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T cells play a prominent role in orchestrating the immune response to viral diseases, but their role in the clinical presentation and subsequent immunity to SARS-CoV-2 infection remains poorly understood. As part of a population-based survey of the municipality of Vo', Italy, conducted after the initial SARS-CoV-2 outbreak, we sampled the T cell receptor (TCR) repertoires of the population 2 months after the initial PCR survey and followed up positive cases 9 and 15 months later. At 2 months, we found that 97.0% (98 of 101) of cases had elevated levels of TCRs associated with SARS-CoV-2. T cell frequency (depth) was increased in individuals with more severe disease. Both depth and diversity (breadth) of the TCR repertoire were positively associated with neutralizing antibody titers, driven mostly by CD4+ T cells directed against spike protein. At the later time points, detection of these TCRs remained high, with 90.7% (78 of 96) and 86.2% (25 of 29) of individuals having detectable signal at 9 and 15 months, respectively. Forty-three individuals were vaccinated by month 15 and showed a significant increase in TCRs directed against spike protein. Taken together, these results demonstrate the central role of T cells in mounting an immune defense against SARS-CoV-2 that persists out to 15 months.
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COVID-19 , Linfócitos T CD4-Positivos , Humanos , Receptores de Antígenos de Linfócitos T/metabolismo , SARS-CoV-2 , Glicoproteína da Espícula de CoronavírusRESUMO
While immunopathology has been widely studied in patients with severe COVID-19, immune responses in non-hospitalized patients have remained largely elusive. We systematically analyze 484 peripheral cellular or soluble immune features in a longitudinal cohort of 63 mild and 15 hospitalized patients versus 14 asymptomatic and 26 household controls. We observe a transient increase of IP10/CXCL10 and interferon-ß levels, coordinated responses of dominant SARS-CoV-2-specific CD4 and fewer CD8 T cells, and various antigen-presenting and antibody-secreting cells in mild patients within 3 days of PCR diagnosis. The frequency of key innate immune cells and their functional marker expression are impaired in hospitalized patients at day 1 of inclusion. T cell and dendritic cell responses at day 1 are highly predictive for SARS-CoV-2-specific antibody responses after 3 weeks in mild but not hospitalized patients. Our systematic analysis reveals a combinatorial picture and trajectory of various arms of the highly coordinated early-stage immune responses in mild COVID-19 patients.
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Antivirais , COVID-19 , Anticorpos Antivirais , Linfócitos T CD8-Positivos , Humanos , SARS-CoV-2RESUMO
Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.
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INTRODUCTION: Research on factors associated with late-life cognitive performance in diverse racial/ethnic groups is increasingly important due to the growing size and racial diversity of the elder population. METHODS: Using data on American Indians (AIs) from the Strong Heart Study, we measured associations between mid-life physical activity (PA), assessed by a questionnaire or pedometer, and performance on tests of general cognitive function, phonemic fluency, verbal learning and memory, and processing speed. Cognitive tests were administered 7-21 years after PA measurements. To estimate associations, we used regression models with and without inverse-probability weights to account for potential attrition bias in the cohort. RESULTS: Questionnaire and pedometer measures of PA were positively associated with cognitive function. Participants in the top quartile of questionnaire-based PA had Modified Mini-Mental State examination scores 3.2 (95% CI: 1.5-4.9) points higher than participants in the lowest quartile. Phonemic fluency scores also trended higher for participants in the top compared to the bottom categories for both PA measures: top questionnaire quartile = 2.7 (95% CI: 0.6-4.8) points higher and top pedometry tertile = 6.7 (95% CI: 2.7-10.7) points higher. We observed no associations between PA and tests assessing verbal learning and memory, or processing speed. Weighted model results were similar, but less precise. CONCLUSIONS: In this cohort of AIs with relatively low levels of PA, positive associations between mid-life PA and late-life cognitive performance were dose-dependent and of modest clinical significance.
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Cognição , Exercício Físico , Idoso , Estudos de Coortes , Humanos , Testes Neuropsicológicos , Indígena Americano ou Nativo do AlascaRESUMO
OBJECTIVES: We examined the prevalence of substance use as a coping mechanism and identified relationships between maternal mental health over time and use of substances to cope during the Coronavirus Disease 2019 (COVID-19) pandemic among pregnant women in the U.S.A. METHODS: Self-reported repeated measures from 83 pregnant women were collected online in April 2020 and May 2020. Women retrospectively reported their mental/emotional health before the pandemic, as well as depression, stress, and substance use as a result of the pandemic at both time points. Linear regression measured cross-sectional and longitudinal associations between mental health and substance use. RESULTS: Pre-COVID-19 reports of poorer mental/emotional health (b = 0.46) were significantly (p < .05) associated with number of substances used to cope with the pandemic. Elevated stress (b = 0.35) and depressive symptoms (b = 0.27) and poorer mental/emotional health (b = 0.14) in April were also significantly related to higher numbers of substances used in May (p < .05). CONCLUSION: Pregnant women's psychological well-being may be a readily measured indicator substance use risk during crises such as the COVID-19 pandemic. Interventions addressing increased stress and depression may also mitigate the emergence of greater substance use among pregnant women.
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COVID-19 , Transtornos Relacionados ao Uso de Substâncias , Feminino , Gravidez , Humanos , Pandemias , COVID-19/epidemiologia , Gestantes/psicologia , Saúde Mental , Estudos Transversais , Estudos Retrospectivos , SARS-CoV-2 , Estresse Psicológico/epidemiologia , Estresse Psicológico/diagnóstico , Transtornos Relacionados ao Uso de Substâncias/epidemiologiaRESUMO
BACKGROUND: Psychological stress and coping experienced during pregnancy can have important effects on maternal and infant health, which can also vary by race, ethnicity, and socioeconomic status. Therefore, we assessed stressors, coping behaviors, and resources needed in relation to the COVID-19 pandemic in a sample of 162 perinatal (125 pregnant and 37 postpartum) women in the United States. METHODS: A mixed-methods study captured quantitative responses regarding stressors and coping, along with qualitative responses to open-ended questions regarding stress and resources needed during the COVID-19 pandemic. Logistic and linear regression models were used to analyze differences between pregnant and postpartum participants, as well as differences across key demographic variables. Qualitative content analysis was used to analyze open-ended questions. RESULTS: During the COVID-pandemic, food scarcity and shelter-in-place restrictions made it difficult for pregnant women to find healthy foods. Participants also reported missing prenatal appointments, though many reported using telemedicine to obtain these services. Financial issues were prevalent in our sample and participants had difficulty obtaining childcare. After controlling for demographic variables, pregnant women were less likely to engage in healthy stress-coping behaviors than postpartum women. Lastly, we were able to detect signals of increased stressors induced by the COVID-19 pandemic, and less social support, in perinatal women of racial and ethnic minority, and lower-income status. Qualitative results support our survey findings as participants expressed concerns about their baby contracting COVID-19 while in the hospital, significant others missing the delivery or key obstetric appointments, and wanting support from friends, family, and birthing classes. Financial resources, COVID-19 information and research as it relates to maternal-infant health outcomes, access to safe healthcare, and access to baby supplies (formula, diapers, etc.) emerged as the primary resources needed by participants. CONCLUSIONS: To better support perinatal women's mental health during the COVID-19 pandemic, healthcare providers should engage in conversations regarding access to resources needed to care for newborns, refer patients to counseling services (which can be delivered online/via telephone) and virtual support groups, and consistently screen pregnant women for stressors.
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Adaptação Psicológica , COVID-19 , Recursos em Saúde/organização & administração , Acessibilidade aos Serviços de Saúde , Poder Familiar/psicologia , Assistência Perinatal , Educação Pré-Natal/métodos , COVID-19/epidemiologia , COVID-19/prevenção & controle , COVID-19/psicologia , Feminino , Alocação de Recursos para a Atenção à Saúde/estatística & dados numéricos , Acessibilidade aos Serviços de Saúde/normas , Acessibilidade aos Serviços de Saúde/tendências , Humanos , Recém-Nascido , Saúde Mental/normas , Avaliação das Necessidades , Assistência Perinatal/métodos , Assistência Perinatal/organização & administração , Assistência Perinatal/tendências , Gravidez , SARS-CoV-2 , Estresse Psicológico/etiologia , Estresse Psicológico/prevenção & controle , Telemedicina/métodos , Telemedicina/organização & administração , Estados UnidosRESUMO
Importance: The incidence of and mortality from coronary heart disease (CHD) are substantially higher among African American individuals compared with non-Hispanic White individuals, even after adjusting for traditional factors associated with CHD. The unexplained excess risk might be due to genetic factors related to African ancestry that are associated with a higher risk of CHD, such as the heterozygous state for the sickle cell variant or sickle cell trait (SCT). Objective: To evaluate whether there is an association between SCT and the incidence of myocardial infarction (MI) or composite CHD outcomes in African American individuals. Design, Setting, and Participants: This cohort study included 5 large, prospective, population-based cohorts of African American individuals in the Women's Health Initiative (WHI) study, the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, the Multi-Ethnic Study of Atherosclerosis (MESA), the Jackson Heart Study (JHS), and the Atherosclerosis Risk in Communities (ARIC) study. The follow-up periods included in this study were 1993 and 1998 to 2014 for the WHI study, 2003 to 2014 for the REGARDS study, 2002 to 2016 for the MESA, 2002 to 2015 for the JHS, and 1987 to 2016 for the ARIC study. Data analysis began in October 2013 and was completed in October 2020. Exposures: Sickle cell trait status was evaluated by either direct genotyping or high-quality imputation of rs334 (the sickle cell variant). Participants with sickle cell disease and those with a history of CHD were excluded from the analyses. Main Outcomes and Measures: Incident MI, defined as adjudicated nonfatal or fatal MI, and incident CHD, defined as adjudicated nonfatal MI, fatal MI, coronary revascularization procedures, or death due to CHD. Cox proportional hazards regression models were used to estimate the hazard ratio for incident MI or CHD comparing SCT carriers with noncarriers. Models were adjusted for age, sex (except for the WHI study), study site or region of residence, hypertension status or systolic blood pressure, type 1 or 2 diabetes, serum high-density lipoprotein level, total cholesterol level, and global ancestry (estimated from principal components analysis). Results: A total of 23â¯197 African American men (29.8%) and women (70.2%) were included in the combined sample, of whom 1781 had SCT (7.7% prevalence). Mean (SD) ages at baseline were 61.2 (6.9) years in the WHI study (n = 5904), 64.0 (9.3) years in the REGARDS study (n = 10â¯714), 62.0 (10.0) years in the MESA (n = 1556), 50.3 (12.0) years in the JHS (n = 2175), and 53.2 (5.8) years in the ARIC study (n = 2848). There were no significant differences in the distribution of traditional factors associated with cardiovascular disease by SCT status within cohorts. A combined total of 1034 participants (76 with SCT) had incident MI, and 1714 (137 with SCT) had the composite CHD outcome. The meta-analyzed crude incidence rate of MI did not differ by SCT status and was 3.8 per 1000 person-years (95% CI, 3.3-4.5 per 1000 person-years) among those with SCT and 3.6 per 1000 person-years (95% CI, 2.7-5.1 per 1000 person-years) among those without SCT. For the composite CHD outcome, these rates were 7.3 per 1000 person-years (95% CI, 5.5-9.7 per 1000 person-years) among those with SCT and 6.0 per 1000 person-years (95% CI, 4.9-7.4 per 1000 person-years) among those without SCT. Meta-analysis of the 5 study results showed that SCT status was not significantly associated with MI (hazard ratio, 1.03; 95% CI, 0.81-1.32) or the composite CHD outcome (hazard ratio, 1.16; 95% CI, 0.92-1.47). Conclusions and Relevance: In this cohort study, there was not an association between SCT and increased risk of MI or CHD in African American individuals. These disorders may not be associated with sickle cell trait-related sudden death in this population.
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Negro ou Afro-Americano/estatística & dados numéricos , Doença das Coronárias , Traço Falciforme , Idoso , Estudos de Coortes , Doença das Coronárias/complicações , Doença das Coronárias/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Traço Falciforme/complicações , Traço Falciforme/epidemiologiaRESUMO
The burden of Alzheimer's disease and related dementias (ADRD) has increased substantially in the United States, particularly in health disparity populations. Little is known about the epidemiology of ADRD in American Indian (AI) adults, although they have a high prevalence of ADRD risk factors including hypertension, diabetes, obesity, and smoking. Using electronic health records from a large health care organization during 2016-18, we describe characteristics of AI patients aged ≥55 years with and without an ADRD diagnosis, assess ADRD risk factors and contrast findings with results from age- and sex-matched non-Hispanic White (NHW) patients. To identify factors associated with ADRD diagnoses, we estimated population-averaged prevalence rate ratios to approximate relative risk (RR) using generalized estimating equations models adjusted for age, sex, and marital and rural residency status. The age-adjusted prevalence of ADRD diagnosis was 6.6% of AI patients, compared with 4.4% in NHW patients. Patient age and diagnosis of hypertension, depression, hyperlipidemia, or diabetes were significantly associated with higher risk of ADRD diagnosis in AIs (RR range: 1.1-2.8) whereas female sex or being married/having a partner were associated with lower risk of ADRD diagnosis (each RR=.7). ADRD risk factors were generally similar between AI and NHW patients, except for sex and marital status. However, the adjusted risk of ADRD was approximately 49% higher in AI patients. To our knowledge, our study is the first to examine ADRD diagnoses and comorbidities in AIs across a large geographical region in southwest United States. Future efforts to confirm our findings in diverse AI communities are warranted.
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Doença de Alzheimer/etnologia , Indígena Americano ou Nativo do Alasca/estatística & dados numéricos , Fatores Etários , Idoso , Estudos de Casos e Controles , Comorbidade , Depressão/etnologia , Diabetes Mellitus/etnologia , Registros Eletrônicos de Saúde , Feminino , Humanos , Hiperlipidemias/etnologia , Hipertensão/etnologia , Masculino , Estado Civil , Pessoa de Meia-Idade , Prevalência , Fatores de Proteção , Fatores de Risco , Fatores Sexuais , Sudoeste dos Estados Unidos/epidemiologia , Estados Unidos/epidemiologia , População Branca/estatística & dados numéricosRESUMO
BACKGROUND AND PURPOSE: Stroke is a complex disease with multiple genetic and environmental risk factors. Blacks endure a nearly 2-fold greater risk of stroke and are 2× to 3× more likely to die from stroke than European Americans. METHODS: The COMPASS (Consortium of Minority Population Genome-Wide Association Studies of Stroke) has conducted a genome-wide association meta-analysis of stroke in >22 000 individuals of African ancestry (3734 cases, 18 317 controls) from 13 cohorts. RESULTS: In meta-analyses, we identified one single nucleotide polymorphism (rs55931441) near the HNF1A gene that reached genome-wide significance (P=4.62×10-8) and an additional 29 variants with suggestive evidence of association (P<1×10-6), representing 24 unique loci. For validation, a look-up analysis for a 100 kb region flanking the COMPASS single nucleotide polymorphism was performed in SiGN (Stroke Genetics Network) Europeans, SiGN Hispanics, and METASTROKE (Europeans). Using a stringent Bonferroni correction P value of 2.08×10-3 (0.05/24 unique loci), we were able to validate associations at the HNF1A locus in both SiGN (P=8.18×10-4) and METASTROKE (P=1.72×10-3) European populations. Overall, 16 of 24 loci showed evidence for validation across multiple populations. Previous studies have reported associations between variants in the HNF1A gene and lipids, C-reactive protein, and risk of coronary artery disease and stroke. Suggestive associations with variants in the SFXN4 and TMEM108 genes represent potential novel ischemic stroke loci. CONCLUSIONS: These findings represent the most thorough investigation of genetic determinants of stroke in individuals of African descent, to date.
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Negro ou Afro-Americano/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único/genética , Acidente Vascular Cerebral/genética , Negro ou Afro-Americano/etnologia , Estudos de Coortes , Predisposição Genética para Doença/etnologia , Humanos , Acidente Vascular Cerebral/etnologiaRESUMO
OBJECTIVE: To investigate the prevalence and risk factors associated with parental depressive symptoms at neonatal intensive care unit (NICU) discharge and determine the relationships among depressive symptoms, stress, and social support. STUDY DESIGN: Parents participating in the Giving Parents Support trial (n = 300) were surveyed before NICU discharge. Depressive symptoms, stress, and social support were assessed using the Center for Epidemiological Studies Depression Scale (CESD-10), Parental Stressor Scale: Neonatal Intensive Care Unit (PSS:NICU), Perceived Stress Scale (PSS-10), and Multidimensional Scale of Perceived Social Support (MSPSS). Regression analyses examined relationships among depressive symptoms, stress, social support, and parent/infant factors. RESULTS: At NICU discharge, 45% of parents reported depressive symptoms and 43% reported elevated perceived stress. Increased odds of elevated depressive symptoms were associated with older gestational age (P = .02), female infant (P = .02), and longer length of stay (P = .045). Odds of depression were 7.87 (95% CI, 2.15-28.75) for parents of infants with gestational age ≥37 weeks compared with gestational age <28 weeks. Parental NICU stress was higher in younger parents (P < .01). Depressive symptoms were positively associated with parental stress. Each 1-point increase in PSS:NICU score was associated with a 2.1-point (95% CI, 1.6-2.9; P < .001) increase in CESD-10 score. Social support was inversely associated with depressive symptoms. CONCLUSION: The prevalence of depressive symptoms in parents at NICU discharge was high, even among parents of term infants. Older gestational age, greater parental stress, and lower levels of social support were strong correlates of depressive symptoms. Strategies to support parents, including depression screening, stress reduction strategies, and mental health referrals, are needed.
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Depressão/epidemiologia , Pais/psicologia , Apoio Social , Estresse Psicológico/epidemiologia , Feminino , Humanos , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Masculino , Alta do Paciente , Prevalência , Fatores de Risco , AutorrelatoRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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BACKGROUND: Clinical stroke is prevalent in American Indians, but the lifestyle risk factors for vascular brain injury have not been well-studied in this population. The purpose of this study was to correlate brain magnetic resonance imaging (MRI) findings with obesity, alcohol use, and smoking behaviors in elderly American Indians from the Strong Heart Study. METHODS: Cranial MRI scans (n = 789) were analyzed for dichotomous measures of infarcts, hemorrhages, white matter hyperintensities (WMH), and cerebral atrophy and continuous measures of total brain, WMH, and hippocampal volume. Poisson regression was used to estimate prevalence ratios, and linear regression was used to estimate measures of association for continuous outcomes. Models were adjusted for the risk factors of interest as well as age, sex, study site, income, education, hypertension, diabetes, and low-density lipoprotein cholesterol. RESULTS: Smoking was associated with increased hippocampal atrophy (p = 0.002) and increased prevalence of sulcal widening (p < 0.001). Relative to nonsmokers, smokers with more than 25 pack-years of smoking had a 27% (95% CI 7-47%) increased prevalence of high-grade sulci, p = 0.005. Body mass index was inversely associated with prevalence of nonlacunar infarcts and sulcal widening (all p = 0.004). Alcohol use was not significantly associated with any of the measured MRI findings. CONCLUSIONS: This study found similar associations between smoking and vascular brain injury among American Indians, as seen in other populations. In particular, these findings support the role of smoking as a key correlate for cerebral atrophy.
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Encéfalo/patologia , Doenças Cardiovasculares/etnologia , Indígenas Norte-Americanos/etnologia , Estilo de Vida , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas/etnologia , Encéfalo/diagnóstico por imagem , Doenças Cardiovasculares/complicações , Feminino , Humanos , Indígenas Norte-Americanos/psicologia , Imageamento por Ressonância Magnética , Masculino , Obesidade/etnologia , Fatores de Risco , Fumar/etnologia , Acidente Vascular Cerebral/etnologia , Acidente Vascular Cerebral/etiologia , Estados Unidos/etnologiaRESUMO
Telomere length is a heritable marker of cellular age that is associated with morbidity and mortality. Poor sleep behaviors, which are also associated with adverse health events, may be related to leukocyte telomere length (LTL). We studied a subpopulation of 3,145 postmenopausal women (1,796 European-American (EA) and 1,349 African-American (AA)) enrolled in the Women's Health Initiative in 1993-1998 with data on Southern blot-measured LTL and self-reported usual sleep duration and sleep disturbance. LTL-sleep associations were analyzed separately for duration and disturbance using weighted and confounder-adjusted linear regression models in the entire sample (AAs + EAs; adjusted for race/ethnicity) and in racial/ethnic strata, since LTL differs by ancestry. After adjustment for covariates, each additional daily hour of sleep beyond 5 hours, approximately, was associated with a 27-base-pair (95% confidence interval (CI): 6, 48) longer LTL in the entire sample. Associations between sleep duration and LTL were strongest among AAs (adjusted ß = 37, 95% CI: 4, 70); a similar, nonsignificant association was observed for EAs (adjusted ß = 20, 95% CI: -7, 48). Sleep disturbance was not associated with LTL in our study. Our models did not show departure from linearity (quadratic sleep terms: P ≥ 0.55). Our results suggest that longer sleep duration is associated with longer LTL in postmenopausal women.
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Sono , Telômero/ultraestrutura , Negro ou Afro-Americano , Idoso , Estudos Transversais , Feminino , Humanos , Modelos Lineares , Pessoa de Meia-Idade , Pós-Menopausa , Estudos Prospectivos , Autorrelato , Sono/genética , Sono/fisiologia , Fatores Socioeconômicos , População Branca , Saúde da MulherRESUMO
BACKGROUND: Clinical stroke is prevalent in American Indians, but the risk factors for cerebrovascular pathology have not been well-studied in this population. The purpose of this study was to correlate abnormalities on brain magnetic resonance imaging (MRI) with clinical risk factors in a cohort of elderly American Indians. METHODS: Brain MRI scans from 789 participants of the Strong Heart Study were analyzed for infarcts, hemorrhage, white matter disease, and measures of cerebral atrophy including ventricular and sulcal grade and total brain volume. Clinical risk factors included measures of hypertension, diabetes, and high levels of low-density lipoprotein (LDL) cholesterol. Regression models adjusted for potential confounders were used to estimate associations between risk factors and brain MRI outcomes. RESULTS: -Hypertension was associated with the presence of infarcts (p = 0.001), ventricle enlargement (p = 0.01), and increased white matter hyperintensity volume (p = 0.01). Diabetes was associated with increased prevalence of cerebral atrophy (p < 0.001), ventricular enlargement (p = 0.001), and sulcal widening (p = 0.001). High LDL was not significantly associated with any of the measured cranial imaging outcomes. CONCLUSIONS: This study found risk factors for cerebrovascular disease in American Indians similar to those seen in other populations and provides additional evidence for the important roles of hypertension and diabetes in promoting cerebral infarcts and brain atrophy, respectively.
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Encéfalo/diagnóstico por imagem , Transtornos Cerebrovasculares/diagnóstico por imagem , Transtornos Cerebrovasculares/etnologia , Indígenas Norte-Americanos/etnologia , Imageamento por Ressonância Magnética/tendências , Adulto , Idoso , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/etnologia , Transtornos Cerebrovasculares/sangue , LDL-Colesterol/sangue , Estudos de Coortes , Diabetes Mellitus/sangue , Diabetes Mellitus/diagnóstico por imagem , Diabetes Mellitus/etnologia , Feminino , Humanos , Hipertensão/sangue , Hipertensão/diagnóstico por imagem , Hipertensão/etnologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Estados Unidos/etnologiaRESUMO
Current knowledge of the genetic architecture of key reproductive events across the female life course is largely based on association studies of European descent women. The relevance of known loci for age at menarche (AAM) and age at natural menopause (ANM) in diverse populations remains unclear. We investigated 32 AAM and 14 ANM previously-identified loci and sought to identify novel loci in a trans-ethnic array-wide study of 196,483 SNPs on the MetaboChip (Illumina, Inc.). A total of 45,364 women of diverse ancestries (African, Hispanic/Latina, Asian American and American Indian/Alaskan Native) in the Population Architecture using Genomics and Epidemiology (PAGE) Study were included in cross-sectional analyses of AAM and ANM. Within each study we conducted a linear regression of SNP associations with self-reported or medical record-derived AAM or ANM (in years), adjusting for birth year, population stratification, and center/region, as appropriate, and meta-analyzed results across studies using multiple meta-analytic techniques. For both AAM and ANM, we observed more directionally consistent associations with the previously reported risk alleles than expected by chance (p-valuesbinomial≤0.01). Eight densely genotyped reproductive loci generalized significantly to at least one non-European population. We identified one trans-ethnic array-wide SNP association with AAM and two significant associations with ANM, which have not been described previously. Additionally, we observed evidence of independent secondary signals at three of six AAM trans-ethnic loci. Our findings support the transferability of reproductive trait loci discovered in European women to women of other race/ethnicities and indicate the presence of additional trans-ethnic associations both at both novel and established loci. These findings suggest the benefit of including diverse populations in future studies of the genetic architecture of female growth and development.
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Variação Biológica da População/genética , Menarca/genética , Menopausa/genética , Fatores Etários , Alelos , Variação Biológica da População/etnologia , Feminino , Loci Gênicos/genética , Genótipo , Humanos , Menarca/etnologia , Menopausa/etnologia , Fenótipo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
C-reactive protein (CRP) is a circulating biomarker indicative of systemic inflammation. We aimed to evaluate genetic associations with CRP levels among non-European-ancestry populations through discovery, fine-mapping and conditional analyses. A total of 30 503 non-European-ancestry participants from 6 studies participating in the Population Architecture using Genomics and Epidemiology study had serum high-sensitivity CRP measurements and â¼200 000 single nucleotide polymorphisms (SNPs) genotyped on the Metabochip. We evaluated the association between each SNP and log-transformed CRP levels using multivariate linear regression, with additive genetic models adjusted for age, sex, the first four principal components of genetic ancestry, and study-specific factors. Differential linkage disequilibrium patterns between race/ethnicity groups were used to fine-map regions associated with CRP levels. Conditional analyses evaluated for multiple independent signals within genetic regions. One hundred and sixty-three unique variants in 12 loci in overall or race/ethnicity-stratified Metabochip-wide scans reached a Bonferroni-corrected P-value <2.5E-7. Three loci have no (HACL1, OLFML2B) or only limited (PLA2G6) previous associations with CRP levels. Six loci had different top hits in race/ethnicity-specific versus overall analyses. Fine-mapping refined the signal in six loci, particularly in HNF1A. Conditional analyses provided evidence for secondary signals in LEPR, IL1RN and HNF1A, and for multiple independent signals in CRP and APOE. We identified novel variants and loci associated with CRP levels, generalized known CRP associations to a multiethnic study population, refined association signals at several loci and found evidence for multiple independent signals at several well-known loci. This study demonstrates the benefit of conducting inclusive genetic association studies in large multiethnic populations.
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Proteína C-Reativa/genética , Estudo de Associação Genômica Ampla , Metagenômica , Epidemiologia Molecular/métodos , Carbono-Carbono Liases , Enoil-CoA Hidratase/genética , Feminino , Glicoproteínas/genética , Fosfolipases A2 do Grupo VI/genética , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único , População Branca/genéticaRESUMO
Parents of infants hospitalized in a neonatal intensive care unit (NICU) experience increased anxiety and stress, which may persist after discharge. The rationale and design of a randomized clinical trial assessing the impact of a 1-year, post-discharge, peer support intervention (parent navigation) on parental mental health and infant health care utilization is described. Qualitative methods guided the adaptation of an existing parent support program to target emotional and resource-related needs of NICU families. Approximately 300 parent-infant dyads were enrolled at discharge and randomized to either receive a care notebook (control group) or a parent navigator and a care notebook (intervention group). We aim to determine if the parent navigator intervention: 1) increases self-efficacy and decreases stress in parents, 2) decreases overall levels of anxiety and depression in parents, 3) decreases infant hospitalizations and emergency department visits, and 4) increases adherence to infant vaccination recommendations during 1â¯year of follow-up. Standardized, self-reported psychological scales to assess parent depression, anxiety, self-efficacy and social support were administered at baseline (NICU discharge) and at 1-week, 1-, 3-, 6- and 12-month intervals. Infant immunization status and health care utilization during the study period were also assessed. This paper reviews challenges and successes during implementation. If this intervention improves outcomes, NICUs may choose to provide similar parent navigation services for infants and families transitioning from the NICU to home. This study was registered with ClinicalTrials.gov (NCT02643472) on December 31, 2015.
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Ansiedade/prevenção & controle , Depressão/prevenção & controle , Unidades de Terapia Intensiva Neonatal , Pais/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Apoio Social , Estresse Psicológico/prevenção & controle , Adulto , Ansiedade/diagnóstico , Ansiedade/etiologia , Depressão/diagnóstico , Depressão/etiologia , District of Columbia , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Recém-Nascido , Masculino , Maryland , Alta do Paciente , Autoeficácia , Autorrelato , Método Simples-Cego , Estresse Psicológico/diagnóstico , Estresse Psicológico/etiologia , VirginiaRESUMO
Importance: African Americans and individuals of African ancestry have a higher risk of stroke compared with non-Hispanic white individuals. Identifying the source of this disparity could provide an opportunity for clinical stroke risk stratification and more targeted therapy. Whether sickle cell trait (SCT) is an indicator of increased risk of ischemic stroke among African Americans is still unclear. Objective: To examine whether SCT is associated with a higher risk of incident ischemic stroke among African Americans. Design, Setting, and Participants: This meta-analysis assessed the association of SCT with the risk of incident ischemic stroke. Four large, prospective, population-based studies with African American cohorts were assessed: Jackson Heart Study (September 1, 2005, through December 31, 2012), Multi-Ethnic Study of Atherosclerosis (July 1, 2002, through December 31, 2012), Reasons for Geographic and Racial Differences in Stroke (January 1, 2003, through December 31, 2014), and Women's Health Initiative (October 1, 1998, through December 31, 2012). Using a Cox proportional hazards regression model adjusted for major stroke risk factors, this study estimated the hazard ratio for incident ischemic stroke associated with SCT. Data analysis was performed from July 10, 2016, to February 2, 2017. Interventions or Exposures: Participants' SCT status determined by polymerase chain reaction assay genotyping or a combination of whole-exome sequencing and imputation. Main Outcomes and Measures: Incident ischemic stroke. Results: This meta-analysis included 19â¯464 African American individuals (1520 with SCT, 17â¯944 without SCT, and 620 with ischemic stroke) from 4 studies, with a mean (SD) age of 60.0 (13.0) years (5257 [27.0%] men and 14 207 [73.0%] women). No differences were found in the distribution of risk factors for ischemic stroke comparing participants with and those without SCT at study visit 1 in each cohort. The crude incidence of ischemic stroke was 2.9 per 1000 person-years (95% CI, 2.2-4.0 per 1000 person-years) among those with SCT and 3.2 per 1000 person-years (95% CI, 2.7-3.8 per 1000 person-years) among those without SCT. After stroke risk factors were adjusted for, the hazard ratio of incident ischemic stroke independently associated with SCT in the meta-analysis of all 4 cohorts was 0.80 (95% CI, 0.47-1.35; P = .82). The results of the meta-analysis were similar to those of individual cohorts, in which the results were also similar. Conclusions and Relevance: Sickle cell trait may not be associated with incidence of ischemic stroke among African Americans. The results of this study suggest performing a more thorough clinical evaluation of a stroke patient with SCT rather than assuming that SCT is the etiologic factor for the stroke.
Assuntos
Negro ou Afro-Americano/estatística & dados numéricos , Isquemia Encefálica/epidemiologia , Traço Falciforme/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Idoso , Feminino , Hemoglobinas/genética , Heterozigoto , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Mutação , Traço Falciforme/genética , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Most of the reduction in malaria prevalence seen in Africa since 2000 has been attributed to vector control interventions. Yet increases in the distribution and intensity of insecticide resistance and higher costs of newer insecticides pose a challenge to sustaining these gains. Thus, endemic countries face challenging decisions regarding the choice of vector control interventions. METHODS: A cluster randomised trial is being carried out in Mopeia District in the Zambezia Province of Mozambique, where malaria prevalence in children under 5 is high (68% in 2015), despite continuous and campaign distribution of long-lasting insecticide-treated nets (LLINs). Study arm 1 will continue to use the standard, LLIN-based National Malaria Control Programme vector control strategy (LLINs only), while study arm 2 will receive indoor residual spraying (IRS) once a year for 2 years with a microencapsulated formulation of pirimiphos-methyl (Actellic 300 CS), in addition to the standard LLIN strategy (LLINs+IRS). Prior to the 2016 IRS implementation (the first of two IRS campaigns in this study), 146 clusters were defined and stratified per number of households. Clusters were then randomised 1:1 into the two study arms. The public health impact and cost-effectiveness of IRS intervention will be evaluated over 2 years using multiple methods: (1) monthly active malaria case detection in a cohort of 1548 total children aged 6-59 months; (2) enhanced passive surveillance at health facilities and with community health workers; (3) annual cross-sectional surveys; and (4) entomological surveillance. Prospective microcosting of the intervention and provider and societal costs will be conducted. Insecticide resistance status pattern and changes in local Anopheline populations will be included as important supportive outcomes. DISCUSSION: By evaluating the public health impact and cost-effectiveness of IRS with a non-pyrethroid insecticide in a high-transmission setting with high LLIN ownership, it is expected that this study will provide programmatic and policy-relevant data to guide national and global vector control strategies. TRIAL REGISTRATION NUMBER: NCT02910934.
RESUMO
Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.