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Human inborn errors of thymic T cell tolerance underlie the production of autoantibodies (auto-Abs) neutralizing type I IFNs, which predispose to severe viral diseases. We analyze 131 female patients with X-linked dominant incontinentia pigmenti (IP), heterozygous for loss-of-function (LOF) NEMO variants, from 99 kindreds in 10 countries. Forty-seven of these patients (36%) have auto-Abs neutralizing IFN-α and/or IFN-ω, a proportion 23 times higher than that for age-matched female controls. This proportion remains stable from the age of 6 years onward. On imaging, female patients with IP have a small, abnormally structured thymus. Auto-Abs against type I IFNs confer a predisposition to life-threatening viral diseases. By contrast, patients with IP lacking auto-Abs against type I IFNs are at no particular risk of viral disease. These results suggest that IP accelerates thymic involution, thereby underlying the production of auto-Abs neutralizing type I IFNs in at least a third of female patients with IP, predisposing them to life-threatening viral diseases.

Worldwide trends to delay childbearing have increased parental ages at birth. Older parental age may harm offspring health, but mechanisms remain unclear. Alterations in offspring DNA methylation (DNAm) patterns could play a role as aging has been associated with methylation changes in gametes of older individuals. We meta-analyzed epigenome-wide associations of parental age with offspring blood DNAm of over 9500 newborns and 2000 children (5-10 years old) from the Pregnancy and Childhood Epigenetics consortium. In newborns, we identified 33 CpG sites in 13 loci with DNAm associated with maternal age (PFDR

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

BACKGROUNDWeakly virulent environmental mycobacteria (EM) can cause severe disease in HLA-DRB1*15:02 or 16:02 adults harboring neutralizing anti-IFN-γ autoantibodies (nAIGAs). The overall prevalence of nAIGAs in the general population is unknown, as are the penetrance of nAIGAs in HLA-DRB1*15:02 or 16:02 individuals and the proportion of patients with unexplained, adult-onset EM infections carrying nAIGAs.METHODSThis study analyzed the detection and neutralization of anti-IFN-γ autoantibodies (auto-Abs) from 8,430 healthy individuals of the general population, 257 HLA-DRB1*15:02 or 16:02 carriers, 1,063 patients with autoimmune disease, and 497 patients with unexplained severe disease due to EM.RESULTSWe found that anti-IFN-γ auto-Abs detected in 4,148 of 8,430 healthy individuals (49.2%) from the general population of an unknown HLA-DRB1 genotype were not neutralizing. Moreover, we did not find nAIGAs in 257 individuals carrying HLA-DRB1* 15:02 or 16:02. Additionally, nAIGAs were absent in 1,063 patients with an autoimmune disease. Finally, 7 of 497 patients (1.4%) with unexplained severe disease due to EM harbored nAIGAs.CONCLUSIONThese findings suggest that nAIGAs are isolated and that their penetrance in HLA-DRB1*15:02 or 16:02 individuals is low, implying that they may be triggered by rare germline or somatic variants. In contrast, the risk of mycobacterial disease in patients with nAIGAs is high, confirming that these nAIGAs are the cause of EM disease.FUNDINGThe Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI095983 and U19AIN1625568), the National Center for Advancing Translational Sciences (NCATS), the NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866), the French National Research Agency (ANR) under the Investments for the Future program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), ANR-GENMSMD (ANR-16-CE17-0005-01), ANR-MAFMACRO (ANR-22-CE92-0008), ANRSECTZ170784, the French Foundation for Medical Research (FRM) (EQU201903007798), the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003), and ANR AI2D (ANR-22-CE15-0046) projects, the ANR-RHU program (ANR-21-RHUS-08-COVIFERON), the European Unions Horizon 2020 research and innovation program under grant agreement no. 824110 (EASI-genomics), the Square Foundation, Grandir - Fonds de solidarité pour lenfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the Battersea & Bowery Advisory Group, William E. Ford, General Atlantics Chairman and Chief Executive Officer, Gabriel Caillaux, General Atlantics Co-President, Managing Director, and Head of business in EMEA, and the General Atlantic Foundation, Institut National de la Santé et de la Recherche Médicale (INSERM) and of Paris Cité University. JR was supported by the INSERM PhD program for doctors of pharmacy (poste daccueil INSERM). JR and TLV were supported by the Bettencourt-Schueller Foundation and the MD-PhD program of the Imagine Institute. MO was supported by the David Rockefeller Graduate Program, the Funai Foundation for Information Technology (FFIT), the Honjo International Scholarship Foundation (HISF), and the New York Hideyo Noguchi Memorial Society (HNMS).

BACKGROUND: Community-acquired Staphylococcus aureus (CA-Sa) skin and soft tissue infections (SSTIs) are historically associated with densely populated urban areas experiencing high poverty rates, intravenous drug use, and homelessness. However, the epidemiology of CA-Sa SSTIs in the United States has been poorly understood since the plateau of the Community-acquired Methicillin-resistant Staphylococcus aureus epidemic in 2010. This study examines the spatial variation of CA-Sa SSTIs in a large, geographically heterogeneous population and identifies neighborhood characteristics associated with increased infection risk. METHODS: Using a unique neighborhood boundary, California Medical Service Study Areas, a hotspot analysis, and estimates of neighborhood infection risk ratios were conducted for all CA-Sa SSTIs presented in non-Federal California emergency departments between 2016 and 2019. A Bayesian Poisson regression model evaluated the association between neighborhood-level infection risk and population structure, neighborhood poverty rates, and being a healthcare shortage area. RESULTS: Emergency departments in more rural and mountainous parts of California experienced a higher burden of CA-Sa SSTIs between 2016 and 2019. Neighborhoods with high infection rates were more likely to have a high percentage of adults living below the federal poverty level and be a designated healthcare shortage area. Measures of population structure were not associated with infection risk in California neighborhoods. CONCLUSIONS: Our results highlight a potential change in the epidemiology of CA-Sa SSTIs in California emergency departments. Future studies should investigate the CA-Sa burden in other geographies to identify whether this shift in epidemiology holds across other states and populations. Further, a more thorough evaluation of potential mechanisms for the clustering of infections seen across California neighborhoods is needed.

Circulating vitamin B12 concentrations during pregnancy are associated with offspring health. Foetal DNA methylation changes could underlie these associations. Within the Pregnancy And Childhood Epigenetics Consortium, we meta-analysed epigenome-wide associations of circulating vitamin B12 concentrations in mothers during pregnancy (n = 2,420) or cord blood (n = 1,029), with cord blood DNA methylation. Maternal and newborn vitamin B12 concentrations were associated with DNA methylation at 109 and 7 CpGs, respectively (False Discovery Rate P-value

Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)1,2, conferring a predisposition to life-threatening COVID-19 pneumonia3. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52LOF/IκBδGOF). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2 variants causing haploinsufficiency of p100 and p52 (hereafter, p52LOF/IκBδLOF) or gain-of-function of p52 (hereafter, p52GOF/IκBδLOF). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.

OBJECTIVE: To examine differences in the use of high- and low-value health care between immigrant and US-born adults. DATA SOURCE: The 2007-2019 Medical Expenditure Panel Survey. STUDY DESIGN: We split the sample into younger (ages 18-64 years) and older adults (ages 65 years and over). Our outcome measures included the use of high-value care (eight services) and low-value care (seven services). Our key independent variable was immigration status. For each outcome, we ran regressions with and without individual-level characteristics. DATA COLLECTION/EXTRACTION METHODS: N/A. PRINCIPAL FINDINGS: Before accounting for individual-level characteristics, the use of high- and low-value care was lower among immigrant adults than US-born adults. After accounting for individual-level characteristics, this difference decreased in both groups of younger and older adults. For high-value care, significant differences were observed in five services and the direction of the differences was mixed. The use of breast cancer screening was lower among immigrant than US-born younger and older adults (-5.7 [95% CI: -7.4 to -3.9] and -2.9 percentage points [95% CI: -5.6 to -0.2]) while the use of colorectal cancer screening was higher among immigrant than US-born younger and older adults (2.6 [95% CI: 0.5 to 4.8] and 3.6 [95% CI: 0.2 to 7.0] percentage points). For low-value care, we did not identify significant differences except for antibiotics for acute upper respiratory infection among younger adults and opioids for back pain among older adults (-3.5 [95% CI: -5.5 to -1.5] and -3.8[95% CI: -7.3 to -0.2] percentage points). Particularly, differences in socioeconomic status, health insurance, and care access between immigrant and US-born adults played a key role in accounting for differences in the use of high- and low-value health care. The use of high-value care among immigrant and US-born adults increased over time, but the use of low-value care did not decrease. CONCLUSION: Differential use of high- and low-value care between immigrant and US-born adults may be partly attributable to differences in individual-level characteristics, especially socioeconomic status, health insurance, and access to care.

BACKGROUND: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear. METHODS: We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points. RESULTS: We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values

IntroductionColorectal cancer (CRC) incidence and mortality rates are increasing in adults aged

BACKGROUND: Overprescription of opioids after surgery remains common. Residual and unnecessarily prescribed opioids can provide a reservoir for nonmedical use. This study therefore tested the hypothesis that a decision-support tool embedded in electronic health records guides clinicians to prescribe fewer opioids at discharge after inpatient surgery. METHODS: This study included 21,689 surgical inpatient discharges in a cluster randomized multiple crossover trial from July 2020 to June 2021 in four Colorado hospitals. Hospital-level clusters were randomized to alternating 8-week periods during which an electronic decision-support tool recommended tailored discharge opioid prescriptions based on previous inpatient opioid intake. During active alert periods, the alert was displayed to clinicians when the proposed opioid prescription exceeded recommended amounts. No alerts were displayed during inactive periods. Carryover effects were mitigated by including 4-week washout periods. The primary outcome was oral morphine milligram equivalents prescribed at discharge. Secondary outcomes included combination opioid and nonopioid prescriptions and additional opioid prescriptions until day 28 after discharge. A vigorous state-wide opioid education and awareness campaign was in place during the trial. RESULTS: The total postdischarge opioid prescription was a median [quartile 1, quartile 3] of 75 [0, 225] oral morphine milligram equivalents among 11,003 patients discharged when the alerts were active and 100 [0, 225] morphine milligram equivalents in 10,686 patients when the alerts were inactive, with an estimated ratio of geometric means of 0.95 (95% CI, 0.80 to 1.13; P = 0.586). The alert was displayed in 28% (3,074 of 11,003) of the discharges during the active alert period. There was no relationship between the alert and prescribed opioid and nonopioid combination medications or additional opioid prescriptions written after discharge. CONCLUSIONS: A decision-support tool incorporated into electronic medical records did not reduce discharge opioid prescribing for postoperative patients in the context of vigorous opioid education and awareness efforts. Opioid prescribing alerts might yet be valuable in other contexts.(Anesthesiology 2023; 139:186-96).

INTRODUCTION: Despite having worse healthcare access and other social disadvantages, immigrants have, on average, better health outcomes than U.S.-born individuals. For Latino immigrants, this is known as the Latino health paradox. It is unknown whether this phenomenon applies to undocumented immigrants. METHODS: This study used restricted California Health Interview Survey data from 2015 to 2020. Data were analyzed to test the relationships between citizenship/documentation status and physical and mental health among Latinos and U.S.-born Whites. Analyses were stratified by sex (male/female) and length of U.S. residence (= 15 years). RESULTS: Undocumented Latino immigrants had lower predicted probabilities of reporting any health condition, asthma, and serious psychological distress and had a higher probability of overweight/obesity than U.S.-born Whites. Despite having a higher probability of overweight/obesity, undocumented Latino immigrants did not have probabilities of reporting diabetes, high blood pressure, or heart disease different from those of U.S.-born Whites after adjusting for having a usual source of care. Undocumented Latina women had a lower predicted probability of reporting any health condition and a higher predicted probability of overweight/obesity than U.S.-born White women. Undocumented Latino men had a lower predicted probability of reporting serious psychological distress than U.S.-born White men. There were no differences in outcomes when comparing shorter- with longer-duration undocumented Latino immigrants. CONCLUSIONS: This study observed that the Latino health paradox may express patterns for undocumented Latino immigrants that are different from those for other Latino immigrant groups, emphasizing the importance of accounting for documentation status when conducting research on this population.

High-quality early childcare and education (ECE) has demonstrated long-term associations with positive educational and life outcomes and can be particularly impactful for children from low-income backgrounds. This study extends the literature on the long-term associations between high-quality caregiver sensitivity and responsiveness and cognitive stimulation (i.e., caregiving quality) in ECE settings and success in science, technology, engineering, and mathematics (STEM) in high school. Using the 1991 National Institute of Child Health and Human Development Study of Early Child Care and Youth Development (n = 1,096; 48.6% female; 76.4% White, 11.3% African American, 5.8% Latine, 6.5% other), results demonstrated that caregiving quality in ECE was associated with reduced disparities between low- and higher-income childrens STEM achievement and school performance at age 15. Disparities in STEM school performance (i.e., enrollment in advanced STEM courses and STEM grade point average) and STEM achievement (i.e., Woodcock-Johnson cognitive battery) were reduced when children from lower-income families experienced more exposure to higher caregiving quality in ECE. Further, results suggested an indirect pathway for these associations from caregiving quality in ECE to age 15 STEM success through increased STEM achievement in Grades 3 through 5 (ages 8-11 years). Findings suggest that community-based ECE is linked to meaningful improvements in STEM achievement in Grades 3 through 5 which in turn relates to STEM achievement and school performance in high school, and caregiving quality in ECE is particularly important for children from lower-income backgrounds. This work has implications for policy and practice positioning caregivers cognitive stimulation and sensitivity in ECE settings across the first 5 years of life as a promising lever for bolstering the STEM pipeline for children from lower-income backgrounds. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by the absence of a functional UBE3A gene, which causes developmental, behavioral, and medical challenges. While currently untreatable, comprehensive data could help identify appropriate endpoints assessing meaningful improvements in clinical trials. Herein are reported the results from the FREESIAS study assessing the feasibility and utility of in-clinic and at-home measures of key AS symptoms. METHODS: Fifty-five individuals with AS (aged

The Ventanillas de Salud (VDS - Health Windows) are a culturally sensitive outreach program within the 49 Mexican Consulates in the United States that provides information and health care navigation support to underserved and uninsured Mexican immigrants. During the COVID-19 pandemic the VDS rapidly transitioned to remote operations adding new services. Based on the EquIR implementation framework, this qualitative study investigates how adaptations to improve emergency preparedness were performed. We conducted motivational interviews with three actors - six VDS coordinators, eight partner organizations, and ten VDS users- in two VDS, Los Angeles and New York, to document specific needs of the target population and identify implementation processes to adapt and continue operating. The VDS adapted their model by adding new services for emerging needs, by switching service provision modalities, and by expanding the network of partner organizations. According to the VDS staff, these adaptations increased their topics, depth, reach, and diversified their users. Users had mostly positive opinions about the VDS adaptation, although they highlighted some heterogeneity across service provision. The VDS is a public health intervention able to serve a marginalized population and its implementation offers valuable lessons to complement health systems and to improve preparedness and resiliency for future crises.

BACKGROUND AND AIMS: Traditional serrated adenomas (TSAs) may confer increased risk for colorectal cancer (CRC). Our objective with this study was to examine clinical characteristics and long-term outcomes associated with TSA diagnosis. METHODS: We conducted a retrospective cohort study of U.S. Veterans ≥18 years of age with ≥1 TSA between 1999 and 2018. Baseline characteristics, colonoscopy findings, and diagnosis of incident and fatal CRC were abstracted. Advanced neoplasia was defined by CRC or adenoma with high-grade dysplasia, villous histology, or size ≥1 cm. Follow-up was through CRC diagnosis, death, or end of study (December 31, 2018). RESULTS: A total of 853 Veterans with a baseline TSA were identified; 74% were ≥60 years of age, 96% were men, 14% were Black, and 73% were non-Hispanic White. About 64% were current or former smokers. Over 2044 total person-years at follow-up, there were 11 incident CRC cases and 1 CRC death. Cumulative CRC incidence was 1.34% (95% confidence interval [CI], 0.67%-2.68%), and cumulative CRC death was 0.12% (95% CI, 0.00%-0.35%). Among the subset of 378 TSA patients with ≥1 surveillance colonoscopy, 65.1% had high-risk neoplasia on follow-up. CRC incidence among TSA patients was significantly higher than in a comparison cohort of patients with normal baseline colonoscopy at baseline (hazard ratio, 3.70; 95% CI, 1.63-8.41) and similar to a comparison cohort with baseline conventional advanced adenoma (hazard ratio, 0.86; 95% CI, 0.45-1.64). CONCLUSION: Individuals with TSA have substantial risk for CRC based on their cumulative CRC incidence, as well as significant risk of developing other high-risk neoplasia at follow-up surveillance colonoscopy. These data underscore importance of current recommendations for close colonoscopy surveillance after TSA diagnosis.

Background & aimsAchalasia is an esophageal motility disorder associated with significant morbidity, yet achalasia-associated risk factors and outcomes are not well-characterized. Our aim was to establish a national cohort of individuals with achalasia, utilizing Veterans Health Administration (VHA) data.MethodsWe iteratively developed combinations of International Classification of Diseases and Current Procedural Terminology code algorithms to validate an approach for identifying achalasia cases. We assessed algorithm accuracy for achalasia diagnosis through manual chart review of candidate achalasia cases and candidate non-achalasia controls. The prespecified end point chosen to establish algorithm performance success was achieving a 1-sided 95% confidence lower bound for a positive predictive value >85% for a random sample of 100 candidate achalasia cases. Once adequate performance was validated, we queried national VHA data to establish and characterize a cohort of individuals diagnosed with achalasia between 1999 and 2020.ResultsThree rounds of algorithm modification and validation were conducted to achieve the prespecified performance endpoint. In the final round, a combination of 3 or more International Classification of Diseases codes for achalasia in the subject's lifetime and a Current Procedural Terminology code for esophageal manometry achieved an observed 94% positive predictive value (1-sided 95% confidence lower bound of 88.5%) for identifying achalasia. Applying the algorithm to national VHA data identified a cohort of 2100 individuals with achalasia, with a median age 65 years and who were 93% male.ConclusionsUsing a rigorous validation approach, we established a national cohort of 2100 individuals with achalasia within the VHA, one of the largest established to date. This cohort can be utilized to study risk factors for achalasia and outcomes over time.

Delays in colonoscopy work-up for red flag signs or symptoms of colorectal cancer (CRC) during the COVID-19 pandemic are not well characterized. To examine colonoscopy uptake and time to colonoscopy after red flag diagnosis, before and during the COVID-19 pandemic. Cohort study of adults ages 50-75 with iron deficiency anemia (IDA), hematochezia, or abnormal stool blood test receiving Veterans Health Administration (VHA) care from April 2019 to December 2020. Index date was first red flag diagnosis date, categorized into "pre" (April-December 2019) and "intra" (April-December 2020) policy implementation prioritizing diagnostic procedures, allowing for a 3-month "washout" (January-March 2020) period. Outcomes were colonoscopy completion and time to colonoscopy pre- vs. intra-COVID-19, examined using multivariable Cox models with hazard ratios (aHRs) and 95% confidence intervals (CIs). There were 52,539 adults with red flag signs or symptoms (pre-COVID: 25,154; washout: 7527; intra-COVID: 19,858). Proportion completing colonoscopy was similar pre- vs. intra-COVID-19 (27.0% vs. 26.5%; p = 0.24). Median time to colonoscopy among colonoscopy completers was similar for pre- vs. intra-COVID-19 (46 vs. 42 days), but longer for individuals with IDA (60 vs. 49 days). There was no association between time period and colonoscopy completion (aHR: 0.99, 95% CI 0.95-1.03). Colonoscopy work-up of CRC red flag signs and symptoms was not delayed within VHA during the COVID-19 pandemic, possibly due to VHA policies supporting prioritization and completion. Further work is needed to understand how COVID-19 policies on screening and surveillance impact CRC-related outcomes, and how to optimize colonoscopy completion after a red flag diagnosis.

OBJECTIVE: This systematic literature review presents an overview of studies that assess the experiences of Hispanic adults with (1) activation of emergency medical services (EMS); (2) on-scene care provided by EMS personnel; (3) mode of transport (EMS vs. non-EMS) to an emergency department (ED); and (4) experiences with EMS before and during the COVID-19 pandemic. METHODS: A bibliographic database search was conducted to identify relevant studies on Ovid MEDLINE (PubMed), Web of Science, EMBASE, and CINAHL. Quantitative, mixed methods, and qualitative studies published in English or Spanish were included if they discussed Hispanic adults experiences with EMS in the US between January 1, 2000 and December 31, 2021. The Hawker and colleagues quality assessment instrument was used to evaluate the quality of studies. RESULTS: Of the 43 included studies, 13 examined EMS activation, 13 assessed on-scene care, 22 discussed the mode of transport to an ED, and 4 described Hispanic adults experiences with EMS during the COVID-19 pandemic. Hispanics were less likely to activate EMS (N=7), less likely to receive certain types of on-scene care (N=6), and less likely to use EMS as the mode of transport to an ED (N=13), compared with non-Hispanic Whites. During the early COVID-19 pandemic period (March to May 2020), EMS use decreased by 26.5% compared with the same months during the previous 4 years. CONCLUSIONS: The contribution of this study is its attention to Hispanic adults experiences with the different phases of the US EMS system.

INTRODUCTION: Telehealth can potentially improve the quality of healthcare through increased access to primary care. While telehealth use increased during the COVID-19 pandemic, racial/ethnic disparities in the use of telemedicine persisted during this period. Little is known about the relationship between health coverage and patient race/ethnicity after the onset of the COVID-19 pandemic. OBJECTIVE: This study examines how differences in patient race/ethnicity and health coverage are associated with the number of in-person vs. telehealth visits among patients with chronic conditions before and after Californias stay-at-home order (SAHO) was issued on 19 March 2020. METHODS: We used weekly patient visit data (in-person (N = 63, 491) and telehealth visits (N = 55, 472)) from seven primary care sites of an integrated, multi-specialty medical group in Los Angeles County that served a diverse patient population between January 2020 and December 2020 to examine differences in telehealth visits reported for Latino and non-Latino Asian, Black, and white patients with chronic conditions (type 2 diabetes, pre-diabetes, and hypertension). After adjusting for age and sex, we estimate differences by race/ethnicity and the type of insurance using an interrupted time series with a multivariate logistic regression model to study telehealth use by race/ethnicity and type of health coverage before and after the SAHO. A limitation of our research is the analysis of aggregated patient data, which limited the number of individual-level confounders in the regression analyses. RESULTS: Our descriptive analysis shows that telehealth visits increased immediately after the SAHO for all race/ethnicity groups. Our adjusted analysis shows that the likelihood of having a telehealth visit was lower among uninsured patients and those with Medicaid or Medicare coverage compared to patients with private insurance. Latino and Asian patients had a lower probability of telehealth use compared with white patients. DISCUSSION: To address access to chronic care management through telehealth, we suggest targeting efforts on uninsured adults and those with Medicare or Medicaid coverage, who may benefit from increased telehealth use to manage their chronic care.

Fecal microbiota transplantation (FMT) is a promising therapeutic modality for the treatment and prevention of metabolic disease. We previously conducted a double-blind, randomized, placebo-controlled pilot trial of FMT in obese metabolically healthy patients in which we found that FMT enhanced gut bacterial bile acid metabolism and delayed the development of impaired glucose tolerance relative to the placebo control group. Therefore, we conducted a secondary analysis of fecal samples collected from these patients to assess the potential gut microbial species contributing to the effect of FMT to improve metabolic health and increase gut bacterial bile acid metabolism. Fecal samples collected at baseline and after 4 weeks of FMT or placebo treatment underwent shotgun metagenomic analysis. Ultra-high-performance liquid chromatography-mass spectrometry was used to profile fecal bile acids. FMT-enriched bacteria that have been implicated in gut bile acid metabolism included Desulfovibrio fairfieldensis and Clostridium hylemonae. To identify candidate bacteria involved in gut microbial bile acid metabolism, we assessed correlations between bacterial species abundance and bile acid profile, with a focus on bile acid products of gut bacterial metabolism. Bacteroides ovatus and Phocaeicola dorei were positively correlated with unconjugated bile acids. Bifidobacterium adolescentis, Collinsella aerofaciens, and Faecalibacterium prausnitzii were positively correlated with secondary bile acids. Together, these data identify several candidate bacteria that may contribute to the metabolic benefits of FMT and gut bacterial bile acid metabolism that requires further functional validation.

OBJECTIVE: To study the impact of Medicaid funding structures before and after the implementation of the Affordable Care Act (ACA) on health care access for Latinos in New York (Medicaid expansion), Florida (Medicaid non-expansion), and Puerto Rico (Medicaid block grant). DATA SOURCES: Pooled state-level data for New York, Florida, and Puerto Rico from the 2011-2019 Behavioral Risk Factor Surveillance System and data from the 2011-2019 American Community Survey and Puerto Rico Community Survey. STUDY DESIGN: Cross-sectional study using probit with predicted margins to separately compare four health care access measures among Latinos in New York, Florida, and Puerto Rico (having health insurance coverage, having a personal doctor, delayed care due to cost, and having a routine checkup). We also used difference-in-differences to measure the probability percent change of having any health insurance and any public health insurance before (2011-2013) and after (2014-2019) the ACA implementation among citizen Latinos in low-income households. DATA COLLECTION: The sample consisted of Latinos aged 18-64 residing in New York, Florida, and Puerto Rico from 2011 to 2019. PRINCIPAL FINDINGS: Latinos in Florida had the lowest probability of having health care access across all four measures and all time periods compared with those in New York and Puerto Rico. While Latinos in Puerto Rico had greater overall health care access compared with Latinos in both states, health care access in Puerto Rico did not change over time. Among citizen Latinos in low-income households, New York had the greatest post-ACA probability of having any health insurance and any public health insurance, with a growing disparity with Puerto Rico (9.7% any [1.6 SE], 5.2% public [1.8 SE]). CONCLUSIONS: Limited Medicaid eligibility (non-expansion of Floridas Medicaid program) and capped Medicaid funds (Puerto Ricos Medicaid block grant) contributed to reduced health care access over time, particularly for citizen Latinos in low-income households.

OBJECTIVE: To estimate the avoidance of Medicaid enrollment among Latino and Asian immigrants due to fears about immigration status. In 2019, changes to the public charge rule made it difficult for immigrants to receive a green card or permanent residence visa, particularly for those who used health and nutrition benefits. Despite the Biden administrations reversal of these changes, fear and misinformation persist among immigrants. DATA SOURCES: Pooled data from the 2017 to 2020 California Health Interview Survey. STUDY DESIGN: We used adjusted predicted probability models to estimate differences in access to and use of health care and health insurance coverage among Latino and Asian immigrant adults with and without green cards, using US citizens as the reference. We estimated the avoidance of Medicaid enrollment among immigrants without a green card, the immigrant population subject to the public charge rule. DATA COLLECTION/EXTRACTION METHODS: Population stratified by race/ethnicity and green card status. PRINCIPAL FINDINGS: Latino immigrants without a green card were -23.1% (CI: -27.8, -18.4) less likely to be insured, -9.2% (CI: -12.8, -5.5) less likely to have Medicaid coverage, -9.3% (CI: -14.5, -4.1) less likely to have a usual source of care, and -8.4% (CI: -13.2, -0.3) less likely to have a physician visit relative to citizens. Asian immigrants without a green card were -11.7% (CI: -19.7, -3.72) less likely to be insured, -8.8% (CI: -11.6, -6.1) less likely to have Medicaid coverage, -11.6% (CI: -19.3, -3.9) less likely to have a usual source of care, and -11.0% (CI: -19.2, -2.3) less likely to have a physician visit. Between 107,956 and 192,905 Latino immigrants and 1294 and 4702 Asian immigrants in California likely avoided Medicaid enrollment due to fears about their immigration status. CONCLUSION: While our estimates are lower than those of previous studies, our findings highlight barriers to health care for immigrants despite the reversal of the changes in the public charge rule. Since the public charge rule was not abolished, immigrants with low incomes might choose not to seek health care, despite recent efforts in California to expand Medicaid coverage to all eligible immigrants regardless of documentation statuses.

Posttraumatic stress disorder (PTSD) is a heritable (h2 = 24-71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10-8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q

The SARS-CoV-2 pandemic has differentially impacted populations across race and ethnicity. A multi-omic approach represents a powerful tool to examine risk across multi-ancestry genomes. We leverage a pandemic tracking strategy in which we sequence viral and host genomes and transcriptomes from nasopharyngeal swabs of 1049 individuals (736 SARS-CoV-2 positive and 313 SARS-CoV-2 negative) and integrate them with digital phenotypes from electronic health records from a diverse catchment area in Northern California. Genome-wide association disaggregated by admixture mapping reveals novel COVID-19-severity-associated regions containing previously reported markers of neurologic, pulmonary and viral disease susceptibility. Phylodynamic tracking of consensus viral genomes reveals no association with disease severity or inferred ancestry. Summary data from multiomic investigation reveals metagenomic and HLA associations with severe COVID-19. The wealth of data available from residual nasopharyngeal swabs in combination with clinical data abstracted automatically at scale highlights a powerful strategy for pandemic tracking, and reveals distinct epidemiologic, genetic, and biological associations for those at the highest risk.

During the first hours after stroke onset, neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between the National Institutes of Health Stroke Scale (NIHSS) within 6 h of stroke onset and NIHSS at 24 h. A total of 5876 individuals from seven countries (Spain, Finland, Poland, USA, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of NIHSS at 24 h of variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture from that of stroke risk. Eight loci (1p21.1, 1q42.2, 2p25.1, 2q31.2, 2q33.3, 5q33.2, 7p21.2 and 13q31.1) were genome-wide significant and explained 1.8% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each locus. Expression quantitative trait loci mapping and summary data-based Mendelian randomization indicate that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke.

The endosomal sorting complexes required for transport (ESCRT) system is an ancient and ubiquitous membrane scission machinery that catalyzes the budding and scission of membranes. ESCRT-mediated scission events, exemplified by those involved in the budding of HIV-1, are usually directed away from the cytosol ("reverse topology"), but they can also be directed toward the cytosol ("normal topology"). The ESCRT-III subunits CHMP1B and IST1 can coat and constrict positively curved membrane tubes, suggesting that these subunits could catalyze normal topology membrane severing. CHMP1B and IST1 bind and recruit the microtubule-severing AAA+ ATPase spastin, a close relative of VPS4, suggesting that spastin could have a VPS4-like role in normal-topology membrane scission. Here, we reconstituted the process in vitro using membrane nanotubes pulled from giant unilamellar vesicles using an optical trap in order to determine whether CHMP1B and IST1 are capable of membrane severing on their own or in concert with VPS4 or spastin. CHMP1B and IST1 copolymerize on membrane nanotubes, forming stable scaffolds that constrict the tubes, but do not, on their own, lead to scission. However, CHMP1B-IST1 scaffolded tubes were severed when an additional extensional force was applied, consistent with a friction-driven scission mechanism. We found that spastin colocalized with CHMP1B-enriched sites but did not disassemble the CHMP1B-IST1 coat from the membrane. VPS4 resolubilized CHMP1B and IST1 without leading to scission. These observations show that the CHMP1B-IST1 ESCRT-III combination is capable of severing membranes by a friction-driven mechanism that is independent of VPS4 and spastin.

ObjectiveTo develop a drug facts label prototype for a combination mifepristone and misoprostol product and to conduct a label-comprehension study to assess understanding of key label concepts.MethodsWe followed U.S. Food and Drug Administration guidance, engaged a multidisciplinary group of experts, and conducted cognitive interviews to develop a drug facts label prototype for medication abortion. To assess label comprehension, we developed 11 primary and 13 secondary communication objectives related to indications for use, eligibility, dosing regimen, contraindications, warning signs, side effects, and recognizing the risk of treatment failure, with corresponding target performance thresholds (80-90% accuracy). We conducted individual structured video interviews with people with a uterus aged 12-49 years, recruited through social media. Participants reviewed the drug facts label and responded to questions to assess their understanding of each communication objective. After transcribing and coding interviews, we estimated the proportion of correct responses and exact binomial 95% CIs by age and literacy group.ResultsWe interviewed 851 people (of 1,507 people scheduled); responses from 844 were eligible for analysis, and 35.7% (n=301) of participants were aged 12-17 years. The overall sample met performance criteria for 10 of the 11 primary communication objectives (93-99% correct) related to indications for use, eligibility for use, the dosing regimen, and contraindications; young people met nine and people with limited literacy met eight of the 11 performance criteria. Only 79% (95% CI 0.76-0.82) of the overall sample understood to contact a health care professional if little or no bleeding occurred soon after taking misoprostol, not meeting the prespecified threshold of 85.0%.ConclusionOverall, high levels of comprehension suggest that people can understand most key drug facts label concepts for a medication abortion product without clinical supervision and recommend minor modifications.

BackgroundPosttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs).MethodsA GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms.ResultsGWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program.ConclusionsThrough using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.

Dialogic reading, when children are read a storybook and engaged in relevant conversation, is a powerful strategy for fostering language development. With the development of artificial intelligence, conversational agents can engage children in elements of dialogic reading. This study examined whether a conversational agent can improve children's story comprehension and engagement, as compared to an adult reading partner. Using a 2 (dialogic reading or non-dialogic reading) × 2 (agent or human) factorial design, a total of 117 three- to six-year-olds (50% Female, 37% White, 31% Asian, 21% multi-ethnic) were randomly assigned into one of the four conditions. Results revealed that a conversational agent can replicate the benefits of dialogic reading with a human partner by enhancing children's narrative-relevant vocalizations, reducing irrelevant vocalizations, and improving story comprehension.

Background and aimsPancreatic cancer incidence and mortality among patients with pancreas cysts are unclear. The aims of this study are to evaluate incidence of pancreatic cancer and cause-specific mortality among patients with pancreatic cysts using a large national cohort over a long follow-up period.MethodsWe conducted a retrospective cohort study of US Veterans diagnosed with a pancreatic cyst 1999-2013, based on International Classification of Diseases, 9th edition (ICD9) coding within national Department of Veterans Affairs (VA) data. Pancreatic cancer incidence was ascertained using VA cancer registry data, ICD-9 codes, and the National Death Index, a national centralized database of death records, including cause-specific mortality.ResultsAmong 7211 Veterans with pancreatic cysts contributing 31,501 person-years of follow-up (median follow-up 4.4 years), 79 (1.1%) developed pancreatic cancer. A total of 1982 patients (27.5%) died during the study follow-up period. Sixty-three patients (3.2% of deaths; 0.9% of pancreas cyst cohort) died from pancreatic cancer, but the leading causes of death in the cohort were non-pancreatic cancer (n = 498, 25% of deaths) and cardiovascular disease (n = 398, 20% of deaths).ConclusionsPancreas cancer incidence and pancreatic cancer-associated mortality are very low in a large national cohort of VA pancreatic cyst patients with long-term follow-up. Most deaths were from non-pancreas cancers and cardiovascular causes, and only a minority (3.2%) were attributable to pancreas cancer. Given death from pancreas cancer is rare, future research should focus on identifying criteria for selecting individuals at high risk for death from pancreatic cancer for pancreatic cyst surveillance.

This cross-sectional study examines changes in levels of health care coverage and cost-related delays in care for Latino individuals after elimination of the individual coverage mandate from the Affordable Care Act (ACA).

BackgroundPlasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants.MethodsProteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics).ResultsWe identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10-11. These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P=3.27×10-30) and MMP-3 (β=-0.60±0.05, P=1.67×10-32), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P=1.34×10-17) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure.ConclusionsTaken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.

COVID-19 has disproportionally affected underrepresented minorities (URM) and low-income immigrants in the United States. The aim of the study is to examine the underlying vulnerabilities of Mexican immigrants in New York City (NYC) and Los Angeles (LA), its correspondence with area-level COVID-19 morbidity and mortality, and to document the role of trusted and culturally sensitive services offered during the pandemic through the Ventanillas de Salud (i.e. VDS, Health Windows) program. The study uses a mixed-methods approach including a cross-sectional survey of Mexican immigrants in LA and NYC collected in the Mexican Consulates at the onset of the pandemic, complemented with a georeferencing analysis and key informant interviews. Data suggested an increased vulnerability to COVID-19 given participants reported health status, health care profile and place of residence, which coincided with the georeferencing analysis. The key informant interviews confirmed the vulnerability of this population and the supporting role of VDS in helping immigrants navigate health systems and disseminate health information. Mexican immigrants had an increased vulnerability to COVID-19 at the individual, geographic and systemic levels. Trusted and culturally sensitive services are needed to overcome some of the barriers and risk factors that increase the vulnerability of URM and immigrant populations to COVID-19.

BACKGROUND: Identification of clinically significant genetic alterations involved in human disease has been dramatically accelerated by developments in next-generation sequencing technologies. However, the infrastructure and accessible comprehensive curation tools necessary for analyzing an individual patient genome and interpreting genetic variants to inform healthcare management have been lacking. RESULTS: Here we present the ClinGen Variant Curation Interface (VCI), a global open-source variant classification platform for supporting the application of evidence criteria and classification of variants based on the ACMG/AMP variant classification guidelines. The VCI is among a suite of tools developed by the NIH-funded Clinical Genome Resource (ClinGen) Consortium and supports an FDA-recognized human variant curation process. Essential to this is the ability to enable collaboration and peer review across ClinGen Expert Panels supporting users in comprehensively identifying, annotating, and sharing relevant evidence while making variant pathogenicity assertions. To facilitate evidence-based improvements in human variant classification, the VCI is publicly available to the genomics community. Navigation workflows support users providing guidance to comprehensively apply the ACMG/AMP evidence criteria and document provenance for asserting variant classifications. CONCLUSIONS: The VCI offers a central platform for clinical variant classification that fills a gap in the learning healthcare system, facilitates widespread adoption of standards for clinical curation, and is available at https://curation.clinicalgenome.org.

BackgroundAmong children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits.MethodsWe performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5-10 years from 8 cohorts (n = 4268).ResultsIn newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p

Higher maternal pre-pregnancy body mass index (ppBMI) is associated with increased neonatal morbidity, as well as with pregnancy complications and metabolic outcomes in offspring later in life. The placenta is a key organ in fetal development and has been proposed to act as a mediator between the mother and different health outcomes in children. The overall aim of the present work is to investigate the association of ppBMI with epigenome-wide placental DNA methylation (DNAm) in 10 studies from the PACE consortium, amounting to 2631 mother-child pairs. We identify 27 CpG sites at which we observe placental DNAm variations of up to 2.0% per 10 ppBMI-unit. The CpGs that are differentially methylated in placenta do not overlap with CpGs identified in previous studies in cord blood DNAm related to ppBMI. Many of the identified CpGs are located in open sea regions, are often close to obesity-related genes such as GPX1 and LGR4 and altogether, are enriched in cancer and oxidative stress pathways. Our findings suggest that placental DNAm could be one of the mechanisms by which maternal obesity is associated with metabolic health outcomes in newborns and children, although further studies will be needed in order to corroborate these findings.

BackgroundCurrent South American populations trace their origins mainly to three continental ancestries, i.e. European, Amerindian and African. Individual variation in relative proportions of each of these ancestries may be confounded with socio-economic factors due to population stratification. Therefore, ancestry is a potential confounder variable that should be considered in epidemiologic studies and in public health plans. However, there are few studies that have assessed the ancestry of the current admixed Chilean population. This is partly due to the high cost of genome-scale technologies commonly used to estimate ancestry. In this study we have designed a small panel of SNPs to accurately assess ancestry in the largest sampling to date of the Chilean mestizo population (n = 3349) from eight cities. Our panel is also able to distinguish between the two main Amerindian components of Chileans: Aymara from the north and Mapuche from the south.ResultsA panel of 150 ancestry-informative markers (AIMs) of SNP type was selected to maximize ancestry informativeness and genome coverage. Of these, 147 were successfully genotyped by KASPar assays in 2843 samples, with an average missing rate of 0.012, and a 0.95 concordance with microarray data. The ancestries estimated with the panel of AIMs had relative high correlations (0.88 for European, 0.91 for Amerindian, 0.70 for Aymara, and 0.68 for Mapuche components) with those obtained with AXIOM LAT1 array. The country's average ancestry was 0.53 ± 0.14 European, 0.04 ± 0.04 African, and 0.42 ± 0.14 Amerindian, disaggregated into 0.18 ± 0.15 Aymara and 0.25 ± 0.13 Mapuche. However, Mapuche ancestry was highest in the south (40.03%) and Aymara in the north (35.61%) as expected from the historical location of these ethnic groups. We make our results available through an online app and demonstrate how it can be used to adjust for ancestry when testing association between incidence of a disease and nongenetic risk factors.ConclusionsWe have conducted the most extensive sampling, across many different cities, of current Chilean population. Ancestry varied significantly by latitude and human development. The panel of AIMs is available to the community for estimating ancestry at low cost in Chileans and other populations with similar ancestry.

BACKGROUND: Epilepsy is highly prevalent in children with Angelman syndrome (AS), and its detailed characterization and relationship to the genotype (deletion vs nondeletion) is important both for medical practice and for clinical trial design. METHODS AND MATERIALS: We retrospectively analyzed the main clinical features of epilepsy in 265 children with AS who were enrolled in the AS Natural History Study, a multicenter, observational study conducted at six centers in the United States. Participants were prospectively followed up and classified by genotype. RESULTS: Epilepsy was reported in a greater proportion of individuals with a deletion than a nondeletion genotype (171 of 187 [91%] vs. 48 of 78 [61%], P

Maternal smoking during pregnancy (MSDP) contributes to poor birth outcomes, in part through disrupted placental functions, which may be reflected in the placental epigenome. Here we present a meta-analysis of the associations between MSDP and placental DNA methylation (DNAm) and between DNAm and birth outcomes within the Pregnancy And Childhood Epigenetics (PACE) consortium (N = 1700, 344 with MSDP). We identify 443 CpGs that are associated with MSDP, of which 142 associated with birth outcomes, 40 associated with gene expression, and 13 CpGs are associated with all three. Only two CpGs have consistent associations from a prior meta-analysis of cord blood DNAm, demonstrating substantial tissue-specific responses to MSDP. The placental MSDP-associated CpGs are enriched for environmental response genes, growth-factor signaling, and inflammation, which play important roles in placental function. We demonstrate links between placental DNAm, MSDP and poor birth outcomes, which may better inform the mechanisms through which MSDP impacts placental function and fetal growth.

Irritable bowel syndrome (IBS) is a gut-brain disorder in which symptoms are shaped by serotonin acting centrally and peripherally. The serotonin transporter gene SLC6A4 has been implicated in IBS pathophysiology, but the underlying genetic mechanisms remain unclear. We sequenced the alternative P2 promoter driving intestinal SLC6A4 expression and identified single nucleotide polymorphisms (SNPs) that were associated with IBS in a discovery sample. Identified SNPs built different haplotypes, and the tagging SNP rs2020938 seems to associate with constipation-predominant IBS (IBS-C) in females. rs2020938 validation was performed in 1978 additional IBS patients and 6,038 controls from eight countries. Meta-analysis on data from 2,175 IBS patients and 6,128 controls confirmed the association with female IBS-C. Expression analyses revealed that the P2 promoter drives SLC6A4 expression primarily in the small intestine. Gene reporter assays showed a functional impact of SNPs in the P2 region. In silico analysis of the polymorphic promoter indicated differential expression regulation. Further follow-up revealed that the major allele of the tagging SNP rs2020938 correlates with differential SLC6A4 expression in the jejunum and with stool consistency, indicating functional relevance. Our data consolidate rs2020938 as a functional SNP associated with IBS-C risk in females, underlining the relevance of SLC6A4 in IBS pathogenesis.

Since the 1960s the immigrant population in the United States has increased fourfold, reaching 44.7 million, or 13.7 percent of the US population, in 2018. The shifting immigrant demography presents several challenges for US health policy makers. We examine recent trends in immigrant health and health care after the Great Recession and the nationwide implementation of the Affordable Care Act. Recent immigrants are more likely to have lower incidence of chronic health conditions than other groups in the US, although these differences vary along the citizenship and documentation status continuum. Health care inequities among immigrants and US-born residents increased after the Great Recession and later diminished after the Affordable Care Act took effect. Unremitting inequities remain, however, particularly among noncitizen immigrants. The number of aging immigrants is growing, which will present a challenge to the expansion of coverage to this population. Health care and immigration policy changes are needed to integrate immigrants successfully into the US health care system.

Autophagy inhibitors are currently being evaluated in clinical trials for the treatment of diverse cancers, largely due to their ability to impede tumor cell survival and metabolic adaptation. More recently, there is growing interest in whether and how modulating autophagy in the host stroma influences tumorigenesis. Fibroblasts play prominent roles in cancer initiation and progression, including depositing type 1 collagen and other extracellular matrix (ECM) components, thereby stiffening the surrounding tissue to enhance tumor cell proliferation and survival, as well as secreting cytokines that modulate angiogenesis and the immune microenvironment. This constellation of phenotypes, pathologically termed desmoplasia, heralds poor prognosis and reduces patient survival. Using mouse mammary cancer models and syngeneic transplantation assays, we demonstrate that genetic ablation of stromal fibroblast autophagy significantly impedes fundamental elements of the stromal desmoplastic response, including collagen and proinflammatory cytokine secretion, extracellular matrix stiffening, and neoangiogenesis. As a result, autophagy in stromal fibroblasts is required for mammary tumor growth in vivo, even when the cancer cells themselves remain autophagy-competent . We propose the efficacy of autophagy inhibition is shaped by this ability of host stromal fibroblast autophagy to support tumor desmoplasia.

Immunogenomics studies have been largely limited to individuals of European ancestry, restricting the ability to identify variation in human adaptive immune responses across populations. Inclusion of a greater diversity of individuals in immunogenomics studies will substantially enhance our understanding of human immunology.

How do people learn when to allocate how much cognitive control to which task? According to the Learned Value of Control (LVOC) model, people learn to predict the value of alternative control allocations from features of a situation. This suggests that people may generalize the value of control learned in one situation to others with shared features, even when demands for control are different. This makes the intriguing prediction that what a person learned in one setting could cause them to misestimate the need for, and potentially overexert, control in another setting, even if this harms their performance. To test this prediction, we had participants perform a novel variant of the Stroop task in which, on each trial, they could choose to either name the color (more control-demanding) or read the word (more automatic). Only one of these tasks was rewarded each trial and could be predicted by one or more stimulus features (the color and/or word). Participants first learned colors and then words that predicted the rewarded task. Then, we tested how these learned feature associations transferred to novel stimuli with some overlapping features. The stimulus-task-reward associations were designed so that for certain combinations of stimuli, transfer of learned feature associations would incorrectly predict that more highly rewarded task would be color-naming, even though the actually rewarded task was word-reading and therefore did not require engaging control. Our results demonstrated that participants overexerted control for these stimuli, providing support for the feature-based learning mechanism described by the LVOC model.

International migration has economic and health implications. The acculturation process to the host country may be linked to childhood obesity. We use the Community Energy Balance (CEB) framework to analyze the relationship between migration and childhood obesity in Mexican households with international migrants. Using longitudinal data from the Mexican Family Life Survey (MxFLS), we examine how migrant networks affect childhood obesity in origin communities. We also review binational health programs that could be effective at tackling childhood obesity in migrant households from Mexico. Children embedded in migrant networks are at greater risk of developing overweight or obesity, suggesting a significant relationship between childhood obesity and international migration in Mexican households. Based on our search criteria, our analysis of health outreach programs shows that Ventanillas de Salud (VDS)/Health Windows has great promise to prevent childhood obesity in a culturally sensitive and trustful environment. The CEB framework is useful to understand how migration contributes to the risk of childhood overweight and obesity in migrant households. VDS is a feasible and replicable strategy with great potential to address childhood obesity among migrant families accounting for the dynamic and binational determinants of childhood obesity.

BACKGROUND AND PURPOSE: Coronavirus disease 2019 (COVID-19) is associated with a small but clinically significant risk of stroke, the cause of which is frequently cryptogenic. In a large multinational cohort of consecutive COVID-19 patients with stroke, we evaluated clinical predictors of cryptogenic stroke, short-term functional outcomes and in-hospital mortality among patients according to stroke etiology. METHODS: We explored clinical characteristics and short-term outcomes of consecutively evaluated patients 18 years of age or older with acute ischemic stroke (AIS) and laboratory-confirmed COVID-19 from 31 hospitals in 4 countries (3/1/20-6/16/20). RESULTS: Of the 14.483 laboratory-confirmed patients with COVID-19, 156 (1.1%) were diagnosed with AIS. Sixty-one (39.4%) were female, 84 (67.2%) white, and 88 (61.5%) were between 60 and 79 years of age. The most frequently reported etiology of AIS was cryptogenic (55/129, 42.6%), which was associated with significantly higher white blood cell count, c-reactive protein, and D-dimer levels than non-cryptogenic AIS patients (p

The COVID-19 pandemic has disproportionately affected Latino adults aged 50 and older in California. Among adults aged 50-64, Latinos constitute approximately one-third (32%) of the population, but over half (52%) of COVID-19 cases, and more than two-thirds (64%) of COVID-related deaths as of June 2, 2021. These health disparities are also prevalent among Latinos 65 years and older who constitute 22% of the population, but 40% of confirmed COVID-19 cases and 50% of COVID-related deaths. Emergency medical services (EMS) are an essential component of the United States healthcare system and a vital sector in COVID-19 response efforts. Using data from the California Emergency Medical Services Information System (CEMSIS), this study examines racial and ethnic differences in respiratory distress related EMS calls among adults aged 50 and older in all counties except Los Angeles. This study compares the early pandemic period, January to June 2020, to the same time period in 2019. Between January and June 2019, Latinos aged 50 and older had statistically significantly lower odds of respiratory distress related EMS calls compared to Blacks, Asians, and Whites. During the early pandemic period, January to June 2020, Latinos aged 50 and older had statistically significantly lower odds of respiratory distress related EMS calls compared to Blacks but slightly higher odds compared to Whites. Differences by race/ethnicity and region were statistically significant. Understanding EMS health disparities is crucial to inform policies that create a more equitable prehospital care system for the heterogeneous population of middle aged and older adults.

BackgroundStudies have observed that recent Latino immigrants tend to have a physical health advantage compared to immigrants who have been in the US for many years or Latinos who are born in the United States. An explanation of this phenomenon is that recent immigrants have positive health behaviors that protect them from chronic disease risk. This study aims to determine if trends in positive cardiovascular disease (CVD) risk behaviors extend to Latino immigrants in California according to citizenship and documentation status.MethodsWe examined CVD behavioral risk factors by citizenship/documentation statuses among Latinos and non-Latino US-born whites in the 2011-2015 waves of the California Health Interview Survey. Adjusted multivariable logistic regressions estimated the odds for CVD behavioral risk factors, and analyses were stratified by sex.ResultsIn adjusted analyses, using US-born Latinos as the reference group, undocumented Latino immigrants had the lowest odds of current smoking, binge drinking, and frequency of fast food consumption. There were no differences across the groups for fruit/vegetable intake and walking for leisure. Among those with high blood pressure, undocumented immigrants were least likely to be on medication. Undocumented immigrant women had better patterns of CVD behavioral risk factors on some measures compared with other Latino citizenship and documentation groups.ConclusionsThis study observes that the healthy Latino immigrant advantage seems to apply to undocumented female immigrants, but it does not necessarily extend to undocumented male immigrants who had similar behavioral risk profiles to US-born Latinos.

BackgroundDNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits.MethodsWe examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment.ResultsDNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P