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OBJECTIVE: The unprecedented events of 2020 required a pivot in scientific training to better prepare the biomedical research workforce to address global pandemics, structural racism, and social inequities that devastate human health individually and erode it collectively. Furthermore, this pivot had to be accomplished in the virtual environment given the nation-wide lockdown. METHODS: These needs and context led to leveraging of the San Francisco Building Infrastructure Leading to Diversity (SF BUILD) theories of change to innovate a Virtual BUILD Research Collaboratory (VBRC). The purpose of VBRC was to train Black, Indigenous, and people of color (BIPOC) students to apply their unique perspectives to biomedical research. These training activities were evaluated using a pre-post survey design that included both validated and new psychosocial scales. A new scale was piloted to measure culturally relevant pedagogy. RESULTS: VBRC scholars increased science identity on two items: thinking of myself as a scientist (+1point, p = 0.006) and belonging to a community of scientists (+1point, p = 0.069). Overall, scholars perceived stress also decreased over VBRC (-2.35 points, p = 0.02). Post VBRC, scholars had high agency scores (μ = 11.02, Md = 12, range = 6-12, σ = 1.62) and cultural humility scores (μ = 22.11, Md = 23, range = 12-24, σ = 2.71). No notable race/ethnic differences were found in any measures. CONCLUSIONS: Taken together, our innovative approach to data science training for BIPOC in unprecedented times shows promise for better preparing the workforce critically needed to address the fundamental gaps in knowledge at the intersection of public health, structural racism, and biomedical sciences.

IntroductionOne goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to define the fluid biomarker characteristics of early-onset Alzheimer's disease (EOAD).MethodsCerebrospinal fluid (CSF) concentrations of Aβ1-40, Aβ1-42, total tau (tTau), pTau181, VILIP-1, SNAP-25, neurogranin (Ng), neurofilament light chain (NfL), and YKL-40 were measured by immunoassay in 165 LEADS participants. The associations of biomarker concentrations with diagnostic group and standard cognitive tests were evaluated.ResultsBiomarkers were correlated with one another. Levels of CSF Aβ42/40, pTau181, tTau, SNAP-25, and Ng in EOAD differed significantly from cognitively normal and early-onset non-AD dementia; NfL, YKL-40, and VILIP-1 did not. Across groups, all biomarkers except SNAP-25 were correlated with cognition. Within the EOAD group, Aβ42/40, NfL, Ng, and SNAP-25 were correlated with at least one cognitive measure.DiscussionThis study provides a comprehensive analysis of CSF biomarkers in sporadic EOAD that can inform EOAD clinical trial design.

ObjectiveInvestigation of learning slopes in early-onset dementias has been limited. The current study aimed to highlight the sensitivity of learning slopes to discriminate disease severity in cognitively normal participants and those diagnosed with early-onset dementia with and without β-amyloid positivity METHOD: Data from 310 participants in the Longitudinal Early-Onset Alzheimer's Disease Study (aged 41 to 65) were used to calculate learning slope metrics. Learning slopes among diagnostic groups were compared, and the relationships of slopes with standard memory measures were determined RESULTS: Worse learning slopes were associated with more severe disease states, even after controlling for demographics, total learning, and cognitive severity. A particular metric-the learning ratio (LR)-outperformed other learning slope calculations across analyses CONCLUSIONS: Learning slopes appear to be sensitive to early-onset dementias, even when controlling for the effect of total learning and cognitive severity. The LR may be the learning measure of choice for such analyses.HighlightsLearning is impaired in amyloid-positive EOAD, beyond cognitive severity scores alone. Amyloid-positive EOAD participants perform worse on learning slopes than amyloid-negative participants. Learning ratio appears to be the learning metric of choice for EOAD participants.

IntroductionWe examined neuropsychiatric symptoms (NPS) and psychotropic medication use in a large sample of individuals with early-onset Alzheimer's disease (EOAD; onset 40-64 years) at the midway point of data collection for the Longitudinal Early-onset Alzheimer's Disease Study (LEADS).MethodsBaseline NPS (Neuropsychiatric Inventory - Questionnaire; Geriatric Depression Scale) and psychotropic medication use from 282 participants enrolled in LEADS were compared across diagnostic groups - amyloid-positive EOAD (n = 212) and amyloid negative early-onset non-Alzheimer's disease (EOnonAD; n = 70).ResultsAffective behaviors were the most common NPS in EOAD at similar frequencies to EOnonAD. Tension and impulse control behaviors were more common in EOnonAD. A minority of participants were using psychotropic medications, and use was higher in EOnonAD.DiscussionOverall NPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants. Future research will investigate moderators and etiological drivers of NPS, and NPS differences in EOAD versus late-onset AD.

ObjectiveThe Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) seeks to provide comprehensive understanding of early-onset Alzheimer's disease (EOAD; onset

IntroductionWe compared white matter hyperintensities (WMHs) in early-onset Alzheimer's disease (EOAD) with cognitively normal (CN) and early-onset amyloid-negative cognitively impaired (EOnonAD) groups in the Longitudinal Early-Onset Alzheimer's Disease Study.MethodsWe investigated the role of increased WMH in cognition and amyloid and tau burden. We compared WMH burden of 205 EOAD, 68 EOnonAD, and 89 CN participants in lobar regions using t-tests and analyses of covariance. Linear regression analyses were used to investigate the association between WMH and cognitive impairment and that between amyloid and tau burden.ResultsEOAD showed greater WMHs compared with CN and EOnonAD participants across all regions with no significant differences between CN and EOnonAD groups. Greater WMHs were associated with worse cognition. Tau burden was positively associated with WMH burden in the EOAD group.DiscussionEOAD consistently showed higher WMH volumes. Overall, greater WMHs were associated with worse cognition and higher tau burden in EOAD.HighlightsThis study represents a comprehensive characterization of WMHs in sporadic EOAD. WMH volumes are associated with tau burden from positron emission tomography (PET) in EOAD, suggesting WMHs are correlated with increasing burden of AD. Greater WMH volumes are associated with worse performance on global cognitive tests. EOAD participants have higher WMH volumes compared with CN and early-onset amyloid-negative cognitively impaired (EOnonAD) groups across all brain regions.

BACKGROUND: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folates role in CRC. OBJECTIVES: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk. METHODS: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO). RESULTS: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate. CONCLUSIONS: Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic/likely pathogenic (P/LP) variants associated with increased risk of breast, ovarian, pancreatic, and prostate cancer, including BRCA1, BRCA2, CDH1, PALB2, PTEN, and TP53, and recommended approaches to genetic counseling/testing and care strategies in individuals with these P/LP variants. These NCCN Guidelines Insights summarize important updates regarding: (1) a new section for transgender, nonbinary and gender diverse people who have a hereditary predisposition to cancer focused on risk reduction strategies for ovarian cancer, uterine cancer, prostate cancer, and breast cancer; and (2) testing criteria and management associated with TP53 P/LP variants and Li-Fraumeni syndrome.

BACKGROUND: There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer. Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for pancreatic cancer. METHODS: Data from genome-wide association studies (GWAS) within the Pancreatic Cancer Cohort Consortium (PanScan; cases n = 5,090, controls n = 8,733) and the Pancreatic Cancer Case Control Consortium (PanC4; cases n = 4,163, controls n = 3,792) were analyzed. We used data on 68 genetic variants with four different MR methods [inverse variance weighting (IVW), MR-Egger, simple median, and penalized weighted median] separately to predict genetic heritability of NAFLD. We then assessed the relationship between each of the four MR methods and pancreatic cancer risk, using logistic regression to calculate ORs and 95% confidence intervals (CI), adjusting for PC risk factors, including obesity and diabetes. RESULTS: No association was found between genetically predicted NAFLD and pancreatic cancer risk in the PanScan or PanC4 samples [e.g., PanScan, IVW OR, 1.04; 95% confidence interval (CI), 0.88-1.22; MR-Egger OR, 0.89; 95% CI, 0.65-1.21; PanC4, IVW OR, 1.07; 95% CI, 0.90-1.27; MR-Egger OR, 0.93; 95% CI, 0.67-1.28]. None of the four MR methods indicated an association between genetically predicted NAFLD and pancreatic cancer risk in either sample. CONCLUSIONS: Genetic predisposition to NAFLD is not associated with pancreatic cancer risk. IMPACT: Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and pancreatic cancer might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and pancreatic cancer.

Wnt5a triggers inflammatory responses and damage via NFkB/p65 in retinal pigment epithelial (RPE) cells undergoing uncompensated oxidative stress (UOS) and in experimental ischemic stroke. We found that Wnt5a-Clathrin-mediated uptake leads to NFkB/p65 activation and that Wnt5a is secreted in an exosome-independent fashion. We uncovered that docosahexaenoic acid (DHA) and its derivative, Neuroprotectin D1 (NPD1), upregulate c-Rel expression that, as a result, blunts Wnt5a abundance by competing with NFkB/p65 on the Wnt5a promoter A. Wnt5a increases in ischemic stroke penumbra and blood, while DHA reduces Wnt5a abundance with concomitant neuroprotection. Peptide inhibitor of Wnt5a binding, Box5, is also neuroprotective. DHA-decreased Wnt5a expression is concurrent with a drop in NFkB-driven inflammatory cytokine expression, revealing mechanisms after stroke, as in RPE cells exposed to UOS. Limiting the Wnt5a activity via Box5 reduces stroke size, suggesting neuroprotection pertinent to onset and progression of retinal degenerations and stroke consequences. NPD1 disrupts Wnt5a feedback loop at two sites: (1) decreasing FZD5, thus Wnt5a internalization, and (2) by enhancing cREL activity, which competes with p65/NFkB downstream endocytosis. As a result, Wnt5a expression is reduced, and so is its inflammatory signaling in RPE cells and neurons in ischemic stroke.

Although prediagnostic circulating concentrations of the immune activation markers soluble CD27 (sCD27), sCD30 and chemokine ligand-13 (CXCL13) have been associated with non-Hodgkin lymphoma (NHL) risk, studies have been limited by sample size in associations with NHL subtypes. We pooled data from eight nested case-control studies to investigate subtype-specific relationships for these analytes. Using polytomous regression, we calculated odds ratios (ORs) with 95% confidence intervals (CIs) relating study-specific analyte tertiles to selected subtypes vs controls (n = 3310): chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 623), diffuse large B cell lymphoma (DLBCL; n = 621), follicular lymphoma (FL; n = 398), marginal zone lymphoma (MZL; n = 138), mantle cell lymphoma (MCL; n = 82) and T cell lymphoma (TCL; n = 92). We observed associations with DLBCL for elevated sCD27 [OR for third vs first tertile (ORT3 ) = 2.2, 95% CI = 1.6-3.1], sCD30 (ORT3  = 2.0, 95% CI = 1.6-2.5) and CXCL13 (ORT3  = 2.3, 95% CI = 1.8-3.0). We also observed associations with sCD27 for CLL/SLL (ORT3  = 3.3, 95% CI = 2.4-4.6), MZL (ORT3  = 7.7, 95% CI = 3.0-20.1) and TCL (ORT3  = 3.4, 95% CI = 1.5-7.7), and between sCD30 and FL (ORT3  = 2.7, 95% CI = 2.0-3.5). In analyses stratified by time from phlebotomy to case diagnosis, the sCD27-TCL and all three DLBCL associations were equivalent across both follow-up periods (

BackgroundMost medical educational programs emphasize clinical observation or clinical skill acquisition, fewer focus upon research. The Danish-American Research Exchange (DARE) program, sponsored by the Lundbeck Foundation, is unique in that the medical student initiates biomedical research collaboration between Danish and US medical institutions. To achieve this, Danish medical students (DARE students) conduct binational mentored research projects while based in the United States for 10 months. In addition, DARE students are introduced to interdisciplinary thinking about how to develop ultra-low-cost healthcare interventions through the '$10 Challenge'.MethodsWe conducted a cross-sectional study of DARE alumni over five consecutive years (2015-2020, n = 24). Research metrics included completion of a research project, primary authorship, and co-authorship of publications. The number of publications, prior to and after the DARE program were enumerated. For the first four cohorts, graduation from medical school and acceptance or intention to enter a joint MD-PhD program also were assessed. Two focus groups were conducted using constructivist grounded theory. Discussions were transcribed, redacted, and coded using Dedoose software.ResultsDARE Medical students were 31.2 years (range 24-35), the majority were women (67%;16/24). The majority (17/24;71%) completed a first author publication in a peer-reviewed journal with a median of 3.9 per DARE alumnus. DARE alumnus reported increased proficiency in biostatistics, epidemiology, coding and public speaking as well as stronger research qualities in creativity, critical thinking, comfort in approaching scientist in both the US and Denmark (p

BACKGROUND AND OBJECTIVE: Cerebral venous thrombosis (CVT) is a rare cause of stroke carrying a nearly 4% risk of recurrence after 1 year. There are limited data on predictors of recurrent venous thrombosis in patients with CVT. In this study, we aim to identify those predictors. METHODS: This is a secondary analysis of the ACTION-CVT study which is a multicenter international study of consecutive patients hospitalized with a diagnosis of CVT over a 6-year period. Patients with cancer-associated CVT, CVT during pregnancy, or CVT in the setting of known antiphospholipid antibody syndrome were excluded per the ACTION-CVT protocol. The study outcome was recurrent venous thrombosis defined as recurrent venous thromboembolism (VTE) or de novo CVT. We compared characteristics between patients with vs without recurrent venous thrombosis during follow-up and performed adjusted Cox regression analyses to determine important predictors of recurrent venous thrombosis. RESULTS: Nine hundred forty-seven patients were included with a mean age of 45.2 years, 63.9% were women, and 83.6% had at least 3 months of follow-up. During a median follow-up of 308 (interquartile range 120-700) days, there were 5.05 recurrent venous thromboses (37 VTE and 24 de novo CVT) per 100 patient-years. Predictors of recurrent venous thrombosis were Black race (adjusted hazard ratio [aHR] 2.13, 95% CI 1.14-3.98, p = 0.018), history of VTE (aHR 3.40, 95% CI 1.80-6.42, p < 0.001), and the presence of one or more positive antiphospholipid antibodies (aHR 3.85, 95% CI 1.97-7.50, p < 0.001). Sensitivity analyses including events only occurring on oral anticoagulation yielded similar findings. DISCUSSION: Black race, history of VTE, and the presence of one or more antiphospholipid antibodies are associated with recurrent venous thrombosis among patients with CVT. Future studies are needed to validate our findings to better understand mechanisms and treatment strategies in patients with CVT.

BackgroundThe use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk.MethodsWe conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2- or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants.ResultsThe use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P

As part of an investment by the Bill & Melinda Gates Foundation to support the Government of Bihar to improve reproductive, maternal, newborn and child health and nutrition (RMNCHN) statewide, BBC Media Action implemented multiple communication tools to support front-line worker (FLW) outreach. We analyse the impacts of a package of mHealth audio messaging and paper-based job aids used by FLWs during government-sponsored village health, sanitation and nutrition days (VHSNDs) on knowledge and practices of childbearing women across the RMNCHN continuum of care. Data from two surveys collected between July and September 2016 were analysed using logistic regression to compare health-related knowledge and behaviours between women who had been exposed at VHSNDs to the mHealth GupShup Potli (GSP) audio recordings or interpersonal communication (IPC) tools versus those who were unexposed. Exposure to GSP recordings (n=2608) was associated with improved knowledge across all continuum-of-care domains, as well as improved health-related behaviours in some domains. The odds of having taken iron-folic acid (IFA) tablets were significantly higher in exposed women (OR 1.5, 95% CI 1.1 to 2.2), as was contraceptive use (OR 2.0, 95% CI 1.2 to 3.2). There were no differences in birth preparedness or complementary feeding practices between groups. Exposure to IPC paper-based tools (n=2002) was associated with a twofold increased odds of IFA consumption (OR 2.3, 95% CI 1.7 to 3.2) and contraceptive use (OR 1.8, 95% CI 1.2 to 2.8). Women exposed to both tools were generally at least twice as likely to subsequently discuss the messages with others. BBC Media Action's mHealth audio messaging job aids and paper-based IPC tools were associated with improved knowledge and practices of women who were exposed to them across multiple domains, suggesting their important potential for improving health outcomes for beneficiaries at scale in low-resource settings. NCT02726230.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a single-pass transmembrane receptor of the immunoglobulin superfamily that is secreted in a soluble (sTREM2) form. Mutations in TREM2 have been linked to increased risk of Alzheimer's disease (AD). A prominent neuropathological component of AD is deposition of the amyloid-β (Aβ) into plaques, particularly Aβ40 and Aβ42. While the membrane-bound form of TREM2 is known to facilitate uptake of Aβ fibrils and the polarization of microglial processes toward amyloid plaques, the role of its soluble ectodomain, particularly in interactions with monomeric or fibrillar Aβ, has been less clear. Our results demonstrate that sTREM2 does not bind to monomeric Aβ40 and Aβ42, even at a high micromolar concentration, while it does bind to fibrillar Aβ42 and Aβ40 with equal affinities (2.6 ± 0.3 µM and 2.3 ± 0.4 µM). Kinetic analysis shows that sTREM2 inhibits the secondary nucleation step in the fibrillization of Aβ, while having little effect on the primary nucleation pathway. Furthermore, binding of sTREM2 to fibrils markedly enhanced uptake of fibrils into human microglial and neuroglioma derived cell lines. The disease-associated sTREM2 mutant, R47H, displayed little to no effect on fibril nucleation and binding, but it decreased uptake and functional responses markedly. We also probed the structure of the WT sTREM2-Aβ fibril complex using integrative molecular modeling based primarily on the cross-linking mass spectrometry data. The model shows that sTREM2 binds fibrils along one face of the structure, leaving a second, mutation-sensitive site free to mediate cellular binding and uptake.

ObjectiveFew studies have explored the shared effects of Parkinson's disease (PD) within patient/caregiver dyads. To fill this gap, we compared stress-health outcomes of patients with those of caregiving-partners, examined individual stress-health associations, and explored stress-health associations within dyads.MethodA total of 18 PD patient/caregiving-partner dyads (N = 36) reported on disease-specific distress, anxiety, quality of life (QOL), and provided saliva samples for cortisol assessment. This cross-sectional, secondary analysis of a prospective pilot study used Actor-Partner Interdependence Models to test aims.ResultsPatients reported greater anxiety, poorer QOL, and demonstrated flatter cortisol slopes and higher mean bedtime cortisol compared to caregiving-partners. Both patients and caregiving-partners with greater anxiety had elevated bedtime cortisol and poorer QOL. Greater disease-specific distress in an individual was associated with higher diurnal mean cortisol in their partner.ConclusionsFindings highlight the potential for psychosocial interventions at the dyadic level to reduce shared burden and promote coping among PD patient/caregiving-partner dyads.

BackgroundThere is a scarcity of research that comprehensively examines programme impact from a context-specific perspective. We aimed to determine the conditions under which the Bihar Technical Support Programme led to more favourable outcomes for maternal and child health in Bihar.MethodsWe obtained block-level data on maternal and child health indicators during the state-wide scale-up of the pilot Ananya programme and data on health facility readiness, along with geographical and sociodemographic variables. We examined the associations of these factors with increases in the levels of indicators using multilevel logistic regression, and the associations with rates of change in the indicators using Bayesian Hierarchical modelling.ResultsFrontline worker (FLW) visits between 2014-2017 were more likely to increase in blocks with better night lighting (odds ratio (OR) = 1.23, 95% confidence interval (CI) = 1.01-1.51). Birth preparedness increased in blocks with increasing FLW visits (OR = 3.43, 95% CI = 1.15-10.21), while dry cord care practice increased in blocks where satisfaction with FLW visits was increasing (OR = 1.52, 95% CI = 1.10-2.11). Age-appropriate frequency of complementary feeding increased in blocks with higher development index (OR = 1.55, 95% CI = 1.16-2.06) and a higher percentage of scheduled caste or tribe (OR = 3.21, 95% CI = 1.13-9.09). An increase in most outcomes was more likely in areas with lower baseline levels.ConclusionsContextual factors (eg, night lighting and development) not targeted by the programme and FLW visits were associated with favourable programme outcomes. Intervention design, including intervention selection for a particular geography, should be modified to fit the local context in the short term. Expanding collaborations beyond the health sector to influence modifiable contextual factors in the long term can result in a higher magnitude and more sustainable impact.RegistrationClinicalTrials.gov: NCT02726230.

ObjectiveTo date, there are no studies of COVID-19 cases and deaths in the Navajo Nation, US. The primary objective of this manuscript is to understand whether counties with a higher proportion of Navajo (Diné) population also had higher cases and deaths of COVID-19 and whether these dropped with vaccination.MethodWe undertook a cross-sectional analysis of county level data from March 16, 2020-May 11, 2021. Data were obtained from public repositories and the US Census for the Navajo Nation, including northeastern Arizona, southeastern Utah, and northwestern New Mexico. The primary outcome measure is the number of individuals with confirmed cases or deaths of COVID-19. A secondary outcome was COVID-19 vaccinations.ResultsThe 11 counties in Navajo Nation have a wide variation in the percent Navajo population, the resources available (ICU beds and occupancy), and COVID-19 outcomes. Overall, there was a substantial increase in the number of cases from March 16 -July 16, 2020 (the height of the pandemic) with a doubling time of 10.12 days on Navajo Nation. The percent Navajo population was a strong predictor of COVID-19 cases and deaths per million population. COVID-19 vaccinations were inversely associated with COVID-19 cases and deaths in these counties.ConclusionsThe COVID-19 pandemic on the Navajo Nation is a story of resilience. Navajo Nation was one of the hardest hit areas of the United States, with peak cases and deaths due to COVID-19. With an aggressive vaccination effort, these cases and deaths were strikingly curtailed, showing the resilience of the Navajo (Diné) people.

PurposeAchondroplasia is caused by pathogenic variants in the fibroblast growth factor receptor 3 gene that lead to impaired endochondral ossification. Vosoritide, an analog of C-type natriuretic peptide, stimulates endochondral bone growth and is in development for the treatment of achondroplasia. This phase 3 extension study was conducted to document the efficacy and safety of continuous, daily vosoritide treatment in children with achondroplasia, and the two-year results are reported.MethodsAfter completing at least six months of a baseline observational growth study, and 52 weeks in a double-blind, placebo-controlled study, participants were eligible to continue treatment in an open-label extension study, where all participants received vosoritide at a dose of 15.0 μg/kg/day.ResultsIn children randomized to vosoritide, annualized growth velocity increased from 4.26 cm/year at baseline to 5.39 cm/year at 52 weeks and 5.52 cm/year at week 104. In children who crossed over from placebo to vosoritide in the extension study, annualized growth velocity increased from 3.81 cm/year at week 52 to 5.43 cm/year at week 104. No new adverse effects of vosoritide were detected.ConclusionVosoritide treatment has safe and persistent growth-promoting effects in children with achondroplasia treated daily for two years.

BackgroundThe Ananya program in Bihar implemented household and community-level interventions to improve reproductive, maternal, newborn and child health and nutrition (RMNCHN) in two phases: a first phase of intensive ancillary support to governmental implementation and innovation testing by non-government organisation (NGO) partners in eight focus districts (2012-2014), followed by a second phase of state-wide government-led implementation with techno-managerial assistance from NGOs (2014 onwards). This paper examines trends in RMNCHN indicators in the program's implementation districts from 2012-2017.MethodsEight consecutive rounds of cross-sectional Community-based Household Surveys conducted by CARE India in 2012-2017 provided comparable data on a large number of indicators of frontline worker (FLW) performance, mothers' behaviours, and facility-based care and outreach service delivery across the continuum of maternal and child care. Logistic regression, considering the complex survey design and sample weights generated by that design, was used to estimate trends using survey rounds 2-5 for the first phase in the eight focus districts and rounds 6-9 for the second phase in all 38 districts statewide, as well as the overall change from round 2-9 in focus districts. To aid in contextualising the results, indicators were also compared amongst the formerly focus and the non-focus districts at the beginning of the second phase.ResultsIn the first phase, the levels of 34 out of 52 indicators increased significantly in the focus districts, including almost all indicators of FLW performance in antenatal and postnatal care, along with mother's birth preparedness, some breastfeeding practices, and immunisations. Between the two phases, 33 of 52 indicators declined significantly. In the second phase, the formerly focus districts experienced a rise in the levels of 14 of 50 indicators and a decline in the levels of 14 other indicators. There was a rise in the levels of 22 out of 50 indicators in the non-focus districts in the second phase, with a decline in the levels of 13 other indicators.ConclusionsImprovements in indicators were conditional on implementation support to program activities at a level of intensity that was higher than what could be achieved at scale so far. Successes during the pilot phase of intensive support suggests that RMNCHN can be improved statewide in Bihar with sufficient investments in systems performance improvements.Study registrationClinicalTrials.gov number NCT02726230.

Whether requiring Graduate Record Examinations (GRE) results for doctoral applicants affects the diversity of admitted cohorts remains uncertain. This study randomized applications to 2 population-health doctoral programs at the University of California San Francisco to assess whether masking reviewers to applicant GRE results differentially affects reviewers' scores for underrepresented minority (URM) applicants from 2018-2020. Applications with GRE results and those without were randomly assigned to reviewers to designate scores for each copy (1-10, 1 being best). URM was defined as self-identification as African American/Black, Filipino, Hmong, Vietnamese, Hispanic/Latinx, Native American/Alaska Native, or Native Hawaiian/Other Pacific Islander. We used linear mixed models with random effects for the applicant and fixed effects for each reviewer to evaluate the effect of masking the GRE results on the overall application score and whether this effect differed by URM status. Reviewer scores did not significantly differ for unmasked versus masked applications among non-URM applicants (β = 0.15; 95% CI: -0.03, 0.33) or URM applicants (β = 0.02, 95% CI: -0.49, 0.54). We did not find evidence that removing GREs differentially affected URM compared with non-URM students (β for interaction = -0.13, 95% CI: -0.55, 0.29). Within these doctoral programs, results indicate that GRE scores neither harm nor help URM applicants.

Comprehensive modeling of a whole cell requires an integration of vast amounts of information on various aspects of the cell and its parts. To divide and conquer this task, we introduce Bayesian metamodeling, a general approach to modeling complex systems by integrating a collection of heterogeneous input models. Each input model can in principle be based on any type of data and can describe a different aspect of the modeled system using any mathematical representation, scale, and level of granularity. These input models are 1) converted to a standardized statistical representation relying on probabilistic graphical models, 2) coupled by modeling their mutual relations with the physical world, and 3) finally harmonized with respect to each other. To illustrate Bayesian metamodeling, we provide a proof-of-principle metamodel of glucose-stimulated insulin secretion by human pancreatic β-cells. The input models include a coarse-grained spatiotemporal simulation of insulin vesicle trafficking, docking, and exocytosis; a molecular network model of glucose-stimulated insulin secretion signaling; a network model of insulin metabolism; a structural model of glucagon-like peptide-1 receptor activation; a linear model of a pancreatic cell population; and ordinary differential equations for systemic postprandial insulin response. Metamodeling benefits from decentralized computing, while often producing a more accurate, precise, and complete model that contextualizes input models as well as resolves conflicting information. We anticipate Bayesian metamodeling will facilitate collaborative science by providing a framework for sharing expertise, resources, data, and models, as exemplified by the Pancreatic β-Cell Consortium.

IntroductionEconomic groups, such as microfinance or self-help groups are widely implemented in low-income and middle-income countries (LMICs). Women's groups are voluntary groups, which aim to improve the well-being of members through activities, such as joint savings, credit, livelihoods development and/or health activities. Health interventions are increasingly added on to existing women's economic groups as a public health intervention for women and their families. Here, we present the protocol for a mixed-methods systematic review we will conduct of the evidence on integrated economic and health interventions on women's groups to assess whether and how they improve health-related knowledge, behaviour and outcomes in LMICs.Methods and analysisWe will search seven electronic databases for published literature, along with manual searches and consultation. The review will include (1) randomised trials and non-randomised quasiexperimental studies of intervention effects of integrated economic and health interventions delivered through women's groups in LMICs, and (2) sibling studies that examine factors related to intervention content, context, implementation processes and costs. We will appraise risk of bias and study quality using standard tools. High and moderate quality studies will be grouped by health domain and synthesised without meta-analysis. Qualitative evidence will be thematically synthesised and integrated into the quantitative synthesis using a matrix approach.Ethics and disseminationThis protocol was reviewed and deemed exempt by the institutional review board at the American Institutes for Research. Findings will be shared through peer-reviewed publication and disseminated with programme implementers and policymakers engaged with women's groups.Prospero registration numberCRD42020199998.

BackgroundThe literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited.ObjectivesTo complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR).MethodsTwo-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions.ResultsNominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of β-carotene, calcium, copper, folate, magnesium, phosphorus, and vitamin B-6 were not associated with disease risk.ConclusionsThese results suggest possible causal associations of circulating iron and vitamin B-12 (positively) and selenium (inversely) with risk of colon cancer.

BackgroundStudies suggest lower risk of breast cancer in women with HIV versus without HIV. These estimates may be biased by lower life expectancy and younger age distribution of women with HIV. Our analysis evaluated this bias and characterized secular trends in breast cancer among women with HIV initiating antiretroviral therapy. We hypothesized breast cancer risk would increase over time as mortality decreased.SettingWomen with HIV prescribed antiretroviral therapy in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) from 1997 through 2016.MethodsWe estimated breast cancer hazard (cause-specific hazard ratios) and cumulative incidence accounting for competing risks (subdistribution hazard ratios) to assess changes in breast cancer risk over time. This was assessed overall (1997-2016) and within/across calendar periods. Analyses were adjusted for race/ethnicity and inverse probability weighted for cohort. Cumulative incidence was graphically assessed by calendar period and race/ethnicity.ResultsWe observed 11,587 women during 1997-2016, contributing 63 incident breast cancer diagnoses and 1,353 deaths [73,445 person-years (median follow-up = 4.5 years)]. Breast cancer cumulative incidence was 3.2% for 1997-2016. We observed no secular trends in breast cancer hazard or cumulative incidence. There were annual declines in the hazard and cumulative incidence of death (cause-specific hazard ratios and subdistribution hazard ratios: 0.89, 95% confidence interval: 0.87 to 0.91) which remained within and across calendar periods.ConclusionsThese findings contradict the hypothesis of increasing breast cancer risk with declining mortality over time among women with HIV, suggesting limited impact of changing mortality on breast cancer risk. Additional inquiry is merited as survival improves among women with HIV.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.

BackgroundSocial innovations in health are inclusive solutions to address the healthcare delivery gap that meet the needs of end users through a multi-stakeholder, community-engaged process. While social innovations for health have shown promise in closing the healthcare delivery gap, more research is needed to evaluate, scale up, and sustain social innovation. Research checklists can standardize and improve reporting of research findings, promote transparency, and increase replicability of study results and findings.Methods and findingsThe research checklist was developed through a 3-step community-engaged process, including a global open call for ideas, a scoping review, and a 3-round modified Delphi process. The call for entries solicited checklists and related items and was open between November 27, 2019 and February 1, 2020. In addition to the open call submissions and scoping review findings, a 17-item Social Innovation For Health Research (SIFHR) Checklist was developed based on the Template for Intervention Description and Replication (TIDieR) Checklist. The checklist was then refined during 3 rounds of Delphi surveys conducted between May and June 2020. The resulting checklist will facilitate more complete and transparent reporting, increase end-user engagement, and help assess social innovation projects. A limitation of the open call was requiring internet access, which likely discouraged participation of some subgroups.ConclusionsThe SIFHR Checklist will strengthen the reporting of social innovation for health research studies. More research is needed on social innovation for health.

In 2010, the Bill and Melinda Gates Foundation (BMGF) partnered with the Government of Bihar (GoB), India to launch the Ananya program to improve reproductive, maternal, newborn and child health and nutrition (RMNCHN) outcomes. The program sought to address supply- and demand-side barriers to the adoption, coverage, quality, equity and health impact of select RMNCHN interventions. Approaches included strengthening frontline worker service delivery; social and behavior change communications; layering of health, nutrition and sanitation into women's self-help groups (SHGs); and quality improvement in maternal and newborn care at primary health care facilities. Ananya program interventions were piloted in approximately 28 million population in eight innovation districts from 2011-2013, and then beginning in 2014, were scaled up by the GoB across the rest of the state's population of 104 million. A Bihar Technical Support Program provided techno-managerial support to governmental Health as well as Integrated Child Development Services, and the JEEViKA Technical Support Program supported health layering and scale-up of the GoB's SHG program. The level of support at the block level during statewide scale-up in 2014 onwards was approximately one-fourth that provided in the pilot phase of Ananya in 2011-2013. This paper - the first manuscript in an 11-manuscript and 2-viewpoint collection on Learning from Ananya: Lessons for primary health care performance improvement - seeks to provide a broad description of Ananya and subsequent statewide adaptation and scale-up, and capture the background and context, key objectives, interventions, delivery approaches and evaluation methods of this expansive program. Subsequent papers in this collection focus on specific intervention delivery platforms. For the analyses in this series, Stanford University held key informant interviews and worked with the technical support and evaluation grantees of the Ananya program, as well as leadership from the India Country Office of the BMGF, to analyse and synthesise data from multiple sources. Capturing lessons from the Ananya pilot program and statewide scale-up will assist program managers and policymakers to more effectively design and implement RMNCHN programs at scale through technical assistance to governments.

BackgroundThe objective of this study was to assess the impact of self-help groups (SHGs) and subsequent scale-up on reproductive, maternal, newborn, child health, and nutrition (RMNCHN) and sanitation outcomes among marginalised women in Bihar, India from 2014-2017.MethodsWe examined RMNCHN and sanitation behaviors in women who were members of any SHGs compared to non-members, without differentiating between types of SHGs. We analysed annual surveys across 38 districts of Bihar covering 62 690 women who had a live birth in the past 12 months. All analyses utilised data from Community-based Household Surveys (CHS) rounds 6-9 collected in 2014-2017 by CARE India as part of the Bihar Technical Support Program funded by the Bill & Melinda Gates Foundation. We examined 66 RMNCHN and sanitation indicators using survey logistic regression; the comparison group in all cases was age-comparable women from the geographic contexts of the SHG members but who did not belong to SHGs. We also examined links between discussion topics in SHGs and changes in relevant behaviours, and stratification of effects by parity and mother's age.ResultsSHG members had higher odds compared to non-SHG members for 60% of antenatal care indicators, 22% of delivery indicators, 70% of postnatal care indicators, 50% of nutrition indicators, 100% of family planning and sanitation indicators and no immunisation indicators measured. According to delivery platform, most FLW performance indicators (80%) had increased odds, followed by maternal behaviours (57%) and facility care and outreach service delivery (22%) compared to non-SHG members. Self-report of discussions within SHGs on specific topics was associated with increased related maternal behaviours. Younger SHG members (

BackgroundSelf-help group (SHG) interventions have been widely studied in low and middle income countries. However, there is little data on specific impacts of health layering, or adding health education modules upon existing SHGs which were formed primarily for economic empowerment. We examined three SHG interventions from 2012-2017 in Bihar, India to test the hypothesis that health-layering of SHGs would lead to improved health-related behaviours of women in SHGs.MethodsA model for health layering of SHGs - Parivartan - was developed by the non-governmental organisation (NGO), Project Concern International, in 64 blocks of eight districts. Layering included health modules, community events and review mechanisms. The health layering model was adapted for use with government-led SHGs, called JEEViKA+HL, in 37 other blocks of Bihar. Scale-up of government-led SHGs without health layering (JEEViKA) occurred contemporaneously in 433 other blocks, providing a natural comparison group. Using Community-based Household Surveys (CHS, rounds 6-9) by CARE India, 62 reproductive, maternal, newborn and child health and nutrition (RMNCHN) and sanitation indicators were examined for SHGs with health layering (Pavivartan SHGs and JEEViKA+HL SHGs) compared to those without. We calculated mean, standard deviation and odds ratios of indicators using surveymeans and survey logistic regression.ResultsIn 2014, 64% of indicators were significantly higher in Parivartan members compared to non-members residing in the same blocks. During scale up, from 2015-17, half (50%) of indicators had significantly higher odds in health layered SHG members (Parivartan or JEEViKA+HL) in 101 blocks compared to SHG members without health layering (JEEViKA) in 433 blocks.ConclusionsHealth layering of SHGs was demonstrated by an NGO-led model (Parivartan), adapted and scaled up by a government model (JEEViKA+HL), and associated with significant improvements in health compared to non-health-layered SHGs (JEEViKA). These results strengthen the evidence base for further layering of health onto the SHG platform for scale-level health change.Study registrationClinicalTrials.gov number NCT02726230.

BackgroundGeographical variations in the levels and trajectory of health indicators at local level can inform the adaptation of interventions and development of targeted approaches for efficient scale-up of intervention impact. We examined the hypothesis that time trends of a set of reproductive, maternal, newborn, and child health and nutrition (RMNCHN) indicators varied at block-level during the statewide scale-up phase of the Ananya program in Bihar, India.MethodsWe used data on 22 selected indicators from four rounds of the Community-based Household Survey carried out between 2014 and 2017. Indicator levels at each round were estimated for each block. We used hierarchical Bayesian spatiotemporal modelling to smooth the raw estimates for each block with the estimates from its neighbouring blocks, and to examine space-time interaction models for evidence of variations in trends of indicators across blocks. We expressed the uncertainty around the smoothed levels and the trends with 95% credible intervals.ResultsThere was evidence of variations in trends at block level in all but three indicators: facility delivery, public facility delivery, and age-appropriate initiation of complementary feeding. Fifteen indicators showed trends in opposite directions (increases in some blocks and declines in others). All blocks had at least 97.5% probability of a rise in immediate breastfeeding, early pregnancy registration, and having at least four antenatal care visits. All blocks had at least 97.5% probability of a decline in seeking care for pregnancy complications.ConclusionsThe findings underscore the value of monitoring and evaluation at local level for targeted implementation of RMNCHN interventions. There is a need for identifying systematic factors leading to universal trends, or variable contextual or implementation factors leading to variable trends, in order to optimise primary health care program impact.Study registrationClinicalTrials.gov number NCT02726230.

BackgroundDespite increasing focus on health inequities in low- and middle income countries, significant disparities persist. We analysed impacts of a statewide maternal and child health program among the most compared to the least marginalised women in Bihar, India.MethodsUtilising survey-weighted logistic regression, we estimated programmatic impact using difference-in-difference estimators from Mathematica data collected at the beginning (2012, n = 10 174) and after two years of program implementation (2014, n = 9611). We also examined changes in disparities over time using eight rounds of Community-based Household Surveys (CHS) (2012-2017, n = 48 349) collected by CARE India.ResultsAt baseline for the Mathematica data, least marginalised women generally performed desired health-related behaviours more frequently than the most marginalised. After two years, most disparities persisted. Disparities increased for skilled birth attendant identification [+16.2% (most marginalised) vs +32.6% (least marginalized), P

BackgroundMobile health (mHealth) tools have potential for improving the reach and quality of health information and services through community health workers in low- and middle-income countries. This study evaluates the impact of an mHealth tool implemented at scale as part of the statewide reproductive,maternal, newborn and child health and nutrition (RMNCHN) program in Bihar, India.MethodsThree survey-based data sets were analysed to compare the health-related knowledge, attitudes and behaviours amongst childbearing women exposed to the Mobile Kunji and Dr. Anita mHealth tools during their visits with frontline workers compared with those who were unexposed.ResultsAn evaluation by Mathematica (2014) revealed that exposure to Mobile Kunji and Dr. Anita recordings were associated with significantly higher odds of consuming iron-folic acid tablets (odds ratio (OR) = 2.3, 95% confidence interval (CI) = 1.8-3.1) as well as taking a set of three measures for delivery preparedness (OR = 2.8, 95% CI = 1.9-4.2) and appropriate infant complementary feeding (OR = 1.9, 95% CI = 1.0-3.5). CARE India's Community-based Household Surveys (2012-2017) demonstrated significant improvements in early breastfeeding (OR = 1.64, 95% CI = 1.5-1.78) and exclusive breastfeeding (OR = 1.46, 95% CI = 1.33-1.62) in addition to birth preparedness practices. BBC Media Action's Usage & Engagement Survey (2014) demonstrated a positive association between exposure to Mobile Kunji and Dr. Anita and exclusive breastfeeding (58% exposed vs 43% unexposed, P

BackgroundThe Government of Bihar (GoB) in India, the Bill and Melinda Gates Foundation and several non-governmental organisations launched the Ananya program aimed to support the GoB to improve reproductive, maternal, newborn and child health and nutrition (RMNCHN) statewide. Here we summarise changes in indicators attained during the initial two-year pilot phase (2012-2013) of implementation in eight focus districts of approximately 28 million population, aimed to inform subsequent scale-up.MethodsThe quasi-experimental impact evaluation included statewide household surveys at two time points during the pilot phase: January-April 2012 ("baseline") including an initial cohort of beneficiaries and January-April 2014 ("midline") with a new cohort. The two arms were: 1) eight intervention districts, and 2) a comparison arm comprised of the remaining 30 districts in Bihar where Ananya interventions were not implemented. We analysed changes in indicators across the RMNCHN continuum of care from baseline to midline in intervention and comparison districts using a difference-in-difference analysis.ResultsIndicators in the two arms were similar at baseline. Overall, 40% of indicators (20 of 51) changed significantly from baseline to midline in the comparison districts unrelated to Ananya; two-thirds (n = 13) of secular indicator changes were in a direction expected to promote health. Statistically significant impact attributable to the Ananya program was found for 10% (five of 51) of RMNCHN indicators. Positive impacts were most prominent for mother's behaviours in contraceptive utilisation.ConclusionsThe Ananya program had limited impact in improving health-related outcomes during the first two-year period covered by this evaluation. The program's theories of change and action were not powered to observe statistically significant differences in RMNCHN indicators within two years, but rather aimed to help inform program improvements and scale-up. Evaluation of large-scale programs such as Ananya using theory-informed, equity-sensitive (including gender), mixed-methods approaches can help elucidate causality and better explain pathways through which supply- and demand-side interventions contribute to changes in behaviour among the actors involved in the production of population-level health outcomes. Evidence from Bihar indicates that deep structural constraints in health system organisation and delivery of interventions pose substantial limitations on behaviour change among health care providers and beneficiaries.Study registrationClinicalTrials.gov number NCT02726230.

A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption1,2. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein-protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.

BACKGROUND: mHealth technology holds promise for improving the effectiveness of frontline health workers (FLWs), who provide most health-related primary care services, especially reproductive, maternal, newborn, child health and nutrition services (RMNCHN), in low-resource - especially hard-to-reach - settings. Data are lacking, however, from rigorous evaluations of mHealth interventions on delivery of health services or on health-related behaviors and outcomes. METHODS: The Information Communication Technology-Continuum of Care Service (ICT-CCS) tool was designed for use by community-based FLWs to increase the coverage, quality and coordination of services they provide in Bihar, India. It consisted of numerous mobile phone-based job aids aimed to improve key RMNCHN-related behaviors and outcomes. ICT-CCS was implemented in Saharsa district, with cluster randomization at the health sub-center level. In total, evaluation surveys were conducted with approximately 1100 FLWs and 3000 beneficiaries who had delivered an infant in the previous year in the catchment areas of intervention and control health sub-centers, about half before implementation (mid-2012) and half two years afterward (mid-2014). Analyses included bivariate and difference-in-difference analyses across study groups. RESULTS: The ICT-CCS intervention was associated with more frequent coordination of AWWs with ASHAs on home visits and greater job confidence among ASHAs. The intervention resulted in an 11 percentage point increase in FLW antenatal home visits during the third trimester (P = 0.04). In the post-implementation period, postnatal home visits during the first week were increased in the intervention (72%) vs the control (60%) group (P

PurposeParkinson's disease (PD) patients and their caregivers experience significant distress that impacts physical, emotional and social functioning in the patient, and in turn, has a significant impact on the caregiver. Lower levels of stress have been associated with a better prognosis in PD. The quality of dispositional mindfulness-innate present moment, non-judgmental awareness-has consistently been associated with less perceived stress, greater well-being, and better physical health in both clinical and healthy populations. To date, associations of mindfulness with distress, depression, sleep problems, and other variables that define health-related quality of life have not been examined in the context of PD patient/caregiver dyads.MethodsWe investigated the impact of dispositional mindfulness in a stress-health model among eighteen dyads consisting of PD patients and their caregivers.ResultsMultilevel linear modeling (actor-partner interdependence models) revealed significant associations between dispositional mindfulness and stress appraisal, interpersonal support, depressive symptoms, sleep, and health-related quality of life (HRQOL) within both dyadic partners. As expected, results demonstrated significant associations of distress with interpersonal support, depressive symptoms, sleep and HRQOL for both PD patients and caregivers.ConclusionsDispositional mindfulness was associated with reduced distress and its downstream clinical consequences. These results support an ameliorative role for dispositional mindfulness among PD patients and caregivers, as a protective factor against psychosocial burdens imposed on couples related to disease and caregiving. Findings suggest future studies should explore mindfulness training as a therapeutic option.

BACKGROUND:Aspirin use is associated with reduced risk of several cancers. A pooled analysis of 12 case-control studies showed a 10% decrease in ovarian cancer risk with regular aspirin use, which was stronger for daily and low-dose users. To prospectively investigate associations of analgesic use with ovarian cancer, we analyzed data from 13 studies in the Ovarian Cancer Cohort Consortium (OC3). METHODS:The current study included 758 829 women who at study enrollment self-reported analgesic use, among whom 3514 developed ovarian cancer. Using Cox regression, we assessed associations between frequent medication use and risk of ovarian cancer. Dose and duration were also evaluated. All statistical tests were two-sided. RESULTS:Women who used aspirin almost daily (≥6 days/wk) vs infrequent/nonuse experienced a 10% reduction in ovarian cancer risk (rate ratio [RR] = 0.90, 95% confidence interval [CI] = 0.82 to 1.00, P = .05). Frequent use (≥4 days/wk) of aspirin (RR = 0.95, 95% CI = 0.88 to 1.03), nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs; RR = 1.00, 95% CI = 0.90 to 1.11), or acetaminophen (RR = 1.05, 95% CI = 0.88 to 1.24) was not associated with risk. Daily acetaminophen use (RR = 1.28, 95% CI = 1.00 to 1.65, P = .05) was associated with elevated ovarian cancer risk. Risk estimates for frequent, long-term (10+ years) use of aspirin (RR = 1.15, 95% CI = 0.98 to 1.34) or nonaspirin NSAIDs (RR = 1.19, 95% CI = 0.84 to 1.68) were modestly elevated, although not statistically significantly so. CONCLUSIONS:This large, prospective analysis suggests that women who use aspirin daily have a slightly lower risk of developing ovarian cancer (∼10% lower than infrequent/nonuse)-similar to the risk reduction observed in case-control analyses. The observed potential elevated risks for 10+ years of frequent aspirin and NSAID use require further study but could be due to confounding by medical indications for use or variation in drug dosing.

Childhood obesity is increasing especially in Latinos and early intervention is essential to prevent later obesity complications. Latino children (n = 201) recruited at two San Francisco hospitals were assessed at birth including infant anthropometrics and feeding practices and followed to age 9 with annual anthropometric assessments. We evaluated the relationship between perinatal risk factors and obesity at age 9 and chronic obesity (obesity at both 5 and 9 years). Higher birthweight [odds ratio (OR) 2.48, 95% confidence interval (CI) 1.06-5.81] and maternal pre-pregnancy body mass index (BMI) (OR 1.09, 95% CI 1.00-1.18) were associated with increased risk for obesity at 9 years. Higher maternal pre-pregnancy BMI (OR 1.10, 95% CI 1.01-1.20) was associated with chronic obesity. Additionally, prenatal depression symptoms were protective (OR 0.33, 95% CI 0.11-0.94) against chronic obesity. We found no association between maternal age and education, exclusive breastfeeding at 4-6 weeks, rapid infant weight gain, and obesity or chronic obesity. Perinatal risk factors for obesity including higher birthweight and maternal pre-pregnancy BMI persisted until age 9, whereas, other variables significant at age 5 in our cohort and other populations including exclusive breastfeeding and rapid infant weight gain were no longer associated with increased risk.

Previous prospective studies assessing the relationship between circulating concentrations of vitamin D and prostate cancer risk have shown inconclusive results, particularly for risk of aggressive disease. In this study, we examine the association between prediagnostic concentrations of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] and the risk of prostate cancer overall and by tumor characteristics. Principal investigators of 19 prospective studies provided individual participant data on circulating 25(OH)D and 1,25(OH)2D for up to 13,462 men with incident prostate cancer and 20,261 control participants. ORs for prostate cancer by study-specific fifths of season-standardized vitamin D concentration were estimated using multivariable-adjusted conditional logistic regression. 25(OH)D concentration was positively associated with risk for total prostate cancer (multivariable-adjusted OR comparing highest vs. lowest study-specific fifth was 1.22; 95% confidence interval, 1.13-1.31; P trend < 0.001). However, this association varied by disease aggressiveness (P heterogeneity = 0.014); higher circulating 25(OH)D was associated with a higher risk of nonaggressive disease (OR per 80 percentile increase = 1.24, 1.13-1.36) but not with aggressive disease (defined as stage 4, metastases, or prostate cancer death, 0.95, 0.78-1.15). 1,25(OH)2D concentration was not associated with risk for prostate cancer overall or by tumor characteristics. The absence of an association of vitamin D with aggressive disease does not support the hypothesis that vitamin D deficiency increases prostate cancer risk. Rather, the association of high circulating 25(OH)D concentration with a higher risk of nonaggressive prostate cancer may be influenced by detection bias. SIGNIFICANCE: This international collaboration comprises the largest prospective study on blood vitamin D and prostate cancer risk and shows no association with aggressive disease but some evidence of a higher risk of nonaggressive disease.

BackgroundIn acute kidney injury (AKI), medication dosing based on Cockcroft-Gault creatinine clearance (CrCl) or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rates (eGFR) are not valid when serum creatinine (SCr) is not in steady state. The aim of this study was to determine the impact of a kinetic estimating equation that incorporates fluctuations in SCrs on drug dosing in critically ill patients.MethodsWe used data from participants enrolled in the NIH Acute Respiratory Distress Syndrome Network Fluid and Catheters Treatment Trial to simulate drug dosing category changes with the application of the kinetic estimating equation developed by Chen. We evaluated whether kinetic estimation of renal function would change medication dosing categories (≥60, 30-59, 15-29, and

BackgroundDementia has a huge physical, psychological, social and economic impact upon caregivers, families and societies at large. There has been a growing impetus to utilize Internet interventions given the potential scalability, and presumed cost-effectiveness and accessibility. In this paper, we describe the design of a randomized controlled trial (RCT) aiming to study the impact of online self-help programs on caregivers of people with dementia in India. The experimental group will receive an interactive training and support program and the comparison group will receive an education-only e-book. It will be among the first online support intervention RCTs for a mental health condition in a lower-middle income country.Methods and designTwo hundred and eight participants are expected to be recruited via several strategies (email, Internet and social media, telephone and face-to-face) starting in the Bangalore region of India. The inclusion criteria for participation in the trial are: (1) being 18 years or older, (2) being a self-reported caregiver of a person with dementia, (3) self-report that a family member has a diagnosis of dementia (AD8 ≥ 2), and experience caregiver distress (≥ 4 on a 1-item burden scale ranging from 1 to 10 or ≥ 4 or

BackgroundLate-onset Pompe disease is a rare genetic neuromuscular disorder caused by lysosomal acid alpha-glucosidase (GAA) deficiency that ultimately results in mobility loss and respiratory failure. Current enzyme replacement therapy with recombinant human (rh)GAA has demonstrated efficacy in subjects with late-onset Pompe disease. However, long-term effects of rhGAA on pulmonary function have not been observed, likely related to inefficient delivery of rhGAA to skeletal muscle lysosomes and associated deficits in the central nervous system. To address this limitation, reveglucosidase alfa, a novel insulin-like growth factor 2 (IGF2)-tagged GAA analogue with improved lysosomal uptake, was developed. This study evaluated the pharmacokinetics, safety, and exploratory efficacy of reveglucosidase alfa in 22 subjects with late-onset Pompe disease who were previously untreated with rhGAA.ResultsReveglucosidase alfa plasma concentrations increased linearly with dose, and the elimination half-life was

ObjectiveThe objective of the study is was investigate the association between hearing impairment and anxiety.MethodWe conducted a cross-sectional analysis of 1,732 community-based adults aged 76 to 85 years who participated in the Health Aging and Body Composition (ABC) study. Logistic regression models were adjusted for demographic and cardiovascular risk factors. Hearing impairment was defined by the speech-frequency pure tone average. Anxiety was defined as reporting two symptoms of at least "a little" or one symptom "quite a bit" on the three-item Hopkins Symptom Checklist.ResultsCompared with individuals with no hearing impairment, the odds of prevalent anxiety were higher among individuals with mild hearing impairment (odds ratio [OR] = 1.32, 95% confidence interval [CI] = [1.01, 1.73]) and moderate or greater hearing impairment (OR = 1.59, 95% CI = [1.14, 2.22]). Hearing aid use was not significantly associated with lower odds of anxiety.DiscussionHearing impairment is independently associated with greater odds of anxiety symptoms in older adults.

ObjectivesTo better understand the potential impact of hearing impairment (HI) and hearing aid use on emotional vitality and mental health in older adults.MethodWe investigated the cross-sectional association of HI with emotional vitality in 1,903 adults aged 76-85 years in the Health ABC study adjusted for demographic and cardiovascular risk factors. Hearing was defined by the speech frequency pure tone average (no impairment < 25 dB, mild impairment 25-40 dB, and moderate or greater impairment > 40 dB). Emotional vitality was defined as having a high sense of personal mastery, happiness, low depressive symptomatology, and low anxiety.ResultsCompared with individuals with no HI, participants with moderate or greater HI had a 23% lower odds of emotional vitality (odds ratio [OR] = 0.77; 95% confidence interval [CI]: 0.59-0.99). Hearing aid use was not associated with better emotional vitality (OR = 0.98; 95% CI: 0.81-1.20).DiscussionHI is associated with lower odds of emotional vitality in older adults. Further studies are needed to examine the longitudinal impact of HI on mental health and well-being.

PurposeOutcomes for early-stage breast cancer have improved. First-generation adjuvant chemotherapy trials reported a 0.27% 8-year cumulative incidence of myelodysplastic syndrome/acute myelogenous leukemia. Incomplete ascertainment and follow-up may have underestimated subsequent risk of treatment-associated marrow neoplasm (MN).Patients and methodsWe examined the MN frequency in 20,063 patients with stage I to III breast cancer treated at US academic centers between 1998 and 2007. Time-to-event analyses were censored at first date of new cancer event, last contact date, or death and considered competing risks. Cumulative incidence, hazard ratios (HRs), and comparisons with Surveillance, Epidemiology, and End Results estimates were obtained. Marrow cytogenetics data were reviewed.ResultsFifty patients developed MN (myeloid, n = 42; lymphoid, n = 8) after breast cancer (median follow-up, 5.1 years). Patients who developed MN had similar breast cancer stage distribution, race, and chemotherapy exposure but were older compared with patients who did not develop MN (median age, 59.1 v 53.9 years, respectively; P = .03). Two thirds of patients had complex MN cytogenetics. Risk of MN was significantly increased after surgery plus chemotherapy (HR, 6.8; 95% CI, 1.3 to 36.1) or after all modalities (surgery, chemotherapy, and radiation; HR, 7.6; 95% CI, 1.6 to 35.8), compared with no treatment with chemotherapy. MN rates per 1,000 person-years were 0.16 (surgery), 0.43 (plus radiation), 0.46 (plus chemotherapy), and 0.54 (all three modalities). Cumulative incidence of MN doubled between years 5 and 10 (0.24% to 0.48%); 9% of patients were alive at 10 years.ConclusionIn this large early-stage breast cancer cohort, MN risk after radiation and/or adjuvant chemotherapy was low but higher than previously described. Risk continued to increase beyond 5 years. Individual risk of MN must be balanced against the absolute survival benefit of adjuvant chemotherapy.

We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74-0.84, P = 3.0 × 10(-12)), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30-1.65, P = 1.1 × 10(-10)), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10-1.20, P = 2.4 × 10(-9)) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12-1.25, P = 1.2 × 10(-8)). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76-0.85, P = 9.8 × 10(-14)). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 × 10(-7)) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies.

BackgroundThe prevalence of class III obesity (body mass index [BMI]≥40 kg/m2) has increased dramatically in several countries and currently affects 6% of adults in the US, with uncertain impact on the risks of illness and death. Using data from a large pooled study, we evaluated the risk of death, overall and due to a wide range of causes, and years of life expectancy lost associated with class III obesity.Methods and findingsIn a pooled analysis of 20 prospective studies from the United States, Sweden, and Australia, we estimated sex- and age-adjusted total and cause-specific mortality rates (deaths per 100,000 persons per year) and multivariable-adjusted hazard ratios for adults, aged 19-83 y at baseline, classified as obese class III (BMI 40.0-59.9 kg/m2) compared with those classified as normal weight (BMI 18.5-24.9 kg/m2). Participants reporting ever smoking cigarettes or a history of chronic disease (heart disease, cancer, stroke, or emphysema) on baseline questionnaires were excluded. Among 9,564 class III obesity participants, mortality rates were 856.0 in men and 663.0 in women during the study period (1976-2009). Among 304,011 normal-weight participants, rates were 346.7 and 280.5 in men and women, respectively. Deaths from heart disease contributed largely to the excess rates in the class III obesity group (rate differences = 238.9 and 132.8 in men and women, respectively), followed by deaths from cancer (rate differences = 36.7 and 62.3 in men and women, respectively) and diabetes (rate differences = 51.2 and 29.2 in men and women, respectively). Within the class III obesity range, multivariable-adjusted hazard ratios for total deaths and deaths due to heart disease, cancer, diabetes, nephritis/nephrotic syndrome/nephrosis, chronic lower respiratory disease, and influenza/pneumonia increased with increasing BMI. Compared with normal-weight BMI, a BMI of 40-44.9, 45-49.9, 50-54.9, and 55-59.9 kg/m2 was associated with an estimated 6.5 (95% CI: 5.7-7.3), 8.9 (95% CI: 7.4-10.4), 9.8 (95% CI: 7.4-12.2), and 13.7 (95% CI: 10.5-16.9) y of life lost. A limitation was that BMI was mainly ascertained by self-report.ConclusionsClass III obesity is associated with substantially elevated rates of total mortality, with most of the excess deaths due to heart disease, cancer, and diabetes, and major reductions in life expectancy compared with normal weight. Please see later in the article for the Editors' Summary.

ObjectivesOff-label medication use for treating cognitive impairments and neuropsychiatric symptoms occurs in frontotemporal dementia (FTD) and Alzheimer disease (AD). We compared the use of cognitive and psychiatric medications in FTD and AD and evaluated the relationship between neuropsychiatric symptoms and medication use.MethodsCognitive and psychiatric medication use, demographic variables, and Neuropsychiatric Inventory (NPI) subscale symptoms were obtained from the National Alzheimer's Coordinating Center Uniform Data Set (n=3958, 8.1% FTD). Bivariate statistics and logistic regressions were calculated to evaluate which demographic or NPI subscale symptoms predicted medication use.ResultsAlthough cognitive medication was used more commonly in AD (78%), it was also commonly used off-label in FTD (56%). Psychiatric medications were in greater use in FTD than in AD (68% vs. 45%, respectively, P