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Importance: In 2013, the Trial to Assess Chelation Therapy (TACT) reported that edetate disodium (EDTA)-based chelation significantly reduced cardiovascular disease (CVD) events by 18% in 1708 patients with a prior myocardial infarction (MI). Objective: To replicate the finding of TACT in individuals with diabetes and previous MI. Design, Setting, and Participants: A 2 × 2 factorial, double-masked, placebo-controlled, multicenter trial at 88 sites in the US and Canada, involving participants who were 50 years or older, had diabetes, and had experienced an MI at least 6 weeks before recruitment compared the effect of EDTA-based chelation vs placebo infusions on CVD events and compared the effect of high doses of oral multivitamins and minerals with oral placebo. This article reports on the chelation vs placebo infusion comparisons. Interventions: Eligible participants were randomly assigned to 40 weekly infusions of an EDTA-based chelation solution or matching placebo and to twice daily oral, high-dose multivitamin and mineral supplements or matching placebo for 60 months. This article addresses the chelation study. Main Outcomes and Measures: The primary end point was the composite of all-cause mortality, MI, stroke, coronary revascularization, or hospitalization for unstable angina. Median follow-up was 48 months. Primary comparisons were made from patients who received at least 1 assigned infusion. Results: Of the 959 participants (median age, 67 years [IQR, 60-72 years]; 27% females; 78% White, 10% Black, and 20% Hispanic), 483 received at least 1 chelation infusion and 476 at least 1 placebo infusion. A primary end point event occurred in 172 participants (35.6%) in the chelation group and in 170 (35.7%) in the placebo group (adjusted hazard ratio [HR], 0.93; 95% CI, 0.76-1.16; P = .53). The 5-year primary event cumulative incidence rates were 45.8% for the chelation group and 46.5% for the placebo group. CV death, MI, or stroke events occurred in 89 participants (18.4%) in the chelation group and in 94 (19.7%) in the placebo group (adjusted HR, 0.89; 95% CI, 0.66-1.19). Death from any cause occurred in 84 participants (17.4%) in the chelation group and in 84 (17.6%) in the placebo group (adjusted HR, 0.96; 95% CI, 0.71-1.30). Chelation reduced median blood lead levels from 9.03 µg/L at baseline to 3.46 µg/L at infusion 40 (P < .001). Corresponding levels in the placebo group were 9.3 µg/L and 8.7 µg/L, respectively. Conclusions and Relevance: Despite effectively reducing blood lead levels, EDTA chelation was not effective in reducing cardiovascular events in stable patients with coronary artery disease who have diabetes and a history of MI. Trial Registration: ClinicalTrials.gov Identifier: NCT02733185.

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BACKGROUND: The reduction in cardiovascular disease (CVD) events with edetate disodium (EDTA) in the Trial to Assess Chelation Therapy (TACT) suggested that chelation of toxic metals might provide novel opportunities to reduce CVD in patients with diabetes. Lead and cadmium are vasculotoxic metals chelated by EDTA. We present baseline characteristics for participants in TACT2, a randomized, double-masked, placebo-controlled trial designed as a replication of the TACT trial limited to patients with diabetes. METHODS: TACT2 enrolled 1,000 participants with diabetes and prior myocardial infarction, age 50 years or older between September 2016 and December 2020. Among 959 participants with at least one infusion, 933 had blood and/or urine metals measured at the Centers for Diseases Control and Prevention using the same methodology as in the National Health and Nutrition Examination Survey (NHANES). We compared metal levels in TACT2 to a contemporaneous subset of NHANES participants with CVD, diabetes and other inclusion criteria similar to TACT2's participants. RESULTS: At baseline, the median (interquartile range, IQR) age was 67 (60, 72) years, 27% were women, 78% reported white race, mean (SD) BMI was 32.7 (6.6) kg/m2, 4% reported type 1 diabetes, 46.8% were treated with insulin, 22.3% with GLP1-receptor agonists or SGLT-2 inhibitors, 90.2% with aspirin, warfarin or P2Y12 inhibitors, and 86.5% with statins. Blood lead was detectable in all participants; median (IQR) was 9.19 (6.30, 13.9) µg/L. Blood and urine cadmium were detectable in 97% and median (IQR) levels were 0.28 (0.18, 0.43) µg/L and 0.30 (0.18, 0.51) µg/g creatinine, respectively. Metal levels were largely similar to those in the contemporaneous NHANES subset. CONCLUSIONS: TACT2 participants were characterized by high use of medication to treat CVD and diabetes and similar baseline metal levels as in the general US population. TACT2 will determine whether chelation therapy reduces the occurrence of subsequent CVD events in this high-risk population. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov. Identifier: NCT02733185. https://clinicaltrials.gov/study/NCT02733185.

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Consumer and community involvement (CCI) in preventive research and health initiatives is not only encouraged but is expected within a rapidly evolving landscape across health policy, practice and research. Here, we summarise the fundamental principles of CCI, as well as outline the barriers and current developments in working towards best practices at organisational and systems levels. CCI stands at a critical juncture. Best practice emphasises meaningful partnerships with consumers and communities to deliver impactful research and prevention activities, yet complex challenges and systematic barriers remain. We need further evidence to demonstrate both 'what' and 'how' CCI should be best implemented in these settings. We present key considerations for researchers, organisations and systems to catalyse the transition of CCI from mere recognition of its importance to pragmatic and optimum implementation and, ultimately, to systemic reform. These include changes to capacity building, funding structures, equitable engagement and transparent evaluation. These must be underpinned by evidence-based approaches, partnership, trust and broad consensus processes to achieve meaningful and impactful CCI in research and healthcare improvement through a lens of inclusivity.

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Ion channels mediate voltage fluxes or action potentials that are central to the functioning of excitable cells such as neurons. The KCNB family of voltage-gated potassium channels (Kv) consists of two members (KCNB1 and KCNB2) encoded by KCNB1 and KCNB2, respectively. These channels are major contributors to delayed rectifier potassium currents arising from the neuronal soma which modulate overall excitability of neurons. In this study, we identified several mono-allelic pathogenic missense variants in KCNB2, in individuals with a neurodevelopmental syndrome with epilepsy and autism in some individuals. Recurrent dysmorphisms included a broad forehead, synophrys, and digital anomalies. Additionally, we selected three variants where genetic transmission has not been assessed, from two epilepsy studies, for inclusion in our experiments. We characterized channel properties of these variants by expressing them in oocytes of Xenopus laevis and conducting cut-open oocyte voltage clamp electrophysiology. Our datasets indicate no significant change in absolute conductance and conductance-voltage relationships of most disease variants as compared to wild type (WT), when expressed either alone or co-expressed with WT-KCNB2. However, variants c.1141A>G (p.Thr381Ala) and c.641C>T (p.Thr214Met) show complete abrogation of currents when expressed alone with the former exhibiting a left shift in activation midpoint when expressed alone or with WT-KCNB2. The variants we studied, nevertheless, show collective features of increased inactivation shifted to hyperpolarized potentials. We suggest that the effects of the variants on channel inactivation result in hyper-excitability of neurons, which contributes to disease manifestations.

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Preconception interventions, specifically addressing general health, lifestyle behaviours and weight management, are limited despite their importance in optimising women's health. The objective of this study is to evaluate the engagement and acceptability of OptimalMe, a digital preconception intervention. Participants, (n = 298) Australian women aged 18-44 with private health insurance planning to conceive within 12 months, received a standardised intervention, including access to a digital healthy lifestyle platform (educational materials, behaviour change activities, and self-monitoring resources), ongoing text messaging, and remotely delivered health coaching (two appointments) with randomised delivery methods (telephone/videoconference). Engagement and acceptability were assessed through mixed method analyses. The results show that 76.2% attended both coaching sessions, with similar participation rates for telehealth (75.2%) and videoconferencing (77.2%) (p = 0.469). All participants logged into the digital platform, with 90.6% accessing educational materials and 91.3% using behaviour change tools. Digital platform engagement declined over time, suggesting potential benefits from additional health coaching support for ongoing participation. The post-intervention evaluation (n = 217 participants) demonstrated that approximately 90% found the digital module engaging, meeting information needs, would recommend the program, and were satisfied with the support. OptimalMe demonstrated positive acceptability and engagement; however, further research is warranted to explore strategies for sustaining engagement with the digital interventions.

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INTRODUCTION: Globally, recognition is growing of the harmful impacts of high ambient temperatures (heat) on health in pregnant women and children. There remain, however, major evidence gaps on the extent to which heat increases the risks for adverse health outcomes, and how this varies between settings. Evidence gaps are especially large in Africa. We will conduct an individual participant data (IPD) meta-analysis to quantify the impacts of heat on maternal and child health in sub-Saharan Africa. A detailed understanding and quantification of linkages between heat, and maternal and child health is essential for developing solutions to this critical research and policy area. METHODS AND ANALYSIS: We will use IPD from existing, large, longitudinal trial and cohort studies, on pregnant women and children from sub-Saharan Africa. We will systematically identify eligible studies through a mapping review, searching data repositories, and suggestions from experts. IPD will be acquired from data repositories, or through collaboration with data providers. Existing satellite imagery, climate reanalysis data, and station-based weather observations will be used to quantify weather and environmental exposures. IPD will be recoded and harmonised before being linked with climate, environmental, and socioeconomic data by location and time. Adopting a one-stage and two-stage meta-analysis method, analytical models such as time-to-event analysis, generalised additive models, and machine learning approaches will be employed to quantify associations between exposure to heat and adverse maternal and child health outcomes. ETHICS AND DISSEMINATION: The study has been approved by ethics committees. There is minimal risk to study participants. Participant privacy is protected through the anonymisation of data for analysis, secure data transfer and restricted access. Findings will be disseminated through conferences, journal publications, related policy and research fora, and data may be shared in accordance with data sharing policies of the National Institutes of Health. PROSPERO REGISTRATION NUMBER: CRD42022346068.

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OptimalMe is a digital healthy lifestyle intervention for women planning a pregnancy, with remotely delivered coaching. This follow-up study of Australian women, stratified by coaching delivery mode (phone vs. videoconferencing), assessed alignment to preconception care guidelines and self-reported behaviour change. Overall, 298 women enrolled with a mean (SD) age of 31.8 (4.3) years and mean BMI of 25.7 (6.1) kg/m2. Suboptimal preconception behaviours were reported at baseline, including alcohol consumption (57.2%), infrequent weighing (37.2%) and incomplete cervical cancer screening (15.8%) and prenatal supplementation (38.5). At follow-up (4.5 months) (n = 217), a statistically significant shift towards desired behaviours was reported for alcohol consumption (z = -2.6045, p = 0.00932), preconception supplementation (z = -2.7288, p = 0.00634) and frequent weight monitoring (z = -5.2911, p < 0.00001). An insignificant shift towards adherence to cervical cancer screening (z = -1.8679, p = 0.06148) was observed, with a positive trend towards adherence. Results indicate that women who are actively planning a pregnancy require support to optimise health and lifestyle in preparation for pregnancy and general health and lifestyle improvement. Women demonstrated improvement in lifestyle behaviours and self-monitoring, indicating the uptake of low-intensity, non-prescriptive information provision. Supporting the provision of knowledge-enhancing tools and general healthy lifestyle information combines with skilled health coaching as an effective method for behaviour change and self-management. OptimalMe also shows significant improvements in rates of healthcare engagement, which suggests coaching-based digital health interventions may decrease women's barriers for preconception care and improve engagement in clinical settings.

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BACKGROUND: Biorepositories archive and distribute well-characterized biospecimens for research to support the development of medical diagnostics and therapeutics. Knowledge of biobanking and associated practices is incomplete in low- and middle-income countries where disease burden is disproportionately high. In 2011, the African Society of Human Genetics (AfSHG), the National Institutes of Health (NIH), and the Wellcome Trust founded the Human Heredity and Health in Africa (H3Africa) consortium to promote genomic research in Africa and established a network of three biorepositories regionally located in East, West, and Southern Africa to support biomedical research. This manuscript describes the processes established by H3Africa biorepositories to prepare research sites to collect high-quality biospecimens for deposit at H3Africa biorepositories. METHODS: The biorepositories harmonized practices between the biorepositories and the research sites. The biorepositories developed guidelines to establish best practices and define biospecimen requirements; standard operating procedures (SOPs) for common processes such as biospecimen collection, processing, storage, transportation, and documentation as references; requirements for minimal associated datasets and formats; and a template material transfer agreements (MTA) to govern biospecimen exchange. The biorepositories also trained and mentored collection sites in relevant biobanking processes and procedures and verified biospecimen deposit processes. Throughout these procedures, the biorepositories followed ethical and legal requirements. RESULTS: The 20 research projects deposited 107,982 biospecimens (76% DNA, 81,067), in accordance with the ethical and legal requirements and established best practices. The biorepositories developed and customized resources and human capacity building to support the projects. [The biorepositories developed 34 guidelines, SOPs, and documents; trained 176 clinicians and scientists in over 30 topics; sensitized ethical bodies; established MTAs and reviewed consent forms for all projects; attained import permits; and evaluated pilot exercises and provided feedback. CONCLUSIONS: Biobanking in low- and middle-income countries by local skilled staff is critical to advance biobanking and genomic research and requires human capacity and resources for global partnerships. Biorepositories can help build human capacity and resources to support biobanking by partnering with researchers. Partnerships can be structured and customized to incorporate document development, ethics, training, mentorship, and pilots to prepare sites to collect, process, store, and transport biospecimens of high quality for future research.

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Heterozygous pathogenic variants in POLR1A, which encodes the largest subunit of RNA Polymerase I, were previously identified as the cause of acrofacial dysostosis, Cincinnati-type. The predominant phenotypes observed in the cohort of 3 individuals were craniofacial anomalies reminiscent of Treacher Collins syndrome. We subsequently identified 17 additional individuals with 12 unique heterozygous variants in POLR1A and observed numerous additional phenotypes including neurodevelopmental abnormalities and structural cardiac defects, in combination with highly prevalent craniofacial anomalies and variable limb defects. To understand the pathogenesis of this pleiotropy, we modeled an allelic series of POLR1A variants in vitro and in vivo. In vitro assessments demonstrate variable effects of individual pathogenic variants on ribosomal RNA synthesis and nucleolar morphology, which supports the possibility of variant-specific phenotypic effects in affected individuals. To further explore variant-specific effects in vivo, we used CRISPR-Cas9 gene editing to recapitulate two human variants in mice. Additionally, spatiotemporal requirements for Polr1a in developmental lineages contributing to congenital anomalies in affected individuals were examined via conditional mutagenesis in neural crest cells (face and heart), the second heart field (cardiac outflow tract and right ventricle), and forebrain precursors in mice. Consistent with its ubiquitous role in the essential function of ribosome biogenesis, we observed that loss of Polr1a in any of these lineages causes cell-autonomous apoptosis resulting in embryonic malformations. Altogether, our work greatly expands the phenotype of human POLR1A-related disorders and demonstrates variant-specific effects that provide insights into the underlying pathogenesis of ribosomopathies.

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Aim: To perform an epigenome-wide association study (EWAS) of serum folate in maternal blood. Methods: Cross-ancestry (Europeans = 302, South Asians = 161) and ancestry-specific EWAS in the EPIPREG cohort were performed, followed by methyl quantitative trait loci analysis and association with cardiometabolic phenotypes. Replication was attempted using maternal folate intake and blood methylation data from the MoBa study and verified if the findings were significant in a previous EWAS of maternal serum folate in cord blood. Results & conclusion: cg19888088 (cross-ancestry) in EBF3, cg01952260 (Europeans) and cg07077240 (South Asians) in HERC3 were associated with serum folate. cg19888088 and cg01952260 were associated with diastolic blood pressure. cg07077240 was associated with variants in CASC15. The findings were not replicated and were not significant in cord blood.

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OBJECTIVES: Infant underrepresentation poses a great risk to accurate palaeodemographic findings when analyzing skeletal samples. Empirically derived palaeodemographic methods all require unbiased or minimally biased pre-adult representation for estimating demographic characteristics, including fertility. Currently, there are no reliable methods for estimating palaeodemographic parameters when pre-adults are underrepresented in skeletal samples, consequently such samples are often excluded from palaeodemographic analyses. The aim of this article is to develop a method for estimating total fertility rate (TFR) using reproductive aged adults, specifically for samples with suspected pre-adult under-enumeration. METHODOLOGY: United Nations mortality data and TFR from the World Population Prospects was utilized. The correlation between known fertility and the proportion of individuals in key reproductive years (15-49 years) to total adult sample (15+ years) was assessed as an indirect means to estimate fertility. RESULTS: It was determined that the proportion of reproductive aged adults is a reasonable proxy for fertility. A significant positive correlation was observed between the TFR and those who died aged 15-49 years of age as a proportion of those who died ≥15 years (D15-49/D15+). SE of the estimate revealed reasonable predictive accuracy. When applied to two modern non-agricultural populations, the method showed some variability in accuracy but good potential for an improved outcome over existing methods when pre-adults are underrepresented. CONCLUSION: This research has provided a new method for estimating fertility in archeological skeletal samples with pre-adult under-enumeration. In combination with a contextually focused approach, this provides a significant step toward further use of biased samples in palaeodemography.

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PURPOSE: This study aimed to assess the amount and types of clinical genetic testing denied by insurance and the rate of diagnostic and candidate genetic findings identified through research in patients who faced insurance denials. METHODS: Analysis consisted of review of insurance denials in 801 patients enrolled in a pediatric genomic research repository with either no previous genetic testing or previous negative genetic testing result identified through cross-referencing with insurance prior-authorizations in patient medical records. Patients and denials were also categorized by type of insurance coverage. Diagnostic findings and candidate genetic findings in these groups were determined through review of our internal variant database and patient charts. RESULTS: Of the 801 patients analyzed, 147 had insurance prior-authorization denials on record (18.3%). Exome sequencing and microarray were the most frequently denied genetic tests. Private insurance was significantly more likely to deny testing than public insurance (odds ratio = 2.03 [95% CI = 1.38-2.99] P = .0003). Of the 147 patients with insurance denials, 53.7% had at least 1 diagnostic or candidate finding and 10.9% specifically had a clinically diagnostic finding. Fifty percent of patients with clinically diagnostic results had immediate medical management changes (5.4% of all patients experiencing denials). CONCLUSION: Many patients face a major barrier to genetic testing in the form of lack of insurance coverage. A number of these patients have clinically diagnostic findings with medical management implications that would not have been identified without access to research testing. These findings support re-evaluation of insurance carriers' coverage policies.

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BACKGROUND: Weight loss could improve fertility, perhaps by reducing insulin resistance. OBJECTIVES: To assess the effect of weight loss interventions on fertility in women with obesity not recruited because of known infertility. SEARCH STRATEGY: Three databases during 1966-2020, trial registry. SELECTION CRITERIA: Randomized controlled trials (RCTs) with a follow-up of 1 year or more, with a mean cohort BMI of 30 kg/m2 or above. DATA COLLECTION AND ANALYSIS: A systematic review and meta-analysis was conducted. The primary outcome was pregnancy. The secondary outcome was weight change. MAIN RESULTS: A total of 27 RCTs (5938 women) were included. Weight loss interventions showed no statistically significant increase in pregnancies compared to control interventions (24 trials, 97 women with pregnancy; risk ratio [RR] 1.43, 95% confidence interval [CI] 0.91-2.23); weight change (mean difference [MD] -2.36 kg, 21 trials, 95% CI -3.17 to -1.55). Compared with low-fat diets, very-low-carbohydrate diets showed no statistically significant effect on women with pregnancy (three trials, 14 women with pregnancy; RR 1.37, 95% CI 0.49-3.84) or weight change (MD -0.32 kg, 95% CI -3.84 to 3.21). CONCLUSIONS: Diet-based weight loss interventions for women with obesity not recruited because of infertility were effective at producing long-term weight loss. The effects on fertility were not statistically significant, but few trials provided data. Weight loss trials should routinely collect fertility outcomes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017078819.

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BACKGROUND: Digital health resources have the potential to assist women in optimizing gestational weight gain (GWG) during pregnancy to improve maternal health outcomes. OBJECTIVE: In this study, we aimed to evaluate the quality and behavior change potential of publicly available digital tools (websites and apps) that facilitate GWG tracking. METHODS: Digital tools were identified using key search terms across website search engines and app stores and evaluated using the Mobile App Rating Scale, the App Behavior Change Scale, as well as criteria to evaluate the rigor and safety of GWG information. RESULTS: Overall, 1085 tools were screened for inclusion (162 websites and 923 apps), and 19 were deemed eligible. The mean Mobile App Rating Scale quality score was 3.31 (SD 0.53) out of 5, ranging from 2.26 to 4.39, and the mean App Behavior Change Scale score was 6 (SD 3.4) out of 21, ranging from 19 to 0. Of the 19 items used to evaluate rigor of GWG advice, most tools (n=11, 57.9%) contained ≤3 items. CONCLUSIONS: This review emphasizes the substantial limitations in current digital resources promoting the monitoring and optimization of GWG. Most tools were of low quality, had minimal behavior change potential, and were potentially unsafe, with minimal linkage to evidence-based information or partnership with health care.

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Quantifying the exposome is key to understanding how the environment impacts human health and disease. However, accurately, and cost-effectively quantifying exposure in large population health studies remains a major challenge. Geospatial technologies offer one mechanism to integrate high-dimensional environmental data into epidemiology studies, but can present several challenges. In June 2021, the National Institute of Environmental Health Sciences (NIEHS) held a workshop bringing together experts in exposure science, geospatial technologies, data science and population health to address the need for integrating multiscale geospatial environmental data into large population health studies. The primary objectives of the workshop were to highlight recent applications of geospatial technologies to examine the relationships between environmental exposures and health outcomes; identify research gaps and discuss future directions for exposure modeling, data integration and data analysis strategies; and facilitate communications and collaborations across geospatial and population health experts. This commentary provides a high-level overview of the scientific topics covered by the workshop and themes that emerged as areas for future work, including reducing measurement errors and uncertainty in exposure estimates, and improving data accessibility, data interoperability, and computational approaches for more effective multiscale and multi-source data integration, along with potential solutions.

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