Single-nucleus multiomic analysis of Beckwith-Wiedemann syndrome liver reveals PPARA signaling enrichment and metabolic dysfunction.

Beckwith-Wiedemann Syndrome (BWS) is an epigenetic overgrowth syndrome caused by methylation changes in the human 11p15 chromosomal locus. Patients with BWS exhibit tissue overgrowth, as well as an increased risk of childhood neoplasms in the liver and kidney. To understand the impact of these 11p15 changes, specifically in the liver, we performed single-nucleus RNA sequencing (snRNA-seq) and single-nucleus assay for transposase-accessible chromatin with sequencing (snATAC-seq) to generate paired, cell-type-specific transcriptional and chromatin accessibility profiles of both BWS-liver and nonBWS-liver nontumorous tissue. Our integrated RNA+ATACseq multiomic approach uncovered hepatocyte-specific enrichment and activation of the peroxisome proliferator-activated receptor α (PPARA) - a liver metabolic regulator. To confirm our findings, we utilized a BWS-induced pluripotent stem cell (iPSC) model, where cells were differentiated into hepatocytes. Our data demonstrates the dysregulation of lipid metabolism in BWS-liver, which coincided with observed upregulation of PPARA during hepatocyte differentiation. BWS liver cells exhibited decreased neutral lipids and increased fatty acid ß-oxidation, relative to controls. We also observed increased reactive oxygen species (ROS) byproducts in the form of peroxidated lipids in BWS hepatocytes, which coincided with increased oxidative DNA damage. This study proposes a putative mechanism for overgrowth and cancer predisposition in BWS liver due to perturbed metabolism.

KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56α to initiate pancreatic cancer development.

Oncogenic mutations in KRAS are present in approximately 95% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) and are considered the initiating event of pancreatic intraepithelial neoplasia (PanIN) precursor lesions. While it is well established that KRAS mutations drive the activation of oncogenic kinase cascades during pancreatic oncogenesis, the effects of oncogenic KRAS signaling on regulation of phosphatases during this process is not fully appreciated. Protein Phosphatase 2A (PP2A) has been implicated in suppressing KRAS-driven cellular transformation. However, low PP2A activity is observed in PDAC cells compared to non-transformed cells, suggesting that suppression of PP2A activity is an important step in the overall development of PDAC. In the current study, we demonstrate that KRASG12D induces the expression of both an endogenous inhibitor of PP2A activity, Cancerous Inhibitor of PP2A (CIP2A), and the PP2A substrate, c-MYC. Consistent with these findings, KRASG12D sequestered the specific PP2A subunit responsible for c-MYC degradation, B56α, away from the active PP2A holoenzyme in a CIP2A-dependent manner. During PDAC initiation in vivo, knockout of B56α promoted KRASG12D tumorigenesis by accelerating acinar-to-ductal metaplasia (ADM) and the formation of PanIN lesions. The process of ADM was attenuated ex vivo in response to pharmacological re-activation of PP2A utilizing direct small molecule activators of PP2A (SMAPs). Together, our results suggest that suppression of PP2A-B56α through KRAS signaling can promote the MYC-driven initiation of pancreatic tumorigenesis.

Association between urban upbringing and functional brain connectivity in schizophrenia.

Background: Environmental factors considerably influence the development of the human cortex during the perinatal period, early childhood, and adolescence. Urban upbringing in the first 15 years of life is a known risk factor for schizophrenia (SCZ). Though the risk of urban birth and upbringing is well-examined from an epidemiological perspective, the biological mechanisms underlying urban upbringing remain unknown. The effect of urban birth and upbringing on functional brain connectivity in SCZ patients is not yet examined. Methods: This is a secondary data analysis of three studies that included 87 patients with SCZ and 70 healthy volunteers (HV) aged 18 to 50 years. We calculated the developmental urbanicity index using a validated method in earlier studies. Following standard pre-processing of resting functional magnetic resonance imaging (fMRI) scans, seed-return on investment (ROI) functional connectivity analysis was performed. Results: The results showed a significant association between urban birth and upbringing on functional connectivity in SCZ patients and HV (P < 0.05). In SCZ patients, connections from the right caudate, anterior cingulate cortex, left and right intracalcarine cortices, left and right lingual gyri, left posterior parahippocampal cortex to the cerebellum, fusiform gyri, lateral occipital cortex, and amygdala were significantly associated with the urbanicity index (P < 0.05). Conclusions: These study findings suggest a significant association between urban birth and upbringing on functional brain connectivity in regions involved in reward processing and social cognition in SCZ. Assessment of social cognition could have implications in developing an in-depth understanding of this impairment in persons with SCZ.

Association of leukergy (in vitro leukocyte aggregation) with systemic inflammation in dogs and cats (2017-2022).

BACKGROUND: Leukergy is the phenomenon of aggregation of leukocytes on a peripheral blood film, and in humans, it is used as an indicator of systemic inflammation and infection. OBJECTIVES: To assess the association of leukergy on blood film examination with biochemical and clinical evidence of systemic inflammation, infection, neoplasia, or specific organ system disease. METHODS: A case-control study using retrospective analysis (2017-2022) identified all canine and feline patients that had been presented to an academic referral center with a finding of leukergy on peripheral blood film and an equal number of species-matched controls. RESULTS: A total of 127 cases (canine n = 44, feline n = 83) were identified, as well as 127 controls. Feline samples were 7.6× more likely to exhibit leukergy (0.019%) than canine (0.0025%). A positive association was noted between leukergy and higher globulin concentrations in dogs (marginal difference 0.5 mg/dL, P = .016) and cats (marginal difference 0.67 mg/dL, P = <.001). Cats with leukergy had higher WBC counts and were less likely to be diagnosed with cardiac or urinary tract disease than controls. Dogs with leukergy had lower WBC counts and were more likely to be febrile but were less likely to have urinary tract disease than controls. No association was found with neutrophil toxic change or band forms, systemic antimicrobial therapy, or signalment. CONCLUSIONS: We conclude that there is a positive association between increased globulin concentrations and leukergy and inconsistent associations between leukergy and other markers of inflammation or infection. Leukergy is rare overall but markedly more common in cats than dogs.

Use of 2% taurolidine lock solution for treatment and prevention of catheter-related bloodstream infections in neonates: a feasibility study.

BACKGROUND: Taurolidine lock, a technique used to prevent or treat catheter-related bloodstream infection (CRBSI), is effective in adult and paediatric patients but has been described rarely in neonates. The aim of this descriptive retrospective study, was to determine the feasibility and direct outcomes of prophylactic and therapeutic taurolidine locks in term and preterm neonates. METHODS: We implemented the use of therapeutic taurolidine lock in addition to antibiotic treatment with the aim of catheter salvage in critical neonates with difficult vascular access (group 1). In addition, we introduced taurolidine lock as a preventive measure in neonates with a central venous catheter (CVC) at high risk of developing CRBSI (group 2). Every 24 h (in the treatment group) a 2% taurolidine solution was injected and the catheter locked for at least 120 min, until infection clearance (group 1). In the preventive group, the catheter was locked for 30 min every 48 h until CVC removal (group 2). FINDINGS: Thirty-seven neonates who received taurolidine were included in this study. We did not observe any major adverse events. In group 1 (21 cases), clinical symptom disappearance and bacteraemia clearance were achieved without catheter removal in 18 cases (85.7%); in the other three neonates the catheter was removed shortly after the start of the locks as it was possible to replace the CVC. In group 2 (16 neonates), no CRBSI was observed during the duration of the catheter placement. CONCLUSIONS: In this retrospective study, taurolidine was successfully used in neonates both for prevention and treatment of CRBSI, without major undesired effects. A larger cohort and a randomized clinical trial is warranted in order to establish its efficacy and safety in neonates.

Genotypic detection of ß-lactamase-producing Escherichia coli isolates obtained from Seven Crater Lakes of San Pablo, Laguna, Philippines.

The extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli is becoming a global public health concern. More comprehensive surveillance of ß-lactam resistance in E. coli would improve monitoring strategies and control resistance transmission in contaminated environments. This study investigated the prevalence of ß-lactamase genes in E. coli isolated from the Seven Crater Lakes in San Pablo, Laguna, Philippines. Water samples from lakes were collected for the isolation of E. coli (n = 846) and molecular characterization by detecting the presence of the uidA gene. The isolates were then tested for the presence of ß-lactamase genes using PCR. Among the screened genes, blaAmpC was the most dominant (91%). Other ß-lactamase genes such as blaTEM, blaSHV, and blaCTXM were also detected with percentage occurrence of 34, 5, and 1%, respectively. Multiple genes within individual isolates were also observed, wherein blaTEM/AmpC was the most prevalent gene combination. Moreover, a significant negative correlation between blaAmpC with blaSHV and blaCTXM was depicted in this study. Overall, these findings demonstrate the presence of ß-lactamase genes in E. coli in the Seven Crater Lakes of San Pablo and can be used in developing effective strategies to control antibiotic resistance in environmental waters.

Perspectives of patients and clinicians on older patient mobility on acute medical wards: a qualitative study.

BACKGROUND: Low mobility during an acute care medical hospitalization is frequent and associated with adverse outcomes, particularly among older patients. Better understanding barriers and facilitators to improve mobility during hospitalization could help develop effective interventions. The goal of this study was to assess barriers and facilitators to older medical patients' hospital mobility, from the point of view of patients and clinicians, to develop a framework applicable in clinical practice. METHODS: We conducted a qualitative study in one university and two non-university hospitals of two different language and cultural regions of Switzerland, including 13 focus groups (FGs; five with patients, eight with clinicians). We included 24 adults aged 60 years or older hospitalized on an acute general internal medicine ward of one of the three participating hospitals during the previous years, and 34 clinicians (15 physicians, nine nurses/nursing assistants, 10 physiotherapists) working on those wards. The FG guides included open-ended questions exploring mobility experiences, expectations, barriers and facilitators to mobility, consequences of low mobility and knowledge on mobility. We applied an inductive thematic analysis. RESULTS: We identified four themes of barriers and facilitators to mobility: 1) patient-related factors; 2) clinician-related factors; 3) social interactions; and 4) non-human factors. Clinician-related factors were only mentioned in clinician FGs. Otherwise, subthemes identified from patient and clinician FGs were similar and codes broadly overlapped. Subthemes included motivation, knowledge, expectations, mental and physical state (theme 1); process, knowledge - skills, mental state - motivation (theme 2); interpersonal relationships, support (theme 3); hospital setting - organization (theme 4). CONCLUSIONS: From patients' and clinicians' perspectives, a broad spectrum of human and structural factors influences mobility of older patients hospitalized on an acute general internal medicine ward. New factors included privacy issues and role perception. Many of those factors are potentially actionable without additional staff resources. This study is a first step in participatory research to improve mobility of older medical inpatients.

Role of grinding method on granular activated carbon characteristics.

A coconut shell (AC1230CX) and a bituminous coal based (F400) granular activated carbon (GAC) were ground with mortar and pestle (MP), a blender, and a bench-scale ball milling unit (BMU). Blender was the most time-efficient for particle size reduction. Four size fractions ranging from 20 × 40 to 200 × 325 were characterized along with the bulk GACs. Compared to bulk GACs, F400 blender and BMU 20 × 40 fractions decreased in specific surface area (SSA, -23% and -31%, respectively) while smaller variations (-14% to 5%) occurred randomly for AC1230CX ground fractions. For F400, the blender and BMU size fraction dependencies were attributed to the combination of (i) radial trends in the F400 particle properties and (ii) importance of shear (outer layer removal) versus shock (particle fracturing) size reduction mechanisms. Compared to bulk GACs, surface oxygen content (At%-O1s) increased up to 34% for the F400 blender and BMU 20 × 40 fractions, whereas all AC1230CX ground fractions, except for the blender 100 × 200 and BMU 60 × 100 and 100 × 200 fractions, showed 25-29% consistent increases. The At%-O1s gain was attributed to (i) radial trends in F400 properties and (ii) oxidization during grinding, both of which supported the shear mechanism of mechanical grinding. Relatively small to insignificant changes in point of zero charge (pHPZC) and crystalline structure showed similar trends with the changes in SSA and At%-O1s. The study findings provide guidance for informed selection of grinding methods based on GAC type and target particle sizes to improve the representativeness of adsorption studies conducted with ground GAC, such as rapid small-scale column tests. When GACs have radial trends in their properties and when the target size fraction only includes larger particle sizes, manual grinding is recommended.

Anion Exchange Resin and Inorganic Anion Parameter Determination for Model Validation and Evaluation of Unintended Consequences during PFAS Treatment.

When implementing anion exchange (AEX) for per- and polyfluoroalkyl substances treatment, temporal drinking water quality changes from concurrent inorganic anion (IA) removal can create unintended consequences (e.g., corrosion control impacts). To understand potential effects, four drinking water-relevant IAs (bicarbonate, chloride, sulfate, and nitrate) and three gel-type, strong-base AEX resins were evaluated. Batch binary isotherm experiments provided estimates of IA selectivity with respect to chloride ( K x ∕ C ) for IA/resin combinations where bicarbonate < sulfate ≤ nitrate at studied conditions. A multi-IA batch experiment demonstrated that binary isotherm-determined K x ∕ C values predicted competitive behavior. Subsequent column experiments with and without natural organic matter (NOM) allowed for the validation of a new ion exchange column model (IEX-CM; https://github.com/USEPA/Water_Treatment_Models). IA breakthrough was well-simulated using binary isotherm-determined K x ∕ C values and was minimally impacted by NOM. Initial AEX effluent water quality changes with corrosion implications included increased chloride and decreased sulfate and bicarbonate concentrations, resulting in elevated chloride-to-sulfate mass ratios (CSMRs) and Larson ratios (LRs) and depressed pH until the complete breakthrough of the relevant IA(s). IEX-CM utility was further illustrated by simulating the treatment of low-IA source water and a change in the source water to understand the resulting duration of changes in IAs and water quality parameters.

Perceptions of farming stakeholders towards automating dairy cattle mobility and body condition scoring in farm assurance schemes.

Animal welfare standards are used within the food industry to demonstrate efforts in reaching higher welfare on farms. To verify compliance with those standards, inspectors conduct regular on-farm animal welfare assessments. Conducting these welfare assessments can, however, be time-consuming and prone to human bias. The emergence of Digital Livestock Technologies (DLTs) offers new ways of monitoring farm animal welfare and can alleviate some of the challenges related to animal welfare assessments by collecting data automatically and more frequently. Whilst automating welfare assessments with DLTs may be promising, little attention has been paid to farmers' perceptions of the challenges that could prevent successful implementation. This study aims to address this gap by focusing on the trial of a DLT (a 3D machinelearning camera) to automate mobility and body condition scoring on 11 dairy cattle farms. Semi-structured, in-depth interviews were conducted with farmers, technology developers and a stakeholder involved in a farm assurance scheme (N14). Findings suggest that stakeholders perceived important benefits to the use of the camera in this context, from building consumer trust by increasing transparency to improved management efficiency. There was also a potential for greater consistency in data collection and thus for enhanced fairness across the UK dairy sector, particularly on the issue of lameness prevalence. However, stakeholders also raised important concerns, such as a lack of clarity around data ownership, reliability, and use, and the possibility of some farmers being penalised (e.g., if the technology failed to work). More clarity should thus be given to farmers in relation to data governance and evidence provided in terms of technical performance and accuracy. The findings of this study highlighted the need for more inclusive approaches to ensure farmers' concerns are adequately identified and addressed. These approaches can help minimise negative consequences to farmers and animal welfare, whilst maximising the potential benefits of automating welfare-related data collection.

Strong Base Anion Exchange Selectivity of Nine Perfluoroalkyl Chemicals Relevant to Drinking Water.

Selectivity with respect to chloride (KPFAS∕C) was determined for nine drinking water relevant perfluoroalkyl and polyfluoroalkyl substances (PFAS): perfluoro-2-propoxypropanoic acid (GenX), five perfluoroalkyl carboxylic acids (PFCAs), and three perfluoroalkyl sulfonic acids (PFSAs). Three single-use strong base anion exchange gel resins were investigated, targeting drinking water relevant equilibrium PFAS liquid concentrations (≤500 ng/L). Except for the longest carbon chain PFCA (perfluorodecanoic acid) and PFSA (perfluorooctanesulfonic acid) studied, PFAS followed traditional ion exchange theory (law of mass action), including increasing equilibrium PFAS liquid concentrations with increasing equilibrium chloride liquid concentrations. Overall, KPFAS∕C values were (i) similar among resins for a given PFAS, (ii) 1-5 orders of magnitude greater than the selectivity of inorganic anions (e.g., nitrate) previously studied, (iii) 2 orders of magnitude greater for the same carbon chain length PFSA versus PFCA, (iv) found to proportionally increase with carbon chain length for both PFSAs and PFCAs, and (v) similar for GenX and perfluorohexanoic acid (six-carbon PFCA). A multisolute competition experiment demonstrated binary isotherm-determined KPFAS∕C values could be applied to simulate a multisolute system, extending work previously done with only inorganic anions to PFAS. Ultimately, estimated KPFAS∕C values allow future extension and validation of an open-source anion exchange column model to PFAS.

Detection of Aeromonas hydrophila possessing aerolysin gene using gold nanoparticle probe.

Objective: The aerolysin (aerA) is a virulence indicator used to identify the pathogenicity of the Aeromonas strain. Targeting a pathogen's crucial virulence gene for detection is essential, as it determines the potential threat to the host. This study aimed to develop a gold nanoparticle (AuNP) probe for detecting the gene aerA in Aeromonas hydrophila among field samples. Materials and Methods: Kidney samples among both healthy and sick Nile tilapias in five provinces of Luzon Island were collected for bacterial analysis. Screening using specific primers targeting aerA was conducted in parallel with testing the AuNPs probe on the same sample set. The positive control provided by BFAR-NFLD, confirmed by polymerase chain reaction (PCR) assay, was used as a positive sample containing the target gene. Results: The AuNP probe demonstrated a computed accuracy of 81.32%, sensitivity of 100%, and specificity of 81.26%. Among the 257 reactions, 59 were false positives, while no false negative results were observed. The AuNP probe could detect aerA at levels as low as 30 ng/µl. The low prevalence of the target gene may be attributed to the use of general media instead of specific media like Rimler-Shotts agar. Conclusion: The established colorimetric detection method for A. hydrophila with the aerA gene offers a swift alternative to PCR, negating the requirement for advanced equipment like a thermal cycler.

Genomics and phenomics of body mass index reveals a complex disease network.

Elevated body mass index (BMI) is heritable and associated with many health conditions that impact morbidity and mortality. The study of the genetic association of BMI across a broad range of common disease conditions offers the opportunity to extend current knowledge regarding the breadth and depth of adiposity-related diseases. We identify 906 (364 novel) and 41 (6 novel) genome-wide significant loci for BMI among participants of European (N~1.1 million) and African (N~100,000) ancestry, respectively. Using a BMI genetic risk score including 2446 variants, 316 diagnoses are associated in the Million Veteran Program, with 96.5% showing increased risk. A co-morbidity network analysis reveals seven disease communities containing multiple interconnected diseases associated with BMI as well as extensive connections across communities. Mendelian randomization analysis confirms numerous phenotypes across a breadth of organ systems, including conditions of the circulatory (heart failure, ischemic heart disease, atrial fibrillation), genitourinary (chronic renal failure), respiratory (respiratory failure, asthma), musculoskeletal and dermatologic systems that are deeply interconnected within and across the disease communities. This work shows that the complex genetic architecture of BMI associates with a broad range of major health conditions, supporting the need for comprehensive approaches to prevent and treat obesity.

Incidence and risk factors of bacterial sepsis and invasive fungal infection in neonates and infants requiring major surgery: an Italian multicentre prospective study.

BACKGROUND: Limited data are currently available on the incidence rates and risk factors for bacterial sepsis and invasive fungal infections (IFIs) among neonates and infants undergoing major surgery. AIM: To assess the incidence of bacterial sepsis and IFI, fungal colonization, risk factors for sepsis, and mortality in neonates and infants aged <3 months undergoing major surgery. METHODS: A multicentre prospective study was conducted involving 13 level-3 neonatal intensive care units in Italy, enrolling all infants aged ≤3 months undergoing major surgery. FINDINGS: From 2018 to 2021, 541 patients were enrolled. During hospitalization, 248 patients had a bacterial infection, and 23 patients had a fungal infection. Eighty-four patients were colonized by fungal strains. Overall, in-hospital mortality was 2.8%, but this was higher in infected than in uninfected infants (P = 0.034). In multivariate analysis, antibiotic exposure before surgery, ultrasound-guided or surgical placement of vascular catheters, vascular catheterization duration, and gestational age ≤28 weeks were all associated with bacterial sepsis. The risk of IFI was markedly higher in colonized infants (odds ratio (OR): 8.20; P < 0.001) and was linearly associated with the duration of vascular catheterization. Fungal colonization in infants with abdominal surgery increased the probability of IFI 11-fold (OR: 11.1; P < 0.001). CONCLUSION: Preventive strategies such as early removal of vascular catheters and the fluconazole prophylaxis should be considered to prevent bacterial and fungal sepsis in infants undergoing abdominal surgery, and even more so in those with fungal colonization.

A MUC5B Gene Polymorphism, rs35705950-T, Confers Protective Effects Against COVID-19 Hospitalization but Not Severe Disease or Mortality.

Rationale: A common MUC5B gene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis (IPF), but its role in severe acute respiratory syndrome coronavirus 2 infection and disease severity is unclear. Objectives: To assess whether rs35705950-T confers differential risk for clinical outcomes associated with coronavirus disease (COVID-19) infection among participants in the Million Veteran Program (MVP). Methods: The MUC5B rs35705950-T allele was directly genotyped among MVP participants; clinical events and comorbidities were extracted from the electronic health records. Associations between the incidence or severity of COVID-19 and rs35705950-T were analyzed within each ancestry group in the MVP followed by transancestry meta-analysis. Replication and joint meta-analysis were conducted using summary statistics from the COVID-19 Host Genetics Initiative (HGI). Sensitivity analyses with adjustment for additional covariates (body mass index, Charlson comorbidity index, smoking, asbestosis, rheumatoid arthritis with interstitial lung disease, and IPF) and associations with post-COVID-19 pneumonia were performed in MVP subjects. Measurements and Main Results: The rs35705950-T allele was associated with fewer COVID-19 hospitalizations in transancestry meta-analyses within the MVP (Ncases = 4,325; Ncontrols = 507,640; OR = 0.89 [0.82-0.97]; P = 6.86 × 10-3) and joint meta-analyses with the HGI (Ncases = 13,320; Ncontrols = 1,508,841; OR, 0.90 [0.86-0.95]; P = 8.99 × 10-5). The rs35705950-T allele was not associated with reduced COVID-19 positivity in transancestry meta-analysis within the MVP (Ncases = 19,168/Ncontrols = 492,854; OR, 0.98 [0.95-1.01]; P = 0.06) but was nominally significant (P < 0.05) in the joint meta-analysis with the HGI (Ncases = 44,820; Ncontrols = 1,775,827; OR, 0.97 [0.95-1.00]; P = 0.03). Associations were not observed with severe outcomes or mortality. Among individuals of European ancestry in the MVP, rs35705950-T was associated with fewer post-COVID-19 pneumonia events (OR, 0.82 [0.72-0.93]; P = 0.001). Conclusions: The MUC5B variant rs35705950-T may confer protection in COVID-19 hospitalizations.

Association of Kidney Comorbidities and Acute Kidney Failure With Unfavorable Outcomes After COVID-19 in Individuals With the Sickle Cell Trait.

Importance: Sickle cell trait (SCT), defined as the presence of 1 hemoglobin beta sickle allele (rs334-T) and 1 normal beta allele, is prevalent in millions of people in the US, particularly in individuals of African and Hispanic ancestry. However, the association of SCT with COVID-19 is unclear. Objective: To assess the association of SCT with the prepandemic health conditions in participants of the Million Veteran Program (MVP) and to assess the severity and sequelae of COVID-19. Design, Setting, and Participants: COVID-19 clinical data include 2729 persons with SCT, of whom 353 had COVID-19, and 129 848 SCT-negative individuals, of whom 13 488 had COVID-19. Associations between SCT and COVID-19 outcomes were examined using firth regression. Analyses were performed by ancestry and adjusted for sex, age, age squared, and ancestral principal components to account for population stratification. Data for the study were collected between March 2020 and February 2021. Exposures: The hemoglobin beta S (HbS) allele (rs334-T). Main Outcomes and Measures: This study evaluated 4 COVID-19 outcomes derived from the World Health Organization severity scale and phenotypes derived from International Classification of Diseases codes in the electronic health records. Results: Of the 132 577 MVP participants with COVID-19 data, mean (SD) age at the index date was 64.8 (13.1) years. Sickle cell trait was present in 7.8% of individuals of African ancestry and associated with a history of chronic kidney disease, diabetic kidney disease, hypertensive kidney disease, pulmonary embolism, and cerebrovascular disease. Among the 4 clinical outcomes of COVID-19, SCT was associated with an increased COVID-19 mortality in individuals of African ancestry (n = 3749; odds ratio, 1.77; 95% CI, 1.13 to 2.77; P = .01). In the 60 days following COVID-19, SCT was associated with an increased incidence of acute kidney failure. A counterfactual mediation framework estimated that on average, 20.7% (95% CI, -3.8% to 56.0%) of the total effect of SCT on COVID-19 fatalities was due to acute kidney failure. Conclusions and Relevance: In this genetic association study, SCT was associated with preexisting kidney comorbidities, increased COVID-19 mortality, and kidney morbidity.

Genome-wide and phenome-wide analysis of ideal cardiovascular health in the VA Million Veteran Program.

BACKGROUND: Genetic studies may help identify causal pathways; therefore, we sought to identify genetic determinants of ideal CVH and their association with CVD outcomes in the multi-population Veteran Administration Million Veteran Program. METHODS: An ideal health score (IHS) was calculated from 3 clinical factors (blood pressure, total cholesterol, and blood glucose levels) and 3 behavioral factors (smoking status, physical activity, and BMI), ascertained at baseline. Multi-population genome-wide association study (GWAS) was performed on IHS and binary ideal health using linear and logistic regression, respectively. Using the genome-wide significant SNPs from the IHS GWAS, we created a weighted IHS polygenic risk score (PRSIHS) which was used (i) to conduct a phenome-wide association study (PheWAS) of associations between PRSIHS and ICD-9 phenotypes and (ii) to further test for associations with mortality and selected CVD outcomes using logistic and Cox regression and, as an instrumental variable, in Mendelian Randomization. RESULTS: The discovery and replication cohorts consisted of 142,404 (119,129 European American (EUR); 16,495 African American (AFR)), and 45,766 (37,646 EUR; 5,366 AFR) participants, respectively. The mean age was 65.8 years (SD = 11.2) and 92.7% were male. Overall, 4.2% exhibited ideal CVH based on the clinical and behavioral factors. In the multi-population meta-analysis, variants at 17 loci were associated with IHS and each had known GWAS associations with multiple components of the IHS. PheWAS analysis in 456,026 participants showed that increased PRSIHS was associated with a lower odds ratio for many CVD outcomes and risk factors. Both IHS and PRSIHS measures of ideal CVH were associated with significantly less CVD outcomes and CVD mortality. CONCLUSION: A set of high interest genetic variants contribute to the presence of ideal CVH in a multi-ethnic cohort of US Veterans. Genetically influenced ideal CVH is associated with lower odds of CVD outcomes and mortality.