Status of high-dose chemotherapy for breast cancer: a review.

The purpose of this review is to analyze the current status of high-dose chemotherapy (HDCT) with autologous stem cell transplantation for patients with breast cancer. Current results from the major prospective phase 2 and phase 3 trials in metastatic breast cancer (MBC) and high-risk primary breast cancer (HRPBC) are reviewed. Prognostic factors and future research directions are also discussed. The encouraging results of phase 2 trials suggested a benefit for HDCT in HRPBC and some categories of patients with MBC. Some investigators have argued that patient selection might have been a critical factor in those studies. Recently reported randomized trials in patients with chemosensitive MBC have included only small numbers of patients in complete remission and thus have not adequately addressed the relative value of HDCT versus maintenance standard-dose chemotherapy in this patient subset. Although initial results of 2 studies have been reported, most randomized phase 3 studies of HDCT in HRPBC require longer follow-up before definitive conclusions can be made about its efficacy in this setting. We conclude that the role of HDCT for HRPBC or MBC patients has not yet been fully defined. Longer follow-up of the ongoing randomized trials is necessary, and their mature results will help clarify this important question. In the meantime, it is imperative that research continues, to enhance the efficacy of the procedure. This may come through incorporating more active drugs into HDCT regimens and combining HDCT with novel strategies aimed at eradication of posttransplantation minimal residual disease.     

A Systematic Review of the Quality of Trials Evaluating Biomedical HIV Prevention Interventions Shows That Many Lack Power

Abstract

Purpose: Several randomized, controlled trials (RCTs) have tested strategies to prevent sexual acquisition of HIV infection, but their quality has been variable. We aimed to identify, describe, and evaluate the quality of RCTs studying biomedical interventions to prevent HIV acquisition by sexual transmission. Method: We conducted a systematic review to identify all RCTs evaluating the efficacy of biomedical HIV prevention interventions. We assessed seven generic and content-specific quality components important in HIV prevention trials, factors influencing study power, co-interventions provided, and trial ethics. Results: We identified 26 eligible RCTs. The median number of quality components judged to be in adequate or unclear was 3 (range 1–4) in 1992–1998, 3 (range 1–4) in 1999–2003, and 0 (range0–2) in 2004–2008 (p < .001). Common problems that may have biased results included low retention (median 84%), poor adherence to interventions requiring on going use (median ≤78%), and lower HIV incidence than expected a priori (in 8 of 11 trials where evaluable). Conclusion: Reporting of trials of biomedical HIV prevention interventions has improved over time. However, quality improvement is needed in several key areas that influence study power, including participant retention, adherence to interventions, and estimation of expected HIV incidence.     

Adherence in Internet Interventions for Anxiety and Depression: Systematic Review

Background

Open access websites which deliver cognitive and behavioral interventions for anxiety and depression are characterised by poor adherence. We need to understand more about adherence in order to maximize the impact of Internet-based interventions on the disease burden associated with common mental disorders.

Objective

The aims of this paper are to review briefly the adherence literature with respect to Internet interventions and to investigate the rates of dropout and compliance in randomized controlled trials of anxiety and depression Web studies.

Methods

A systematic review of randomized controlled trials using Internet interventions for anxiety and depression was conducted, and data was collected on dropout and adherence, predictors of adherence, and reasons for dropout.

Results

Relative to reported rates of dropout from open access sites, the present study found that the rates of attrition in randomized controlled trials were lower, ranging from approximately 1 - 50%. Predictors of adherence included disease severity, treatment length, and chronicity. Very few studies formally examined reasons for dropout, and most studies failed to use appropriate statistical techniques to analyze missing data.

Conclusions

Dropout rates from randomized controlled trials of Web interventions are low relative to dropout from open access websites. The development of theoretical models of adherence is as important in the area of Internet intervention research as it is in the behavioral health literature. Disease-based factors in anxiety and depression need further investigation.     

The prevention and treatment of complicated grief: a meta-analysis

Background

Bereaved individuals are at increased risk of mental and physical disorders, and prevention and treatment of complicated grief is indicated. Earlier quantitative reviews have not focused on the effect of bereavement interventions on (complicated) grief. Therefore the main objective of this meta-analysis was to determine the short-term and long-term effect of both preventive and treatment interventions on complicated grief.

Methods

Randomized controlled trials for prevention or treatment of complicated grief were identified through a systematic literature search. Electronic databases and reference lists of earlier review articles served as data sources. Data were analyzed with REVMAN 5.0.14.

Results

Fourteen randomized controlled trials met the inclusion criteria. Study quality differed among the trials. Contrary to preventive interventions, treatment interventions yielded significant pooled standardized mean differences in favor of the (specific) grief intervention at post-test and follow-up. During the follow-up period, the positive effect of treatment interventions for complicated grief even increased.

Conclusions

Treatment interventions can effectively diminish complicated grief symptoms. Preventive interventions, on the other hand, do not appear to be effective. Limitations of the meta-analysis and future research options are discussed.     

Impact and costs of incentives to reduce attrition in online trials: two randomized controlled trials

Background

Attrition from follow-up is a major methodological challenge in randomized trials. Incentives are known to improve response rates in cross-sectional postal and online surveys, yet few studies have investigated whether they can reduce attrition from follow-up in online trials, which are particularly vulnerable to low follow-up rates.

Objectives

Our objective was to determine the impact of incentives on follow-up rates in an online trial.

Methods

Two randomized controlled trials were embedded in a large online trial of a Web-based intervention to reduce alcohol consumption (the Down Your Drink randomized controlled trial, DYD-RCT). Participants were those in the DYD pilot trial eligible for 3-month follow-up (study 1) and those eligible for 12-month follow-up in the DYD main trial (study 2). Participants in both studies were randomly allocated to receive an offer of an incentive or to receive no offer of an incentive. In study 1, participants in the incentive arm were randomly offered a £5 Amazon.co.uk gift voucher, a £5 charity donation to Cancer Research UK, or entry in a prize draw for £250. In study 2, participants in the incentive arm were offered a £10 Amazon.co.uk gift voucher. The primary outcome was the proportion of participants who completed follow-up questionnaires in the incentive arm(s) compared with the no incentive arm.

Results

In study 1 (n = 1226), there was no significant difference in response rates between those participants offered an incentive (175/615, 29%) and those with no offer (162/611, 27%) (difference = 2%, 95% confidence interval [CI] –3% to 7%). There was no significant difference in response rates among the three different incentives offered. In study 2 (n = 2591), response rates were 9% higher in the group offered an incentive (476/1296, 37%) than in the group not offered an incentive (364/1295, 28%) (difference = 9%, 95% CI 5% to 12%, P < .001). The incremental cost per extra successful follow-up in the incentive arm was £110 in study 1 and £52 in study 2.

Conclusion

Whereas an offer of a £10 Amazon.co.uk gift voucher can increase follow-up rates in online trials, an offer of a lower incentive may not. The marginal costs involved require careful consideration.

Trial registration

ISRCTN31070347; http://www.controlled-trials.com/ISRCTN31070347 (Archived by WebCite at http://www.webcitation.org/5wgr5pl3s)     

Study designs of randomized controlled trials not based on Chinese medicine theory are improper

Current biomedical research methods to evaluate the efficacy of Chinese medicine interventions are often conceptually incompatible with the theory and clinical practice of Chinese medicine. In this commentary, we (1) highlight the theory and principles underlying Chinese medicine clinical practice; (2) use ginseng as an example to describe clinical indications in Chinese medicine; (3) propose a framework guided by Chinese medicine theory for the evaluation of study designs in Chinese medicine research; and (4) evaluate 19 randomized, double-blind, placebo-controlled trials of ginseng. Our analysis indicates that all 19 trials with both positive and negative results confirm the specific effects of ginseng indicated by Chinese medicine theory. Study designs guided by Chinese medicine theory are necessary to validate and improve future randomized controlled clinical trials in Chinese medicine.     

Retention in clinical trials after prison release: results from a clinical trial with incarcerated men with HIV and opioid dependence in Malaysia

Background: Study retention is a major challenge in HIV clinical trials conducted with persons recruited from correctional facilities.

Objective: To examine study retention in a trial of within-prison methadone initiation and a behavioral intervention among incarcerated men with HIV and opioid dependence in Malaysia.

Methods: In this 2x2 factorial trial, 296 incarcerated men with HIV and opioid dependence were allocated to (1) an HIV risk reduction intervention, the Holistic Health Recovery Program for Malaysia (HHRP-M), (2) pre-release methadone initiation, (3) both interventions, or (4) standard care (NCT02396979). Here we estimate effects of these interventions on linkage to the study after prison release and completion of post-release study visits.

Results: Most participants (68.9%) completed at least one post-release study visit but few (18.6%) completed all 12. HHRP-M was associated with a 13.5% (95% confidence interval (CI): 3.8%, 23.2%) increased probability of completing at least one post-release study visit. Although not associated with initial linkage, methadone treatment was associated with an 11% (95% CI: 2.0%, 20.6%) increased probability of completing all twelve post-release study visits. Being subject to forced relocation outside Kuala Lumpur after prison release decreased retention by 43.3% (95% CI: ?51.9%, ?34.8%).

Conclusion: Retaining study participants in HIV clinical trials following prison release is challenging and potentially related to the broader challenges that participants experience during community reentry. Researchers conducting clinical trials with this population may want to consider methadone and HHRP as means to improve post-release retention, even in clinical trials where these interventions are not being directly evaluated.     

Impact of length or relevance of questionnaires on attrition in online trials: randomized controlled trial

Background

There has been limited study of factors influencing response rates and attrition in online research. Online experiments were nested within the pilot (study 1, n = 3780) and main trial (study 2, n = 2667) phases of an evaluation of a Web-based intervention for hazardous drinkers: the Down Your Drink randomized controlled trial (DYD-RCT).

Objectives

The objective was to determine whether differences in the length and relevance of questionnaires can impact upon loss to follow-up in online trials.

Methods

A randomized controlled trial design was used. All participants who consented to enter DYD-RCT and completed the primary outcome questionnaires were randomized to complete one of four secondary outcome questionnaires at baseline and at follow-up. These questionnaires varied in length (additional 23 or 34 versus 10 items) and relevance (alcohol problems versus mental health). The outcome measure was the proportion of participants who completed follow-up at each of two follow-up intervals: study 1 after 1 and 3 months and study 2 after 3 and 12 months.

Results

At all four follow-up intervals there were no significant effects of additional questionnaire length on follow-up. Randomization to the less relevant questionnaire resulted in significantly lower rates of follow-up in two of the four assessments made (absolute difference of 4%, 95% confidence interval [CI] 0%-8%, in both study 1 after 1 month and in study 2 after 12 months). A post hoc pooled analysis across all four follow-up intervals found this effect of marginal statistical significance (unadjusted difference, 3%, range 1%-5%, P = .01; difference adjusted for prespecified covariates, 3%, range 0%-5%, P = .05).

Conclusions

Apparently minor differences in study design decisions may have a measurable impact on attrition in trials. Further investigation is warranted of the impact of the relevance of outcome measures on follow-up rates and, more broadly, of the consequences of what we ask participants to do when we invite them to take part in research studies.

Trial registration

ISRCTN Register 31070347; http://www.controlled-trials.com/ISRCTN31070347/31070347 Archived by WebCite at (http://www.webcitation.org/62cpeyYaY)     

Psychological treatments in schizophrenia: I. Meta-analysis of family intervention and cognitive behaviour therapy

BACKGROUND: While there is a growing body of evidence on the efficacy of psychological interventions for schizophrenia, this meta-analysis improves upon previous systematic and meta-analytical reviews by including a wider range of randomized controlled trials and providing comparisons against both standard care and other active interventions. METHOD: Literature searches identified randomized controlled trials of four types of psychological interventions: family intervention, cognitive behavioural therapy (CBT), social skills training and cognitive remediation. These were then subjected to meta-analysis on a variety of outcome measures. This paper presents results relating to the first two. RESULTS: Family therapy, in particular single family therapy, had clear preventative effects on the outcomes of psychotic relapse and readmission, in addition to benefits in medication compliance. CBT produced higher rates of 'important improvement' in mental state and demonstrated positive effects on continuous measures of mental state at follow-up. CBT also seems to be associated with low drop-out rates. CONCLUSIONS: Family intervention should be offered to people with schizophrenia who are in contact with carers. CBT may be useful for those with treatment resistant symptoms. Both treatments, in particular CBT, should be further investigated in large trials across a variety of patients, in various settings. The factors mediating treatment success in these interventions should be researched.     

Long-term effectiveness of health coaching in rehabilitation and prevention: A systematic review

ObjectiveThis systematic review aims to evaluate the long-term effectiveness of health coaching interventions in rehabilitation and prevention.MethodsDatabases and a manual search were used to identify randomized controlled trials (RCTs) in English through to June 2015. Studies were included if: (1) the target population were people of employment age, (2) the intervention addressed either people suffering from a diagnosed disease or healthy people, (3) the intervention included health coaching to influence health-related outcomes and/or processes and (4) the study had a follow-up of at least 24 weeks after the end of the intervention period.ResultsOut of 90 RCTs, 14 studies were selected using the inclusion criteria: seven were designed for the rehabilitative setting and seven for the preventive setting. Three studies of each setting found statistically significant long-term effectiveness.ConclusionsThe high number of studies evaluating health coaching underlines the relevance of this approach. Despite the increasing popularity of health coaching, a research gap exists in regard to its long-term effectiveness.Practice implicationsIt is of utmost importance to consider the sustainability already during planning of health coaching interventions. The involvement of the target group and the setting seems to be a promising strategy.     

Effects of Systemic Therapy on Mental Health of Children and Adolescents: A Meta-Analysis

Systemic therapy is a frequently used form of psychotherapy for the treatment of mental disorders in children and adolescents. The present study reports the results of the first meta-analysis on the effects of systemic treatment of mental disorders and behavior problems in children and adolescents. Based on systematic search in electronic databases (PsycINFO, Psyndex, PubMed, ISI Web of Knowledge, CINAHL), k?=?56 randomized, controlled trials met the inclusion criteria. We computed a random-effects meta-analysis. Systemic therapy showed small-to-medium effects in comparison with an untreated control group (posttest: k?=?7, g?=?.59 standard deviation units, follow-up: k?=?2, g?=?.27) and alternative treatment (posttest: k?=?43, g?=?.32, follow-up: k?=?38, g?=?.28). At follow-up, longer interventions produced larger effect sizes. No other moderator effects were identified. Although available randomized, controlled trials show convincing results, their effects refer to a limited number of systemic approaches and mental disorders, and also pertain to adolescents rather than younger children. Thus, more research is needed before more general conclusions about the effects of systemic therapy can be drawn.     

A meta-analysis of randomized trials of behavioural treatment of depression

BACKGROUND: Depression is a common, disabling condition for which psychological treatments, in particular cognitive behavioural therapies are recommended. Promising results in recent randomized trials have renewed interest in behavioural therapy. This systematic review sought to identify all randomized trials of behavioural therapy for depression, determine the effect of such interventions and examine any moderators of such effect. METHOD: Randomized trials of behavioural treatments of depression versus controls or other psychotherapies were identified using electronic database searches, previous reviews and reference lists. Data on symptom-level, recovery/dropout rate and study-level moderators (study quality, number of sessions, severity and level of training) were extracted and analysed using meta-analysis and meta-regression respectively. RESULTS: Seventeen randomized controlled trials including 1109 subjects were included in this meta-analysis. A random-effects meta-analysis of symptom-level post-treatment showed behavioural therapies were superior to controls [standardized mean difference (SMD) -0.70, 95% CI -1.00 to -0.39, k=12, n=459], brief psychotherapy (SMD -0.56, 95% CI -1.0 to -0.12, k=3, n=166), supportive therapy (SMD -0.75, 95% CI -1.37 to -0.14, k=2, n=45) and equal to cognitive behavioural therapy (SMD 0.08, 95% CI -0.14 to 0.30, k=12, n=476). CONCLUSIONS: The results in this study indicate behavioural therapy is an effective treatment for depression with outcomes equal to that of the current recommended psychological intervention. Future research needs to address issues of parsimony of such interventions.     

Contingent reinforcement increases cocaine abstinence during outpatient treatment and 1 year of follow-up

This study assessed whether contingent incentives can be used to reinforce cocaine abstinence in dependent outpatients. Seventy cocaine-dependent outpatients were randomized into 2 conditions. All participants received 24 weeks of treatment and 1 year of follow-up. The treatment provided to all participants combined counseling based on the community reinforcement approach with incentives in the form of vouchers exchangeable for retail items. In 1 condition, incentives were delivered contingent on cocaine-free urinalysis results, whereas in the other condition incentives were delivered independent of urinalysis results. Abstinence-contingent incentives significantly increased cocaine abstinence during treatment and 1 year of follow-up compared with noncontingent incentives.     

Defining, designing, implementing, and evaluating phase 4 HIV prevention effectiveness trials for vulnerable populations

The efficacy of behavioral HIV prevention interventions has been convincingly demonstrated in a large number of randomized controlled phase 3 research outcome trials. Little research attention has been directed toward studying the effectiveness of the same interventions when delivered by providers to their own clients or community members, however. This article argues for the need to conduct phase 4 effectiveness trials of HIV prevention interventions that have been found efficacious in the research arena. Such trials can provide important information concerning the impact of interventions when applied in heterogeneous "real-world" circumstances. This article raises design issues and methodologic questions that need to be addressed in the conduct of phase 4 trials of behavioral interventions. These issues include the selection and training of service providers engaged in such trials, maintenance of fidelity to intervention protocol in provider-delivered interventions, determination of intervention core elements versus aspects that require tailoring, selection of relevant phase 4 study outcomes, interpretation of findings indicative of field effectiveness, sustainability, and other aspects of phase 4 trial design.     

Online and Social Networking Interventions for the Treatment of Depression in Young People: A Systematic Review

Background

Major depression accounts for the greatest burden of all diseases globally. The peak onset of depression occurs between adolescence and young adulthood, and for many individuals, depression displays a relapse-remitting and increasingly severe course. Given this, the development of cost-effective, acceptable, and population-focused interventions for depression is critical. A number of online interventions (both prevention and acute phase) have been tested in young people with promising results. As these interventions differ in content, clinician input, and modality, it is important to identify key features (or unhelpful functions) associated with treatment outcomes.

Objective

A systematic review of the research literature was undertaken. The review was designed to focus on two aspects of online intervention: (1) standard approaches evaluating online intervention content in randomized controlled designs (Section 1), and (2) second-generation online interventions and services using social networking (eg, social networking sites and online support groups) in any type of research design (Section 2).

Methods

Two specific literature searches were undertaken. There was no date range specified. The Section 1 search, which focused on randomized controlled trials, included only young people (12-25 years) and yielded 101 study abstracts, of which 15 met the review inclusion criteria. The Section 2 search, which included all study design types and was not restricted in terms of age, yielded 358 abstracts, of which 22 studies met the inclusion criteria. Information about the studies and their findings were extracted and tabulated for review.

Results

The 15 studies identified in Section 1 described 10 trials testing eight different online interventions, all of which were based on a cognitive behavioral framework. All but one of the eight identified studies reported positive results; however, only five of the 15 studies used blinded interviewer administered outcomes with most trials using self-report data. Studies varied significantly in presentation of intervention content, treatment dose, and dropout. Only two studies included moderator or clinician input. Results for Section 2 were less consistent. None of the Section 2 studies reported controlled or randomized designs. With the exception of four studies, all included participants were younger than 25 years of age. Eight of the 16 social networking studies reported positive results for depression-related outcomes. The remaining studies were either mixed or negative. Findings for online support groups tended to be more positive; however, noteworthy risks were identified.

Conclusions

Online interventions with a broad cognitive behavioral focus appear to be promising in reducing depression symptomology in young people. Further research is required into the effectiveness of online interventions delivering cognitive behavioral subcomponents, such as problem-solving therapy. Evidence for the use of social networking is less compelling, although limited by a lack of well-designed studies and social networking interventions. A range of future social networking therapeutic opportunities are highlighted.     

Predictors of retention in an online follow-up study of men who have sex with men

Background

In the past 10 years, the Internet has emerged as a venue for men who have sex with men (MSM) to meet sex partners. Because online sex seeking has increased among MSM, Internet-based human immunodeficiency virus (HIV) prevention interventions are of interest. However, few online studies to date have demonstrated an ability to retain study participants, specifically MSM of color, in longitudinal online studies.

Objective

The current analysis examines data from a 3-month online prospective study of MSM to determine the association of race and incentive level with two retention outcomes: (1) agreeing to participate in a follow-up survey and providing an email address and (2) linking into the follow-up survey at the follow-up time point.

Methods

Internet-using MSM were recruited through banner advertisements on MySpace.com. White, black, and Hispanic participants from 18 to 35 years of age were randomized to an offer of enrollment in an online follow-up survey at four levels of incentive (US $0, US $5, US $10, and US $20). Multivariable logistic regression models were used to estimate the odds of the two outcome measures of interest controlling for additional independent factors of interest.

Results

Of eligible participants, 92% (2405/2607) agreed to participate in the follow-up survey and provided an email address. Hispanic men had decreased odds (adjusted odds ratio [OR] = 0.66, 95% confidence interval [CI] 0.47-0.92) of agreeing to participate in the follow-up survey compared with white men. Men reporting unprotected anal intercourse with a male sex partner in the past 12 months had increased odds of agreeing to participate in the follow-up survey (adjusted OR = 1.42, 95% CI 1.05-1.93). Of the participants who provided an email address, 22% (539/2405) linked into the follow-up survey at the 3-month follow-up time point. The odds of linking into the follow-up survey for black men were approximately half the odds for white men (adjusted OR = 0.47, 95% CI 0.35-0.63). Participants who were offered an incentive had increased odds of linking into the follow-up survey (adjusted OR = 1.29, 95% CI 1.02-1.62). Email addresses provided by participants that were used for online financial management and email accounts that were checked daily were associated with increased odds of linking into the follow-up survey (adjusted OR = 1.97, 95% CI 1.54-2.52; adjusted OR = 1.51, 95% CI 1.22-1.87, respectively).

Conclusions

This analysis identified factors that predicted retention in an online, prospective study of MSM. Hispanic and black study participants were less likely to be retained in the study compared with white study participants. Because these men bear the greatest burden of HIV incidence among MSM in the United States, it is critical that new research methods be developed to increase retention of these groups in online research studies.     

A comparison of observational studies and randomized, controlled trials

BACKGROUND: For many years it has been claimed that observational studies find stronger treatment effects than randomized, controlled trials. We compared the results of observational studies with those of randomized, controlled trials. METHODS: We searched the Abridged Index Medicus and Cochrane data bases to identify observational studies reported between 1985 and 1998 that compared two or more treatments or interventions for the same condition. We then searched the Medline and Cochrane data bases to identify all the randomized, controlled trials and observational studies comparing the same treatments for these conditions. For each treatment, the magnitudes of the effects in the various observational studies were combined by the Mantel-Haenszel or weighted analysis-of-variance procedure and then compared with the combined magnitude of the effects in the randomized, controlled trials that evaluated the same treatment. RESULTS: There were 136 reports about 19 diverse treatments, such as calcium-channel-blocker therapy for coronary artery disease, appendectomy, and interventions for subfertility. In most cases, the estimates of the treatment effects from observational studies and randomized, controlled trials were similar. In only 2 of the 19 analyses of treatment effects did the combined magnitude of the effect in observational studies lie outside the 95 percent confidence interval for the combined magnitude in the randomized, controlled trials. CONCLUSIONS: We found little evidence that estimates of treatment effects in observational studies reported after 1984 are either consistently larger than or qualitatively different from those obtained in randomized, controlled trials.     

How pragmatic or explanatory is the randomized, controlled trial? The application and enhancement of the PRECIS tool to the evaluation of a smoking cessation trial

ABSTRACT: BACKGROUND: Numerous explanatory randomized trials support the efficacy of chronic disease interventions, including smoking cessation treatments. However, there is often inadequate adoption of these interventions for various reasons, one being the limitation of generalizability of the explanatory studies in real-world settings. Randomized controlled trials can be rated as more explanatory versus pragmatic along 10 dimensions. Pragmatic randomized clinical trials generate more realistic estimates of effectiveness with greater relevance to clinical practice and for health resource allocation decisions. However, there is no clear method to scale each dimension during the trial design phase to ensure that the design matches the intended purpose of the study. METHODS: We designed a pragmatic, randomized, controlled study to maximize external validity by addressing several barriers to smoking cessation therapy in ambulatory care. We analyzed our design and methods using the recently published 'Pragmatic-Explanatory Continuum Indicatory Summary (PRECIS)' tool, a qualitative method to assess trial design across 10 domains. We added a 20-point numerical rating scale and a modified Delphi process to improve consensus in rating these domains. RESULTS: After two rounds of review, there was consensus on all 10 domains of study design. No single domain was scored as either fully pragmatic or fully explanatory; but overall, the study scored high on pragmatism. CONCLUSIONS: This addition to the PRECIS tool may assist other trial designers working with interdisciplinary co-investigators to rate their study design while building consensus.     

Transient environmental exposures on the developing immune system: implications for allergy and asthma

PURPOSE OF REVIEW: Early environmental exposures have been extensively studied as potential causes of the observed increase in allergic disease over time. Transient fetal or neonatal exposures in particular are of interest in that they may occur during critical windows of immune system development. Due to the tremendous complexity of variables in early life, as well as the difficulty in randomizing many interventions, it is very difficult to properly study these exposures. Some progress, however, has been made and some more candidates for study may be emerging. Of particular interest are micronutrients, whose ever-changing use and immunomodulatory capabilities make them prime targets for study. RECENT FINDINGS: New risk factors for atopic disease have emerged from the pool of early life interventions, such as caesarian section, prolonged labor and infant multivitamin supplementation. Data are emerging regarding micronutrient status and supplementation and their effects on the developing immune system and risk for allergic disease. Clinical trials have yet to demonstrate much causality but, in some cases, it is too early to make any judgments. SUMMARY: The gold standard of randomized clinical trials has not borne out a number of proposed early-life allergic risk factors, while other trials are too incomplete to draw any conclusions so far. Properly designed studies for other risk factor interventions may still be achievable, provided that there is a proper understanding of the interventions, populations and outcomes.