Less severe clinical symptoms of Norwalk virus 8fIIb inoculum compared to its precursor 8fIIa from human challenge studies.

Noroviruses (NoV) are a leading cause of epidemic gastroenteritis. Human challenge studies have been used to examine the infectivity, pathogenicity, and host immune response to NoV as well as vaccine efficacy. The goal of this study was to conduct a meta-analysis of data from five previously completed human challenge trials and compare the response to the secondary NV inoculum (8fIIb) to its precursor (8fIIa). We investigated a total of 158 subjects: 76 subjects were experimentally challenged with NV inoculum 8fIIa, and 82 subjects were challenged with 8fIIb. We compared demographic characteristics, infection, illness, mean severity score, blood types, and duration of viral shedding between the two groups of subjects. There were no statistically significant differences in overall infection and illness rates between subjects inoculated with 8fIIa and 8fIIb. However, individuals challenged with 8fIIa had significantly higher severity scores (5.05 vs. 3.22, p = .008) compared with those challenged with 8fIIb. We also observed that infection with 8fIIb was associated with significantly longer duration of viral shedding compared with 8fIIa (11.0 days vs. 5.0 days, p = .0005). These results have serious implications for the development of new NoV inocula for human challenge studies to test candidate vaccine efficacy-where illness severity and duration of viral shedding are important outcomes.

Nazi Medical Research in Neuroscience: Medical Procedures, Victims, and Perpetrators.

Issues relating to the euthanasia killings of the mentally ill, the medical research conducted on collected body parts, and the clinical investigations on living victims under National Socialism are among the best-known abuses in medical history. But to date, there have been no statistics compiled regarding the extent and number of the victims and perpetrators, or regarding their identities in terms of age, nationality, and gender. "Victims of Unethical Human Experiments and Coerced Research under National Socialism," a research project based at Oxford Brookes University, has established an evidence-based documentation of the overall numbers of victims and perpetrators through specific record linkages of the evidence from the period of National Socialism, as well as from post-WWII trials and other records. This article examines the level and extent of these unethical medical procedures as they relate to the field of neuroscience. It presents statistical information regarding the victims, as well as detailing the involvement of the perpetrators and Nazi physicians with respect to their post-war activities and subsequent court trials.

Unsuccessful trial accrual and human subjects protections: an empirical analysis of recently closed trials.

BACKGROUND: Ethical evaluation of risk-benefit in clinical trials is premised on the achievability of resolving research questions motivating an investigation. OBJECTIVE: To determine the fraction and number of patients enrolled in trials that were at risk of not meaningfully addressing their primary research objective due to unsuccessful patient accrual. METHODS: We used the National Library of Medicine clinical trial registry to capture all initiated phases 2 and 3 intervention clinical trials that were registered as closed in 2011. We then determined the number that had been terminated due to unsuccessful accrual and the number that had closed after less than 85% of the target number of human subjects had been enrolled. Five factors were tested for association with unsuccessful accrual. RESULTS: Of 2579 eligible trials, 481 (19%) either terminated for failed accrual or completed with less than 85% expected enrolment, seriously compromising their statistical power. Factors associated with unsuccessful accrual included greater number of eligibility criteria (p = 0.013), non-industry funding (25% vs 16%, p < 0.0001), earlier trial phase (23% vs 16%, p < 0.0001), fewer number of research sites at trial completion (p < 0.0001) and at registration (p < 0.0001), and an active (non-placebo) comparator (23% vs 16%, p < 0.001). CONCLUSION: A total of 48,027 patients had enrolled in trials closed in 2011 who were unable to answer the primary research question meaningfully. Ethics bodies, investigators, and data monitoring committees should carefully scrutinize trial design, recruitment plans, and feasibility of achieving accrual targets when designing and reviewing trials, monitor accrual once initiated, and take corrective action when accrual is lagging.

Motives for participating in a clinical research trial: a pilot study in Brazil.

BACKGROUND: In the past, clinical study participants have suffered from the experiments that they were subjected to. Study subjects may not understand the study process or may participate in clinical studies because they do not have access to medical care. The objectives of the present study were 1. to analyze the motives that might cause a volunteer to participate as a study subject; 2. to identify the social-demographic profile of this study subjects; and 3. to determine whether the motives to volunteer as a study subject are in accordance with the established legal and ethical principles for research in Brazil. METHODS: Mixed-methods research was used (a qualitative-quantitative approach). A sample of 80 volunteers underwent a semi-structured interview, which was based on a survey script that was elaborated from discussions with key informants. The sample was randomly selected from a database of clinical study volunteers that was provided by Brazilian clinical study centers. The interviews were recorded and transcribed. Descriptive statistics were used for content analysis, including contingency tables with hypothesis testing. RESULTS: The motivations for clinical study participation were linked to types of benefit. The most frequently encountered motivations were financial gain and therapeutic alternative. Altruism was not a common motivator, and when altruism was present, it was observed as a secondary motivator. All participants reported that they understood the Informed Consent Statement (ICS). However, only two parts of the form were remembered by all of the volunteers: the section on being able to leave the study at any point and the section that stated that there would be some responsible professional at their disposal for the entirety of the study. CONCLUSIONS: The present study shows that study participants are primarily motivated by personal benefit when volunteering to participate in clinical studies. Whether these study participants had an integral understanding of the ICS is not clear.

Assessment of donor fear enhances prediction of presyncopal symptoms among volunteer blood donors.

BACKGROUND: Fear is an important contributor to the risk of presyncopal reactions to blood donation. However, concern that asking donors about their fears may increase the risk of reactions is a potential impediment to incorporating fear assessment into donor screening. STUDY DESIGN AND METHODS: Before donation, participants responded to a series of questions that either did (n = 488) or did not (n = 494) include questions related to fear of seeing blood drawn. Immediately after donation all participants provided ratings of presyncopal reactions. RESULTS: Among those asked predonation fear questions, fear was most strongly related to presyncopal symptoms when compared against other donor characteristics (e.g., age, number of prior donations, body mass index, estimated blood volume, blood pressure, and pulse). However, Mann-Whitney U tests revealed that being asked about fear before donation was not associated with higher reports of presyncopal reactions for the sample as a whole, nor among novice donors. Further, regression analyses indicated that fear remained a significant predictor of presyncopal reactions in final models that included age and number of prior donations as significant predictors. CONCLUSION: Predonation assessment of fear of blood draws may help to identify donors who are most likely to benefit from brief interventions designed to enhance donor coping, reduce risk of presyncopal reactions, and increase donor retention.

Shigella-Specific Immune Profiles Induced after Parenteral Immunization or Oral Challenge with Either Shigella flexneri 2a or Shigella sonnei.

Shigella spp. are a leading cause of diarrhea-associated global morbidity and mortality. Development and widespread implementation of an efficacious vaccine remain the best option to reduce Shigella-specific morbidity. Unfortunately, the lack of a well-defined correlate of protection for shigellosis continues to hinder vaccine development efforts. Shigella controlled human infection models (CHIM) are often used in the early stages of vaccine development to provide preliminary estimates of vaccine efficacy; however, CHIMs also provide the opportunity to conduct in-depth immune response characterizations pre- and postvaccination or pre- and postinfection. In the current study, principal-component analyses were used to examine immune response data from two recent Shigella CHIMs in order to characterize immune response profiles associated with parenteral immunization, oral challenge with Shigella flexneri 2a, or oral challenge with Shigella sonnei. Although parenteral immunization induced an immune profile characterized by robust systemic antibody responses, it also included mucosal responses. Interestingly, oral challenge with S. flexneri 2a induced a distinctively different profile compared to S. sonnei, characterized by a relatively balanced systemic and mucosal response. In contrast, S. sonnei induced robust increases in mucosal antibodies with no differences in systemic responses across shigellosis outcomes postchallenge. Furthermore, S. flexneri 2a challenge induced significantly higher levels of intestinal inflammation compared to S. sonnei, suggesting that both serotypes may also differ in how they trigger induction and activation of innate immunity. These findings could have important implications for Shigella vaccine development as protective immune mechanisms may differ across Shigella serotypes. IMPORTANCE Although immune correlates of protection have yet to be defined for shigellosis, prior studies have demonstrated that Shigella infection provides protection against reinfection in a serotype-specific manner. Therefore, it is likely that subjects with moderate to severe disease post-oral challenge would be protected from a homologous rechallenge, and investigating immune responses in these subjects may help identify immune markers associated with the development of protective immunity. This is the first study to describe distinct innate and adaptive immune profiles post-oral challenge with two different Shigella serotypes. Analyses conducted here provide essential insights into the potential of different immune mechanisms required to elicit protective immunity, depending on the Shigella serotype. Such differences could have significant impacts on vaccine design and development within the Shigella field and should be further investigated across multiple Shigella serotypes.

Research on prisoners - a comparison between the IOM Committee recommendations (2006) and European regulations.

The Institute of Medicine (IOM) Committee on Ethical Considerations for Revisions to DHHS Regulations for Protection of Prisoners Involved in Research published its report in 2006. It was charged with developing an ethical framework for the conduct of research with prisoners and identifying the safeguards and conditions necessary to ensure that research with prisoners is conducted ethically. The recommendations contained in the IOM report differ from current European regulations in several ways, some being more restrictive and some less so. For example, the IOM report suggests limiting the percentage of prisoners that should be involved in a biomedical study to 50%, a limit that does not exist in Europe. However, the report does not specifically advise against research without a direct benefit to an individual prisoner: the European regulations are more restrictive than the IOM committee recommendations in this respect. The definition of minimal risk varies, as well as the proposed role of the minimal risk requirement and of the principle of subsidiarity (research that can only be done effectively in prisons). The IOM report proposes a number of thoughtful suggestions, which it would be beneficial to implement everywhere, such as registers of research on prisoners. The European regulations offer pragmatic solutions to several thorny issues. In summary, the IOM committee report represents an admirable effort to tackle the present inconsistencies and deficiencies of federal regulations in the US on research on prisoners (45 CFR 46 Subpart C). Nonetheless, before acting on the recommendations, US regulators might consider revisiting international guidelines such as those published by the Council for International Organizations of Medical Science (CIOMS) and the Declaration of Helsinki.

Community collaboration in a community H1N1 vaccination program.

This community's utilization of their Medical Reserve Corps (MRC) unit proved to be a valuable resource in their vaccination clinics as part of their response to the novel influenza A (H1N1) virus. Early planning, mock vaccination drills, and use of a strategic analysis process aided in the formulation and development of an efficient vaccination campaign.

A roadmap for enterotoxigenic Escherichia coli vaccine development based on volunteer challenge studies.

Enterotoxigenic Escherichia coli (ETEC) is a major cause of travelers' diarrhea and of diarrhea among young children in developing countries. Experimental challenge studies in adult volunteers have played a pivotal role in establishing ETEC as an enteric pathogen, elucidating its pathogenesis by identifying specific virulence attributes, characterizing the human immune response to clinical and sub-clinical ETEC infection and assessing preliminarily the clinical acceptability, immunogenicity and efficacy of prototype ETEC vaccines. This review provides a historical perspective of experimental challenge studies with ETEC. It summarizes pioneering early studies carried out by investigators at the University of Maryland School of Medicine to show how those studies provided key information that influenced the directions taken by many research groups to develop vaccines to prevent ETEC. In addition, key experimental challenge studies undertaken at other institutions will also be cited.

Volunteer-based vision nongovernmental organizations and VISION 2020.

BACKGROUND: The World Health Organization and the International Agency for the Prevention of Blindness developed the global initiative, VISION 2020, with the goal of eliminating avoidable blindness by 2020. An unknown number of volunteer-based organizations conduct short-term vision camps as a means of eliminating blindness in developing countries. METHODS: VISION 2020 strategies are reviewed and volunteer organizations' understanding of VISION 2020 and methods of service delivery are considered through survey results. RESULTS: From the surveys it is apparent that volunteer organizations are not aware of the VISION 2020 initiative and do not conduct their projects and programs in a way that is supported by VISION 2020. CONCLUSION: Volunteer organizations have the skills, resources, and enthusiasm to make an impact on the burden of visual impairment. They do not, however, follow strategies accepted as most appropriate by the larger global eye health care community. Volunteer organizations are encouraged to reprioritize the work they do and change the methods they use.

Analysis of the first 2645 registrations at the research registry®: A global repository for all study types involving human participants.

BACKGROUND: The Declaration of Helsinki has called for the registration of all research studies involving human participants. Despite this, prior registries did not allow registration certain study types, or retrospective registration. The Research Registry® (www.researchregistry.com) was established in 2015 to provide a venue of registration for any study involving human participants. METHODS: and analysis: This retrospective database analysis describes the first 3000 registrations received by the Research Registry®. Since the launch of the Registry in 2015, we have collected data on each registration and excluded inappropriate registrations through a weekly curation process. The characteristics of all studies registered is presented. Each registration was marked against a quality score by two researchers acting independently, and we describe how this has changed over time. No ethical approval was required for this data only study including no human participants. RESULTS: Of 3000 registrations, we included 2645 that were submitted to the registry between February 2015 and October 2017. The number of registrations increased year on year, and we now receive between 60 and 80 registrations per month. One fifth of registrations were from China (537 [20.3%]). Retrospective observational studies were most commonly registered (1125 [42.5%]), and studies included in excess of 20 million patients (median 80 [IQR:25-200]). The quality score of registrations improved over the time (Kruskal-Wallis p < 0.05), and the 'control/comparator' component of the quality score was most poorly completed (completed by 1199 [54%]). CONCLUSION: The Research Registry® has received registrations on over 2500 registrations, including in excess of 20 million patients, with the quality of registrations improving over time. Retrospective observational studies and case series are the most commonly registered.

Munich anatomy and the distribution of bodies from the Stadelheim execution site during National Socialism.

During the reign of National Socialism (NS) anatomical institutes regularly received bodies of executed prisoners in steadily increasing numbers. After 1939, the execution site at Stadelheim prison in Munich supplied not only Munich anatomy but also the institutes in Erlangen, Innsbruck and Würzburg. Due to the disappearance of the Munich body journals, the exact dimension and procedure of body procurement from Stadelheim remained unknown for 70 years. After consultation of a wide range of sources, including rediscovered fragments of the body journals, it is now possible to give an almost comprehensive account of the developments. This article deals with the attempts at recovering information on body procurement from Stadelheim prison during the NS period, which already indicated the significance of Munich anatomy in organizing the distribution of bodies. Thereafter, it addresses the number and distinct groups of Stadelheim prisoners, executed and delivered to the four anatomical institutes, the differences in the handling of their bodies, and the extent to which in particular Munich anatomy profited from the massive increase in executions. Finally, it unveils the role of the Munich Anatomical Institute in distributing those bodies among the anatomies during the Second World War, making it not only the main beneficiary but also the interim center of this process.

Controlled human infections: A report from the controlled human infection models workshop, Leiden University Medical Centre 4-6 May 2016.

The principle of deliberately infecting humans with infectious agents in a controlled setting, so-called controlled human infections (CHI), is not novel. Many CHI models have a long history and were established decades ago such as the intentional exposure to yellow fever and dengue performed in the 1900's (Reed, 1902) [2]. In these times bioethics and scientific reasoning were in their infancy. Nowadays, clinical trials are highly regulated and CHI are executed worldwide. Controlled human malaria infections and influenza infections are the two most frequently practiced. Others are experiencing a revival or are being carefully developed. Because CHI models test the efficacy of promising vaccine or drug candidates early in clinical development, they offer the potential to decrease the number of failing phase 2 and 3 trials, reducing risks for patients and saving costs and efforts. In addition, CHI models provide unprecedented opportunities to dissect the physiological, immunological and metabolic changes that occur upon infection. However, it is clear that controlled infections require careful deliberation of safety, ethics, quarantine, scientific output and the production of infectious material. An independent international workshop was hosted by the Leiden University Medical Centre in The Netherlands, bringing together clinical investigators, basic scientists, regulators, funders and policy makers from 22 different countries to discuss the opportunities and challenges in CHI. The aim of the workshop was to discuss CHI as a tool to advance science, drug and vaccine development, share the challenges of establishing a CHI model with specific focus on neglected tropical diseases and the possibilities to transfer models to endemic sites. Noticeably, among the 128 participants were clinical investigators from ten different countries in Sub-Saharan Africa. An important dimension of the meeting was to give the floor to young established clinicians and scientists to voice their perspective on the future of CHI models.