[Principles of clinical pharmacology]. Design and Implementation of an Interactive Website to Support Long-Term Maintenance of Weight Loss Serotonergic psychedelics and personality: A systematic review of contemporary research Biological Treatment for Osteoarthritis of the Knee: Moving from Bench to Bedside-Current Practical Concepts. 12-step affiliation and attendance following treatment for comorbid substance dependence and depression: a latent growth curve mediation model. Effects of behavioral intervention on substance use among people living with HIV: the Healthy Living Project randomized controlled study. [Combination of physiotherapeutic exercise therapy with bencyclane in intermittent claudication (author's transl)]. Implementation Outcomes of Multidimensional Family Therapy-Detention to Community: A Reintegration Program for Drug-Using Juvenile Detainees Psilocybin with psychological support for treatment-resistant depression: six-month follow-up Introduction to SMART designs for the development of adaptive interventions: with application to weight loss research Cessation and reduction in alcohol consumption and misuse after psychedelic use Long-term follow-up of psilocybin-facilitated smoking cessation Monitoring plasma concentrations to individualize treatment with clomiphene citrate. Psychedelics not linked to mental health problems or suicidal behavior: A population study Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin How can we best categorize cognitive impairment in nondemented older adults? Lessons from a repeat pregnancy prevention program for Hispanic teenage mothers in east Los Angeles. Are distinctive ethical principles required for cluster randomized controlled trials? Design of the Study of Tranexamic Acid during Air Medical Prehospital Transport (STAAMP) Trial: Addressing the Knowledge Gaps Chloroquine treatment of uncomplicated Plasmodium falciparum malaria in Mali: parasitologic resistance versus therapeutic efficacy. Explanatory and pragmatic attitudes in therapeutical trials. Randomized clinical trials: alternatives to conventional randomization. Evaluating the Lions-Quest "Skills for Adolescence" drug education program. Second-year behavior outcomes. Sensible guidelines for the conduct of large randomized trials Pre- and post-admission attrition of homeless, mentally ill chemical abusers referred to residential treatment programs.
626 pages , 2012 , Academic Press , 2012 , Arthur J. Atkinson ( Jr. ) , Shiew-Mei Huang , Principles of Clinical Pharmacology , 0123854717 , 9780123854711 , Principles of Clinical Pharmacology is a successful survey covering the pharmacologic principles underlying the individualization of patient therapy and contemporary drug development . This essential reference continues to focus on the basics of clinical pharmacology for the development , evaluation , and clinical use of pharmaceutical products while also addressing the most recent advances in the field . Written by leading experts in academia , industry , clinical and regulatory setting s , the third edition has been thoroughly up date d to provide readers with an ideal reference covering the wide range of important topics impacting clinical pharmacology as the discipline plays an increasingly significant role in drug development and regulatory science . The Third Edition has been endorsed by the American Society for Clinical Pharmacology and Therapeutics * Includes new chapters on imaging and the pharmacogenetic basis of adverse drug reactions . * Offers an exp and ed regulatory section that addresses US and international issues and guidelines . * Provides extended coverage of earlier chapters on transporters , pharmacogenetics and biomarkers and also illustrates the impact of gender on drug response . * Presents a broadened discussion of clinical trials from Phase 1 to incorporate Phases II and III . file download Background For most individuals , long-term maintenance of weight loss requires long-term , supportive intervention . Internet-based weight loss maintenance programs offer considerable potential for meeting this need . Careful design processes are required to maximize adherence and minimize attrition . Objective This paper describes the development , implementation and use of a Web-based intervention program design ed to help those who have recently lost weight sustain their weight loss over 1 year . Methods The weight loss maintenance website was developed over a 1-year period by an interdisciplinary team of public health research ers , behavior change intervention experts , applications developers , and interface design ers . Key interactive features of the final site include social support , self-monitoring , written guidelines for diet and physical activity , links to appropriate websites , supportive tools for behavior change , check-in accountability , tailored reinforcement messages , and problem solving and relapse prevention training . The weight loss maintenance program included a reminder system ( automated email and telephone messages ) that prompted participants to return to the website if they missed their check-in date . If there was no log-in response to the email and telephone automated prompts , a staff member called the participant . We tracked the proportion of participants with at least one log-in per month , and analyzed log-ins as a result of automated prompts . Results The mean age of the 348 participants enrolled in an ongoing r and omized trial and assigned to use the website was 56 years ; 63 % were female , and 38 % were African American . While weight loss data will not be available until mid-2008 , website use remained high during the first year with over 80 % of the participants still using the website during month 12 . During the first 52 weeks , participants averaged 35 weeks with at least one log-in . Email and telephone prompts appear to be very effective at helping participants sustain ongoing website use . Conclusions Developing interactive websites is expensive , complex , and time consuming . We found that extensive paper prototyping well in advance of programming and a versatile product manager who could work with project staff at all levels of detail were essential to keeping the development process efficient . Trial Registration clinical trials.gov HighlightsSerotonergic psychedelics act as agonists at cortical 5‐HT2A receptors.5‐HT2A receptors are expressed in fronto‐temporo‐parieto‐occipital areas .Some personality traits seem to be related to 5‐HT2A receptor expression . Acute and long‐term use of psychedelics is associated with personality changes  . Personality changes induced by psychedelics may have therapeutic effects . & NA ; Serotonergic psychedelics act as agonists at cortical 5‐HT2A receptors and seem to induce personality changes . We conducted a systematic review of studies assessing the effects of these drugs on personality . Papers published from 1985–2016 were included from PubMed , LILACS , and SciELO data bases . Three hundred and sixty‐nine studies were identified , and 18 were included . Specific personality traits , such as Absorption and Self‐Transcendence , seem to influence the effects of psychedelics , and  psychedelic drug users and nonusers appear to differ in some personality traits . Psychedelics administered in controlled setting s may induce personality changes , such as increased Openness and Self‐Transcendence . Increases in global brain entropy induced by acute psychedelic administration predicted changes in Openness , and Self‐Transcendence was negatively correlated with cortical thinning of the posterior cingulate cortex in long‐term religious ayahuasca users . Acute and long‐term use of psychedelics is associated with personality changes that appear to be modulated by 5‐HT2A receptors . These changes seem to induce therapeutic effects that should be further explored in r and omized controlled studies Biological-based therapies for cartilage pathology have gained considerable recognition in the last few decades due to their potential benefits including their minimal invasiveness , capacity for unprecedented healing , and potential for rapid recovery . Consequently , these therapies are likely to have the most noteworthy impact on patients with degenerative joint changes who want to remain active . Currently , the most research ed treatments include platelet-rich plasma ( PRP ) , bone marrow aspirate concentrate ( BMAC ) , and cell-based therapies . Although further basic science research and well- design ed r and omized clinical trials are needed to eluci date the long-term role of these therapies in the treatment of osteoarthritis , there is compelling evidence for their use for certain indications . This article aims to review the existing literature for biological-based treatment options for osteoarthritis , critically assessing the current evidence -based recommendations and identify potential avenues for development Among substance-dependent individuals , comorbid major depressive disorder ( MDD ) is associated with greater severity and poorer treatment outcomes , but little research has examined mediators of posttreatment substance use outcomes within this population . Using latent growth curve models , the authors tested relationships between individual rates of change in 12-step involvement and substance use , utilizing posttreatment follow-up data from a trial of group Twelve-Step Facilitation ( TSF ) and integrated cognitive-behavioral therapy ( ICBT ) for veterans with substance dependence and MDD . Although TSF patients were higher on 12-step affiliation and meeting attendance at end-of-treatment as compared with ICBT , they also experienced significantly greater reductions in these variables during the year following treatment , ending at similar levels as ICBT . Veterans in TSF also had significantly greater increases in drinking frequency during follow-up , and this group difference was mediated by their greater reductions in 12-step affiliation and meeting attendance .  Patients with comorbid depression appear to have difficulty sustaining high levels of 12-step involvement after the conclusion of formal 12-step interventions , which predicts poorer drinking outcomes over time . Modifications to TSF and other formal 12-step protocol s or continued therapeutic contact may be necessary to sustain 12-step involvement and reduced drinking for patients with substance dependence and MDD AIM Reductions in substance use were examined in response to an intensive intervention with people living with human immunodeficiency virus ( HIV ) ( PLH ) . DESIGN , SETTING AND PARTICIPANTS A r and omized controlled trial was conducted with 936 PLH who had recently engaged in unprotected sexual risk acts recruited from four US cities : Milwaukee , San Francisco , New York and Los Angeles .  Substance use was assessed as the number of days of use of 19 substances recently ( over the last 90 days ) , evaluated at 5-month intervals over 25 months . INTERVENTION A 15-session case management intervention was delivered to PLH in the intervention condition ; the control condition received usual care . MEASUREMENTS An intention-to-treat analysis was conducted examining reductions on multiple indices of recent substance use calculated as the number of days of use . FINDINGS Reductions in recent substance use were significantly greater for intervention PLH compared to control PLH : alcohol and /or marijuana use , any substance use , hard drug use and a weighted index adjusting for seriousness of the drug . While the intervention-related reductions in substance use were larger among women than men , men also reduced their use . Compared to controls , gay and heterosexual men in the intervention reduced significantly their use of alcohol and marijuana , any substance , stimulants and the drug severity-weighted frequency of use index . Gay men also reduced their hard drug use significantly in the intervention compared to the control condition . CONCLUSIONS A case management intervention model , delivered individually , is likely to result in significant and sustained reductions in substance use among PLH Earlier investigations had shown that an intensive physiotherapy program with 30 treatments in 6 weeks was the most rational therapy for intermittent claudication , but the question whether the therapeutic success could be improved by the addition of " vasoactive " substances remained open . For this reason , bencyclane was added to the basic physiotherapy in a double blind trial involving 109 ambulant patients . 91 or these were evaluated . The treatment group ( n = 45 ) showed a greater increase in walking distance of 21.7 % compared with the placebo group ( n = 46 ) . Also in the evaluation of the therapeutic success rate , the treatment group showed better results ( 84.4 % ) than the placebo group ( 71.7 % ) . From this it can be concluded that the basic physiotherapy can be effectively supported with bencyclane Responding to urgent calls for effective interventions to address young offenders ’ multiple and interconnected problems , a new variant of an existing empirically-vali date d intervention for drug-using adolescents , Multidimensional Family Therapy (MDFT)—Detention to Community ( DTC ) was tested in a two-site controlled trial . This article ( a ) outlines the rationale and protocol basics of the MDFT-DTC intervention , a program for substance-using juvenile offenders that links justice and substance abuse treatment systems to facilitate adolescents ’ postdetention community reintegration ; ( b ) presents implementation outcomes , including fidelity , treatment engagement and retention rates , amount of services received , treatment satisfaction , and substance abuse — juvenile justice system collaboration outcomes ; and ( c ) details the implementation and sustainability challenges in a cross-system ( substance abuse treatment and juvenile justice ) adolescent intervention . Findings support the effectiveness of the MDFT-DTC intervention , and the need to develop a full implementation model in which transfer and dissemination issues could be explored more fully , and tested experimentally Rationale Recent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy . Objectives Here , we report on safety and efficacy outcomes for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression . Methods Twenty patients ( six females ) with ( mostly ) severe , unipolar , treatment-resistant major depression received two oral doses of psilocybin ( 10 and 25 mg , 7 days apart ) in a supportive setting . Depressive symptoms were assessed from 1 week to 6 months post-treatment , with the self-rated QIDS-SR16 as the primary outcome measure . Results Treatment was generally well tolerated . Relative to baseline , marked reductions in depressive symptoms were observed for the first 5 weeks post-treatment ( Cohen ’s d = 2.2 at week 1 and 2.3 at week 5 , both p < 0.001 ) ; nine and four patients met the criteria for response and remission at week 5 . Results remained positive at 3 and 6 months ( Cohen ’s d = 1.5 and 1.4 , respectively , both p < 0.001 ) . No patients sought conventional antidepressant treatment within 5 weeks of psilocybin . Reductions in depressive symptoms at 5 weeks were predicted by the quality of the acute psychedelic experience . Conclusions Although limited conclusions can be drawn about treatment efficacy from open-label trials , tolerability was good , effect sizes large and symptom improvements appeared rapidly after just two psilocybin treatment sessions and remained significant 6 months post-treatment in a treatment-resistant cohort . Psilocybin represents a promising paradigm for unresponsive depression that warrants further research in double-blind r and omised control trials The management of many health disorders often entails a sequential , individualized approach whereby treatment is adapted and readapted over time in response to the specific needs and evolving status of the individual . Adaptive interventions provide one way to operationalize the strategies ( e.g. , continue , augment , switch , step-down ) leading to individualized sequences of treatment . Often , a wide variety of critical questions must be answered when developing a high- quality adaptive intervention . Yet , there is often insufficient empirical evidence or theoretical basis to address these questions . The Sequential Multiple Assignment R and omized Trial (SMART)—a type of research design —was developed explicitly for the purpose of building optimal adaptive interventions by providing answers to such questions . Despite increasing popularity , SMARTs remain relatively new to intervention scientists . This manuscript provides an introduction to adaptive interventions and SMARTs . We discuss SMART design considerations , including common primary and secondary aims . For illustration , we discuss the development of an adaptive intervention for optimizing weight loss among adult individuals who are overweight Background : Meta- analysis of r and omized studies using lysergic acid diethylamide ( LSD ) for alcohol use disorder ( AUD ) showed large , significant effects for LSD efficacy compared to control conditions . Clinical studies suggest potential anti-addiction effects of LSD and mechanistically-related classic psychedelics for alcohol and other substance use disorders . Aims : To supplement clinical studies , reports of psychedelic use in naturalistic setting s can provide further data regarding potential effects of psychedelics on alcohol use . Methods : An anonymous online survey of individuals with prior AUD reporting cessation or reduction in alcohol use following psychedelic use in non- clinical setting s. Results : 343 respondents , mostly White ( 89 % ) , males ( 78 % ) , in the USA ( 60 % ) completed the survey . Participants reported seven years of problematic alcohol use on average before the psychedelic experience to which they attributed reduced alcohol consumption , with 72 % meeting retrospective criteria for severe AUD . Most reported taking a moderate or high dose of LSD ( 38 % ) or psilocybin ( 36 % ) , followed by significant reduction in alcohol consumption . After the psychedelic experience 83 % no longer met AUD criteria . Participants rated their psychedelic experience as highly meaningful and insightful , with 28 % endorsing psychedelic-associated changes in life priorities or values as facilitating reduced alcohol misuse . Greater psychedelic dose , insight , mystical-type effects , and personal meaning of experiences were associated with a greater reduction in alcohol consumption , controlling for prior alcohol consumption and related distress . Conclusions : Although results can not demonstrate causality , they suggest that naturalistic psychedelic use may lead to cessation or reduction in problematic alcohol use , supporting further investigation of psychedelic-assisted treatment for AUD ABSTRACT Background : A recent open-label pilot study ( N = 15 ) found that two to three moderate to high doses ( 20 and 30 mg/70 kg ) of the serotonin 2A receptor agonist , psilocybin , in combination with cognitive behavioral therapy ( CBT ) for smoking cessation , result ed in substantially higher 6-month smoking abstinence rates than are typically observed with other medications or CBT alone . Objectives : To assess long-term effects of a psilocybin-facilitated  smoking cessation program at ≥12 months after psilocybin administration . Methods : The present report describes biologically verified smoking abstinence outcomes of the previous pilot study at ≥12 months , and related data on subjective effects of psilocybin . Results : All 15 participants completed a 12-month follow-up , and 12 ( 80 % ) returned for a long-term ( ≥16 months ) follow-up , with a mean interval of 30 months ( range = 16–57 months ) between target-quit date ( i.e. , first psilocybin session ) and long-term follow-up . At 12-month follow-up , 10 participants ( 67 % ) were confirmed as smoking abstinent . At long-term follow-up , nine participants ( 60 % ) were confirmed as smoking abstinent . At 12-month follow-up 13 participants ( 86.7 % ) rated their psilocybin experiences among the five most personally meaningful and spiritually significant experiences of their lives . Conclusion : These results suggest that in the context of a structured treatment program , psilocybin holds considerable promise in promoting long-term smoking abstinence . The present study adds to recent and historical evidence suggesting high success rates when using classic psychedelics in the treatment of addiction . Further research investigating psilocybin-facilitated treatment of substance use disorders is warranted OBJECTIVE Recent reports have indicated that a number of individual patient characteristics are responsible for the success or failure of  clomiphene citrate treatment . However , a priori individualization of doses in different patients has not been investigated . We examined the thesis that wide variability in the metabolism of the active component ( zuclomiphene ) contributes to variability in response . METHODS The dose-response relationship of clomiphene was established from a meta- analysis of data from 13 published reports . Limited data relating plasma drug concentrations to treatment outcome were examined to determine whether insufficient systemic exposure at a fixed dosage might contribute to therapeutic failure . RESULTS A fixed-dosage regimen of 50 mg clomiphene per day is likely to cause ovulation in only 46 % of patients ; subsequent increment in dosage increases the number of responders but at the expense of considerable delay in individualization of treatment . Case reports indicated that dosage based on plasma drug concentration monitoring could improve patient management , and an algorithm is proposed to facilitate treatment . CONCLUSIONS Prospect i ve studies of clomiphene citrate should be performed to confirm the hypothesis that the monitoring of plasma zuclomiphene concentrations can significantly accelerate dose individualization and improve the therapeutic outcome with this " orphan " drug A recent large population study of 130,000 adults in the United States failed to find evidence for a link between psychedelic use ( lysergic acid diethylamide , psilocybin or mescaline ) and  mental health problems . Using a new data set consisting of 135,095 r and omly selected United States adults , including 19,299 psychedelic users , we examine the associations between psychedelic use and mental health . After adjusting for sociodemographics , other drug use and childhood depression , we found no significant associations between lifetime use of  psychedelics  and increased likelihood of past year serious psychological distress , mental health treatment , suicidal thoughts , suicidal plans and suicide attempt , depression and anxiety . We failed to find evidence that psychedelic use is an independent risk factor for mental health problems .  Psychedelics are not known to harm the brain or other body organs or to cause addiction or compulsive use ; serious adverse events involving psychedelics are extremely rare . Overall , it is difficult to see how prohibition of psychedelics can be justified as a public health measure Psychedelic drugs have a long history of use in healing ceremonies , but despite renewed interest in their therapeutic potential , we continue to know very little about how they work in the brain . Here we used psilocybin , a classic psychedelic found in magic mushrooms , and a task-free functional MRI ( fMRI ) protocol design ed to capture the transition from normal waking consciousness to the psychedelic state . Arterial spin labeling perfusion and blood-oxygen level-dependent ( BOLD ) fMRI were used to map cerebral blood flow and changes in venous oxygenation before and after intravenous infusions of placebo and psilocybin .  Fifteen healthy volunteers were scanned with arterial spin labeling and a separate 15 with BOLD . As predicted , profound changes in consciousness were observed after psilocybin , but surprisingly , only decreases in cerebral blood flow and BOLD signal were seen , and these were maximal in hub regions , such as the thalamus and anterior and posterior cingulate cortex ( ACC and PCC ) . Decreased activity in the ACC/medial prefrontal cortex ( mPFC ) was a consistent finding and the magnitude of this decrease predicted the intensity of the subjective effects . Based on these results , a seed-based pharmaco-physiological interaction/functional connectivity analysis was performed using a medial prefrontal seed . Psilocybin caused a significant decrease in the positive coupling between the mPFC and PCC . These results strongly imply that the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brain 's key connector hubs , enabling a state of unconstrained cognition Cognitive disorders in elderly individuals frequently have a basis in neurodegenerative or vascular brain diseases , which typically evolve over a long period of time . By the time a diagnosis of dementia is made , the individual has often suffered some deficits in cognition over many years . The predementia phase of cognitive impairment has been of much recent interest because research ers focus on strategies to prevent dementia . There are also many conditions such as brain trauma , cerebral infection , cerebrovascular disease , neoplasia , or depression , in which decline in cognition is incontrovertible but insufficiently disabling to justify a diagnosis of dementia . Some of these individuals do not have a predementia cognitive syndrome but a subthreshold one , i.e. , their cognitive impairment , while clinical ly significant , is often nonprogressive and , therefore , not a prodrome of dementia . Nosologists , epidemiologists , clinicians , and clinical research ers have all struggled with defining this syndrome , especially in the last 2 decades . A plethora of terms has emerged , some of which include Benign or Malignant Senescent Forgetfulness , Age-Associated Memory Impairment , Aging-Associated Cognitive Decline , Cognitive Impairment Not Dementia , Mild Neurocognitive Disorder , and Question able Dementia with a Clinical Dementia Rating ( CDR ) scale rating of 0.5 . The term that has achieved the most widespread usage is Mild Cognitive Impairment ( MCI ) , originally proposed in 1988 , for which diagnostic criteria were first described in 1999 . More than a decade after these criteria were proposed , the construct of MCI remains imprecise , with considerable variability in studies examining its prevalence estimates , the heterogeneity in its clinical features , and its variable predictive value for dementia . The publication of consensus criteria by an international working group on MCI made some headway toward resolving the discrepancies , but many difficulties remain in its operationalization . The use of  MCI  , both in clinical work and research , has , however , been widespread , and there has been an exponential increase in publications related to MCI in recent years . Neurology service providers in the United States reported frequently using the  MCI diagnosis for diagnostic and billing purpose s , and most use cholinesterase inhibitors and other drugs at least sometimes for these patients . Thus , despite remaining uncertainties , the concept of MCI has importantly served to focus our attention on the early and prodromal stages of cognitive decline . There are many reasons for the highly variable use of MCI and related terms . The 1999 criteria for MCI focused on it as a prodrome of Alzheimer disease , with an emphasis on memory impairment that does not equally apply to other types of dementia . The original and revised definitions of MCI were intended more as guidelines for experienced clinicians and clinician research ers than as operational criteria in and of themselves . Population studies have operationalized these definitions in different ways and applied them retrospectively or prospect ively The conclusion of this quantitative and qualitative evaluation of 350 mothers delivering at Women 's Hospital in East Los Angeles and recruited between April 1989 and December 1990 was that basic ethnographic research on teenage sexual and reproductive behavior is needed . Target groups of Hispanics , for instance , may not be homogenous and may require multiple strategies . New interventions should accommo date the effects of poverty , the influence of significant others , and the cultural meaning of relationships , pregnancy , childbearing , contraceptive use , and gender roles . Concern focused on the notion that limited program effects can be considered trivial . The point was made that bilingual mothers who had been in the US for some time and desired upward socioeconomic mobility were helped by the program . Also , the program developed referral re sources in child care , school programs , employment , housing , emergency aid , and services for physical and sexual abuse . Additional funding was able to provide part-time work experiences in the clinic for a few of the teenagers , which provided more social support , solid work experience , and incentives . Through the use of qualitative data , counselors were able to prioritize teenage needs and thus supply needed food and housing before contraception . Qualitative data also helped to distinguish several different groups of Hispanics : those recent immigrants who wanted to be wives and mothers ; bilingual adolescents desiring economic advancement ; throw-away kids involved with drugs and gangs ; and Central American teenagers who fled war-torn countries and desired a better life . There were pressing needs related to poverty and social circumstances that interfered with family planning program implementation . Recognition of the different lifestyles helped to direct services in appropriate ways . The statistical demographic profiles were presented and indicated that these teenage obstetric persons had significant social , economic , and medical risks . Many were at risk of repeat pregnancy because of living with their partner and not using contraception . Most were high school drop-outs . There was a high probability that many were illegal immigrants . Postpartum program drop-out rates were very high . Only 37 out of 244 cases and 106 controls remained after 2 years and 105 cases and 16 controls after 1 year . Residential mobility and poverty were obstacles to follow-up Cluster r and omized trials are increasingly used in research into health care and health services . Ethics of  individual patient r and omized trials have been eluci date d in a number of different codes , but less attention has been given to the ethical issues raised by cluster r and omized trials . I assess the challenges raised by cluster r and omized controlled trials by considering three questions : What are the essential elements of ethical medical research , particularly experiments on people ? What are the features which distinguish cluster r and omized controlled trials from ordinary RCTs ? Do the distinctive features of cluster r and omized trials entail new ethical principles , or careful application of existing principles ? I conclude that cluster r and omized controlled trials raise new issues on the nature and practice of informed consent , because of the levels at which consent can be sought , and for which it can be sought . In addition , careful consideration of the principles relating to the quality of the scientific design and analysis , balance of risk and benefit , liberty to leave a trial , early stopping of a trial and the power to exclude people from potential benefits is required Abstract Hemorrhage and coagulopathy remain major drivers of early preventable mortality in military and civilian trauma . The development of trauma-induced coagulopathy and hyperfibrinolysis is associated with poor outcomes . Interest in the use of tranexamic acid ( TXA ) in hemorrhaging patients as an antifibrinolytic agent has grown recently . Additionally , several reports describe immunomodulatory effects of TXA that may confer benefit independent of its antifibrinolytic actions . A large trial demonstrated a mortality benefit for early TXA administration in patients at risk for hemorrhage ; however , questions remain about the applicability in developed trauma systems and the mechanism by which TXA reduces mortality . We describe here the rationale , design , and challenges of the Study of Tranexamic Acid during Air Medical Prehospital transport ( STAAMP ) trial . The primary objective is to determine the effect of prehospital TXA infusion during air medical transport on 30-day mortality in patients at risk of traumatic hemorrhage . This study is a multicenter , placebo-controlled , double-blind , r and omized clinical trial . The trial will enroll trauma patients with hypotension and tachycardia from 4 level I trauma center air medical transport programs . It includes a 2-phase intervention , with a prehospital and in-hospital phase to investigate multiple dosing regimens . The trial will also explore the effects of TXA on the coagulation and inflammatory response following injury . The trial will be conducted under exception for informed consent for emergency research and thus required an investigational new drug approval from the U.S. Food and Drug Administration as well as a community consultation process . It was design ed to address several existing knowledge gaps and research priorities regarding TXA use in trauma Whether and when to replace chloroquine with other antimalarial drugs is an urgent public health question in much of Africa , where Plasmodium falciparum , which is increasingly resistant to chloroquine , continues to kill millions each year . Antimalarial drug efficacy has traditionally been measured as parasitologic resistance , but recent guidelines use both clinical and parasitologic criteria to monitor therapeutic efficacy . To assess the new efficacy protocol , we measured parasitologic and therapeutic outcomes in 514 patients treated with chloroquine for uncomplicated P. falciparum malaria in Mali . There was a general agreement between parasitologic and therapeutic outcomes at two sites , with 13 - 17 % parasitologic resistance rates and 10 - 15 % treatment failure rates . However , the new protocol overestimated early treatment failure rates ( 21 - 71 % of cases classified as early treatment failure had sensitive or RI parasitologic responses ) , particularly where resistance was rare , and missed low-level parasitologic resistance . Modifications of the protocol for monitoring antimalarial therapeutic efficacy are recommended IT IS the thesis of this paper that most therapeutic trials are inadequately formulated , and this from the earliest stages of their conception . Their inadequacy is basic , in that the trials may be aim ed at the solution of one or other of two radically different kinds of problem ; the result ing ambiguity affects the definition of the treatments , the assessment of the results , the choice of subjects and the way in which the treatments are compared . It often occurs that one type of approach is ethically less defensible than the other , or may even be ruled out altogether on ethical grounds . We postpone consideration of this aspect of the question until a later section The r and omized allocation format remains an exceedingly powerful tool for clinical research . Because humans are the subjects in clinical research , this area of scientific study must operate within the limits dictated by such basic principles as individual autonomy , justice , and beneficence . As r and omized studies have become more common in clinical research , it has become apparent that there is often need for modification of the basic r and omized format or for alternatives . The most widespread modification is the use of sequential analyses to monitor the progress of a trial and ensure early identification of either unanticipated adverse effects or more pronounced differences than expected . Although this modification does not affect the basic r and omized allocation format , it does provide a protection that is lacking in the conventional trial and should be utilized whenever feasible . Modifications that do affect the basic structure of the r and omized trial include adaptive allocation and pre-r and omization . The former is attractive and useful but limited to studies in which results from early enrollees are known before late enrollees are allocated . The greater the linkage between preceding subject results and subsequent assignments , the greater is the protection afforded by such a format . Pre-r and omization , more universally applicable than adaptive allocation , suffers from pronounced cross-over potential and has been criticized on ethical grounds , a combination of weaknesses that raises questions of whether pre-r and omization truly offers advantages to conventional r and omized formats . True alternatives to the r and omized format include the self-controlled study and the historical control design . Both possess significant ethical advantages over the simple r and omized study . Unfortunately , both are at some method ological disadvantage when the same comparison is made . The self-controlled study is limited to the study of conditions sufficiently stable or recurrent that they permit two or more treatment courses in a single patient . In emergency medicine and critical care , this description fits only a small proportion of the illness spectrum . This design is underutilized in clinical research focused on less severe problems of the type seen in ambulatory and primary -care setting s. Such problems can be suitable topics for research by emergency medicine specialists . Historical control studies are eminently applicable in the emergency and critical-care setting . ( ABSTRACT TRUNCATED AT 400 WORDS Thirty-four schools ( n=7426 consented sixth grade rs , 71 % of the eligible population ) were r and omized to conditions to test the hypothesis that Skills for Adolescence ( SFA ) , a widely used comprehensive life skills training curriculum with a dedicated drug education unit , is more effective than st and ard care in deterring and delaying substance use through middle school . Two-year posttest ( 1-year post-intervention ) data were collected from 5691 eighth grade rs ( 77 % of those who completed the sixth- grade survey and 87 % of those who completed the seventh- grade survey ) .  Lifetime and recent ( last 30 days ) use of five substances or combinations of substances was compared using mixed-model regression to control for school clustering . There were two significant treatment main effects at the end of the eighth grade : lifetime ( P=.05 ) and recent ( P<.03 ) marijuana use were lower in SFA than control schools with pretest usage and salient demographic and psychosocial variables controlled . There was also one significant Treatment x Pretest Usage interaction around binge drinking .  Baseline binge drinkers in SFA schools were less likely to report recent binge drinking than students in control schools ( P<.01 ) ; there were no treatment differences among baseline nonbinge drinkers . Analyses of potential mediators of SFA treatment effects on eighth- grade binge drinking and marijuana use suggested that SFA increased self-efficacy around drug refusal skills , but did not affect behavioral intentions , perceptions of harm , or perceived peer norms . These 2-year ( 1-year post-intervention ) outcomes offer some additional support for SFA effectiveness and the general thrust of school-based , life skills-based prevention programs . The promising sixth- through eighth- grade findings for SFA , a commercially available program , provide a further step in bridging a major gap in the " research to practice " literature : theory-based interventions that have documented behavioral effects have not enjoyed large-scale implementation , while intuition-based programs that have no documented effects still enjoy wide exposure Since the first r and omized controlled trial ( RCT ) in the 1950s , RCTs have had an enormous influence on the evaluation of various forms of interventions ( both preventative and therapeutic ) in a large range of medical conditions . The design and conduct of trials have evolved considerably and RCTs have become the ‘ gold ’ st and ard for the evaluation of therapies . Initial trials were funded by governments and were design ed and conducted largely by academic investigators . In recent times , the majority of trials are funded by industry and often run by for-profit contract research organizations . Over the last 25 years , there have also been marked changes in the design and conduct of RCTs . While some of these changes have been positive , many are not . A positive development was the increasing recognition that many treatments were likely to have , at best , moderate benefits ( or harm ) , which has led to very large trials , at times involving several thous and s or even several tens of thous and s of subjects . Although many have argued for extreme simplicity in various aspects of trial conduct , most large trials involve various degrees of , and at times substantial , complexity . Consequently , these trials have become extremely expensive to conduct . When trials evaluate new or patented products or devices , the sponsors of these products have sufficient re sources to invest tens of millions and at times even over a hundred million dollars into a single trial . What has caused the cost of trials to skyrocket ? Are the complexities and high costs necessary and justifiable ? What are the associated opportunity costs ? There is little evidence that many procedures and processes for RCTs that are widely accepted , or even required , have improved the trials . Regulatory guidelines for the conduct of RCTs ( e.g. , Good Clinical Practice [ GCP ] guidelines ) are being held as the new st and ard , particularly the described st and ards for study monitoring , and the flexibility in the GCP guidelines is not often utilized . What is the basis for asserting that the procedures enshrined in these GCPs are indeed good , clinical ly relevant , or even practical ? Collection of excess data , number of visits , and in particular onsite monitoring , considerably increase the cost of trials . While the intent of these guidelines is to improve the quality of trials , do we really know whether any improvements have been worthwhile or whether the additional re sources could have been spent more effectively ? Indeed , are there alternate and more efficient ways to enhance the quality of trials ? Should there be flexible and differing approaches based on the stage of development of various interventions ? How much of the complexity is driven by actual government regulations vs. overly cautious interpretation by industry regulatory departments ? In recent years , a growing number of approvals ( national , local , institutional ) are required before trials can be initiated . These multiple approvals are lengthy , and can delay the initiation of studies by a year or two , and add considerably to the costs of RCTs . Are these multiple approvals of any value ? Are there simpler ways to safeguard the science and ethics of trials ? For a scientific method that is at the heart of evidence -based medicine , there is no good evidence that the layers of complexity , approvals , processes , and laws to protect subjects entering RCTs have actually achieved their purpose . What is clear is that such processes are extremely expensive and delay studies . At times , they even prevent the conduct of important trials of generic questions , especially those that are not supported by industry . We are concerned that multiple layers of complexity , approvals , and laws may actually be damaging public health by preventing the conduct of important trials of major public health importance . Over the last decade , many thoughtful leaders in clinical trials methodology have question ed current practice s. In order to get a broad perspective from academia , regulators , and industry , we convened a two-day workshop in Washington , DC on January 25 and 26 , 2007 , in which 66 scientists participated . These scientists drawn from around the world involved clinical trial practitioners from industry , academia , and government . Their deliberations are summarized in six position papers , which AIMS To assess the magnitude and psychopathologic predictors of attrition among homeless , mentally ill chemical abusers ( MICAs ) referred to residential treatment programs in New York City . DESIGN Homeless , MICAs were r and omly referred to a therapeutic community ( TC ) or community residence ( CR ) and monitored with regard to pre- and post-admission attrition . SETTING S  Community based treatment facilities modified to treat both substance abuse and major mental illness . PARTICIPANTS Homeless individuals with a major mental illness ( DSM-III-R ) and a history of abusing alcohol or other drugs . MEASUREMENTS Attrition rates and selected scales of psychopathology . FINDINGS From an initial pool of 694 treatment c and i date s , 147 ( 22 % ) were rejected for admission at their assigned facility ; 247 ( 36 % ) failed to show up for treatment ; and 212 ( 31 % ) dropped out of treatment at some point during the first 12 months . Contrary to expectation , those with severe levels of psychotic ideation , depressive symptoms and hostility were admitted to treatment more frequently and stayed in treatment longer at the TC , a high dem and approach , than the CR , a low dem and approach . CONCLUSION Clinicians should consider the TC as a viable treatment option for MICAs
Enduring changes in personality/attitudes , depression , spirituality , anxiety , wellbeing , substance misuse , meditative practice s , and mindfulness were documented .
Mystical experiences , connectedness , emotional breakthrough , and increased neural entropy were related to these long-term changes in psychological functioning .
Finally , with proper screening , preparation , supervision , and integration , limited aversive side effects were noted by study participants .
Research into the basic effects and therapeutic applications of  psychedelic drugs  has grown considerably in recent years .
Yet , pressing questions remain regarding the substances ' lasting effects .
Although individual studies have begun monitoring sustained changes , no study to- date has synthesized this information .