking cessation.", "To determine whether antioxidant therapy alters the disease process in severe early onset pre-eclampsia, in support of the hypothesis that increased lipid peroxides and reactive oxygen species production-play an important role in the pathogenesis of the disease.\n Randomised, double-blind, placebo controlled trial.\n Two tertiary care, referral hospitals in Johannesburg, South Africa.\n Women with severe pre-eclampsia diagnosed between 24 and 32 weeks of gestation.\n Combined antioxidant treatment with vitamin E (800 IU/day), vitamin C (1000 mg/day), and allopurinol (200 mg/day).\n Primary outcomes: 1. prolongation of pregnancy and 2, biochemical assessment of lipid peroxides and antioxidants. Secondary outcomes: data on maternal complications, side effects of treatment, infant outcomes and regular assessment of haematologic and renal parameters.\n The proportion of women delivered within 14 days in the antioxidant group was 52% (14/27) compared with 76% (22/29) in the placebo group (relative risk 0.68, 95% confidence interval 0.45-1.04). One woman in each group had eclampsia. Eleven women (42%) in the antioxidant and 16 (59%) in the placebo group required two antihypertensives for blood pressure control. Trial medications were well tolerated with few side effects. Lipid peroxide levels were not significantly altered in the antioxidant and placebo groups. Serum uric acid levels decreased and vitamin E levels increased significantly.\n The results of this explanatory randomised trial do not encourage the routine use of antioxidants against pre-eclampsia. However, further research with modified strategies such as earlier initiation of therapy or different combinations seem worthwhile.", "The effect of periconceptional multivitamin/trace element supplementation on pregnancy outcomes was evaluated in a randomised controlled trial. The final data-base included 5,502 females with confirmed pregnancy. A multivitamin including 0.8 mg folic acid or a trace element were supplemented for at least 28 days before conception and continuing for at least until the second missed menstrual period. Number of pregnancies, terminations of pregnancies, four types of fetal deaths, livebirths including low birth weight, preterm birth and sex ratio were analysed. Periconceptional multivitamin supplementation increased fertility (higher rates of cumulative conceptions and multiple births), had no significant effect on the rate of different groups of fetal deaths, low birth weight and preterm birth in singletons. This primary preventive method can reduce the occurrence and recurrence of neural-tube defects and had no other significant effect on pregnancy outcomes except multiple births.", "To examine whether antioxidant supplement use is associated with melanoma risk in light of recently published data from the Supplementation in Vitamins and Mineral Antioxidants (SUVIMAX) study, which reported a 4-fold higher melanoma risk in women randomized to receive a supplement with nutritionally appropriate doses of antioxidants.\n Population-based prospective study (Vitamins and Lifestyle [VITAL] cohort).\n Western Washington State.\n A total of 69 671 men and women who self-reported (1) intake of multivitamins and supplemental antioxidants, including selenium and beta carotene, during the past 10 years and (2) melanoma risk factors on a baseline questionnaire. Main Outcome Measure Incident melanoma identified through linkage to the Surveillance, Epidemiology, and End Results (SEER) cancer registry.\n Cox proportional hazards regression models were used to estimate multivariable relative risks (RRs) and 95% confidence intervals (CIs) for multivitamin, supplemental selenium, and supplemental beta carotene use. After adjusting for melanoma risk factors, we did not detect a significant association between multivitamin use and melanoma risk in women (RR, 1.14; 95% CI, 0.78-1.66) or in men (RR, 1.09; 95% CI, 0.83-1.43). Moreover, we did not observe increased melanoma risk with the use of supplemental beta carotene (RR, 0.87; 95% CI, 0.48-1.56) or selenium (RR, 0.98; 95% CI, 0.69-1.41) at doses comparable with those of the SUVIMAX study. Conclusion Antioxidants taken in nutritional doses do not seem to increase melanoma risk.", "In the present investigation, we studied the effect of recombinant human erythropoietin (r-HuEPO) on serum malondialdehyde (MDA) as an index of lipid peroxidation, related to iron-catalyzed free radical reaction and erythrocyte superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities in very-low-birth weight (VLBW) infants. Forty premature infants, at gestational ages were less than 33 weeks and birthweights were less than 1,500 g, were enrolled in the study. The study population was randomly divided into 2 groups. Twenty infants in Group 1 (treatment group) were given r-HuEPO, and 20 infants in Group 2 served as the control. r-HuEPO treatment (750 U/kg a week) was initiated on the 10th day of life and continued for 6 weeks. Preterm infants given erythrocyte transfusions during the study were excluded from the results. Serum ferritin and MDA levels, and erythrocyte superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities were analyzed at the end of the first week of life (at the beginning of the study). Subsequently, serum ferritin, and MDA levels were measured at the end of the 3rd and the 6th week. SOD, CAT, and GPX activities in the hemolysate were analyzed at the end of the 4th week. Six infants in the control group and 1 infant in the r-HuEPO group received transfusions through the end of the study, and these infants were excluded from the results. Significantly decreased serum ferritin concentrations were found in the r-HuEPO group compared to those in the control group both at the end of the 3rd and the 6th week (P < 0.05, and P < 0.01, respectively). In addition, serum MDA levels were also significantly reduced in Group 1 compared to control both at the end of the 3rd and the 6th week (P < 0.01 and P < 0.05, respectively). A good correlation was found between serum MDA and ferritin levels in Group 1. When the 2 groups were compared with respect to activities of SOD, CAT, and GPX at the end of the 4th week, no differences were observed. Our findings in this study show that administration of r-HuEPO significantly decreases lipid peroxidation, but does not affect erythrocyte antioxidant enzyme(s) activities in preterm infants. The mechanism responsible for the r-HuEPO-induced decrease in lipid peroxidation may concern inhibition to iron-catalyzed free radical reactions.", "The high concentration of carotenoids in the macula, plus evidence linking oxidative stress to age-related macular degeneration (AMD) and carotenoids to antioxidation, generated the hypothesis that higher antioxidant intakes can prevent AMD. The aim of this study was to determine whether nutritional supplementation with a targeted nutritional supplement improves visual acuity and visual function in AMD.\n In this multicenter, prospective open-label randomized study, 145 patients were randomly assigned to 2 different treatment groups. Interventions were lutein (10 mg), zeaxanthin (1 mg), astaxanthin (4 mg; AZYR SIFI, Catania, Italy), and antioxidants/vitamins supplementation formula or no dietary supplementation for 2 years. Primary outcome was mean changes in visual acuity (VA) at 12 and 24 months. Other measures included contrast sensitivity (CS) and National Eye Institute visual function questionnaire (NEI VFQ-25) scores at 12 and 24 months.\n Patients in the treated group showed stabilization of VA with significantly (p=0.003) better VA scores (81.4 ± 7.2) compared to the nontreated group (76.8 ± 8.9) at 24-month follow-up. An improvement in CS (p=0.001) and final mean NEI VFQ-25 composite scores at 12 and 24 months higher in treated group compared to nontreated group were also shown (p<0.001).\n Patients treated with lutein/zeaxanthin and astaxanthin together with other nutrients were more likely to report clinically meaningful stabilization/improvements in VA, CS, and visual function through 24 months compared with nontreated subjects. Further studies are needed with more patients and for longer periods of time.", "To assess the effect of antioxidant supplementation on hepatitis C viral load, transaminases and oxidative status.\n We performed a randomized, placebo-controlled, double-blind trial to assess the effect of antioxidant supplementation on serum alanine aminotransferase, plasma hepatitis C viral load as well as oxidative and antioxidant markers in patients with hepatitis C virus infection. The participants received a daily dose of ascorbic acid (500 mg), D-alpha-tocopherol (945 IU) and selenium (200 microg) or placebo tablets for 6 months.\n Twenty-three patients were included. During supplementation, the antioxidant group had significantly higher levels of plasma ascorbic acid and alpha-tocopherol than the placebo group and the activity of erythrocyte glutathione peroxidase had significantly increased from baseline to month 6. No differences were observed in serum alanine aminotransferase and log10-transformed plasma hepatitis C virus-RNA between the groups or changes from the baseline at any time. No consistent differences between groups or changes from the baseline with respect to erythrocyte activities of antioxidative enzymes (glutathione reductase, superoxide dismutase and catalase) or plasma levels of oxidative markers (malondialdehyde and 2-amino-adipic semialdehyde) were found.\n Supplementation with vitamin C, E and selenium increased the antioxidant status, but had no effects on alanine aminotransferase, viral load or oxidative markers.", "To evaluate the effect of estradiol addition to progesterone supplementation during the luteal phase on pregnancy and implantation rates in patients undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) cycles.\n In this prospective, randomized study, carried out in an IVF unit of a university hospital, we studied patients who were undergoing IVF/ICSI with controlled ovarian hyperstimulation using a gonadotropin-releasing hormone agonist/human recombinant gonadotropin long protocol. The main outcome measures were the pregnancy and implantation rates measured in the two groups.\n Our results suggest higher pregnancy and implantation rates in IVF/ICSI-ET cycles that were supplemented with estradiol in the luteal phase.\n Estradiol supplementation during the luteal phase in women undergoing IVF/ICSI-ET has a beneficial effect on the outcome without (at least, as seems from this study) having any adverse effects.", "Self-selected supplementation of vitamin E has been associated with reduced coronary events and atherosclerotic progression, but the evidence from clinical trials is controversial. In the first 3 years of the ASAP trial, the supplementation with 136 IU of vitamin E plus 250 mg of slow-release vitamin C twice daily slowed down the progression of carotid atherosclerosis in men but not women. This article examines the 6-year effect of supplementation on common carotid artery (CCA) intima-media thickness (IMT).\n The subjects were 520 smoking and nonsmoking men and postmenopausal women aged 45 to 69 years with serum cholesterol > or =5.0 mmol/L (193 mg/dL), 440 (84.6%) of whom completed the study. Atherosclerotic progression was assessed ultrasonographically. In covariance analysis in both sexes, supplementation reduced the main study outcome, the slope of mean CCA-IMT, by 26% (95% CI, 5 to 46, P=0.014), in men by 33% (95% CI, 4 to 62, P=0.024) and in women by 14% (not significant). In both sexes combined, the average annual increase of the mean CCA-IMT was 0.014 mm in the unsupplemented and 0.010 mm in the supplemented group (25% treatment effect, 95% CI, 2 to 49, P=0.034). In men, this treatment effect was 37% (95 CI, 4 to 69, P=0.028). The effect was larger in subjects with either low baseline plasma vitamin C levels or CCA plaques. Vitamin E had no effect on HDL cholesterol.\n These data replicate our 3-year findings confirming that the supplementation with combination of vitamin E and slow-release vitamin C slows down atherosclerotic progression in hypercholesterolemic persons.", "To determine the effectiveness of the in vivo administration of vitamin E as treatment for reactive oxygen species-associated male infertility.\n University-based center for reproductive medicine.\n Double-blind randomized placebo cross-over controlled trial.\n Thirty healthy men with high levels of reactive oxygen species generation in semen and a normal female partner.\n Patients were allocated to two groups according to the blinded randomization. Each patient received either 600 mg/d of vitamin E (Ephynal, 300 mg tablets; F. Hoffman-La Roche Ltd., Basle, Switzerland) (order A) or identical placebo tablets (order B) for 3 months. Then after a 1-month wash-out period the patients were crossed-over to the other treatment.\n Improvement in the in vitro function of the spermatozoa measured by conventional semen analysis, computerized motility assessment, determination of reactive oxygen species generation, binding to the zona pellucida of the unfertilized human oocyte in a competitive zona binding assay, development of hyperactivated motility (both spontaneous and in the presence of 20% of the natural agonist, human follicular fluid) and pregnancy.\n Rise in the blood serum vitamin E levels after treatment accompanied by improvement in one of the sperm function tests: the zona binding assay. The zona binding ratio for order A improved from 0.2 (range 0 to 0.5) before treatment to 0.5 (range 0.1 to 1.0) after treatment, the corresponding values for order B were 0.2 (range 0 to 1.0) before treatment and 0.3 (range 0.1 to 0.7) after treatment.\n Oral administration of vitamin E significantly improves the in vitro function of human spermatozoa as assessed by the zona binding test.", "Oxidative stress is putatively involved in the pathogenesis of alcohol-induced liver injury. This trial was devised to determine whether antioxidant therapy, alone or as an adjunct to corticosteroids, improved survival in patients with acute alcoholic hepatitis.\n Patients with a severe alcoholic hepatitis were stratified by sex and steroid use, and then randomized. The active group received N-acetylcysteine for one week, and vitamins A-E, biotin, selenium, zinc, manganese, copper, magnesium, folic acid and Coenzyme Q daily for 6 months. The trial was double blinded and placebo controlled. The primary end-point was mortality within 6 months.\n Thirty-six (20 male, 16 female; mean discriminant function (DF) 86.6) received active drug, and 34 (18 male, 16 female; mean DF 76.4) received placebo. 180-day survival was not significantly different between patients receiving drug and placebo (52.8% vs. 55.8%, p=0.699). This was not affected by stratification for steroid use or sex. The only predictors of survival in multivariate analysis were initial bilirubin (p=0.017), white cell count (p=0.016) and age (p=0.037). Treatment allocation did not affect survival in multivariate analysis (p=0.830).\n Antioxidant therapy, alone or in combination with corticosteroids, does not improve 6-month survival in severe alcoholic hepatitis.", "Increased Se intakes have been associated with decreased risk of cancer and CVD. Several mechanisms have been proposed, including antioxidant effects through selenoproteins, induction of carcinogen metabolism and effects on the blood lipid profile. In a 4 x 1 week randomised, double-blind cross-over study, healthy young men supplemented their usual diet with selenate, Se-enriched yeast, Se-enriched milk or placebo (Se dose was 300 microg/d for selenate and Se-enriched yeast, and about 480 microg/d for Se-enriched milk) followed by 8-week washout periods. All Se sources increased serum Se levels after supplementation for 1 week. The effect of the organic forms did not differ significantly and both increased serum Se more than selenate. Conversely, thrombocyte glutathione peroxidase (GPX) was increased in the periods where subjects were supplemented with selenate but not in those where they were given Se-enriched yeast or Se-enriched milk. We found no effect on plasma lipid resistance to oxidation, total cholesterol, TAG, HDL- and LDL-cholesterol, GPX, glutathione reductase (GR) and glutathione S-transferase (GST) activities measured in erythrocytes, GPX and GR activities determined in plasma, or GR and GST activities in thrombocytes. Leucocyte expression of genes encoding selenoproteins (GPX1, TrR1 and SelP), and of electrophile response element-regulated genes (GCLC, Fra1 and NQO1) were likewise unaffected at all time points following intervention. We conclude that thrombocyte GPX is specifically increased by short-term selenate supplementation, but not by short-term supplementation with organic Se. Short-term Se supplementation does not seem to affect blood lipid markers or expression and activity of selected enzymes and a transcription factor involved in glutathione-mediated detoxification and antioxidation.", "Oxidative stress could play a part in pre-eclampsia, and there is some evidence to suggest that vitamin C and vitamin E supplements could reduce the risk of the disorder. Our aim was to investigate the potential benefit of these antioxidants in a cohort of women with a range of clinical risk factors.\n We did a randomised, placebo-controlled trial to which we enrolled 2410 women identified as at increased risk of pre-eclampsia from 25 hospitals. We assigned the women 1000 mg vitamin C and 400 IU vitamin E (RRR alpha tocopherol; n=1199) or matched placebo (n=1205) daily from the second trimester of pregnancy until delivery. Our primary endpoint was pre-eclampsia, and our main secondary endpoints were low birthweight (<2.5 kg) and small size for gestational age (<5th customised birthweight centile). Analyses were by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 62368611 .\n Of 2404 patients treated, we analysed 2395 (99.6%). The incidence of pre-eclampsia was similar in treatment placebo groups (15% [n=181] vs 16% [n=187], RR 0.97 [95% CI 0.80-1.17]). More low birthweight babies were born to women who took antioxidants than to controls (28% [n=387] vs 24% [n=335], 1.15 [1.02-1.30]), but small size for gestational age did not differ between groups (21% [n=294] vs 19% [n=259], 1.12 [0.96-1.31]).\n Concomitant supplementation with vitamin C and vitamin E does not prevent pre-eclampsia in women at risk, but does increase the rate of babies born with a low birthweight. As such, use of these high-dose antioxidants is not justified in pregnancy.", "To evaluate the effect of multimicronutrient supplementation for undernourished pregnant women on the birth size of their offspring, incidence of low-birth-weight infants (<2500 g), and early neonatal morbidity.\n Randomized, double-blind, placebo-controlled trial.\n Tertiary care hospital.\n Two hundred pregnant women (of 13 465 approached) with a body mass index (calculated as weight in kilograms divided by the square of height in meters) of less than 18.5 and/or a hemoglobin level of 7 to 9 g/dL were enrolled at 24 to 32 weeks of gestation. One hundred forty-six neonates (73.0%) were available for analysis of birth size and 170 (85.0%) for analysis of morbidity in the 7 days after delivery. Intervention The micronutrient supplementation group (n = 99) received a multimicronutrient supplement containing 29 vitamins and minerals once a day, from enrollment until delivery (median duration, 58 days; interquartile range, 37-77 days; compliance, 87%). The comparison group (n = 101) received placebo for 52 (15-66) days, with 85% compliance. All subjects also received supplements of iron (given in the form of ferrous sulfate, containing 60 mg of elemental iron), 60 mg/d, and folic acid, 500 mug/d.\n Birth weight, length, midarm circumference, incidence of low birth weight, and early neonatal morbidity.\n Infants in the micronutrient group were heavier by 98 g (95% confidence interval [CI], -16 to 213 g) and measured 0.80 cm (95% CI, 0.03-1.57 cm) longer and 0.20 cm (95% CI, 0.04-0.36 cm) larger in midarm circumference compared with the placebo group. Incidence of low birth weight declined from 43.1% to 16.2% with multimicronutrient supplementation a (a 70% decrease; relative risk, 0.30; 95% CI, 0.13-0.71; P=.006), and that of early neonatal morbidity declined from 28.0% to 14.8% (a 58% decrease; relative risk, 0.42; 95% CI, 0.19-0.94; P=.04).\n Compared with iron and folic acid supplementation, the administration of multimicronutrients to undernourished pregnant women may reduce the incidence of low birth weight and early neonatal morbidity." ]	Preliminary evidence from three small randomised controlled trials suggests that antioxidant supplementation in subfertile males may improve live birth rates for subfertile couples undergoing ART cycles. However, further large well-designed randomised placebo-controlled trials are needed to confirm this.

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