The Intersections of COVID-19, HIV, and Race/Ethnicity: Machine Learning Methods to Identify and Model Risk Factors for Severe COVID-19 in a Large U.S. National Dataset.

We investigate risk factors for severe COVID-19 in persons living with HIV (PWH), including among racialized PWH, using the U.S. population-sampled National COVID Cohort Collaborative (N3C) data released from January 1, 2020 to October 10, 2022. We defined severe COVID-19 as hospitalized with invasive mechanical ventilation, extracorporeal membrane oxygenation, discharge to hospice or death. We used machine learning methods to identify highly ranked, uncorrelated factors predicting severe COVID-19, and used multivariable logistic regression models to assess the associations of these variables with severe COVID-19 in several models, including race-stratified models. There were 3 241 627 individuals with incident COVID-19 cases and 81 549 (2.5%) with severe COVID-19, of which 17 445 incident COVID-19 and 1 020 (5.8%) severe cases were among PWH. The top highly ranked factors of severe COVID-19 were age, congestive heart failure (CHF), dementia, renal disease, sodium concentration, smoking status, and sex. Among PWH, age and sodium concentration were important predictors of COVID-19 severity, and the effect of sodium concentration was more pronounced in Hispanics (aOR 4.11 compared to aOR range: 1.47-1.88 for Black, White, and Other non-Hispanics). Dementia, CHF, and renal disease was associated with higher odds of severe COVID-19 among Black, Hispanic, and Other non-Hispanics PWH, respectively. Our findings suggest that the impact of factors, especially clinical comorbidities, predictive of severe COVID-19 among PWH varies by racialized groups, highlighting a need to account for race and comorbidity burden when assessing the risk of PWH developing severe COVID-19.

Epidemiology of Infantile Ureteropelvic Junction Obstruction in the US.

OBJECTIVE: To describe sex- and diagnosis-specific comorbidities, outcomes, and secular trends associated with ureteropelvic junction obstruction (UPJO) in a large, real-world population diagnosed with hydronephrosis in infancy. MATERIALS AND METHODS: We identified all infants ≤1 year old with ≥1 claim in the Optum Clinformatics 2007-2020 nationwide population database and used univariable and multivariable Cox regression analyses to estimate associations of demographic and clinical characteristics of infants with a UPJO diagnosis with surgical status. RESULTS: Of 22,349 infants with hydronephrosis (1.1% of infants; males-1.4%, females-0.7%), 1722 (7.7%; 7.9%-males, 7.2%-females) had UPJO. Follow-up was ≥1 year in 1198 (70%) and ≥3 years in 555 (32%) cases, and UPJO repair was performed in 542 children (31.5%; 32.3%-males, 29.5%-females); 77.7% within 1 year and 97.3% within 3 years. UPJO repair was associated with prior urinary tract infection (UTI) (hazard ratio (HR) 1.41, 95% confidence interval (CI) 1.12-1.76) and South (HR 1.42, 95% CI 1.14-1.78) or Midwest (HR 1.60, 95% CI 1.26-2.04) geographic region but did not change over time. CONCLUSION: This population-based study provides a real-world view of postnatally diagnosed hydronephrosis, focusing on UPJO, for which 522 cases (∼1/3) had ≥3 years continuous coverage. UPJO-associated comorbidities were more common in females, and the frequencies of UPJO-associated surgery and comorbidities were higher than in other studies. Other than UTI, no other associated kidney or urinary tract diagnoses were associated with UPJO repair. We identified unique sex- and diagnosis-specific differences in associated comorbidities and interventions in children diagnosed with UPJO in the first year of life.

Vitamin C Urinary Loss and Deficiency in Human Immunodeficiency Virus (HIV): Cross-sectional Study of Vitamin C Renal Leak in Women With HIV.

BACKGROUND: Reduced plasma vitamin C (vitC) concentrations in human immunodeficiency virus (HIV) may result from abnormal urinary excretion: a renal leak. VitC renal leak indicates underlying nutritional dysregulation independent of diet. We hypothesized that increased renal leak prevalence in HIV would be associated with deficient vitC concentrations. METHODS: We conducted an outpatient cross-sectional study of 96 women (40 HIV [PWH] and 56 without HIV [PWOH]) at the National Institutes of Health and Georgetown University. Renal leak was defined as abnormal urinary vitC excretion at fasting plasma concentrations <43.2µM, 2 SDs below vitC renal threshold in healthy women. To determine the primary outcome of renal leak prevalence, matched urine and plasma samples were collected the morning after overnight fast. Secondary outcomes assessed group differences in mean plasma vitC concentrations and prevalence of vitC deficiency. Exploratory outcomes assessed clinical parameters associated with renal leak. VitC was measured by high-performance liquid chromatography with coulometric electrochemical detection. RESULTS: PWH had significantly higher renal leak prevalence (73%vs14%; OR (odds ratio):16; P<.001), lower mean plasma vitC concentrations (14µMvs50µM; P<.001), and higher prevalence of vitC deficiency (43%vs7%; OR:10; P<.001) compared with PWOH, unchanged by adjustments for confounding factors. Significant predictors of renal leak included antiretroviral therapy (ART), Black race, older age, and metabolic comorbidities but not viral load or CD4 count. When compared with other chronic disease cohorts, PWH had the highest prevalence of renal leak and vitC deficiency (P<.001). CONCLUSIONS: High prevalence of vitC renal leak in HIV was associated with vitC deficiency, ART use, and race/ethnicity differences.

Vitamin C Urinary Loss in Fabry Disease: Clinical and Genomic Characteristics of Vitamin C Renal Leak.

BACKGROUND: Reduced plasma vitamin C concentrations in chronic diseases may result from abnormal urinary excretion of vitamin C: a renal leak. We hypothesized that vitamin C renal leak may be associated with disease-mediated renal dysregulation, resulting in aberrant vitamin C renal reabsorption and increased urinary loss. OBJECTIVES: We investigated the prevalence, clinical characteristics, and genomic associations of vitamin C renal leak in Fabry disease, an X-linked lysosomal disease associated with renal tubular dysfunction and low plasma vitamin C concentrations. METHODS: We conducted a non-randomized cross-sectional cohort study of men aged 24-42 y, with Fabry disease (n = 34) and controls without acute or chronic disease (n = 33). To match anticipated plasma vitamin C concentrations, controls were placed on a low-vitamin C diet 3 wk before inpatient admission. To determine the primary outcome of vitamin C renal leak prevalence, subjects were fasted overnight, and matched urine and fasting plasma vitamin C measurements were obtained the following morning. Vitamin C renal leak was defined as presence of urinary vitamin C at plasma concentrations below 38 µM. Exploratory outcomes assessed the association between renal leak and clinical parameters, and genomic associations with renal leak using single nucleotide polymorphisms (SNPs) in the vitamin C transporter SLC23A1. RESULTS: Compared with controls, the Fabry cohort had 16-fold higher odds of renal leak (6% vs. 52%; OR: 16; 95% CI: 3.30, 162; P < 0.001). Renal leak was associated with higher protein creatinine ratio (P < 0.01) and lower hemoglobin (P = 0.002), but not estimated glomerular filtration rate (P = 0.54). Renal leak, but not plasma vitamin C, was associated with a nonsynonymous single nucleotide polymorphism in vitamin C transporter SLC23A1 (OR: 15; 95% CI: 1.6, 777; P = 0.01). CONCLUSIONS: Increased prevalence of renal leak in adult men with Fabry disease may result from dysregulated vitamin C renal physiology and is associated with abnormal clinical outcomes and genomic variation.

Metformin is associated with reduced COVID-19 severity in patients with prediabetes.

AIMS: Studies suggest that metformin is associated with reduced COVID-19 severity in individuals with diabetes compared to other antihyperglycemics. We assessed if metformin is associated with reduced incidence of severe COVID-19 for patients with prediabetes or polycystic ovary syndrome (PCOS), common diseases that increase the risk of severe COVID-19. METHODS: This observational, retrospective study utilized EHR data from 52 hospitals for COVID-19 patients with PCOS or prediabetes treated with metformin or levothyroxine/ondansetron (controls). After balancing via inverse probability score weighting, associations with COVID-19 severity were assessed by logistic regression. RESULTS: In the prediabetes cohort, when compared to levothyroxine, metformin was associated with a significantly lower incidence of COVID-19 with "mild-ED" or worse (OR [95% CI]: 0.636, [0.455-0.888]) and "moderate" or worse severity (0.493 [0.339-0.718]). Compared to ondansetron, metformin was associated with lower incidence of "mild-ED" or worse severity (0.039 [0.026-0.057]), "moderate" or worse (0.045 [0.03-0.069]), "severe" or worse (0.183 [0.077-0.431]), and "mortality/hospice" (0.223 [0.071-0.694]). For PCOS, metformin showed no significant differences in severity compared to levothyroxine, but was associated with a significantly lower incidence of "mild-ED" or worse (0.101 [0.061-0.166]), and "moderate" or worse (0.094 [0.049-0.18]) COVID-19 outcome compared to ondansetron. CONCLUSIONS: Metformin use is associated with less severe COVID-19 in patients with prediabetes or PCOS.

Cell-free DNA maps COVID-19 tissue injury and risk of death and can cause tissue injury.

INTRODUCTIONThe clinical course of coronavirus 2019 (COVID-19) is heterogeneous, ranging from mild to severe multiorgan failure and death. In this study, we analyzed cell-free DNA (cfDNA) as a biomarker of injury to define the sources of tissue injury that contribute to such different trajectories.METHODSWe conducted a multicenter prospective cohort study to enroll patients with COVID-19 and collect plasma samples. Plasma cfDNA was subject to bisulfite sequencing. A library of tissue-specific DNA methylation signatures was used to analyze sequence reads to quantitate cfDNA from different tissue types. We then determined the correlation of tissue-specific cfDNA measures to COVID-19 outcomes. Similar analyses were performed for healthy controls and a comparator group of patients with respiratory syncytial virus and influenza.RESULTSWe found markedly elevated levels and divergent tissue sources of cfDNA in COVID-19 patients compared with patients who had influenza and/or respiratory syncytial virus and with healthy controls. The major sources of cfDNA in COVID-19 were hematopoietic cells, vascular endothelium, hepatocytes, adipocytes, kidney, heart, and lung. cfDNA levels positively correlated with COVID-19 disease severity, C-reactive protein, and D-dimer. cfDNA profile at admission identified patients who subsequently required intensive care or died during hospitalization. Furthermore, the increased cfDNA in COVID-19 patients generated excessive mitochondrial ROS (mtROS) in renal tubular cells in a concentration-dependent manner. This mtROS production was inhibited by a TLR9-specific antagonist.CONCLUSIONcfDNA maps tissue injury that predicts COVID-19 outcomes and may mechanistically propagate COVID-19-induced tissue injury.FUNDINGIntramural Targeted Anti-COVID-19 grant, NIH.

Vitamin E sequestration by liver fat in humans.

BACKGROUNDWe hypothesized that obesity-associated hepatosteatosis is a pathophysiological chemical depot for fat-soluble vitamins and altered normal physiology. Using α-tocopherol (vitamin E) as a model vitamin, pharmacokinetics and kinetics principles were used to determine whether excess liver fat sequestered α-tocopherol in women with obesity-associated hepatosteatosis versus healthy controls.METHODSCustom-synthesized deuterated α-tocopherols (d3- and d6-α-tocopherols) were administered to hospitalized healthy women and women with hepatosteatosis under investigational new drug guidelines. Fluorescently labeled α-tocopherol was custom-synthesized for cell studies.RESULTSIn healthy subjects, 85% of intravenous d6-α-tocopherol disappeared from the circulation within 20 minutes but reappeared within minutes and peaked at 3-4 hours; d3- and d6-α-tocopherols localized to lipoproteins. Lipoprotein redistribution occurred only in vivo within 1 hour, indicating a key role of the liver in uptake and re-release. Compared with healthy subjects who received 2 mg, subjects with hepatosteatosis had similar d6-α-tocopherol entry rates into liver but reduced initial release rates (P < 0.001). Similarly, pharmacokinetics parameters were reduced in hepatosteatosis subjects, indicating reduced hepatic d6-α-tocopherol output. Reductions in kinetics and pharmacokinetics parameters in hepatosteatosis subjects who received 2 mg were echoed by similar reductions in healthy subjects when comparing 5- and 2-mg doses. In vitro, fluorescent-labeled α-tocopherol localized to lipid in fat-loaded hepatocytes, indicating sequestration.CONCLUSIONSThe unique role of the liver in vitamin E physiology is dysregulated by excess liver fat. Obesity-associated hepatosteatosis may produce unrecognized hepatic vitamin E sequestration, which might subsequently drive liver disease. Our findings raise the possibility that hepatosteatosis may similarly alter hepatic physiology of other fat-soluble vitamins.TRIAL REGISTRATIONClinicalTrials.gov, NCT00862433.FUNDINGNational Institute of Diabetes and Digestive and Kidney Diseases and NIH grants DK053213-13, DK067494, and DK081761.

MutLγ promotes repeat expansion in a Fragile X mouse model while EXO1 is protective.

The Fragile X-related disorders (FXDs) are Repeat Expansion Diseases resulting from an expansion of a CGG-repeat tract at the 5' end of the FMR1 gene. The mechanism responsible for this unusual mutation is not fully understood. We have previously shown that mismatch repair (MMR) complexes, MSH2/MSH3 (MutSß) and MSH2/MSH6 (MutSα), together with Polß, a DNA polymerase important for base excision repair (BER), are important for expansions in a mouse model of these disorders. Here we show that MLH1/MLH3 (MutLγ), a protein complex that can act downstream of MutSß in MMR, is also required for all germ line and somatic expansions. However, exonuclease I (EXO1), which acts downstream of MutL proteins in MMR, is not required. In fact, a null mutation in Exo1 results in more extensive germ line and somatic expansions than is seen in Exo1+/+ animals. Furthermore, mice homozygous for a point mutation (D173A) in Exo1 that eliminates its nuclease activity but retains its native conformation, shows a level of expansion that is intermediate between Exo1+/+ and Exo1-/- animals. Thus, our data suggests that expansion of the FX repeat in this mouse model occurs via a MutLγ-dependent, EXO1-independent pathway, with EXO1 protecting against expansion both in a nuclease-dependent and a nuclease-independent manner. Our data thus have implications for the expansion mechanism and add to our understanding of the genetic factors that may be modifiers of expansion risk in humans.

Antagonism of scavenger receptor CD36 by 5A peptide prevents chronic kidney disease progression in mice independent of blood pressure regulation.

Scavenger receptor CD36 participates in lipid metabolism and inflammatory pathways important for cardiovascular disease and chronic kidney disease (CKD). Few pharmacological agents are available to slow the progression of CKD. However, apolipoprotein A-I-mimetic peptide 5A antagonizes CD36 in vitro. To test the efficacy of 5A, and to test the role of CD36 during CKD, we compared wild-type to CD36 knockout mice and wild-type mice treated with 5A, in a progressive CKD model that resembles human disease. Knockout and 5A-treated wild-type mice were protected from CKD progression without changes in blood pressure and had reductions in cardiovascular risk surrogate markers that are associated with CKD. Treatment with 5A did not further protect CD36 knockout mice from CKD progression, implicating CD36 as its main site of action. In a separate model of kidney fibrosis, 5A-treated wild-type mice had less macrophage infiltration and interstitial fibrosis. Peptide 5A exerted anti-inflammatory effects in the kidney and decreased renal expression of inflammasome genes. Thus, CD36 is a new therapeutic target for CKD and its associated cardiovascular risk factors. Peptide 5A may be a promising new agent to slow CKD progression.