Search

BackgroundWhile large genome-wide association studies have identified nearly one thousand loci associated with variation in blood pressure, rare variant identification is still a challenge. In family-based cohorts, genome-wide linkage scans have been successful in identifying rare genetic variants for blood pressure. This study aims to identify low frequency and rare genetic variants within previously reported linkage regions on chromosomes 1 and 19 in African American families from the Trans-Omics for Precision Medicine (TOPMed) program. Genetic association analyses weighted by linkage evidence were completed with whole genome sequencing data within and across TOPMed ancestral groups consisting of 60,388 individuals of European, African, East Asian, Hispanic, and Samoan ancestries.ResultsAssociations of low frequency and rare variants in RCN3 and multiple other genes were observed for blood pressure traits in TOPMed samples. The association of low frequency and rare coding variants in RCN3 was further replicated in UK Biobank samples (N = 403,522), and reached genome-wide significance for diastolic blood pressure (p = 2.01 × 10- 7).ConclusionsLow frequency and rare variants in RCN3 contributes blood pressure variation. This study demonstrates that focusing association analyses in linkage regions greatly reduces multiple-testing burden and improves power to identify novel rare variants associated with blood pressure traits.

In this study, we investigated low-frequency and rare variants associated with blood pressure (BP) by focusing on a linkage region on chromosome 16p13. We used whole genome sequencing (WGS) data obtained through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program on 395 Cleveland Family Study (CFS) European Americans (CFS-EA). By analyzing functional coding variants and non-coding rare variants with CADD score > 10 residing within the chromosomal region in families with linkage evidence, we observed 25 genes with nominal statistical evidence (burden or SKAT p

Objectives: People with childhood-onset disabilities are living into adulthood, and the prevalence of smoking and illicit drug use among adults with disabilities is high. We evaluated the relationship between disability status and age of disability onset, current cigarette smoking status, and heavy alcohol drinking. Methods: We conducted a secondary data analysis of the National Health Interview Survey (NHIS), a US survey on illness and disability. Among 2020 NHIS participants aged 22-80 years (n = 28 225), we compared self-reported prevalence of current cigarette smoking and heavy alcohol drinking among those with and without disabilities and among those with childhood- versus adult-onset disabilities. We used adjusted logistic regression analysis to calculate the adjusted odds ratios (AORs) of current smoking and heavy alcohol drinking based on disability status and age of disability onset. Results: Compared with adults without disabilities, adults with disabilities were significantly more likely to report current smoking (23.5% vs 11.2%; P <.001) and significantly less likely to report heavy alcohol drinking (5.3% vs 7.4%; P =.001). The prevalence of these behaviors did not vary significantly by age of disability onset. In adjusted logistic regression models, adults with disabilities had significantly higher odds of current smoking (AOR = 1.76; 95% CI, 1.53-2.03) and similar odds of heavy alcohol drinking (AOR = 0.82; 95% CI, 0.65-1.04) compared with adults without disabilities. The odds of these health behaviors did not vary significantly by age of disability onset. Conclusions: Adults with disabilities overall may be at high risk for these unhealthy behaviors, particularly smoking, regardless of age of disability onset. Routine screening and cessation counseling related to smoking and unhealthy alcohol use are important for all people with disabilities. [ABSTRACT FROM AUTHOR]

Background: Neuropsychiatric systemic lupus erythematosus (NPSLE) is a poorly understood and heterogeneous manifestation of SLE. Common major NPSLE syndromes include strokes, seizures, myelitis, and aseptic meningitis. Easily obtainable biomarkers are needed to assist in early diagnosis and improve outcomes for NPSLE. A frequent end-result of major syndromes is neuronal or glial injury. Blood-based neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) have been utilized as markers for monitoring disease activity and/or severity in other neurodegenerative and neuroinflammatory diseases; however, they have not been evaluated in active major NPSLE. Methods: This was a case-control study. We enrolled patients aged 12-60 years with active major NPSLE, SLE without active major NPSLE, and healthy controls. Active NPSLE was defined as being <6 months from last new or worsening neuropsychiatric symptom. Demographics, clinical data, and serum or plasma biosamples were collected. Results: Thirteen patients with active major NPSLE, 13 age/sex/kidney function matched SLE controls without active major NPSLE, and 13 age/sex matched healthy controls (mean ages 26.8, 27.3, 26.6 years) were included. 92% of each group were female. Major syndromes included stroke (5), autonomic disorder (3), demyelinating disease (2), aseptic meningitis (2), sensorimotor polyneuropathy (2), cranial neuropathy (1), seizures (1), and myelopathy (2). Mean (standard deviation) blood NfL and GFAP were 3.6 pg/ml (2.0) and 50.4 pg/ml (15.0), respectively, for the healthy controls. Compared to healthy controls, SLE without active major NPSLE had mean blood NfL and GFAP levels 1.3 pg/ml (p =.42) and 1.2 pg/ml higher (p =.53), respectively. Blood NfL was on average 17.9 pg/ml higher (95% CI: 9.2, 34.5; p <.001) and blood GFAP was on average 3.2 pg/ml higher (95% CI: 1.9, 5.5; p <.001) for cases of active major NPSLE compared to SLE without active major NPSLE. In a subset of 6 patients sampled at multiple time points, blood NfL and GFAP decreased after immunotherapy. Conclusions: Blood NfL and GFAP levels are elevated in persons with SLE with active major NPSLE compared to disease matched controls and may lower after immunotherapy initiation. Larger and longitudinal studies are needed to ascertain their utility in a clinical setting. [ABSTRACT FROM AUTHOR]

Background. Postpartum weight retention is a risk factor for obesity and is particularly important among Hispanic women who have an increased rate of obesity. Given its broad reach, the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) program provides an ideal setting to implement community-based interventions for low-income postpartum women. Purpose. To examine the feasibility, acceptability, and preliminary efficacy of a multicomponent intervention delivered by staff within the WIC program designed to promote behavior changes in urban, postpartum women with overweight/obesity. Method. This was a 12-week pilot trial randomizing participants to a health behavior change (Intervention) or control (Observation) group. The Intervention included monthly visits with trained WIC staff providing patient-centered behavior change counseling, with multiple touchpoints between visits promoting self-monitoring and offering health behavior change support. Results. Participants (n = 41), who were mainly Hispanic (n = 37, 90%) and Spanish-speaking (n = 33, 81%), were randomized to the Intervention (n = 19) or Observation (n = 22) group. In the Intervention group, 79% (n = 15) of eligible participants were retained for the study duration. All Intervention participants endorsed that they would participate again. Regarding physical activity, participant readiness to change and self-efficacy improved for Intervention participants. About one-quarter of women in the Intervention group (27%, n = 4) had a 5% weight loss compared with one woman (5%) in the Observation group; this difference was not statistically significant (p =.10). Conclusions. This pilot demonstrated the feasibility and acceptability of delivering a low-intensity behavior change intervention within the WIC setting for postpartum women with overweight/obesity. Findings support the role of WIC in addressing postpartum obesity. [ABSTRACT FROM AUTHOR]

Turner syndrome (TS) is a genetic condition occurring in ~1 in 2000 females characterized by the complete or partial absence of the second sex chromosome. TS research faces similar challenges to many other pediatric rare disease conditions, with homogenous, single‐center, underpowered studies. Secondary data analyses utilizing electronic health record (EHR) have the potential to address these limitations; however, an algorithm to accurately identify TS cases in EHR data is needed. We developed a computable phenotype to identify patients with TS using PEDSnet, a pediatric research network. This computable phenotype was validated through chart review; true positives and negatives and false positives and negatives were used to assess accuracy at both primary and external validation sites. The optimal algorithm consisted of the following criteria: female sex, ≥1 outpatient encounter, and ≥3 encounters with a diagnosis code that maps to TS, yielding an average sensitivity of 0.97, specificity of 0.88, and C‐statistic of 0.93 across all sites. The accuracy of any estradiol prescriptions yielded an average C‐statistic of 0.91 across sites and 0.80 for transdermal and oral formulations separately. PEDSnet and computable phenotyping are powerful tools in providing large, diverse samples to pragmatically study rare pediatric conditions like TS. [ABSTRACT FROM AUTHOR]

Objective Both high altitude and trisomy 21 (T21) status can negatively impact respiratory outcomes. The objective of this study was to examine the association between altitude and perinatal respiratory support in neonates with T21 compared with those without T21. Study Design This retrospective cohort study used the United States all-county natality files that included live, singleton, in-hospital births from 2015 to 2019. Descriptive statistics for neonates with and without the primary outcome of sustained assisted ventilation (>6 hours) were compared using t -tests and Chi-squared analyses. Multivariable logistic regression was used to determine the association between respiratory support and the presence of T21, and included an interaction term to determine whether the association between respiratory support and the presence of T21 was modified by elevation at delivery. Results A total of 17,939,006 neonates, 4,059 (0.02%) with T21 and 17,934,947 (99.98%) without, were included in the study. The odds of requiring sustained respiratory support following delivery were 5.95 (95% confidence interval [CI]: 5.31, 6.66), 4.06 (95% CI: 2.39, 6.89), 2.36 (95% CI: 1.64, 3.40), and 5.04 (95% CI: 1.54, 16.54) times as high for neonates with T21 than without T21 when born at low, medium, high, and very high elevations, respectively. The odds of requiring immediate ventilation support following delivery were 5.01 (95% CI: 4.59, 5.46), 5.90 (95% CI: 4.16, 8.36), 2.86 (95% CI: 2.15, 3.80), and 12.08 (95% CI: 6.78, 21.51) times as high for neonates with T21 than without T21 when born at low, medium, high, and very high elevation, respectively. Conclusion Neonates with T21 have increased odds of requiring respiratory support following delivery when compared with neonates without T21 at all categories of altitude. However, the odds ratios did not increase monotonically with altitude which indicates additional research is critical in understanding the effects of altitude on neonates with T21. Key Points Neonates with T21 have an increased need for perinatal respiratory support at all altitudes. The odds of needing perinatal respiratory support did not increase monotonically with elevation. Additional research is critical to understanding the effects of altitude on neonates with T21. [ABSTRACT FROM AUTHOR]

Background. In the aging process, loss of muscle is relatively continuous, but the initiation, timing, and amount of muscle loss that relate to functional compromise are poorly described. Also poorly understood is whether strength and functioning in aging are related to the amount of lean mass and its change as well as to the amount of fat mass and its change. Methods. The purpose of the study was to ascertain whether 3-year lean and fat mass change predicted functional status in 712 African American and Caucasian women, aged 34-58 years. Fat and lean mass were assessed with bioelectrical impedance. Lower leg strength (torque) was measured with a portable isometric chair, and two indices of physical functioning, walking velocity and double support (both feet touching the surface while walking), were measured with an instrumented gait mat. Results. Almost 9% of middle-aged women had at least a 6%, loss (>2.5 kg) of lean mass over the 3-year observation period. Women who lost at least 2.5 kg of lean mass had slower walking velocity and less leg strength, although women who simultaneously gained more than 2.5 kg of fat mass (at least 7.5%) did not have less leg strength. Age was significantly associated with less velocity, less leg strength, and more time in double support. Conclusions. Even in middle-aged women, there is loss of lean mass among almost 1 woman in 10, and this loss of lean mass (sarcopenia) is associated with greater compromise in physical functioning.

Context: Diabetes and cardiovascular diseases are common among men with Klinefelter syndrome (KS) and contribute to high morbidity and mortality. Objective: To determine if cardiometabolic-related diagnoses are more prevalent among youth with KS than matched controls in a large population-based cohort. Methods: Secondary data analysis of electronic health records from 6 pediatric institutions in the United States (PEDSnet). Patients included all youth with KS in the database (n = 1080) and 4497 youth without KS matched for sex, age (mean 13 years at last encounter), year of birth, race, ethnicity, insurance, site, and duration of care (mean 7 years). The main outcome measures were prevalence of 5 cardiometabolic-related outcomes: overweight/obesity, dyslipidemia, dysglycemia, hypertension, and liver dysfunction. Results: The odds of overweight/obesity (OR 1.6; 95% CI 1.4-1.8), dyslipidemia (3.0; 2.2-3.9), and liver dysfunction (2.0; 1.6-2.5) were all higher in KS than in controls. Adjusting for covariates (obesity, testosterone treatment, and antipsychotic use) attenuated the effect of KS on these outcomes; however, boys with KS still had 45% greater odds of overweight/obesity (95% CI 1.2-1.7) and 70% greater odds of liver dysfunction (95% CI 1.3-2.2) than controls, and both dyslipidemia (1.6; 1.1-2.4) and dysglycemia (1.8; 1.1-3.2) were higher in KS but of borderline statistical significance when accounting for multiple comparisons. The odds of hypertension were not different between groups. Conclusion: This large, population-based cohort of youth with KS had a higher odds of most cardiometabolic-related diagnoses than matched controls. [ABSTRACT FROM AUTHOR]