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Hasso Plattner Institute 22

BACKGROUND Handheld inhalers are used to deliver treatment for COPD. Incorrect usage leads to suboptimal disease control. Complex treatment regimens and use of multiple inhalers may reduce patient compliance. The Anoro Ellipta™ dry powder inhaler (DPI) simultaneously delivers umeclidinium bromide (UMEC) and vilanterol (VI) without coformulation being required. AIM To assess the correct usage and ease of use of the Ellipta™ DPI administering UMEC/VI and to compare patient preference for Ellipta™ with the HandiHaler(®) through exploratory analyses of patient and observer questionnaires in five Phase III studies. METHODS Two Phase III, 3-month double-blind, placebo-controlled studies assessed the correct usage of the Ellipta™ DPI at Day 1 and after 6 weeks, and ease of use of the Ellipta™ DPI using a nonvalidated patient questionnaire after 6 weeks or early withdrawal. In three 6-month, blinded double-dummy, active comparator studies (two Phase IIIa and one Phase IIIb), patients completed a COPD device preference questionnaire between the Ellipta™ DPI and the Handi-Haler(®) at Day 168 (Week 24) or early withdrawal. RESULTS In the 3-month placebo-controlled studies, ≥98% of patients used the Ellipta™ DPI correctly and 99% of patients found the inhaler easy/very easy-to-use and the dose counter easy/very easy to read. Across the two Phase IIIa active comparator studies, patients consistently stated a preference for the Ellipta™ DPI over HandiHaler(®) regarding the number of steps to use (59% vs 17%), time taken to use (62% vs 14%), and ease of use (63% vs 15%) regardless of which inhaler contained active drug. Results were consistent in the Phase IIIb active comparator study. CONCLUSION Delivery of UMEC/VI via the Ellipta™ DPI was considered easy-to-use, and patients with COPD demonstrated clear preference for this inhaler compared with HandiHaler(®).

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BACKGROUND Pomegranate juice (PJ) is rich in bioactive phytochemicals with antioxidant, and anti-inflammatory and cardioprotective functions. The present trial investigated the acute effects of PJ consumption on blood pressure and markers of endothelial function. METHODS In this single-arm study, thirteen hypertensive men aged 39-68 years were recruited. Included subjects were assigned to natural PJ (150 ml/day) following a 12 hour fast. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and flow-mediated dilation (FMD), along with serum concentrations of C-reactive protein (CRP), intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), E-selectin and interleukin-6 (IL-6) were measured at baseline and 4-6 hours after PJ consumption. RESULTS Comparison of pre- vs. post-trial values revealed a significant reduction in both SBP (7%; P = 0.013) and DBP (6%; P < 0.010). However, changes in FMD (20%) as well as circulating levels of CRP, ICAM-1, VCAM-1, E-selectin, and IL-6 did not reach statistical significance (P = 0.172). CONCLUSION PJ has promising acute hypotensive properties. Consumption of PJ could be considered in the context of both dietary and pharmacological interventions for hypertension.

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INTRODUCTION The aim of the study was to assess the clinical efficacy, safety, and disease-modification effects of tramiprosate (homotaurine, ALZHEMED(TM)) in mild-to-moderate Alzheimer's disease (AD). MATERIAL AND METHODS Double-blind, placebo-controlled, randomized trial in 67 clinical centres across North America. Patients aged ≥ 50 years, with mild-to-moderate AD (Mini-Mental State Examination score between 16 and 26) and on stable doses of cholinesterase inhibitors, alone or with memantine. INTERVENTION 78-week treatment with placebo, tramiprosate 100 mg or tramiprosate 150 mg BID. MEASUREMENTS Alzheimer Disease Assessment Scale - cognitive subscale (ADAS-cog) and Clinical Dementia Rating - Sum of Boxes (CDR-SB) assessments were performed at baseline and every 13 weeks. Baseline and 78-week magnetic resonance imaging (MRI) hippocampus volume (HV) measurements were conducted in a subgroup of patients. RESULTS A total of 1,052 patients were enrolled and 790 (75.1%) completed the 78-week trial. Patient discontinuation and reasons for withdrawal were similar across groups. Planned analyses did not reveal statistically significant between-group differences. Lack of adequate statistical validity of the planned analysis models led to the development of revised predictive models. These adjusted models showed a trend toward a treatment effect for ADAS-cog (P = 0.098) and indicated significantly less HV loss for tramiprosate 100 mg (P = 0.035) and 150 mg (P = 0.009) compared to placebo. The incidence of adverse events was similar across treatment groups. CONCLUSIONS The primary planned analyses did not show a significant treatment effect, but were confounded by unexplained variance. Post-hoc analyses showed a significant treatment-related reduction in HV loss. However, there was only a trend towards slowing of decline on the ADAS-cog and no slowing of decline on the CDR-SB. These results must be interpreted in consideration of the limitations of clinical and disease-modification outcome measures and their relationship, the heterogeneity of the disease and the impact of confounding demographic and clinical variables.

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BACKGROUND Infant massage is a natural way for caregivers to improve health, sleep patterns, and reduce colic. We aimed to investigate the effects of infant massage on neonates with jaundice who are also receiving phototherapy. METHODS Full-term neonates with jaundice, admitted for phototherapy at a regional teaching hospital, were randomly allocated to either a control group or a massage group. The medical information for each neonate, including total feeding amount, body weight, defecation frequency, and bilirubin level, was collected and compared between two groups. RESULTS A total of 56 patients were enrolled in the study. This included 29 neonates in the control group and 27 in the experimental group. On the third day, the massage group showed significantly higher defecation frequency (p = 0.045) and significantly lower bilirubin levels (p = 0.03) compared with the control group. No significant differences related to feeding amount or body weight were observed between the two groups. CONCLUSION Infant massage could help to reduce bilirubin levels and increase defecation frequency in neonates receiving phototherapy for jaundice.

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BACKGROUND Postoperative bleeding after heart operations is still a common finding, leading to allogeneic blood products transfusion. Fibrinogen and coagulation factors deficiency are possible determinants of bleeding. The experimental hypothesis of this study is that a first-line fibrinogen supplementation avoids the need for fresh frozen plasma (FFP) and reduces the need for any kind of transfusions. METHODS AND RESULTS This was a single-center, prospective, randomized, placebo-controlled, double-blinded study. One-hundred sixteen patients undergoing heart surgery with an expected cardiopulmonary bypass duration >90 minutes were admitted to the study. Patients in the treatment arm received fibrinogen concentrate after protamine administration; patients in the control arm received saline solution. In case of ongoing bleeding, patients in the treatment arm could receive prothrombin complex concentrates (PCCs) and those in the control arm saline solution. The primary endpoint was avoidance of any allogeneic blood product. Patients in the treatment arm had a significantly lower rate of any allogeneic blood products transfusion (odds ratio, 0.40; 95% confidence interval, 0.19 to 0.84, P=0.015). The total amount of packed red cells and FFP units transfused was significantly lower in the treatment arm. Postoperative bleeding was significantly (P=0.042) less in the treatment arm (median, 300 mL; interquartile range, 200 to 400 mL) than in the control arm (median, 355 mL; interquartile range, 250 to 600 mL). CONCLUSIONS Fibrinogen concentrate limits postoperative bleeding after complex heart surgery, leading to a significant reduction in allogeneic blood products transfusions. No safety issues were raised. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01471730.

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BACKGROUND AND OBJECTIVE During atrial fibrillation ablation, heparin is required and is guided by the activated clotting time (ACT). Differences in the ACT before ablation and adequate initial heparin dosing in patients receiving non-vitamin K antagonist oral anticoagulants (NOACs) were examined. METHODS Patients who received warfarin (control, N = 90), dabigatran etexilate (N = 90), rivaroxaban (N = 90) and apixaban (N = 90) were studied. A 100 U/kg dose of heparin was administered as a reliable control dose for warfarin, and the remaining patients were randomly administered 110, 120 or 130 U/kg of heparin in each NOAC group, followed by a continuous heparin infusion. RESULTS Periprocedural thromboembolic and major bleeding were not observed. Minor bleeding occurred rarely without significant differences among the groups examined. Baseline ACTs were longer in the warfarin (152 ± 16 s) and dabigatran (153 ± 13 s) groups than in the rivaroxaban (134 ± 13 s) and apixaban (133 ± 20 s) groups. The initial bolus heparin dosages required to produce an ACT 15 min after the initial bolus that was identical to the control (333 ± 32 s) were 120 U/kg (318 ± 29 s) and 130 U/kg (339 ± 43 s) for dabigatran, 130 U/kg (314 ± 31 s) for rivaroxaban and 130 U/kg (317 ± 39 s) for apixaban. The NOAC groups required significantly larger doses of total heparin than the warfarin group. CONCLUSION The baseline ACTs differed among the three NOAC groups. The results of the comparison with warfarin (the control) indicated that dosages of 120 or 130 U/kg for dabigatran, and 130 U/kg for rivaroxaban and apixaban, were adequate initial heparin dosages.

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INTRODUCTION Adequate pain control is an important consideration in the post-surgical management of patients. Local nerve blockade added to general anesthesia can provide excellent pain control during and after most nasal surgical procedures. The aim of this study was to determine the combined effect of local anesthetic drugs with corticosteroids in nasal surgery. MATERIALS AND METHODS In this double-blind clinical study, 60 patients who underwent different nasal surgical procedures were matched and divided into two equal groups. Bilateral local nerve blockade was used in both groups. Bupivacaine or bupivacaine plus dexamethasone was administered by injection (groups B and B+D, respectively). Postoperative visual analog scale (VAS) pain values and the need for oral/intramuscular analgesic treatment in the first 24 h were recorded in all patients. RESULTS Thirty-eight male (63.3%) and 22 female (36.7%) patients were included in this study, with a mean age of 28.3 ± 8.2 years. At 1, 2, 4, 6, and 12 h post surgery, VAS pain values were significantly lower in the B+D group than in the B group. The analgesic requirement was significantly lower in the B+D group compared with the B group. No relevant complications were seen during surgery or postoperative hospitalization.

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BACKGROUND Pertuzumab plus trastuzumab provides a more comprehensive blockade of HER2 signalling than trastuzumab alone. Therefore, we conducted a phase IIa study of the pharmacokinetics and safety of pertuzumab plus trastuzumab and chemotherapy in advanced gastric cancer (aGC). METHODS Patients received pertuzumab 840 mg for cycle 1 and 420 mg q3w for cycles 2-6 (Arm A) or pertuzumab 840 mg q3w for six cycles (Arm B). Trastuzumab, cisplatin and capecitabine were also given for six cycles, then trastuzumab q3w until disease progression or unmanageable toxicity. The co-primary endpoints were day 43 pertuzumab serum trough concentration (Cmin) and safety. RESULTS Thirty patients were randomised. Mean pertuzumab Cmin at day 43 was 40.0 μg ml(-1) (s.d.: 17.3) in Arm A and 62.7 μg ml(-1) (29.1) in Arm B. Mean day 43 Cmin in Arm A was ~37% lower than that seen in metastatic breast cancer. The safety profiles were similar between arms and treatment was well tolerated. Partial responses were achieved by 86% and 55% of patients in Arms A and B, respectively. CONCLUSIONS On the basis of the pharmacokinetic and safety data, the 840 mg q3w pertuzumab dose has been selected for a phase III study of pertuzumab, trastuzumab and chemotherapy in HER2-positive aGC.

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BACKGROUND High-amylose maize resistant starch type 2 (HAM-RS2) stimulates gut-derived satiety peptides and reduces adiposity in animals. Human studies have not supported these findings despite improvements in glucose homeostasis and insulin sensitivity after HAM-RS2 intake which can lower adiposity-related disease risk. The primary objective of this study was to evaluate the impact of HAM-RS2 consumption on blood glucose homeostasis in overweight, healthy adults. We also examined changes in biomarkers of satiety (glucagon-like peptide-1 [GLP-1], peptide YY [PYY], and leptin) and body composition determined by anthropometrics and dual-energy x-ray absorptiometry, dietary intake, and subjective satiety measured by a visual analogue scale following HAM-RS2 consumption. METHODS Using a randomized-controlled, parallel-arm, double-blind design, 18 overweight, healthy adults consumed either muffins enriched with 30 g HAM-RS2 (n = 11) or 0 g HAM-RS2 (control; n = 7) daily for 6 weeks. The HAM-RS2 and control muffins were similar in total calories and available carbohydrate. RESULTS At baseline, total PYY concentrations were significantly higher 120 min following the consumption of study muffins in the HAM-RS2 group than control group (P = 0.043). Within the HAM-RS2 group, the area under the curve (AUC) glucose (P = 0.028), AUC leptin (P = 0.022), and postprandial 120-min leptin (P = 0.028) decreased independent of changes in body composition or overall energy intake at the end of 6 weeks. Fasting total PYY increased (P = 0.033) in the HAM-RS2 group, but changes in insulin or total GLP-1 were not observed. Mean overall change in subjective satiety score did not correlate with mean AUC biomarker changes suggesting the satiety peptides did not elicit a satiation response or change in overall total caloric intake. The metabolic response from HAM-RS2 occurred despite the habitual intake of a moderate-to-high-fat diet (mean range 34.5% to 39.4% of total calories). CONCLUSION Consuming 30 g HAM-RS2 daily for 6 weeks can improve glucose homeostasis, lower leptin concentrations, and increase fasting PYY in healthy overweight adults without impacting body composition and may aid in the prevention of chronic disease. However, between-group differences in biomarkers were not observed and future research is warranted before specific recommendations can be made. TRIAL REGISTRATION None.

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INTRODUCTION Physical fitness is an important prognostic factor in heart failure (HF). To improve fitness, different types of exercise have been explored, with recent focus on high-intensity interval training (HIT). We comprehensively compared effects of HIT versus continuous training (CT) in HF patients NYHA II-III on physical fitness, cardiovascular function and structure, and quality of life, and hypothesize that HIT leads to superior improvements compared to CT. METHODS Twenty HF patients (male:female 19:1, 64±8 yrs, ejection fraction 38±6%) were allocated to 12-weeks of HIT (10*1-minute at 90% maximal workload-alternated by 2.5 minutes at 30% maximal workload) or CT (30 minutes at 60-75% of maximal workload). Before and after intervention, we examined physical fitness (incremental cycling test), cardiac function and structure (echocardiography), vascular function and structure (ultrasound) and quality of life (SF-36, Minnesota living with HF questionnaire (MLHFQ)). RESULTS Training improved maximal workload, peak oxygen uptake (VO2peak) related to the predicted VO2peak, oxygen uptake at the anaerobic threshold, and maximal oxygen pulse (all P<0.05), whilst no differences were present between HIT and CT (N.S.). We found no major changes in resting cardiovascular function and structure. SF-36 physical function score improved after training (P<0.05), whilst SF-36 total score and MLHFQ did not change after training (N.S.). CONCLUSION Training induced significant improvements in parameters of physical fitness, although no evidence for superiority of HIT over CT was demonstrated. No major effect of training was found on cardiovascular structure and function or quality of life in HF patients NYHA II-III. TRIAL REGISTRATION Nederlands Trial Register NTR3671.

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OBJECTIVE The objective of the trial was to evaluate in a pilot setting the safety and efficacy of interleukin-2 (IL-2) therapy when used without concomitant antiretroviral therapy as a treatment for HIV infection. DESIGN AND SETTING This was a multicentre randomised three-arm trial conducted between September 1998 and March 2001 at three clinical centres in the United Kingdom. PARTICIPANTS Participants were 36 antiretroviral treatment naïve HIV-1-infected patients with baseline CD4 T lymphocyte counts of at least 350 cells/mm(3). INTERVENTIONS Participants were randomly assigned to receive IL-2 at 15 million international units (MIU) per day (12 participants) or 9 MIU/day (12 participants) or no treatment (12 participants). IL-2 was administered by twice-daily subcutaneous injections for five consecutive days every 8 wk. OUTCOME MEASURES Primary outcome was the change from baseline CD4 T lymphocyte count at 24 wk. Safety and plasma HIV RNA levels were also monitored every 4 wk through 24 wk. The two IL-2 dose groups were combined for the primary analysis. RESULTS Area under curve (AUC) for change in the mean CD4 T lymphocyte count through 24 wk was 129 cells/mm(3) for those assigned IL-2 (both dose groups combined) and 13 cells/mm(3) for control participants (95% CI for difference, 51.3-181.2 cells/mm(3); p = 0.0009). Compared to the control group, significant increases in CD4 cell count were observed for both IL-2 dose groups: 104.2/mm(3) (p = 0.008) and 128.4 cells/mm(3) (p = 0.002) for the 4.5 and 7.5 MIU dose groups, respectively. There were no significant differences between the IL-2 (0.13 log(10) copies/ml) and control (0.09 log(10) copies/ml) groups for AUC of change in plasma HIV RNA over the 24-wk period of follow-up (95% CI for difference, -0.17 to 0.26; p = 0.70). Grade 4 and dose-limiting side effects were in keeping with those previously reported for IL-2 therapy. CONCLUSIONS In participants with HIV infection and baseline CD4 T lymphocyte counts of at least 350 cells/mm(3), intermittent subcutaneous IL-2 without concomitant antiretroviral therapy was well tolerated and produced significant increases in CD4 T lymphocyte counts and did not adversely affect plasma HIV RNA levels.

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INTRODUCTION The most frequent reason for ureterorenoscopy is the necessity to remove calculi from the ureter and/or kidney. After completing this procedure the Foley catheter is inserted in the bladder. The aim of the study is to show whether catheterisation of the bladder after ureterorenoscopic stone removal in patients with a low-risk of complications is necessary and indicated. MATERIAL AND METHODS This is a comparative, prospective and randomized study. 100 patients meeting the assumed criteria, subjected to the ureterorenoscopy due to ureter and/or kidney stones participated in the study. The patients were divided into the experimental (Group I) and control (Group II) groups. Group I did not have a catheter, Group II was catheterised. There were two subgroups: female and male in each group. Mean values of the following parameters were calculated: intensity of postoperative pain measured by Visual Analog Pain Scale, the number of additional doses of painkillers administered after the procedure, hospital stay, occurrence of fever, significant bacteriuria, acute urinary retention and post- void retention greater than 30 ml. RESULTS Intensity of pain measured by the Visual Analog Scale was higher in Group II. Catheterisation does not influence: the number of additional doses of ketoprofen and pethidine administered during the 1 st day after the operation, the duration of hospitalization, the occurrence of fever, significant bacteriuria, the postoperative acute urinary retention and the post-void residual urine volume. CONCLUSIONS In patients with a low risk of postoperative complications who did not have any intraoperative complications, catheterisation of the urinary bladder increases discomfort without bringing any benefits.

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AIM To evaluate the efficacy and safety of adding insulin degludec (IDeg) to treatment in patients with type 2 diabetes receiving liraglutide and metformin and qualifying for treatment intensification because of inadequate glycaemic control. METHODS In this 26-week, double-blind trial, patients who still had inadequate glycaemic control after a 15-week run-in period with initiation and dose escalation of liraglutide to 1.8 mg in combination with metformin (≥1500 mg) were randomized to addition of once-daily IDeg ('IDeg add-on to liraglutide' arm; n = 174) or placebo ('placebo add-on to liraglutide' arm; n = 172), with dosing of both IDeg and placebo based on titration guidelines. RESULTS At 26 weeks, the mean change in glycated haemoglobin level was greater in the IDeg add-on to liraglutide arm (-1.04%) than in the placebo add-on to liraglutide arm (-0.16%; p < 0.0001). Similarly, the mean fasting plasma glucose reduction was greater, and self-measured plasma glucose values were lower at all eight time points, with IDeg add-on versus placebo add-on (both p < 0.0001). At 26 weeks, the IDeg dose was 51 U (0.54 U/kg). During the run-in period with liraglutide, body weight decreased by ∼3 kg in both groups. After 26 weeks, the mean change was +2.0 kg (IDeg add-on to liraglutide) and -1.3 kg (placebo add-on to liraglutide). Confirmed hypoglycaemia rates were low in both groups, although higher with IDeg than with placebo (0.57 vs. 0.12 episodes/patient-years of exposure; p = 0.0002). Nocturnal confirmed hypoglycaemia was infrequent in both groups, with no episodes of severe hypoglycaemia, and no marked differences in adverse events with either treatment approach. CONCLUSION The addition of liraglutide and IDeg to patients sub-optimally treated with metformin and liraglutide and requiring treatment intensification was found to be effective and well-tolerated.

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BACKGROUND Opioids, such as alfentanil, are used to facilitate endotracheal intubation without the use of neuromuscular blocking agents in patients undergoing elective surgery. OBJECTIVES The goal of this study was to evaluate the endotracheal intubation conditions when remifentanil or alfentanil was used with propofol without the application of neuromuscular blocking agents. PATIENTS AND METHODS One hundred American Society of Anesthesiologists (ASA) grade I patients scheduled for elective surgery were enrolled in this prospective, randomized, triple-blinded study. The patients were randomized to group A (alfentanil) or R (remifentanil). In group A, alfentanil (50 mcg/kg) was intravenously injected over 10 seconds, and after 45 seconds or at the occurrence of apnea, propofol (2 mg/kg) was intravenously injected over 5 seconds. Thirty seconds after the administration of propofol, laryngoscopy and endotracheal intubation were attempted. In group R, remifentanil (5 mcg/kg) was administered instead of alfentanil. Intubation conditions, including ease of laryngoscopy, patency of the vocal cords, jaw relaxation, limb movement (1-4 score), and also, demographic data were evaluated. RESULTS There were no demographic data differences between groups (age, weight, and sex). Further, laryngoscopy, jaw relaxation, and limb movement scores were similar in the R and A groups and there were no significant differences, but vocal cords were significantly more patent in group R than those in group A (P = 0. 028). CONCLUSIONS The results of this study showed that remifentanil, similar to alfentanil, provided excellent conditions for endotracheal intubation when used with propofol for the induction of anesthesia; however, remifentanil improved the patency of the vocal cords to a greater extent than alfentanil.

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BACKGROUND The effectiveness of a theory-based educational intervention on intension for sexual abstinence among female university students was evaluated. MATERIALS AND METHODS Female students were recruited from humanity sciences department through cluster sampling. Educational intervention was applied for four 90-min sessions and by application of cognitive theories during 4 weeks. RESULTS One hundred and nine female students with mean age of 20.74 ± 1.57 years took part in the study. Despite the similarity of two groups of intervention (n = 53) and control (n = 59) at baseline, there were significant differences between the two groups in mean scores of the variables, knowledge (4.62 ± 1.38 vs. 3.53 ± 1.61), perceived susceptibility (14.05 ± 1.51 vs. 12.37 ± 2.11), and perceived benefits (28.41 ± 2.14 vs. 27.51 ± 3.05), at follow-up time after 3 months (P < 0.05). Additionally, these variables were observed with improvement over 3 months in the intervention group (P < 0.05). However, this study showed no significant effect on the behavior intention and self-efficacy. CONCLUSION This study showed that educational intervention could improve knowledge, perceived benefits, and self-efficacy of the female students regarding HIV/AIDS.

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RATIONALE Lysergic acid diethylamide (LSD) is used recreationally and in clinical research. Acute mystical-type experiences that are acutely induced by hallucinogens are thought to contribute to their potential therapeutic effects. However, no data have been reported on LSD-induced mystical experiences and their relationship to alterations of consciousness. Additionally, LSD dose- and concentration-response functions with regard to alterations of consciousness are lacking. METHODS We conducted two placebo-controlled, double-blind, cross-over studies using oral administration of 100 and 200 μg LSD in 24 and 16 subjects, respectively. Acute effects of LSD were assessed using the 5 Dimensions of Altered States of Consciousness (5D-ASC) scale after both doses and the Mystical Experience Questionnaire (MEQ) after 200 μg. RESULTS On the MEQ, 200 μg LSD induced mystical experiences that were comparable to those in patients who underwent LSD-assisted psychotherapy but were fewer than those reported for psilocybin in healthy subjects or patients. On the 5D-ASC scale, LSD produced higher ratings of blissful state, insightfulness, and changed meaning of percepts after 200 μg compared with 100 μg. Plasma levels of LSD were not positively correlated with its effects, with the exception of ego dissolution at 100 μg. CONCLUSIONS Mystical-type experiences were infrequent after LSD, possibly because of the set and setting used in the present study. LSD may produce greater or different alterations of consciousness at 200 μg (i.e., a dose that is currently used in psychotherapy in Switzerland) compared with 100 μg (i.e., a dose used in imaging studies). Ego dissolution may reflect plasma levels of LSD, whereas more robustly induced effects of LSD may not result in such associations.

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BACKGROUND Cardiovascular disease (CVD) is the leading cause of death in China and worldwide. Whole grain oats can reduce risk of CVD by reducing total and LDL-cholesterol, major risk factors for CVD. While this association has been established in many populations, data from Asian populations is limited. Thus, this study investigated the impact of oat consumption on cholesterol levels in Chinese adults. Male and female data from this work were previously published separately in mandarin in two Chinese journals. The combined male and female data were reanalyzed and are presented here. METHODS A randomized, controlled, parallel-arm study was conducted at Beijing Hospital, Beijing china. Subjects were adults (men and women) with mild to moderate hypercholesterolemia. The oat group (n=85) consumed 100 grams of instant oat cereal versus the control group (n=81) who consumed 100 grams of wheat flour-based noodles daily for 6 weeks. Laboratory and anthropometric measurements were conducted at baseline and at the end of the 6-week intervention. RESULTS Dietary fiber intake increased significantly in the oat group compared to the control group at the end of the 6-week intervention. Total-, LDL-cholesterol and waist circumference decreased significantly in the oat group compared to the control. HDL-cholesterol decreased significantly in the control group versus the oat group. There were no significant changes in blood pressure, other anthropometric or laboratory measures between the two groups at the end of the intervention. CONCLUSIONS Instant oatmeal consumed daily for 6 weeks significantly increased fiber intake and decreased major risk factors for CVD in Chinese adults with hypercholesterolemia. Increased consumption of whole grains, including oats, should continue to be encouraged.

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BACKGROUND AND OBJECTIVES Major abdominal cancer surgeries are associated with significant perioperative mortality and morbidity due to myocardial ischemia and infarction. This study examined the effect of perioperative patient controlled epidural analgesia (PCEA) on occurrence of ischemic cardiac injury in ischemic patients undergoing major abdominal cancer surgery. PATIENTS AND METHODS One hundred and twenty patients (American Society of Anesthesiologists grade II and III) of either sex were scheduled for elective upper gastrointestinal cancer surgeries. Patients were allocated randomly into two groups (60 patients each) to receive, besides general anesthesia: continuous intra and postoperative intravenous (IV) infusion with fentanyl for 72 h postoperatively (patient controlled intravenous analgesia [PCIA] group) or continuous intra and postoperative epidural infusion with bupivacaine 0.125% and fentanyl (PCEA group) for 72 h postoperatively. Perioperative hemodynamics were recorded. Postoperative pain was assessed over 72 h using visual analog scale (VAS). All patients were screened for occurrence of myocardial injury (MI) by electrocardiography, echocardiography, and cardiac troponin I serum level. Other postoperative complications as arrhythmia, deep venous thrombosis (DVT), pulmonary embolism, pneumonia, and death were recorded. RESULTS There was a significant reduction in overall adverse cardiac events (myocardial injury, arrhythmias, angina, heart failure and nonfatal cardiac arrest) in PCEA group in comparison to PCIA group. Also, there was a significant reduction in dynamic VAS pain score in group PCEA in comparison to PCIA at all measured time points. Regarding perioperative hemodynamics, there was a significant reduction in intra-operative mean arterial pressure (MAP); and heart rate in PCEA group in comparison to PCIA group at most of measured time points while there was not a significant reduction in postoperative MAP and heart rate in the second and third postoperative days. The incidence of other postoperative complications such as DVT, pneumonia and in hospital mortality were decreased in PCEA group. CONCLUSION Perioperative thoracic epidural analgesia in patients suffering from coronary artery disease subjected to major abdominal cancer surgery reduced significantly postoperative major adverse cardiac events with better pain control in comparison with perioperative IV analgesia.

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BACKGROUND Accumulating evidence suggests that the brain's nitric oxide (NO) signalling system may be involved in the pathophysiology of schizophrenia and could thus constitute a novel treatment target. The study was designed to investigate the benefit of L-lysine, an amino acid that interferes with NO production, as an add-on treatment for schizophrenia. METHODS L-lysine, 6 g/day, was administered to 10 patients with schizophrenia as an adjunctive to their conventional antipsychotic medication. The study was designed as a single-blinded, cross-over study where patients were randomly assigned to initial treatment with either L-lysine or placebo and screened at baseline, after four weeks when treatment was crossed over, and after eight weeks. RESULTS L-lysine treatment caused a significant increase in blood concentration of L-lysine and was well tolerated. A significant decrease in positive symptom severity, measured by the Positive And Negative Syndrome Scale (PANSS), was detected. A certain decrease in score was also observed during placebo treatment and the effects on PANSS could not unequivocally be assigned to the L-lysine treatment. Furthermore, performance on the Wisconsin Card Sorting Test was significantly improved compared to baseline, an effect probably biased by training. Subjective reports from three of the patients indicated decreased symptom severity and enhanced cognitive functioning. CONCLUSIONS Four-week L-lysine treatment of 6 g/day caused a significant increase in blood concentration of L-lysine that was well tolerated. Patients showed a significant decrease in positive symptoms as assessed by PANSS in addition to self-reported symptom improvement by three patients. The NO-signalling pathway is an interesting, potentially new treatment target for schizophrenia; however, the effects of L-lysine need further evaluation to decide the amino acid's potentially beneficial effects on symptom severity in schizophrenia.

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BACKGROUND The efficacy of subpleural analgesia to reduce postoperative pain intensity in patients after lateral thoracotomy is controversial. In this study, we demonstrated the efficacy of two types of subpleural analgesia. METHODS This prospective, controlled, randomized, double-blind trial was performed in Department of Thoracic Surgery of Alzahra Hospital associated with Isfahan University of Medical Sciences from June 2009 until August 2010. After posterolateral thoracotomy and admission to the ICU, patients were randomly assigned into two groups of subpleural patient-controlled analgesia (SPCA) (0.02 cc/kg/h of 0.5% bupivacaine) and subpleural intermittent analgesia (SIA) (0.1cc/kg/6h of 0.5% bupivacaine). The data regarding age, sex, visual analog scale (VAS) (at 8, 16 and 24 hours after initiation of analgesia), morphine consumption, systemic adverse effects, length of ICU and hospital stay, complications, public health service (PHS) criteria, and cost was recorded. Data was analyzed by Mann-Whitney U-test, repeated measured test, chi-square test and the Fisher's exact test. A p < 0.05 was considered significant. RESULTS The study population consisted of 90 patients. There were no significant differences in sex, age, weight, intraoperative analgesics, duration of one-lung ventilation, and adverse effects between the SPCA and SIA groups. Although pain scores were significantly reduced at 16 hours after the first subpleural instillation of bupivacaine 0.5% with patient-controlled analgesia, comparison between mean pain scores in the two groups at 8 and 24 hours after the first subpleural instillation of bupivacaine 0.5% revealed no significant difference. In addition, no significant difference was found in VAS scores at the three evaluated times (p < 0.05). CONCLUSIONS Optimal use of SPCA bupivacaine for postoperative pain treatment is more effective in pain reduction than SIA bupivacaine. The consumption rate of opioid and bupivacaine was also decreased in SPCA group.

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OBJECTIVE To determine abnormal MRI findings in adults hospitalized with acute severe axial LBP. METHOD Sixty patients with back pain were divided into 3 groups consisting of 1) 23 adults with acute axial severe LBP who could not sit up or stand up for several days, but had not experienced previous back-related diseases or trauma (group A), 2) 19 adults who had been involved in a minor traffic accident, and had mild symptoms but not limited mobility (group B), and 3) 18 adults with LBP with radicular pain (group C)., Various MRI findings were assessed among the above 3 groups and compared as follows: disc herniation (protrusion, extrusion), lumbar disc degeneration (LDD), annular tear, high intensity zone (HIZ), and endplate changes. RESULTS THE MRI FINDINGS OF A GROUP WERE AS FOLLOWS: disc herniation (87%), LDD (100%), annular tear (100%), HIZ (61%), and end plate changes (4.4%). The findings of disc herniation, annular tear, HIZ, and LDD were more prevalent in A group than in B group (p<0.01). HIZ findings were more prevalent in A group than in group B or group C (p<0.05). CONCLUSION Patients with acute severe axial LBP were more likely to have disc herniation, LDD, annular tear, HIZ. Among LBP groups, there was a significant association of HIZ on MRI with acute severe axial LBP.

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BACKGROUND Endotracheal intubation and mechanical ventilation (MV) are often needed in patients of chronic obstructive pulmonary disease (COPD) with acute hypercapnic respiratory failure. The rate of weaning failure is high and prolonged MV increases intubation associated complications. OBJECTIVE To evaluate the role of Noninvasive ventilation (NIV) in weaning patients of chronic obstructive pulmonary disease (COPD) from MV, after T piece trial failure. DESIGN A prospective, randomized, controlled study was conducted in a tertiary care centre. 30 patients of acute exacerbation of COPD with acute on chronic hypercapnic respiratory failure, who were mechanically ventilated, were included in the study A T-piece weaning trial was attempted once the patients achieved satisfactory clinical and biochemical parameters. After T-piece failure, defined as pH < 7.35, PaCO(2) >50 mmHg, PaO(2) <50 mmHg, HR >100/min, RR >35, patients were randomized to receive either NIV or PSV. RESULTS Demography, severity of disease and clinical profiles were similar in both groups. No significant difference between the two groups in duration of MV (6.20 +/- 5.20 days vs. 7.47 +/- 6.38 days, P > 0.05), duration of weaning (35.17 +/- 16.98 and 47.05 +/- 20.98 hours, P > 0.05) or duration of ICU stay (8.47 +/- 4.79 and 10.80 +/- 5.28 days, P > 0.05) in Gp I and Gp II, respectively. Five patients developed VAP in the PSV group, where as only one patient had pneumonia in the NIV group. Lesser number of deaths in the NIV group at discharge from ICU (3 vs. 5 patients, respectively) and at 30 days (5 vs. 9 patients, respectively), it did not achieve statistical significance (P > 0.05). CONCLUSION NIV is as useful as PSV in weaning and can be better in weaning failure especially in COPD for earlier weaning, decrease ICU stay, complications and mortality.

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BACKGROUND Median sternotomy, sternal spreading, and sternal wiring are the main causes of pain during the early recovery phase following cardiac surgery. AIM This study was designed to evaluate the analgesic efficacy of continuous presternal bupivacaine infusion through a single catheter after parasternal block following cardiac surgery. MATERIALS AND METHODS The total of 40 patients (American Society of Anesthesiologist status II, III), 45-60 years old, undergoing coronary-artery bypass grafting were enrolled in this prospective, randomized, double-blind study. A presternal catheter was inserted with continuous infusion of 5 mL/h bupivacaine 0.25% (Group B) or normal saline (Group C) during the first 48 postoperative hrs. Primary outcomes were postoperative morphine requirements and pain scores, secondary outcomes were extubation time, postoperative respiratory parameters, incidence of wound infection, Intensive Care Unit (ICU) and hospital stay duration, and bupivacaine level in blood. STATISTICAL METHODS Student's t-test was used to analyze the parametric data and Chi-square test for categorical variables. RESULTS During the postoperative 48 h, there was marked reduction in morphine requirements in Group B compared to Group C, (8.6 ± 0.94 mg vs. 18.83 ± 3.4 mg respectively, P = 0.2), lower postoperative pain scores, shorter extubation time (117 ± 10 min vs. 195 ± 19 min, respectively, P = 0.03), better respiratory parameters (PaO 2 /FiO 2, PaCO 2 and pH), with no incidence of wound infection, no differences in ICU or hospital stay duration. The plasma concentration of bupivacaine remained below the toxic threshold (at T24, 1.2 ug/ml ± 0.3 and T48 h 1.7 ± 0.3 ug/ml). CONCLUSION Continuous presternal bupivacaine infusion has resulted in better postoperative analgesia, reduction in morphine requirements, shorter time to extubation, and better postoperative respiratory parameters than the control group.

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BACKGROUND Due to the floating of the guideline, there is no evidence-based evaluation index on when to start the blood transfusion for patients with hemoglobin (Hb) level between 7 and 10 g/dl. As a result, the trigger point of blood transfusion may be different in the emergency use of the existing transfusion guidelines. The present study was designed to evaluate whether the scheme can be safely and effectively used for emergency patients, so as to be supported by multicenter and large sample data in the future. METHODS From June 2013 to June 2014, patients were randomly divided into the experimental group (Peri-operative Transfusion Trigger Score of Emergency [POTTS-E] group) and the control group (control group). The between-group differences in the patients' demography and baseline information, mortality and blood transfusion-related complications, heart rate, resting arterial pressure, body temperature, and Hb values were compared. The consistency of red blood cell (RBC) transfusion standards of the two groups of patients with the current blood transfusion guideline, namely the compliance of the guidelines, utilization rate, and per-capita consumption of autologous RBC were analyzed. RESULTS During the study period, a total of 72 patients were recorded, and 65 of them met the inclusion criteria, which included 33 males and 32 females with a mean age of (34.8 ± 14.6) years. 50 underwent abdomen surgery, 4 underwent chest surgery, 11 underwent arms and legs surgery. There was no statistical difference between the two groups for demography and baseline information. There was also no statistical differences between the two groups in anesthesia time, intraoperative rehydration, staying time in postanesthetic care unit, emergency hospitalization, postoperative 72 h Acute Physiologic Assessment and Chronic Health Evaluation II scores, blood transfusion-related complications and mortality. Only the POTTS-E group on the 1 st postoperative day Hb was lower than group control, P < 0.05. POTTS-E group was totally (100%) conformed to the requirements of the transfusion guideline to RBC infusion, which was higher than that of the control group (81.25%), P < 0.01.There were no statistical differences in utilization rates of autologous blood of the two groups; the utilization rates of allogeneic RBC, total allogeneic RBC and total RBC were 48.48%, 51.5%, and 75.7% in POTTS-E group, which were lower than those of the control group (84.3%, 84.3%, and 96.8%) P < 0.05 or P < 0.01. Per capita consumption of intraoperative allogeneic RBC, total allogeneic RBC and total RBC were 0 (0, 3.0), 2.0 (0, 4.0), and 3.1 (0.81, 6.0) in POTTS-E groups were all lower than those of control group (4.0 [2.0, 4.0], 4.0 [2.0, 6.0] and 5.8 [2.7, 8.2]), P < 0.05 or P < 0.001. CONCLUSIONS Peri-operative Transfusion Trigger Score-E evaluation scheme is used to guide the application of RBC. There are no differences in the recent prognosis of patients with the traditional transfusion guidelines. This scheme is safe; Compared with doctor experience-based subjective assessment, the scoring scheme was closer to patient physiological needs for transfusion and more reasonable; Utilization rate and the per capita consumption of RBC are obviously declined, which has clinical significance and is feasible. Based on the abovementioned three points, POTTS-E scores scheme is safe, reasonable, and practicable and has the value for carrying out multicenter and large sample clinical researches.

1significant effect

BACKGROUND Pain management after abdominal surgery is a critical issue in cancer patients undergoing laparotomy. Opioid analgesics commonly used postoperatively have significant side effects and can postpone restoring normal life. Administration of analgesics before the surgery by inhibiting pain cascades may be an effective method for more efficient pain control. OBJECTIVES This study aimed to investigate the effect of the preemptive use of oral pregabalin-acetaminophen-naproxen on pain control and morphine consumptions in cancer patients undergoing laparotomy. PATIENTS AND METHODS A total of 40 cancer patients scheduled for open abdominal surgery were randomized into the two groups. one group received combination of pregabalin 150 mg, acetaminophen 1 g and naproxen 250 mg (the PAN group) an hour before laparotomy. Following the surgery, morphine was administered on a protocolized schedule based on patients' demand for pain control. Postoperative pain level was assessed using universal pain assessment tool (UPAT) at 0, 2, 4, 6, 12, 24 and 48 hours after the operation. The postoperative morphine dose and complications were noted. Data were analyzed using SPSS version 16. RESULTS Patients in the PAN group had significantly lower UPAT scores at 0, 2, 4, 6, 12, 24 and 48 hours after the surgery than those in the control group (P = 0.008, 0.021, 0.008, 0.047, 0.004, 0.001, and 0.001). The mean dose of postoperative morphine consumption in the PAN group was 37% less than the control group (P = 0.001). The complications were not significantly different between the two groups. CONCLUSIONS Preemptive use of pregabalin-acetaminophen-naproxen decreases intensity of pain and morphine consumption in the cancer patients after laparotomy without significant complications.

1significant effect

BACKGROUND Home fortification using sachets of micronutrient powder (e.g. "Sprinkles") is a food-based approach offering an alternative to high dose vitamin A (VA) supplements for infants. The primary objective was to investigate the impact of VA-home fortification on infant VA pool size. The secondary objective was to compare VA status of infants assessed by the modified relative dose response (MRDR) test before and the (13)C-retinol isotope dilution ((13)C-RID) test in the same infants after vitamin A supplementation. METHODS A randomized-controlled trial was conducted in 7-9 month old infants in Ghana. Eligible children were randomly allocated to receive a daily sachet of "Sprinkles" with or without VA for 5 months added to complementary foods. The MRDR test indirectly determined VA liver reserves at baseline and the (13)C-RID determined VA body pool at follow-up in the same cohort of children. RESULTS At baseline, the MRDR values (95 % CI) for infants were comparable in the intervention and control groups: normal at 0·032 (SD 0·018) (0·025-0·038) and 0·031 (SD 0·018) (0·024-0·038), respectively. After intervention, total body stores (TBS) and liver retinol concentrations did not differ between intervention and control groups; TBS were 436 (SD 303) and 434 (SD 186) μmol, respectively, and estimated liver concentrations were 0·82 (SD 0·53) and 0·79 (SD 0·36) μmol/g liver, indicating adequate reserves in all children. CONCLUSIONS Both the MRDR and (3)C-RID tests confirmed that the infants had adequate VA status before and after home fortification of their complementary foods. These tests offered more information than serum retinol concentrations alone, which predicted VA deficiency using current suggested cutoffs not corrected for inflammation status.

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CONTEXT Sympathoadrenal response to laryngoscopy and tracheal intubation manifests as transient, but distinct tachycardia and hypertension. AIMS The objective of this study is to compare the clinical effects of dexmedetomidine with esmolol and control in attenuating the presser response during laryngoscopy. SETTINGS AND DESIGN A randomized, prospective, double-blind, controlled study. SUBJECTS AND METHODS We studied consented, 90 adult, American Society of Anesthesiologists physical status I and II patients of either sex, scheduled for non-cardiac surgery requiring intubation. The patients were randomly divided into three groups (n = 30). Group C received placebo, Group E received 2.0 mg/kg of esmolol and Group D received 1.0 μg/kg of dexmedetomidine, intravenously over 10 min and 3 min before induction of general anesthesia. All patients were uniformly pre-medicated, induced and intubated using thiopentone and succinylcholine as per standard protocol. Heart rate (HR), systemic arterial pressures were recorded at baseline, after study drug infusion, after induction, immediately and 3, 5, 7, 10 min after intubation. STATISTICAL ANALYSIS Analysis of variance and t-test as appropriate. RESULTS The mean arterial pressure was significantly increased in patients receiving placebo (P < 0.0001) and esmolol (P < 0.0001) after laryngoscopy and intubation compared with baseline value and Group D (P = 0.6294). The rise in HR (P = 0.08481) and rate pressure product (P = 0.0666) at the time of intubation were minimal and was statistically significant up to 15 min in Group D. CONCLUSIONS Both the drugs attenuated the pressure response. Of the two drugs administered, dexmedetomidine 1.0 μg/kg provides a consistent, reliable and effective attenuation of pressure responses when compared to esmolol 2.0 mg/kg.

1significant effect

OBJECTIVES The purpose of this double-blind, parallel clinical study was to assess clinical efficacy in supragingival calculus formation reduction using Abhaibhubejhr Herbal Toothpaste compared to Colgate Total and Colgate Cavity Protection toothpastes. MATERIALS AND METHODS A total of 150 subjects participated in the pretest phase. All subjects were given oral soft/hard tissue evaluation, calculus examination using Volpe-Manhold calculus, and whole mouth oral prophylaxis. They received noncalculus control fluoride toothpaste and a soft-bristled toothbrush to brush for 1 min two times daily for 8 weeks. After which, subjects were given a test phase oral soft/hard tissue evaluation and calculus examination and were randomized into one of the three toothpaste groups. All subjects in the test phase received a whole mouth oral prophylaxis and were given their assigned toothpaste and a soft-bristled toothbrush to brush for 1 min two times a day for 12 weeks. Thereafter, subjects were assessed for their oral soft/hard tissue and calculus formation. RESULTS Mean Volpe-Manhold calculus index scores for the Cavity Protection, Abhaibhubejhr, and Total toothpaste groups were 0.78, 0.62, and 0.48, respectively, at the 12-week test phase evaluation. Abhaibhubejhr and Total toothpaste groups show 20.51% and 38.46% significantly less calculus formation than the Cavity Protection toothpaste group ( P < 0.05). Total toothpaste group also show 22.58% significantly less calculus formation than the Abhaibhubejhr toothpaste group ( P < 0.05). CONCLUSION The use of Colgate Total toothpaste over a 12-week period was clinically more effective than either Abhaibhubejhr or Colgate Cavity Protection toothpastes in controlling supragingival calculus formation.

1significant effect

BACKGROUND Recommended management of attacks of hereditary angioedema (HAE) due to C1 esterase inhibitor (C1-INH) deficiency (C1-INH-HAE) includes therapy with exogenous C1INH. Thrombotic/thromboembolic events (TEE) have been reported with plasma-derived C1INH, but so far none with recombinant human C1INH (rhC1INH). This phase III, randomized, placebo (saline)-controlled study evaluated the safety of rhC1INH 50 IU/kg for the treatment of acute attacks in 74 patients with C1-INH-HAE. METHODS Monitoring for TEE and assessment of risk of deep vein thrombosis (DVT) by the Wells prediction rule were performed, and levels of fibrin degradation products (plasma D-dimers) were assessed before study drug administration (baseline), 2 h, and 7 days posttreatment. RESULTS Plasma D-dimer levels were elevated in 80% of the patients (median [25th-75th percentiles]: 2149 [480-5105] μg/l; normal ≤250 μg/l) and were higher in patients with submucosal (abdominal, oropharyngeal-laryngeal) attacks (3095 [890-10000] μg/l; n = 29) compared with subcutaneous (peripheral, facial) attacks (960 [450-4060] μg/l; n = 35). Median plasma D-dimer levels were comparable across treatment groups at baseline (1874 [475-4568] μg/l rhC1INH; 2259 [586-7533] μg/l saline) and 2 h postinfusion (2389 [760-4974] μg/l rhC1INH; 2550 [310-8410] μg/l saline); median plasma D-dimer levels were decreased by Day 7 in both groups (425 [232-3240] μg/l rhC1INH; 418 [246-2318] μg/l saline). No increased risk of DVT was identified, nor any TEE reported in rhC1INH treated or controls. CONCLUSION Elevated plasma D-dimer levels were associated with acute C1-INH-HAE attacks, particularly with submucosal involvement. However, rhC1INH therapy was not associated with thrombotic events.

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BACKGROUND For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. METHODS TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. FINDINGS Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140-146) in children who received standard transfusions and 138 cm/s (135-142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10-8·98). Non-inferiority (p=8·82 × 10(-16)) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). INTERPRETATION For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. FUNDING National Heart, Lung, and Blood Institute, National Institutes of Health.

1significant effect

BACKGROUND In numerous animal and human studies, it could be detected that in bone augmentation procedures, material's physicochemical characteristics can influence the cellular inflammatory pattern and therefore the integration in the host tissue. Histological, histomorphometrical, and clinical analyses of the integration of the biomaterial in the surrounding tissue are well established methodologies; however, they do not make a statement on volume and density changes of the augmented biomaterial. AIMS The aim of the present study was to assess the volume and density of a xenogeneic (Bio-Oss ® , BO) and a synthetic (NanoBone ® , NB) bone substitute material in split-mouth sinus augmentations in former tumor patients to complete histological and histomorphometrical assessment. METHODS Immediately and 6 months after sinus augmentation computed tomography scans were recorded, bone grafts were marked, and the volume was calculated with radiologic RIS-PACS software (General Electric Healthcare, Chalfont St. Giles, Great Britain) to determine the integration and degradation behavior of both biomaterials. RESULTS Radiographic analysis revealed a volume reduction of the initial augmented bone substitute material (i.e. 100%) to 77.36 (±11.68) % in the BO-group, respectively, 75.82 (±22.28) % in the NB-group six months after augmentation. In both materials, the volume reduction was not significant. Bone density significantly increased in both groups. CONCLUSION The presented radiological investigation presents a favorable method to obtain clinically relevant information concerning the integration and degradation behavior of bone substitute materials.

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OBJECTIVES Within a randomised trial of neonatal vitamin A supplementation (VAS) in Guinea-Bissau, neonatal VAS did not affect overall infant mortality. We conducted a post-hoc analysis to test the hypothesis that neonatal VAS primes the response to subsequent vitamin A. METHODS All trial children were offered VAS after follow-up ended at 1 year of age (FU-VAS). We compared mortality between 1 and 3 years of age according to initial randomization to neonatal VAS or placebo in Cox-regression models; we expected that children randomized to neonatal VAS compared with those randomized to placebo would have lower mortality after reception of FU-VAS. RESULTS Of 4345 infants enrolled in the original trial, 3646 lived in the study area at 1 year of age and 2958 received FU-VAS. Between 1 and 3 years of age, 112 children died. After FU-VAS, neonatal VAS was associated with lower mortality than placebo: Mortality Rate Ratio (MRR) = 0.54 (95%CI: 0.31-0.94). The effect was more pronounced in girls (MRR = 0.37 (0.16-0.89)) than boys (MRR = 0.73 (0.35-1.51)). The beneficial effect of neonatal VAS may have been particularly strong for girls who received both VAS in a campaign and FU-VAS (MRR = 0.15 (0.03-0.67)). Among children who had not received FU-VAS, mortality in the second and third year of life did not differ according to reception of neonatal VAS or placebo. Hence, in the second and third year of life the effect of neonatal VAS versus placebo was different in girls who had or had not received FU-VAS (p for homogeneity = 0.01). CONCLUSIONS The present results suggest that neonatal VAS primes the response in girls such that they get a beneficial effect after a subsequent dose of VAS. TRIAL REGISTRATION Clinicaltrials.gov NCT00168597.

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BACKGROUND Prednisolone and pentoxifylline (PTX) have been shown to be individually useful in severe alcoholic hepatitis with Maddrey discriminant function (MDF) score ≥32. Previous report suggests that PTX is probably superior to prednisolone alone. However the efficacy of PTX and prednisolone combination over PTX alone in the management of acute alcoholic hepatitis (MDF score ≥32) is yet unrevealed. AIM The present study was initiated to find out the efficacy of combined pentoxifylline and prednisolone versus PTX alone in acute alcoholic hepatitis in respect of short and intermediate term outcomes. SUBJECTS AND METHODS A total of 124 patients with severe alcoholic hepatitis (MDF score ≥ 32) initially were evaluated. 62 patients who fulfilled the inclusion and exclusion criteria were randomized and divided into 2 groups. Group 1 received PTX only, whereas Group 2 received PTX plus Prednisolone. The total duration of follow-up was 12 months. Student's t-test, Chi-square test, the Kaplan-Meier methods were used for statistical analysis. RESULTS A total of 60 patients, 30 in each group were available for final analysis. In Group-1, 6 patients expired at the end of 1 year (5 within 3 months and another after 3 months). In Group 2, 10 patients expired at the end of 1 year (9 within 3 months and another after 3 months). Though survival probability is higher among Group 1 patients but the difference is not statistically significant. CONCLUSION The combination of PTX plus Prednisolone yields no additional benefit in terms of mortality and morbidity from that of PTX monotherapy.

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BACKGROUND Dabigatran 150 mg twice daily was shown to be superior to warfarin in preventing stroke in subjects with nonvalvular atrial fibrillation (SPAF) in the RE-LY (Randomized Evaluation of Long-term anticoagulation therapY) trial. Numerically, more myocardial infarctions occurred in patients receiving dabigatran compared with well-controlled warfarin. This observation prompted a comprehensive analysis of cardiovascular outcomes, including myocardial infarction, in all completed Phase II and III trials of dabigatran etexilate. METHODS The analysis included comparisons of dabigatran with warfarin, enoxaparin, and placebo. Data were analyzed for the occurrence of cardiovascular events from 14 comparative trials (n = 42,484) in five different indications. Individual study data were evaluated, as well as pooled subject-level data grouped by comparator. RESULTS In the pooled analysis of individual patient data comparing dabigatran with warfarin (SPAF and venous thromboembolism treatment indications), myocardial infarction occurrence favored warfarin (odds ratio [OR] 1.30, 95% confidence interval [CI] 0.96-1.76 for dabigatran 110 mg twice daily and OR 1.42, 95% CI 1.07-1.88 for dabigatran 150 mg twice daily). The clinically relevant composite endpoint of myocardial infarction, total stroke, and vascular death demonstrated numerically fewer events in dabigatran 150 mg patients (OR 0.87, 95% CI 0.77-1.00), but was similar for dabigatran 110 mg (OR 0.99, 95% CI 0.87-1.13). Dabigatran had similar myocardial infarction rates when compared with enoxaparin or placebo. CONCLUSION These analyses suggest a more protective effect of well-controlled warfarin, but not enoxaparin, compared with dabigatran in preventing myocardial infarction in multiple clinical settings. Dabigatran showed an overall positive benefit-risk ratio for multiple clinically important cardiovascular composite endpoints in all evaluated clinical indications. In conclusion, these data suggest that myocardial infarction is not an adverse drug reaction associated with use of dabigatran.

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UNLABELLED Worldwide, paracetamol is administered as a remedy for complaints that occur after vaccination. Recently published results indicate that paracetamol inhibits the vaccination response in infants when given prior to vaccination. The goal of this study was to establish whether paracetamol exerts similar effects in young adults. In addition, the effect of timing of paracetamol intake was investigated. In two randomized, controlled, open-label studies 496 healthy young adults were randomly assigned to three groups. The study groups received paracetamol for 24 hours starting at the time of (prophylactic use) - or 6 hours after (therapeutic use) the primary (0 month) and first booster (1 month) hepatitis B vaccination. The control group received no paracetamol. None of the participants used paracetamol around the second booster (6 months) vaccination. Anti-HBs levels were measured prior to and one month after the second booster vaccination on ADVIA Centaur XP. One month after the second booster vaccination, the anti-HBs level in the prophylactic paracetamol group was significantly lower (p = 0.048) than the level in the control group (4257 mIU/mL vs. 5768 mIU/mL). The anti-HBs level in the therapeutic paracetamol group (4958 mIU/mL) was not different (p = 0.34) from the level in the control group. Only prophylactic paracetamol treatment, and not therapeutic treatment, during vaccination has a negative influence on the antibody concentration after hepatitis B vaccination in adults. These findings prompt to consider therapeutic instead of prophylactic treatment to ensure maximal vaccination efficacy and retain the possibility to treat pain and fever after vaccination. TRIAL REGISTRATION Controlled-Trials.com ISRCTN03576945.

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BACKGROUND Amygdala hemodynamic responses to positive stimuli are attenuated in major depressive disorder (MDD), and normalize with remission. Real-time functional MRI neurofeedback (rtfMRI-nf) offers a non-invasive method to modulate this regional activity. We examined whether depressed participants can use rtfMRI-nf to enhance amygdala responses to positive autobiographical memories, and whether this ability alters symptom severity. METHODS Unmedicated MDD subjects were assigned to receive rtfMRI-nf from either left amygdala (LA; experimental group, n = 14) or the horizontal segment of the intraparietal sulcus (HIPS; control group, n = 7) and instructed to contemplate happy autobiographical memories (AMs) to raise the level of a bar representing the hemodynamic signal from the target region to a target level. This 40s Happy condition alternated with 40s blocks of rest and counting backwards. A final Transfer run without neurofeedback information was included. RESULTS Participants in the experimental group upregulated their amygdala responses during positive AM recall. Significant pre-post scan decreases in anxiety ratings and increases in happiness ratings were evident in the experimental versus control group. A whole brain analysis showed that during the transfer run, participants in the experimental group had increased activity compared to the control group in left superior temporal gyrus and temporal polar cortex, and right thalamus. CONCLUSIONS Using rtfMRI-nf from the left amygdala during recall of positive AMs, depressed subjects were able to self-regulate their amygdala response, resulting in improved mood. Results from this proof-of-concept study suggest that rtfMRI-nf training with positive AM recall holds potential as a novel therapeutic approach in the treatment of depression.

1significant effect

BACKGROUND To improve patient health, recent research urges for medical decision aids that are designed to enhance the effectiveness of specific medically related decisions. Many such decisions involve complex information, and decision aids that independently use deliberative (analytical and slower) or intuitive (more affective and automatic) cognitive processes for such decisions result in suboptimal decisions. Unconscious thought can arguably use both intuitive and deliberative (slow and analytic) processes, and this combination may further benefit complex patient (or practitioner) decisions as medical decision aids. Indeed, mounting research demonstrates that individuals render better decisions generally if they are distracted from thinking consciously about complex information after it is presented (but can think unconsciously), relative to thinking about that information consciously or not at all. OBJECTIVE The current research tested whether the benefits of unconscious thought processes can be replicated using an Internet platform for a patient medical decision involving complex information. This research also explored the possibility that judgments reported after a period of unconscious thought are actually the result of a short period of conscious deliberation occurring during the decision report phase. METHODS A total of 173 participants in a Web-based experiment received information about four medical treatments, the best (worst) associated with mostly positive (negative) side-effects/attributes and the others with equal positive-negative ratios. Next, participants were either distracted for 3 minutes (unconscious thought), instructed to think about the information for 3 minutes (conscious thought), or moved directly to the decision task (immediate decision). Finally, participants reported their choice of, and attitudes toward, the treatments while experiencing high, low, or no cognitive load, which varied their ability to think consciously while reporting judgments. Cognitive load was manipulated by having participants memorize semi-random (high), line structured (low), or no dot patterns and recall these intermittently with their decision reports. Overall then, participants were randomly assigned to the conditions of a 3 (thought condition) by 3 (cognitive-load level) between-subjects design. RESULTS A logistic regression analysis indicated that the odds of participants choosing the best treatment were 2.25 times higher in the unconscious-thought condition compared to the immediate-decision condition (b=.81, Wald=4.32, P=.04, 95% CI 1.048-4.836), and 2.39 times greater compared to the conscious-thought condition (b=.87, Wald=4.87, P=.027, 95% CI 1.103-5.186). No difference was observed between the conscious-thought condition compared to the immediate-decision condition, and cognitive load manipulations did not affect choices or alter the above finding. CONCLUSIONS This research demonstrates a plausible benefit of unconscious thinking as a decision aid for complex medical decisions, and represents the first use of unconscious thought processes as a patient-centered medical decision aid. Further, the quality of decisions reached unconsciously does not appear to be affected by the amount of cognitive load participants experienced.

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BACKGROUND Plasmalogens (Pls) reportedly decreased in postmortem brain and in the blood of patients with Alzheimer's disease (AD). Recently we showed that intraperitoneal administration of Pls improved cognitive function in experimental animals. In the present trial, we tested the efficacy of oral administration of scallop-derived purified Pls with respect to cognitive function and blood Pls changes in patients with mild AD and mild cognitive impairment (MCI). METHODS The study was a multicenter, randomized, double-blind, placebo-controlled trial of 24weeks. Participants were 328 patients aged 60 to 85years who had 20 to 27 points in Mini Mental State Examination-Japanese (MMSE-J) score and five or less points in Geriatric Depression Scale-Short Version-Japanese (GDS-S-J). They were randomized to receive either 1mg/day of Pls purified from scallop or placebo. The patients and study physicians were masked to the assignment. The primary outcome was MMSE-J. The secondary outcomes included Wechsler Memory Scale-Revised (WMS-R), GDS-S-J and concentration of phosphatidyl ethanolamine plasmalogens (PlsPE) in erythrocyte membrane and plasma. This trial is registered with the University Hospital Medical Information Network, number UMIN000014945. FINDINGS Of 328 patients enrolled, 276 patients completed the trial (140 in the treatment group and 136 in the placebo group). In an intention-to-treat analysis including both mild AD (20≤MMSE-J≤23) and MCI (24≤MMSE-J≤27), no significant difference was shown between the treatment and placebo groups in the primary and secondary outcomes, with no severe adverse events in either group. In mild AD patients, WMS-R improved significantly in the treatment group, and the between group difference was nearly significant (P=0.067). In a subgroup analysis of mild AD patients, WMS-R significantly improved among females and those aged below 77years in the treatment group, and the between-group differences were statistically significant in females (P=0.017) and in those aged below 77years (P=0.029). Patients with mild AD showed a significantly greater decrease in plasma PlsPE in the placebo group than in the treatment group. INTERPRETATION Oral administration of scallop-derived purified Pls may improve cognitive functions of mild AD. FUNDING The Japanese Plasmalogen Society.

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BACKGROUND For ages various adjuvants have been tried to prolong axillary brachial plexus block. We compared the effect of adding dexmedetomidine versus clonidine to ropivacaine for axillary brachial plexus blockade. The primary endpoints were the onset and duration of sensory and motor block and duration of analgesia. MATERIALS AND METHODS A total of 90 patients (20-40 years) posted for ambulatory elective hand surgery under axillary brachial plexus block were divided into two equal groups (groups ropivacaine dexmedetomidine [RD] and ropivacaine clonidine [RC]) in a randomized, double-blind fashion. In group RD (n = 45) 30 ml 0.5% ropivacaine + 100 μg of dexmedetomidine and group RC (n = 45) 30 ml 0.5% ropivacaine + 75 μg clonidine were administered in axillary plexus block. Sensory and motor block onset times and block durations, time to first analgesic use, total analgesic need, postoperative visual analog scale (VAS), hemodynamics and side-effects were recorded for each patient. RESULTS Though with similar demographic profile in both groups, sensory and motor block in group RD (P < 0.05) was earlier than group RC. Sensory and motor block duration and time to first analgesic use were significantly longer and the total need for rescue analgesics was lower in group RD (P < 0.05) than group RC. Postoperative VAS value at 18 h were significantly lower in group RD (P < 0.05). Intraoperative hemodynamics were insignificantly lower in group RD (P < 0.05) without any appreciable side-effects. CONCLUSION It can be concluded that adding dexmedetomidine to axillary plexus block increases the sensory and motor block duration and time to first analgesic use, and decreases total analgesic use with no side-effects.

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BACKGROUND Emergence agitation (EA) after sevoflurane anesthesia is common in children during recovery from general anesthesia and may result in postoperative complications. This study investigated safety and effectiveness of intranasal dexmedetomidine in reducing the incidence and severity of EA. METHODS This prospective, randomized double-blinded controlled trial included 86 patients scheduled for the tonsillectomy and/or adenoidectomy under general anesthesia with sevoflurane. They were randomly allocated into two groups. Group D received intranasal dexmedetomidine at 1 μg/kg, and Group C received intranasal saline 0.9% after the induction of general anesthesia. Four-point agitation scale and Face, Legs, Activity, Cry and Consolability (FLACC) scale for pain assessment were measured at six time points (after extubation, leaving the operating room, on arrival to postanesthesia care unit [PACU], 10, 20, and 30 min after arrival in PACU). Extubation, emergence, and discharge times were recorded in addition to any adverse effects. RESULTS There was a significant difference in the incidence of EA between Groups D and C (6.98% and 58%, respectively, with P = 0.001). The median four-point agitation scales and the median scores of FLACC pain scales of Group D were significantly lower than those of Group C at the all six time points with P < 0.05. Extubation, emergence, and discharge times were comparable in both groups, and none of the subjects reported any adverse effects. CONCLUSION This study demonstrates that a 1 μg/kg dose of intranasal dexmedetomidine administered after the induction of anesthesia reduces post-sevoflurane incidence and severity of EA in children undergone tonsillectomy and/or adenoidectomy with no adverse effects and smooth recovery profile.

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BACKGROUND The high-density lipoprotein cholesterol (HDL-C) level has been shown to have a significant role in the prevention of cardiovascular diseases and atherosclerosis. Low vitamin D levels have been shown to be correlated with dyslipidemia, but limited data exist on indigenous children. OBJECTIVES We aimed to investigate the effect of vitamin D supplementation on HDL-C levels in school-aged Iranian children. METHODS In this prospective controlled clinical trial, 47 healthy children (23 boys) aged 10 - 14 years, students of Birjand (Iran) elementary schools, were selected and randomly divided into two groups. The study group received a vitamin D supplement (1000 mg capsule) daily for one month, and placebo tablets were prescribed to the controls. Before and after the treatment course, the serum HDL-C and 25-hydroxy vitamin D levels of both groups were measured. The data were analyzed by SPSS, ver. 16, and Chi-square tests, Fisher's exact test, paired-sample t-tests, and Pearson's correlation were used, wherever appropriate. The significance level was set at P < 0.05. RESULTS Forty children completed the study; their mean age was 11.5 ± 1.175 years. The mean serum levels of both HDL-C and vitamin D showed a significant rise following the treatment in the study group (P = 0.007 and P < 0.001, respectively), whereas both variables decreased slightly in the control group (P = 0.27). There was no statistically significant difference in the mean serum levels of HDL-C and vitamin D between the two groups after the intervention (P = 0.11 and P = 0.20, respectively). CONCLUSIONS Vitamin D supplements seem to have a positive impact on serum HDL-C levels and may be effective in reducing the risk of cardiovascular diseases in the long term.

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INTRODUCTION We tested the hypothesis that dipeptidyl peptidase-4 (DPP-4) inhibitors are effective in preserving the β-cell function for long-term periods in patients with slowly progressive type 1 diabetes (SPIDDM) or latent autoimmune diabetes in adults (LADA). METHODS In the present open-label, randomized, controlled trial, 14 non-insulin-requiring diabetic patients with glutamic acid decarboxylase autoantibodies (GADAb) were randomly assigned to receive either sitagliptin (S group) or pioglitazone (P group). As a historical control, the Tokyo Study, in which non-insulin-dependent patients with SPIDDM were assigned to receive treatment by either insulin or sulfonylurea (SU), was used. RESULTS On average, the ∑C-peptide values during the oral glucose tolerance test through the follow-up periods showed a nonsignificant increase in the S group (n = 6, n = 5 at 48 months) compared to the P group (n = 5, n = 2 at 48 months). In comparison to the data in the Tokyo Study, treatment by sitagliptin significantly influenced the longitudinal changes in the ∑C-peptide values with a more increased direction than insulin or SU, especially in patients with 48 months of follow-up (p = 0.014 and p = 0.007, respectively). Although the titers of GADAb were not significantly different between the S and P groups during the study, the change ratio of the GADAb titers from baseline was significantly inversely correlated with the change ratio of the ∑C-peptide values from baseline in the S group (p = 0.003); in particular, when the GADAb titers decreased from baseline, the ∑C-peptide values frequently increased. CONCLUSION The present pilot trial suggests that treatment of SPIDDM/LADA by sitagliptin, a DPP-4 inhibitor, may be more effective in preserving the β-cell function than insulin treatment for at least 4 years, possibly through the immune modulatory effects of DPP-4 inhibitors. CLINICAL TRIAL REGISTRATION Japanese Clinical Trials Registry UMIN000003693.

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AIM To study the effect of integrated yoga on pain, morning stiffness and anxiety in osteoarthritis of knees. MATERIALS AND METHODS Two hundred and fifty participants with OA knees (35-80 years) were randomly assigned to yoga or control group. Both groups had transcutaneous electrical stimulation and ultrasound treatment followed by intervention (40 min) for two weeks with follow up for three months. The integrated yoga consisted of yogic loosening and strengthening practices, asanas, relaxation, pranayama and meditation. The control group had physiotherapy exercises. Assessments were done on 15(th) (post 1) and 90(th) day (post 2). RESULTS Resting pain (numerical rating scale) reduced better (P<0.001, Mann-Whitney U test) in yoga group (post 1=33.6% and post 2=71.8%) than control group (post 1=13.4% and post 2=37.5%). Morning stiffness decreased more (P<0.001) in yoga (post 1=68.6% and post 2=98.1%) than control group (post 1=38.6% and post 2=71.6%). State anxiety (STAI-1) reduced (P<0.001) by 35.5% (post 1) and 58.4% (post 2) in the yoga group and 15.6% (post 1) and 38.8% (post 2) in the control group; trait anxiety (STAI 2) reduced (P<0.001) better (post 1=34.6% and post 2=57.10%) in yoga than control group (post 1=14.12% and post 2=34.73%). Systolic blood pressure reduced (P<0.001) better in yoga group (post 1=-7.93% and post 2=-15.7%) than the control group (post 1=-1.8% and post 2=-3.8%). Diastolic blood pressure reduced (P<0.001) better in yoga group (post 1=-7.6% and post 2=-16.4%) than the control group (post 1=-2.1% and post 2=-5.0%). Pulse rate reduced (P<0.001) better in yoga group (post 1=-8.41% and post 2=-12.4%) than the control group (post 1=-5.1% and post 2=-7.1%). CONCLUSION Integrated approach of yoga therapy is better than physiotherapy exercises as an adjunct to transcutaneous electrical stimulation and ultrasound treatment in reducing pain, morning stiffness, state and trait anxiety, blood pressure and pulse rate in patients with OA knees.

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OBJECTIVES The objective of this study is to assess the dose-related effects of tramadol on a group of patients with premature ejaculation (PE). SUBJECTS AND METHODS During the period of months between June 2010 and July 2012, 180 PE patients presented to outpatient clinic of our hospital. Patients were randomized in a 1:1:1 fashion to receive different sequences of the three medications: placebo, 50 mg of tramadol and 100 mg of tramadol. Every patient received 10 doses of each medication for 2 months. Intra-vaginal ejaculatory latency time (IELT) was recorded in seconds initially and for each arm. Successful treatment of PE is defined if IELT exceeded 120 s. Side-effects of medications were reported. RESULTS Of patients enrolled, 125 (69.4%) continued the study. Patients' age range was 20-55 years with PE complaint of 1 to 10 years duration. Mean IELT was 72 at presentation, 82 for placebo, 150 for tramadol 50 mg, and 272 for tramadol 100 mg (P < 0.001 for all comparisons). PE was successfully treated in only 2.4% of patients with placebo, in contrast to 53.6% and 85.6% with 50 and 100 mg tramadol, respectively (P < 0.001 for all comparisons). On multivariate logistic regression analysis, baseline IELT was the only predictor of successful treatment of PE with both tramadol 50 mg (odds ratio [OR]: 1.05, 95% confidence interval [CI]: 1.03-1.07, P < 0.001) and tramadol 100 mg (OR: 1.07, 95% CI: 1.04-1.11, P < 0.001). Postmicturition dribble annoyed 12.8% of those who received 50 mg tramadol and 33.6% of those who received 100 mg tramadol (P < 0.001). Weak scanty ejaculation was the main complaint in 7.2% versus 21.6% of those using 50 and 100 mg tramadol, respectively (P = 0.002). Two patients discontinued tramadol 100 mg due to side-effects. CONCLUSION Tramadol hydrochloride exhibits a significant dose-related efficacy and side-effects over placebo for treatment of PE.

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BACKGROUND Extensive studies have confirmed the efficacy of taxanes in combination with anthracycline-based chemotherapy on breast cancer. However, few studies have assessed the efficacy of weekly taxane-anthracycline regimens on locally advanced breast cancer. This study was to compare the efficacy and safety of a weekly taxane-anthracycline regimen with those of tri-weekly anthracycline-based regimen in patients with locally advanced breast cancer. METHODS Patients with locally advanced breast cancer were randomized to receive 4-6 cycles of neoadjuvant chemotherapy with tri-weekly 5-fluorouracil-epirubicin-cyclophosphamide (FEC) regimen or weekly paclitaxel-epirubicin (PE) regimen. The primary endpoint was the pathologic complete response (pCR) rate. Other endpoints included the clinical tumor response, breast-conserving surgery rate, and adverse events. RESULTS Between March 2010 and September 2013, 293 patients were randomized to the FEC (n = 151) and PE (n = 142) arms. The overall clinical response rate was significantly higher in the PE arm than in the FEC arm (76.06% vs. 59.95%, P = 0.001). Consistently, the post-chemotherapy pathologic T and N stages were significantly lower in the PE arm than in the FEC arm (P < 0.001). However, the pCR rate was similar in the two arms (10.61% vs. 12.31%, P = 0.665). Overall, 36 (27.27%) patients in the FEC arm and 6 (35.28%) in the PE arm were qualified for breast-conserving surgery. Most adverse events were comparable in both arms, with more severe neutropenia in the PE arm than in the FEC arm (11.97% vs. 5.96%, P = 0.031). CONCLUSIONS In patients with locally advanced breast cancer, weekly PE was not superior to FEC in terms of pCR. However, weekly PE has a higher response rate and superior down-staging effects. On this account, the PE regimen may be considered an alternative option for locally advanced breast cancer. Long-term follow-up data are needed to confirm the efficacy of this regimen on locally advanced breast cancer. Trial registration Chinese clinical trial registry, ChiCTR-TRC-10001043, September 21, 2014.

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Objectives The purpose of this study is to evaluate the effects of a tailor-made, non-technical skills seminar on medical student's behaviour, attitudes, and performance during simulated patient treatment. Methods Seventy-seven students were randomized to either a non-technical skills seminar (NTS group, n=43) or a medical seminar (control group, n=34). The human patient simulation was used as an evaluation tool. Before the seminars, all students performed the same simulated emergency scenario to provide baseline measurements. After the seminars, all students were exposed to a second scenario, and behavioural markers for evaluating their non-technical skills were rated. Furthermore, teamwork-relevant attitudes were measured before and after the scenarios, and perceived stress was measured following each simulation. All simulations were also evaluated for various medical endpoints. Results Non-technical skills concerning situation awareness (p<.01, r=0.5) and teamwork (p<.01, r=0.45) improved from simulation I to II in the NTS group. Decision making improved in both groups (NTS: p<.01, r=0.39; control: p<.01, r=0.46). The attitude 'handling errors' improved significantly in the NTS group (p<.05, r=0.34). Perceived stress decreased from simulation I to II in both groups. Medical endpoints and patients´ outcome did not differ significantly between the groups in simulation II. Conclusions This study highlights the effectiveness of a single brief seminar on non-technical skills to improve student's non-technical skills. In a next step, to improve student's handling of emergencies and patient outcomes, non-technical skills seminars should be accompanied by exercises and more broadly embedded in the medical school curriculum.

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BACKGROUND Orgasmic disorder can create a feeling of deprivation and failure and provide mental problems, incompatibility and marital discord. This study aimed to compare the effects of Elaeagnus angustifolia flower extract and sildenafil citrate on female orgasmic disorder in women in 2013. METHODS In this randomized clinical trial, 125 women between 18-40 years old who suffered from orgasmic disorder were divided into three E. angustifolia, sildenafil citrate and control groups. The data were gathered using Female Sexual Function Index and through measurement of TSH and prolactin. The first intervention group had to consume 4.5 gr E. angustifolia extract in two divided doses for 35 days and the second one had to use 50 mg sildenafil citrate tablets for 4 weeks one hour before their sexual relationship. However, the control group had to consume the placebo. The data were analyzed using paired t-test, one-way ANOVA, and Bonferroni posthoc test and p<0.05 was considered significant. RESULTS The frequency of orgasmic disorder before the intervention was 41.5%, 40.5%, and 57.1% in E. angustifolia, sildenafil citrate, and control groups, respectively (p=0.23). However, these measures were respectively 29.3%, 16.7%, and 50% after the intervention (p=0.004). A significant difference between the two groups regarding sexual satisfaction after the intervention (p=0.003) compared to the beginning of the study (p=0.356). Besides, the highest reduction of changes after the intervention (58.82%) was observed in the sildenafil citrate group. CONCLUSION Both E. angustifolia extract and sildenafil citrate were effective in reduction of the frequency of orgasmic disorder in women.

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BACKGROUND Hypnotherapy has been reported as being beneficial in the treatment of irritable bowel syndrome (IBS). We aimed to test the hypothesis that patients with IBS treated 'holistically' by hypnosis (i.e. by combined psychological and physiological symptom imagery) would have greater improvement in their IBS symptoms than patients treated by hypnosis using standard 'gut-directed' hypnotherapy, and both would be superior to simple relaxation therapy. METHODS Patients ( n  = 51) with Rome II criteria were randomised to 'individualised' (holistic) hypnotherapy, standard 'gut-directed' hypnotherapy or relaxation therapy for a period of 11 weeks with two follow-up assessments at 2 weeks and at 3 months after the completion of the trial. The primary outcome was bowel symptom severity scale (BSSS). RESULTS All the participants in this study improved their IBS symptoms (pain, bloating, constipation and diarrhoea) and physical functioning at the end of the treatment from baseline, but this was not significantly different across the treatment arms. CONCLUSION Neither 'individualised' nor 'gut-directed' hypnotherapy is superior to relaxation therapy in IBS.

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BACKGROUND Advanced cardiovascular magnetic resonance (CMR) acquisitions often require long scan durations that necessitate respiratory navigator gating. The tradeoff of navigator gating is reduced scan efficiency, particularly when the patient's breathing patterns are inconsistent, as is commonly seen in children. We hypothesized that engaging pediatric participants with a navigator-controlled videogame to help control breathing patterns would improve navigator efficiency and maintain image quality. METHODS We developed custom software that processed the Siemens respiratory navigator image in real-time during CMR and represented diaphragm position using a cartoon avatar, which was projected to the participant in the scanner as visual feedback. The game incentivized children to breathe such that the avatar was positioned within the navigator acceptance window (±3 mm) throughout image acquisition. Using a 3T Siemens Tim Trio, 50 children (Age: 14 ± 3 years, 48 % female) with no significant past medical history underwent a respiratory navigator-gated 2D spiral cine displacement encoding with stimulated echoes (DENSE) CMR acquisition first with no feedback (NF) and then with the feedback game (FG). Thirty of the 50 children were randomized to undergo extensive off-scanner training with the FG using a MRI simulator, or no off-scanner training. Navigator efficiency, signal-to-noise ratio (SNR), and global left-ventricular strains were determined for each participant and compared. RESULTS Using the FG improved average navigator efficiency from 33 ± 15 to 58 ± 13 % (p < 0.001) and improved SNR by 5 % (p = 0.01) compared to acquisitions with NF. There was no difference in navigator efficiency (p = 0.90) or SNR (p = 0.77) between untrained and trained participants for FG acquisitions. Circumferential and radial strains derived from FG acquisitions were slightly reduced compared to NF acquisitions (-16 ± 2 % vs -17 ± 2 %, p < 0.001; 40 ± 10 % vs 44 ± 11 %, p = 0.005, respectively). There were no differences in longitudinal strain (p = 0.38). CONCLUSIONS Use of a respiratory navigator feedback game during navigator-gated CMR improved navigator efficiency in children from 33 to 58 %. This improved efficiency was associated with a 5 % increase in SNR for spiral cine DENSE. Extensive off-scanner training was not required to achieve the improvement in navigator efficiency.

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BACKGROUND Central retinal vein occlusion (CRVO), is the second-most common disorder after diabetic retinopathy that threatens the vision related to retinal vessels. One of the main reasons of vision loss is CRVO in acute and chronic forms. OBJECTIVE The aim of this study was to investigate the response to intravitreal injection of triamcinolone, bevacizumab, and a combined form in patients with CRVO. METHODS This study was a double-blinded randomized clinical trial conducted on patients with CRVO who were referred to the ophthalmology clinic of Urmia Imam Khomeini Hospital from May 2015 to May 2016. In total, ninety patients were divided into three groups using random numbers table. The first group received intravitreal triamcinolone acetonide (IVT) for treatment of macular edema due to CRVO, the second group received intravitreal bevacizumab (IVB) and the third group received a combination of IVT and IVB. The best corrected visual acuity (BCVA) and central macular thickness (CMT) were recorded and analyzed using optical coherence tomography system. RESULTS In this study a total of 90 eyes were studied, 41 case (45.55%) were male and 49 cases (54.44%) were female. The mean age of patients was 68.41±8.32 years. The mean score of final visual acuity was 0.293±0.11 in the IVT group, 0.25±0.10 in the IVB group and 0.48±0.15 in the IVB+IVT group. The differences between groups considering final visual acuity was significant (p<0.001). The mean thickness of final macular was 383.33±97.70 micrometer in IVT group, 386.33±136.79 micrometers in IVB group and 307.33±110.79 micrometers in IVT+IVB group which were significant (p=0.014). CONCLUSION Using a combination of bevacizumab and triamcinolone in the treatment of central retinal vein occlusion compared with using each of them separately, had a better result and can be used as a solution in this disease. TRIAL REGISTRATION The trial was registered at the Thai Registry of Clinical Trials (http://www.clinicaltrials.in.th) with the TCTR ID: TCTR20170612005. FUNDING The authors received no financial support for the research, authorship, and/or publication of this article.

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PURPOSE Dinutuximab (Unituxin™; ch14.18), a monoclonal antibody against disialoganglioside, improved survival as part of post-consolidation therapy for high-risk neuroblastoma. United Therapeutics Corporation (UTC) assumed ch14.18 production from the National Cancer Institute (NCI); this study evaluates pharmacokinetic comparability, safety, and tolerability of UTC and NCI products. METHODS In this randomized, two-sequence crossover study, 28 patients aged ≤8 years with high-risk neuroblastoma received equivalent ch14.18-UTC or ch14.18-NCI doses. Despite comparable protein content, nominal doses differed: 17.5 mg/m(2)/day (ch14.18-UTC) and 25 mg/m(2)/day (ch14.18-NCI). Patients received one product during therapy cycles 1 and 2, the other during cycles 3-5. Ch14.18 pharmacokinetic profile characterization used population modeling (NONMEM(®) version 7.2). A two-compartment model with first-order distribution and elimination processes described pharmacokinetic data. Estimated product parameters were normalized to UTC nominal dose. For pharmacokinetic comparability, the final model was used to estimate exposure ratios (UTC/NCI) and associated 90 % confidence intervals (CIs) for area under the curve from time zero to infinity (AUCinf) and maximum concentration (C max). All comparisons were based on a standardized single-dose regimen (17.5 mg/m(2) over 10 h). RESULTS Final-model pharmacokinetic parameters were similar to previously published ch14.18-NCI parameters and comparable for UTC and NCI products. Products' systemic exposures were comparable, with 90 % CIs around ratios for AUCinf (0.96; 90 % CI 0.88-1.04) and C max (1.04; 90 % CI 0.98-1.11) within standard bioequivalence bounds (90 % CI 0.80-1.25). Products' adverse events were similar and consistent with those previously reported. CONCLUSIONS Equivalent actual ch14.18-UTC and ch14.18-NCI doses produced comparable exposures, with no notable safety or tolerability differences.

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INTRODUCTION Patients of lung volume reduction surgery (LVRS) having an ASA status III or more are likely to be further downgraded by surgery to critical levels of pulmonary function. AIM To compare the efficacy of thoracic epidural block with (0.125%) bupivacaine, fentanyl combination and (0.125%) bupivacaine, fentanyl combination with adjunctive intravenous magnesium infusion for the relief of postoperative pain in patients undergoing LVRS. METHODS Patients were operated under general anesthesia. Thirty minutes before the anticipated completion of skin closure in both groups, (Group A and Group B) 7 ml of (0.125%) bupivacaine calculated as 1.5 ml/thoracic segment space for achieving analgesia in dermatomes of T4, T5, T6, T7, and T8 segments, along with fentanyl 50 μg (0.5 ml), was administered through the catheter, activating the epidural block, and the time was noted. Thereafter, in patients of Group A, magnesium sulfate injection 30 mg/kg i.v. bolus was followed by infusion of magnesium sulfate at 10 mg/kg/hr and continued up to 24 hours. Group B was treated as control. RESULTS AND ANALYSIS A significant increase in the mean and maximum duration of analgesia in Group A in comparison with Group B (P<0.05) was observed. Total epidural dose of fentanyl and bupivacaine required in Group A was significantly lower in comparison with Group B in 24 hours. DISCUSSION Requirement of total doses of local anesthetics along with opioids could be minimized by magnesium infusion; therefore, the further downgradation of patients of LVRS may be prevented. CONCLUSION Intravenous magnesium can prolong opioid-induced analgesia while minimizing nausea, pruritus, and somnolence.

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BACKGROUND Heart transplant surgeries using cardiopulmonary bypass (CPB) typically requires mechanical ventilation in intensive care units (ICU) in post-operation period. Ultra fast-track extubation (UFE) have been described in patients undergoing various cardiac surgeries. AIM To determine the possibility of ultra-fast-track extubation instead of late extubation in post heart transplant patients. MATERIALS AND METHODS Patients randomly assigned into two groups; Ultra fast-track extubation (UFE) group was defined by extubation inside operating room right after surgery. Late extubation group was defined by patients who were not extubated in operating room and transferred to post operation cardiac care unit (CCU) to extubate. RESULTS The mean cardiopulmonary bypass time was 136.8 ± 25.7 minutes in ultra-fast extubation and 145.3 ± 29.8 minutes in late extubation patients (P > 0.05). Mechanical ventilation duration (days) was 0 days in ultra-fast and 2.31 ± 1.8 days in late extubation. Length of ICU stay was significantly higher in late extubation group (4.2 ± 1.2 days) than the UFE group (1.72 ± 1.5 days) (P = 0.02). In survival analysis there was no significant difference between ultra-fast and late extubation groups (Log-rank test, P = 0.9). CONCLUSIONS Patients undergoing cardiac transplant could be managed with "ultra-fast-track extubation", without increased morbidity and mortality.

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OBJECTIVE To model the cost-effectiveness impact of routine use of an antimicrobial chlorhexidine gluconate-containing securement dressing compared to non-antimicrobial transparent dressings for the protection of central vascular lines in intensive care unit patients. DESIGN This study uses a novel health economic model to estimate the cost-effectiveness of using the chlorhexidine gluconate dressing versus transparent dressings in a French intensive care unit scenario. The 30-day time non-homogeneous markovian model comprises eight health states. The probabilities of events derive from a multicentre (12 French intensive care units) randomized controlled trial. 1,000 Monte Carlo simulations of 1,000 patients per dressing strategy are used for probabilistic sensitivity analysis and 95% confidence intervals calculations. The outcome is the number of catheter-related bloodstream infections avoided. Costs of intensive care unit stay are based on a recent French multicentre study and the cost-effectiveness criterion is the cost per catheter-related bloodstream infections avoided. The incremental net monetary benefit per patient is also estimated. PATIENTS 1000 patients per group simulated based on the source randomized controlled trial involving 1,879 adults expected to require intravascular catheterization for 48 hours. INTERVENTION Chlorhexidine Gluconate-containing securement dressing compared to non-antimicrobial transparent dressings. RESULTS The chlorhexidine gluconate dressing prevents 11.8 infections /1,000 patients (95% confidence interval: [3.85; 19.64]) with a number needed to treat of 85 patients. The mean cost difference per patient of €141 is not statistically significant (95% confidence interval: [€-975; €1,258]). The incremental cost-effectiveness ratio is of €12,046 per catheter-related bloodstream infection prevented, and the incremental net monetary benefit per patient is of €344.88. CONCLUSIONS According to the base case scenario, the chlorhexidine gluconate dressing is more cost-effective than the reference dressing. TRIAL REGISTRATION This model is based on the data from the RCT registered with www.clinicaltrials.gov (NCT01189682).

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BACKGROUND: Hypotensive epidural anaesthesia (HEA) combines a high epidural anaesthesia, performing a sympathetic blockade, with low-dose iv-infusion of epinephrine to stabilize circulation in the conscious patient. Mean artery blood pressure is reduced to 45-50 mmHg and hereby a reduced blood loss. In this study we have combined HEA with preoperative acute normovolaemic hemodilution (ANH) in attempt to further reduce the blood loss and need for blood transfusion in total knee arthroplasty surgery (TKR). METHODS: Twenty-eight patients scheduled for TKR are randomised to ANH or no hemodilution (non-ANH). Both groups are anaesthetized with HEA. ANH is established with predonation of 20 % of the total blood volume, and replacement with equal volume of HAES 6 %. Blood re-transfusion is completed within 6 h. RESULTS: A mean of 877 ml blood was predonated (19.7 % of the total blood volume). Blood loss was, except from the intraoperative loss, significantly higher in ANH group. The total loss was 1306 mL (ANH) vs. 1026 mL (non-ANH), p < 0.05. Except from the first hour postoperatively, hematocrit was identical in between groups postoperatively. The amount of blood transfusion was identical 386 ml (ANH) vs. 343 ml (non-ANH) (ns). 50 % went through surgery without receiving blood (ANH) vs. 58 % (non-ANH). No renal, neurological or cardiopulmonary complications were registered. CONCLUSIONS: These data suggest no benefits in combining HEA and ANH in TKR surgery. Probably because of the reduced viscosity of the blood after ANH, there is an increased postoperative blood loss. The need for homologous blood transfusion was identical.

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BACKGROUND A cluster randomised trial was conducted to determine the effectiveness of locally adapted practice guidelines and education about paediatric asthma management, delivered to general practitioners (GPs) in small group interactive workshops. METHODS Twenty-nine practices were randomly allocated to one of three study arms. Australian asthma management guidelines were adapted to accommodate characteristics of the local area. GPs in the intervention arm (Group 1, n = 18 GPs) participated in a small group based education program and were provided with the adapted guidelines. One control arm (Group 2, n = 18 GPs) received only the adapted guidelines, while the other control arm (Group 3, n = 15 GPs) received an unrelated education intervention. GPs' knowledge, attitudes and management of paediatric asthma was assessed. RESULTS Post intervention, intervention arm GPs were no more likely to provide a written asthma action plan, but were better able to assess the severity of asthma attack (Group 1vs Group 2 p = 0.05 and Group 1 vs Group 3 p = 0.01), better able to identify patients at high risk of severe attack (Group 1vs Group 3 p = 0.06), and tended to score higher on the asthma knowledge questionnaire (Group 1 vs Group 2 p = 0.06 and Group 1 vs Group 3 p = 0.2). Most intervention arm GPs felt more confident than control GPs to manage acute asthma attack and ongoing management of infrequent episodic asthma. CONCLUSION Using interactive small group workshops to disseminate locally adapted guidelines was associated with improvement in GP's knowledge and confidence to manage asthma, but did not change GP's self-reported provision of written action plans.

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BACKGROUND Rocuronium has been well known to produce withdrawal response in 50-80% patients when administered intravenously. Several drugs are administered prior injection of rocuronium to prevent the withdrawal response. We compared the preventive effect of lidocaine, ketamine, and remifentanil on the withdrawal response of rocuronium. METHODS A total of 120 patients undergoing various elective surgeries were enrolled. Patients were allocated into 4 groups according to the pretreatment drugs (Group N, normal saline; Groups L, lidocaine 40 mg; Group K, ketamine 0.5 mg/kg; Group R, remifentanil 1 µg/kg). Patients received drugs prepared by dilution to 3 ml volume before injection of rocuronium. Withdrawal responses after injection of rocuronium were graded on a 4-point scale. Hemodynamic changes were observed before and after administration of pretreatment drugs and after endotracheal intubation. RESULTS Incidence of withdrawal response was significantly lower in group L (20%), group K (30%), and group R (0%), than group N (87%). Severe withdrawal response was observed in 5 of the 30 patients (17%) in group L, and in 9 of the 30 patients (30%) in group K. There was no severe withdrawal response in group R. Mean blood pressure and heart rate were significantly decreased in group R compared to other groups. CONCLUSIONS It seems that remifentanil (1 µg/kg intravenously) was the strongest and most effective in prevention of withdrawal response after rocuronium injection among the 3 drugs.

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AIMS To compare the efficacy and safety of new insulin glargine 300 U/ml (Gla-300) with insulin glargine 100 U/ml (Gla-100) over 12 months of treatment in people with type 2 diabetes using basal insulin and oral antihyperglycaemic drugs (OADs). METHODS EDITION 2 (NCT01499095) was a randomized, 6-month, multicentre, open-label, two-arm, phase IIIa study investigating once-daily Gla-300 versus Gla-100, plus OADs (excluding sulphonylureas), with a 6-month safety extension. RESULTS Similar numbers of participants in each group completed 12 months of treatment [Gla-300, 315 participants (78%); Gla-100, 314 participants (77%)]. The reduction in glycated haemoglobin was maintained for 12 months with both treatments: least squares (LS) mean (standard error) change from baseline -0.55 (0.06)% for Gla-300 and -0.50 (0.06)% for Gla-100; LS mean difference -0.06 [95% confidence interval (CI) -0.22 to 0.10)%]. A significant relative reduction of 37% in the annualized rate of nocturnal confirmed [≤3.9 mmol/l (≤70 mg/dl)] or severe hypoglycaemia was observed with Gla-300 compared with Gla-100: rate ratio 0.63 [(95% CI 0.42-0.96); p = 0.031], and fewer participants experienced ≥1 event [relative risk 0.84 (95% CI 0.71-0.99)]. Severe hypoglycaemia was infrequent. Weight gain was significantly lower with Gla-300 than Gla-100 [LS mean difference -0.7 (95% CI -1.3 to -0.2) kg; p = 0.009]. Both treatments were well tolerated with a similar pattern of adverse events (incidence of 69 and 60% in the Gla-300 and Gla-100 groups). CONCLUSIONS In people with type 2 diabetes treated with Gla-300 or Gla-100, and non-sulphonylurea OADs, glycaemic control was sustained over 12 months, with less nocturnal hypoglycaemia in the Gla-300 group.

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PURPOSE Enhanced recovery protocols are being implemented into the standard of care in surgical practice. This study aimed to insert a steadfast set of elements into the perioperative care pathway to establish an improved recovery program for colorectal cancer patients. METHODS Seventy patients planned for elective laparoscopic colorectal resection were randomized into 2 groups: conventional recovery group (n = 35) and enhanced recovery group (n = 35). The primary outcome was the length of hospital stay. Secondary outcomes included the times of removal of nasogastric tubes (NGTs), successful enteral feeding, and removal of drains, postoperative complications, intra-hospital mortality, and rate of readmission. RESULTS The mean postoperative hospital stay was 4.49 ± 0.85 days vs. 13.31 ± 6.9 days (P < 0.001), the mean time of removal of NGTs was 0.77 ± 1.031 days vs. 3.26 ± 2.737 days (P < 0.001), the mean time of successful enteral feeding was 1.89 ± 1.13 days vs. 5.46 ± 1.67 days (P < 0.001), and the mean time for removal of intra-abdominal drains was 2.94 ± 1.056 days vs. 9.06 ± 3.757 days (P < 0.001) for the enhanced and the conventional groups, respectively. Complications were significantly lower among patients in the enhanced group (25.7% vs. 65.7%) (P = 0.001). The rates of readmission were similar in the 2 groups. CONCLUSION Applying definite evidence-based elements to the colorectal rehabilitation program significantly boosts the recovery pathway with favorable outcomes, including faster recovery of gastrointestinal tract functions, lower morbidities, and eventually earlier discharge from the hospital.

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BACKGROUND The indwelling urinary catheter is an essential part of modern medical care. Unfortunately, when poorly managed, the indwelling catheter may present a hazard to the very patients it is designed to protect. Catheter-associated urinary tract infection (CAUTI) is the most common nosocomial infection in hospitals and nursing homes. AIMS AND OBJECTIVES The primary objective was to study the effect of amikacin sulfate bladder wash on CAUTI in neurosurgical patients. The other objectives were to study the various organisms causing CAUTI and their antibiotic sensitivity and resistance pattern. MATERIALS AND METHODS This was a prospective randomized controlled study performed on 60 patients who met the inclusion criteria at the neurosurgical intensive care of the All India Institute of Medical Sciences between June and December 2006. The patients were randomized into two groups - one was the trial group which received amikacin bladder wash, while the other was the control group that did not receive any bladder wash. RESULTS Forty percent of the subjects in the control group developed CAUTI, while none of the subjects in study group developed CAUTI. (Fisher's exact test, P value < 0.001) Pseudomonas aeruginosa (51%) was the commonest pathogen. CONCLUSIONS Amikacin sulfate bladder wash was effective in preventing CAUTI. It can thus decrease the antibiotic usage thereby preventing the emergence of antibiotic resistance.

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BACKGROUND/OBJECTIVES Certain populations with a large proportion of indigenous American (IA) genetic ancestry may be evolutionarily adapted to traditional diets high in legumes and complex carbohydrates, and may have a detrimental metabolic response to US diets high in refined carbohydrates and added sugars. We tested whether IA ancestry modified the metabolic response to a US versus traditional Mexican diet in a controlled dietary intervention. SUBJECTS/METHODS First and second generation Mexican immigrant women (n=53) completed a randomized crossover feeding trial testing the effects of a US versus traditional Mexican diet. The metabolic response to the diets was measured by fasting serum concentrations of glucose, insulin, insulin-like growth factor-1 (IGF-1), IGF-binding protein-3 (IGFBP-3), adiponectin, C-reactive protein, interleukin-6 and computed homeostasis model assessment for insulin resistance (HOMA IR ). Blood collected at baseline was used for genotyping, and estimation of African, European and IA ancestries with the use of 214 ancestry informative markers. RESULTS The genetic ancestral background was 56% IA, 38% European and 6% African. Women in the highest IA ancestry tertile (>62%) were shorter in height, less educated and less acculturated to the US lifestyle, and tended to have higher waist-to-hip ratio compared with women in the middle and lowest IA ancestry tertiles, respectively. Compared with the US diet, the traditional Mexican diet tended to reduce glucose, insulin, IGF-1, IGFBP-3 and HOMA IR among women in the middle IA ancestry group (IA ancestry ⩽45-62%), whereas having no effect on biomarkers related to inflammation. CONCLUSIONS We observed modest interactions between IA ancestry and the metabolic response to a US versus traditional Mexican diet among Mexican immigrant women.

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PURPOSE Patients with glaucoma who do not keep their follow-up eye care appointments are at risk for developing more severe ocular disease. The primary aim of the current study was to evaluate whether the use of a patient navigator altered adherence to follow-up eye care appointments in community-versus office-based settings. PATIENTS AND METHODS Patients diagnosed with a glaucoma-related condition following a comprehensive eye examination at 43 community sites in Philadelphia, PA, USA, were enrolled in this prospective, randomized, controlled trial. Patients were randomized into three groups for a 1-year period: Group 1 (G1) received follow-up eye care in a community-based setting with assistance from a patient navigator; Group 2 (G2) received follow-up eye care in an office-based setting with assistance from a patient navigator; and Group 3 (G3) received follow-up eye care in an office-based setting without a patient navigator (usual care). Adherence rates were compared among these three groups using a chi-squared test at a significance level of 0.05. RESULTS A total of 155 patients with glaucoma-related diagnoses were enrolled. The mean age (±standard deviation) was 71.2 (±10.0) years. Patients were predominantly female (65.8%, n=102/155) and African-American (71.6%, n=111/155). The mean (±standard deviation) number of follow-up visits during the 1-year study period was 1.3 (±1.3) for G1, 1.6 (±1.3) for G2, and 1.3 (±1.1) for G3 (P=0.48). Appointment adherence, defined as attendance of ≥1 follow-up visit, was 69.8% (n=37/53) for G1, 82.5% (n=47/57) for G2, and 73.3% (n=33/45) for G3, (P=0.28). Sub-analysis of adherence rates for patients who attended ≥2 follow-up visits were 91.3% (n=21/23) for G1, 74.3% (n=26/35) for G2, and 66.7% (n=18/27) for G3, (P=0.11). CONCLUSION Help from a patient navigator did not increase the likelihood of keeping ≥1 follow-up appointment in an office-based setting. Adherence rates for follow-up appointments reached close to 70% or above in a self-selected patient population.

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OBJECTIVES Intranasal corticosteroids (INCs) are the most effective modality for treating allergic rhinitis and their sensory attributes are important in patient compliance. This study aimed to compare the sensory attributes (scent, immediate taste, aftertaste, run down to throat, nose run off, soothing feel, nasal irritation, and urge to sneeze) and immediate response to the new intranasal steroid, ciclesonide (CIC), with fluticasone propionate (FLP) in allergic rhinitis. MATERIALS AND METHODS A randomized, double blind, single dose, crossover study was done with 74 patients presenting with acute allergic rhinitis. Eligible subjects were randomized in 1:1 ratio to one of the two treatment sequences - CIC followed by FLP or vice versa. Sensory attributes were assessed using a questionnaire to score each item on a seven-point Likert scale, immediately and 2 min after dosing. Total nasal symptom score (TNSS) was calculated to evaluate immediate efficacy 10 min after first drug administration. Overall preference was recorded 10 min after the second drug administration. Patients were queried about treatment emergent adverse events following study drug administration and also 24 h later over the phone. RESULTS Patients (58% males; pooled median age 32 years [Interquartile range, IQR, 25-41]; pooled median symptom duration 24 months [IQR 12-72]) preferred FLP over CIC nasal spray overall (55.41% vs. 25.68%, P = 0.007) and also with respect to attributes of scent, soothing feel, and nasal irritation. There was no statistically significant difference in immediate efficacy. Two patients reported mild headache following CIC first, while three felt mild headache, one dizziness, and one nasal congestion following FLP first administration. There were no delayed adverse events. CONCLUSIONS There was no difference in immediate outcome following use of either of the two INCs. FLP was preferred over CIC with respect to scent, soothing feel and nasal irritation, and also overall. There were no significant adverse events.

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AIMS To assess the prognostic importance of high-sensitive C reactive protein (hsCRP) in patients with mild to moderate aortic valve stenosis during placebo or simvastatin/ezetimibe treatment in Simvastatin and Ezetimibe in Aortic Stenosis (SEAS). METHODS AND RESULTS In 1620 SEAS patients, we measured lipids and hsCRP at baseline and after 1 year of treatment and registered during 4 years of follow-up major cardiovascular events (MCE) composed of ischaemic cardiovascular events (ICE) and aortic valve-related events (AVE). Simvastatin/ezetimibe reduced low-density lipoprotein cholesterol (3.49 (2.94 to 4.15) to 1.32 (1.02 to 1.69) vs 3.46 (2.92 to 4.08) to 3.34 (2.81 to 3.92) mmol/L) and hsCRP (2.1 (0.9 to 4.1) to 1.2 (0.6 to 2.4) vs 2.2 (0.9 to 4.9) to 1.8 (0.85 to 4.35) mg/L, all p<0.05) during the first year of treatment. In multivariable Cox regression analysis adjusting for traditional risk factors and baseline hsCRP, ICE was associated with a 1-year increase of hsCRP (HR=1.19 (95% CI 1.12 to 1.25), p<0.001) but not with active treatment (HRTreatment=0.86 (0.67 to 1.13), p=0.28). Patients in the top quartile of baseline hsCRP versus the rest were associated with a higher risk of MCE (HR=1.34(1.09 to 1.64), p=0.02). The prognostic benefit of reduction in hsCRP after 1 year was significantly larger (p<0.01 for interaction) in patients with high versus low baseline hsCRP; hence, a reduction in hsCRP abolished the difference in incidence of MCE between high versus low baseline hsCRP in patients with reduced hsCRP (31.1 vs 31.9%, NS) in contrast to patients with increased hsCRP. CONCLUSIONS The treatment-associated reduction in ICE was in part related to a reduction in hsCRP but not in lipids. hsCRP reduction was associated with less MCE, especially in patients with high baseline hsCRP. TRIAL REGISTRATION NCT00092677.

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INTRODUCTION This study is aimed at evaluating root canal transportation in the mesiobuccal canal of mandibular first molars prepared with One Shape, Reciproc, and M-One nickel titanium (NiTi) single-file rotary systems using cone beam computed tomography (CBCT). MATERIALS AND METHODS In this ex vivo study, CBCT scans of 45 extracted human mandibular first molars with 20-40° curvature were obtained. The teeth were randomly divided into three groups ( n =15) for preparation of the mesiobuccal canal with One Shape, Reciproc, and M-One rotary systems according to the manufacturers' instructions. CBCT scans were obtained again after canal preparation. Changes caused by preparation in the coronal, middle, and apical thirds were determined on CBCT scans and analyzed using the Kruskal-Wallis test at P ≤ 0.05 level of significance. RESULTS No significant difference was noted in the amount of canal transportation among the three groups ( P > 0.05). M-One caused greater transportation in the apical third compared with Reciproc and One Shape, and One Shape caused greater transportation in the coronal third compared with other groups, although its magnitude was less than 0.3 mm. CONCLUSION Reciproc, One Shape, and M-One are not significantly different in terms of canal transportation.

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BACKGROUND Myocardial infarction is the leading cause of death in fire fighters and has been linked with exposure to air pollution and fire suppression duties. We therefore investigated the effects of wood smoke exposure on vascular vasomotor and fibrinolytic function, and thrombus formation in healthy fire fighters. METHODS In a double-blind randomized cross-over study, 16 healthy male fire fighters were exposed to wood smoke (~1 mg/m³ particulate matter concentration) or filtered air for one hour during intermittent exercise. Arterial pressure and stiffness were measured before and immediately after exposure, and forearm blood flow was measured during intra-brachial infusion of endothelium-dependent and -independent vasodilators 4-6 hours after exposure. Thrombus formation was assessed using the ex vivo Badimon chamber at 2 hours, and platelet activation was measured using flow cytometry for up to 24 hours after the exposure. RESULTS Compared to filtered air, exposure to wood smoke increased blood carboxyhaemoglobin concentrations (1.3% versus 0.8%; P < 0.001), but had no effect on arterial pressure, augmentation index or pulse wave velocity (P > 0.05 for all). Whilst there was a dose-dependent increase in forearm blood flow with each vasodilator (P < 0.01 for all), there were no differences in blood flow responses to acetylcholine, sodium nitroprusside or verapamil between exposures (P > 0.05 for all). Following exposure to wood smoke, vasodilatation to bradykinin increased (P = 0.003), but there was no effect on bradykinin-induced tissue-plasminogen activator release, thrombus area or markers of platelet activation (P > 0.05 for all). CONCLUSIONS Wood smoke exposure does not impair vascular vasomotor or fibrinolytic function, or increase thrombus formation in fire fighters. Acute cardiovascular events following fire suppression may be precipitated by exposure to other air pollutants or through other mechanisms, such as strenuous physical exertion and dehydration.

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BACKGROUND Dexmedetomidine is a useful sedative drug with various uses. We designed this study to investigate the clinical effects and complications of different loading doses, 0.5 and 1.0 µg/kg. METHODS Forty six patients, of American Society of Anesthesiologists physical status I and II, who required elective and emergency operation under spinal anesthesia were randomly assigned to group L or group H. Group L received a loading dose of 0.5 µg/kg for 10 minutes while group H received 1.0 µg/kg. Bispectral index (BIS), systolic blood pressure, heart rate, and Ramsay score were recorded at T0 (before loading), TL (just after loading) and T10, 20, 30 (10, 20, 30 minutes after TL). Complications, drug use, lowest BIS and time to reach BIS 80 after termination of dexmedetomidine were recorded during this study. RESULTS In group H, BIS value decreased significantly after TL compared to the baseline (T0), while in group L after T10. Between two groups, BIS values showed a significant differences only at T10, BIS of group H was lower than that of group L. Ramsay score showed no significant differences except in TL; the score of group L was significantly lower than that of group H. Other vital signs and complications showed a minimal differences between two groups. CONCLUSIONS Higher loading dose (1.0 µg/kg) of dexmedetomidine can lead to faster sedation without any severe complications.

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BACKGROUND About 10-15% patients who take statins experience skeletal muscle problems. Red yeast rice has a good safety profile could provide a compromise therapeutic strategy. Therefore, the aim of this study was to evaluate the effects of red yeast rice, when compared to simvastatin, on the muscle fatigue symptom and the serum lipid level in dyslipidemic patients with low to moderate cardiovascular risk. METHODS A total of 60 dyslipidemic patients with low to moderate cardiovascular risk were recruited and randomly assigned to receive either simvastatin (n = 33) or red yeast rice (n = 27) for 4 weeks. The muscle fatigue score, the physical activity, the serum lipid profile and the safety profile were then evaluated. RESULTS At the end of study, the fatigue score was significantly increased in patients treated with simvastatin, whereas no significant change was observed in patients receiving red yeast rice. In addition, the physical activity level was significantly decreased in patients from simvastatin group when compared to those from red yeast rice group. Similar lipid-lowering effects were observed in two groups. The safety profile was not affected after the treatments. CONCLUSIONS Among dyslipidemic patients with low to moderate cardiovascular risk, red yeast rice induced less fatigue side effect and exerted comparable lipid-lowering effects when compared to simvastatin in this pilot primary prevention study. TRIAL REGISTRATION NCT01686451 .

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OBJECTIVE This study was conducted to compare the effect of low-dose isotretinoin with its conventional dose in patients with moderate and severe acne. METHODS This was a clinical trial conducted on 60 male and female patients with moderate and severe acne vulgaris. The patients were divided into two treatment groups: 0.5 mg/kg/day isotretinoin capsule and low-dose isotretinoin capsule (0.25 mg/kg/day). Patients in both groups received 6-month treatment. At the end of the 6 th month and 12 th month (6 months after the end of the treatment), they were examined again, and their improvement was determined and compared. FINDINGS The average severity of acne in the two treatment groups did not differ significantly within any of the study periods. The most common side effects were nose dryness in the low-dose group (17%) and hair thinning and loss in the conventional-dose group (33.2%), although all the patients had dry lips. CONCLUSION According to the same severity of the acne in two groups in different study periods, as well as fewer side effects and more patients' satisfaction, the low-dose isotretinoin can be considered in the treatment of acne.

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BACKGROUND Cough and sputum are troublesome symptoms in chronic obstructive pulmonary disease (COPD) and are associated with adverse outcomes. The efficacy of aclidinium bromide 400 µg twice daily in patients with stable COPD has been established in two phase III studies (ACCORD COPD I and ATTAIN) and a phase IIIb active-comparator study. This analysis evaluated cough-related symptoms across these studies. METHOD Patients were randomised to placebo, aclidinium 200 µg or 400 µg twice daily in ACCORD (12 weeks) and ATTAIN (24 weeks), or to placebo, aclidinium 400 µg twice daily or tiotropium 18 µg once daily (6-week active-comparator study). Analysed end points included changes from baseline in Evaluating Respiratory Symptoms (E-RS; formerly known as EXAcerbations of Chronic pulmonary disease Tool), total and cough/sputum scores and frequency/severity of morning and night-time cough and sputum symptoms. RESULTS Data for 1792 patients were evaluated. E-RS cough/sputum domain scores were significantly reduced with aclidinium 400 µg versus placebo in ATTAIN (-0.7 vs -0.3, respectively; p<0.01) and the active-comparator study (-0.6 vs -0.2, respectively; p<0.01). In the active-comparator study, significantly greater improvements were observed with aclidinium versus placebo for severity of morning cough (-0.19 vs -0.02; p<0.01) and phlegm (-0.19 vs -0.02; p<0.05). In ACCORD, aclidinium reduced night-time cough frequency (-0.36 vs 0.1 for placebo; p<0.001) and severity (-0.24 vs -0.1 for placebo; p<0.05), and frequency of night-time sputum production (-0.37 vs 0.05 for placebo; p<0.001). CONCLUSIONS Aclidinium 400 µg twice daily improves cough and sputum expectoration versus placebo in stable COPD. TRIAL REGISTRATION NUMBERS NCT00891462; NCT01001494; NCT01462929.

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AIMS AND OBJECTIVES To assess the efficacy of flapless implant surgery on soft-tissue profile and to compare the clinical outcomes of flapless implant therapy on immediate loading (IL) implants to delayed loading (DL) implants. MATERIALS AND METHODS The study sample consisted of 20 patients who were partially edentulous in the anterior maxillary region. They were divided into two groups. In group I (IL) 10 implants were placed and immediately provisionalized and restored with a metal ceramic crown on the 14th day. In group II (DL) 10 implants were placed and loaded after 4 months. Single-piece implants were used for the IL group and two-piece implants were used for the DL group. All soft tissue parameters i.e., modified plaque index (mPI), modified bleeding index (mBI), papillary index (PPI), marginal level of soft tissue (ML) and width of keratinized mucosa (WKM) were recorded at baseline, Day 60, Day 120 and Day 180. RESULTS The success rate in group I was found to be 80%, which was lower than the success rate in group II which was found to be 90%. On comparison, there is no statistically significant difference in success rate between the two study groups. There was no statistically significant difference between the groups over time in parameters like mPI, mBI, ML and WKM. The mean PPI score in group II showed a significant increase from when compared to group I. CONCLUSION The results of this study indicated that flapless implant surgery using either immediately loading implants or DL implants, demonstrate enhancement of implant esthetics.

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BACKGROUND To compare long term effects of two bariatric procedures for Chinese type 2 diabetes mellitus (T2DM) patients with a body mass index (BMI) of 28-35 kg/m(2). METHODS Sixty four T2DM patients with Glycated hemoglobin A1c (HbA1c) ≧ 7.0 % were randomly assigned to receive laparoscopic sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB) procedure. Weight, percentage of excess weight loss (%EWL), BMI, waist circumference, HbA1c, fasting blood glucose (FBG), and C-peptide were measured. Serum lipid levels were also measured during three-year postoperative follow-up visits. RESULTS Fifty five patients completed the 36-month follow-up. Both groups had similar baseline anthropometric and biochemical measures. At the end point, 22 patients (78.6 %) in SG group and 23 patients (85.2 %) in RYGB group achieved complete remission of diabetes mellitus with HbA1c < 6.0 % (P = 0.525) and without taking diabetic medications, and 25 patients in each group (89.3 % vs. 92.6 %) gained successful treatment of diabetes with HbA1c≦6.5 % (P = 0.100). Change in HbA1c, FBG and C peptide were comparable in the two groups. The RYGB group had significantly greater weight loss than the SG group [percentage of total weight loss (%TWL) of 31.0 % vs. 27.1 % (P = 0.049), %EWL of 92.3 % vs. 81.9 % (P = 0.003), and change in BMI of 11.0 vs. 9.1 kg/m(2)(P = 0.017), respectively]. Serum lipids in each group were also greatly improved. CONCLUSION In this three-year study, SG had similar positive effects on diabetes and dyslipidemia compared to RYGB in Chinese T2DM patients with BMI of 28-35 kg/m(2). Longer term follow-ups and larger sample studies are needed to confirm these outcomes, however.

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BACKGROUND Antibiotics are overused in children and adolescents with lower respiratory tract infection (LRTI). Serum-procalcitonin (PCT) can be used to guide treatment when bacterial infection is suspected. Its role in pediatric LRTI is unclear. METHODS Between 01/2009 and 02/2010 we randomized previously healthy patients 1 month to 18 years old presenting with LRTI to the emergency departments of two pediatric hospitals in Switzerland to receive antibiotics either according to a PCT guidance algorithm established for adult LRTI or standard care clinical guidelines. In intention-to-treat analyses, antibiotic prescribing rate, duration of antibiotic treatment, and number of days with impairment of daily activities within 14 days of randomization were compared between the two groups. RESULTS In total 337 children, mean age 3.8 years (range 0.1-18), were included. Antibiotic prescribing rates were not significantly different in PCT guided patients compared to controls (OR 1.26; 95% CI 0.81, 1.95). Mean duration of antibiotic exposure was reduced from 6.3 to 4.5 days under PCT guidance (-1.8 days; 95% CI -3.1, -0.5; P = 0.039) for all LRTI and from 9.1 to 5.7 days for pneumonia (-3.4 days 95% CI -4.9, -1.7; P<0.001). There was no apparent difference in impairment of daily activities between PCT guided and control patients. CONCLUSION PCT guidance reduced antibiotic exposure by reducing the duration of antibiotic treatment, while not affecting the antibiotic prescribing rate. The latter may be explained by the low baseline prescribing rate in Switzerland for pediatric LRTI and the choice of an inappropriately low PCT cut-off level for this population. TRIAL REGISTRATION Controlled-Trials.com ISRCTN17057980 http://www.controlled-trials.com/ISRCTN17057980.

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BACKGROUND The present study aimed to compare the safety and efficacy for novices to conduct intubation with the Bonfils intubation fiberscope (BIF) using the transillumination-assisted or midline approach technique in patients with normal airways. METHODS In this prospective randomized control study, 10 trainees were assigned to the transillumination-assisted technique group (T group) or the midline approach technique group (R group). Each trainee was required to conduct intubation in 50 patients. The primary outcome was intubation time. The secondary outcomes were success rate (%), number of attempts, and complications. RESULTS Among the cases of successful intubation, the intubation time was not significantly different between the two groups (P > 0.05). The overall success rate of intubation was not significantly different between the two groups (P > 0.05). The intubation success rates at the first, second, and third attempts as well as the average intubation times were similar between the two groups (P > 0.05), but in patients receiving successful intubation at the second attempt, the intubation time was longer in the T group (P = 0.0006). The incidences of dry throat, sore throat, and hoarseness were higher in the T group (all P < 0.05). CONCLUSIONS For patients with a normal airway, the transillumination-assisted technique was unlikely to increase the success rate of intubation with the BIF compared with the midline approach technique, but led to more complications. TRIAL REGISTRATION ChiCTR-INR-16009967 , retrospectively registered on November 22, 2016.

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OBJECTIVE This study was conducted with the aim to investigate and compare Iranian produced and foreign oxytocin for use in induction of labor. MATERIALS AND METHODS This random clinical trial was conducted on a population of 198 pregnant women with live fetus and cephalic presentation and conditions conducive to induction of labor, monitored by obstetricians and gynecologists. They were randomly divided into group A (n = 99) received 10 units of Syntocinon (Novartis Pharma Canada) in 500 cc Ringer lactate, and group B (n = 99) received 10 units of Oxytip (Caspian Tamin Company Iran) in 500 cc serum, who entered the study to commence induction, by signing written consent. Study variables such as induction indications (post-term, ruptured membranes, diabetes, and..), induction duration, duration of the 1(st) and the 2(nd) stages of labor, and delivery method; as well as labor outcomes like hyper-stimulation of uterine, postpartum bleeding, 5-minute Apgar score, and infant's birth weight; and neonatal outcomes (admission to NICU, oxygen and intubation) were assessed for the two groups by a trained midwife and registered in the patient's questionnaire. Data were analyzed in SPSS software using statistical tests: t-test, Chi-square, and Mann-Whitney. RESULTS Two groups were similar in demographic variables such as; age, BMI, parity, education. There was no significant difference regarding to obstetric and gynecologic characteristics such as: gestational age, dilatation, effacement, and fetal positioning, as well as the indication for labor induction when the study began. After intervention, variables including: induction duration, duration of the 1(st) and the 2(nd) stages of labor, delivery method; and labor outcomes such as: hyper-stimulation of uterine, postpartum bleeding, 5-minute Apgar score, and infant's birth weight; and neonatal outcomes (admission to NICU, oxygen and intubation), in the two groups, were found to be the same (P < 0.05). Mean oxytip dosage needed was less than that of oxytocin to reach for appropriate pain (P = 0.042). CONCLUSION The two drugs in terms of labor induction and neonatal complications had similar outcomes and the locally made drug with a lower dosage appears to produce the desired outcome.

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AIMS The aim was to compare efficacy and cost-effectiveness of bimatoprost 0.03% and brimonidine 0.2% in primary open-angle glaucoma (POAG)/ocular hypertension (OHT). SETTINGS AND DESIGN Open, randomized, cross-over, comparative study. MATERIALS AND METHODS Forty patients of POAG or OHT with intraocular pressure (IOP) <30 mm Hg were included in the study after a written informed consent. The patients were divided randomly into two groups of 20 patients each. Patients of group A were administered bimatoprost 0.03% eye drops once daily, and those of group B brimonidine 0.2% eye drops twice daily for a period of 4 weeks. After a washout period of 4 weeks, the patients were crossed over that is, group A was administered brimonidine 0.2% and group B bimatoprost 0.03%. Fall in IOP at 4 weeks was recorded. The daily cost of each drug was calculated by maximum retail price and the average number of drops per bottle. The cost-effectiveness was then calculated as the cost of drug/mm Hg fall in IOP. STATISTICS Independent samples t-test was used to compare the efficacy of both drugs. RESULTS IOP lowering with bimatoprost (8.9 ± 1.598 mm Hg) was significantly (P < 0.0001) higher than brimonidine (6.55 ± 1.26 mm Hg). The number of drops/ml were 33.43 ± 0.52 and 25.49 ± 0.26, respectively, for bimatoprost and brimonidine. Treatment with bimatoprost was costlier than brimonidine with daily costs/eye Rs. 4.02 ± 0.06 and 3.14 ± 0.03, yearly costs/eye Rs. 1467.46 ± 20.74 and 1147.75 ± 11.15, respectively. Bimatoprost was more cost-effective than brimonidine with the cost-effectiveness ratio (CER) respectively Rs. 13.10 ± 2.61/mm Hg and Rs. 13.96 ± 2.86/mm Hg. Incremental CER Rs. 10.43/mm Hg implies lower costs/mm Hg extra IOP lowering by bimatoprost than Rs. 13.96 for brimonidine. CONCLUSION In spite of being costlier, bimatoprost is more efficacious and cost-effective than brimonidine.

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OBJECTIVE To determine the effectiveness of a provider-based intervention to improve medication intensification among patients with diabetes. DESIGN Effectiveness cluster-randomised trial. Baseline and follow-up cross-sections of diabetes physicians' patients. SETTING Eleven U.S. Southeastern states, 2006-2008. PARTICIPANTS 205 Rural primary care physicians, 95 completed the study. INTERVENTION Multicomponent interactive intervention including web-based continuing medical education (CME), performance feedback and quality improvement tools. PRIMARY OUTCOME MEASURES Medication intensification, a dose increase of an existing medication or the addition of a new class of medication for glucose, blood pressure and lipids control on any of the three most recent office visits. RESULTS Of 364 physicians attempting to register, 102 were randomised to the intervention and 103 to the control arms; 95 physicians (intervention, n=48; control, n=47) provided data on their 1182 of their patients at baseline (intervention, n=715; control, n=467) and 945 patients at follow-up (intervention, n=479; control, n=466). For A1c control, medication intensification increased in both groups (intervention, pre 26.4% vs post 32.6%, p=0.022; control, pre 24.8% vs post 31.1%, p=0.033) (intervention, adjusted OR (AOR) 1.37; 95% CI 1.06 to 1.76; control, AOR 1.41 (95% CI 1.06 to 1.89)); however, we observed no incremental benefit solely due to the intervention (group-by-time interaction, p=0.948). Among patients with the worst glucose control (A1c >9%), intensification increased in both groups (intervention, pre 34.8% vs post 62.5%, p=0.002; control, pre 35.7% vs post 61.4%, p=0.008). CONCLUSIONS A wide-reach, low-intensity, web-based interactive multicomponent intervention had no significant incremental effect on medication intensification for control of glucose, blood pressure or lipids for patients with diabetes of physicians practising in the rural Southeastern USA. TRIAL REGISTRATION NCT00403091.

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OBJECTIVE The statistical analysis for a 2-arm randomised controlled trial (RCT) with a baseline outcome followed by a few assessments at fixed follow-up times typically invokes traditional analytic methods (eg, analysis of covariance (ANCOVA), longitudinal data analysis (LDA)). 'Constrained' longitudinal data analysis (cLDA) is a well-established unconditional technique that constrains means of baseline to be equal between arms. We use an analysis of fasting lipid profiles from the Group Medical Clinics (GMC) longitudinal RCT on patients with diabetes to illustrate applications of ANCOVA, LDA and cLDA to demonstrate theoretical concepts of these methods including the impact of missing data. METHODS For the analysis of the illustrated example, all models were fit using linear mixed models to participants with only complete data and to participants using all available data. RESULTS With complete data (n=195), 95% CI coverage are equivalent for ANCOVA and cLDA with an estimated 11.2 mg/dL (95% CI -19.2 to -3.3; p=0.006) lower mean low-density lipoprotein (LDL) cholesterol in GMC compared with usual care. With all available data (n=233), applying the cLDA model yielded an LDL improvement of 8.9 mg/dL (95% CI -16.7 to -1.0; p=0.03) for GMC compared with usual care. The less efficient, LDA analysis yielded an LDL improvement of 7.2 mg/dL (95% CI -17.2 to 2.8; p=0.15) for GMC compared with usual care. CONCLUSIONS Under reasonable missing data assumptions, cLDA will yield efficient treatment effect estimates and robust inferential statistics. It may be regarded as the method of choice over ANCOVA and LDA.

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AIM The present ex vivo study aimed to evaluate the debris extrusion after instrumenting the root canals by three different files systems. MATERIALS AND METHODS Sixty extracted human mandibular premolars with single canals were selected and randomly divided into three groups (n = 20) for instrumentation with three different files. Group 1: WaveOne (primary) single reciprocating file (WO; Dentsply Maillefer, Ballaigues, Switzerland) (25/08), Group 2: Self-adjusting file (SAF; ReDent-Nova, Ra'anana, Israel) (1.5 mm), and Group 3: ProTaper NEXT X1 and X2 (PTN; Dentsply Tulsa Dental, Tulsa, OK) (25/06). Debris extruding by instrumentation were collected into pre-weighed Eppendorf tubes. These tubes were then stored in an incubator at 70°C for 5 days. The tubes were then weighed to obtain the final weight, with the extruded debris. Statistical analysis for the debris extruded apically was performed using one-way analysis of variance and post hoc Tukey's test. RESULTS The statistical analysis showed a significant difference between all the three groups tested (P < 0.01). The following post hoc Tukey's test confirmed that Group 2 (SAF) exhibited significantly least (P < 0.01) debris extrusion between the three groups tested. CONCLUSIONS The SAF resulted in significantly less extrusion of debris when compared to reciprocating WO and rotary PTN.

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BACKGROUND Despite the large number of papers published on the efficiency of different exogenous gonadotropins, no confirmed protocol exists. Therefore, the aim of the present study was to compare the efficacy of 4 exogenous gonadotropins in IVF/ICSI cycles. METHODS This study, performed from January 2014 to May 2014, recruited 160 women referred to Ghadir Mother and Child Hospital and Dena Hospital, Shiraz, Iran. The patients underwent standard downregulation and were randomly divided into 4 groups of A, B, C, and D and were administered hMG, hFSH, rFSH, and combined sequential hFSH/rFSH, respectively. Then, the duration of stimulation, number of oocytes and embryos as well as their quality, implantation rate, biochemical and clinical pregnancy rate, and live birth rate in each group were evaluated. RESULTS Group D patients required significantly fewer ampoules of FSH than did the women in groups A, B, and C (P=0.004). The duration of stimulation was significantly longer in group C than in groups A and D (P=0.030). The serum estradiol level was significantly higher in group D than in groups B and C (P=0.005). A significantly higher number of large-sized follicles was observed in group D than in group B (P=0.036). CONCLUSION Our data revealed no statistically significant differences in the mean oocyte number, embryo quality, clinical pregnancy rate, or live birth rate between the hMG, hFSH, rFSH, and sequential hFSH/rFSH protocols. However, several differences in the duration of stimulation, serum estradiol levels, and number of large-sized follicles were detected between the groups. Trial Registration Number: IRCT201408116541N7.

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BACKGROUND Recent research has emphasized that the human circadian rhythm system is differentially sensitive to short wavelength light. Light treatment devices using efficient light-emitting diodes (LEDs) whose output is relatively concentrated in short wavelengths may enable a more convenient effective therapy for Seasonal Affective Disorder (SAD). METHODS The efficacy of a LED light therapy device in the treatment of SAD was tested in a randomized, double-blind, placebo-controlled, multi-center trial. Participants aged 18 to 65 with SAD (DSM-IV major depression with seasonal pattern) were seen at Baseline and Randomization visits separated by 1 week, and after 1, 2, 3 and 4 weeks of treatment. Hamilton Depression Rating Scale scores (SIGH-SAD) were obtained at each visit. Participants with SIGH-SAD of 20 or greater at Baseline and Randomization visits were randomized to active or control treatment: exposure to the Litebook LED treatment device (The Litebook Company Ltd., Alberta, Canada) which delivers 1,350 lux white light (with spectral emission peaks at 464 nm and 564 nm) at a distance of 20 inches or to an inactivated negative ion generator at a distance of 20 inches, for 30 minutes a day upon awakening and prior to 8 A.M. RESULTS Of the 26 participants randomized, 23 completed the trial. Mean group SIGH-SAD scores did not differ significantly at randomization. At trial end, the proportions of participants in remission (SIGH-SAD less than 9) were significantly greater (Fisher's exact test), and SIGH-SAD scores, as percent individual score at randomization, were significantly lower (t-test), with active treatment than with control, both in an intent-to-treat analysis and an observed cases analysis. A longitudinal repeated measures ANOVA analysis of SIGH-SAD scores also indicated a significant interaction of time and treatment, showing superiority of the Litebook over the placebo condition. CONCLUSION The results of this pilot study support the hypothesis that light therapy with the Litebook is an effective treatment for SAD. TRIAL REGISTRATION Clinicaltrials.gov: NCT00139997.

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BACKGROUND CEA is expressed in >90% of pancreatic cancers (PC) and may be an appropriate immunotherapy target. CEA is poorly immunogenic due to immune tolerance; CAP1-6D, an altered peptide ligand can help bypass tolerance. We conducted a pilot randomized phase I trial in PC patients to determine the peptide dose required to induce an optimal CD8(+) T cell response. METHODS Patients with a PS 0-1, HLA-A2+ and CEA-expressing, previously-treated PC were randomized to receive 10 μg (arm A), 100 μg (arm B) or 1000 μg (arm C) of CEA peptide emulsified in Montanide and GM-CSF, given every 2 weeks until disease progression. RESULTS Sixty-six patients were screened and 19 enrolled of whom 14 received at least 3 doses of the vaccine and thus evaluated for the primary immunologic endpoint. A median of 4 cycles (range 1-81) was delivered. Median and mean peak IFN-γ T cell response by ELISPOT (spots per 10(4) CD8(+) cells, Arm A/B/C) was 11/52/271 (A vs. C, p = 0.028) for medians and 37/148/248 (A vs. C, p = 0.032) for means. T cell responses developed or increased in 20%/60%/100% of pts in Arms A/B/C. Seven of the 19 patients remain alive at a minimum 32 months from trial initiation, including three with unresectable disease. CONCLUSIONS The T cell response in this randomized phase I trial was dose-dependent with the 1 mg CEA peptide dose eliciting the most robust T cell responses. A signal of clinical benefit was observed and no significant toxicity was noted. Further evaluation of 1 mg CEA peptide with stronger adjuvants, and/or combined with agents to overcome immune inhibitory pathways, may be warranted in PC pts. TRIAL REGISTRATION ClinicalTrials.gov NCT00203892.

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BACKGROUND Urinary retention is a common postoperative complication that mandates urinary catheterization. Urinary catheterization is associated with different physical, mental, and financial problems for both patients and healthcare systems. The patient inconvenience, urinary tract infections, and increase in hospital stay and expenses are common problems of urinary retention and urinary catheterization. Therefore, alternative ways of relieving urinary retention, preferably noninvasive interventions, are of great interest. OBJECTIVES The aim of this study was to compare the effects of placing hot pack and lukewarm-water-soaked gauze on the suprapubic region on male patients with postoperative urinary retention. PATIENTS AND METHODS This was a three-group, randomized, controlled trial. A convenience sample of 126 male patients who had undergone general, orthopedic, or urologic surgeries were recruited. The block randomization method was used for allocating patients to either the two experimental groups (the hot pack and the lukewarm-water-soaked gauze groups) or the control one. Patients in the experimental groups were treated by placing either hot pack or lukewarm-water-soaked gauze on the suprapubic region. All patients were monitored for 20 minutes for urinary retention relief. If they did not experience urinary retention relief (starting urine flow and bladder evacuate), urinary catheterization would be performed. The data was collected using information sheet. Elimination of urinary retention was compared among study groups. The one-way analysis of variance and the Chi-square tests were used for analyzing data. RESULTS Respectively, 59.5%, 71.4%, and 7.1% of patients in the hot pack, the soaked gauze, and the control groups experienced relief from urinary retention and the bladder was emptied. There was a significant difference among study groups in percentage of patients who experienced urinary retention relief. However, the difference between the two experimental groups was not significant. The time to urinary retention relief in hot pack, soaked gauze, and control groups was 15.45 ± 3.15, 13.83 ± 3.80, and 14.59 ± 3.29 minutes, respectively. The difference among the study groups in time to urinary retention relief was not statistically significant. CONCLUSIONS Both the lukewarm-water-soaked gauze and the hot pack techniques had significant effects on postoperative urinary retention and significantly reduced the need for urinary catheterization. Using these two simple and cost-effective techniques for managing postoperative urinary retention is recommended.

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INTRODUCTION The 15-minute work break provides an opportunity to promote health, yet few studies have examined this part of the workday. We studied physical activity and sedentary behavior among office workers and compared the results of the Booster Break program with those of a second intervention and a control group to determine whether the Booster Break program improved physical and behavioral health outcomes. METHODS We conducted a 3-arm, cluster-randomized controlled trial at 4 worksites in Texas from 2010 through 2013 to compare a group-based, structured Booster Break program to an individual-based computer-prompt intervention and a usual-break control group; we analyzed physiologic, behavioral, and employee measures such as work social support, quality of life, and perceived stress. We also identified consistent and inconsistent attendees of the Booster Break sessions. RESULTS We obtained data from 175 participants (mean age, 43 y; 67% racial/ethnic minority). Compared with the other groups, the consistent Booster Break attendees had greater weekly pedometer counts (P < .001), significant decreases in sedentary behavior and self-reported leisure-time physical activity (P < .001), and a significant increase in triglyceride concentrations (P = .02) (levels remained within the normal range). Usual-break participants significantly increased their body mass index, whereas Booster Break participants maintained body mass index status during the 6 months. Overall, Booster Break participants were 6.8 and 4.3 times more likely to have decreases in BMI and weekend sedentary time, respectively, than usual-break participants. CONCLUSION Findings varied among the 3 study groups; however, results indicate the potential for consistent attendees of the Booster Break intervention to achieve significant, positive changes related to physical activity, sedentary behavior, and body mass index.

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BACKGROUND Universal interventions to prevent postnatal mental disorders in women have had limited success, perhaps because they were insufficiently theorized, not gender-informed and overlooked relevant risk factors. This study aimed to determine whether an innovative brief psycho-educational program for mothers, fathers and first newborns, which addressed salient learning needs about infant behaviour management and adjustment tasks in the intimate partner relationship, prevented postpartum mental health problems in primiparous women. METHODS A before and after controlled study was conducted in primary care in seven local government areas in Victoria, Australia. English-speaking couples with one-week old infants were invited consecutively to participate by the maternal and child health nurse at the universal first home visit. Two groups were recruited and followed sequentially: both completed telephone interviews at four weeks and six months postpartum and received standard health care. Intervention group participants were also invited to attend a half-day program with up to five couples and one month old infants, facilitated by trained, supervised nurses. The main outcome was any Composite International Diagnostic Interview (CIDI) diagnosis of Depression or Anxiety or Adjustment Disorder with Depressed Mood, Anxiety, or Mixed Anxiety and Depressed Mood in the first six months postpartum. Factors associated with the outcome were established by logistic regression controlling for potential confounders and analysis was by intention to treat. RESULTS In total 399/646 (62%) women were recruited; 210 received only standard care and 189 were also offered the intervention; 364 (91%) were retained at follow up six months postpartum. In women without a psychiatric history (232/364; 64%), 36/125 (29%) were diagnosed with Depression or Anxiety or Adjustment Disorder with Depressed Mood, Anxiety, or Mixed Anxiety and Depressed Mood in the control group, compared with 16/107 (15%) in the intervention group. In those without a psychiatric history, the adjusted odds ratio for diagnosis of a common postpartum mental disorder was 0.43 (95% CI 0.21, 0.89) in the intervention group compared to the control group. CONCLUSIONS A universal, brief psycho-educational group program for English-speaking first time parents and babies in primary care reduces de novo postpartum mental disorders in women. A universal approach supplemented by an additional program may improve effectiveness for women with a psychiatric history. TRIAL REGISTRATION ACTRN 12605000567628.

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OBJECTIVES To compare the effectiveness of different oral analgesics for relieving pain and distress in adults following the extraction of teeth and deep cavity preparations under local anesthesia. Methods: This randomized controlled study was conducted between November 2015 and May 2016. One hundred and twenty patients were randomly allocated to 3 groups. Forty patients were in the paracetamol (1 gram) group, 40 in the ibuprofen (400 mg) group and 40 in the diclofenac potassium (50 mg) group. Evaluation of the post extraction and deep cavity preparations pain was made by patients immediately postoperatively, 2, 4 and 6 hours postoperatively on standard 100 mm visual analogue scales (VAS). Furthermore, each patient was observed preoperatively and immediately postoperatively for signs of distress by using a 5 point face scale. Results: There were significant decreases in mean pain VAS scores for diclofenac potassium group compared to paracetamol and ibuprofen groups at 4 hours postoperatively (one-way Analysis of Variance: p=0.0001, p=0.001) and 6 hours postoperatively (p=0.04, p=0.005). Changes in distress scores from the preoperative score to the postoperative score were made using the paired sample t-test. There were significant decreases in distress scores between the preoperative and postoperative scores (p=0.0001). Conclusions: Diclofenac potassium was more effective than paracetamol or ibuprofen for reducing postoperative pain associated with tooth extraction and deep cavity preparation. Patients' distress levels can be alleviated by using preemptive analgesics.

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BACKGROUND Adequate estimation and communication of risks is a critical competence of physicians. Due to an evident lack of these competences, effective training addressing risk competence during medical education is needed. Test-enhanced learning has been shown to produce marked effects on achievements. This study aimed to investigate the effect of repeated tests implemented on top of a blended learning program for risk competence. METHODS We introduced a blended-learning curriculum for risk estimation and risk communication based on a set of operationalized learning objectives, which was integrated into a mandatory course "Evidence-based Medicine" for third-year students. A randomized controlled trial addressed the effect of repeated testing on achievement as measured by the students' pre- and post-training score (nine multiple-choice items). Basic numeracy and statistical literacy were assessed at baseline. Analysis relied on descriptive statistics (histograms, box plots, scatter plots, and summary of descriptive measures), bootstrapped confidence intervals, analysis of covariance (ANCOVA), and effect sizes (Cohen's d, r) based on adjusted means and standard deviations. RESULTS All of the 114 students enrolled in the course consented to take part in the study and were assigned to either the intervention or control group (both: n = 57) by balanced randomization. Five participants dropped out due to non-compliance (control: 4, intervention: 1). Both groups profited considerably from the program in general (Cohen's d for overall pre vs. post scores: 2.61). Repeated testing yielded an additional positive effect: while the covariate (baseline score) exhibits no relation to the post-intervention score, F(1, 106) = 2.88, p > .05, there was a significant effect of the intervention (repeated tests scenario) on learning achievement, F(1106) = 12.72, p < .05, d = .94, r = .42 (95% CI: [.26, .57]). However, in the subgroup of participants with a high initial numeracy score no similar effect could be observed. CONCLUSION Dedicated training can improve relevant components of risk competence of medical students. An already promising overall effect of the blended learning approach can be improved significantly by implementing a test-enhanced learning design, namely repeated testing. As students with a high initial numeracy score did not profit equally from repeated testing, target-group specific opt-out may be offered.

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BACKGROUND Divergent strategies have emerged for the management of severe asthma. One strategy utilises high and fixed doses of maintenance treatment, usually inhaled corticosteroid/long-acting β2-agonist (ICS/LABA), supplemented by a short-acting β2-agonist (SABA) as needed. Alternatively, budesonide/formoterol is used as both maintenance and reliever therapy. The latter is superior to fixed-dose treatment in reducing severe exacerbations while achieving similar or better asthma control in other regards. Exacerbations may be reduced by the use of budesonide/formoterol as reliever medication during periods of unstable asthma. We examined the risk of a severe exacerbation in the period after a single day with high reliever use. METHODS Episodes of high reliever use were quantified and exacerbations occurring post-index day with these episodes were examined post hoc in two double-blind studies comparing the efficacy and safety of budesonide/formoterol maintenance and reliever therapy (Symbicort SMART™, Turbuhaler®) 160/4.5 μg twice daily plus as needed with similar or higher maintenance doses of ICS/LABA plus SABA or formoterol. RESULTS Budesonide/formoterol maintenance and reliever therapy significantly reduced the risk of episodes of high reliever use (>6 inhalations/day) vs. all alternative ICS/LABA regimens. With conventional fixed-dose treatment the need for exacerbation treatment within 21 days ranged from 6.0-10.1% of days post-index for all regimens compared with 2.5-3.4% of days with budesonide/formoterol maintenance and reliever therapy. CONCLUSIONS Budesonide/formoterol maintenance and reliever therapy reduces the incidence of high reliever episodes and the exacerbation burden immediately following these episodes vs. alternative ICS/LABA plus SABA regimens at up to double the maintenance dose of ICS. TRIAL REGISTRATION These studies do not have registration numbers as they were conducted before clinical trial registration was required.

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BACKGROUND We aimed to compare hemodynamic and endocrine alterations caused by stress response due to Proseal laryngeal mask airway and endotracheal tube usage in laparoscopic cholecystectomy. MATERIALS AND METHODS Sixty-three ASA I-II patients scheduled for elective laparoscopic cholecystectomy were included in the study. Patients were randomly allocated into two groups of endotracheal tube and Proseal laryngeal mask airway. Standard general anaesthesia was performed in both groups with the same drugs in induction and maintenance of anaesthesia. After anaesthesia induction and 20 minutes after CO(2) insufflations, venous blood samples were obtained for measuring adrenalin, noradrenalin, dopamine and cortisol levels. Hemodynamic and respiratory parameters were recorded at the 1(st), 5(th), 15(th), 30(th) and 45(th) minutes after the insertion of airway devices. RESULTS No statistically significant differences in age, body mass index, gender, ASA physical status, and operation time were found between the groups (p > 0.05). Changes in hemodynamic and respiratory parameters were not statistically significant when compared between and within groups (p > 0.05). Although no statistically significant differences were observed between and within groups when adrenalin, noradrenalin and dopamine values were compared, serum cortisol levels after CO(2) insufflation in PLMA group were significantly lower than the ETT group (p = 0.024). When serum cortisol levels were compared within groups, cortisol levels 20 minutes after CO(2) insufflation were significantly higher (46.1 (9.5-175.7) and 27.0 (8.3-119.4) in the ETT and PLMA groups, respectively) than cortisol levels after anaesthesia induction (11.3 (2.8-92.5) and 16.6 (4.4-45.4) in the ETT and PLMA groups, respectively) in both groups (p = 0.001). CONCLUSION PLMA usage is a suitable, effective and safe alternative to ETT in laparoscopic cholecystectomy patients with lower metabolic stress.

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PURPOSE Sonic hedgehog (SHH), an activating ligand of smoothened (SMO), is overexpressed in > 70% of pancreatic cancers (PCs). We investigated the impact of vismodegib, an SHH antagonist, plus gemcitabine (GV) or gemcitabine plus placebo (GP) in a multicenter phase Ib/randomized phase II trial and preclinical PC models. PATIENTS AND METHODS Patients with PC not amenable to curative therapy who had received no prior therapy for metastatic disease and had Karnofsky performance score ≥ 80 were enrolled. Patients were randomly assigned in a one-to-one ratio to GV or GP. The primary end point was progression-free-survival (PFS). Exploratory correlative studies included serial SHH serum levels and contrast perfusion computed tomography imaging. To further investigate putative biologic mechanisms of SMO inhibition, two autochthonous pancreatic cancer models (Kras(G12D); p16/p19(fl/fl); Pdx1-Cre and Kras(G12D); p53(R270H/wt); Pdx1-Cre) were studied. RESULTS No safety issues were identified in the phase Ib portion (n = 7), and the phase II study enrolled 106 evaluable patients (n = 53 in each arm). Median PFS was 4.0 and 2.5 months for GV and GP arms, respectively (95% CI, 2.5 to 5.3 and 1.9 to 3.8, respectively; adjusted hazard ratio, 0.81; 95% CI, 0.54 to 1.21; P = .30). Median overall survival (OS) was 6.9 and 6.1 months for GV and GP arms, respectively (95% CI, 5.8 to 8.0 and 5.0 to 8.0, respectively; adjusted hazard ratio, 1.04; 95% CI, 0.69 to 1.58; P = .84). Response rates were not significantly different. There were no significant associations between correlative markers and overall response rate, PFS, or OS. Preclinical trials revealed no significant differences with vismodegib in drug delivery, tumor growth rate, or OS in either model. CONCLUSION The addition of vismodegib to gemcitabine in an unselected cohort did not improve overall response rate, PFS, or OS in patients with metastatic PC. Our preclinical and clinical results revealed no statistically significant differences with respect to drug delivery or treatment efficacy using vismodegib.

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OBJECTIVE To evaluate over 108 weeks the effect of phentermine and topiramate extended release (PHEN/TPM ER) treatment on progression to type 2 diabetes and/or cardiometabolic disease in subjects with prediabetes and/or metabolic syndrome (MetS) at baseline. RESEARCH DESIGN AND METHODS Subanalysis of a phase 3, randomized, placebo-controlled, double-blind study of overweight/obese subjects (BMI ≥27 to ≤45 kg/m(2)) with two or more comorbidities. Subjects were randomized to placebo, PHEN 7.5 mg/TPM ER 46 mg (7.5/46), or PHEN 15 mg/TPM ER 92 mg (15/92) plus lifestyle modifications for 108 weeks. Percent weight loss in the intent-to-treat population using multiple imputation (ITT-MI), annualized incidence rate of progression to type 2 diabetes, and changes in glycemia, lipid parameters, blood pressure, and waist circumference were evaluated. RESULTS At baseline, 475 subjects met the criteria for prediabetes and/or MetS. After 108 weeks, subjects with prediabetes and/or MetS in the placebo, 7.5/46, and 15/92 groups experienced mean percent weight loss of 2.5, 10.9, and 12.1%, respectively (ITT-MI; P < 0.0001 vs. placebo), associated with reductions of 70.5 and 78.7% in the annualized incidence rate of type 2 diabetes for those receiving 7.5/46 and 15/92, respectively (ITT, P < 0.05), versus placebo. The ability of PHEN/TPM ER to prevent diabetes was related to degree of weight lost and was accompanied by significant improvements in cardiometabolic parameters. PHEN/TPM ER was well tolerated by this subgroup over 2 years. CONCLUSIONS PHEN/TPM ER plus lifestyle modification produced significant weight loss and markedly reduced progression to type 2 diabetes in overweight/obese patients with prediabetes and/or MetS, accompanied by improvements in multiple cardiometabolic disease risk factors.

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BACKGROUND Inflammation may play an important role in type 2 diabetes. It has been proposed that dietary strategies can modulate inflammatory activity. METHODS We investigated the effects of diet on inflammation in type 2 diabetes by comparing a traditional low-fat diet (LFD) with a low-carbohydrate diet (LCD). Patients with type 2 diabetes were randomized to follow either LFD aiming for 55-60 energy per cent (E%) from carbohydrates (n = 30) or LCD aiming for 20 E% from carbohydrates (n = 29). Plasma was collected at baseline and after 6 months. C-reactive protein (CRP), interleukin-1 receptor antagonist (IL-1Ra), IL-6, tumour necrosis factor receptor (TNFR) 1 and TNFR2 were determined. RESULTS Both LFD and LCD led to similar reductions in body weight, while beneficial effects on glycaemic control were observed in the LCD group only. After 6 months, the levels of IL-1Ra and IL-6 were significantly lower in the LCD group than in the LFD group, 978 (664-1385) versus 1216 (974-1822) pg/mL and 2.15 (1.65-4.27) versus 3.39 (2.25-4.79) pg/mL, both P < 0.05. CONCLUSIONS To conclude, advice to follow LCD or LFD had similar effects on weight reduction while effects on inflammation differed. Only LCD was found significantly to improve the subclinical inflammatory state in type 2 diabetes.

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INTRODUCTION The objective of the study is to share the results and development findings on the laparoscopic closure technique applied in our centre during a 15-year period (1998-2012). AIM To compare statistically the standard parameters (hospitalization, duration of operation) versus conventional surgery, and at the same time we compared mainly morbidity and mortality. MATERIAL AND METHODS During the period under review we operated on a total of 259 patients, 115 (44.4%) of them laparoscopically, and 144 (55.6%) of them conventionally. The sample was divided into two groups: patients with ASA physical status classification system 1-3, and patients with ASA 4-5. RESULTS The results favour laparoscopy within the group with ASA 1-3 in terms of several parameters, namely: duration of hospitalization - 7.7 days in the case of laparoscopic intervention, vs. 10.6 days for conventional surgery (p < 0.05); and duration of operation - 61 min vs. 85.1 min respectively (p < 0.05). Total morbidity was 27.5% in the case of patients with conventional surgery, vs. 10.9% with laparoscopic intervention (p < 0.05). The sample of patients with ASA 4-5 suffered a high mortality of 82.7%. CONCLUSIONS Laparoscopic closure of perforated ulcer is a safe therapeutic method, as confirmed by the results of many other studies around the world, which in many aspects favour the laparoscopic technique.

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BACKGROUND Extended use of combined pharmacotherapies to treat tobacco dependence may increase smoking abstinence; few studies have examined their effectiveness. The objective of this study was to evaluate smoking abstinence with standard nicotine patch (NRT), extended use of combined formulations of nicotine replacement therapy (NRT+), or varenicline (VR). METHODS A total of 737 smokers, including those with medical and psychiatric comorbidities, were randomly assigned to one of the above three treatment conditions. The NRT group received 10 weeks of patches (21 mg daily maximum); the NRT+ group received patches (35 mg daily maximum) and gum or inhaler for up to 22 weeks; and the VR group received 1 mg twice daily for up to 24 weeks (22 weeks post target quit date). All participants also received six standardized 15-minute smoking cessation counseling sessions by nurses experienced in tobacco dependence treatment. The primary outcome was carbon monoxide-confirmed continuous abstinence rates (CAR) from weeks 5-52. Secondary outcomes were: CAR from weeks 5-10 and 5-22, and carbon monoxide-confirmed 7-day point prevalence (7PP) at weeks 10, 22, and 52. Adjusted and unadjusted logistic regression analyses were conducted using intention-to-treat procedures. RESULTS The CARs for weeks 5-52 were 10.0 %, 12.4 %, and 15.3 % in the NRT, NRT+, and VR groups, respectively; no group differences were observed. Results with 7PP showed that VR was superior to NRT at week 52 (odds ratio (OR), 1.84; 97.5 % Confidence Interval (CI), 1.04-3.26) in the adjusted intention-to-treat analysis. Those in the VR group had higher CAR at weeks 5-22 (OR, 2.01; CI, 1.20-3.36) than those in the NRT group. Results with 7PP revealed that both NRT+ (OR, 1.72; CI, 1.04-2.85) and VR (OR, 1.96; CI, 1.20-3.23) were more effective than NRT at 22 weeks. As compared to NRT monotherapy, NRT+ and VR produced significant increases in CAR for weeks 5-10 (OR, 1.52; CI, 1.00-2.30 and OR, 1.58; CI, 1.04-2.39, respectively); results were similar, but somewhat stronger, when 7PP was used at 10 weeks (OR, 1.57; CI, 1.03-2.41 and OR, 1.79; CI, 1.17-2.73, respectively). All medications were well tolerated, but participants in the VR group experienced more fatigue, digestive symptoms (e.g., nausea, diarrhea), and sleep-related concerns (e.g., abnormal dreams, insomnia), but less dermatologic symptoms than those in the NRT or NRT+ groups. The frequency of serious adverse events did not differ between groups. CONCLUSIONS Flexible and combination NRT and varenicline enhance success in the early phases of quitting. Varenicline improves abstinence in the medium term; however, there is no clear evidence that either varenicline or flexible, dual-form NRT increase quit rates in the long-term when compared to NRT monotherapy. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01623505 ; Retrospectively registered on July 13, 2011.

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CONTEXT Denosumab 60 mg sc injection every 6 months for 36 months was well tolerated and effective in reducing the incidence of vertebral, nonvertebral, and hip fracture in predominantly Caucasian postmenopausal women with osteoporosis. OBJECTIVE The objective of this phase 3 fracture study was to examine the antifracture efficacy and safety of denosumab 60 mg in Japanese women and men with osteoporosis compared with placebo. DESIGN AND SETTING A randomized, double-blind, placebo-controlled trial with an open-label active comparator as a referential arm was conducted. PATIENTS Subjects were 1262 Japanese patients with osteoporosis aged 50 years or older, who had one to four prevalent vertebral fractures. INTERVENTION Subjects were randomly assigned to receive denosumab 60 mg sc every 6 months (n = 500), placebo for denosumab (n = 511), or oral alendronate 35 mg weekly (n = 251). All subjects received daily supplements of calcium and vitamin D. MAIN OUTCOME MEASURE The primary endpoint was the 24-month incidence of new or worsening vertebral fracture for denosumab vs placebo. RESULTS Denosumab significantly reduced the risk of new or worsening vertebral fracture by 65.7%, with incidences of 3.6% in denosumab and 10.3% in placebo at 24 months (hazard ratio 0.343; 95% confidence interval 0.194-0.606, P = .0001). No apparent difference in adverse events was found between denosumab and placebo during the first 24 months of the study. CONCLUSION These results provide evidence of the efficacy and safety of denosumab 60 mg sc every 6 months in Japanese subjects with osteoporosis.

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BACKGROUND The prevalence of abnormal nutritional status has increased in children and adolescents. Nutritional assessment is important for monitoring the health and nutritional status. Bioelectrical impedance vector analysis (BIVA) combines changes in tissue hydration and structure and body composition that can be assessed. OBJECTIVES The objective of this study was to use BIVA to evaluate nutritional status in 60 prepubertal children, aged between 8 and 9 years, supplemented with zinc, to detect possible changes in body composition. DESIGN We performed a randomized, controlled, triple-blind study. The children were divided into the control group (CG; sorbitol 10%, n=29) or the experimental group (EG; 10 mg Zn/day, n=31), and the duration of the experiment was 3 months. Anthropometric assessments were performed for all of the children. RESULTS The body mass index-for-age increased after oral zinc supplementation in the EG (p=0.005). BIVA indicated that the CG demonstrated a tendency for dehydration and decreased soft tissue and the EG demonstrated a tendency for increased soft tissue, primarily the fat-free mass. After analyses of BIVA ellipses, we observed that this method could detect improvements in body composition in healthy children supplemented with zinc. CONCLUSIONS These results suggest that BIVA could be an auxiliary method for studying a small population undergoing zinc intervention.

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OBJECTIVE We investigated the effect of early-phase insulin secretion on the incidence of type 2 diabetes in individuals with impaired glucose tolerance (IGT) participating in the Finnish Diabetes Prevention Study (DPS). We examined how a lifestyle intervention affected early-phase insulin secretion (ratio of total insulin area under the curve [AUC] and total glucose AUC [AIGR] from 0 to 30 min) during a 4-year follow-up intervention trial and whether AIGR(0-30) response was modified by insulin sensitivity (IS) and obesity. RESEARCH DESIGN AND METHODS A total of 443 participants with IGT originally randomized to a lifestyle intervention or control group were studied. IS and AIGR(0-30) were estimated from an oral tolerance glucose test administered annually during the 4-year follow-up trial and were related to the risk of diabetes onset over a 6-year follow-up. RESULTS Lifestyle intervention resulted in higher IS (P = 0.02) and lower unadjusted AIGR(0-30) (P = 0.08) during the 4-year follow-up. A higher IS and a lower BMI during the follow-up were associated with a lower unadjusted AIGR(0-30) during the follow-up, independently of study group (P < 0.001). A greater increase in IS on the median cutoff point of a 0.69 increase was associated with higher IS-adjusted AIGR(0-30) during the follow-up (P = 0.002). In multivariate models, IS and IS-adjusted AIGR(0-30) were both inversely associated with diabetes incidence (P < 0.001). Participants who progressed to type 2 diabetes were more obese and had lower IS and Matsuda IS index-AIGR(0-30) than nonprogressors. CONCLUSIONS Our results indicate that the reduction in the risk of developing type 2 diabetes after lifestyle intervention is related to the improvement of IS along with weight loss. Improved IS may also have beneficial effects on preservation of β-cell function.

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BACKGROUND This study is to investigate the effect of Body Awareness Therapy (BAT) and Aerobic Exercises on pain and quality of life in patients with Tension-Type Headache (TTH). MATERIALS AND METHOD Sixty individuals with TTH diagnosis who referred Neurologist were incorporated into study. The individuals were randomly grouped into 3 as BAT (n=20), aerobic exercise (n=20) and control group (n=20). Pain severity of the individuals was evaluated by Visual Analog Scale (VAS) and pain diary, disability with ache; by Pain Disability Index (PDI) and Headache Impact Tests (HIT) and quality of life was evaluated by SF-36. Subsequent to first assessments, 3 sessions of 60 minutes per week throughout 6 weeks totally. RESULTS When the groups were compared at the end of the study, a significant decrease was observed in VAS, PDI and HIT values in the individuals in the BAT and aerobic exercise groups. With the individuals in group BAT and aerobic exercise all parameters of quality of life were observed to be increased significantly. CONCLUSION BAT and aerobic exercise programs to be applied on TTH patients were concluded to be important in decreasing the pain, in increasing the quality of life and in reducing pain-related daily constraints of the individuals.

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BACKGROUND Mental disorders are highly prevalent for the people who are aged between 16 and 25 years and can permanently disrupt the development of these individuals. Easily available mobile health (mHealth) apps for mobile phones have great potential for the prevention and early intervention of mental disorders in young adults, but interventions are required that can help individuals to both identify high-quality mobile apps and use them to change health and lifestyle behavior. OBJECTIVES The study aimed to assess the efficacy of a Web-based self-guided app recommendation service ("The Toolbox") in improving the well-being of young Australians aged between 16 and 25 years. The intervention was developed in collaboration with young adults and consists of a curated list of 46 readily available health and well-being apps, assessed and rated by professionals and young people. Participants are guided by an interactive quiz and subsequently receive recommendations for particular apps to download and use based on their personal goals. METHODS The study was a waitlist, parallel-arm, randomized controlled trial. Our primary outcome measure was change in well-being as measured by the Mental Health Continuum-Short Form (MHC-SF). We also employed ecological momentary assessments (EMAs) to track mood, energy, rest, and sleep. Participants were recruited from the general Australian population, via several Web-based and community strategies. The study was conducted through a Web-based platform consisting of a landing Web page and capabilities to administer study measures at different time points. Web-based measurements were self-assessed at baseline and 4 weeks, and EMAs were collected repeatedly at regular weekly intervals or ad hoc when participants interacted with the study platform. Primary outcomes were analyzed using linear mixed-models and intention-to-treat (ITT) analysis. RESULTS A total of 387 participants completed baseline scores and were randomized into the trial. Results demonstrated no significant effect of "The Toolbox" intervention on participant well-being at 4 weeks compared with the control group (P=.66). There were also no significant differences between the intervention and control groups at 4 weeks on any of the subscales of the MHC-SF (psychological: P=.95, social: P=.42, emotional: P=.95). Repeat engagement with the study platform resulted in a significant difference in mood, energy, rest, and sleep trajectories between intervention and control groups as measured by EMAs (P<.01). CONCLUSIONS This was the first study to assess the effectiveness of a Web-based well-being intervention in a sample of young adults. The design of the intervention utilized expert rating of existing apps and end-user codesign approaches resulting in an app recommendation service. Our finding suggests that recommended readily available mental health and well-being apps may not lead to improvements in the well-being of a nonclinical sample of young people, but might halt a decline in mood, energy, rest, and sleep. TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12614000710628; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=366145 (Archived by WebCite at http://www.webcitation.org/ 6pWDsnKme).

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BACKGROUND Most nasal bone fractures are corrected using non-invasive methods. Often, patients are dissatisfied with surgical outcomes following such closed approach. In this study, we compare surgical outcomes following blind closed reduction to that of ultrasound-guided reduction. METHODS A single-institutional prospective study was performed for all nasal fracture patients (n=28) presenting between May 2013 and November 2013. Upon research consent, patients were randomly assigned to either the control group (n=14, blind reduction) or the experimental group (n=14, ultrasound-guided reduction). Surgical outcomes were evaluated using preoperative and 3-month postoperative X-ray images by two independent surgeons. Patient satisfaction was evaluated using a questionnaire survey. RESULTS The experimental group consisted of 4 patients with Plane I fracture and 10 patients with Plane II fracture. The control group consisted of 3 patients with Plane I fracture and 11 patients with Plane II fracture. The mean surgical outcomes score and the mean patient dissatisfaction score were found not to differ between the experimental and the control group in Plane I fracture ( p =0.755, 0.578, respectively). In a subgroup analysis consisting of Plane II fractures only, surgeons graded outcomes for ultrasound-guided reduction higher than that for the control group ( p =0.007). Likewise, among the Plane II fracture patients, those who underwent ultrasound-guided reduction were less dissatisfied than those who underwent blind reduction ( p =0.043). CONCLUSION Our study result suggests that ultrasound-guided closed reduction is superior to blind closed reduction in those patients with Plane II nasal fractures.

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