Volatile organic compound exposure and cardiometabolic syndrome risk in a nationally representative cohort.

BACKGROUND: The relative importance of environmental exposures such as volatile organic compounds (VOCs) is one of the paramount public health priorities of our time, yet is presently unstudied. VOCs are ubiquitous in the environment and have been associated with numerous adverse health effects, including a number of cardiovascular and metabolic effects that are components of Cardiometabolic Syndrome (CMS). OBJECTIVES: To examine the relationship between CMS and individual-level exposures to VOCs, measured as urinary metabolites of VOCs (UM-VOCs), in a nationally representative sample. METHODS: Associations between urinary biomarkers of exposure to 19 parent VOCs and CMS were assessed using the National Health and Nutrition Examination Survey (NHANES). To isolate effects from environmental VOC exposures, analyses were stratified by tobacco-smoke exposure status. CMS was treated dichotomously as well as ordinally and associations with VOCs were considered from a single pollutant, as well as multi-pollutant perspectives. Potential important groupings and interactions among VOCs, and their associations with CMS were evaluated using numerous traditional regression modeling and exploratory modeling methods including: backwards-selection model-building, factor analysis, LASSO penalized regression, and a cumulative VOC exposure score. RESULTS: Concentrations of eight UM-VOCs were significantly different between individuals with and without CMS. Among the non-smoke exposed participants, 6 UM-VOCs were significantly associated with increased odds of CMS. These associations were observed with metabolites from acrolein, 1,3-butadiene, crotonaldehyde, cyanide, and ethylbenzene/styrene. Furthermore, dose-response type relationships were observed with metabolites of acrolein, 1,3-butadiene, and crotonaldehyde. Metabolites from acrolein and ethylbenzene/styrene were associated with disease progression in ordinal logistic regression models and a cumulative VOC exposure score was significantly associated with the progression of disease towards clinically diagnosable CMS (OR: 1.015, 95% CI: 1.007, 1.024). DISCUSSION: This novel quantitative and nationally representative study investigated associations between individual-level exposures to VOCs and CMS. The results of this study point toward a potential causal role for certain VOCs in the development of CMS, a condition which ultimately greatly increases one’s risk of the deadliest non-communicable disease in the world, cardiovascular disease. These findings are important for the development of public health interventions and policies surrounding modifiable environmental pollution exposures

What is the status of the Lee’s Lane Landfill Superfund Site?

The Lee’s Lane Landfill is located in western Louisville, KY along the Ohio River (Fig. 1) [1]. The site was used as a quarry in the 1940s before being repurposed as a landfill from 1948 to 1975 (Fig. 2). At least 212,400 tons of municipal and industrial waste were disposed of in the landfill during this period. In 1980, the Kentucky Department of Hazardous Materials and Waste Management discovered approximately 400 drums of hazardous waste within the landfill; these drums were removed by the landfill owners in the fall of 1981, but the remaining drums of non-hazardous material, as well as any empty drums, were buried in place on the landfill. The buried and capped landfill waste covers an area of 112 acres. The United States Environmental Protection Agency (EPA) placed the Lee’s Lane Landfill site on the National Priorities List (NPL) in 1983. Cleanup efforts concluded in 1988 and monitoring of the site has continued since. This white paper summarizes reports published from 2013 through 2018 documenting Lee’s Lane Landfill site conditions and the effectiveness of the cap and other remedies put in place to protect human health. The condition of the site must be reviewed every five years by the EPA, and those results are made available to the public in what is referred to as a Five-Year Review (FYR). The Lee’s Lane Landfill FYR relies on information provided to the EPA by the Kentucky State Department of Environmental Protection (KDEP), information collected by the Lee’s Lane Landfill Group, monitoring data and conclusions from the Louisville and Jefferson County Metropolitan Sewer District’s (MSD) Conceptual Site Model (CSM) report, [2] and other interim communications. Using the information in these reports as well as relevant current and historical research documents, we identify questions that remain unanswered and need to be addressed in order to confirm that the contaminants present on the site do not pose a risk to public health and to determine whether the site is ready for re-use. We conclude by proposing several next steps to fill the identified gaps in information and confirm the conclusions in the reports

Household Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Alpha Variant-United States, 2021.

BACKGROUND: In Spring 2021, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.7 (Alpha) became the predominant variant in the United States. Research suggests that Alpha has increased transmissibility compared with non-Alpha lineages. We estimated household secondary infection risk (SIR), assessed characteristics associated with transmission, and compared symptoms of persons with Alpha and non-Alpha infections. METHODS: We followed households with SARS-CoV-2 infection for 2 weeks in San Diego County and metropolitan Denver, January to April 2021. We collected epidemiologic information and biospecimens for serology, reverse transcription-polymerase chain reaction (RT-PCR), and whole-genome sequencing. We stratified SIR and symptoms by lineage and identified characteristics associated with transmission using generalized estimating equations. RESULTS: We investigated 127 households with 322 household contacts; 72 households (56.7%) had member(s) with secondary infections. SIRs were not significantly higher for Alpha (61.0% [95% confidence interval, 52.4-69.0%]) than non-Alpha (55.6% [44.7-65.9%], P = .49). In households with Alpha, persons who identified as Asian or Hispanic/Latino had significantly higher SIRs than those who identified as White (P = .01 and .03, respectively). Close contact (eg, kissing, hugging) with primary cases was associated with increased transmission for all lineages. Persons with Alpha infection were more likely to report constitutional symptoms than persons with non-Alpha (86.9% vs 76.8%, P = .05). CONCLUSIONS: Household SIRs were similar for Alpha and non-Alpha. Comparable SIRs may be due to saturation of transmission risk in households due to extensive close contact, or true lack of difference in transmission rates. Avoiding close contact within households may reduce SARS-CoV-2 transmission for all lineages among household members

Genetic Control of mRNA Splicing as a Potential Mechanism for Incomplete Penetrance of Rare Coding Variants

Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-sequencing data in GTEx V8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased whole genome sequencing data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common splice-regulatory variants may play a role in reducing the damaging effects of rare exonic variants

Efanesoctocog Alfa Prophylaxis for Patients with Severe Hemophilia A.

BACKGROUND: Efanesoctocog alfa provides high sustained factor VIII activity by overcoming the von Willebrand factor-imposed half-life ceiling. The efficacy, safety, and pharmacokinetics of efanesoctocog alfa for prophylaxis and treatment of bleeding episodes in previously treated patients with severe hemophilia A are unclear. METHODS: We conducted a phase 3 study involving patients 12 years of age or older with severe hemophilia A. In group A, patients received once-weekly prophylaxis with efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. In group B, patients received on-demand treatment with efanesoctocog alfa for 26 weeks, followed by once-weekly prophylaxis with efanesoctocog alfa for 26 weeks. The primary end point was the mean annualized bleeding rate in group A; the key secondary end point was an intrapatient comparison of the annualized bleeding rate during prophylaxis in group A with the rate during prestudy factor VIII prophylaxis. Additional end points included treatment of bleeding episodes, safety, pharmacokinetics, and changes in physical health, pain, and joint health. RESULTS: In group A (133 patients), the median annualized bleeding rate was 0 (interquartile range, 0 to 1.04), and the estimated mean annualized bleeding rate was 0.71 (95% confidence interval [CI], 0.52 to 0.97). The mean annualized bleeding rate decreased from 2.96 (95% CI, 2.00 to 4.37) to 0.69 (95% CI, 0.43 to 1.11), a finding that showed superiority over prestudy factor VIII prophylaxis (P<0.001). A total of 26 patients were enrolled in group B. In the overall population, nearly all bleeding episodes (97%) resolved with one injection of efanesoctocog alfa. Weekly prophylaxis with efanesoctocog alfa provided mean factor VIII activity of more than 40 IU per deciliter for the majority of the week and of 15 IU per deciliter at day 7. Prophylaxis with efanesoctocog alfa for 52 weeks (group A) improved physical health (P<0.001), pain intensity (P = 0.03), and joint health (P = 0.01). In the overall study population, efanesoctocog alfa had an acceptable side-effect profile, and the development of inhibitors to factor VIII was not detected. CONCLUSIONS: In patients with severe hemophilia A, once-weekly efanesoctocog alfa provided superior bleeding prevention to prestudy prophylaxis, normal to near-normal factor VIII activity, and improvements in physical health, pain, and joint health. (Funded by Sanofi and Sobi; XTEND-1 ClinicalTrials.gov number, NCT04161495.)

Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2-6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but&nbsp;this effect was not seen in&nbsp;clones with&nbsp;driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental&nbsp;knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation

Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis(1). These lesions are precursors for blood cancers(2-6), but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation