SD Increase Research Articles

Association between serum uric acid levels and peripheral artery disease in Chinese adults with hypertension.

Higher serum uric acid (SUA) can cause gout, which is principally characterized by arthritis due to monosodium urate crystal deposition in the lower extremities. High levels of SUA have been linked to endothelial dysfunction, oxidative stress, and inflammation, all of which are involved in the pathogenesis of peripheral artery disease(PAD). To date, the relationship between SUA levels and PAD is still poorly understood. An analysis of 9,839 Chinese adults with essential hypertension from the ongoing China H-type Hypertension Registry Study was conducted in this cross-sectional study. Patients with an ABI ≤0.9 was diagnosed with PAD. Hyperuricemia was defined as SUA levels >420 mol/L in men and >360 mol/L in women. The association between SUA levels and PAD was evaluated using multivariable logistic regression models based on odds ratios (ORs) and their 95% confidence intervals (CIs). The enrolled subjects ranged in age from 27 to 93 years, with a mean age of 63.14 ± 8.99 years. The proportion of male patients was 46.22%, and the prevalence of hyperuricemia was 50.72%. In males, hyperuricemia was positively associated with the risk of PAD (adjusted OR per SD increase: 1.72, 95% CI 1.17 to 2.53, P =0.006). Males in the highest SUA tertile were significantly more likely to have PAD (adjusted OR: 2.63, 95% CI 1.42 to 4.86, P = 0.002; P for trend = 0.001). However, this positive relationship was not observed in females (adjusted OR: 1.29, 95% CI 0.77 to 2.17, P = 0.327; P for trend = 0.347). According to this cross-sectional study, higher SUA levels were positively associated with PAD in male hypertensive patients, while this positive relationship disappeared in female participants.

Midlife Systemic Inflammatory Markers Are Associated With Late-Life Brain Volume

Background and Objectives To clarify the temporal relationship between systemic inflammation and neurodegeneration, we examined whether a higher level of circulating inflammatory markers during midlife was associated with smaller brain volumes in late-life using a large biracial prospective cohort study. Methods Plasma levels of systemic inflammatory markers (fibrinogen, albumin, white blood cell count, von Willebrand factor, and factor VIII) were assessed at baseline in 1,617 participants (mean age 52 [8] years, 61% female, 26% African American) enrolled in the Atherosclerosis Risk in Communities Study. Using all 5 inflammatory markers, an inflammation composite score was created for each participant. We assessed episodic memory and regional brain volumes, using 3 T MRI, 24 years later. Results Each SD increase in midlife inflammation composite score was associated with 42 mm3 smaller hippocampal (p = 0.08), 204 mm3 smaller occipital (p = 0.07), and 197 mm3 smaller Alzheimer disease (AD) signature region (p = 0.010) volumes 24 years later. Compared with participants with no elevated (fourth quartile) midlife inflammatory markers, participants with elevations in 3 or more markers had significantly smaller AD signature region (−751 mm3; p = 0.038) and hippocampal (−148 mm3; p = 0.038) volumes and reduced episodic memory (p = 0.049). The association between midlife inflammation and late-life brain volume was modified by age, whereby younger participants with higher levels of systemic inflammation during midlife demonstrated significantly reduced late-life brain volumes subsequently. Discussion Our prospective findings provide evidence for what may be an early contributory role of systemic inflammation in neurodegeneration and cognitive aging.

Association of anxiety and depressive symptoms with C-reactive protein in diverse Latinos: Results from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

High sensitivity C-reactive protein (hsCRP) is a marker of systemic inflammation that has been associated with persistent depressive symptoms. Depression and anxiety are frequently associated with a chronic inflammatory state, yet the nature of this relationship has not been rigorously examined in diverse Hispanic/Latino populations. We aimed to study the association of anxiety and depressive symptoms as well as comorbid presentations, with circulating high sensitivity C-reactive protein (hsCRP) levels in a large Latino cohort of diverse heritages. We hypothesized a significant positive associations of both anxiety and depressive symptoms and hsCRP levels and potential variations among the heritage groups. Depressive symptoms and anxiety were measured by the Center for Epidemiological Studies Depression Scale (CES-D) and State-Trait Anxiety Inventory (STAI), respectively. Serum hsCRP (hsCRP) levels of 15,448 participants (age 18 to 75 years; 52.3% women) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) were measured and categorized based on the established cardiovascular disease (CVD) risk reference values (< 1mg/L, low; 1-<3 mg/L, intermediate; ≥ 3mg/L, high). Mean CES-D, STAI scores, and hsCRP levels were 7.0 (SD = 5.9), 17.0 (SD = 5.7), and 3.84 (SD = 7.85), respectively. Generalized linear modeling, adjusted for sociodemographic characteristics revealed significant associations between depression (exp(β) = 1.12; p<0.01) and anxiety symptoms (exp(β) = 1.10; p<0.05) with continuous hsCRP levels. For categorical values of hsCRP, one SD increase in CES-D and STAI scores was associated with a 10% and 8% increase in the RRRs of high vs. low hsCRP, respectively. However, these relationships between CES-D or STAI and hsCRP were no longer statistically significant after adjustment for CVD risk factors and medications. We found modest associations between anxiety and depressive symptoms and systemic inflammation measured by hsCRP among diverse Hispanics/Latinos that did not appreciably differ between heritage groups.

Association of Serum Very-Long-Chain Saturated Fatty Acids With Changes in Insulin Sensitivity and β-Cell Function: The Prospective Metabolism and Islet Cell Evaluation (PROMISE) Cohort.

A unique group of circulating very long-chain saturated fatty acids (VLCSFA), including arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0), have been associated with lower risk of type 2 diabetes, although associations with early metabolic risk phenotypes preceding type 2 diabetes have received limited study. We aimed to examine the associations of VLCSFA with longitudinal changes in insulin sensitivity and beta-cell function in a cohort at risk of type 2 diabetes. VLCSFA in the four main serum pools (phospholipid, triacylglycerol, cholesteryl ester, and non-esterified fatty acid) were extracted from fasting baseline samples (n=467). Generalized Estimating Equations were used to determine the associations between VLCSFA and changes over 9 years in validated indices of insulin sensitivity (HOMA2-%S and ISI) and beta-cell function (IGI, IGI/IR and ISSI-2). Associations of VLCSFA with outcomes were strongest in the triacylglycerol lipid pool: 20:0 was positively associated with both insulin sensitivity and beta-cell function (5.01% increase in HOMA2-%S and 4.01-6.28% increase in IGI/IR and ISSI-2 per SD increase in 20:0); 22:0 was positively associated with insulin sensitivity with 6.55% increase in HOMA2-%S and a 5.80% increase in ISI per SD increase in 22:0. Lastly, 24:0 was positively associated with insulin sensitivity and beta-cell function (7.94-8.45% increase in HOMA2-%S and ISI, and 4.61-6.93% increase in IGI/IR and ISSI-2 per SD increase in 24:0). Fewer significant associations were observed in the cholesteryl ester and non-esterified pools. Overall, our results indicate positive longitudinal associations of VLCSFA with insulin sensitivity and beta-cell function, especially within the triacylglycerol pool.

Psychosis Endophenotypes: A Gene-Set-Specific Polygenic Risk Score Analysis.

Endophenotypes can help to bridge the gap between psychosis and its genetic predispositions, but their underlying mechanisms remain largely unknown. This study aims to identify biological mechanisms that are relevant to the endophenotypes for psychosis, by partitioning polygenic risk scores into specific gene sets and testing their associations with endophenotypes. We computed polygenic risk scores for schizophrenia and bipolar disorder restricted to brain-related gene sets retrieved from public databases and previous publications. Three hundred and seventy-eight gene-set-specific polygenic risk scores were generated for 4506 participants. Seven endophenotypes were also measured in the sample. Linear mixed-effects models were fitted to test associations between each endophenotype and each gene-set-specific polygenic risk score. After correction for multiple testing, we found that a reduced P300 amplitude was associated with a higher schizophrenia polygenic risk score of the forebrain regionalization gene set (mean difference per SD increase in the polygenic risk score: -1.15 µV; 95% CI: -1.70 to -0.59 µV; P = 6 × 10-5). The schizophrenia polygenic risk score of forebrain regionalization also explained more variance of the P300 amplitude (R2 = 0.032) than other polygenic risk scores, including the genome-wide polygenic risk scores. Our finding on reduced P300 amplitudes suggests that certain genetic variants alter early brain development thereby increasing schizophrenia risk years later. Gene-set-specific polygenic risk scores are a useful tool to elucidate biological mechanisms of psychosis and endophenotypes, offering leads for experimental validation in cellular and animal models.

Association Between Prekallikrein and Stroke: A Mendelian Randomization Study.

Background High plasma prekallikrein was reported to be associated with increased risks of stroke, but the causality for these associations remains unclear. We aimed to investigate the associations of genetically predicted plasma prekallikrein concentrations with all-cause stroke, ischemic stroke, 3 ischemic stroke subtypes, and intracerebral hemorrhage (ICH) using a 2-sample Mendelian randomization approach. Methods and Results Seven independent prekallikrein-related single-nucleotide polymorphisms were identified as genetic instruments for prekallikrein based on a genome-wide association study with 1000 European individuals. The summary statistics for all-cause stroke, ischemic stroke, and ischemic stroke subtypes were obtained from the Multiancestry Genome-wide Association Study of Stroke Consortium with 40 585 cases and 406 111 controls of European ancestry. The summary statistics for ICH were obtained from the ISGC (International Stroke Genetics Consortium) with 1545 ICH cases and 1481 controls of European ancestry. In the main analysis, the inverse-variance weighted method was applied to estimate the associations of plasma prekallikrein concentrations with all-cause stroke, ischemic stroke, ischemic stroke subtypes, and ICH. Genetically predicted high plasma prekallikrein levels were significantly associated with elevated risks of all-cause stroke (odds ratio [OR] per SD increase, 1.04 [95% CI, 1.02-1.06]; P=5.44×10-5), ischemic stroke (OR per SD increase, 1.05 [95% CI, 1.03-1.07]; P=1.42×10-5), cardioembolic stroke (OR per SD increase, 1.08 [95% CI, 1.03-1.12]; P=3.75×10-4), and small vessel stroke (OR per SD increase, 1.11 [95% CI, 1.06-1.17]; P=3.02×10-5). However, no significant associations were observed for genetically predicted prekallikrein concentrations with large artery stroke and ICH. Conclusions This Mendelian randomization study found that genetically predicted high plasma prekallikrein concentrations were associated with increased risks of all-cause stroke, ischemic stroke, cardioembolic stroke, and small vessel stroke, indicating that prekallikrein might have a critical role in the development of stroke.

High levels of high-sensitivity C reactive protein to albumin ratio can increase the risk of cardiovascular disease

BackgroundThe high levels of C reactive protein (CRP) to albumin ratio (CAR) is thought to increase the risk of poor outcomes for cancer and cardiovascular disease (CVD). However, the association...

Metabolomic profiles of chronic distress are associated with cardiovascular disease risk and inflammation-related risk factors

BackgroundChronic psychological distress is associated with increased risk of cardiovascular disease (CVD) and investigators have posited inflammatory factors may be centrally involved in these relationships. However, mechanistic evidence and molecular underpinnings of these processes remain unclear, and data are particularly sparse among women. This study examined if a metabolite profile linked with distress was associated with increased CVD risk and inflammation-related risk factors. MethodsA plasma metabolite-based distress score (MDS) of twenty chronic psychological distress-related metabolites was developed in cross-sectional, 1:1 matched case-control data comprised of 558 women from the Nurses’ Health Study (NHS; 279 women with distress, 279 controls). This MDS was then evaluated in two other cohorts: the Women’s Health Initiative Observational Cohort (WHI-OS) and the Prevención con Dieta Mediterránea (PREDIMED) trial. We tested the MDS's association with risk of future CVD in each sample and with levels of C-reactive protein (CRP) in the WHI-OS. The WHI-OS subsample included 944 postmenopausal women (472 CHD cases; mean time to event = 5.8 years); the PREDIMED subsample included 980 men and women (224 CVD cases, mean time to event = 3.1 years). ResultsIn the WHI-OS, a 1-SD increase in the plasma MDS was associated with a 20% increased incident CHD risk (odds ratio [OR] = 1.20, 95% CI: 1.04 – 1.38), adjusting for known CVD risk factors excluding total and HDL cholesterol. This association was attenuated after including total and HDL cholesterol. CRP mediated an average 12.9% (95% CI: 4.9% – 28%, p < 10-15) of the total effect of MDS on CHD risk when adjusting for matching factors. This effect was attenuated after adjusting for known CVD risk factors. Of the metabolites in the MDS, tryptophan and threonine were inversely associated with incident CHD risk in univariate models. In PREDIMED, each one SD increase in the MDS was associated with an OR of 1.19 (95% CI: 1.00 – 1.41) for incident CVD risk, after adjusting all risk factors. Similar associations were observed in men and women. Four metabolites in the MDS were associated with incident CVD risk in PREDIMED in univariate models. Biliverdin and C36:5 phosphatidylcholine (PC) plasmalogen had inverse associations; C16:0 ceramide and C18:0 lysophosphatidylethanolamine(LPE) each had positive associations with CVD risk. ConclusionsOur study points to molecular alterations that may underlie the association between chronic distress and subsequent risk of cardiovascular disease in adults.

Genetic association of lipids and lipid-lowering drugs with sepsis: a Mendelian randomization and mediation analysis.

The impact of lipid-lowering medications on sepsis is still not well defined. A Mendelian randomization (MR) study was carried out to probe the causal connections between genetically determined lipids, lipid-reducing drugs, and the risk of sepsis. Data on total serum cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A-I (ApoA-I), apolipoprotein B (ApoB), and triglycerides (TG) were retrieved from the MR-Base platform and the Global Lipids Genetics Consortium in 2021 (GLGC2021). Our study categorized sepsis into two groups: total sepsis and 28-day mortality of sepsis patients (sepsis28). The inverse-variance weighted (IVW) method was the primary method used in MR analysis. Cochran's Q test and the MR-Egger intercept method were used to assess the heterogeneity and pleiotropy. In the MR analysis, we found that ApoA-I played a suggestively positive role in protecting against both total sepsis (OR, 0.863 per SD increase in ApoA-I; 95% CI, 0.780-0.955; P = 0.004) and sepsis28 (OR, 0.759; 95% CI, 0.598-0.963; P = 0.023). HDL-C levels were also found to suggestively reduce the incidence of total sepsis (OR, 0.891 per SD increase in HDL-C; 95% CI, 0.802-0.990; P = 0.031). Reverse-MR showed that sepsis28 led to a decrease in HDL-C level and an increase in TG level. In drug-target MR, we found that HMGCR inhibitors positively protected against total sepsis (, 0.719 per SD reduction in LDL-C; 95% CI, 0.540-0.958; P = 0.024). LDL-C and HDL-C proxied CETP inhibitors were found to have a protective effect on total sepsis, with only LDL-C proxied CETP inhibitors showing a suggestively protective effect on sepsis28. In Mediated-MR, BMI exhibited a negative indirect effect in HMGCR inhibitors curing sepsis. The indirect impact of ApoA-I explained over 50% of the curative effects of CETP inhibitors in sepsis. Our MR study suggested that ApoA-I and HDL-C protected against sepsis, while HMGCR and CETP inhibitors showed therapeutic potential beyond lipid-lowering effects. ApoA-I explained the effects of CETP inhibitors. Our study illuminates how lipids affect sepsis patients and the effectiveness of new drugs, opening new avenues for sepsis treatment.

Does physical activity moderate the association between shorter leukocyte telomere length and incident coronary heart disease? Data from 54,180 UK Biobank participants.

Telomere shortening is a biological aging hallmark. The effect of short telomere length may be targeted by increased physical activity to reduce the risk of multiple aging-related diseases, including coronary heart disease (CHD). The objective was to assess the moderation effect of accelerometer-based physical activity (aPA) on the association between shorter leukocyte telomere length (LTL) relatively in the population sample and incident CHD. Data were from the UK Biobank participants with well-calibrated accelerometer data for at least 6.5days (n = 54,180). Relative mean LTL at baseline (5-6years prior to aPA assessment) was measured in T/S ratio, using a multiplex quantitative polymerase chain reaction (qPCR) technology, by comparing the amount of the telomere amplification product (T) to that of a single-copy gene (S). aPA measures included total number of events (at least 10-s continued physical activity > 32 milligravities [mg]), total volume, mean duration, mean intensity, and peak intensity of all events. LTL, aPA measures, and their interactions were associated with incident CHD (mean follow-up 6.8years) using Cox proportional hazards models adjusting for covariates. Longer LTL (relative to the sample distribution) was associated with reduced incidence of CHD (adjusted hazard ratio [aHR] = 0.94 per standard deviation [SD] increase in LTL, [95% CI, 0.90 to 0.99], P = .010). Incidence of CHD was reduced by higher total volume of aPA (aHR = 0.82 per SD increase in LTL, [95% CI, 0.71 to 0.95], P = .010) but increased by higher total number of events (aHR = 1.11 per SD increase in LTL, [95% CI, 1.02 to 1.21], P = .020) after controlling for other aPA measures and covariates. However, none of the interactions between LTL and aPA measures was statistically significant (P = .171).

Growth Velocities Across Distinct Early Life Windows and Child Cognition: Insights from a Contemporary US Cohort

To evaluate the relative importance of overall and period-specific postnatal growth and their interaction with fetal growth on cognition in a generally well-nourished population. We included 1052 children from Project Viva, a prospective cohort in Boston, Massachusetts. Using linear spline mixed-effects models, we modeled length/height and body mass index (BMI) trajectories from birth to 7years and estimated standardized overall (0-7years) and period-specific growth velocities ie, early infancy (0-4months), late infancy (4-15months), toddlerhood (15-37months), and early childhood (37-84months). We investigated associations of growth velocities as well as their interactions with birthweight-for-gestational age on mid-childhood (mean age: 7.9years) IQ, visual memory and learning, and visual motor ability. Greater overall height velocity was associated with modestly higher design memory score, (adjusted β [95% CI] 0.19 [-0.01,0.38] P=.057])points per SD increase but lower verbal IQ (-0.88 [-1.76,0.00] P=.051). Greater early infancy height velocity was associated with higher visual motor score (1.92 [0.67,3.18]). Greater overall BMI velocity was associated with lower verbal IQ (-0.71 [-1.52,0.11] P=.090). Greater late infancy BMI velocity was associated with lower verbal IQ (-1.21 [-2.07,-0.34]), design memory score (-0.22 [-0.42,-0.03)], but higher picture memory score (0.22 [0.01,0.43]). Greater early infancy height velocity (-1.5 SD vs 1.5 SD) was associated with higher nonverbal IQ (margins [95% CI] 102.6 [98.9106.3] vs 108.2 [104.9111.6]) among small-for-gestational age infants (P-interaction=0.04). Among generally well-nourished children, there might not be clear cognitive gains with faster linear growth except for those with lower birthweight-for-gestational age, revealing the potential importance of early infancy compensatory growth.

Prenatal exposure to perfluoroalkyl substances and inflammatory biomarker concentrations.

We analyzed data from 1411 participants, recruited between 2008 and 2011, in the Maternal-Infant Research on Environmental Chemicals study. Our primary outcome was a composite inflammatory index derived by summing the z-scores of eight proinflammatory biomarkers. Using multivariable linear regression models, we quantified associations between each PFAS and the inflammatory index and individual biomarkers. We quantified the effects of the PFAS mixture using weighted quantile sum regression, and evaluated effect modification using product terms and sex-stratified models. Each doubling of PFOA and PFHxS was associated with a 0.38 (95% CI, 0.09, 0.67) and 0.21 (95% CI, 0.01, 0.41) SD increase in the proinflammatory index, respectively. A one-quartile increase in the PFAS mixture was associated with a 0.40 (95% CI, 0.09, 0.71) SD increase in the proinflammatory index. In individual models, we observed positive associations between PFAS and concentrations of monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and matrix metalloproteinases-9; however, the magnitude and precision varied according to the specific PFAS. Sex-specific findings were identified in few PFAS-biomarker associations. PFOA, PFOS, and PFHxS, individually and as a mixture, were positively associated with proinflammatory biomarkers during pregnancy.

Uric acid to high-density lipoprotein cholesterol ratio predicts adverse cardiovascular events in patients with coronary chronic total occlusion

Background and aimsUric acid to high-density lipoprotein cholesterol ratio (UHR) is a novel index of metabolism and inflammation proposed by recent studies. The prognostic value of UHR is undetermined in patients with coronary chronic total occlusion (CTO). The aim of this study was to investigate the association of UHR with adverse cardiovascular events in patients with CTO. Methods and resultsIn this retrospective cohort study, we enrolled 566 patients with CTO lesion in our hospital from January 2016 to December 2019. Patients were divided into three groups based on UHR level. The primary endpoint was major adverse cardiovascular event (MACE), defined as a combination of death, non-fatal MI, target vessel revascularization (TVR), and non-fatal stroke. The median follow-up time of this study was 43 months. During the follow-up, 107 (18.9%) MACEs were recorded. Kaplan–Meier survival plots show the cumulative incidence of MACE-free decreased across tertile of UHR (log-rank test, p < 0.001). In the fully adjusted model, the Hazard ratio (95% CI) of MACE was 2.16 (1.17–3.99) in tertile 3 and 2.01 (1.62–2.49) for per SD increase in UHR. ConclusionElevated UHR predicts an increasing risk of MACE in patients with CTO. UHR is a simple and reliable indicator for risk stratification and early intervention in CTO patients.

Prognostic Value of Urinary N-Acetyl-β-d-Glucosaminidase as a Marker of Tubular Damage in Patients with Heart Failure and Mitral Regurgitation.

Mitral regurgitation (MR) has a high prevalence and aggravates hypoperfusion and hypoxia in heart failure (HF). Renal tubular epithelial cells are sensitive to hypoxia, and therefore tubulointerstitial damage is quite common in HF. However, the correlation between tubular dysfunction and MR has not been studied. The aim of this work was to evaluate the prognostic significance of urinary N-acetyl- -d-glucosaminidase (uNAG), a biomarker of renal tubular damage, in patients with HF and MR. This was a prospective cohort study of 390 patients (mean age 64 years; 65.6% male) with uNAG measurement on admission (expressed as urinary NAG/urinary creatinine) and at least 1 year of follow-up data. The pre-defined primary endpoint was the composite of all-cause mortality or rehospitalization for HF after discharge. Cox regression analysis, restricted cubic splines, and subgroup analysis were used to investigate the prognostic value of uNAG modeled as a categorical (quartiles) or continuous (per SD increase) variable. A total of 153 (39.23%) patients reached the composite endpoint over a median follow-up time of 1.2 years. The uNAG level correlated with the severity of HF and with the incidence of adverse events. In a multivariable Cox regression model, each SD (13.80 U/g Cr) of increased uNAG was associated with a 17% higher risk of death or HF rehospitalization (95% confidence interval, 2-33%, p = 0.022), and a 19% higher risk of HF rehospitalization (p = 0.027). Subgroup analysis revealed the associations between uNAG and poor prognosis were only significant in younger patients ( 65 years) and in patients without obvious cardiovascular comorbidities. uNAG levels at admission were associated with the risk of adverse outcomes in patients with HF and MR. Additional studies are needed to further investigate the heart-kidney interaction.

Biomarkers Associated With Severe COVID-19 Among Populations With High Cardiometabolic Risk

Cardiometabolic parameters are established risk factors for COVID-19 severity. The identification of causal or protective biomarkers for COVID-19 severity may facilitate the development of novel therapies. To identify protein biomarkers that promote or reduce COVID-19 severity and that mediate the association of cardiometabolic risk factors with COVID-19 severity. This genetic association study using 2-sample mendelian randomization (MR) was conducted in 2022 to investigate associations among cardiometabolic risk factors, circulating biomarkers, and COVID-19 hospitalization. Inputs for MR included genetic and proteomic data from 4147 participants with dysglycemia and cardiovascular risk factors collected through the Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial. Genome-wide association study summary statistics were obtained from (1) 3 additional independent plasma proteome studies, (2) genetic consortia for selected cardiometabolic risk factors (including body mass index [BMI], type 2 diabetes, type 1 diabetes, and systolic blood pressure; all n >10 000), and (3) the COVID-19 Host Genetics Initiative (n = 5773 hospitalized and 15 497 nonhospitalized case participants with COVID-19). Data analysis was performed in July 2022. Genetically determined concentrations of 235 circulating proteins assayed with a multiplex biomarker panel from the ORIGIN trial for the initial analysis. Hospitalization status of individuals from the COVID-19 Host Genetics Initiative with a positive COVID-19 test result. Among 235 biomarkers tested in samples totaling 22 101 individuals, MR analysis showed that higher kidney injury molecule-1 (KIM-1) levels reduced the likelihood of COVID-19 hospitalization (odds ratio [OR] per SD increase in KIM-1 levels, 0.86 [95% CI, 0.79-0.93]). A meta-analysis validated the protective association with no observed directional pleiotropy (OR per SD increase in KIM-1 levels, 0.91 [95% CI, 0.88-0.95]). Of the cardiometabolic risk factors studied, only BMI was associated with KIM-1 levels (0.17 SD increase in biomarker level per 1 kg/m2 [95% CI, 0.08-0.26]) and COVID-19 hospitalization (OR per 1-SD biomarker level, 1.33 [95% CI, 1.18-1.50]). Multivariable MR analysis also revealed that KIM-1 partially mitigated the association of BMI with COVID-19 hospitalization, reducing it by 10 percentage points (OR adjusted for KIM-1 level per 1 kg/m2, 1.23 [95% CI, 1.06-1.43]). In this genetic association study, KIM-1 was identified as a potential mitigator of COVID-19 severity, possibly attenuating the increased risk of COVID-19 hospitalization among individuals with high BMI. Further studies are required to better understand the underlying biological mechanisms.

Bilirubin-associated single nucleotide polymorphism (SNP) and respiratory health outcomes: a mendelian randomization study

BackgroundObservational studies have shown an association between higher bilirubin levels and improved respiratory health outcomes. Targeting higher bilirubin levels has been proposed as a novel therapeutic strategy in COPD. However, bilirubin levels are influenced by multiple intrinsic and extrinsic factors, and these observational studies are prone to confounding. Genetic analyses are one approach to overcoming residual confounding in observational studies.ObjectivesTo test associations between a genetic determinant of bilirubin levels and respiratory health outcomes.MethodsCOPDGene participants underwent genotyping at the baseline visit. We confirmed established associations between homozygosity for rs6742078 and higher bilirubin, and between higher bilirubin and decreased risk of acute respiratory events within this cohort. For our primary analysis, we used negative binomial regression to test associations between homozygosity for rs6742078 and rate of acute respiratory events.Results8,727 participants (n = 6,228 non-Hispanic white and 2,499 African American) were included. Higher bilirubin was associated with decreased rate of acute respiratory events [incidence rate ratio (IRR) 0.85, 95% CI 0.75 to 0.96 per SD increase in bilirubin intensity]. We did not find significant associations between homozygosity for rs6742078 and acute respiratory events (IRR 0.94, 95% CI 0.70 to 1.25 for non-Hispanic white and 1.09, 95% CI 0.91 to 1.31 for African American participants).ConclusionsA genetic determinant of higher bilirubin levels was not associated with better respiratory health outcomes. These results do not support targeting higher bilirubin levels as a therapeutic strategy in COPD.

Time series modelling for wastewater-based epidemiology of COVID-19: A nationwide study in 40 wastewater treatment plants of Belgium, February 2021 to June 2022

BackgroundWastewater-based epidemiology (WBE) has been implemented to monitor surges of COVID-19. Yet, multiple factors impede the usefulness of WBE and quantitative adjustment may be required. AimWe aimed to model the relationship between WBE data and incident COVID-19 cases, while adjusting for confounders and autocorrelation. MethodsThis nationwide WBE study includes data from 40 wastewater treatment plants (WWTPs) in Belgium (02/2021–06/2022). We applied ARIMA-based modelling to assess the effect of daily flow rate, pepper mild mottle virus (PMMoV) concentration, a measure of human faeces in wastewater, and variants (alpha, delta, and omicron strains) on SARS-CoV-2 RNA levels in wastewater. Secondly, adjusted WBE metrics at different lag times were used to predict incident COVID-19 cases. Model selection was based on AICc minimization. ResultsIn 33/40 WWTPs, RNA levels were best explained by incident cases, flow rate, and PMMoV. Flow rate and PMMoV were associated with −13.0 % (95 % prediction interval: −26.1 to +0.2 %) and +13.0 % (95 % prediction interval: +5.1 to +21.0 %) change in RNA levels per SD increase, respectively. In 38/40 WWTPs, variants did not explain variability in RNA levels independent of cases. Furthermore, our study shows that RNA levels can lead incident cases by at least one week in 15/40 WWTPs. The median population size of leading WWTPs was 85.1 % larger than that of non‑leading WWTPs. In 17/40 WWTPs, however, RNA levels did not lead or explain incident cases in addition to autocorrelation. ConclusionThis study provides quantitative insights into key determinants of WBE, including the effects of wastewater flow rate, PMMoV, and variants. Substantial inter-WWTP variability was observed in terms of explaining incident cases. These findings are of practical importance to WBE practitioners and show that the early-warning potential of WBE is WWTP-specific and needs validation.

Epigenome-wide association study using peripheral blood leukocytes identifies genomic regions associated with periodontal disease and edentulism in the Atherosclerosis Risk in Communities study.

To investigate individual susceptibility to periodontitis by conducting an epigenome-wide association study using peripheral blood. We included 1077 African American and 457 European American participants of the Atherosclerosis Risk in Communities (ARIC) study who had completed a dental examination or reported being edentulous at Visit 4 and had available data on DNA methylation from Visit 2 or 3. DNA methylation levels were compared by periodontal disease severity and edentulism through discovery analyses and subsequent testing of individual CpGs. Our discovery analysis replicated findings from a previous study reporting a region in gene ZFP57 (6p22.1) that was significantly hypomethylated in severe periodontal disease compared with no/mild periodontal disease in European American participants. Higher methylation levels in a separate region in an unknown gene (located in Chr10: 743,992-744,958) was associated with significantly higher odds of edentulism compared with no/mild periodontal disease in African American participants. In subsequent CpG testing, four CpGs in a region previously associated with periodontitis located within HOXA4 were significantly hypermethylated in severe periodontal disease compared with no/mild periodontal disease in African American participants (odds ratio per 1 SD increase in methylation level: cg11015251: 1.28 (1.02, 1.61); cg14359292: 1.24 (1.01, 1.54); cg07317062: 1.30 (1.05, 1.61); cg08657492: 1.25 (1.01, 1.55)). Our study highlights epigenetic variations in ZPF57 and HOXA4 that are significantly and reproducibly associated with periodontitis. Future studies should evaluate gene regulatory mechanisms in the candidate regions of these loci.

Sleep Apnea Physiological Burdens and Cardiovascular Morbidity and Mortality.

Rationale: Obstructive sleep apnea is characterized by frequent reductions in ventilation, leading to oxygen desaturations and/or arousals. Objectives: In this study, association of hypoxic burden with incident cardiovascular disease (CVD) was examined and compared with that of "ventilatory burden" and "arousal burden." Finally, we assessed the extent to which the ventilatory burden, visceral obesity, and lung function explain variations in hypoxic burden. Methods: Hypoxic, ventilatory, and arousal burdens were measured from baseline polysomnograms in the Multi-Ethnic Study of Atherosclerosis (MESA) and the Osteoporotic Fractures in Men (MrOS) studies. Ventilatory burden was defined as event-specific area under ventilation signal (mean normalized, area under the mean), and arousal burden was defined as the normalized cumulative duration of all arousals. The adjusted hazard ratios for incident CVD and mortality were calculated. Exploratory analyses quantified contributions to hypoxic burden of ventilatory burden, baseline oxygen saturation as measured by pulse oximetry, visceral obesity, and spirometry parameters. Measurements and Main Results: Hypoxic and ventilatory burdens were significantly associated with incident CVD (adjusted hazard ratio [95% confidence interval] per 1 SD increase in hypoxic burden: MESA, 1.45 [1.14, 1.84]; MrOS, 1.13 [1.02, 1.26]; ventilatory burden: MESA, 1.38 [1.11, 1.72]; MrOS, 1.12 [1.01, 1.25]), whereas arousal burden was not. Similar associations with mortality were also observed. Finally, 78% of variation in hypoxic burden was explained by ventilatory burden, whereas other factors explained only <2% of variation. Conclusions: Hypoxic and ventilatory burden predicted CVD morbidity and mortality in two population-based studies. Hypoxic burden is minimally affected by measures of adiposity and captures the risk attributable to ventilatory burden of obstructive sleep apnea rather than a tendency to desaturate.

Treatment burden and health-related quality of life of patients with multimorbidity: a cross-sectional study

PurposeThe aim of this study was to investigate treatment burden and its relationship with health-related quality of life (HRQoL) among patients with multimorbidity (two or more chronic diseases) who were taking prescription medications and attending the outpatient department of the University of Gondar Comprehensive Specialized Teaching Hospital.MethodsA cross-sectional study was conducted between March 2019 and July 2019. Treatment burden was measured using the Multimorbidity Treatment Burden Questionnaire (MTBQ), while HRQoL was captured using the Euroqol-5-dimensions-5-Levels (EQ-5D-5L).ResultsA total of 423 patients participated in the study. The mean global MTBQ, EQ-5D index, and EQ-VAS scores were 39.35 (± 22.16), 0.83 (± 0.20), and 67.32 (± 18.51), respectively. Significant differences were observed in the mean EQ-5D-Index (F [2, 81.88] 33.1) and EQ-VAS (visual analogue scale) scores (F [2, 75.48] = 72.87) among the treatment burden groups. Follow up post-hoc analyses demonstrated significant mean differences in EQ-VAS scores across the treatment burden groups and in EQ-5D index between the no/low treatment burden and high treatment burden, as well as between the medium treatment burden and high treatment burden. In the multivariate linear regression model, every one SD increase in the global MTBQ score (i.e., 22.16) was associated with a decline of 0.08 in the EQ-5D index (β − 0.38, 95%CI − 0.48, − 0.28), as well as a reduction of 9.4 in the EQ-VAS score (β − 0.51, 95%CI -0.60, − 0.42).ConclusionTreatment burden was inversely associated with HRQoL. Health care providers should be conscious in balancing treatment exposure with patients’ HRQoL.