Towards transparency: adoption of WHO best practices in clinical trial registration and reporting among top medical research funders in the USA.

OBJECTIVE: To assess to what extent the clinical trial policies of the largest public and philanthropic funders of clinical research in the United States meet WHO best practices in trial registration and reporting. METHODS: Public and philanthropic funders of clinical trials in the USA with >US$50 million annual spend were selected. The funders were assessed using an 11-item scoring tool based on WHO Joint Statement benchmarks. These 11 items fell into 4 categories, namely: trial registration, academic publication, monitoring and sanctions. An additional item captured whether and how funders referred to Consolidated Standards of Reporting Trials (CONSORT) within their trial policies. Each funder was independently assessed by two or three researchers. Funders were contacted to flag possible errors and omissions. Ambiguous or difficult-to-score items were settled by an independent adjudicator. RESULTS: Fourteen funders were assessed. Our cross-sectional study found that, on average, funders have only implemented 4.1/11 (37%) of WHO best practices in clinical trial transparency. The most frequently adopted requirement was open access publishing (14/14 funders). The least frequently adopted were (1) requiring trial ID to appear in all publications (2/14 funders, 14%) and (2) making compliance reports public (2/14 funders, 14%). Public funders, on average, adopted more policy elements (5.2/11 items, 47%) than philanthropic funders (2.8/11 items, 25%). Only one funder's policy documents mentioned the CONSORT statement. CONCLUSIONS: There is a significant variation between the number of best practice policy items adopted by medical research funders in the USA. Many funders fell significantly short of WHO Joint Statement benchmarks. Each funder could benefit from policy revision and strengthening.

Srd5a1 is Differentially Regulated and Methylated During Prepubertal Development in the Ovary and Hypothalamus.

5α-reductase-1 catalyzes production of various steroids, including neurosteroids. We reported previously that expression of its encoding gene, Srd5a1, drops in murine ovaries and hypothalamic preoptic area (POA) after early-life immune stress, seemingly contributing to delayed puberty and ovarian follicle depletion, and in the ovaries the first intron was more methylated at two CpGs. Here, we hypothesized that this CpG-containing locus comprises a methylation-sensitive transcriptional enhancer for Srd5a1. We found that ovarian Srd5a1 mRNA increased 8-fold and methylation of the same two CpGs decreased up to 75% between postnatal days 10 and 30. Estradiol (E2) levels rise during this prepubertal stage, and exposure of ovarian cells to E2 increased Srd5a1 expression. Chromatin immunoprecipitation in an ovarian cell line confirmed ESR1 binding to this differentially methylated genomic region and enrichment of the enhancer modification, H3K4me1. Targeting dCas9-DNMT3 to this locus increased CpG2 methylation 2.5-fold and abolished the Srd5a1 response to E2. In the POA, Srd5a1 mRNA levels decreased 70% between postnatal days 7 and 10 and then remained constant without correlation to CpG methylation levels. Srd5a1 mRNA levels did not respond to E2 in hypothalamic GT1-7 cells, even after dCas9-TET1 reduced CpG1 methylation by 50%. The neonatal drop in POA Srd5a1 expression occurs at a time of increasing glucocorticoids, and treatment of GT1-7 cells with dexamethasone reduced Srd5a1 mRNA levels; chromatin immunoprecipitation confirmed glucocorticoid receptor binding at the enhancer. Our findings on the tissue-specific regulation of Srd5a1 and its methylation-sensitive control by E2 in the ovaries illuminate epigenetic mechanisms underlying reproductive phenotypic variation that impact life-long health.

Biosecurity and water, sanitation, and hygiene (WASH) interventions in animal agricultural settings for reducing infection burden, antibiotic use, and antibiotic resistance: a One Health systematic review.

Prevention and control of infections across the One Health spectrum is essential for improving antibiotic use and addressing the emergence and spread of antibiotic resistance. Evidence for how best to manage these risks in agricultural communities-45% of households globally-has not been systematically assembled. This systematic review identifies and summarises evidence from on-farm biosecurity and water, sanitation, and hygiene (WASH) interventions with the potential to directly or indirectly reduce infections and antibiotic resistance in animal agricultural settings. We searched 17 scientific databases (including Web of Science, PubMed, and regional databases) and grey literature from database inception to Dec 31, 2019 for articles that assessed biosecurity or WASH interventions measuring our outcomes of interest; namely, infection burden, microbial loads, antibiotic use, and antibiotic resistance in animals, humans, or the environment. Risk of bias was assessed with the Systematic Review Centre for Laboratory Animal Experimentation tool, Risk of Bias in Non-Randomized Studies of Interventions, and the Appraisal tool for Cross-Sectional Studies, although no studies were excluded as a result. Due to the heterogeneity of interventions found, we conducted a narrative synthesis. The protocol was pre-registered with PROSPERO (CRD42020162345). Of the 20 672 publications screened, 104 were included in this systematic review. 64 studies were conducted in high-income countries, 24 studies in upper-middle-income countries, 13 studies in lower-middle-income countries, two in low-income countries, and one included both upper-middle-income countries and lower-middle-income countries. 48 interventions focused on livestock (mainly pigs), 43 poultry (mainly chickens), one on livestock and poultry, and 12 on aquaculture farms. 68 of 104 interventions took place on intensive farms, 22 in experimental settings, and ten in smallholder or subsistence farms. Positive outcomes were reported for ten of 23 water studies, 17 of 35 hygiene studies, 15 of 24 sanitation studies, all three air-quality studies, and 11 of 17 other biosecurity-related interventions. In total, 18 of 26 studies reported reduced infection or diseases, 37 of 71 studies reported reduced microbial loads, four of five studies reported reduced antibiotic use, and seven of 20 studies reported reduced antibiotic resistance. Overall, risk of bias was high in 28 of 57 studies with positive interventions and 17 of 30 studies with negative or neutral interventions. Farm-management interventions successfully reduced antibiotic use by up to 57%. Manure-oriented interventions reduced antibiotic resistance genes or antibiotic-resistant bacteria in animal waste by up to 99%. This systematic review highlights the challenges of preventing and controlling infections and antimicrobial resistance, even in well resourced agricultural settings. Most of the evidence emerges from studies that focus on the farm itself, rather than targeting agricultural communities or the broader social, economic, and policy environment that could affect their outcomes. WASH and biosecurity interventions could complement each other when addressing antimicrobial resistance in the human, animal, and environmental interface.

Adoption of World Health Organization Best Practices in Clinical Trial Transparency Among European Medical Research Funder Policies.

Importance: Research funders can reduce research waste and publication bias by requiring their grantees to register and report clinical trials. Objective: To determine the extent to which 21 major European research funders' efforts to reduce research waste and publication bias in clinical trials meet World Health Organization (WHO) best practice benchmarks and to investigate areas for improvement. Design, Setting, and Participants: This cross-sectional study was based on 2 to 3 independent assessments of each funder's publicly available documentation and validation of results with funders during 2021. Included funders were the 21 largest nonmultilateral public and philanthropic medical research funders in Europe, with a combined budget of more than US $22 billion. Exposures: Scoring of funders using an 11-item assessment tool based on WHO best practice benchmarks, grouped into 4 broad categories: trial registries, academic publication, monitoring, and sanctions. Funder references to reporting standards were captured. Main Outcomes and Measures: The primary outcome was funder adoption or nonadoption of 11 policy and monitoring measures to reduce research waste and publication bias as set out by WHO best practices. The secondary outcomes were whether and how funder policies referred to reporting standards. Outcomes were preregistered after a pilot phase that used the same outcome measures. Results: Among 21 of the largest nonmultilateral public and philanthropic funders in Europe, some best practices were more widely adopted than others, with 14 funders (66.7%) mandating prospective trial registration and 6 funders (28.6%) requiring that trial results be made public on trial registries within 12 months of trial completion. Less than half of funders actively monitored whether trials were registered (9 funders [42.9%]) or whether results were made public (8 funders [38.1%]). Funders implemented a mean of 4 of 11 best practices in clinical trial transparency (36.4%) set out by WHO. The extent to which funders adopted WHO best practice items varied widely, ranging from 0 practices for the French Centre National de la Recherche Scientifique and the ministries of health of Germany and Italy to 10 practices (90.9%) for the UK National Institute of Health Research. Overall, 9 funders referred to reporting standards in their policies. Conclusions and Relevance: This study found that many European medical research funder policy and monitoring measures fell short of WHO best practices. These findings suggest that funders worldwide may need to identify and address gaps in policies and processes.

Acoustic regularities in infant-directed speech and song across cultures.

When interacting with infants, humans often alter their speech and song in ways thought to support communication. Theories of human child-rearing, informed by data on vocal signalling across species, predict that such alterations should appear globally. Here, we show acoustic differences between infant-directed and adult-directed vocalizations across cultures. We collected 1,615 recordings of infant- and adult-directed speech and song produced by 410 people in 21 urban, rural and small-scale societies. Infant-directedness was reliably classified from acoustic features only, with acoustic profiles of infant-directedness differing across language and music but in consistent fashions. We then studied listener sensitivity to these acoustic features. We played the recordings to 51,065 people from 187 countries, recruited via an English-language website, who guessed whether each vocalization was infant-directed. Their intuitions were more accurate than chance, predictable in part by common sets of acoustic features and robust to the effects of linguistic relatedness between vocalizer and listener. These findings inform hypotheses of the psychological functions and evolution of human communication.

Thyroid Function at Age Fifty After Prenatal Famine Exposure in the Dutch Famine Birth Cohort.

Background: Early-life exposures during gestation may permanently alter thyroid physiology and health in adulthood. We investigated whether exposure to the Dutch Famine (1944-1945) in late, mid, or early gestation influences thyroid function (i.e., incidence of thyroid disease, thyroid autoantibodies, thyroid stimulating hormone (TSH), and free thyroxine (FT4) levels) in adulthood. We specifically assessed whether potential effects of famine differed for men and women. Methods: This study includes 910 men and women born as term singletons in the Wilhelmina Gasthuis in Amsterdam, the Netherlands, shortly before, during, or after the Dutch Famine. We evaluated medical histories for previous diagnosis or current treatment for thyroid dysfunction. At age 50 blood samples were drawn from 728 individuals for tests of thyroid function. We studied the prevalence of overt hypo- and hyperthyroidism and thyroid autoimmunity using medical histories, and measurements of TSH, FT4, anti-TPO and anti-TG, comparing participants exposed to famine at different pregnancy trimesters or born before or conceived after the famine. Additionally, we studied associations of TSH and FT4 levels with in utero famine exposure in a subsample of men and women free of thyroid disease that were exposed in late, mid, or early gestation. Results: There were no differences in thyroid dysfunction diagnosis or current treatment between participants at age 50 years who been exposed to famine during different periods of gestation and those born before or conceived after. There was no association between famine exposure and overt hypo- or hyperthyroidism or thyroid autoantibody positivity. Women who had been exposed to famine in mid gestation had slightly lower TSH levels than women who had not been exposed to famine prenatally (b=-0.06; 95%; CI=[-0.11,-0.02]; p<0.01). No differences in TSH levels were observed in men, and no differences in FT4 levels were observed in men or women. Conclusions: There are no differences in adult thyroid disease at age 50 years according to prenatal famine exposure. However, the lower TSH levels in women exposed to famine in the second trimester suggest that there may be sex-specific effects of famine exposure during a critical period of thyroid development on hypothalamic-pituitary-thyroid axis regulation in adulthood.

Global COVID-19 Vaccine Inequity: Failures in the First Year of Distribution and Potential Solutions for the Future.

Within the first year of distribution of vaccines against COVID-19, high-income countries (HICs) have achieved vaccination rates of 75-80%, whilst low-income countries (LICs) vaccinated <10%. This disparity in access has been one of the greatest failures of international cooperation during the SARS-CoV-2 pandemic. Global COVID-19 vaccine inequity affects us all, with ongoing risk of new variants emerging until global herd immunity is strengthened. The current model of global vaccine distribution is based on financial competition for limited vaccine supplies, resulting in HICs getting first access to vaccines, with LICs being forced to rely on voluntary donations through schemes like COVAX. Pharmaceutical companies own the intellectual property (IP) rights for COVID-19 vaccines, allowing them to control manufacturing, distribution, and pricing. However, the pharmaceutical industry did not develop these vaccines alone, with billions of dollars of public funding being instrumental in their discovery and development. Solutions to enable global equitable access already exist. The next step in scale up of manufacture and distribution worldwide is equitable knowledge sharing and technology transfer. The World Health Organization centralized technology transfer hub would facilitate international cooperation. Investments made into developing this infrastructure benefit the COVID-19 response whilst promoting future pandemic preparedness. Whilst globally there is majority support for waivers of IP to facilitate this next step, key opponents blocking this move include the UK and other European countries which host large domestic pharmaceutical industries. A nationalistic approach is not effective during a global pandemic. International cooperation is essential to achieve global goals against COVID-19.

University patenting and licensing practices in the United Kingdom during the first year of the COVID-19 pandemic.

Universities' decisions during technology transfer may affect affordability, accessibility, and availability of COVID-19 health technologies downstream. We investigated measures taken by the top 35 publicly funded UK universities to ensure global equitable access to COVID-19 health technologies between January and end of October 2020. We sent Freedom Of Information (FOI) requests and analysed universities' websites, to (i) assess institutional strategies on the patenting and licensing of COVID-19-related health technologies, (ii) identify all COVID-19-related health technologies licensed or patented and (iii) record whether universities engaged with the Open COVID pledge, COVID-19 Technology Access Pool (C-TAP), or Association of University Technology Managers (AUTM) COVID-19 licensing guidelines during the time period assessed. Except for the Universities of Oxford and Edinburgh, UK universities did not update their institutional strategies during the first year of the pandemic. Nine universities licensed 22 COVID-19 health technologies. Imperial College London disclosed ten patents relevant to COVID-19. No UK universities participated in the Open COVID Pledge or C-TAP, but discussions were ongoing in autumn 2020. The University of Bristol endorsed the AUTM guidelines. Despite important COVID-19 health technologies being developed by UK universities, our findings suggest minimal engagement with measures that may promote equitable access downstream. We suggest universities review their technology transfer policies and implement global equitable access strategies for COVID-19 health technologies. We furthermore propose that public and charitable funders can play a larger role in encouraging universities to adopt such practices by making access and transparency clauses a mandatory condition for receiving public funds for research.

Improving clinical trial transparency at UK universities: Evaluating 3 years of policies and reporting performance on the European Clinical Trial Register.

BACKGROUND: January 2019, the House of Commons' Science and Technology Committee sent letters to UK universities admonishing them to achieve compliance with results reporting requirements for Clinical Trials of Investigative Medicinal Products by summer 2019. This study documents changes in the clinical trial policies and Clinical Trials of Investigative Medicinal Product reporting performance of 20 major UK universities following that intervention. METHODS: Freedom of Information requests were filed in June 2018 and June 2020 to obtain clinical trial registration and reporting policies covering both Clinical Trials of Investigative Medicinal Products and all other clinical trials. Two independent reviewers assessed policies against transparency benchmarks based on World Health Organization best practices. To evaluate universities' trial reporting performance, we used a public online tracking tool, the European Union Trials Tracker, which assesses universities' compliance with regulatory Clinical Trials of Investigative Medicinal Product disclosure requirements on the European Clinical Trial Register. Specifically, we evaluated whether universities were adhering to the European Union requirement to post summary results on the trial registry within 12 months of completion. RESULTS: Mean policy strength increased from 2.8 to 4.9 points (out of a maximum of 7 points) between June 2018 and June 2020. In October 2018 the average percentage of due Clinical Trials of Investigative Medicinal Products that had results available on the European trial registry across university sponsors included in the cohort was 29%. By June 2021, this had increased to 91%, with 5 universities achieving a reporting performance of 100%. All 20 universities reported more than 70% of their due trial results on the European trial registry. INTERPRETATION: Political pressure appears to have a significant positive impact on UK universities' clinical trial reporting policies and performance. Similar approaches could be used to improve reporting performance for other types of sponsors, other types of trials, and in other countries.

Public Risk-Taking and Rewards During the COVID-19 Pandemic - A Case Study of Remdesivir in the Context of Global Health Equity.

Public investment, through both research grants and university funding, plays a crucial role in the research and development (R&D) of novel health technologies, including diagnostics, therapies, and vaccines, to address the coronavirus disease 2019 (COVID-19) pandemic. Using the example of remdesivir, one of the most promising COVID-19 treatments, this paper traces back public contributions to different stages of the innovation process. Applying the Risk-Reward Nexus framework to the R&D of remdesivir, we analyse the role of the public in risk-taking and reward and address inequities in the biomedical innovation system. We discuss the collective, cumulative and uncertain characteristics of innovation, highlighting the lack of transparency in the biomedical R&D system, the need for public investment in the innovation process, and the "time-lag" between risk-taking and reward. Despite the significant public transnational contributions to the R&D of remdesivir, the rewards are extracted by few actors and the return to the public in the form of equitable access and affordable pricing is limited. Beyond the necessity to treat remdesivir as a global public good, we argue that biomedical innovation needs to be viewed in the broader concept of public value to prevent the same equity issues currently seen in the COVID-19 pandemic. This requires the state to take a market-shaping rather than market-fixing role, thereby steering innovation, ensuring that patents do not hinder global equitable access and affordable pricing and safeguarding a global medicines supply.

Who funded the research behind the Oxford-AstraZeneca COVID-19 vaccine?

OBJECTIVES: The Oxford-AstraZeneca COVID-19 vaccine (ChAdOx1 nCoV-19, Vaxzevira or Covishield) builds on two decades of research and development (R&D) into chimpanzee adenovirus-vectored vaccine (ChAdOx) technology at the University of Oxford. This study aimed to approximate the funding for the R&D of ChAdOx and the Oxford-AstraZeneca vaccine and to assess the transparency of funding reporting mechanisms. METHODS: We conducted a scoping review and publication history analysis of the principal investigators to reconstruct R&D funding the ChAdOx technology. We matched award numbers with publicly accessible grant databases. We filed freedom of information (FOI) requests to the University of Oxford for the disclosure of all grants for ChAdOx R&D. RESULTS: We identified 100 peer-reviewed articles relevant to ChAdOx technology published between January 2002 and October 2020, extracting 577 mentions of funding bodies from acknowledgements. Government funders from overseas (including the European Union) were mentioned 158 times (27.4%), the UK government 147 (25.5%) and charitable funders 138 (23.9%). Grant award numbers were identified for 215 (37.3%) mentions; amounts were publicly available for 121 (21.0%). Based on the FOIs, until December 2019, the biggest funders of ChAdOx R&D were the European Commission (34.0%), Wellcome Trust (20.4%) and Coalition for Epidemic Preparedness Innovations (17.5%). Since January 2020, the UK government contributed 95.5% of funding identified. The total identified R&D funding was £104 226 076 reported in the FOIs and £228 466 771 reconstructed from the literature search. CONCLUSION: Our study approximates that public and charitable financing accounted for 97%-99% of identifiable funding for the ChAdOx vaccine technology research at the University of Oxford underlying the Oxford-AstraZeneca vaccine until autumn 2020. We encountered a lack of transparency in research funding reporting.

Quantifying patterns of alcohol consumption and its effects on health and wellbeing among BaYaka hunter-gatherers: A mixed-methods cross-sectional study.

Ethnographers frequently allude to alcoholism and related harms in Indigenous hunter-gatherer communities, but very few studies have quantified patterns of alcohol consumption or its health and social impacts. We present a case study of the Mbendjele BaYaka, a Congolese population undergoing socioeconomic transition. 83 adults answered questions about their frequency and quantity of alcohol consumption, underwent biometric measurements and reported whether they were currently experiencing a cough or diarrhoea; 56 participated in structured interviews about their experiences with alcohol. Based on WHO standards, we found 44.3% of the full sample, and 51.5% of drinkers (excluding abstainers), had a hazardous volume of alcohol consumption; and 35.1% of the full sample, and 40.9% of drinkers, engaged in heavy episodic drinking; consumption habits varied with sex and age. Total weekly consumption was a positive predictor of blood pressure and the likelihood of experiencing diarrhoea; associations with other biometric variables were not statistically significant. Interview responses indicated numerous other economic, mental and physical health harms of alcohol use, the prevalence of which demonstrate some variability between forest camps and permanent village settlements. These include high rates of drinking during pregnancy and breastfeeding (~40%); frequent alcohol-induced violence; and considerable exchange of foraged foods and engagement in exploitative labour activities to acquire alcohol or repay associated debts. Our findings demonstrate the prevalence of hazardous alcohol consumption among transitioning hunter-gatherers is higher than other segments of the Congolese population and indicate negative impacts on health and wellbeing, highlighting an urgent need for targeted public health interventions.

Reinterpreting patterns of variation in human thyroid function: An evolutionary ecology perspective.

Two hundred million people worldwide experience some form of thyroid disorder, with women being especially at risk. However, why human thyroid function varies between populations, individuals, and across the lifespan has attracted little research to date. This limits our ability to evaluate the conditions under which patterns of variation in thyroid function are best understood as 'normal' or 'pathological'. In this review, we aim to spark interest in research aimed at understanding the causes of variation in thyroid phenotypes. We start by assessing the biomedical literature on thyroid imbalance to discuss the validity of existing reference intervals for diagnosis and treatment across individuals and populations. We then propose an evolutionary ecological framework for understanding the phylogenetic, genetic, ecological, developmental, and physiological causes of normal variation in thyroid function. We build on this approach to suggest testable predictions for how environmental challenges interact with individual circumstances to influence the onset of thyroid disorders. We propose that dietary changes, ecological disruptions of co-evolutionary processes during pregnancy and with pathogens, emerging infections, and exacerbated stress responses can contribute to explaining the onset of thyroid diseases. For patients to receive the best personalized care, research into the causes of thyroid variation at multiple levels is needed.

Improving the Quality of Life of Patients with an Underactive Thyroid Through mHealth: A Patient-Centered Approach.

Background: Three hundred fifty million people worldwide suffer from underactive thyroid conditions, which can lead to infertility, obesity, heart disease, and impaired mental health when poorly managed. Although mobile health (mHealth) applications can be a useful solution for self-managing one's condition, the impact of digital solutions for improving the health of thyroid patients remains unknown. Methods: We used a mixed methods analysis to assess the ways in which a digital approach might benefit thyroid patients. A cross-sectional study was conducted among users of BOOST Thyroid, an mHealth application for patients with an underactive thyroid. We collected data using a modified Short Form 36 Health Survey Questionnaire to measure the impact of in the app on participants' perceived health and quality of life. Participants were asked to (1) score their quality of life before and after using the app, and (2) describe whether and how using the app helped them. Results: We enrolled 406 users (380 females and 26 males), aged 18-78 years. Most participants (95.8%) reported using the app was helpful; of which 68% reported it improved their quality of life and 70.8% reported it had a positive impact on their health. Participants who found the app useful experienced less symptoms and a lower intensity of remaining symptoms. A key factor reported by these participants as helping with managing their health is the information provided in the app. Conclusions: The results support the idea that a patient-centered treatment would benefit from including mHealth tools for a daily self-management of underactive thyroid condition, as it can increase health literacy and improve both one's health status and quality of life.

Clinical trial reporting performance of thirty UK universities on ClinicalTrials.gov-evaluation of a new tracking tool for the US clinical trial registry.

Clinical trial transparency forms the foundation of evidence-based medicine, and trial sponsors, especially publicly funded institutions such as universities, have an ethical and scientific responsibility to make the results of clinical trials publicly available in a timely fashion. We assessed whether the thirty UK universities receiving the most Medical Research Council funding in 2017-2018 complied with World Health Organization best practices for clinical trial reporting on the US Clinical Trial Registry ( ClinicalTrials.gov ). Firstly, we developed and evaluated a novel automated tracking tool ( clinical-trials-tracker.com ) for clinical trials registered on ClinicalTrials.gov . This tracker identifies the number of due trials (whose completion lies more than 395 days in the past) that have not reported results on the registry and can now be used for all sponsors. Secondly, we used the tracker to determine the number of due clinical trials sponsored by the selected UK universities in October 2020. Thirdly, using the FDAAA Trials Tracker, we identified trials sponsored by these universities that are not complying with reporting requirements under the Food and Drug Administration Amendments Act 2007. Finally, we quantified the average and median number of days between primary completion date and results posting. In October 2020, the universities included in our study were sponsoring 1634 due trials, only 1.6% (n = 26) of which had reported results within a year of completion. 89.8% (n = 1468) of trials remained unreported, and 8.6% (n = 140) of trials reported results late. We also identified 687 trials that contained inconsistent data, suggesting that UK universities often fail to update their data adequately on ClinicalTrials.gov . The mean reporting delay after primary completion for trials that posted results was 981 days, the median 728 days. Only four trials by UK universities violated the FDAAA 2007. We suggest a number of reasons for the poor reporting performance of UK universities on ClinicalTrials.gov : (i) efforts to improve clinical trial reporting in the UK have to date focused on the European clinical trial registry (EU CTR), (ii) the absence of a tracking tool for timely reporting on ClinicalTrials.gov has limited the visibility of institutions' reporting performance on the US registry and (iii) there is currently a lack of repercussions for UK sponsors who fail to report results on ClinicalTrials.gov which should be addressed in the future.

Out of balance: the role of evolutionary mismatches in the sex disparity in autoimmune disease.

Over the past century autoimmune disease incidence has increased rapidly in (post-) industrialised, affluent societies, suggesting that changes in ecology and lifestyle are driving this development. Epidemiological studies show that (i) 80% of autoimmune disease patients are female, (ii) autoimmune diseases co-occur more often in women, and (iii) the incidence of some autoimmune diseases is increasing faster in women than in men. The female preponderance in autoimmunity is most pronounced between puberty and menopause, suggesting that diverging sex hormone levels during the reproductive years are implicated in autoimmune disease development. Using an evolutionary perspective, we build on the hypotheses that female immunity is cyclical in menstruating species and that natural selection shaped the female immune system to optimise the implantation and gestation of a semi-allogeneic foetus. We propose that cyclical immunomodulation and female immune tolerance mechanisms are currently out of balance because of a mismatch between the conditions under which they evolved and (post-)industrialised, affluent lifestyles. We suggest that current changes in autoimmune disease prevalence may be caused by increases in lifetime exposure to cyclical immunomodulation and ovarian hormone exposure, reduced immune challenges, increased reproductive lifespan, changed reproductive patterns, and enhanced positive energy balance associated with (post-)industrialised, affluent lifestyles. We discuss proximate mechanisms by which oestrogen and progesterone influence tolerance induction and immunomodulation, and review the effect of the menstrual cycle, pregnancy, and contraceptive use on autoimmune disease incidence and symptoms.

Making a COVID-19 vaccine that works for everyone: ensuring equity and inclusivity in clinical trials.

Coronavirus disease 2019 (COVID-19) mortality and morbidity have been shown to increase with deprivation and impact non-White ethnicities more severely. Despite the extra risk Black, Asian and Minority Ethnicity (BAME) groups face in the pandemic, our current medical research system seems to prioritise innovation aimed at people of European descent. We found significant difficulties in assessing baseline demographics in clinical trials for COVID-19 vaccines, displaying a lack of transparency in reporting. Further, we found that most of these trials take place in high-income countries, with only 25 of 219 trials (11.4%) taking place in lower middle- or low-income countries. Trials for the current best vaccine candidates (BNT162b2, ChadOx1, mRNA-173) recruited 80.0% White participants. Underrepresentation of BAME groups in medical research will perpetuate historical distrust in healthcare processes, and poses a risk of unknown differences in efficacy and safety of these vaccines by phenotype. Limiting trial demographics and settings will mean a lack of global applicability of the results of COVID-19 vaccine trials, which will slow progress towards ending the pandemic.

Missing clinical trial data: the evidence gap in primary data for potential COVID-19 drugs.

BACKGROUND: Several drugs are being repurposed for the treatment of the coronavirus disease 2019 (COVID-19) pandemic based on in vitro or early clinical findings. As these drugs are being used in varied regimens and dosages, it is important to enable synthesis of existing safety data from clinical trials. However, availability of safety information is limited by a lack of timely reporting of overall clinical trial results on public registries or through academic publication. We aimed to analyse the evidence gap in this data by conducting a rapid review of results posting on ClinicalTrials.gov and in academic publications to quantify the number of trials missing results for drugs potentially being repurposed for COVID-19. METHODS: ClinicalTrials.gov was searched for 19 drugs that have been identified as potential treatments for COVID-19. Relevant clinical trials for any prior indication were listed by identifier (NCT number) and checked for results and for timely result reporting (within 395 days of the primary completion date). Additionally, PubMed and Google Scholar were searched to identify publications of results not listed on the registry. A second, blinded search of 10% of trials was conducted to assess reviewer concordance. RESULTS: Of 3754 completed trials, 1516 (40.4%) did not post results on ClinicalTrials.gov or in the academic literature. Tabular results were available on ClinicalTrials.gov for 1172 (31.2%) completed trials. A further 1066 (28.4%) had published results in the academic literature, but did not report results on ClinicalTrials.gov . Key drugs missing clinical trial results include hydroxychloroquine (37.0% completed trials unreported), favipiravir (77.8%) and lopinavir (40.5%). CONCLUSIONS: There is an important evidence gap for the safety of drugs being repurposed for COVID-19. This uncertainty could cause unnecessary additional morbidity and mortality during the pandemic. We recommend caution in experimental drug use for non-severe disease and urge clinical trial sponsors to report missing results retrospectively.