Sarai Keestra

Sarai Keestra

Sarai Keestra

Sarai Keestra

I am a medical researcher and medical student at Amsterdam UMC, in the departments of epidemiology and pediatrics. My PhD research focuses on the first 1000 days of life—a crucial period in which health is formed. From an evolutionary perspective, I primarily study the role of the thyroid gland, a key organ in our energy metabolism. From an evolutionary perspective, I primarily study the role of the thyroid gland, a key organ in our energy metabolism.

With a background in Human Sciences (UCL) and Medical Anthropology (Durham University), I am fascinated by the interaction between genes and environment. The thyroid gland serves as a unique window into this: evolutionarily ancient, hormonally active, and often dysregulated in women during vulnerable stages of life. As a female scientist, I am particularly eager to contribute to knowledge about understudied conditions that affect women.

Publications

Human Biology & DevelopmentGlobal Health & Health Technology AccessClinical Trial Transparency & Research Ethics
2025
Nature Medicine | Vol. 31 | No. 3
Human Biology & Development
M. Austin Argentieri,...Najaf Amin,Alejo J. Nevado-Holgado,William Sproviero,Jennifer A. Collister,Sarai M. Keestra,Midas M. Kuilman,Bigina N. R. Ginos,Mohsen Ghanbari,Aiden Doherty,David J. Hunter,Alexandra Alvergne,...Cornelia M. van Duijn
Both environmental exposures and genetics are known to play important roles in shaping human aging. Here we aimed to quantify the relative contributions of environment (referred to as the exposome) and genetics to aging and premature mortality. To systematically identify environmental exposures associated with aging in the UK Biobank, we first conducted an exposome-wide analysis of all-cause mortality (n = 492,567) and then assessed the associations of these exposures with a proteomic age clock (n = 45,441), identifying 25 independent exposures associated with mortality and proteomic aging. These exposures were also associated with incident age-related multimorbidity, aging biomarkers and major disease risk factors. Compared with information on age and sex, polygenic risk scores for 22 major diseases explained less than 2 percentage points of additional mortality variation, whereas the exposome explained an additional 17 percentage points. Polygenic risk explained a greater proportion of variation (10.3–26.2%) compared with the exposome for incidence of dementias and breast, prostate and colorectal cancers, whereas the exposome explained a greater proportion of variation (5.5–49.4%) compared with polygenic risk for incidence of diseases of the lung, heart and liver. Our findings provide a comprehensive map of the contributions of environment and genetics to mortality and incidence of common age-related diseases, suggesting that the exposome shapes distinct patterns of disease and mortality risk, irrespective of polygenic disease risk.
2025
Global Public Health | Vol. 20 | No. 1
Clinical Trial Transparency & Research Ethics
Ayolola Eni-Olotu,...Rebecca Hotchkin,Rachel McCormick,Molly Pugh-Jones,Sarai Mirjam Keestra
The COVID-19 pandemic underlined stark inequalities in timely access to health technologies worldwide. Universities, by conducting a significant amount of early biomedical research and development, have a critical but often overlooked role in determining downstream equitable access to health technologies. This paper reviews university's policies and practices regarding COVID-19 health technologies in the United Kingdom (UK) during the recent pandemic using annual freedom of Information (FOI) requests between 2019 and 2023 to a cohort of 35 UK universities and website searches. We provide an overview of all patents and licenses filed for COVID-19 technologies, changes in technology transfer policies or strategies, and engagement with international mechanisms designed to enhance equitable transfer of knowledge and intellectual property rights during the pandemic. Despite a time-limited increase in non-exclusive licensing of COVID-19 health technologies at the height of the pandemic, there was a lack of systemic change in university policies for technology transfer, and limited to no engagement with international mechanisms to promote equitable access. Universities can promote global equitable access to health technologies by publishing clear technology transfer policies, attaching conditions to technology transfer agreements, increasing transparency, and engaging with non-exclusive licensing mechanisms, now and in future health emergencies.
2024
BMJ Evidence-Based Medicine | Vol. 29 | No. 2
Clinical Trial Transparency & Research Ethics
Elise Gamertsfelder,...Netzahualpilli Delgado Figueroa,Sarai Keestra,Alan Rossi Silva,Ronak Borana,Maximilian Siebert,...Till Bruckner
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{\textquoteright
2024
Human Reproduction | Vol. 39 | No. Supplement_1
Human Biology & Development
S Keestra,C Kooper,N Van Welie,K Dreyer,R Van Eekelen,T Roseboom,J Oosterlaan,B  W Mol,M  J J Finken,V Mijatovic,...M Königs
How does conception \<6 months after hysterosalpingography (HSG) with iodinated contrast media affect the neurodevelopment of the offspring compared to naturally-conceived peers at a school-age?Children conceived \<6 months after HSG with iodinated contrast media perform lower on intelligence tests and information processing and attention control compared to naturally-conceived peers.Tubal patency in subfertile women is commonly assessed using hysterosalpingography (HSG), but the potential risks of exposure to high iodine content in contrast media used remains unknown. Exposure to iodine excess can cause transient reduction in thyroid hormone synthesis due to the Wolff-Chaikoff effect. Thyroid hormone sufficiency in early pregnancy is vital for children's neurodevelopment. When conception occurs shortly after HSG with iodinated contrast, a temporary reduction of maternal and/or foetal thyroid hormone supply could jeopardize children's neurodevelopment.We evaluated neurodevelopmental outcomes of 6–9-year-old children conceived \<6 months after HSG with oil-based (iodine content: 480mg/ml) or water-based contrast (iodine content: 240-300mg/ml) in a nationwide randomised controlled trial (H2Oil trial; Netherlands; 2012-2014; NCT05168228). Naturally-conceived children (n = 44) with similar age, sex and parental education were used as a comparison group (NTR9574). We also compared children conceived \<4w, 4-12w, \>12w after HSG with those conceived naturally. The study took place January 2022 until November 2023.We contacted 140 mothers from the H2Oil trial, 69 children conceived \<6m after HSG participated, and parallelly we recruited 44 naturally-conceived children. Primary outcomes were intelligence (Wechsler's Intelligence Scale for Children V), behavioural functioning (SDQ and SWAN, administered to parents and teachers), and academic performance. Secondary outcomes were neurocognitive function assessed by a battery of computerized tests. We used linear regression adjusted for age, sex, and parental education and applied FDR correction.Compared to naturally conceived children, children conceived \<6m after HSG had lower performance on intelligence tests (-6.81; 95\%CI-10.97 to -2.65; p = 0.02) and the neurocognitive domain Processing \& Control (-0.52; 95\%CI-0.84 to -0.19; p = 0.02), with functions relating to information processing speed and consistency affected. No differences were found for other neurocognitive domains, behaviour or academic performance. Considering time between HSG and conception, intelligence scores were lower for children conceived \<4w after HSG compared to naturally-conceived peers (-11.47; 95\%CI-17.98 to -4.95; p = 0.03), while no significant differences were found for the groups of children conceived 4-12 weeks after HSG (-7.17; 95\%CI -12.28 to -2.06; p = 0.10) or \> 12 weeks after HSG (-4.20; 95\%CI -9.33 to 0.94; p = 0.52). The findings of this study warrant replication in larger independent samples in order to evaluate the long-term neurodevelopment of children conceived after HSG with iodinated contrast media.We aimed to recruit 64 children for each group, but our study was not sufficiently powered for small- and medium-sized differences. We did not collect information on the thyroid or iodine status of the mothers following HSG, and there is limited knowledge about pharmacokinetics of iodinated contrast media in humans.Replication studies with are needed to further evaluate the safety of iodinated contrast media use periconception, including their effects on thyroid function and children's neurodevelopment. Closer monitoring and treatment of thyroid dysfunction in the months following HSG may be warranted.NCT05168228
2024
Journal of the Endocrine Society | Vol. 8 | No. Supplement_1
Human Biology & Development
S Keestra,C Kooper,N van Welie,K Dreyer,R van Eekelen,T Roseboom,J Oosterlaan,B Mol,M Finken,V Mijatovic,...M Königs
Disclosure: S. Keestra: None. C. Kooper: None. N. van Welie: None. K. Dreyer: Grant Recipient; Self; research grants from Guerbet. Speaker; Self; travel and speaker fees Guerbet. R. van Eekelen: None. T. Roseboom: None. J. Oosterlaan: None. B. Mol: Consulting Fee; Self; Organon Laboratories, Norgine, Merck. Grant Recipient; Self; Merck. Stock Owner; Self; ObsEva. M. Finken: None. V. Mijatovic: Grant Recipient; Self; Guerbet, Merck, Ferring Pharmaceuticals. Speaker; Self; Guerbet, Merck, Ferring Pharmaceuticals. M. Königs: None.Thyroid hormone sufficiency in pregnancy is vital for children's neurodevelopment. Exposure to iodine excess can cause transient disruption of thyroid hormone synthesis through the Wolff-Chaikoff effect. Iodinated contrast media are commonly utilized in hysterosalpingography (HSG) as part of female fertility work-up. When conception occurs shortly after HSG with iodinated contrast, a temporary reduction of maternal and/or foetal thyroid hormone synthesis could jeopardize children's neurodevelopment. We compared the neurodevelopmental outcomes of 6-9-year-old children (n=69) conceived \<6 months after HSG with 5-10 ml of oil-based contrast (iodine content: 480mg/ml) or water-based contrasts (iodine content: 250mg/ml) in the follow-up of a nationwide randomised controlled trial (H2Oil trial; Netherlands; 2012-2014; NCT05168228). A community sample of naturally-conceived children (n=44) with similar age, sex and parental education was used as a comparison group (NTR9574). Primary outcomes were intelligence (Wechsler's Intelligence Scale for Children V), behaviour questionnaires for parents and teachers (Strengths and Difficulties Questionnaire (SDQ); Strengths and Weaknesses of ADHD Symptoms And Normal behaviour (SWAN)), and academic performance. Secondary outcomes were neurocognitive domains assessed in computerized tasks focussing on Processing \& Control, Verbal Memory, Visual Memory, Verbal Working Memory, Visual Working Memory, and Visuomotor Integration (Emma Toolbox for Neurocognitive Functioning). We adjusted linear regression models for age, sex, and parental education, applying FDR correction for multiple comparisons. Additional analysis looked at children conceived within 4 weeks, 4-12 weeks, or \>12 weeks after HSG. Children conceived \<6 months after HSG had lower performance on intelligence tests (-6.81; 95\%CI -10.97 to -2.65; p=0.02) and the neurocognitive domain Processing \& Control (-0.52; 95\%CI-0.84 to -0.19; p=0.02), with processing speed and consistency affected. No differences were found for other neurocognitive domains, behaviour or academic performance. In comparison to naturally-conceived children, children conceived \<4 weeks after HSG had lower performance on intelligence tests, but there was no difference for children conceived 4-12 weeks and \>12 weeks after HSG. Replication studies with higher power are needed to further evaluate the safety of iodinated contrast media use periconception, including their effects on thyroid function and children's neurodevelopment. Closer monitoring and treatment of thyroid dysfunction in the months following HSG may be warranted.Presentation: 6/1/2024
2024
Human Reproduction | Vol. 39 | No. 10
Human Biology & Development
Sarai M Keestra,Nienke Van Welie,Kim Dreyer,Rik Van Eekelen,Tessa J Roseboom,Jaap Oosterlaan,Ben W Mol,Martijn J J Finken,Velja Mijatovic,...Marsh Königs
Does preconceptional exposure to oil-based iodinated contrast media during hysterosalpingography (HSG) impact children's neurodevelopment compared with exposure to water-based alternatives?Our study found no large-sized effects for neurodevelopment in children with preconceptional exposure to oil-based iodinated contrast media during HSG compared with water-based alternatives.HSG is widely used as a diagnostic tool in the female fertility work-up. Tubal flushing with oil-based iodinated contrast has been shown to enhance fertility outcomes in couples with unexplained infertility, increasing the chances of pregnancy and live birth compared with water-based alternatives. However, oil-based contrast contains higher doses of iodine and has a longer half-life, and concerns exist that iodinated contrast media can affect women's iodine status and cause temporary (sub)clinical hypothyroidism in mothers and/or foetuses. Considering that thyroid hormones are vital to embryonal and foetal brain development, oil-based contrast media use could increase the risk of impaired neurodevelopment in children conceived shortly after HSG. Here we examine neurodevelopmental outcomes in school-aged children conceived after HSG.This is a long-term follow-up of the H2Oil trial in which oil-based or water-based contrast was used during HSG (Netherlands; 2012–2014; NTR3270). Of 369 children born \<6 months after HSG in the study, we contacted the mothers of 140 children who gave consent to be contacted for follow-up. The follow-up study took place from January to July 2022 (NCT05168228).The study included 69 children aged 6–9 years who were conceived after HSG with oil-based (n = 42) or water-based contrast (n = 27). The assessments targeted intelligence (Wechsler Intelligence Scale for Children), neurocognitive outcomes (computerized neurocognitive tests), behavioural functioning (parent and teacher questionnaires), and academic performance. Linear regression models, adjusted for age, sex, and parental educational attainment were employed to compare groups.School-aged children born to mothers after oil-based contrast HSG did not significantly differ from children born to mothers after water-based contrast HSG, in regards to intelligence, neurocognitive functioning, behavioural functioning, or academic performance, with the exception of better performance for visuomotor integration functions in children exposed to oil-based contrast preconception. After exploratory correction for multiple comparisons, none of the group differences was statistically significant.The small sample size of this follow-up study limited statistical power. This study provides evidence for the absence of large-sized differences between preconceptional exposure to the two contrast media types but does not rule out more subtle effects on neurodevelopment compared to naturally conceived children without preconceptional exposure to HSG.This study contributes to our knowledge about the long-term effects of different types of iodinated contrast media used in fertility work-up, indicating that choosing oil-based over water-based iodinated contrast media is unlikely to have major effect on the long-term neurodevelopmental outcomes of children conceived shortly after HSG. However, further research should focus on the overall safety of iodine exposure during HSG, comparing children conceived after HSG to those conceived naturally as both types of contrast contain high amounts of iodine.The original H2Oil randomized controlled trial was an investigator-initiated study that was funded by the two academic hospitals now merged into the Amsterdam University Medical Centre. The current follow-up study (Neuro-H2Oil) is funded through a research grant awarded to the authors by the Amsterdam Reproduction \& Development (AR\&D) research institute. S.K. is funded by a AMC MD/PhD Scholarship from the Amsterdam UMC. S.K. reports holding voluntary roles in the civil society organizations Universities Allied for Essential Medicines and People's Health Movement. V.M. reports receiving travel and speaker fees as well as research grants from Guerbet, Merck and Ferring. K.D. reports receiving travel and speaker fees as well as research grants from Guerbet. BWM is supported by a NHMRC Investigator grant (GNT1176437) and reports consultancy, travel support and research funding from Merck, consultancy for Organon and Norgine, and holding stock from ObsEva. The other authors report no conflict of interest.NCT05168228
2023
medRxiv
Human Biology & Development
M. Austin Argentieri,...Najaf Amin,Alejo J. Nevado-Holgado,William Sproviero,Jennifer A. Collister,Sarai M. Keestra,Aiden Doherty,David J. Hunter,Alexandra Alvergne,...Cornelia M. van Duijn
It has long been suggested that environmental exposures (i.e., the exposome) play a dominant role in shaping trajectories of human aging and premature mortality. Here we aimed to quantify the contribution of the exposome and genome to aging and mortality. We conducted an exposome-wide analysis in the UK Biobank (n=492,567) to systematically identify exposures associated with mortality while accounting for exposure correlation and mismeasurement. We found that the exposome is a major mortality determinant irrespective of genetic disease risk via shaping distinct biological and multimorbidity patterns. We identified 41 independent exposures associated with mortality, and demonstrate that most identified exposures are associated with a common signature of age-related multimorbidity, aging biomarkers, and major cardiometabolic risk factors. Compared with age and sex, polygenic risk for 22 major diseases and aging phenotypes explained an additional 2\% of mortality variation, whereas the exposome explained an additional 19\%. While genetics explained the majority of variation in dementias and breast, prostate, and colorectal cancers, the exposome explained the majority of variation for diseases of the lung, heart, and liver. Our findings provide a comprehensive map of the contributions of environment and genetics to mortality and common age-related diseases.Competing Interest StatementThe authors have declared no competing interest.Funding StatementA.N-H. receives research funding from Novo Nordisk, GSK, and Ono Pharma. A.D. is supported by the Wellcome Trust [223100/Z/21/Z], Novo Nordisk, Swiss Re, the British Heart Foundation Centre of Research Excellence (grant number RE/18/3/34214), and Health Data Research UK, an initiative funded by UK Research and Innovation, Department of Health and Social Care (England) and the devolved administrations, and leading medical research charities. C.M.vD. is supported by the common mechanisms and pathways in Stroke and Alzheimer{\textquoteright
2023
Journal of the Endocrine Society | Vol. 7 | No. 10
Human Biology & Development
Ben Bar-Sadeh,...Lilach Pnueli,Sarai Keestra,Gillian R Bentley,...Philippa Melamed
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.
2023
medRxiv
Clinical Trial Transparency & Research Ethics
Elise Gamertsfelder,...Netzahualpilli Delgado Figueroa,Sarai Keestra,Alan Silva,Ronak Borana,Maximilian Siebert,...Till Bruckner
Background/Aims Clinical trial funders in the United States have the opportunity to promote transparency, reduce research waste, and prevent publication bias by adopting policies that require grantees to appropriately preregister trials and report their results, as well as monitor trialists{\textquoteright
2023
The Lancet Planetary Health | Vol. 7 | No. 5
Global Health & Health Technology Access
Chris E Pinto Jimenez,...Sarai Keestra,Pranav Tandon,Oliver Cumming,Amy J Pickering,Arshnee Moodley,...Clare I R Chandler
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.
2023
BMJ Global Health | Vol. 8 | No. 3
Global Health & Health Technology Access
Chris E Pinto Jimenez,...Sarai M Keestra,Pranav Tandon,Amy J Pickering,Arshnee Moodley,Oliver Cumming,...Clare I R Chandler
Prevention is a critical, yet neglected, cornerstone for the response to antimicrobial resistance (AMR). 1 The importance of a multitude of preventative measures is recognised across the One Health spectrum, with attention drawn to the issue by multilateral institutions. The 2022 World Antimicrobial Awareness Week saw the World Health Organization, the Food and Agriculture Organization, the United Nations Environment Programme and the World Organisation for Animal Health focused their campaign on the theme 'Preventing AMR together' to improve awareness and understanding of AMR and encourage best practices.2 While a One Health framework is now promoted for conceptualising the complex problem of AMR, the evidence base of interventions designed within this rubric is thin. Outstanding questions remain, for example, about how best to prevent and control infection across humans, animals, and the environment.
2022
JAMA Network Open | Vol. 5 | No. 8
Clinical Trial Transparency & Research Ethics
Till Bruckner,...Florence Rodgers,Lea Styrmisdóttir,Sarai Keestra
Research funders can reduce research waste and publication bias by requiring their grantees to register and report clinical trials.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.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.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.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.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.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.
2022
Nature Human Behaviour | Vol. 6 | No. 11
Human Biology & Development
Courtney B. Hilton,...Cody J. Moser,Mila Bertolo,Harry Lee-Rubin,Dorsa Amir,Constance M. Bainbridge,Jan Simson,Dean Knox,Luke Glowacki,Elias Alemu,Andrzej Galbarczyk,Grazyna Jasienska,Cody T. Ross,Mary Beth Neff,Alia Martin,Laura K. Cirelli,Sandra E. Trehub,Jinqi Song,Minju Kim,Adena Schachner,Tom A. Vardy,Quentin D. Atkinson,Amanda Salenius,Jannik Andelin,Jan Antfolk,Purnima Madhivanan,Anand Siddaiah,Caitlyn D. Placek,Gul Deniz Salali,Sarai Keestra,Manvir Singh,Scott A. Collins,John Q. Patton,Camila Scaff,Jonathan Stieglitz,Silvia Ccari Cutipa,Cristina Moya,Rohan R. Sagar,Mariamu Anyawire,Audax Mabulla,Brian M. Wood,Max M. Krasnow,...Samuel A. Mehr
The forms of many species' vocal signals are shaped by their functions1–15. In humans, a salient context of vocal signaling is infant care, as human infants are altricial16,17. Humans often alter their vocalizations to produce "parentese", speech and song produced for infants that differ acoustically from ordinary speech and song18–35 in fashions that have been proposed to support parent-infant communication and infant language learning36–39; modulate infant affect33,40–45; and/or coordinate communicative interactions with infants46–48. These theories predict a form-function link in infant-directed vocalizations, with consistent acoustic differences between infant-directed and adult-directed vocalizations across cultures. Some evidence supports this prediction23,27,28,32,49–52, but the limited generalizability of individual ethnographic reports and laboratory experiments53 and small stimulus sets54, along with intriguing reports of counterexamples55–62, leave the question open. Here, we show that people alter the acoustic forms of their vocalizations in a consistent fashion across cultures when speaking or singing to infants. We collected 1,615 recordings of infant- and adult-directed singing and speech produced by 410 people living in 21 urban, rural, and small-scale societies. First, we analyzed their acoustic forms. We found cross-culturally robust regularities in the acoustics of infant-directed vocalizations, such that infant-directed speech and song were reliably classified from acoustic features found across the 21 societies studied. The acoustic profiles of infant-directedness differed across language and music, but in a consistent fashion worldwide. Then, we studied whether listeners are sensitive to these acoustic features, playing the recordings to 49,241 people recruited online, from many countries, who guessed whether each vocalization was infant-directed. Their intuitions were largely accurate, predictable in part by acoustic features of the recordings, and robust to the effects of linguistic relatedness between vocalizer and listener. By uniting rich cross-cultural data with computational methods, we show links between the production of vocalizations and cross-species principles of bioacoustics, informing hypotheses of the psychological functions and evolution of human communication.
2022
bioRxiv
Human Biology & Development
Sarai Keestra,Edmond Sylvestre Miabangana,Nikhil Chaudhary,Inez Derkx,Gaurav Sikka,...Gul Deniz Salali
Aversion towards bitter tastes evolved across vertebrate species to enable the recognition of harmful plant toxins. Most studies to date have investigated the variation in bitter taste sensitivity between human populations. However, there is a lack of research investigating phenotypic plasticity and the variation in bitter taste perception within the same population. Here we examined bitter taste perception among the Mbendjele BaYaka hunter-gatherers from Congo, a group of forest hunter-gatherers who exhibit a variation in their levels of market integration. We conducted an experiment using phenylthiocarbamide (PTC) and thiourea infused paper strips and compared the prevalence of bitter tasting phenotypes between the BaYaka who grew up in town and forest camps. We found that 45.1\% of BaYaka experience PTC as bitter, and 42.5\% experience thiourea as bitter. There were no sex and age differences in bitter taste perception. Despite a shared genetic background, we found that BaYaka who grew up in town were more sensitive to bitter taste than those living in the forest, suggesting a developmental component in taste perception. We suggest that a decreased use of traditional plant medicine in town-born BaYaka may underlie this variation in bitter taste perception.Competing Interest StatementThe authors have declared no competing interest.
2022
medRxiv
Global Health & Health Technology Access
Sarai Keestra,Florence Rodgers,Rhiannon Osborne,...Sabrina Wimmer
Universities play a vital role in biomedical innovation during the COVID-19 pandemic, and decisions made during technology transfer may affect affordability, accessibility, and availability of health technologies downstream. We investigated the measures the top 35 UK universities receiving most Medical Research Council funding have taken in technology transfer to ensure global equitable access to health technologies. We sent Freedom Of Information (FOI) requests and analysed universities{\textquoteright
2022
Frontiers in Endocrinology | Vol. 13
Clinical Trial Transparency & Research Ethics
Sarai M. Keestra,Irina Motoc,Anita C.J. Ravelli,Tessa J. Roseboom,...Martijn J.J. Finken
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.
2022
Clinical Trials | Vol. 19 | No. 2
Clinical Trial Transparency & Research Ethics
Sarai Mirjam Keestra,Florence Rodgers,Sophie Gepp,Peter Grabitz,...Till Bruckner
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.
2022
Frontiers in Public Health | Vol. 10
Global Health & Health Technology Access
Victoria Pilkington,Sarai Mirjam Keestra,Andrew Hill
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.
2021
medRxiv
Clinical Trial Transparency & Research Ethics
Samuel Cross,...Yeanuk Rho,Henna Reddy,Toby Pepperrell,Florence Rodgers,Rhiannon Osborne,Ayolola Eni-Olotu,Rishi Banerjee,Sabrina Wimmer,Sarai Keestra
Objectives The Oxford-AstraZeneca COVID-19 vaccine (ChAdOx1 nCoV-19 or Vaxzevira) builds on nearly two decades of research and development (R\&D) into Chimpanzee adenovirus-vectored vaccine (ChAdOx) technology at the University of Oxford. This study aims to approximate the funding for the R\&D of the ChAdOx technology and the Oxford-AstraZeneca vaccine, and assess the transparency of funding reporting mechanisms.Design We conducted a scoping review and publication history analysis of the principal investigators to reconstruct the funding for the R\&D of 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 01/2002 and 10/2020, extracting 577 mentions of funding bodies from funding acknowledgement statements. Government funders from overseas were mentioned 158 (27.4\%), the U.K. government 147 (25.5\%) and charitable funders 138 (23.9\%) times. Grant award numbers were identified for 215 (37.3\%) mentions, amounts were available in the public realm for 121 (21.0\%) mentions. Based on the FOIs, until 01/2020, the European Commision (34.0\%), Wellcome Trust (20.4\%) and CEPI (17.5\%) were the biggest funders of ChAdOx R\&D. From 01/2020, the U.K. Department of Health and Social Care was the single largest funder (89.3\%). The identified R\&D funding was {\textsterling
2021
Women's Health Reports | Vol. 2 | No. 1
Human Biology & Development
Vedrana Högqvist Tabor,...Mikael Högqvist Tabor,Sarai Keestra,Jean-Etienne Parrot,...Alexandra Alvergne
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.
2021
American Journal of Human Biology | Vol. 33 | No. 2
Human Biology & Development
Sarai M. Keestra,Gillian R. Bentley,Alejandra Núñez-de la Mora,Lauren C. Houghton,Hannah Wilson,Adriana Vázquez-Vázquez,Gillian D. Cooper,Federico Dickinson,Paula Griffiths,Barry A. Bogin,...Maria Inês Varela-Silva
Abstract Background Adrenarche involves maturation of the hypothalamic-pituitary-adrenal axis and increased production of dehydroepiandrosterone and its sulfate ester, dehydroepiandrosterone-sulfate (DHEA-S). It occurs at ages 6 to 8 in industrialized populations, marking the transition from childhood to juvenility and cognitive development at middle childhood. Studies in subsistence level populations indicate a later age (8-9) for adrenarche, but only two such studies currently exist for comparison. Aims To investigate adrenarcheal age among Maya girls and its association with body composition and dietary variables. We hypothesized adrenarche would occur earlier given the current dual burden of nutrition in Mexico. Materials and Methods 25 Maya girls aged 7 to 9 from Merida, Mexico using ELISAs to measure salivary DHEA-S, standard anthropometry for height, weight, and skinfolds, bioelectrical impedance for body composition variables, as well as a food frequency questionnaire for dietary information. Results Our hypothesis was rejected—adrenarche occurred close to 9 years. While no measures of body composition were significantly associated with adrenarcheal status, girls eating meat and dairy products more frequently had significantly higher DHEA-S levels. Discussion Like other populations living in ecologically challenging environments, adrenarche occurred relatively late among Maya girls. Adrenarche has been linked to measures of body composition, particularly, the adiposity or body mass index rebound, but no relevant anthropometric measures were associated, possibly because of the small sample. Conclusion Further studies are required to illuminate how adrenarcheal variation relates to developmental plasticity, body composition, pubertal progression, and animal product consumption in other transitional populations.
2021
Trials | Vol. 22 | No. 1
Clinical Trial Transparency & Research Ethics
Sarai Mirjam Keestra,Florence Rodgers,Daphne Lenz,Rhiannon Osborne,Till Bruckner,...Sean Lee
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.
2021
Plos One | Vol. 16 | No. 10
Human Biology & Development
Jessica K. Knight,...Gul Deniz Salali,Gaurav Sikka,Inez Derkx,Sarai M. Keestra,...Nikhil Chaudhary
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.
2021
Global Health Action | Vol. 14 | No. 1
Clinical Trial Transparency & Research Ethics
Toby Pepperrell,...Florence Rodgers,Pranav Tandon,Kelly Sarsfield,Molly Pugh-Jones,Theo Rashid,Sarai Keestra
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.
2021
Global Health: Annual Review | Vol. 1 | No. 6
Human Biology & Development
Sarai Keestra
2021
BMJ Global Health | Vol. 6 | No. 5
Global Health & Health Technology Access
Sarai Keestra
Universities intend to create knowledge that serves the needs of the public, yet this does not always happen in practice. By engaging in inequitable technology transfer practices, such as the exclusive licensing of a novel health technology to a private company or a spin-off, universities enable the downstream formation of pricing monopolies that limit affordable access to health technologies. 1 2 The WHO defines health technologies as 'the application of organized knowledge and skills in the form of devices, medicines, vaccines, procedures and systems developed to solve a health problem and improve quality of lives'.3 Worldwide nearly 2 billion people lack access to essential medicines and 100 million people are pushed into extreme poverty annually due to their inability to pay for their healthcare expenditures.4 5 While revenues from licensing contribute less than 4% to universities' income, since the introduction of the Bayh-Dole Act (1980) the pursuit of intellectual property (IP) rights has become common practice at higher education institutions.2 6 Universities occupy an unique position in the innovation ecosystem between upstream research and development (R&D), which is often publicly funded, and downstream commercialisation by the private sector. Universities' decisions on the conditions of technology transfer are an opportunity to resist the status quo of a system that is causing a global tragedy of preventable deaths by prioritising profits over health.
2021
Medical Hypotheses | Vol. 151
Human Biology & Development
Sarai M. Keestra,Victoria Male,Gul Deniz Salali
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.
2021
Forced Migration Review | Vol. 67
Human Biology & Development
Edward Stevenson,Lucie Buffavand,Sarai Keestra
A case-study from the Lower Omo Valley explores some of the challenges to water security for people who have been displaced within their own homelands
2020
medRxiv
Clinical Trial Transparency & Research Ethics
Florence Rodgers,...Toby Pepperrell,Sarai Keestra,...Victoria Pilkington
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 clinical trial results on public registries or through academic publication. We aimed to analyse the evidence gap in safety data by quantifying the number of missing clinical trial results for drugs potentially being repurposed for COVID-19 by conducting a rapid review of results posting on ClinicalTrials.gov and in academic publications.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. 1172 (31.2\%) completed trials had tabular results on ClinicalTrials.gov. A further 1066 (28.4\%) completed trials had results from the literature search, 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 a large burden of 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.Competing Interest StatementSeveral of the co-authors on this paper are part of Universities Allied for Essential Medicines U.K. However, views expressed in this paper are not necessarily that of Universities Allied for Essential Medicines Europe.Funding StatementThis research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:N/AAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData is publicly available from the U.S. National Library of Medicine (https://clinicaltrials.gov/ct2/home) https://clinicaltrials.gov/ct2/home
2020
Evolutionary Human Sciences | Vol. 2
Human Biology & Development
Gul Deniz Salali,...Mark Dyble,Nikhil Chaudhary,Gaurav Sikka,Inez Derkx,Sarai M. Keestra,Daniel Smith,James Thompson,Lucio Vinicius,...Andrea Bamberg Migliano
Cultures around the world are converging as populations become more connected. On the one hand this increased connectedness can promote the recombination of existing cultural practices to generate new ones, but on the other it may lead to the replacement of traditional practices and global WEIRDing. Here we examine the process and causes of changes in cultural traits concerning wild plant knowledge in Mbendjele BaYaka hunter–gatherers from Congo. Our results show that the BaYaka who were born in town reported knowing and using fewer plants than the BaYaka who were born in forest camps. Plant uses lost in the town-born BaYaka related to medicine. Unlike the forest-born participants, the town-born BaYaka preferred Western medicine over traditional practices, suggesting that the observed decline of plant knowledge and use is the result of replacement of cultural practices with the new products of cumulative culture.
2020
Evolution, Medicine, and Public Health | Vol. 9 | No. 1
Human Biology & Development
Sarai Keestra,Vedrana Högqvist Tabor,Alexandra Alvergne
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.
2020
Global Health & Health Technology Access
C Pinto J,...S Keestra,P Tandon,...CIR Chandler
Background: Infection prevention and control (IPC) is recognised as essential to addressing the emergence and spread of antimicrobial resistance (AMR) in human health, food production and the environment. How best to address this through a One Health perspective remains a challenge. This systematic review addresses this gap by identifying and synthesising evidence from interventions designed to improve water, hygiene, sanitation (WASH), and biosecurity in animal agriculture and in people that live and/or work with animals. This review aimed to capture evidence of effects of all types of intervention and across different settings. Methods: We conducted a systematic search for studies that reported on WASH and biosecurity interventions with the potential to reduce the burden of infections and reliance on antibiotics in animal production for populations living with animals and/or involved in agriculture/aquaculture with a primary focus on LMICs. We searched the following databases: Web of Science, PubMed, OVID, ProQuest, Epistemonikos, Trip, AgEcon, and Cochrane Library. For articles in Spanish, we searched Scielo, BIREME, E-Revistas, Redalyc, Lilacs, AfricaPortal, IMSEAR and WPRIM. A hand search of literature was also conducted in relevant sources, and Google Scholar and Open Grey were used for grey literature. The main outcomes of interest were: (i) reduction of infections/cases, (ii) reduction of bacterial load, and (iii) reduction of antimicrobial use and AMR. We extracted data from selected studies, performed a narrative synthesis, and developed a framework. PROSPERO Registration: The protocol for the systematic review was registered at PROSPERO, registration number CRD42020162345. Findings: A total of 104 studies were included in this systematic review. The majority of studies (64/104) (61.5\%) were conducted in HICs, especially in Europe and the USA. Only 13 (12.5\%) studies took place in LMICs. The majority of studies (77) were animal based, followed by 12 targeting both animals and the environment, nine focused exclusively on the environment, and only one study was exclusively about humans. Most studies were conducted in poultry (36) and pigs (27), and assessed impacts on multiple types of bacteria (commonly Salmonella spp. and Campylobacter spp.). Eighty-seven (87) studies assessed impact on IPC, 3 on AMU, and 14 on AMR. The interventions were classified as follows: 57 applied biological or chemical products to eliminate pathogens; 26 modified infrastructure and apparatus; 15 were educational/behavioural and one was a structural intervention. Around 52.8\% (55/104) studies included WASH interventions focused on water quality (20), water quantity (2), hygiene (30), and sanitation (3). Likewise, 47.1\% (49/104) included biosecurity interventions focused on bio-management (34), bio-containment (10), and bio-exclusion (5). Positive impacts were reported for 64 (61.5\%) interventions, on infection burden (54/87), antibiotic use (3/3) or AMR (7/14). The majority were non-randomised studies (55), although a quarter were randomised controlled trials (26). A total of 27 studies were classified as having low risk of bias, 21 moderate and 56 high risk of bias. Interpretation: This review identifies a number of effective interventions to reduce the burden of infections, antimicrobial resistance and antibiotic use in animal agricultural settings. Interventions which undertook bio-management and bio-containment measures appeared to have positive effects most often. These measures attempted to create and maintain a conducive environment for animal raising in terms of physical infrastructure and protocols. The few studies reporting sanitation measures - which were similar to bio-containment interventions - all reported positive effects. By contrast, efforts to impact water quantity, water quality, and hygiene had more mixed effects on the outcomes assessed. Bio-exclusion interventions had mostly negative effects. Risk of bias was high or moderate in many studies, however, and publication bias should also be considered. The paucity of studies evaluating structural interventions needs to be addressed. There are opportunities to learn from biosecurity Interventions for WASH and we propose the 'A' In WASH represents both 'Animals' and 'Air' in recognition of pathways of infection that can be addressed to also impact AMR.
2020
International Journal of Health Policy and Management
Clinical Trial Transparency & Research Ethics
Sabrina Wimmer,Sarai M. Keestra
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.
2019
3 Minute Quick Fire
Clinical Trial Transparency & Research Ethics
Sarai Keestra,Sophie Gepp,Peter Grabitz,Yi Nian Lee,...Till Bruckner
Objectives In February 2019, the Chair of the House of Commons' Science and Technology Committee sent a letter to forty universities warning them to upload their backlog of missing summary results from clinical trials listed on EUCTR by the end of summer 2019. The objective of the present study is to Track the progress of UK universities in the process of uploading their backlog of overdue summary results on EUCTR and clinicaltrials.gov Elucidate if UK universities take steps towards both prospective and retrospective trial registration. Method We selected the 25 UK universities receiving most UK Medical Research Council funding in 2015-2016 and included two universities that were part of previous UAEM Global Health Report Cards. We filed FOIs in June 2018 to obtain universities' institutional policies regarding clinical trial registration and prospective and retrospective summary results posting, assessing them based on predetermined criteria taken from WHO and EU guidelines. We filed further FOIs due in May 2019 to track progress. To evaluate reporting performance we utilised the EBM Data Lab's EU Trials Tracker and a python script coded by one of the authors (YNL) to extract key information on results posting from clinicaltrials.gov(https://github.com/LeeSean96/GlobalHealthRanking?fbclid=IwAR00rTbendLByaqoPNhUZRrLo_iJlYib_gbtce9QjW9x3gX47-OKcaMrKxQ). A sample of results was manually checked for accuracy. We will collect data from the European and American registries in April&June make comparisons with results collected before the Committee's letter in January 2019. Results We identified 27 universities in the UK that together received £343,742,000 in research grants from the Medical Research Council in the year 2015–2016. Firstly, significant gaps of university's institutional policies regarding clinical trial registration and summary result posting persist: i.e. 25/27 universities do not have a publicly available policy requiring university sponsored clinical trials to report summary results. Secondly, preliminary results from January 2019 show that the reporting performance of UK universities in the European Registry increased from 51% to 62% [Nov:120/234; Jan: 158/254]. However, no such progress is seen on the American Registry, where still 97% of due trials are missing summary result posting [Jan:1575/1624]. Conclusions Preliminary results for January 2019 show that some universities in particular are on the right track to upload summary results of clinical trials, although progress is mostly limited to the EU registry. This is most likely due to increased public and political pressure to comply with EU guidelines regarding clinical trials. Our final results will clarify whether a wider set of universities will enhance clinical trial summary results posting on both key registries or if progress remains to be propelled by a smaller number of universities only. We will also discuss if universities are taking active steps towards both prospective and retrospective summary result posting by analyzing FOI requests due in May 2019. Further research should be conducted on the quality and completeness of summary result postings and the potential overlap of universities' trial registrations on the European and American databases.