Highlights • The prevalence of albuminuria in adults with established CHF remains unclear. • Among adults with CHF, 22.1% and 10.4% had micro- and macroalbuminuria, respectively • Adults with CHF had ...higher odds of albuminuria (odds ratio 1.89, 95% CI 1.59–2.26).
Development assistance for health (DAH) and foreign aid have been criticized for being poorly associated with health and economic outcomes on a national level. This study is an attempt to examine ...whether DAH targeted specifically to malaria, HIV and tuberculosis (TB) is associated with changes in malaria, HIV and TB mortality, respectively. A dataset of DAH targeted to malaria, HIV and TB and corresponding malaria-, HIV- and TB-specific mortality was compiled for 120 low- and middle-income countries. Regression analysis was performed using country and time-period fixed effects and control variables. While malaria and HIV DAH were associated with reductions in malaria and HIV mortality, respectively, TB DAH was not significantly associated with reductions in TB mortality. Estimates were consistent in various sensitivity analyses, including generalized method of moments estimation, addition of extra controls and analysis of a multiply imputed dataset. In conclusion, targeted DAH is associated with reduction of HIV and malaria mortality on a national level.
Abstract Sequence-based genetic testing identifies causative variants in ~ 50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are ...implicated in various neurodevelopmental disorders but remain unstudied in DEEs. We interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 582 individuals with genetically unsolved DEEs. We identify rare differentially methylated regions (DMRs) and explanatory episignatures to uncover causative and candidate genetic etiologies in 12 individuals. Using long-read sequencing, we identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and four copy number variants. We also identify pathogenic variants associated with episignatures. Finally, we refine the CHD2 episignature using an 850 K methylation array and bisulfite sequencing to investigate potential insights into CHD2 pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate variants as 2% (12/582) for unsolved DEE cases.
In utero particulate matter exposure produces oxidative stress that impacts cellular processes that include telomere biology. Newborn telomere length is likely critical to an individual's telomere ...biology; reduction in this initial telomere setting may signal increased susceptibility to adverse outcomes later in life. We examined associations between prenatal particulate matter with diameter ≤2.5 µm (PM2.5) and relative leukocyte telomere length (LTL) measured in cord blood using a data-driven approach to characterize sensitive windows of prenatal PM2.5 effects and explore sex differences.
Women who were residents of Mexico City and affiliated with the Mexican Social Security System were recruited during pregnancy (n = 423 for analyses). Mothers’ prenatal exposure to PM2.5 was estimated based on residence during pregnancy using a validated satellite-based spatio-temporally resolved prediction model. Leukocyte DNA was extracted from cord blood obtained at delivery. Duplex quantitative polymerase chain reaction was used to compare the relative amplification of the telomere repeat copy number to single gene (albumin) copy number. A distributed lag model incorporating weekly averages for PM2.5 over gestation was used in order to explore sensitive windows. Sex-specific associations were examined using Bayesian distributed lag interaction models.
In models that included child's sex, mother's age at delivery, prenatal environmental tobacco smoke exposure, pre-pregnancy BMI, gestational age, birth season and assay batch, we found significant associations between higher PM2.5 exposure during early pregnancy (4–9 weeks) and shorter LTL in cord blood. We also identified two more windows at 14–19 and 34–36 weeks in which increased PM2.5 exposure was associated with longer LTL. In stratified analyses, the mean and cumulative associations between PM2.5 and shortened LTL were stronger in girls when compared to boys.
Increased PM2.5 during specific prenatal windows was associated with shorter LTL and longer LTL. PM2.5 was more strongly associated with shortened LTL in girls when compared to boys. Understanding sex and temporal differences in response to air pollution may provide unique insight into mechanisms.
•Examined sensitive windows of prenatal PM2.5 exposure on LTL in cord blood.•Sensitive window identified at gestational weeks 4–9, 14–19 and 34–36.•Findings suggest sex-specific associations.•PM2.5 more strongly associated with shortened LTL in girls compared to boys.
Changes in mitochondrial DNA (mtDNA) can serve as a marker of cumulative oxidative stress (OS) due to the mitochondria's unique genome and relative lack of repair systems. In utero particulate matter ...≤2.5μm (PM2.5) exposure can enhance oxidative stress. Our objective was to identify sensitive windows to predict mtDNA damage experienced in the prenatal period due to PM2.5 exposure using mtDNA content measured in cord blood.
Women affiliated with the Mexican social security system were recruited during pregnancy in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study. Mothers with cord blood collected at delivery and complete covariate data were included (n=456). Mothers' prenatal daily exposure to PM2.5 was estimated using a satellite-based spatio-temporally resolved prediction model and place of residence during pregnancy. DNA was extracted from umbilical cord leukocytes. Quantitative real-time polymerase chain reaction (qPCR) was used to determine mtDNA content. A distributive lag regression model (DLM) incorporating weekly averages of daily PM2.5 predictions was constructed to plot the association between exposure and OS over the length of pregnancy.
In models that included child's sex, mother's age at delivery, prenatal environmental tobacco smoke exposure, birth year, maternal education, and assay batch, we found significant associations between higher PM2.5 exposure during late pregnancy (35–40weeks) and lower mtDNA content in cord blood.
Increased PM2.5 during a specific prenatal window in the third trimester was associated with decreased mtDNA content suggesting heightened sensitivity to PM-induced OS during this life stage.
•Examined sensitive windows of prenatal PM2.5 exposure on mtDNA in cord blood•Sensitive window identified at gestational weeks 35–40•Higher PM2.5 during sensitive window associated with lower mtDNA content•Findings suggest sex-specific associations.
Summary
Some patients with therapy‐related myeloid neoplasms (t‐MN) may have unsuspected inherited cancer predisposition syndrome (CPS). We propose a set of clinical criteria to identify t‐MN ...patients with high risk of CPS (HR‐CPS). Among 225 t‐MN patients with an antecedent non‐myeloid malignancy, our clinical criteria identified 52 (23%) HR‐CPS patients. Germline whole‐exome sequencing identified pathogenic or likely pathogenic variants in 10 of 27 HR‐CPS patients compared to 0 of 9 low‐risk CPS patients (37% vs. 0%, p = 0.04). These simple clinical criteria identify t‐MN patients most likely to benefit from genetic testing for inherited CPS.
•Prenatal fine particulate matter (PM2.5) exposure may increase placental mutational load.•PM2.5-related mutations may accumulate in genes coding for NADH dehydrogenase and subunits of ATP ...synthase.•Participants of African ancestry may represent an at-risk population.
Prenatal ambient particulate matter (PM2.5) exposure impacts infant development and alters placental mitochondrial DNA abundance. We investigated whether the timing of PM2.5 exposure predicts placental mitochondrial mutational load using NextGen sequencing in 283 multi-ethnic mother-infant dyads. We observed increased PM2.5exposure, particularly during mid- to late-pregnancy and among genes coding for NADH dehydrogenase and subunits of ATP synthase, was associated with a greater amount of nonsynonymous mutations. The strongest associations were observed for participants of African ancestry. Further work is needed to tease out the role of mitochondrial genetics and its impact on offspring development and emerging disease disparities.
Air pollution exposure in childhood is associated with greater incidence and exacerbation of asthma, particularly in children whose parents report high levels of psychological stress. However, this ...interaction has not been completely elucidated in pregnancy.
To examine whether the association between prenatal exposure to particulate matter no larger than 2.5 μm in diameter (PM
) and wheeze in children is modified by prenatal stress.
Mexican women were recruited during pregnancy (N = 552). Residential prenatal daily exposure to PM
was estimated using a satellite-based spatiotemporally resolved prediction model and averaged over trimesters. Maternal stress was indexed by maternal negative life events (NLE) score (range 0-11) ascertained during mid to late pregnancy. NLE scores were dichotomized at the median as low (NLE score ≤ 3) and high (NLE score > 3) stress. Reports of ever wheeze and wheeze in the past 12 months (current wheeze) for children were obtained using the International Study of Asthma and Allergies in Childhood survey at 48 months. The association between prenatal PM
and wheeze was analyzed using a modified Poisson regression and stratified by low vs high stress.
Greater PM
exposure during the first trimester was associated with increased risk of current wheeze among children with mothers reporting high prenatal stress (relative risk 1.35, 95% confidence interval 1.00-1.83, per interquartile range increase 3.8 μg/m
) but not among those reporting low stress (relative risk 0.84, 95% confidence interval 0.61-1.16, per interquartile range increase 3.8 μg/m
; P for interaction = .04).
Increased prenatal stress enhanced the association between PM
exposure in early pregnancy, and child wheeze at 48 months of age. It is important to consider chemical and nonchemical stressors together to more comprehensively characterize children's environmental risk.
Two Epstein-Barr virus (EBV)-based testing approaches have shown promise for early detection of nasopharyngeal carcinoma (NPC). Neither has been independently validated nor their performance ...compared. We compared their diagnostic performance in an independent population.
We tested blood samples from 819 incident Taiwanese NPC cases (213 early-stage, American Joint Committee on Cancer version 7 stages I and II) diagnosed from 2010 to 2014 and from 1,768 controls from the same region, frequency matched to cases on age and sex. We compared an EBV antibody score using immunoglobulin A antibodies measured by enzyme-linked immunosorbent assay (EBV antibody score) and plasma EBV DNA load measured by real-time PCR followed by next-generation sequencing (NGS) among EBV DNA-positive individuals (EBV DNA algorithm).
EBV antibodies and DNA load were measured for 2,522 (802 cases; 1,720 controls) and 2,542 (797 cases; 1,745 controls) individuals, respectively. Of the 898 individuals positive for plasma EBV DNA and therefore eligible for NGS, we selected 442 (49%) for NGS testing. The EBV antibody score had a sensitivity of 88.4% (95% CI, 86.1 to 90.6) and a specificity of 94.9% (95% CI, 93.8 to 96.0) for NPC. The EBV DNA algorithm yielded significantly higher sensitivity (93.2%; 95% CI, 91.3 to 94.9;
= 1.33 × 10
) and specificity (98.1%; 95% CI, 97.3 to 98.8;
= 3.53 × 10
). For early-stage NPC, the sensitivities were 87.1% (95% CI, 82.7 to 92.4) for the EBV antibody score and 87.0% (95% CI, 81.9 to 91.5) for the EBV DNA algorithm (
= .514). For regions with a NPC incidence of 20-100/100,000 person-years (eg, residents in southern China and Hong Kong), these two approaches yielded similar numbers needed to screen (EBV antibody score: 5,656-1,131; EBV DNA algorithm: 5,365-1,073); positive predictive values ranged from 0.4% to 1.7% and 1.0% to 4.7%, respectively.
We demonstrated high sensitivity and specificity of EBV antibody and plasma EBV DNA for NPC detection, with slightly inferior performance of the EBV antibody score. Cost-effectiveness studies are needed to guide screening implementation.
PDF
