Clinically Important Benefits and Harms of Monoclonal Antibodies Targeting Amyloid for the Treatment of Alzheimer Disease: A Systematic Review and Meta-Analysis.

PURPOSE: We conducted a meta-analysis to evaluate clinically meaningful benefits and harms of monoclonal antibodies targeting amyloid in patients with Alzheimer dementia. METHODS: We searched PubMed, Cochrane CENTRAL, and 5 trial registries, as well as the reference lists of identified studies. We included randomized controlled trials comparing a monoclonal antibody with placebo at a dose consistent with that used in phase 3 trials or for Food and Drug Administration approval. Studies had to report at least 1 clinically relevant benefit or harm. Data were extracted independently by at least 2 researchers for random effects meta-analysis. Changes in cognitive and functional scales were compared between groups, and each difference was assessed to determine if it met the minimal clinically important difference (MCID). RESULTS: We identified 19 publications with 23,202 total participants that evaluated 8 anti-amyloid antibodies. There were small improvements over placebo in the Alzheimer's Disease Assessment Scale (ADAS)-Cog-11 to -14 score (standardized mean difference = -0.07; 95% CI, -0.10 to -0.04), Mini Mental State Examination score (0.32 points; 95% CI, 0.13 to 0.50), and Clinical Dementia Rating-Sum of Boxes scale score (mean difference =-0.18 points; 95% CI, -0.34 to -0.03), and the combined functional scores (standardized mean difference = 0.09; 95% CI, 0.05 to 0.13). None of the changes, including those for lecanemab, aducanumab, and donanemab, exceeded the MCID. Harms included significantly increased risks of amyloid-related imaging abnormalities (ARIA)-edema (relative risk [RR] = 10.29; number needed to harm [NNH] = 9), ARIA-hemorrhage (RR = 1.74; NNH = 13), and symptomatic ARIA-edema (RR = 24.3; NNH = 86). CONCLUSIONS: Although monoclonal antibodies targeting amyloid provide small benefits on cognitive and functional scales in patients with Alzheimer dementia, these improvements are far below the MCID for each outcome and are accompanied by clinically meaningful harms.

Oestrogen-based therapies for menopausal symptoms.

PURPOSE: To summarise the dosing options, regimens, pharmacokinetics, risks and benefits of oestrogen-based therapies for the treatment of menopausal symptoms. METHODS: A review of the literature was undertaken using multiple databases. Randomised trials, observational studies, meta-analyses and review papers were included. RESULTS: Multiple systemic preparations of oestrogen exist and all appear comparable in terms of efficacy. They differ by pharmacokinetics and those preparations that avoid hepatic metabolism have a lower risk profile in general although their use can be limited by skin barriers or patient acceptability. All vaginal oestrogen treatments are comparable in efficacy and have not been associated with any health risks. Side-effects between all preparations differ. CONCLUSIONS: With regards to oestrogen treatments there is not a one size fits all. Multiple treatments are available and a clinician's role is to guide and help women make evidence based, unbiased and informed choices.

OSH related risks and opportunities for industrial human-robot interaction: results from literature and practice.

Robotic systems are an integral component of today's work place automation, especially in industrial settings. Due to technological advancements, we see new forms of human-robot interaction emerge which are related to different OSH risks and benefits. We present a multifaceted analysis of risks and opportunities regarding robotic systems in the context of task automation in the industrial sector. This includes the scientific perspective through literature review as well as the workers' expectations in form of use case evaluations. Based on the results, with regards to human-centred workplace design and occupational safety and health (OSH), implications for the practical application are derived and presented. For the literature review a selected subset of papers from a systematic review was extracted. Five systematic reviews and meta-analysis (492 primary studies) focused on the topic of task automation via robotic systems and OSH. These were extracted and categorised into physical, psychosocial and organisational factors based on an OSH-factors framework for advanced robotics developed for the European Agency for Safety and Health at Work (EU-OSHA). To assess the workers' perspective, 27 workers from three European manufacturing companies were asked about their expectations regarding benefits and challenges of robotic systems at their workplace. The answers were translated and categorised in accordance with the framework as well. The statements, both from literature and the survey were then analysed according to the qualitative content analysis, to gain additional insight into the underlying structure and trends in them. As a result, new categories were formed deductively. The analysis showed that the framework is capable to help categorise both findings from literature and worker survey into basic categories with good interrater reliability. Regarding the proposed subcategories however, it failed to reflect the complexity of the workers' expectations. The results of the worker evaluation as well as literature findings both predominantly highlight the psychosocial impact these systems may have on workers. Organisational risks or changes are underrepresented in both groups. Workers' initial expectations lean towards a positive impact.

Three-Dimensional Printing of Foods: A Critical Review of the Present State in Healthcare Applications, and Potential Risks and Benefits.

Three-dimensional printing is one of the most precise manufacturing technologies with a wide variety of applications. Three-dimensional food printing offers potential benefits for food production in terms of modifying texture, personalized nutrition, and adaptation to specific consumers' needs, among others. It could enable innovative and complex foods to be presented attractively, create uniquely textured foods tailored to patients with dysphagia, and support sustainability by reducing waste, utilizing by-products, and incorporating eco-friendly ingredients. Notable applications to date include, but are not limited to, printing novel shapes and complex geometries from candy, chocolate, or pasta, and bio-printed meats. The main challenges of 3D printing include nutritional quality and manufacturing issues. Currently, little research has explored the impact of 3D food printing on nutrient density, bioaccessibility/bioavailability, and the impact of matrix integrity loss on diet quality. The technology also faces challenges such as consumer acceptability, food safety and regulatory concerns. Possible adverse health effects due to overconsumption or the ultra-processed nature of 3D printed foods are major potential pitfalls. This review describes the state-of-the-art of 3D food printing technology from a nutritional perspective, highlighting potential applications and current limitations of this technology, and discusses the potential nutritional risks and benefits of 3D food printing.

Delivery after a previous cesarean section reviewed.

At the start of the 20th century, cesarean section (CS) was uncommon in obstetrics. By the end of the century, CS rates had increased dramatically worldwide. Although the explanation for the increase is multifactorial, a major driver in the ongoing escalation is the increase in women who are delivered by repeat CS. This is due, in part, to the fact that there has been a sharp fall in vaginal birth after CS (VBAC) rates as fewer women are offered a trial of labor after CS (TOLAC), due principally to fears of a catastrophic intrapartum uterine rupture. This paper reviewed international VBAC policies and trends. A number of themes emerged. The risk of intrapartum rupture and its associated complications is low and may sometimes be overestimated. Individual maternity hospitals in both developed and developing countries are inadequately resourced to safely supervise a TOLAC. Efforts to mitigate the risks of TOLAC by careful patient selection and good clinical practices may be underutilized. Given the serious short-term and long-term consequences of rising CS rates for women and for maternity services generally, a review of TOLAC policies worldwide should be prioritized and consideration given to convening a Global Consensus Development Conference on Delivery after CS.

High-Dose Prophylactic Anticoagulation for COVID-19 Pneumonia: A Review of Benefits and Risks.

The COVID-19 pandemic has had a devastating impact on a global scale, causing significant morbidity and mortality. The virus affects multiple organ systems, including the respiratory, cardiovascular, and coagulation systems, leading to severe pneumonia in some patients. Moreover, COVID-19 patients with severe pneumonia have a high incidence of thrombotic events, which can result in significant morbidity and mortality. Given the potential benefits of anticoagulation therapy in COVID-19 patients with thrombotic complications, recent studies have proposed high-dose prophylactic anticoagulation (HD-PA) therapy as a potential treatment option. In fact, some studies have suggested that HD-PA therapy may be more effective in reducing thrombotic events and mortality rates than other treatment options. This review aims to provide a comprehensive overview of the benefits and risks of HD-PA therapy for COVID-19 pneumonia patients. By synthesizing and analyzing the latest available research, we highlight patient selection criteria and discuss the optimal dosage, duration, and timing of therapy. Additionally, we review the potential risks associated with HD-PA therapy and provide recommendations for clinical practice. Ultimately, this review provides valuable insights into the use of HD-PA therapy in COVID-19 pneumonia patients and paves the way for further research in this critical area. By exploring the benefits and risks of this treatment option, we hope to provide healthcare professionals with the information they need to make informed decisions about the best course of treatment for their patients.

Nutritional profiling and contaminant levels of five underutilized fish species in Norway.

Exploring and making use of underutilized marine resources can be a sustainable approach to achieve future demands of fish consumption by the ever-growing population. Five species, namely European plaice (Pleuronectes platessa), European flounder (Platichthys flesus), lemon sole (Microstomus kitt), megrim (Lepidorhombus whiffiagonis), and thornback ray (Raja clavate), often captured as by-catch in Norway, were characterized for their nutritional value and potential accumulation of hazardous components. The proximate composition, protein profile, fatty acid profile as well as essential and toxic trace elements and polychlorinated biphenyls (PCBs) were analyzed. Digestible indispensable amino acid (DIAA) ratios and scores (DIAAS) and contributions of omega-3 fatty acids to the diet were calculated. Analysis on proximate composition revealed low fat contents of 0.74 to 1.25% and sufficient protein contents between 16.9 and 24% in the five species. Results of DIAA indicate a profitable distribution, with contributions exceeding the daily intake recommendations for an adult person related to a 200 g fillet. Moreover, findings on the distribution of eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) showed remarkable results, considering that the investigated species are lean fish. All five investigated fish exceed the recommended average daily intake level (AI) of EPA + DHA in a 200 g portion. As to toxic trace elements and PCBs, no significantly elevated levels were found considering a portion size of 200 g. Consequently, the nutritional quality of the investigated fish can be regarded as profitable with overall low potential health risks.

The transparency of reporting 'harms' encountered with the surgically assisted acceleration of orthodontic tooth movement in the published randomized controlled trials: a meta-epidemiological study.

BACKGROUND: Surgical-assisted accelerated orthodontics (SAAO) has become very popular recently. Therefore, this study aimed to investigate the extent to which researchers adhere to Item 19 (harms) of the Consolidated Standards of Reporting Trials (CONSORT) in the published studies in the field of SAAO. In addition, the study evaluated the possible association between harm reporting and the human development index (HDI) of the recruited research sample country, CiteScore-based quartile (CSBQ) of the publishing journal, invasiveness of the surgical intervention (ISI), and the type of orthodontic tooth movement (TOTM). Moreover, it aimed to summarize the different possible harms and complications that maybe encountered in the course of SAAO. MATERIALS AND METHODS: Electronic searching of six databases was conducted for SAAO-related English RCTs published between January 2000 and April 2022. For the RCTs that did not report harms, information was sought by contacting the corresponding authors. Descriptive statistics of the evaluated variables were performed. The association between 'harm reporting' and the HDI of the research team, the BDRQ of the publication journal, the ISI, and the TOTM were investigated. Binary logistic regression was used, and the odds ratios (ORs) with 95% confidence interval (CIs) of the evaluated variables were obtained. Moreover, the risk of bias of the included RCTs was assessed using the RoB2 tool. RESULTS: Among the 91 included RCTs, 54 RCTs (59.3%) did not adhere to reporting harm associated with the SAAO. The non-adherence was significantly associated with the ISI (OR 0.16; CI 0.03-0.73; p < 0.018) for invasive methods compared with minimally invasive ones). There was a significant positive correlation between harm reporting and both the CSBQ of the publishing journal and the HDI of the recruited research sample country (p = 0.001, p = 0.003, respectively). On the contrary, a non-significant association was found between harm reporting and the type of OTM (p = 0.695). The incidence of harms associated with SAAO was approximately 17.5%. LIMITATIONS: Assessment was restricted to English RCTs related to SAAO. CONCLUSION AND IMPLICATIONS: The adherence to reporting harms in the field of SAAO was deficient. Efforts should be made by authors, peer reviewers, and editors to improve compliance with the CONSORT guidelines regarding harms reporting. Additionally, there is a wide spectrum of harms that could be associated with SAAO that the practitioner should pay attention to and alert the patient to the possibility of their occurrence.

Reflections on abortion rights: From policy to medicine.

On June 24, 2022, the US Supreme Court overturned Roe v. Wade, which marked a further restriction on women's abortion rights in the US. It has sparked a wide range of societal reactions around the world. Women in different countries enjoy diverse abortion rights due to conditions in their respective nations and cultures. Abortion protects women's rights to a certain extent, and especially in the event of unintended pregnancy. An inappropriate abortion ban will affect women's health and lives and all aspects of medicine, including the lives of doctors, patient access, and the development of medical technology. This review provides a gynecologist's perspective on the impact of abortion policies on women's health and the medical system. This review also attempts to determine the reason for the government's abortion ban.

Reevaluating the Ethical Issues in Porcine-to-Human Heart Xenotransplantation.

A major limiting factor with heart allotransplantation remains the availability of organs from deceased donors. Porcine heart xenotransplantation could serve as an alternative source of organs for patients with terminal heart failure. A first-in-human porcine xenotransplantation that occurred in January 2022 at the University of Maryland Medical Center provided an opportunity to examine several ethical issues to guide selection criteria for future xenotransplantation clinical trials. In this article, the authors, who are clinicians at UMMC, discuss the appropriate balancing of risks and benefits and the significance, if any, of clinical equipoise. The authors also review the alleged role of the psychosocial evaluation in identifying patients at an elevated risk of posttransplant noncompliance, and they consider how the evaluation's implementation might enhance inequities among diverse populations. The authors argue that, based on the principle of reciprocity, psychosocial criteria should be used, not to exclude patients, but instead to identify patients who need additional support. Finally, the authors discuss the requirements for and the proper assessment of informed and voluntary consent from patients being considered for xenotransplantation.

Physical activity, cardiorespiratory fitness, and cardiovascular health: A clinical practice statement of the ASPC Part I: Bioenergetics, contemporary physical activity recommendations, benefits, risks, extreme exercise regimens, potential maladaptations.

Regular moderate-to-vigorous physical activity (PA) and increased levels of cardiorespiratory fitness (CRF) or aerobic capacity are widely promoted as cardioprotective measures in the primary and secondary prevention of atherosclerotic cardiovascular (CV) disease (CVD). Nevertheless, physical inactivity and sedentary behaviors remain a worldwide concern. The continuing coronavirus (COVID-19) pandemic has been especially devastating to patients with known or occult CVD since sitting time and recreational PA have been reported to increase and decrease by 28% and 33%, respectively. Herein, in this first of a 2-part series, we discuss foundational factors in exercise programming, with specific reference to energy metabolism, contemporary PA recommendations, the dose-response relationship of exercise as medicine, the benefits of regular exercise training, including the exercise preconditioning cardioprotective phenotype, as well as the CV risks of PA. Finally, we discuss the 'extreme exercise hypothesis,' specifically the potential maladaptations resulting from high-volume, high-intensity training programs, including accelerated coronary artery calcification and incident atrial fibrillation. The latter is commonly depicted by a reverse J-shaped or U-shaped curve. On the other hand, longevity data argue against this relationship, as elite endurance athletes live 3-6 years longer than the general population.

Patient preferences for mitral valve regurgitation treatment: a discrete choice experiment.

INTRODUCTION: This study aimed to quantify patients' preferences for benefits and risks associated with treating degenerative mitral regurgitation (DMR) via open heart surgical repair versus a beating heart surgical approach. METHODS: A D-efficient main effects discrete choice experiment (DCE) survey with 10 choice tasks that involved trade-offs across six attributes varying between two and four levels each (procedure invasiveness, recovery intensity, risk of disabling stroke, risk of new onset atrial fibrillation, risk of symptom reappearance and risk of reintervention) was administered online to either clinically confirmed (n = 30) or self-reported DMR (n = 88) patients recruited from either cardiovascular clinics or online clinical patient databases. The error component logit (ECL) analysis combined both patient cohorts after performing a Swait-Louviere scale test. Patient trade-offs across attributes were estimated in relation to either an open-heart surgery (OHS) treatment profile or a beating heart approach. RESULTS: Patients demonstrated clear preferences across all attributes for the beating heart treatment. 76.0% (95% CI: 68.1,83.9) of patients would prefer a 'beating heart' intervention relative to the 'open heart' approach despite the higher likelihood of symptom recurrence and reintervention. In exchange for the combined net benefits associated with a 'beating heart' treatment, on average, participants were willing to accept a maximum acceptable risk (MAR) of 34.6 percentage points (95% CI: 23.8,45.4) for increased risk of symptom reappearance or 22.6 percentage points (95% CI: 14.7,30.4) increased risk of reintervention. CONCLUSION: This study of US adults with DMR provides quantitative measures of risk tolerance for tradeoffs related to repair by a beating heart approach relative to conventional open-heart surgery (standard of care). These results may inform DMR treatment choices from regulatory agencies, payers, clinicians, and patients considering a beating heart repair or treatments with similar attributes as potential new alternatives to conventional surgery.

Men's willingness to support HPV vaccination and cervical cancer screening in Nigeria.

Cervical cancer is the second most common female cancer in Nigeria, even though it can be prevented by vaccination and screening. The uptake of these preventive services is extremely low due to lack of spousal support and cost. Human papilloma virus (HPV) vaccines and cervical screening require finance as health services are mostly paid out of pocket. This study explored Nigerian men's willingness to encourage and pay for family member to obtain HPV vaccine and cervical screening. This is a cross-sectional study of 352 men aged 18-65 years living in 12 communities in the 6-geopolitical region. We found poor perception of HPV risk, and believed their family was not susceptible to cervical cancer. However, the majority (>80%) believed HPV vaccine and cervical screenings are important. Additionally, a good number (>58%) would encourage and pay for their family member to receive HPV vaccine and cervical screening. Residency, educational level and monthly income were significantly associated with willingness to encourage their family to receive HPV vaccine and cervical screening. Also, age group, marital status, residency, educational level and monthly income were significantly associated with the willingness to pay for HPV vaccine and cervical cancer screening. Majority were willing to encourage and pay for their family member to get vaccinated and receive cervical screening. This supports the findings that lack of male involvement may be an overlooked obstacle to cervical cancer prevention in developing countries.

Perceptions of HIV Research Participation Among Gay, Bisexual, and Other Men who Have Sex with Men and Transgender and Nonbinary Adults: Results From a Midwest Pride Event.

Human immunodeficiency virus (HIV) continues to disproportionately affect gay, bisexual, and other men who have sex with men (GBM) and transgender and nonbinary (trans/NB) individuals. This study investigated attitudes toward participation in HIV survey research, guided by Emanuel's framework for ethical clinical research (e.g., risk-benefit ratio, fair participant selection, respect for participants, social value, and collaborative partnership). GBM (n = 294) and trans/NB (n = 86) persons recruited at a Pride event in Milwaukee completed a survey assessing risks and benefits of participation in, and comfort responding to, sexual health surveys. Participants reported few ethical concerns (e.g., privacy and confidentiality), with notable differences by race, sexual orientation and gender identity, and prior research experiences. Implications for HIV research with GBM and trans/NB individuals are discussed.

A Participant-Centered Approach to Understanding Risks and Benefits of Participation in Research Informed by the Kidney Precision Medicine Project.

An understanding of the ethical underpinnings of human subjects research that involves some risk to participants without anticipated direct clinical benefit-such as the kidney biopsy procedure as part of the Kidney Precision Medicine Project (KPMP)-requires a critical examination of the risks as well as the diverse set of countervailing potential benefits to participants. This kind of deliberation has been foundational to the development and conduct of the KPMP. Herein, we use illustrative features of this research paradigm to develop a more comprehensive conceptualization of the types of benefits that may be important to research participants, including respecting pluralistic values, supporting the opportunity to act altruistically, and enhancing benefits to a participant's community. This approach may serve as a model to help researchers, ethicists, and regulators to identify opportunities to better respect and support participants in future research that entails some risk to these participants as well as to improve the quality of research for people with kidney disease.

Lessons Learned: Beta-Testing the Digital Health Checklist for Researchers Prompts a Call to Action by Behavioral Scientists.

Digital technologies offer unique opportunities for health research. For example, Twitter posts can support public health surveillance to identify outbreaks (eg, influenza and COVID-19), and a wearable fitness tracker can provide real-time data collection to assess the effectiveness of a behavior change intervention. With these opportunities, it is necessary to consider the potential risks and benefits to research participants when using digital tools or strategies. Researchers need to be involved in the risk assessment process, as many tools in the marketplace (eg, wellness apps, fitness sensors) are underregulated. However, there is little guidance to assist researchers and institutional review boards in their evaluation of digital tools for research purposes. To address this gap, the Digital Health Checklist for Researchers (DHC-R) was developed as a decision support tool. A participatory research approach involving a group of behavioral scientists was used to inform DHC-R development. Scientists beta-tested the checklist by retrospectively evaluating the technologies they had chosen for use in their research. This paper describes the lessons learned because of their involvement in the beta-testing process and concludes with recommendations for how the DHC-R could be useful for a variety of digital health stakeholders. Recommendations focus on future research and policy development to support research ethics, including the development of best practices to advance safe and responsible digital health research.

Risk Stratification in Patients with Ischemic Stroke and Residual Cardiovascular Risk with Current Secondary Prevention.

PURPOSE: Suboptimal secondary prevention in patients with stroke causes a remaining cardiovascular risk desirable to reduce. We have validated a prognostic model for secondary preventive settings and estimated future cardiovascular risk and theoretical benefit of reaching guideline recommended risk factor targets. PATIENTS AND METHODS: The SMART-REACH (Secondary Manifestations of Arterial Disease-Reduction of Atherothrombosis for Continued Health) model for 10-year and lifetime risk of cardiovascular events was applied to 465 patients in the Norwegian Cognitive Impairment After Stroke (Nor-COAST) study, a multicenter observational study with two-year follow-up by linkage to national registries for cardiovascular disease and mortality. The residual risk when reaching recommended targets for blood pressure, low-density lipoprotein cholesterol, smoking cessation and antithrombotics was estimated. RESULTS: In total, 11.2% had a new event. Calibration plots showed adequate agreement between estimated and observed 2-year prognosis (C-statistics 0.63, 95% confidence interval 0.55-0.71). Median estimated 10-year risk of recurrent cardiovascular events was 42% (Interquartile range (IQR) 32-54%) and could be reduced to 32% by optimal guideline-based therapy. The corresponding numbers for lifetime risk were 70% (IQR 63-76%) and 61%. We estimated an overall median gain of 1.4 (IQR 0.2-3.4) event-free life years if guideline targets were met. CONCLUSION: Secondary prevention was suboptimal and residual risk remains elevated even after optimization according to current guidelines. Considerable interindividual variation in risk exists, with a corresponding variation in benefit from intensification of treatment. The SMART-REACH model can be used to identify patients with the largest benefit from more intensive treatment and follow-up.

Participatory design and qualitative evaluation of a decision guide for workplace human immunodeficiency virus self-disclosure: The importance of a socio-ecological perspective.

BACKGROUND: Disclosure of human immunodeficiency virus (HIV)-positive status in a workplace can be a complex social decision for a person living with HIV. OBJECTIVE: To design a Decision Guide to support people living with HIV in assessing contexts, risks and benefits of workplace disclosure in choosing whether or not, or to what extent, to disclose. In this report, we review the participatory design of a Decision Guide prototype and focus on its evaluation. METHODS: We began with stakeholder input through an environmental scan and community consultation that informed the development of an online Decision Guide prototype. To evaluate the comprehensiveness, acceptability and usability of the prototype, we used qualitative methodology involving individual interviews and the think-aloud technique. Interviews were transcribed and analysed qualitatively. RESULTS: Fourteen people, including people living with HIV and service providers, participated. We identified benefits of the Decision Guide related to comprehensiveness, acceptability and usability. Additional interview themes focused on disclosure concerns, mitigating risks associated with disclosure and additional considerations for the Decision Guide. CONCLUSIONS: The Decision Guide was perceived to be acceptable, comprehensive and useful. The findings endorse the application of a socio-ecological perspective when designing decision support aids for complex social decisions. PATIENT OR PUBLIC CONTRIBUTION: People with lived experience of HIV were involved in the prototype design phases as research team members. They, along with community leaders and service providers, also participated in a community forum and were key informants for the evaluation of the Workplace Disclosure Decision Guide prototype.

The Ethics of Research That May Disadvantage Others.

In prospective interventional research, a treatment may provide an advantage for the recipient over other people who do not receive it. If the intervention proves successful, the treated are better able to compete for such things as a scarce ventilator, a class grade, or a litigation outcome, potentially risking the deaths, jobs, or incomes of nontreated persons. Discussions of ethical concerns related to "bystanders" have typically focused on direct harms (such as infecting them with a virus), rather than the competition for a rivalrous good (such as a ventilator or clinical outcome). After broadly scoping this problem of advantage, this article reveals several reasons that such interventional research is typically permissible, notwithstanding the potential setbacks to nonparticipants. I consider the almost-dispositive concept of clinical equipoise and then glean insights from the harm principle, status quo bias, the leveling-down problem, and a potential bias against prospective interventional research versus program interventions with retrospective study. My consideration of institutional relationships does not change the analysis that such research is permissible.