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The methodology of randomized clinical trials is essential for the critical assessment and registration of therapeutic interventions. The CONSORT (Consolidated Standards of Reporting Trials) statement was developed to alleviate the problems arising from the inadequate reporting of randomized controlled trials. The present article reflects on the items that we believe should be included in the CONSORT checklist in the context of conducting and reporting trials in allergen-specific immunotherapy. Only randomized, blinded (in particular blinding of patients, health care providers, and outcome assessors), placebo-controlled Phase III studies in this article. Our analysis focuses on the definition of patients’ inclusion and exclusion criteria, allergen standardization, primary, secondary and exploratory outcomes, reporting of adverse events and analysis. [ABSTRACT FROM AUTHOR]

The article comments on the study "Prevention of Cardiovascular Events With an Antihypertensive Regimen of Amlodipine Adding Perindopril as Required Versus Atenolol Adding Bendroflumethiazide as Required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm: A Multicentre Randomised Controlled Trial," by B. Dahlof, P. S. Sever, N. R. Poulter and colleagues. It explains that the trial suggests that atenolol is not an acceptable therapy for the treatment hypertension. Further, it suggests that a strategy using a calcium channel blockers is more effective than the β-blocker atenolol. It argues that the trial was not a trial of combination agent therapy and should not be interpreted as such. It also states the blood pressure in the trial was poorly controlled.

Presents developments related to clinical trials of various diseases and their treatment. Role of delirium in the mortality rate of hospitalized older adults.

An addendum of the ICH E9 guideline on Statistical Principles for Clinical Trials was released in November 2019 introducing the estimand framework. This new framework aims to align trial objectives and statistical analyses by requiring a precise definition of the inferential quantity of interest, that is, the estimand. This definition explicitly accounts for intercurrent events, such as switching to new anticancer therapies for the analysis of overall survival (OS), the gold standard in oncology. Traditionally, OS in confirmatory studies is analyzed using the intention‐to‐treat (ITT) approach comparing treatment groups as they were initially randomized regardless of whether treatment switching occurred and regardless of any subsequent therapy (treatment‐policy strategy). Regulatory authorities and other stakeholders often consider ITT results as most relevant. However, the respective estimand only yields a clinically meaningful comparison of two treatment arms if subsequent therapies are already approved and reflect clinical practice. We illustrate different scenarios where subsequent therapies are not yet approved drugs and thus do not reflect clinical practice. In such situations the hypothetical strategy could be more meaningful from patient's and prescriber's perspective. The cross‐industry Oncology Estimand Working Group (www.oncoestimand.org) was initiated to foster a common understanding and consistent implementation of the estimand framework in oncology clinical trials. This paper summarizes the group's recommendations for appropriate estimands in the presence of treatment switching, one of the key intercurrent events in oncology clinical trials. We also discuss how different choices of estimands may impact study design, data collection, trial conduct, analysis, and interpretation. [ABSTRACT FROM AUTHOR]

Abstract: According to results of a recent literature search performed by the European Academy of Dermatology and Venereology (EADV) Task Forces (TF) on Quality of Life and Patient Oriented Outcomes (QoL and PO) and Acne, Rosacea and Hidradenitis Suppurativa (ARHS), most of the publications where health‐related (HR) QoL of acne patients was studied were clinical trials. Members of the EADV TF on QoL and PO decided to detect which acne treatment has the best influence on HRQoL of acne patients. A new literature search was organized to find publications on acne treatment where the HRQoL of patients was assessed as an outcome measure. From 186 papers with HRQoL assessment, 37 papers were included for further analysis. Our results revealed that oral isotretinoin had the best influence on HRQoL of acne patients. Several other treatment methods also showed good effects on the HRQoL of acne patients. Oral isotretinoin and norethindrone acetate/ethinyl estradiol, topical clindamycin phosphate/benzoyl peroxide and adapalene/benzoyl peroxide showed significantly better effect on HRQoL than placebo. There is limited number of the high‐quality studies on acne treatment where HRQoL was assessed. Dermatology‐specific and acne‐specific instruments showed much better sensitivity to successful therapeutic intervention than generic HRQoL instruments. The most frequently used HRQoL instrument was the Dermatology Life Quality Index questionnaire. [ABSTRACT FROM AUTHOR]

Equal randomization has been a popular choice in clinical trial practice. However, in trials with heterogeneous variances and/or variable treatment costs, as well as in settings where maximization of every trial participant's benefit is an important design consideration, optimal allocation proportions may be unequal across study treatment arms. In this paper, we investigate optimal allocation designs minimizing study cost under statistical efficiency constraints for parallel group clinical trials comparing several investigational treatments against the control. We show theoretically that equal allocation designs may be suboptimal, and unequal allocation designs can provide higher statistical power for the same budget or result in a smaller cost for the same level of power. We also show how optimal allocation can be implemented in practice by means of restricted randomization procedures and how to perform statistical inference following these procedures, using invoked population-based or randomization-based approaches. Our results provide further support to some previous findings in the literature that unequal randomization designs can be cost efficient and can be successfully implemented in practice. We conclude that the choice of the target allocation, the randomization procedure, and the statistical methodology for data analysis is an essential component in ensuring valid, powerful, and robust clinical trial results. [ABSTRACT FROM AUTHOR]

It is well known that the treatment effect of a molecularly targeted agent (MTA) may vary dramatically, depending on each patient's biomarker profile. Therefore, for a clinical trial evaluating MTA, it is more reasonable to evaluate its treatment effect within different marker subgroups rather than evaluating the average treatment effect for the overall population. The marker-stratified design (MSD) provides a useful tool to evaluate the subgroup treatment effects of MTAs. Under the Bayesian framework, the beta-binomial model is conventionally used under the MSD to estimate the response rate and test the hypothesis. However, this conventional model ignores the fact that the biomarker used in the MSD is, in general, predictive only for the MTA. The response rates for the standard treatment can be approximately consistent across different subgroups stratified by the biomarker. In this paper, we proposed a Bayesian hierarchical model incorporating this biomarker information into consideration. The proposed model uses a hierarchical prior to borrow strength across different subgroups of patients receiving the standard treatment and, therefore, improve the efficiency of the design. Prior informativeness is determined by solving a "customized" equation reflecting the physician's professional opinion. We developed a Bayesian adaptive design based on the proposed hierarchical model to guide the treatment allocation and test the subgroup treatment effect as well as the predictive marker effect. Simulation studies and a real trial application demonstrate that the proposed design yields desirable operating characteristics and outperforms the existing designs. [ABSTRACT FROM AUTHOR]

Summary: When a candidate predictive marker is available, but evidence on its predictive ability is not sufficiently reliable, all‐comers trials with marker stratification are frequently conducted. We propose a framework for planning and evaluating prospective testing strategies in confirmatory, phase III marker‐stratified clinical trials based on a natural assumption on heterogeneity of treatment effects across marker‐defined subpopulations, where weak rather than strong control is permitted for multiple population tests. For phase III marker‐stratified trials, it is expected that treatment efficacy is established in a particular patient population, possibly in a marker‐defined subpopulation, and that the marker accuracy is assessed when the marker is used to restrict the indication or labelling of the treatment to a marker‐based subpopulation, ie, assessment of the clinical validity of the marker. In this paper, we develop statistical testing strategies based on criteria that are explicitly designated to the marker assessment, including those examining treatment effects in marker‐negative patients. As existing and developed statistical testing strategies can assert treatment efficacy for either the overall patient population or the marker‐positive subpopulation, we also develop criteria for evaluating the operating characteristics of the statistical testing strategies based on the probabilities of asserting treatment efficacy across marker subpopulations. Numerical evaluations to compare the statistical testing strategies based on the developed criteria are provided. [ABSTRACT FROM AUTHOR]

Meibomian gland dysfunction is one of the most common ocular disorders encountered by ophthalmologists and is the leading cause of evaporative dry eye. The disease causes significant morbidity in the population such that patients seek treatment. Multiple clinical studies on pharmacological and mechanical interventions for the treatment of meibomian gland dysfunction have been evaluated. However, there is limited comparative clinical evidence for the effectiveness of these interventions. This review paper aims to report the clinical evidence for pharmaceutical interventions for meibomian gland dysfunction in order to guide clinicians in the management of the disease. [ABSTRACT FROM AUTHOR]

Stopping rules for clinical trials are primarily intended to control Type I error rates if interim analyses are planned, but less is known about the impact that potential stopping has on estimating treatment benefit. In this paper, we derive analytic expressions for (1) the over-estimation of benefit in studies that stop early, (2) the under-estimation of benefit in completed studies, and (3) the overall bias in studies with a stopping rule. We also examine the probability of stopping early and the situation in meta-analyses. Numerical evaluations show that the greatest concern is with over-estimation of benefit in stopped studies, especially if the probability of stopping early is small. The overall bias is usually less than 10% of the true benefit, and under-estimation in completed studies is also typically small. The probability of stopping depends on the true treatment effect and sample size. The magnitude of these effects depends on the particular rule adopted, but we show that the maximum overall bias is the same for all stopping rules. We also show that an essentially unbiased meta-analysis estimate of benefit can be recovered, even if some component studies have stopping rules. We illustrate these methods using data from three clinical trials. The results confirm our earlier empirical work on clinical trials. Investigators may consult our numerical results for guidance on potential mis-estimation and bias in the treatment effect if a stopping rule is adopted. Particular concern is warranted in studies that actually stop early, where interim results may be quite misleading. [ABSTRACT FROM AUTHOR]

Subgroup analyses are an essential part of fully understanding the complete results from confirmatory clinical trials. However, they come with substantial methodological challenges. In case no statistically significant overall treatment effect is found in a clinical trial, this does not necessarily indicate that no patients will benefit from treatment. Subgroup analyses could be conducted to investigate whether a treatment might still be beneficial for particular subgroups of patients. Assessment of the level of evidence associated with such subgroup findings is primordial as it may form the basis for performing a new clinical trial or even drawing the conclusion that a specific patient group could benefit from a new therapy. Previous research addressed the overall type I error and the power associated with a single subgroup finding for continuous outcomes and suitable replication strategies. The current study aims at investigating two scenarios as part of a nonconfirmatory strategy in a trial with dichotomous outcomes: (a) when a covariate of interest is represented by ordered subgroups, eg, in case of biomarkers, and thus, a trend can be studied that may reflect an underlying mechanism, and (b) when multiple covariates, and thus multiple subgroups, are investigated at the same time. Based on simulation studies, this paper assesses the credibility of subgroup findings in overall nonsignificant trials and provides practical recommendations for evaluating the strength of evidence of subgroup findings in these settings. [ABSTRACT FROM AUTHOR]

Lin et al. (http://www.biostatsresearch.com/upennbiostat/papers/, 2006) proposed a nested Markov compliance class model in the Imbens and Rubin compliance class model framework to account for time-varying subject noncompliance in longitudinal randomized intervention studies. We use superclasses, or latent compliance class principal strata, to describe longitudinal compliance patterns, and time-varying compliance classes are assumed to depend on the history of compliance. In this paper, we search for good subject-level baseline predictors of these superclasses and also examine the relationship between these superclasses and all-cause mortality. Since the superclasses are completely latent in all subjects, we utilize multiple imputation techniques to draw inferences. We apply this approach to a randomized intervention study for elderly primary care patients with depression. [ABSTRACT FROM AUTHOR]

When recruitment into a clinical trial is limited due to rarity of the disease of interest, or when recruitment to the control arm is limited due to ethical reasons (eg, pediatric studies or important unmet medical need), exploiting historical controls to augment the prospectively collected database can be an attractive option. Statistical methods for combining historical data with randomized data, while accounting for the incompatibility between the two, have been recently proposed and remain an active field of research. The current literature is lacking a rigorous comparison between methods but also guidelines about their use in practice. In this paper, we compare the existing methods based on a confirmatory phase III study design exercise done for a new antibacterial therapy with a binary endpoint and a single historical dataset. A procedure to assess the relative performance of the different methods for borrowing information from historical control data is proposed, and practical questions related to the selection and implementation of methods are discussed. Based on our examination, we found that the methods have a comparable performance, but we recommend the robust mixture prior for its ease of implementation. [ABSTRACT FROM AUTHOR]

Purpose To critically appraise scientific evidence regarding the efficacy of nutritional supplementation with omega-3 and omega-6 fatty acids for the treatment of dry eye syndrome (DES). Methods A systematic review of randomized clinical trials was performed. Two independent reviewers selected and analysed the scientific papers that met inclusion and exclusion criteria. Objective and subjective efficacy outcomes were assessed. Results The trials involved a total of 2591 patients in fifteen independent studies. All studies were published between 2005 and 2015. The supplements used were mostly omega-3 and omega-6 in different proportions. Subjective improvement was measured using mainly Ocular Surface Disease Index ( OSDI) test and Dry Eye Severity Score ( DESS) test: significant differences in favour of the experimental group were found in seven of the studies. The objective amelioration was assessed by lacrimal function parameters: Tear break-up time ( TBUT) significantly increased in nine studies and Schirmer's test in four studies. Conclusion We observed a discrete improvement in the parameters of tear function. Scientific evidence is not strong enough to systematically recommend the use of omega-3 and omega-6 fatty acids as a standalone treatment of DES independently from its aetiology. However, they could be considered as an effective alternative to topical treatment in patients with DES secondary to certain pathologies. [ABSTRACT FROM AUTHOR]

Objective To systematically review the published clinical trials, case series, and case reports on left unilateral ( LUL) electrode placement for clinical electroconvulsive therapy ( ECT). Method PubMed, Ovid Medline, and the Cochrane Library were searched for articles concerning LUL ECT. Number of patients, efficacy, and cognitive outcomes were extracted from the papers that met our inclusion criteria. Results A total of 52 articles were included in this review, consisting of 33 clinical trials, seven case series, and 12 case reports. Conclusion Overall, the efficacy of LUL electrode placement for the treatment of depression and psychosis is similar to that of right unilateral ( RUL) and bilateral ( BL) electrode placements. Patients receiving LUL ECT tend to experience more verbal memory impairment than patients receiving RUL ECT, but less verbal impairment than patients receiving BL ECT. In contrast, patients receiving LUL ECT tended to experience the least visual and nonverbal memory impairment, compared to patients receiving RUL or BL ECT. [ABSTRACT FROM AUTHOR]

Despite the availability of a number of different classes of therapeutic agents with proven efficacy in heart failure, the clinical course of heart failure patients is characterized by a reduction in life expectancy, a progressive decline in health-related quality of life and functional status, as well as a high risk of hospitalization. New approaches are needed to address the unmet medical needs of this patient population. The European Medicines Agency (EMA) is undertaking a revision of its Guideline on Clinical Investigation of Medicinal Products for the Treatment of Chronic Heart Failure. The draft version of the Guideline was released for public consultation in January 2016. The Cardiovascular Round Table of the European Society of Cardiology (ESC), in partnership with the Heart Failure Association of the ESC, convened a dedicated two-day workshop to discuss three main topic areas of major interest in the field and addressed in this draft EMA guideline: (i) assessment of efficacy (i.e. endpoint selection and statistical analysis); (ii) clinical trial design (i.e. issues pertaining to patient population, optimal medical therapy, run-in period); and (iii) research approaches for testing novel therapeutic principles (i.e. cell therapy). This paper summarizes the key outputs from the workshop, reviews areas of expert consensus, and identifies gaps that require further research or discussion. Collaboration between regulators, industry, clinical trialists, cardiologists, health technology assessment bodies, payers, and patient organizations is critical to address the ongoing challenge of heart failure and to ensure the development and market access of new therapeutics in a scientifically robust, practical and safe way. [ABSTRACT FROM AUTHOR]

The aim of this paper is to provide a description of a significant process which takes place during a first psychiatric hospitalization and to shed some light on its context. This process involves a transformation of an individual considered mentally disturbed into a psychiatric patient which affects the person's identity. The ‘person’ becomes a ‘psychiatric patient’. Although it is self-evident that a patient never stops being a person, the context of the first hospitalization merits attention as it is the time when the patient is in most danger of being objectified and depersonalized. The paper describes a study of forty-six patients hospitalized for the first time on a psychiatric ward and their seventy-five parents. Their narratives from the beginning and the end of stay in hospital were compared and the language used during the introductory consultation and discharge consultation analysed. In this process an important role is played by patients' parents. The parents' narratives are seen to change in a direction of acceptance but at the same time a process of stigmatization is apparent. [ABSTRACT FROM AUTHOR]

Background: Reading and interpreting results from research can be challenging. Many therapists read the abstract and discussion but confess to bypassing the results section of journal articles. Methods: This paper discusses necessary steps to reading the results section of a published randomised controlled trial. Recent clinical trials are used as examples. Results: An ability to read and interpret the results section of a paper requires the therapist to consider whether the tests conducted are appropriate, the results reported are accurate and the conclusions drawn by the authors are appropriate. Estimates of treatment effect sizes can be calculated by the therapist and used to determine if the effect of treatment is likely to be large enough to be “clinically worthwhile”. Conclusions: The ability to extract meaningful statistical information from clinical trials is a fundamental skill that will enhance therapists’ knowledge and understanding of evidence-based practice. [ABSTRACT FROM AUTHOR]

What is already known about this subject • The reviews already published on population pharmacokinetic/pharmacodynamic (PK/PD) analyses have focused on theory and have presented some clinical applications, evaluated validation practices in limited circumstances, defined the interest and sometimes the complexity of this approach in drug development or proposed a list of relevant articles. • None of them has exhaustively evaluated published analyses and more precisely the model-building steps. • In view of the statistical complexity of population PK/PD methodology, more attention is required to how models are built and how they are reported in the literature. What this study adds • With a strict methodology and by establishing a standardized tool, this survey provides an exhaustive, objective and up-to-date review of model-building practices. • It reveals deficiencies in information reporting in most articles and the genuine need for guidance in publishing. • An initial, minimal list of items is suggested, which can be used by authors and reviewers in pharmacology journals. • The value of published peer-reviewed papers could be greatly improved if authors were to address the suggested list of items systematically. Aims A descriptive survey of published population pharmacokinetic and/or pharmacodynamic (PK/PD) analyses from 2002 to 2004 was conducted and an evaluation made of how model building was performed and reported. Methods We selected 324 articles in Pubmed using defined keywords. A data abstraction form (DAF) was then built comprising two parts: general characteristics including article identification, context of the analysis, description of clinical studies from which the data arose, and model building, including description of the processes of modelling. The papers were examined by two readers, who extracted the relevant information and transmitted it directly to a MySQL database, from which descriptive statistical analysis was performed. Results Most published papers concerned patients with severe pathology and therapeutic classes suffering from narrow therapeutic index and/or high PK/PD variability. Most of the time, modelling was performed for descriptive purposes, with rich rather than sparse data and using NONMEM software. PK and PD models were rarely complex (one or two compartments for PK; Emax for PD models). Covariate testing was frequently performed and essentially based on the likelihood ratio test. Based on a minimal list of items that should systematically be found in a population PK–PD analysis, it was found that only 39% and 8.5% of the PK and PD analyses, respectively, published from 2002 to 2004 provided sufficient detail to support the model-building methodology. Conclusions This survey allowed an efficient description of recent published population analyses, but also revealed deficiencies in reporting information on model building. [ABSTRACT FROM AUTHOR]

Aims Over the last three decades, the randomized controlled trial or ‘psychotherapy technology’ approach has been the dominant model of inquiry in research on addiction treatment. This period has yielded impressive discoveries, but recent failures to confirm core research hypotheses such as occurred in Project MATCH and the Cocaine Collaborative Treatment Study have raised questions about future research directions. The paper identifies several testable assumptions of the psychotherapy technology model. Methods A review is conducted on four substance use disorder behavioral interventions—motivational interviewing, cognitive–behavioral treatment, behavioral couples treatment and 12-Step-oriented treatment—to determine whether these assumptions are supported by research findings. Results Overall, the review suggests weak support for the technology model of psychotherapy research. Lack of support is interpreted as indicating flaws in several model assumptions about how to conceptualize and measure patient responsivity and the interaction of non-specific and specific therapeutic factors. The paper offers alternative strategies for addressing these issues drawn from the general psychotherapy process literature and provides illustrative examples of how these could be used to spur innovation in addiction treatment research. Conclusions The addiction treatment research field is coming up against the limitations of the psychotherapy technology model as the dominant paradigm guiding treatment research. It is important for addiction treatment researchers to explore alternative conceptualizations and methodologies in order to understand more clearly how treatment works. [ABSTRACT FROM AUTHOR]

Purpose This is the third paper in a series that reviews strategies for optimizing the validity and utility of randomized clinical trials (RCTs) in addictions treatment research. Whereas the two previous papers focused on design and implementation, here we address issues pertaining to data processing and statistical analysis. Scope Recommendations for enhancing data quality and utility are offered in sections on data coding and entry; and data format, structure and management. We discuss the need for preliminary data analyses that examine statistical power; patterns of attrition; between-group equivalence; and treatment integrity and discriminability. We discuss tests of treatment efficacy, as well as ancillary analyses aimed at explicating treatment processes. Conclusions Safeguards are necessary to protect data quality, and advance planning is needed to ensure that data formats are compatible with statistical objectives. In addition to treatment efficacy, statistical analyses should evaluate study internal and external validity, and investigate the change mechanisms that underlie treatment effects. [ABSTRACT FROM AUTHOR]

Antimuscarinic drugs are generally thought to exert their therapeutic action on detrusor overactivity by reducing the ability of the detrusor muscle to contract. We review currently available published data to establish whether there is any evidence to support this contention. Using a PubMed data search, only 14 original articles (including two abstracts) were found that contained cystometric data for both filling and voiding phases and where the actions of antimuscarinic drugs have been reported in detail. These articles were separated into three groups dealing with neuropathic patients (three papers), patients with idiopathic overactive bladder (four papers) and a group whose aetiology was unclear (seven papers). Variables relating to bladder function during the filling phase (time of first desire to void, time to first unstable contraction, and bladder capacity) were identified. Similarly, variables relating to voiding were identified and compared (e.g. maximum detrusor pressure and detrusor pressure at maximum flow rate). The antimuscarinic drugs have a clearly significant effect on sensations of urge, time to first sensation to void, maximum bladder capacity, decrease in voiding frequency and reduction in incontinence episodes. However, only one article (studying neuropaths) reported a significant reduction of the variables associated with detrusor contraction. The remaining four studies (idiopaths/not stated), reported no change in bladder contractility with antimuscarinic drugs. Thus the available data do not support the conclusion that antimuscarinic drugs at doses used in current clinical practice exert their therapeutic action by inhibiting detrusor contractility, but they suggest effects on variables associated with sensation. [ABSTRACT FROM AUTHOR]

The purpose of this paper is to summarize the state of the art in measuring quality of life in haemophila populations. The paper reviews the measures recently included in haemophila trials in the published literature. It also summarizes the development of four new disease-specific measures of health-related quality of life. Two of these were developed for children (the Haemo-QoL and the CHO-KLAT), and two for adults (the Hemofilia-QoL and the Hemolatin-QoL). These new measures show promise for use in clinical trials. Further research is in progress to complete the psychometric testing and cross-cultural validation. [ABSTRACT FROM AUTHOR]

Although alcohol use disorders are commonly associated with co-morbid drug use and psychiatric disorders, such co-morbidity is frequently underdiagnosed and inadequately treated. This paper reviews the epidemiological, diagnostic, and treatment literature on the co-morbidity of alcoholism, with a focus on the most common co-morbid disorders: drug abuse, mood disorders, anxiety disorders, and antisocial personality disorder. The paper goes on to describe a number of promising approaches to the treatment of these common co-morbid disorders in alcoholics. Despite the difficulties inherent in treating dual diagnosis patients, the clinician must recognize that it is possible to derive valid diagnoses and deliver efficacious treatment to such patients. [ABSTRACT FROM AUTHOR]

The current popularity of complementary therapies presents an interesting challenge to nurses and midwives. If they are to deliver such therapies themselves, or support patients in choosing appropriate therapies they will need to consider the professional and legal issues, in particular those regarding safety. Evidence for the effectiveness for complementary therapies is also a requirement in order that their integration into nursing practice can be justified. Purchasers are currently hampered by the lack of credible evidence for effectiveness and until that evidence is provided, access to such therapies through the National Health Service (NHS) will remain limited. The form that evidence should take has led to a lively debate about possible methodological approaches. There appears to be a clash between the medical profession and those working in the field of complementary therapy research, with the medical establishment advocating randomized control trials (RCTs). This contrasts with the view held by some advocates of complementary therapies that the RCT approach is reductionist and not applicable to such approaches. The pivot of the debate on the methodological approaches for evaluating complementary therapies is the contrast of two apparently different and diverse world-views, and the assertion that methods developed in one world-view are not transferable to the other. There is also some confusion within the field of complementary therapy over the applicability of RCTs to therapies such as acupuncture, and the mistaken assumption that trials which include a control group, are also required to be double-blind. This paper is based on the need for good quality evidence of effectiveness in complementary therapy. It will set out the concerns associated with the use of RCTs within complementary therapy, together with the benefits and limitations of this approach. The paper will go on to review research options and propose some suggestions for future methodological approaches. [ABSTRACT FROM AUTHOR]

Generalized estimating equations (GEE) is a general statistical method to fit marginal models for longitudinal data in biomedical studies. The variance-covariance matrix of the regression parameter coefficients is usually estimated by a robust "sandwich" variance estimator, which does not perform satisfactorily when the sample size is small. To reduce the downward bias and improve the efficiency, several modified variance estimators have been proposed for bias-correction or efficiency improvement. In this paper, we provide a comprehensive review on recent developments of modified variance estimators and compare their small-sample performance theoretically and numerically through simulation and real data examples. In particular, Wald tests and t-tests based on different variance estimators are used for hypothesis testing, and the guideline on appropriate sample sizes for each estimator is provided for preserving type I error in general cases based on numerical results. Moreover, we develop a user-friendly R package "geesmv" incorporating all of these variance estimators for public usage in practice. [ABSTRACT FROM AUTHOR]

In many randomized controlled trials, treatment groups are of equal size, but this is not necessarily the best choice. This paper provides a methodology to calculate optimal treatment allocations for longitudinal trials when we wish to compare multiple treatment groups with a placebo group, and the comparisons may have unequal importance. The focus is on trials with a survival endpoint measured in discrete time. We assume the underlying survival process is Weibull and show that values for the parameters in the Weibull distribution have an impact on the optimal treatment allocation scheme in an interesting way. Additionally, we incorporate different cost considerations at the subject and measurement levels and determine the optimal number of time periods. We also show that when many events occur at the beginning of the trial, fewer time periods are more efficient. As an application, we revisit a risperidone maintenance treatment trial in schizophrenia and use our proposed methodology to redesign it and compare merits of our optimal design. [ABSTRACT FROM AUTHOR]

Background The primary goals in conducting clinical trials of treatments for alcohol use disorders ( AUDs) are to identify efficacious treatments and determine which treatments are most efficacious for which patients. Accurate reporting of study design features and results is imperative to enable readers of research reports to evaluate to what extent a study has achieved these goals. Guidance on quality of clinical trial reporting has evolved substantially over the past 2 decades, primarily through the publication and widespread adoption of the Consolidated Standards of Reporting Trials statement. However, there is room to improve the adoption of those standards in reporting the design and findings of treatment trials for AUD. Methods This paper provides a narrative review of guidance on reporting quality in AUD treatment trials. Results Despite improvements in the reporting of results of treatment trials for AUD over the past 2 decades, many published reports provide insufficient information on design or methods. Conclusions The reporting of alcohol treatment trial design, analysis, and results requires improvement in 4 primary areas: (i) trial registration, (ii) procedures for recruitment and retention, (iii) procedures for randomization and intervention design considerations, and (iv) statistical methods used to assess treatment efficacy. Improvements in these areas and the adoption of reporting standards by authors, reviewers, and editors are critical to an accurate assessment of the reliability and validity of treatment effects. Continued developments in this area are needed to move AUD treatment research forward via systematic reviews and meta-analyses that maximize the utility of completed studies. [ABSTRACT FROM AUTHOR]

A previous paper described a suggested protocol which could be used for testing therapeutic measures. In this paper the protocol has been used as a basis for testing experimental toothpastes over short and medium periods of time. The effects on plaque and gingivitis of a chlorhexidine paste used for 4 weeks, and of two other experimental products used over 8 weeks, have been investigated. Statistically significant improvements in gingivitis were observed during the use of chlorhexidine and one of the experimental pastes compared with their respective placebo pastes. The benefit observed for the experimental paste became evident when the data were analyzed considering only participants with 'frank' gingivitis. The findings have also been presented in various ways in attempts to express the benefits of the therapeutic measures in clinical terms by using arbitrarily determined success criteria. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is one of the most disabling diseases worldwide and is becoming a significant public health threat. Current treatments forMDDprimarily consist of monoamine-targeting agents and have limited efficacy. However, the glutamate neurotransmitter system has recently come into focus as a promising alternative for novel antidepressant treatments. We review the current data on the glutamate NMDA receptor antagonist ketamine, which has been shown in clinical trials to act as a rapid antidepressant inMDD.We also examine ketamine efficacy on dimensions of psychopathology, including anhedonia, cognition, and suicidality, consistent with theNIMH Research Domain Criteria initiative. Other aspects of ketamine reviewed in this paper include safety and efficacy, different administration methods, and the risks of misuse of ketamine outside of medical settings. Finally, we conclude with a discussion of glutamatergic agents other than ketamine currently being tested as novel antidepressants. [ABSTRACT FROM AUTHOR]

Background Maternal depression is associated with poor child development and growth in low-income countries. This paper evaluates the effect of a community-based trial providing psychosocial stimulation and food supplements to severely malnourished children on maternal depressive symptoms in Bangladesh. Methods Severely underweight (weight-for-age Z-score < −3) hospitalized children aged 6-24 months ( n = 507), were randomly assigned to: psychosocial stimulation ( PS), food supplementation ( FS), PS+ FS, clinic control ( CC) and hospital control ( CH) at discharge. PS included play sessions with children and parental counselling to mothers during fortnightly follow-up visit at community clinics, conducted by trained play leaders for 6 months. FS involved cereal-based supplements (150-300 kcal/day) for 3 months. All groups received medical care, micronutrient supplements and growth monitoring. We used Bayley scales, Home Observation for Measurement of Environment ( HOME) inventory and a parenting questionnaire to assess child development, home stimulation and mothers' child-rearing practices, respectively. We assessed mothers' depressive symptoms using a modified version of Centre for Epidemiologic Studies Depression Scale at baseline and at 6 months post intervention. Results Maternal depressive symptoms were significantly lower in the CH group at baseline ( P = 0.014). After 6 months of intervention there was no significant effect of intervention after adjusting for baseline scores and all possible confounders. Maternal depressive symptoms were higher among poorer ( P = 0.06), older ( P = 0.057) and less educated ( P = 0.019) mothers, who were housewives ( P = 0.053), and whose husbands had more unstable jobs ( P = 0.058). At 6 months post intervention, children's cognitive ( P = 0.045) and motor ( P = 0.075) development, HOME ( P = 0.012) and mother's parenting score ( P = 0.057) were higher among mothers with lower depressive symptoms. Conclusion The study did not show a significant effect of the intervention on the level of maternal depressive symptoms. Interventions with higher intensity and/or of longer duration focusing directly on maternal psychosocial functioning are probably needed to reduce maternal depressive symptoms. [ABSTRACT FROM AUTHOR]

Multi-country randomised clinical trials (MRCTs) are common in the medical literature, and their interpretation has been the subject of extensive recent discussion. In many MRCTs, an evaluation of treatment effect homogeneity across countries or regions is conducted. Subgroup analysis principles require a significant test of interaction in order to claim heterogeneity of treatment effect across subgroups, such as countries in an MRCT. As clinical trials are typically underpowered for tests of interaction, overly optimistic expectations of treatment effect homogeneity can lead researchers, regulators and other stakeholders to over-interpret apparent differences between subgroups even when heterogeneity tests are insignificant. In this paper, we consider some exploratory analysis tools to address this issue. We present three measures derived using the theory of order statistics, which can be used to understand the magnitude and the nature of the variation in treatment effects that can arise merely as an artefact of chance. These measures are not intended to replace a formal test of interaction but instead provide non-inferential visual aids, which allow comparison of the observed and expected differences between regions or other subgroups and are a useful supplement to a formal test of interaction. We discuss how our methodology differs from recently published methods addressing the same issue. A case study of our approach is presented using data from the Study of Platelet Inhibition and Patient Outcomes (PLATO), which was a large cardiovascular MRCT that has been the subject of controversy in the literature. An R package is available that implements the proposed methods. [ABSTRACT FROM AUTHOR]

Objective: Inattention is a core feature of delirium, and valid assessment of attention is central to diagnosis. Methods of measuring attention in delirium can be divided into two broad categories: (i) objective neuropsychological testing; and (ii) subjective grading of behaviour during interview and clinical examination. Here, we review and critically evaluate studies of objective neuropsychological testing of attention in delirium. We examine the implications of these studies for delirium detection and monitoring in clinical practice and research, and how these studies inform understanding of the nature of attentional deficits in delirium. Methods: Searches of MEDLINE and ISI Web of Knowledge databases were performed to identify studies in which objective tests of attention had been administered to patients with delirium, who had been diagnosed using DSM or ICD criteria. Results: Sixteen publications were identified. The attention tests administered in these studies were grouped into the following categories: measures of attention span, vigilance tests, other pen-andpaper tests (e.g. Trail Making Test) and computerised tests of speeded reaction, vigilance and sustained attention. Patients with delirium showed deficits on all tasks, although most tasks were not considered pure measures of attention. Five papers provided data on differential diagnosis from dementia. Cancellation tests, spatial span tests and computerised tests of sustained attention discriminated delirium from dementia. Five studies presented reliability or validity statistics. Conclusions: The existing evidence base on objective assessment of attention in delirium is small. Objective testing of attention is underdeveloped but shows considerable promise in clinical practice and research. [ABSTRACT FROM AUTHOR]

Prior to 2010, docetaxel was the standard option for chemotherapy in men with metastatic castration-resistant prostate cancer ( mCRPC). Today, the picture is vastly different: several additional therapies have each demonstrated a survival benefit such that we now have chemotherapy (cabazitaxel), androgen suppressive agents (abiraterone acetate and enzalutamide), a cellular vaccine (sipuleucel- T) and radium-233 (for symptomatic bone metastases). With several other agents in the pipeline for late-stage disease, the future looks promising for mCRPC. As the available data are not able to inform as to the optimum sequencing of therapy, this remains a challenge. This paper draws on insights from published and ongoing clinical studies to provide a practical patient-focused approach to maximize the benefits of the current therapeutic armamentarium. Preliminary sequencing suggestions are made based on clinical trial criteria. But until more data become available, clinical gestalt, experience, cost and individual patient preferences will continue to drive choices. [ABSTRACT FROM AUTHOR]

Comorbidity is a well-established and documented phenomenon in mental disorders and medicine with heuristic value. The concept of comorbidity remains however poorly defined and lacks a comprehensive and coherent theoretical framework. There is a need to develop coherent methodological strategies in order to promote a fuller understanding of the implications of comorbidity and to exploit its potential value with regard to etiopathogenic and therapeutic issues. This position paper makes recommendations of improved methodological standards and procedures and discusses a range of options that can provide incremental information that is likely to improve therapeutic outcomes. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The safety of trial subjects is the tenet that guides the regulatory assessment of a Clinical Trial Authorization application and applies equally to trials involving small molecules and those with biological/biotechnological products, including Advanced Therapy Medicinal Products. The objective of a regulator is to ensure that the potential risk faced by a trial subject is outweighed by the potential benefit to them from taking part in the trial. The focus of the application review is to assess whether risks have been identified and appropriate steps taken to alleviate these as much as possible. Other factors are also taken into account during a review, such as regulatory requirements, and emerging non-clinical and clinical data from other trials on the same or similar products. This paper examines the regulatory review process of a Clinical Trial Authorization application from the perspectives of Quality, Non- Clinical and Clinical Regulatory Assessors at the Medicines and Healthcare products Regulatory Agency. It should be noted that each perspective has highlighted specific issues from their individual competence and that these can be different between the disciplines. [ABSTRACT FROM AUTHOR]

Pirfenidone has been shown in three recently published trials to slow down the progression of the devastating interstitial lung disease, idiopathic pulmonary fibrosis ( IPF). The precise mechanisms that initiate and perpetuate the histopathological process leading to lung fibrosis in IPF are still uncertain, but increased concentrations of reactive oxidative species and fibrogenetic factors have been observed in the pulmonary tissue of patients. Although the exact mechanisms of its action are unknown, pirfenidone is a small molecule with antifibrotic and some hydroxyl scavenger properties that has recently been approved in Europe and elsewhere for the treatment of IPF. Along with the new ATS/ ERS/ JRS/ ALAT 2011 statement for ' Evidence Based Guidelines for Diagnosis and Management', there is now a more profound basis for offering IPF patients an evidence-based evaluation and treatment. This review summarizes the background to the recommended use of pirfenidone for the treatment of IPF. Please cite this paper as: Hilberg O, Simonsen U, du Bois R and Bendstrup E. Pirfenidone: significant treatment effects in idiopathic pulmonary fibrosis. Clin Respir J 2012; 6: 131-143. [ABSTRACT FROM AUTHOR]

The endogenous opioid system has been implicated in the pathophysiology of alcoholism as it modulates the neurobehavioral effects of alcohol. A variant in the mu opioid receptor gene ( OPRM1), the Asn40Asp polymorphism, has received attention as a functional variant that may influence a host of behavioral phenotypes for alcoholism as well as clinical response to opioid antagonists. This paper will review converging lines of evidence on the effect of the Asn40Asp SNP on alcoholism phenotypes, including: (i) genetic association studies; (ii) behavioral studies of alcoholism; (iii) neuroimaging studies; (iv) pharmacogenetic studies and clinical trials; and (v) preclinical animal studies. Together, these lines of research seek to elucidate the effects of this functional polymorphism on alcoholism etiology and treatment response. [ABSTRACT FROM AUTHOR]

What's known on the subject? and What does the study add? Robotic surgery in its current form has established itself as a viable treatment option for several indications and the gold standard for a few indications. This has occurred because of the improved technology built into the robotics system. This paper looks at the brief history of robotics in surgery. Then we review in more detail some of the future possible additions to the technological armamentarium that might significantly improve the ways that surgeons perform robotic surgery. [ABSTRACT FROM AUTHOR]

OBJECTIVE • To evaluate the impact of urisheaths vs absorbent products (APs) on quality of life (QoL) in men with moderate to severe urinary incontinence (UI). PATIENTS AND METHODS • A randomized, controlled, crossover trial in 61 outpatient adult men with stable, moderate to severe UI, with no concomitant faecal incontinence, was conducted from June 2007 to February 2009 in 14 urology centres. • Participants tested Conveen Optima urisheaths (Coloplast, Humlebaek, Denmark) with collecting bags and their usual AP in random order for 2 weeks each. • The impact of each on QoL was measured using the King’s Health Questionnaire (KHQ) and the short form-12 acute questionnaire, and each patient’s preference was recorded. • A 10-item patient questionnaire was also used to assess the product main advantages on an 11 point scale (0: worst; 10: best). A 72-h leakage diary was used to record the number and severity of leaks and daily product consumption. Safety was measured as the number of local adverse events. RESULTS • All dimensions of the KHQ were scored lower with urisheaths, indicating an improvement in QoL. The greatest mean score reductions were in Limitations of Daily Activities ( − 10.24, P= 0.01) and Incontinence Impact ( −7.05, P = 0.045). • The majority (69%) of patients preferred Conveen Optima urisheaths to their usual AP ( P = 0.002). • Urisheaths scored significantly higher for all categories in the patient questionnaire (efficacy, self-image, odour management, discretion, skinintegrity) except ease of use. • Safety was considered to be good. CONCLUSIONS • Conveen Optima urisheaths showed apositive impact on QoL (according to the KHQ results) in moderate to severe incontinent men, who were long-term usersof APs, and participants largely preferred urisheaths. • Conveen Optima urisheaths should be recommended to incontinent men in preference to APs. [ABSTRACT FROM AUTHOR]

The paper proposes the Brick tunnel (BT) randomization for studies with unequal allocation to two or more treatment groups. This allocation procedure generalizes the maximal procedure by V. W. Berger, A. Ivanova, and M. Knoll to the case of "K is greater than or equal to 2" treatment groups and any allocation ratio. The employment of unequal allocation in clinical trials, the features of permuted block randomization, and the important property of BT randomization are also discussed.

Mayer KH, Venkatesh KK. Interactions of HIV, other sexually transmitted diseases, and genital tract inflammation facilitating local pathogen transmission and acquisition. Am J Reprod Immunol 2011; 65: 308-316 Despite several decades of clinical trials assessing the impact of etiological treatment of sexually transmitted diseases (STDs) to decrease HIV acquisition and transmission, almost all of these trials have not proven to be efficacious. Increasing evidence suggests that specific STD treatment alone may not be sufficient to alter the genital tract inflammatory milieu that is created by STDs. This paper examines the associations between STDs and HIV susceptibility and infectiousness, and considers the role of chronic and refractory inflammation to create an environment that potentiates HIV and STD transmission and acquisition by reviewing biological, observational, and clinical trial data [ABSTRACT FROM AUTHOR]

Some participants will get HIV-infected in HIV prevention trials, despite risk reduction measures. The subsequent treatment responsibilities of sponsor-investigators have been widely debated, especially where access to antiretroviral therapy (ART) is not available. In this paper, we explore two accounts of beneficence to establish whether they can shed light on sponsor-investigator responsibilities. We find the notion of general beneficence helpful insofar as it clarifies that some beneficent actions will be obligatory where they can be dispensed without scuppering the trial. We find the notion of specific beneficence helpful insofar as it directs investigators to attend to the needs of trial participants; however the range of interventions that could be provided remains unhelpfully broad. We then examine accounts of the investigator-participant relationship to narrow the range of interventions that investigators should provide, concluding that health-care, and HIV infection, are appropriate foci. We conclude that when investigators are able to meet the ART needs of their participants (e.g. referral, assisted referral or direct provision) without sacrificing trial quality, they must do so. However, there is little of this explicit direction to be found in the account of specific beneficence itself, but rather it is found in accounts of the relationship that are compatible with beneficence. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Meisner and Price (2010). Spatial and Temporal Coordination of Bone Marrow-Derived Cell Activity during Arteriogenesis: Regulation of the Endogenous Response and Therapeutic Implications. Microcirculation 17(8), 583-599. Abstract Arterial occlusive disease is the leading cause of morbidity and mortality throughout the developed world, which creates a significant need for effective therapies to halt disease progression. Despite success of animal and small-scale human therapeutic arteriogenesis studies, this promising concept for treating arterial occlusive disease has yielded largely disappointing results in large-scale clinical trials. One reason for this lack of successful translation is that endogenous arteriogenesis is highly dependent on a poorly understood sequence of events and interactions between bone marrow derived cells (BMCs) and vascular cells, which makes designing effective therapies difficult. We contend that the process follows a complex, ordered sequence of events with multiple, specific BMC populations recruited at specific times and locations. Here, we present the evidence suggesting roles for multiple BMC populations-from neutrophils and mast cells to progenitor cells-and propose how and where these cell populations fit within the sequence of events during arteriogenesis. Disruptions in these various BMC populations can impair the arteriogenesis process in patterns that characterize specific patient populations. We propose that an improved understanding of how arteriogenesis functions as a system can reveal individual BMC populations and functions that can be targeted for overcoming particular impairments in collateral vessel development. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Siassakos D, Draycott T, Crofts J, Hunt L, Winter C, Fox R. More to teamwork than knowledge, skill and attitude. BJOG 2010;117:1262–1269. Objective To assess whether team performance in simulated eclampsia is related to the knowledge, skills and attitudes of individual team members. Design Cross-sectional analysis of data from the Simulation and Fire Drill Evaluation randomised controlled trial. Setting Six secondary and tertiary maternity units in south-west England. Participants One hundred and fourteen maternity professionals in 19 teams of six members; one senior and one junior obstetrician; two senior and two junior midwives. Methods We validated a team performance ranking scheme with respect to magnesium administration (Magnesium Administration Rank, MAR) by expert consensus (face validity) and correlation with clinical measures (construct validity). We tested for correlation between MAR and measures of knowledge, skills and attitudes. Main outcome measures Correlation between team performance (MAR) and scores in validated multiple-choice questionnaires (MCQs) (knowledge), a measure of individual manual skill to manage an obstetric emergency (skill) and scores in a widely used teamwork/safety attitude questionnaire (attitude). Results There was no relationship between team performance and cumulative individual MCQs, skill or teamwork/safety attitude scores. Conclusions The knowledge, manual skills and attitudes of the individuals comprising each team, measured by established methods, did not correlate in this study with the team’s clinical efficiency in the management of simulated eclampsia. The inference is that unidentified characteristic(s) play a crucial part in the efficiency of teams managing emergencies. Any emphasis of training programmes to promote individual knowledge, skills and attitudes alone may have to be re-examined. This highlights a need to understand what makes a team efficient in dealing with clinical emergencies. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Naik R, Jackson K, Lopes A, Cross P, Henry J. Laparoscopic assisted radical vaginal hysterectomy versus radical abdominal hysterectomy—a randomised phase II trial: perioperative outcomes and surgicopathological measurements. BJOG 2010; DOI: 10.1111/j.1471-0528.2010.02479.x. Objective To evaluate perioperative surgical outcomes and resection size for laparoscopically assisted radical vaginal hysterectomy (LARVH) compared with radical abdominal hysterectomy (RAH). Design A prospective randomised phase II trial. Population Early stage IB cervical cancer requiring radical surgical treatment. Setting Northern Gynaecological Oncology Centre, Gateshead, UK. Methods Fifteen women were randomised to LARVH and to RAH. Main outcome measures Outcomes included requirement in days for bladder catheterisation after surgery, operating time, blood loss, hospital stay, opiate pain relief, complication rate, time to normal activities and resection size of major ligaments and vaginal cuff. Results Statistically significant differences were found between LARVH and RAH, respectively: median duration of bladder catheterisation, 4 days versus 21 days ( P = 0.003); median operating time, 180 minutes versus 138 minutes ( P = 0.05); median blood loss, 400 ml versus 1000 ml ( P = 0.05), median hospital stay, 5 days versus 7 days ( P = 0.04) and median opiate requirement in the first 36 hours postoperatively, 30 mg versus 53 mg ( P = 0.004). The mean resected lengths for LARVH versus RAH, respectively, were: mean resected vaginal cuff, 1.26 cm versus 2.16 cm ( P = 0.014); mean resected cardinal ligament length, 1.30 cm versus 2.79 cm ( P = 0.013) and mean resected uterosacral ligament length, 1.47 cm versus 4.68 cm ( P = 0.034). Conclusions This study confirms the short-term surgical benefits of LARVH. In addition, LARVH has been shown to be a less radical procedure than RAH, supporting the need for strict patient selection and to restrict the procedure to small tumours. [ABSTRACT FROM AUTHOR]

Aim: To assess the use of a new repaglinide/metformin fixed-dose combination (FDC) tablet for the treatment of type 2 diabetes. Methods: In this 26-week, multicentre, open-label, parallel-group trial, subjects poorly controlled with mono- or dual-oral antidiabetic therapy were randomized 1 : 1 : 1 to receive a repaglinide/metformin FDC tablet either two times daily (BID) or three times daily (TID) or a rosiglitazone/metformin FDC tablet BID. The primary objective comprised two hypotheses tested in a hierarchical order: (i) that treatment with the repaglinide/metformin FDC BID is non-inferior to that of a rosiglitazone/metformin FDC tablet BID as measured by changes in haemoglobin A1c (HbA1c) (results presented here) and (ii) if true, that treatment with the repaglinide/metformin FDC BID was non-inferior to that of the repaglinide/metformin FDC TID as measured by changes in HbA1c (results presented in a companion paper). Additional efficacy and safety end-points were also assessed. Results: Of the 561 subjects randomized, 383 completed the study. Reductions in HbA1c values became apparent at earlier times for repaglinide/metformin FDC BID treatment than rosiglitazone/metformin FDC BID, and final changes in HbA1c were not significantly different between treatment arms (p = 0.8186); thus, the predefined statistical criterion for non-inferiority was met. Overall adverse event profiles were comparable between treatment groups, and no major hypoglycaemic episodes were reported during the study. Conclusions: The repaglinide/metformin FDC BID regimen showed efficacy that was non-inferior to that of the rosiglitazone/metformin FDC BID regimen currently in clinical use and a more rapid reduction of HbA1c values. Thus, repaglinide/metformin FDC BID is a clinically feasible alternative to rosiglitazone/metformin FDC BID. [ABSTRACT FROM AUTHOR]

The paper proposes an optimal response-adaptive procedure for a general class of responses using a combination of two clinically relevant optimality criteria. We provide a thorough development for trials involving two treatments and sketch the possible extension for multiple treatments. Some related asymptotic results are worked out. We provide simulation studies to compare the performance of the proposed procedure with some of the existing competitors. We illustrate our methodology on data from a real clinical trial. [ABSTRACT FROM AUTHOR]

Pathological vascular remodelling is a key contributor to the symptomatology of pulmonary arterial hypertension (PAH), and reversing this process may offer the best hope for improving this debilitating condition. The vascular remodelling process is believed to be due to endothelial cell dysfunction and to involve altered production of endothelial cell-derived vasoactive mediators. The observation that circulating plasma levels of the vasoactive peptide endothelin (ET)-1 are raised in patients with PAH, and that ET-1 production is increased in the pulmonary tissue of affected individuals, makes it a particularly interesting target for a therapeutic intervention in PAH. Clinical trials with ET receptor antagonists (ETRAs) show that they provide symptomatic benefit in patients with PAH, thereby proving the clinical relevance of the ET system as a therapeutic target. In this paper, we review the role of ET-1 together with the available data on the roles of the specific ET receptors and ETRAs in PAH. In particular, we discuss the possible role of ET receptor selectivity in the vascular remodelling process in PAH and whether selective ETA or nonselective ETA/ETB blockade offers the greatest potential to improve symptoms and alter the clinical course of the disease. [ABSTRACT FROM AUTHOR]