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As prevention trials advance with autosomal dominant Alzheimer disease (ADAD) participants, understanding the similarities and differences between ADAD and "sporadic" late-onset AD (LOAD) is critical to determine generalizability of findings between these cohorts. Cognitive trajectories of ADAD mutation carriers (MCs) and autopsy-confirmed LOAD individuals were compared to address this question. Longitudinal rates of change on cognitive measures were compared in ADAD MCs (n = 310) and autopsy-confirmed LOAD participants (n = 163) before and after symptom onset (estimated/observed). LOAD participants declined more rapidly in the presymptomatic (preclinical) period and performed more poorly at symptom onset than ADAD participants on a cognitive composite. After symptom onset, however, the younger ADAD MCs declined more rapidly. The similar but not identical cognitive trajectories (declining but at different rates) for ADAD and LOAD suggest common AD pathologies but with some differences.

Introduction A major change in the ethics framework for preventive HIV vaccine trials worldwide is the release of the UNAIDS 2021 ethical considerations in HIV prevention trials. This new guidance comes at an exciting time when there are multiple HIV vaccine efficacy trials in the field. Research Ethics Committees (RECs) or Institutional Review Boards are a most likely audience for these guidelines. Our objective is to highlight shifts in ethics recommendations from the earlier 2012 UNAIDS guidance. Discussion We review recommendations related to four key issues, namely standard of prevention, post‐trial access to safe and effective vaccines, enrolment of adolescents and enrolment of pregnant women. We outline implications and make recommendations for the ethics review process, including suggested lines of inquiry by RECs and responses by applicants. Conclusions There have been several shifts in the UNAIDS ethics guidance with implications for HIV vaccine researchers submitting applications for initial ethics review or re‐certification, and for RECs conducting such reviews. This review may assist RECs in a more efficient and consistent application of ethics recommendations. However, additional tools and training may further help stakeholders comply with new UNAIDS ethics recommendations during protocol development and ethics review.

Author(s): Keret, Ophir; Staffaroni, Adam M; Ringman, John M; Cobigo, Yann; Goh, Sheng-Yang M; Wolf, Amy; Allen, Isabel Elaine; Salloway, Stephen; Chhatwal, Jasmeer; Brickman, Adam M; Reyes-Dumeyer, Dolly; Bateman, Randal J; Benzinger, Tammie LS; Morris, John C; Ances, Beau M; Joseph-Mathurin, Nelly; Perrin, Richard J; Gordon, Brian A; Levin, Johannes; Voglein, Jonathan; Jucker, Mathias; la Fougere, Christian; Martins, Ralph N; Sohrabi, Hamid R; Taddei, Kevin; Villemagne, Victor L; Schofield, Peter R; Brooks, William S; Fulham, Michael; Masters, Colin L; Ghetti, Bernardino; Saykin, Andrew J; Jack, Clifford R; Graff-Radford, Neill R; Weiner, Michael; Cash, David M; Allegri, Ricardo F; Chrem, Patricio; Yi, Su; Miller, Bruce L; Rabinovici, Gil D; Rosen, Howard J; Dominantly Inherited Alzheimer Network | Abstract: IntroductionAsymptomatic and mildly symptomatic dominantly inherited Alzheimer's disease mutation carriers (DIAD-MC) are ideal candidates for preventative treatment trials aimed at delaying or preventing dementia onset. Brain atrophy is an early feature of DIAD-MC and could help predict risk for dementia during trial enrollment.MethodsWe created a dementia risk score by entering standardized gray-matter volumes from 231 DIAD-MC into a logistic regression to classify participants with and without dementia. The score's predictive utility was assessed using Cox models and receiver operating curves on a separate group of 65 DIAD-MC followed longitudinally.ResultsOur risk score separated asymptomatic versus demented DIAD-MC with 96.4% (standard errorn=n0.02) and predicted conversion to dementia at next visit (hazard ration=n1.32, 95% confidence interval [CI: 1.15, 1.49]) and within 2 years (area under the curven=n90.3%, 95% CI [82.3%-98.2%]) and improved prediction beyond established methods based on familial age of onset.DiscussionIndividualized risk scores based on brain atrophy could be useful for establishing enrollment criteria and stratifying DIAD-MC participants for prevention trials.

Introduction Despite the increase in Alzheimer's disease (AD) cases in the United States, no new treatments have been approved in the United States since 2003. The costs associated with drug development programs are high and serve as a significant deterrent to AD therapeutic investigations. In this study, we analyze the sponsorship data for AD clinical trials conducted since 2016 to assess the fiscal support for AD clinical trials. Methods We analyzed the funding sources of all AD trials over the past 5 years as reported on ClinicalTrials.gov. Results There were 136 trials being conducted for treatments in the US AD therapeutic pipeline on the index date of this study. Among non‐prevention trials, disease‐modifying therapies (DMT) in Phase 3 were almost entirely sponsored by the biopharmaceutical industry; Phase 2 DMT trials were split between the biopharmaceutical industry and funding from the National Institutes of Health (NIH) to academic medical centers (AMCs). The majority of prevention trials received sponsorship from public–private partnerships (PPP). Trials of symptomatic agents are equally likely to have biopharmaceutical or NIH/AMC sponsorship. Most trials with repurposed agents had NIH/AMC funding (89%). Since 2016, there has been consistent growth in the number of trials sponsored both in part and fully by NIH/AMC sources and in PPP, and there has been a reduction in biopharmaceutical company–sponsored trials. Discussion The number of trials supported by the biopharmaceutical industry has decreased over the past 5 years; trials supported from federal sources and PPP have increased. Repurposed compounds are mostly in Phase 2 trials and provide critical mechanistic information.

Introduction Little is known about factors affecting motivation and satisfaction of participants in dementia prevention trials. Methods A Research Satisfaction Survey was administered to 422 nondemented older adults who participated in the Home-Based Assessment trial. Results Overall satisfaction was high, with means of all individual items near to above a value of 3 on a scale from 1 (worst) to 4 (best). Greater satisfaction was associated with staff-administered interviews versus automated technologies. The most liked aspects of research participation were volunteerism, opportunity to challenge and improve mental function, and positive interactions with staff. The least liked aspect was repetitiveness of the assessments. Participants requested more contact with staff and other older adults and more feedback on performance. Discussion Older adults' participation in research was primarily motivated by altruism. Methodologies that facilitate human contact, encourage feedback and novelty of tasks should be incorporated into future trial design.

CITATION: Bock, P., et al. 2019. Renal dysfunction by baseline CD4 cell count in a cohort of adults starting antiretroviral treatment regardless of CD4 count in the HIV Prevention Trials Network 071 [HPTN 071; Population Effect of Antiretroviral Therapy to Reduce HIV Transmission (PopART)] study in South Africa. HIV Medicine, 20(6): 392-403, doi:10.1111/hiv.12729.

BACKGROUND: There has been increasing interest in the potential for pre-emptive interventions in the prodrome of autism, but little investigation as to their effect. METHODS: A two-site, two-arm assessor-blinded randomised controlled trial (RCT) of a 12-session parent-mediated social communication intervention delivered between 9 and 14 months of age (Intervention in the British Autism Study of Infant Siblings-Video Interaction for Promoting Positive Parenting), against no intervention. Fifty-four infants (28 intervention, 26 nonintervention) at familial risk of autism but not otherwise selected for developmental atypicality were assessed at 9-month baseline, 15-month treatment endpoint, and 27- and 39-month follow-up. PRIMARY OUTCOME: severity of autism prodromal symptoms, blind-rated on Autism Observation Schedule for Infants or Autism Diagnostic Observation Schedule 2nd Edition across the four assessment points. SECONDARY OUTCOMES: blind-rated parent-child interaction and child language; nonblind parent-rated communication and socialisation. Prespecified intention-to-treat analysis combined estimates from repeated measures within correlated regressions to estimate the overall effect of the infancy intervention over time. RESULTS: Effect estimates in favour of intervention on autism prodromal symptoms, maximal at 27 months, had confidence intervals (CIs) at each separate time point including the null, but showed a significant overall effect over the course of the intervention and follow-up period (effect size [ES] = 0.32; 95% CI 0.04, 0.60; p = .026). Effects on proximal intervention targets of parent nondirectiveness/synchrony (ES = 0.33; CI 0.04, 0.63; p = .013) and child attentiveness/communication initiation (ES = 0.36; 95% CI 0.04, 0.68; p = .015) showed similar results. There was no effect on categorical diagnostic outcome or formal language measures. CONCLUSIONS: Follow-up to 3 years of the first RCT of a very early social communication intervention for infants at familial risk of developing autism has shown a treatment effect, extending 24 months after intervention end, to reduce the overall severity of autism prodromal symptoms and enhance parent-child dyadic social communication over this period. We highlight the value of extended follow-up and repeat assessment for early intervention trials.

Author(s): Warren, John J; Weber-Gasparoni, Karin; Tinanoff, Norman; Batliner, Terence S; Jue, Bonnie; Santo, William; Garcia, Raul I; Gansky, Stuart A; Early Childhood Caries Collaborating Centers | Abstract: ObjectivesTo summarize diagnostic criteria and examiner training and calibration of the National Institute of Dental and Craniofacial Research-funded Early Childhood Caries Collaborating Centers (EC4) and report examiner calibration results from 2010 to 2014. The EC4 at Boston University, University of Colorado, and University of California San Francisco are performing randomized controlled early childhood caries (ECC) prevention trials with caries as the main outcome measure.MethodsThe EC4 with University of Iowa consultants developed standardized tooth and tooth surface status examination criteria for use in field conditions, examiner training materials, and examiner calibration and re-calibration methodologies. Calibration and re-calibration were performed with 1- to 5-year-old children in the San Francisco Mission District in which assessments from each examiner to be calibrated were compared with those from a single gold standard examiner from 2010 to 2014. Cohen's kappa statistic was used to determine inter-examiner agreement.ResultsA total of seven examiners were successfully (re)calibrated during that period, examining a total of 231 children. Overall unweighted Cohen's kappas for 10 surface conditions exceeded the criterion of 0.70. However, separate agreement for assessment of noncavitated lesions, as in other studies, was lower.ConclusionsAn experienced multidisciplinary and multi-institutional team was able to develop criteria and training materials to anticipate situations and field conditions the main trials would encounter. Examiners were successfully trained and (re)calibrated.

Background We examined differences in response to self-reported alcohol use items by survey mode, whether self-report differences were the result of modality effects or self-selection, and whether these differences varied across the treatment and control arms of a preventative intervention trial. Methods Data from an existing alcohol prevention trial were used to estimate the effect of survey modality on adolescent's self-reported alcohol use at ages 17 to 18. Estimates were derived from regression models controlling for self-reported alcohol use during 8th grade, measured using a single survey modality, as well as time invariant selection factors. Results No statistically significant survey modality effects were found. No differential effects of survey modality were observed by assigned intervention group. Conclusions We provide initial evidence that adolescent alcohol prevention trials may use multiple survey modalities when necessary to increase response rates without harming interpretation of intervention effects.

Aims The objective of the 5th International Consultation on Incontinence (ICI) chapter on Adult Conservative Management was to review and summarize the new evidence on conservative management of urinary incontinence (UI) and pelvic organ prolapse (POP) in order to compile a current reference source for clinicians, health researchers, and service planners. In this paper, we present the review highlights and new evidence on female conservative management. Methods Revision and updates of the 4th ICI Report using systematic review covering years 2008–2012. Results Each section begins with a brief definition and description of the intervention followed by a summary, where possible, of both the state and level of evidence for prevention and treatment, and ends with a “grade of recommendation.” The paper concludes with areas identified as requiring further research. Conclusions For UI, there are no prevention trials on lifestyle interventions. There are, however, few new intervention trials of lifestyle interventions involving weight loss and fluid intake with improved levels of evidence and grade of recommendation. Outside of pre- and post-natal pelvic floor muscle training (PFMT) trials for the prevention of female UI, there is a dearth of PFMT prevention trials for women with UI. PFMT remains the first-line treatment for female UI with high levels of evidence and grades of recommendation. Bladder training levels of evidence and grades of recommendation are maintained. For POP, new evidence supports the effectiveness of physiotherapy in the treatment of POP and there are now improved levels of evidence and grades of recommendation. Neurourol. Urodynam. © 2014 Wiley Periodicals, Inc.

Author(s): Amico, K Rivet; Ramirez, Catalina; Caplan, Margaret R; Montgomery, Brooke Ee; Stewart, Jennifer; Hodder, Sally; Swaminathan, Shobha; Wang, Jing; Darden-Tabb, Noshima Y; McCauley, Marybeth; Mayer, Kenneth H; Wilkin, Timothy; Landovitz, Raphael J; Gulick, Roy; Adimora, Adaora A; HPTN 069/A5305 Study Team and HPTN Women at Risk Committee | Abstract: IntroductionLimited data exist on acceptability of candidate pre-exposure prophylaxis (PrEP) regimens among US women. We evaluated PrEP experiences, attitudes and future use intentions among sexually active women who completed the US-based HIV Prevention Trials Network 069/AIDS Clinical Trials Group 5305 study.MethodsWomen participated in the study between March 2013 and November 2015. We analysed computer-assisted self-interview (CASI) surveys among 130 women and conducted in-depth interviews among a subset of 26 women from three sites. Interviews were conducted in mid/late-2015.ResultsMost women (57%) reported very good/excellent PrEP adherence on CASI, although 21% acknowledged over-reporting adherence at least some of the time. Commitment to preventing HIV infection, a sense of ownership of the study, and keeping pills stored in a visible location facilitated adherence. Adherence barriers included "simply forgetting" and being away from home. Most women interviewed did not intend to use PrEP in the future because of lack of perceived need due to their own (as opposed to their partners') low-risk behaviour and concerns about affordability - but not because of side effects or other characteristics of the regimens.DiscussionImproving HIV prevention options for US women will require access to affordable PrEP as well as expanding women's understanding of relationship- and community-level factors that increase their risk of acquiring HIV.

The successful demonstration that antiretroviral (ARV) drugs can be used in diverse ways to reduce HIV acquisition or transmission risks – either taken as pre-exposure prophylaxis (PrEP) by those who are uninfected or as early treatment for prevention (T4P) by those living with HIV – expands the armamentarium of existing HIV prevention tools. These findings have implications for the design of future HIV prevention research trials. With the advent of multiple effective HIV prevention tools, discussions about the ethics and the feasibility of future HIV prevention trial designs have intensified. This article outlines arguments concerning the inclusion of newly established ARV-based HIV prevention interventions as standard of prevention in HIV prevention trials from multiple perspectives. Ultimately, there is a clear need to incorporate stakeholders in a robust discussion to determine the appropriate trial design for each study population.

Early sociodemographic risk, parenting, and temperament were examined as predictors of the activity of children's (N = 148; 81 boys, 67 girls) hypothalamic-pituitary-adrenal axis and autonomic nervous system. Demographic risk was assessed at 18 months (T1), intrusive/overcontrolling parenting and effortful control were assessed at 30 months (T2), and salivary cortisol and alpha-amylase were collected at 72 (T3) months of age. Demographic risk at T1 predicted lower levels of children's effortful control and higher levels of mothers' intrusive/overcontrolling parenting at T2. Intrusive/overcontrolling parenting at T2 predicted higher levels of children's cortisol and alpha-amylase at T3, but effortful control did not uniquely predict children's cortisol or alpha-amylase levels. Findings support the open nature of stress responsive physiological systems to influence by features of the early caregiving environment and underscore the utility of including measures of these systems in prevention trials designed to influence child outcomes by modifying parenting behavior.

Many recent articles argue that participants who seroconvert during HIV prevention trials deserve treatment when they develop AIDS, and there is a general consensus that the participants in HIV/AIDS treatment trials should have continuing post-trial access. As a result, the primary concern of many ethicists and activists has shifted from justifying an obligation to treat trial participants, to working out mechanisms through which treatment could be provided. In this paper I argue that this shift frequently conceals an important assumption: that if there is an obligation to supply treatment, then any party who could provide it may be prevailed upon to discharge the obligation. This assumption is false. The reasons why trial participants should get ART affect who has the duty to provide it. We should not burden governments with the obligations of sponsors, nor researchers with the obligations of the international community. And we should not deprive a group of treatment because their need is less salient than that of research participants. Insisting otherwise may lead to people being wrongfully deprived of access to antiretrovirals.

After one or more Phase 2 trials show that a candidate preventive vaccine induces immune responses that putatively protect against an infectious disease for which there is no licensed vaccine, the next step is to evaluate the efficacy of the candidate. The trial-designer faces the question of what is the optimal size of the initial efficacy trial? Part of the answer will entail deciding between a large Phase 3 licensure trial or an intermediate-sized Phase 2b screening trial, the latter of which may be designed to directly contribute to the evidence-base for licensing the candidate, or, to test a scientific concept for moving the vaccine field forward, acknowledging that the particular candidate will never be licensable. Using the HIV vaccine field as a case study, we describe distinguishing marks of Phase 2b and Phase 3 prevention efficacy trials, and compare the expected utility of these trial types using Pascal's decision-theoretic framework. By integrating values/utilities on (1) correct or incorrect conclusions resulting from the trial; (2) timeliness of obtaining the trial results; (3) precision for estimating the intervention effect; and (4) resources expended; this decision framework provides a more complete approach to selecting the optimal efficacy trial size than a traditional approach that is based primarily on power calculations. Our objective is to help inform the decision-process for planning an initial efficacy trial design.

We reviewed the efficacy and effectiveness of home fortification of complementary foods with micronutrient powders (e.g. Sprinkles®), crushable tablets and lipid‐based or soy‐based products. Sixteen studies (5 anaemia treatment trials, 11 prevention trials) met the inclusion criteria. The treatment trials indicate that Sprinkles were as effective as iron drops, and were better accepted and had fewer side effects. In the prevention trials, the risk of anaemia was cut in half. The effect of home fortification with multiple micronutrients on plasma zinc and vitamin A levels was mixed. The impact on child growth of home fortification using only micronutrients was not significant. However, with products containing both micronutrients and a small amount of energy (including fat and protein), the pooled data from two efficacy trials in Africa suggest an effect size of ∼0.4 for both weight and height. Home fortification with products that include some energy also showed positive effects on indices of child development in two studies. There was a beneficial impact of home fortification on morbidity in high‐risk populations in some studies, but most showed no significant impact. Acceptability of home fortification by caregivers and young children is high, and side effects are rare. The safety of home fortification using ‘bolus’ doses of iron, particularly in malarial areas, needs further investigation. In one study of Sprinkles in a low‐income country, the estimates of cost per disability‐adjusted life year regained compared favourably with other approaches, but more data on operational and cost considerations for the various home fortification products are needed.

Summary Background In clinical trials of peptic ulcer prevention, the most appropriate definition of an ulcer remains challenging. Aims To evaluate the ulcer definitions used in clinical trials of ulcer prevention among non-steroidal anti-inflammatory drug users and to determine whether any specific definition is preferred. Methods A systematic literature search of the PubMed, Medline and EMBASE databases was conducted. Results were limited to full papers published in English from June 1987 to June 2007 that met the following criteria: randomized, controlled non-steroidal anti-inflammatory drug trials of ≥8 weeks’ duration, with a primary end point of ulcer upon endoscopy. Results Forty five publications met the inclusion criteria and were reviewed. Overall, an ulcer diameter of ≥3 mm was used in 25 publications and most included a description of ulcer depth. Of the remainder, ulcer was defined as any lesion with unequivocal/observable depth (with no lower limit for ulcer diameter; five publications) or an excavated mucosal break >3 mm (one publication), whereas nine defined a minimum ulcer size of ≥5 or >5 mm. Ulcer definition was unclear in the remaining five publications. Conclusion In clinical trials of ulcer prevention among non-steroidal anti-inflammatory drug users, a gastric or duodenal lesion ≥3 mm in diameter with significant depth is the preferred definition.

The available results from breast cancer chemoprevention trials are reviewed. Four trials using tamoxifen have been performed, of which three have reported efficacy results. A fifth trial using raloxifene has also been published. The largest tamoxifen trial shows approximately a 50% reduction in breast cancer incidence in the short term, but the two smaller trials have not found any incidence reduction. Greater agreement exists for side effects: thromboembolic disease and endometrial cancers are raised about 2- to 3-fold when tamoxifen is used for 5 years. The possible reasons for the discrepancy in breast cancer reduction are explored. A review of trial parameters does not clearly explain this difference, and a metanalysis indicates that all results are compatible with a 42% reduction in short-term incidence. Several important questions remain about the clinical implication of this result, including the effect on mortality, the appropriate risk groups for chemoprevention, and the long-term effects on incidence. Continued follow-up of these trials is crucial for resolving these issues.

Group randomized trials (GRT) are often designed with relatively little preliminary data available to estimate key parameters. In this paper, however, the opposite situation is considered-very good baseline data are available on the primary outcome of interest. These data can then be used to inform key design and analysis decisions such as (i) should the trial be designed as an unmatched or pair-matched study, or stratified in some other fashion; (ii) is analysis of "change from baseline" preferable to using end-of-study data alone; and (iii) what power might be expected by pursuing these various strategies. The results are applied to a GRT for sexually transmitted diseases prevention in Peru.

Allergic conditions continue to increase steeply. The last two decades have seen many prevention trials, studying the effect of dietary and environmental interventions. These trials have yielded invaluable information about the atopic march and also highlighted the need for a clear and commonly used nomenclature as well as a need for better outcome measures. This review discusses primary and secondary prevention studies and their results.

sequence (n1⁄423), were evaluated on the Saykin scale modified for severity (Saykin-mod-sev), (Saykin, Reisberg modification, 2013), and an Emotional Severity Scale (ESS), (Guillo BenArous, 2013). We compared the scales with respect to scores on a battery of psychological tests and demographic variables, specifically, age, gender, and education. Results: We found a significant relationship between the Saykin ADNI Self Report Index and the Trail Making Test B (P1⁄40.009) (see figure). We also found a significant relationship between the Visual Analogue Scale and the Paired Associates Delayed Recall measure (p1⁄40.028). For the demographic variables a significant relationship was found with selected tests (see Figure). Conclusions: These findings could be of relevance for future prevention trials. Ultimately, we need to determine the sensitivity of temporally based scales in comparison with severity based scales and identify optimal predictors of eventual MCI and AD.

High levels of low-density lipoprotein cholesterol may contribute to the development of coronary heart disease in the absence of other risk factors. This paper reviews major cholesterol prevention trials since 1994 concerning possible beneficial results of lowering cholesterol in persons over 65 years of age.

Recruitment of subjects is a critical aspect of prevention trials that is often overlooked by investigators. As a consequence, accrual time is often extended, workloads may become heavy, and resource utilization is increased in an effort to complete projects. Recruitment of healthy subjects in cancer prevention and control studies presents unique issues that need to be considered. The barriers to recruitment include participant issues, physician variables, features of the study design, and characteristics of the health care system in the United States. The authors provide their experience in overcoming these difficulties. J. Cell. Biochem. Suppl. 34:80-83, 2000. r 2000 Wiley-Liss, Inc.

Improved molecular-based detection of early epithelial cancer creates an oupportunity for selective pharmacologic agents to arrest the development of emerging cancers. Developing a successful prevention approach to cancer control could eventually lead to a significant decline in cancer mortality rates; progress depends on the amount of resources committed to this area. Most major prevention trials are federally supported due to their size, duration, and cost. Much of the initial developmental cost for advanced cancer treatment agents was supported by the pharmaceutical industry. Developing a cancer treatment agent is perceived as more clearly defined and achievable than for prevention agents. Preliminary discussions with representatives of the pharmaceutical and biotech industry have identified a number of barriers to chemoprevention product development. Researchers agree that a number of promising agents are being passed over for expeditious development due to the uncertainty associated with chemoprevention drug development. The major factors affecting this circumstance are considered, including cost of clinical trials, absence of a positive model, and inability to project liability exposure. Similar problems were encountered in the area of childhood vaccine development. Insights from that process may have applicability to prevention drug development. Resolving these problems now can have a significant effect on the rate of progress in this promising new approach to cancer control.

The results of early cancer prevention trials now are being reported, and new trials have begun or are being designed. Initial trials used agents such as vitamins and minerals, generally regarded as safe. The trials in progress are using similar agents or macronutrient manipulation, but some have incorporated drugs with low but definite toxic potential, such as tamoxifen. Appropriate prevention trial design requires careful consideration of agent toxicity and the use of such agents in healthy individuals. Full disclosure of risks and benefits to potential subjects is necessary. Other considerations are study duration (usually very long) and subject number (usually very large), both of which increase the cost of a trial. Successful prevention trials must overcome these barriers through innovative design. Possible innovations include the use of intermediate marker end-points, the enrollment of subjects at high risk for a specific cancer, and the use of volunteers to help conduct trials.

Markers of early events in the development of breast cancer are potential candidates for surrogate endpoints in chemoprevention trials. There are many such markers and the challenge is to identify truly relevant markers. If successful, surrogate endpoints offer several potential benefits in the conduct of prevention trials, including: shorter latency and hence shorter trials; reductions in size and cost of trials; and the opportunity to study prevention measures where use of primary outcomes would be excessively invasive or unethical. Although there are currently no validated surrogate endpoints for breast cancer, criteria for the discovery and validation of surrogates have been proposed. Putative surrogate endpoints should be biologically plausible, represent an early event in the causal pathway, be measurable by a standardized and reliable assay, and exhibit a dose-response. Perhaps most importantly, surrogates should statistically capture the effect of the intervention on outcome. The identification and establishment of a biomarker as a valid surrogate for cancer is a stepwise process that involves both smaller “transitional” studies and larger second-generation chemoprevention trials in which both primary outcome and putative surrogates are measured. Transitional studies are used to move new markers from the laboratory into use in human populations, and are designed to address specific questions of assay validity, treatment/marker associations, marker/disease associations, and inter- and intra-individual variability. Promising markers should be added to current and planned, large, traditionally designed chemoprevention trials in order to definitively address the issues of optimal representation, and to test the adequacy with which the marker(s) captures the effect of treatment on outcome. Ancillary studies of markers attached to these second-generation prevention trials must be powerful enough to detect clinically important differences, to elucidate potentially complex multivariate markers, and to validate hypothesized relationships.

Carotenoids continue to be important dietary sources of vitamin A, and also continue to be used in the treatment of certain human photosensitive skin diseases. Animal and epidemiologic studies are strongly suggestive that carotenoids may have an anti-cancer role, but the clinical prevention trials designed to determine if this is true have not yet been completed. Another interesting possible role of carotenoids is as modulators of immunologic responses: investigations on this aspect of carotenoid function are also ongoing. In this paper we survey the recent literature on these diverse roles of carotenoids.

The approach toward treatment of Alzheimer's disease has evolved out of a large body of research, resulting in a common trial paradigm directed toward establishing efficacy and safety of putative treatments for dementia. To achieve the ultimate goal of preventing dementia, the future will build on this model but will need to incorporate new paradigms to more efficiently detect meaningful change over time. Among new innovations needed is the capability for assessing trajectories of change over many years. Intrinsic to this success is the ability to capture increasing variability as well as subject heterogeneity inherent in longitudinal aging cohorts. New methods of ubiquitous embedded home sensing and computing afford the opportunity to assess volunteers not only during long periods of time but with greater frequency and convenience. Clinical studies identifying the optimal ways of using these methods are needed.

Benefit/risk assessment (B/RA) is a mathematical procedure to estimate the probability of detrimental outcomes, beneficial outcomes and the net-effect anticipated from exposure to a given agent or procedure. B/RAs of health-related outcomes are used for public health planning, decision-making regarding health care financing, and therapeutic decision-making in clinical practice. Information obtained from B/RAs based on findings from controlled clinical trials, particularly those with double-masking of treatment, are most informative for health care planning and decision making because such information is less likely to be bias than is information obtained from observational studies. Thus, B/RAs in prevention trials are an excellent source of information to use as the basis for health care planning and decision-making. Applications of R/BA in prevention trials are performed as supplements for planning, monitoring and analyzing the trial. These applications can be categorized into three types of assessments. This article provides a description of the three types of assessment performed in prevention trials, defines the statistical algorithms used for each type of assessment and discusses several key methodological and practical issues involve with the application of B/RA to health-related outcomes. Keywords: benefit/risk; risk assessment; health risk assessment; net-effect; global monitoring

are in a period of ethical uncertainty regarding the design and conduct of biomedical and public health research in developing countries.1,2 While some of the assumptions and practices associated with this research warrant questioning, doing so has resulted in some conflicting guidance and opinion about when and how this research is appropriate. At the same time, the HIV/AIDS epidemic has surged, especially among populations in the developing world, making even more urgent the need for proven methods of prevention and treatment of the disease.3 The HIV Prevention Trials Network (HPTN) constitutes one of the major U.S.-based sponsors of HIV prevention research in both the U.S. and international settings (see www.hptn.org). To accomplish its mission, the HPTN must navigate a morally defensible path between ethical uncertainty about research and the public health imperative of halting a global epidemic. Tasked with addressing this need, the HPTN Ethics Working Group commissioned the authors to draft an ethics guidance document that would be responsive to the complexity of the network and the types of research it conducts. Here we describe the process we are using to perform this task.

Important considerations in the design and conduct of cancer and other long-term prevention trials include intervention compliance and frequency of events during follow-up. Each of these can produce observed proportions of events for control and test groups that differ less than anticipated. Methods and approximate 'rules of thumb' are presented that relate power and sample size to the impact of compliance and latent intervention effect. Results are based upon specific modifications in well-known formulae that reflect long-term prevention trials. Data from an ongoing cancer prevention trial illustrate the methods. Compliance was estimated accurately using the low cost capsule count method.