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Microbial communities along mucosal surfaces throughout the digestive tract are hypothesized as risk factors for impaired glucose regulation and the development of clinical cardiometabolic disease. We investigated whether baseline measures of subgingival microbiota predicted fasting plasma glucose (FPG) longitudinally. The Oral Infections, Glucose Intolerance and Insulin Resistance Study (ORIGINS) enrolled 230 diabetes-free adults (77% female) aged 20 to 55 y (mean ± SD, 34 ± 10 y) from whom baseline subgingival plaque and longitudinal FPG were measured. DNA was extracted from subgingival plaque, and V3 to V4 regions of the 16S rRNA gene were sequenced. FPG was measured at baseline and again at 2 y; glucose change was defined as follow-up minus baseline. Multivariable linear models regressed 2-y glucose change onto baseline measures of community diversity and abundances of 369 individual taxa. A microbial dysbiosis index (MDI) summarizing top individual taxa associated with glucose change was calculated and used in regression models. Models were adjusted for age, sex, race/ethnicity, education, smoking status, body mass index, and baseline glucose levels. Statistical significance was based on the false discovery rate (FDR;

Objective: Adverse microbial exposures might contribute to diabetogenesis. We hypothesized that clinical periodontal disease (a manifestation of microbial exposures in dysbiotic biofilms) would be related to insulin resistance among diabetes-free participants. The roles of inflammatory mediation and effect modification were also studied.Research Design and Methods: The continuous National Health and Nutrition Examination Survey 1999-2004 enrolled 3,616 participants (51% women) who received a periodontal examination and fasting blood draw. Participants were mean age (± SD) 43 ± 17 years and 28% Hispanic, 52% Caucasian, 17% African American, and 3% other. Log-transformed values of the homeostasis model assessment of insulin resistance (HOMA-IR) or HOMA-IR ≥3.30 (75th percentile) were regressed across full-mouth periodontal probing depth (PD) levels using linear and logistic models. White blood cell (WBC) count and C-reactive protein (CRP) were considered as either mediators or effect modifiers in separate analyses. Risk ratios (RRs) stem from marginal predictions derived from the logistic model. Results were adjusted for multiple periodontal disease and insulin resistance risk factors.Results: In linear regression, geometric mean HOMA-IR levels increased by 1.04 for every 1-mm PD increase (P = 0.007). WBC mediated 6% of the association (P < 0.05). Among participants with WBC ≤6.4 × 10(9), PD was unrelated to HOMA-IR ≥3.30. Fourth-quartile PD was associated with HOMA-IR ≥3.30 among participants with WBC >7.9 × 10(9); RR 2.60 (1.36-4.97) (P for interaction = 0.05). Findings were similar among participants with CRP >3.0 mg/L (P for interaction = 0.04).Conclusions: Periodontal infection was associated with insulin resistance in a nationally representative U.S. sample of diabetes-free adults. These data support the role of inflammation as both mediator and effect modifier of the association. [ABSTRACT FROM AUTHOR]

Objective: To explore associations between diabetes etiology (type 1 diabetes mellitus [T1DM] vs. T2DM) and glycemic control in the prediction of 5-year periodontal status change.Research Design and Methods: The Study of Health in Pomerania (SHIP) is a population-based stratified sample of German men and women. Healthy participants and those determined to have T2DM arose from the SHIP cohort, and T1DM participants were recruited from diabetes clinics in the catchment area that gave rise to SHIP. Dentate participants (n = 2,626; 53% women; 20-81 years of age) were included. Diabetes was determined via physician diagnosis and/or HbA(1c) ≥6.5% (uncontrolled diabetes >7.0%). Examiners blinded to diabetes status performed random half-mouth periodontal examinations, assessing probing depth (PD) and attachment loss (AL) (four sites/tooth) at baseline and follow-up. Participants were categorized into six groups as follows: 1) diabetes free (n = 2,280), 2) incident T2DM (n = 79), 3) controlled T2DM (n = 80), 4) uncontrolled T2DM (n = 72), 5) controlled T1DM (n = 43), and 6) uncontrolled T1DM (n = 72). In multivariable regressions, mean PD change (ΔMPD), mean AL change (ΔMAL), or incident tooth-loss values were regressed across the aforementioned diabetes categories.Results: Mean (SD) ΔMPD and ΔMAL values among all participants were -0.08 ± 0.5 mm and 0.08 ± 1.03 mm, respectively, and 34% lost one or more teeth. Relative to diabetes-free participants, those with uncontrolled T2DM experienced greater ΔMPD ± SE (P < 0.05), whereas participants with either uncontrolled T1DM or uncontrolled T2DM realized greater ΔMAL (P < 0.05). Uncontrolled T1DM and T2DM were both associated with an increased risk of future tooth loss (P < 0.05).Conclusions: Diabetes control, but not etiology, was associated with future tooth loss and accelerated AL progression. [ABSTRACT FROM AUTHOR]

Evidence from epidemiologic studies suggests that periodontal infections are independently associated with subclinical and clinical atherosclerotic vascular disease. Although the strength of the reported associations is modest, the consistency of the data across diverse populations and a variety of exposure and outcome variables suggests that the findings are not spurious or attributable only to the effects of confounders. Analysis of limited data from interventional studies suggests that periodontal treatment generally results in favorable effects on subclinical markers of atherosclerosis, although such analysis also indicates considerable heterogeneity in responses. Experimental mechanistic in vitro and in vivo studies have established the plausibility of a link between periodontal infections and atherogenesis, and have identified biological pathways by which these effects may be mediated. However, the utilized models are mostly mono-infections of host cells by a limited number of 'model' periodontal pathogens, and therefore may not adequately portray human periodontitis as a polymicrobial, biofilm-mediated disease. Future research must identify in vivo pathways in humans that may (i) lead to periodontitis-induced atherogenesis, or (ii) result in treatment-induced reduction of atherosclerosis risk. Data from these studies will be essential for determining whether periodontal interventions have a role in the primary or secondary prevention of atherosclerosis. [ABSTRACT FROM AUTHOR]

Objective: Infection may be a type 2 diabetes risk factor. Periodontal disease is a chronic infection. We hypothesized that periodontal disease was related to A1C progression in diabetes-free participants.Research Design and Methods: The Study of Health in Pomerania (SHIP) is a population-based cohort in Germany including 2,973 diabetes-free participants (53% women; aged 20-81 years). Participants were categorized into four groups according to increasing baseline periodontal disease levels (percentage of sites per mouth with attachment loss >or=5 mm, determined a priori); sample sizes for each respective category were 1,122, 488, 463, and 479 (241 participants were edentulous). Mean absolute changes (year 5 minus baseline) in A1C (DeltaA1C) were regressed across periodontal categories while adjusting for confounders (e.g., age, sex, smoking, obesity, physical activity, and family history).Results: Across baseline periodontal disease categories, DeltaA1C +/- SEM values were 0.023 +/- 0.02, 0.023 +/- 0.02, 0.065 +/- 0.03, and 0.106 +/- 0.03 (P(trend) = 0.02), yielding an approximate fivefold increase in the absolute difference in DeltaA1C when dentate participants in the highest versus lowest periodontal disease category were compared; these results were markedly stronger among participants with high-sensitivity C-reactive protein >or=1.0 mg/l (P(interaction) = 0.01). When individuals who had neither baseline periodontal disease nor deterioration in periodontal status at 5 years were compared with individuals with both poor baseline periodontal health and longitudinal periodontal deterioration, mean DeltaA1C values were 0.005 vs. 0.143% (P = 0.003).Conclusions: Periodontal disease was associated with 5-year A1C progression, which was similar to that observed for a 2-SD increase in either waist-to-hip ratio or age in this population. [ABSTRACT FROM AUTHOR]

Objective: Type 2 diabetes and periodontal disease are known to be associated, but the temporality of this relationship has not been firmly established. We investigated whether baseline periodontal disease independently predicts incident diabetes over two decades of follow-up.Research Design and Methods: A total of 9,296 nondiabetic male and female National Health and Nutrition Examination Survey (NHANES I) participants aged 25-74 years who completed a baseline dental examination (1971-1976) and had at least one follow-up evaluation (1982-1992) were studied. We defined six categories of baseline periodontal disease using the periodontal index. Of 7,168 dentate participants, 47% had periodontal index = 0 (periodontally healthy); the remaining were classified into periodontal index quintiles. Incident diabetes was defined by 1) death certificate (ICD-9 code 250), 2) self-report of diabetes requiring pharmacological treatment, or 3) health care facility stay with diabetes discharge code. Multivariable logistic regression models assessed incident diabetes odds across increasing levels of periodontal index in comparison with periodontally healthy participants.Results: The adjusted odds ratios (ORs) for incident diabetes in periodontal index categories 1 and 2 were not elevated, whereas the ORs in periodontal index categories 3 through 5 were 2.26 (95% CI 1.56-3.27), 1.71 (1.0-2.69), and 1.50 (0.99-2.27), respectively. The OR in edentulous participants was 1.30 (1.00-1.70). Dentate participants with advanced tooth loss had an OR of 1.70 (P < 0.05) relative to those with minimal tooth loss.Conclusions: Baseline periodontal disease is an independent predictor of incident diabetes in the nationally representative sample of NHANES I. [ABSTRACT FROM AUTHOR]

AIM: Various bacterial species are differentially prevalent in periodontal health, gingivitis or periodontitis. We tested the independent associations between three bacterial groupings and gingival inflammation in an epidemiological study. MATERIAL AND METHODS: In 706 Oral Infections and Vascular Disease Epidemiology Study (INVEST) participants > or =55 years, bleeding on probing (BoP), pocket depth (PD) and subgingival plaque samples (n=4866) were assessed in eight sites per mouth. Eleven bacterial species were quantitatively assayed and grouped as follows: (i) aetiologic burden (EB, Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia); (ii) putative burden (PB, Campylobacter rectus, Eikenella corrodens, Fusobacterium nucleatum, Micromonas micros, Prevotella intermedia); (iii) health-associated burden (HAB, Actinomyces naeslundii, Veillonella parvula). RESULTS: After mutual adjustment for EB, PB and HAB, the BoP prevalence increased by 45% ( p<0.0001) across increasing quartiles of EB while BoP decreased by 13% ( p<0.0001) across increasing quartiles of HAB. Mean PD increased 0.8 mm and decreased 0.3 mm from the first to fourth quartiles of EB (p<0.0001) and HAB ( p<0.0001), respectively. Among 1214 plaque samples with fourth quartile EB, 60% were collected from sites with PD < or =3 mm. CONCLUSION: Bacterial species believed to be aetiologically related to periodontitis were associated with BoP in sites with minimal PD and/or attachment level (AL). Species presumed to be associated with periodontal health demonstrated inverse associations with BoP. [ABSTRACT FROM AUTHOR]

We surveyed (September 9-17, 2021) students, staff, and faculty at the University of Minnesota, a large, highly vaccinated university, to evaluate whether the COVID-19 vaccine mandate increased self-reported vaccine uptake. Vaccine mandates have the potential to improve public health but should consider the context of implementation and costs associated with infringements on personal choice. Policymakers need to be equipped with data to inform decisions about vaccine mandates in light of contextual factors and potential backlash affecting public health interventions. ( Am J Public Health . 2024;114(11):1222-1227. https://doi.org/10.2105/AJPH.2024.307804).

Objective: To study the association between dietary patterns and subgingival microbiota., Methods: Participants (n = 651) who were enrolled in the Oral Infections, Glucose Intolerance, and Insulin Resistance Study (ORIGINS) with subgingival plaque sampling (n = 890 plaques) and a dietary assessment were included. 16S rRNA gene amplicon sequences of subgingival plaque from sites with either probing depth <4 or ≥4 mm were processed separately and used to obtain α-diversity metrics (Faith, Shannon, Simpson, Observed) and taxa ratios (Red Complex to Corynebacterium [RCLR], Treponema to Corynebacterium [TCLR], and Treponema to Neisseria [TNLR]). Food frequency questionnaires (FFQs) were processed to calculate Alternate Healthy Eating Index (AHEI) and A Priori Diet Quality Score (APDQS) scores. Mixed regression models examined the mean levels of microbial metrics across quartiles of diet quality. Means ± standard errors are reported along with p-values., Results: In multivariable models assessing the association between diet scores and α-diversity metrics, higher AHEI values were significantly associated with lower Faith (p-value = 0.01) and Observed (p-value = 0.04) diversity values; similar findings were observed for APDQS (p-value = 0.01, p-value = 0.04). In multivariable models assessing the association between diet scores (AHEI and APDQS) and taxa ratios (RCLR, TCLR and TNLR), as the AHEI quartile increased, all taxa ratios decreased significantly as follows: -1.06 ± 0.093 in Q1 to -1.34 ± 0.099 in Q4 (RCLR), -0.43 ± 0.077 in Q1 to -0.64 ± 0.083 in Q4 (TCLR) and -0.09 ± 0.083 in Q1 to -0.38 ± 0.089 in Q4 (TNLR), respectively. In contrast, as the APDQS quartiles increased, only TNLR decreased significantly from -0.08 ± 0.085 in Q1 to -0.34 ± 0.091 in Q4., Conclusion: Diets rich in fruits, vegetables, whole grains and other nutritionally rich plant foods are associated with lower oral microbial diversity and favourable ratios of pathogenic to commensal microbiota., (© 2024 The Author(s). Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)

Background: Systemic arterial compliance and venous capacitance are typically impaired in patients with heart failure with preserved ejection fraction (HFpEF), contributing to hemodynamic congestion with stress. Sodium-glucose cotransporter-2 inhibitors reduce hemodynamic congestion and improve clinical outcomes in patients with HFpEF, but the mechanisms remain unclear. This study tested the hypothesis that Dapagliflozin would improve systemic arterial compliance and venous capacitance during exercise in patients with HFpEF., Methods: In this secondary analysis from the CAMEO-DAPA trial (Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction Trial), 37 patients with HFpEF (mean age 68 ± 9 years, women 65%) underwent invasive hemodynamic exercise testing with simultaneous echocardiography at baseline and following treatment for 24 weeks with Dapagliflozin or placebo. Radial artery pressure (BP) was measured continuously using a fluid-filled catheter with transformation to aortic pressure, central hemodynamics were measured using high-fidelity micromanometers, and stressed blood volume was estimated from hemodynamic indices fit to a comprehensive cardiovascular model., Results: There was no statistically significant effect of Dapagliflozin on resting BP, but Dapagliflozin reduced systolic BP during peak exercise (estimated treatment difference [ETD], -18.8 mm Hg [95% CI, -33.9 to -3.7] P =0.016). Reduction in BP was related to improved exertional total arterial compliance (ETD, 0.06 mL/mm Hg/m 2 [95% CI, 0.003-0.11] P =0.039) and aortic root characteristic impedance (ETD, -2.6 mm Hg/mL*sec [95% CI: -5.1 to -0.03] P =0.048), with no significant effect on systemic vascular resistance. Dapagliflozin reduced estimated stressed blood volume at rest and during peak exercise (ETD, -292 mm Hg [95% CI, -530 to -53] P =0.018), and improved venous capacitance evidenced by a decline in ratio of estimated stressed blood volume to total blood volume (ETD, -7.3% [95% CI, -13.3 to -1.3] P =0.020). Each of these effects of Dapagliflozin at peak exercise were also observed during matched 20W exercise intensity. Improvements in total arterial compliance and estimated stressed blood volume were correlated with decreases in body weight, and reduction in systolic BP with treatment was correlated with the change in estimated stressed blood volume during exercise (r=0.40, P =0.019). Decreases in BP were correlated with reduction in pulmonary capillary wedge pressure during exercise (r=0.56, P <0.001)., Conclusions: In patients with HFpEF, treatment with Dapagliflozin improved systemic arterial compliance and venous capacitance during exercise, while reducing aortic characteristic impedance, suggesting a reduction in arterial wall stiffness. These vascular effects may partially explain the clinical benefits with sodium-glucose cotransporter-2 inhibitors in HFpEF., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04730947., Competing Interests: Dr Borlaug receives research support from the National Institutes of Health (NIH) and the United States Department of Defense, as well as research grant funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, and Tenax Therapeutics. Dr Borlaug has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT, and VADovations, and is named inventor (US Patent no. 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure, Dr Chirinos has recently consulted for Bayer, Fukuda-Denshi, Bristol-Myers Squibb, JNJ, Edwards Life Sciences, Merck, and NGM Biopharmaceuticals. He received University of Pennsylvania research grants from National Institutes of Health, Fukuda-Denshi, Bristol-Myers Squibb, Microsoft and Abbott. He is named as inventor in a University of Pennsylvania patent for the use of inorganic nitrates/nitrites for the treatment of HFpEF and for the use of biomarkers in heart failure. He has received research device loans from Atcor Medical, Fukuda-Denshi, Unex, Uscom, NDD Medical Technologies, Microsoft and MicroVision Medical. B. Pourmussa has no relevant disclosures.

Background: Sarcopenia, characterized by loss of muscle mass and function, is prevalent in heart failure (HF) and predicts poor outcomes. We investigated alterations in sarcopenia index (SI), a surrogate for skeletal muscle mass, in HF, left ventricular assist device (LVAD), and heart transplant (HT), and assessed its relationship with inflammation and digestive tract (gut and oral) microbiota., Methods: We enrolled 460 HF, LVAD, and HT patients. Repeated measures pre/post-procedures were obtained prospectively in a subset of LVAD and HT patients. SI (serum creatinine/cystatin C) and inflammatory biomarkers (C-reactive protein, interleukin-6, tumor necrosis factor-alpha) were measured in 271 and 622 blood samples, respectively. Gut and saliva microbiota were assessed via 16S ribosomal ribonucleic acid sequencing among 335 stool and 341 saliva samples. Multivariable regression assessed the relationship between SI and (1) New York Heart Association class; (2) pre- versus post-LVAD or HT; and (3) biomarkers of inflammation and microbial diversity., Results: Median (interquartile range) natural logarithm (ln)-SI was -0.13 (-0.32, 0.05). Ln-SI decreased across worsening HF class, further declined at 1 month after LVAD and HT, and rebounded over time. Ln-SI was correlated with inflammation (r = -0.28, p < 0.01), gut (r = 0.28, p < 0.01), and oral microbial diversity (r = 0.24, p < 0.01). These associations remained significant after multivariable adjustment in the combined cohort but not for all individual cohorts. The presence of the gut taxa Roseburia inulinivorans was associated with increased SI., Conclusions: SI levels decreased in symptomatic HF and remained decreased long-term after LVAD and HT. In the combined cohort, SI levels covaried with inflammation in a similar fashion and were significantly related to overall microbial (gut and oral) diversity, including specific taxa compositional changes., (Copyright © 2024. Published by Elsevier Inc.)

Background: Among heart transplantation (HT) recipients, the accuracy of serum creatinine (sCr)-based estimated glomerular filtration rate (eGFR) may be limited by fluctuations in muscle mass. Cystatin C (cysC) is less influenced by muscle mass, but its levels may increase with obesity and steroid use. Herein, we (1) longitudinally compared eGFRcysC and eGFRsCr among HT recipients; (2) investigated the association of body mass index (BMI), steroid use, and muscle mass with discrepancies between eGFRs; and (3) explored the implications of eGFRcysC use on valganciclovir (VGC) dosing., Methods: cysC and sCr were measured in 294 blood samples obtained from 80 subjects. Intraindividual differences between eGFRs (eGFRdiff cysC-sCr ) were calculated with negative values corresponding to eGFRsCr > eGFRcysC and positive values to eGFRcysC > eGFRsCr. In a patient subset (n = 21), pectoralis muscle measures were obtained., Results: Marked differences between eGFRcysC and eGFRsCr were observed, particularly early post-HT (1-week post-HT, median eGFRdiff cysC-sCr -28 ml/min/1.73 m 2 ). eGFRcysC demonstrated stability following a transient postoperative decline, while eGFRsCr decreased in the first year post-HT. Lower BMI and higher prednisone dose displayed a modest association with more negative eGFRdiff cysC-sCr values. Pectoralis muscle measures indicative of greater muscle mass and better tissue quality exhibited a stronger association with more positive eGFRdiff cysC-sCr values. The use of eGFRcysC would have led to VGC dose adjustment in 46% of samples, predominantly resulting in dose reduction., Conclusions: Among HT recipients, eGFRcysC and eGFRsCr markedly differ with implications for VGC dosing. The observed discrepancies may reflect changes in body composition and steroid use., (Copyright © 2024. Published by Elsevier Inc.)

Several bacterial taxa enriched in inflammatory bowel diseases and colorectal cancer (CRC) are found in the oral cavity. We conducted a pilot study nested within a six-week aspirin intervention in a randomized placebo-controlled trial to test their response to aspirin intervention. Fifty healthy subjects, 50-75 years old, were randomized to receive 325 mg aspirin (n = 30) or placebo (n = 20) orally once daily for six weeks. Oral tongue swabs were collected at baseline and week six. We estimated the association between aspirin use and the temporal changes in the relative abundance of pre-specified genus level taxa from pre- to post-treatment. The temporal change in relative abundance differed for eight genus level taxa between the aspirin and placebo groups. In the aspirin group, there were significant increases in the relative abundances of Neisseria , Streptococcus , Actinomyces , and Rothia and significant decreases in Prevotella , Veillonella , Fusobacterium , and Porphyromonas relative to placebo. The log ratio of Neisseria to Fusobacterium declined more in the aspirin group than placebo, signaling a potential marker associated with aspirin intervention. These preliminary findings should be validated using metagenomic sequencing and may guide future studies on the role of aspirin on taxa in various oral ecological niches.

Importance: Persistent symptoms and disability following SARS-CoV-2 infection, known as post-COVID-19 condition or "long COVID," are frequently reported and pose a substantial personal and societal burden., Objective: To determine time to recovery following SARS-CoV-2 infection and identify factors associated with recovery by 90 days., Design, Setting, and Participants: For this prospective cohort study, standardized ascertainment of SARS-CoV-2 infection was conducted starting in April 1, 2020, across 14 ongoing National Institutes of Health-funded cohorts that have enrolled and followed participants since 1971. This report includes data collected through February 28, 2023, on adults aged 18 years or older with self-reported SARS-CoV-2 infection., Exposure: Preinfection health conditions and lifestyle factors assessed before and during the pandemic via prepandemic examinations and pandemic-era questionnaires., Main Outcomes and Measures: Probability of nonrecovery by 90 days and restricted mean recovery times were estimated using Kaplan-Meier curves, and Cox proportional hazards regression was performed to assess multivariable-adjusted associations with recovery by 90 days., Results: Of 4708 participants with self-reported SARS-CoV-2 infection (mean [SD] age, 61.3 [13.8] years; 2952 women [62.7%]), an estimated 22.5% (95% CI, 21.2%-23.7%) did not recover by 90 days post infection. Median (IQR) time to recovery was 20 (8-75) days. By 90 days post infection, there were significant differences in restricted mean recovery time according to sociodemographic, clinical, and lifestyle characteristics, particularly by acute infection severity (outpatient vs critical hospitalization, 32.9 days [95% CI, 31.9-33.9 days] vs 57.6 days [95% CI, 51.9-63.3 days]; log-rank P < .001). Recovery by 90 days post infection was associated with vaccination prior to infection (hazard ratio [HR], 1.30; 95% CI, 1.11-1.51) and infection during the sixth (Omicron variant) vs first wave (HR, 1.25; 95% CI, 1.06-1.49). These associations were mediated by reduced severity of acute infection (33.4% and 17.6%, respectively). Recovery was unfavorably associated with female sex (HR, 0.85; 95% CI, 0.79-0.92) and prepandemic clinical cardiovascular disease (HR, 0.84; 95% CI, 0.71-0.99). No significant multivariable-adjusted associations were observed for age, educational attainment, smoking history, obesity, diabetes, chronic kidney disease, asthma, chronic obstructive pulmonary disease, or elevated depressive symptoms. Results were similar for reinfections., Conclusions and Relevance: In this cohort study, more than 1 in 5 adults did not recover within 3 months of SARS-CoV-2 infection. Recovery within 3 months was less likely in women and those with preexisting cardiovascular disease and more likely in those with COVID-19 vaccination or infection during the Omicron variant wave.

Objectives: People living with HIV (PLWH) have been shown to have lower bone density at the spine, hip, and radius. However, whether a similar bone phenotype is seen in craniofacial bones is not known. The goal of this study was to evaluate the bone microarchitecture of the mandibular condyle in PLWH., Methods: We recruited 212 participants, which included 88 HIV-negative participants and 124 PLWH on combination antiretroviral therapy with virological suppression from a single academic center. Each participant filled out a validated temporomandibular disorder (TMD) pain screening questionnaire and had cone beam computed tomography (CBCT) of their mandibular condyles. Qualitative radiographic evidence of temporomandibular joint disorders-osteoarthritis (TMJD-OA) assessment and quantitative microarchitecture analysis of their mandibular condylar bones were conducted., Results: There was no statistically significant difference in either self-reported TMD or in radiographic evidence of TMJD-OA in PLWH compared with HIV-negative controls. Linear regression analysis revealed that positive HIV status remained significantly associated with increased trabecular thickness, decreased cortical porosity, and increased cortical bone volume fraction after adjusting for race, diabetes, sex, and age., Conclusion: PLWH have increased mandibular condylar trabecular bone thickness and cortical bone volume fraction compared with HIV-negative controls., (© 2023 Wiley Periodicals LLC.)

Aim: We investigated whether periodontal measures are cross-sectionally associated with prediabetes and cardiometabolic biomarkers among non-diabetic younger adults., Materials and Methods: One thousand seventy-one participants (mean age = 32.2 years [SE = 0.3]; 73% female) from the Oral Infections, Glucose Intolerance and Insulin Resistance Study were enrolled. Full-mouth clinical attachment loss (fm-CAL), probing depth (fm-PD) and bleeding on probing were ascertained. Interproximal CAL (i-CAL) and probing depths (i-PD) served as our primary exposures. Glucose, HbA1c, insulin and insulin resistance (HOMA-IR) outcomes were assessed from fasting blood. Prediabetes was defined per American Diabetes Association guidelines. Prediabetes prevalence ratios (PR [95% CI]) and mean [SE] cardiometabolic biomarkers were regressed on periodontal variables via multivariable robust variance Poisson regression or multivariable linear regression., Results: Prevalence of prediabetes was 12.5%. Fully adjusted prediabetes PR in Tertiles 3 versus 1 of mean i-CAL was 2.42 (1.77, 3.08). Fully adjusted fasting glucose estimates across i-CAL tertiles were 83.29 [0.43], 84.31 [0.37], 86.48 [0.46]; p for trend <.01. Greater percent of sites with i-PD ≥3 mm showed elevated natural-log-HOMA-IR after adjustment (0%-12% of sites = 0.33 [0.03], 13%-26% of sites = 0.39 [0.03], ≥27% of sites = 0.42 [0.03]; p for trend = .04)., Conclusions: i-CAL (vs. fm-CAL) was associated with elevated fasting glucose and prediabetes, whereas i-PD (vs. fm-PD) was associated with insulin resistance. Future studies are needed to examine periodontal disease and incident prediabetes., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Venous congestion (VC) is a hallmark of symptomatic heart failure (HF) requiring hospitalization; however, its role in the pathogenesis of HF progression remains unclear. We investigated whether peripheral VC exacerbates inflammation, oxidative stress and neurohormonal and endothelial cell (EC) activation in patients with HF with reduced ejection fraction (HFrEF)., Methods and Results: Two matched groups of patients with HFrEF and with no peripheral VC vs without recent HF hospitalization were studied. We modeled peripheral VC by inflating a cuff around the dominant arm, targeting ∼ 30 mmHg increase in venous pressure (venous stress test [VST]). Blood and ECs were sampled before and after 90 minutes of VST. We studied 44 patients (age 53 ± 12 years, 32% female). Circulating endothelin-1, tumor necrosis factor-α, interleukin-6, isoprostane, angiotensin II (ang-2), angiopoietin-2, vascular cell adhesion molecule-1, and CD146 significantly increased after the VST. Enhanced endothelin-1 and angiopoietin-2 responses to the VST were present in patients with vs without recent hospitalization and were prospectively associated with incident HF-related events; 6698 messenger ribonucleic acid (mRNA probe sets were differentially expressed in ECs after VST., Conclusions: Experimental VC exacerbates inflammation, oxidative stress, neurohormonal and EC activation and promotes unfavorable transcriptome remodeling in ECs of patients with HFrEF. A distinct biological sensitivity to VC appears to be associated with high risk for HF progression., (Copyright © 2023 Elsevier Inc. All rights reserved.)

This study investigates correlates of anti-S1 antibody response following COVID-19 vaccination in a U.S. population-based meta-cohort of adults participating in longstanding NIH-funded cohort studies. Anti-S1 antibodies were measured from dried blood spots collected between February 2021-August 2022 using Luminex-based microsphere immunoassays. Of 6245 participants, mean age was 73 years (range, 21-100), 58% were female, and 76% were non-Hispanic White. Nearly 52% of participants received the BNT162b2 vaccine and 48% received the mRNA-1273 vaccine. Lower anti-S1 antibody levels are associated with age of 65 years or older, male sex, higher body mass index, smoking, diabetes, COPD and receipt of BNT16b2 vaccine (vs mRNA-1273). Participants with a prior infection, particularly those with a history of hospitalized illness, have higher anti-S1 antibody levels. These results suggest that adults with certain socio-demographic and clinical characteristics may have less robust antibody responses to COVID-19 vaccination and could be prioritized for more frequent re-vaccination., (© 2024. The Author(s).)

Habitual physical activity (PA) impacts the plasma proteome and reduces the risk of developing type 2 diabetes (T2D). Using a large-scale proteome-wide approach in Atherosclerosis Risk in Communities study participants, we aimed to identify plasma proteins associated with PA and determine which of these may be causally related to lower T2D risk. PA was associated with 92 plasma proteins in discovery (P < 1.01 × 10-5), and 40 remained significant in replication (P < 5.43 × 10-4). Eighteen of these proteins were independently associated with incident T2D (P < 1.25 × 10-3), including neuronal growth regulator 1 (NeGR1; hazard ratio per SD 0.85; P = 7.5 × 10-11). Two-sample Mendelian randomization (MR) inverse variance weighted analysis indicated that higher NeGR1 reduces T2D risk (odds ratio [OR] per SD 0.92; P = 0.03) and was consistent with MR-Egger, weighted median, and weighted mode sensitivity analyses. A stronger association was observed for the single cis-acting NeGR1 genetic variant (OR per SD 0.80; P = 6.3 × 10-5). Coupled with previous evidence that low circulating NeGR1 levels promote adiposity, its association with PA and potential causal role in T2D shown here suggest that NeGR1 may link PA exposure with metabolic outcomes. Further research is warranted to confirm our findings and examine the interplay of PA, NeGR1, adiposity, and metabolic health., (© 2024 by the American Diabetes Association.)

Background: With effective antiretroviral therapy, people with HIV (PWH) are living longer and aging; the majority of PWH in the United States are now over the age of 50 and in women have gone through the menopause transition. Menopause potentiates skeletal bone loss at the spine, hip, and radius in PWH. The alveolar bone which surronds the teeth is different than long bones because it is derived from the neural crest. However, few studies have assessed the oral health and alveolar bone in middle aged and older women with HIV. Therefore, the objective of this study was to evaluate periodontal disease and alveolar bone microarchitecture in postmenopausal women with HIV., Methods: 135 self-reported postmenopausal women were recruited (59 HIV-, 76 HIV + on combination antiretroviral therapy with virological suppression) from a single academic center. The following parameters were measured: cytokine levels (IFN-γ, TNF-α, IL-1β, IL-2, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-17 A, OPG, and RANKL) in gingival crevicular fluid, bleeding on probing, probing depth, clinical attachment loss, number of teeth present, alveolar crestal height, and alveolar bone microarchitecture., Results: The mean age of participants was 57.04+/-6.25 years and a greater proportion of women with HIV were black/African American (HIV + 68.42%, HIV- 23.73%; p < 0.001). There was no significant difference in bleeding on probing (p = 0.17) and attachment loss (p = 0.39) between women who were HIV infected vs. HIV uninfected. Women with HIV had significantly higher RANKL expression in Gingival Crevicular Fluid (HIV + 3.80+/-3.19 pg/ul, HIV- 1.29+/-2.14 pg/ul ; p < 0.001), fewer teeth present (HIV + 17.75+/-7.62, HIV- 22.79+/-5.70; p < 0.001), ), lower trabecular number (HIV + 0.08+/-0.01, HIV- 0.09+/-0.02; p = 0.004) and greater trabecular separation (HIV + 9.23+/-3.11, HIV- 7.99+/-3.23; p = 0.04) compared to women without HIV that remained significant in multivariate logistic regression analysis in a sub-cohort after adjusting for age, race/ethnicity, smoking status, and diabetes., Conclusion: Postmenopausal women with HIV have deterioration of the alveolar trabecular bone microarchitecture that may contribute to greater tooth loss., (© 2023. The Author(s).)

Tobacco taxes have reduced smoking and coronary heart disease (CHD) mortality, yet few studies have examined heterogeneity of these associations by race and gender. We constructed a yearly panel (2005-2016) that included age-adjusted cigarette smoking prevalence and CHD mortality rates across all 50 U.S. States and the District of Columbia using the Behavioral Risk Factor Surveillance System and Wide-ranging Online Data for Epidemiological Research. We examined associations between changes in total cigarette excise taxes (i.e., federal and state) and changes in smoking prevalence and CHD mortality, using linear regression models with state and year fixed effects. Each dollar of tobacco tax was associated with a reduction in age-adjusted smoking prevalence 1 year later of -0.4 [95% CIs: -0.6, -0.2] percentage points; and a relative reduction in the rate of CHD mortality 2 years later of -2.0% [95% CIs: -3.7%, -0.3%], or -5 deaths/100,000 in absolute terms. Associations between tobacco taxes and smoking prevalence were statistically significantly different by race and gender and were strongest among Black non-Hispanic women (-1.2 [95% CIs: -1.6, -0.8] percentage points). Associations between tobacco taxes and CHD mortality were not statistically significantly different by race and gender, but point estimates for percent changes were highest among Black non-Hispanic men (-2.9%) and Black non-Hispanic women (-3.5%) compared to White non-Hispanic men (-1.8%) and White non-Hispanic women (-1.5%). These findings suggest that tobacco taxation is an effective intervention for reducing smoking prevalence and CHD mortality among White and Black non-Hispanic populations in the United States., Competing Interests: Declaration of Competing Interest None to report., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: We investigated the relationship between the cognitive status of participants' spouses and participants' own cognitive outcomes, controlling for mid-life factors. Methods: Participants ( n = 1845; baseline age 66-90 years) from the prospective Atherosclerosis Risk in Communities Study were followed from 2011 to 2019. We used linear regression and Cox proportional hazard models to estimate whether spouses of people with MCI/dementia had lower cognitive functioning and elevated risk of incident dementia. Results: Having a spouse with MCI/dementia was associated with a deficit in cognitive function (b = -0.09 standard deviations; 95% CI = -0.18, 0.00). Adjustment for mid-life risk factors attenuated this association (b = -0.02 standard deviations; 95% CI = -0.10, 0.06). We observed no significant relationship between spousal MCI/dementia status and incident dementia (hazard ratio = 0.97; 95% CI = 0.69, 1.38). Discussion: Spousal cognitive status is not associated with poor cognitive outcomes independent of mid-life factors.

Objective: Healthcare workers (HCWs) in long-term care facilities (LTCFs) are disproportionately affected by severe acute respiratory coronavirus virus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19). To characterize factors associated with SARS-CoV-2 positivity among LTCF HCWs, we performed a retrospective cohort study among HCWs in 32 LTCFs in the Minneapolis-St Paul region., Methods: We analyzed the outcome of SARS-CoV-2 polymerase chain reaction (PCR) positivity among LTCF HCWs during weeks 34-52 of 2020. LTCF and HCW-level characteristics, including facility size, facility risk score for resident-HCW contact, and resident-facing job role, were modeled in univariable and multivariable generalized linear regressions to determine their association with SARS-CoV-2 positivity., Results: Between weeks 34 and 52, 440 (20.7%) of 2,130 unique HCWs tested positive for SARS-CoV-2 at least once. In the univariable model, non-resident-facing HCWs had lower odds of infection (odds ratio [OR], 0.50; 95% confidence interval [CI], 0.36-0.70). In the multivariable model, the odds remained lower for non-resident-facing HCW (OR, 0.50; 95% CI, 0.36-0.71), and those in medium- versus low-risk facilities experienced higher odds of testing positive for SARS-CoV-2 (OR, 1.47; 95% CI, 1.08-2.02)., Conclusions: Our findings suggest that COVID-19 cases are related to contact between HCW and residents in LTCFs. This association should be considered when formulating infection prevention and control policies to mitigate the spread of SARS-CoV-2 in LTCFs.

Background: Heart transplantation (HT) is the gold standard therapy for advanced heart failure, providing excellent long-term outcomes. However, postoperative outcomes are limited by bleeding, infections, and primary graft dysfunction (PGD) that contribute to early mortality after HT. HT candidates with pre-existing hematologic disorders, bleeding, and clotting, may represent a higher risk population. We assessed the short- and long-term outcomes of patients with pre-existing hematologic disorders undergoing HT., Methods and Results: Medical records of all adult patients who received HT from January 2010 to December 2019 at our institution were retrospectively reviewed. Hematologic disorders were identified via chart review and adjudicated by a board-certified hematologist. Inverse probability weighting and multivariable models were used to adjust for potential pretransplant confounders. Four hundred and ninety HT recipients were included, of whom 29 (5.9%) had a hematologic disorder. Hematologic disorders were associated with severe PGD requiring mechanical circulatory support (aOR 3.15 [1.01-9.86]; p = .049), postoperative infections (aOR 2.93 [1.38-6.23]; p = .01), and 3-year acute cellular rejection (ACR) (≥1R/1B) (aSHR 2.06 [1.09-3.87]; p = .03). There was no difference in in-hospital mortality (aOR 1.23 [.20-7.58], p = .82) or 3-year mortality (aHR 1.58 [.49-5.12], p = .44)., Conclusions: Patients with hematologic disorders undergoing HT are at increased risk of severe PGD, postoperative infections, and ACR, while in-hospital and 3-year mortality remain unaffected., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Evidence suggests that periodontal disease is associated with increased lung cancer risk, but whether periodontal pathogens are explanatory is unknown. We prospectively studied associations of prediagnostic circulating antibodies with oral bacteria and of periodontal bacteria in subgingival plaque with lung cancer., Methods: We included 4,263 cancer-free participants in the Atherosclerosis Risk in Communities study with previously measured serum IgG antibodies to 18 oral bacteria. In 1,287 participants for whom subgingival plaque was collected, counts for 8 periodontal bacteria were previously measured. Incident lung cancers (N = 118) were ascertained through 2015 (median follow-up = 17.5 years). We used Cox regression to estimate multivariable-adjusted associations, including for sums of antibodies to orange (C. rectus, F. nucleatum, P. intermedia, P. micra, and P. nigrescens) and red (P. gingivalis, T. forsythensis, and T. denticola) complex bacteria., Results: Orange complex bacteria antibodies were positively associated with lung cancer [per IQR hazard ratios (HR) = 1.15; 95% confidence intervals (CI), 1.02-1.29], which was stronger in men (HR = 1.27, 95% CI 1.08-1.49), and explained by P. intermedia and P. nigrescens (HR = 1.15; 95% CI, 1.04-1.26). Suggestive positive associations with lung cancer (N = 40) were observed for F. nucleatum, A. actinomycetemcomitans, and P. gingivalis counts. Significant positive associations were found for the count to antibody ratio for P. intermedia and P. gingivalis., Conclusions: We identified positive associations with lung cancer for oral bacteria, especially orange complex that are moderately pathogenic for periodontal disease., Impact: This prospective study supports the need for more research on periodontal bacteria in lung cancer etiology. If associations are supported, this may inform novel lung cancer prevention strategies., (©2022 American Association for Cancer Research.)

Objective: The plasma proteome preceding diabetes can improve our understanding of diabetes pathogenesis., Research Design and Methods: In 8,923 Atherosclerosis Risk in Communities (ARIC) Study participants (aged 47-70 years, 57% women, 19% Black), we conducted discovery and internal validation for associations of 4,955 plasma proteins with incident diabetes. We externally validated results in the Singapore Multi-Ethnic Cohort (MEC) nested case-control (624 case subjects, 1,214 control subjects). We used Cox regression to discover and validate protein associations and risk-prediction models (elastic net regression with cardiometabolic risk factors and proteins) for incident diabetes. We conducted a pathway analysis and examined causality using genetic instruments., Results: There were 2,147 new diabetes cases over a median of 19 years. In the discovery sample (n = 6,010), 140 proteins were associated with incident diabetes after adjustment for 11 risk factors (P < 10-5). Internal validation (n = 2,913) showed 64 of the 140 proteins remained significant (P < 0.05/140). Of the 63 available proteins, 47 (75%) were validated in MEC. Novel associations with diabetes were found for 22 the 47 proteins. Prediction models (27 proteins selected by elastic net) developed in discovery had a C statistic of 0.731 in internal validation, with ΔC statistic of 0.011 (P = 0.04) beyond 13 risk factors, including fasting glucose and HbA1c. Inflammation and lipid metabolism pathways were overrepresented among the diabetes-associated proteins. Genetic instrument analyses suggested plasma SHBG, ATP1B2, and GSTA1 play causal roles in diabetes risk., Conclusions: We identified 47 plasma proteins predictive of incident diabetes, established causal effects for 3 proteins, and identified diabetes-associated inflammation and lipid pathways with potential implications for diagnosis and therapy., (© 2023 by the American Diabetes Association.)

Background: OSA has been linked to microaspiration, systemic inflammation, and suboptimal immune function., Research Question: Is OSA prospectively associated with risk of hospitalization for pneumonia, respiratory, and total infections?, Study Design and Methods: Prospective cohort. Participants in the Atherosclerosis Risk in Communities (ARIC) study (N = 1,586) underwent polysomnography in 1996-1998 and were followed up through 2018 for infection-related hospitalizations. The apnea-hypopnea index (AHI; events/h) was used to categorize participants as having severe OSA (≥ 30), moderate OSA (15-29), mild OSA (5-14), or a normal breathing pattern (< 5). Cox regression was used to calculate hazard ratios (HRs) and 95% CIs., Results: ARIC participants were on average 62.7 (SD = 5.5) years of age, and 52.8% were female. Severe OSA was present in 6.0%, moderate OSA in 12.7%, mild OSA in 30.0%, and normal breathing in 51.3%. A total of 253 hospitalizations with pneumonia occurred over a median 20.4 (max, 22.9) years' follow-up. Participants with severe OSA were at 1.87 times (95% CI, 1.19-2.95) higher risk of hospitalization with pneumonia compared with those with a normal breathing pattern after adjustment for demographics and lifestyle behaviors. Results were attenuated modestly after adjustment for BMI (1.62 [0.99-2.63]), and prevalent asthma and COPD (1.62 [0.99-2.63]). A similar pattern existed for hospitalization with respiratory infection and composite infection (demographic and behavior-adjusted HRs: 1.47 [0.96-2.25] and 1.48 [1.07-2.04], respectively)., Interpretation: Severe OSA was associated with increased risk of hospitalizations with pneumonia in this community-based cohort. OSA patients may benefit from more aggressive efforts to prevent pneumonia and other infectious conditions., (Copyright © 2023. Published by Elsevier Inc.)

COVID-19 continues to be a public health concern in the United States. Although safe and effective vaccines have been developed, a significant proportion of the US population has not received a COVID-19 vaccine. This cross-sectional study aimed to describe the demographics and behaviors of Minnesota adults who have not received the primary series of the COVID-19 vaccine, or the booster shot using data from the Minnesota COVID-19 Antibody Study (MCAS) collected through a population-based sample between September and December 2021. Data were collected using a web-based survey sent to individuals that responded to a similar survey in 2020 and their adult household members. The sample was 51% female and 86% White/Non-Hispanic. A total of 9% of vaccine-eligible participants had not received the primary series and 23% of those eligible to receive a booster had not received it. Older age, higher education, better self-reported health, $75,000 to $100,000 annual household income, mask-wearing, and social distancing were associated with lower odds of hesitancy. Gender, race, and previous COVID-19 infection were not associated with hesitancy. The most frequently reported reason for not receiving a COVID-19 vaccination was safety concerns. Mask-wearing and being age 65 or older were the only strong predictors of lower odds of vaccine hesitancy for both the primary series and booster analyses.

Recent advances in microbiome research have informed the potential role of the gut microbiota in the regulation of metabolic, cardiovascular, and renal systems, and, when altered, in the pathogenesis of various cardiometabolic disorders, including chronic kidney disease (CKD). The improved understanding of gut dysbiosis in cardiometabolic pathologies in turn has led to a vigorous quest for developing therapeutic strategies. These therapeutic strategies aim to investigate whether interventions targeting gut dysbiosis can shift the microbiota toward eubiosis and if these shifts, in turn, translate into improvements in (or prevention of) CKD and its related complications, such as premature cardiovascular disease. Existing evidence suggests that multiple interventions (eg, plant-based diets; prebiotic, probiotic, and synbiotic supplementation; constipation treatment; fecal microbiota transplantation; and intestinal dialysis) might result in favorable modulation of the gut microbiota in patients with CKD, and thereby potentially contribute to improving clinical outcomes in these patients. In this review, we summarize the current understanding of the characteristics and roles of the gut microbiota in CKD and discuss the potential of emerging gut microbiota-targeted interventions in the management of CKD., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Despite significant advances in therapies, heart failure (HF) remains a progressive disease that, once advanced, is associated with significant death and disability. Cardiac replacement therapies with left ventricular assist device (LVAD) and heart transplantation (HT) are the only treatment options for advanced HF, while lifesaving they can also be lifespan limiting due to the associated complications. Systemic inflammation is mechanistically important in HF pathophysiology and progression. However, directly targeting inflammation in HF has not been beneficial thus far. These failed attempts at therapeutics might be related to our limited understanding of the factors that cause inflammation in HF, and, therefore, to our inability to investigate these triggers in interventional studies. Observational studies have consistently demonstrated associations between alterations in the digestive (gut and oral) microbiome, inflammation and HF risk and progression. Additionally, recent data indicate that these microbial perturbations persist following LVAD and HT, along with residual inflammation and oxidative stress. Furthermore, there is rising recognition of the critical contribution of the microbiome to the metabolism of immunosuppressive drugs after HT. Cumulatively, these findings might posit a mechanistic link between microbiome alterations, systemic inflammation, and adverse outcomes in HF patients before and after cardiac replacement therapies. This review (1) provides an update on available data linking changes in digestive tract microbiota, inflammation, and oxidative stress, to HF pathogenesis and progression; (2) describes evolution of these relationships following LVAD and HT; and (3) outlines present and future intervention strategies that can manipulate the microbiome and possibly modify HF disease trajectory., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Statins are prescribed to reduce LDL-c and risk of CVD. Statins have pleiotropic effects, affecting pathophysiological functions beyond LDL-c reduction. We compared the proteome of statin users and nonusers (controls). We hypothesized that statin use is associated with proteins unrelated to lipid metabolism., Methods: Among 10,902 participants attending ARIC visit 3 (1993-95), plasma concentrations of 4955 proteins were determined using SOMAlogic's DNA aptamer-based capture array. 379 participants initiated statins within the 2 years prior. Propensity scores (PS) were calculated based on visit 2 (1990-92) LDL-c levels and visit 3 demographic/clinical characteristics. 360 statin users were PS matched to controls. Log2-transformed and standardized protein levels were compared using t-tests, with false discovery rate (FDR) adjustment for multiple comparisons. Analyses were replicated in visit 2., Results: Covariates were balanced after PS matching, except for higher visit 3 LDL-c levels among controls (125.70 vs 147.65 mg/dL; p < 0.0001). Statin users had 11 enriched and 11 depleted protein levels after FDR adjustment (q < 0.05). Proteins related and unrelated to lipid metabolism differed between groups. Results were largely replicated in visit 2., Conclusion: Proteins unrelated to lipid metabolism differed by statin use. Pending external validation, exploring their biological functions could elucidate pleiotropic effects of statins., Significance: Statins are the primary pharmacotherapy for lowering low-density lipoprotein (LDL) cholesterol and preventing cardiovascular disease. Their primary mechanism of action is through inhibiting the protein 3hydroxy-3-methylglutaryl CoA reductase (HMGCR) in the mevalonate pathway of LDL cholesterol synthesis. However, statins have pleiotropic effects and may affect other biological processes directly or indirectly, with hypothesized negative and positive effects. The present study contributes to identifying these pathways by comparing the proteome of stain users and nonusers with propensity score matching. Our findings highlight potential biological mechanisms underlying statin pleiotropy, informing future efforts to identify statin users at risk of rare nonatherosclerotic outcomes and identify health benefits of statin use independent of LDL-C reduction., Competing Interests: Declaration of Competing Interest None, (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Genome-wide association studies have reported 23 gene loci related to abdominal aortic aneurysm (AAA)-a potentially lethal condition characterized by a weakened dilated vessel wall. This study aimed to identify proteomic signatures and pathways related to these risk loci to better characterize AAA genetic susceptibility., Methods: Plasma concentrations of 4870 proteins were determined using a DNA aptamer-based array. Linear regression analysis estimated the associations between the 23 risk alleles and plasma protein levels with adjustments for potential confounders in a race-stratified analysis of 1671 Black and 7241 White participants. Significant proteins were then evaluated for their prediction of clinical AAA (454 AAA events in 11 064 individuals), and those significantly associated with AAA were further interrogated using Mendelian randomization analysis., Results: Risk variants proximal to PSRC1-CELSR2-SORT1 , PCIF1-ZNF335-MMP9, RP11-136O12.2/TRIB1 , ZNF259/APOA5, IL6R , PCSK9 , LPA , and APOE were associated with 118 plasma proteins in Whites and 59 were replicated in Black participants. Novel associations with clinical AAA incidence were observed for kit ligand (HR, 0.59 [95% CI, 0.42-0.82] for top versus first quintiles) and neogenin (HR, 0.64 [95% CI, 0.46-0.88]) over a median 21.2-year follow-up; neogenin was also associated with ultrasound-detected asymptomatic AAA (N=4295; 57 asymptomatic AAA cases). Mendelian randomization inverse variance weighted estimates suggested that AAA risk is promoted by lower levels of kit ligand (OR per SD=0.67; P =1.4×10 -5 ) and neogenin (OR per SD=0.50; P =0.03)., Conclusions: Low levels of neogenin and kit ligand may be novel risk factors for AAA development in potentially causal pathways. These findings provide insights and potential targets to reduce AAA susceptibility.

Importance: Factors associated with the risk of dementia remain to be fully understood. Systemic infections are hypothesized to be such factors and may be targets for prevention and screening., Objective: To investigate the association between hospitalization with infection and incident dementia., Design, Setting, and Participants: Data from the community-based Atherosclerosis Risk in Communities (ARIC) study, a prospective cohort study, were used. Enrollment occurred at 4 research centers in the US, initiated in 1987 to 1989. The present study includes data up to 2019, for 32 years of follow-up. Data analysis was performed from April 2021 to June 2022., Exposures: Hospitalizations with infections were identified via medical record review for selected International Classification of Diseases, Ninth Revision (ICD-9) and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes, from baseline until administrative censoring or dementia diagnosis. Participants were considered unexposed until first hospitalization with infection and exposed thereafter. Selected infection subtypes were also considered., Main Outcomes and Measures: Incident dementia and time-to-event data were identified through surveillance of ICD-9 and ICD-10 hospitalization and death certificate codes, in-person assessments, and telephone interviews. A sensitivity analysis was conducted excluding cases occurring within 3 years or beyond 20 years from exposure. Data were collected before study hypothesis formulation., Results: Of the 15 792 ARIC study participants, an analytical cohort of 15 688 participants who were dementia free at baseline and of Black or White race were selected (8658 female [55.2%]; 4210 Black [26.8%]; mean [SD] baseline age, 54.7 [5.8] years). Hospitalization with infection occurred among 5999 participants (38.2%). Dementia was ascertained in 2975 participants (19.0%), at a median (IQR) of 25.1 (22.2-29.1) years after baseline. Dementia rates were 23.6 events per 1000 person-years (95% CI, 22.3-25.0 events per 1000 person-years) among the exposed and 5.7 events per 1000 person-years (95% CI, 5.4-6.0 events per 1000 person-years) among the unexposed. Patients hospitalized with infection were 2.02 (95% CI, 1.88-2.18; P < .001) and 1.70 (95% CI, 1.55-1.86; P < .001) times more likely to experience incident dementia according to unadjusted and fully adjusted Cox proportional hazards models compared with individuals who were unexposed. When excluding individuals who developed dementia less than 3 years or more than 20 years from baseline or the infection event, the adjusted hazard ratio was 5.77 (95% CI, 4.92-6.76; P < .001). Rates of dementia were significantly higher among those hospitalized with respiratory, urinary tract, skin, blood and circulatory system, or hospital acquired infections. Multiplicative and additive interactions were observed by age and APOE-ε genotype., Conclusions and Relevance: Higher rates of dementia were observed among participants who experienced hospitalization with infection. These findings support the hypothesis that infections are factors associated with higher risk of dementias.

Aims/hypothesis: Genetic predisposition to type 2 diabetes is well-established, and genetic risk scores (GRS) have been developed that capture heritable liabilities for type 2 diabetes phenotypes. However, the proteins through which these genetic variants influence risk have not been thoroughly investigated. This study aimed to identify proteins and pathways through which type 2 diabetes risk variants may influence pathophysiology., Methods: Using a proteomics data-driven approach in a discovery sample of 7241 White participants in the Atherosclerosis Risk in Communities Study (ARIC) cohort and a replication sample of 1674 Black ARIC participants, we interrogated plasma levels of 4870 proteins and four GRS of specific type 2 diabetes phenotypes related to beta cell function, insulin resistance, lipodystrophy, BMI/blood lipid abnormalities and a composite score of all variants combined., Results: Twenty-two plasma proteins were identified in White participants after Bonferroni correction. Of the 22 protein-GRS associations that were statistically significant, 10 were replicated in Black participants and all but one were directionally consistent. In a secondary analysis, 18 of the 22 proteins were found to be associated with prevalent type 2 diabetes and ten proteins were associated with incident type 2 diabetes. Two-sample Mendelian randomisation indicated that complement C2 may be causally related to greater type 2 diabetes risk (inverse variance weighted estimate: OR 1.65 per SD; p=7.0 × 10 -3 ), while neuropilin-2 was inversely associated (OR 0.44 per SD; p=8.0 × 10 -3 )., Conclusions/interpretation: Identified proteins may represent viable intervention or pharmacological targets to prevent, reverse or slow type 2 diabetes progression, and further research is needed to pursue these targets., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Driveline infection (DLI) is common after left ventricular assist device (LVAD). Limited data exist on DLI prevention and management. We investigated the impact of standardized driveline care initiatives, specific pathogens, and chronic antibiotic suppression (CAS) on DLI outcomes. 591 LVAD patients were retrospectively categorized based on driveline care initiatives implemented at our institution (2009-2019). Era (E)1: nonstandardized care; E2: standardized driveline care protocol; E3: addition of marking driveline exit site; E4: addition of "no shower" policy. 87(15%) patients developed DLI at a median (IQR) of 403(520) days. S. aureus and P. aeruginosa were the most common pathogens. 31 (36%) of DLI patients required incision and drainage (I&D) and 5 (5.7%) device exchange. P. aeruginosa significantly increased risk for initial I&D (HR 2.7, 95% CI, 1.1-6.3) and recurrent I&D or death (HR 4.2, 95% CI, 1.4-12.5). Initial I&D was associated with a significant increased risk of death (HR 2.92 (1.33-6.44); P = 0.008) when compared to patients who did not develop DLI. Implementation of standardized driveline care protocol (E2) was associated with increased 2-year freedom from DLI compared to nonstandardized care (HR 0.36, 95% CI, 0.2-0.6, P < 0.01). Additional preventive strategies (E3&E4) showed no further reduction in DLI rates. 57(65%) DLI patients received CAS, 44% of them required escalation to intravenous antibiotics and/or I&D. Presence of P. aeruginosa DLI markedly increased risk for I&D or death. Conditional survival of patients progressing to I&D is diminished. Standardized driveline care protocol was associated with a significant reduction in DLI, while additional preventive strategies require further testing., Competing Interests: Disclosure: P.C.C. is recipient of a research grant from Abbott; he also serves as a consultant for the same company. Y.N. serves as a consultant for Abbott, CryoLife, and Zimmer-Biomet, and as a speaker for Nipro Co. G.T.S. serves as a consultant for Abbott. N.U. serves on advisory boards for Leviticus and Livemetric/Cormetric; he also serves as a consultant for Abbott and Medtronic. The remaining authors have no conflicts of interest to report., (Copyright © ASAIO 2022.)

Type 2 diabetes (T2D) has a complex etiology which is not yet fully elucidated. The identification of gene perturbations and hub genes of T2D may deepen our understanding of its genetic basis. We aimed to identify highly perturbed genes and hub genes associated with T2D via an extensive bioinformatics analytic workflow consisting of five steps: systematic review of Gene Expression Omnibus and associated literature; identification and classification of differentially expressed genes (DEGs); identification of highly perturbed genes via meta-analysis; identification of hub genes via network analysis; and downstream analysis of highly perturbed genes and hub genes. Three meta-analytic strategies, random effects model, vote-counting approach, and p value combining approach, were applied. Hub genes were defined as those nodes having above-average betweenness, closeness, and degree in the network. Downstream analyses included gene ontologies, Kyoto Encyclopedia of Genes and Genomes pathways, metabolomics, COVID-19-related gene sets, and Genotype-Tissue Expression profiles. Analysis of 27 eligible microarrays identified 6284 DEGs (4592 downregulated and 1692 upregulated) in four tissue types. Tissue-specific gene expression was significantly greater than tissue non-specific (shared) gene expression. Analyses revealed 79 highly perturbed genes and 28 hub genes. Downstream analyses identified enrichments of shared genes with certain other diabetes phenotypes; insulin synthesis and action-related pathways and metabolomics; mechanistic associations with apoptosis and immunity-related pathways; COVID-19-related gene sets; and cell types demonstrating over- and under-expression of marker genes of T2D. Our approach provided valuable insights on T2D pathogenesis and pathophysiological manifestations. Broader utility of this pipeline beyond T2D is envisaged., (© 2022. The Author(s).)

Background: Periodontal disease (PD), resulting from inflammatory host response to dysbiotic subgingival microbiota, has been linked to cardiovascular disease; however, its relationship to heart failure (HF) and its subtypes (heart failure with reduced ejection fraction [HFrEF] and heart failure with preserved ejection fraction [HFpEF]) is unexplored., Objectives: The authors hypothesize that the presence of PD is associated with increased risk of incident HF, HFpEF, and HFrEF., Methods: A total of 6,707 participants (mean age 63 ± 6 years) of the ARIC (Atherosclerosis Risk In Communities) study with full-mouth periodontal examination at visit 4 (1996-1998) and longitudinal follow-up for any incident HF (visit 4 to 2018), or incident HFpEF and HFrEF (2005-2018) were included. Periodontal status was classified as follows: healthy, PD (as per Periodontal Profile Classification [PPC]), or edentulous. Multivariable-adjusted Cox proportional hazards models were used to calculate HRs and 95% CIs for the association between PPC levels and incident HF, HFpEF, or HFrEF. Additionally, biomarkers of inflammation (C-reactive protein [CRP]) and congestion (N-terminal brain natriuretic peptide [NT-proBNP]) were assessed., Results: In total, 1,178 incident HF cases occurred (350 HFpEF, 319 HFrEF, and 509 HF of unknown type) over a median of 13 years. Of these cases, 59% had PD, whereas 18% were edentulous. PD was associated with an increased risk for HFpEF (HR: 1.35 [95% CI: 0.98-1.86]) and significantly increased risk for HFrEF (HR: 1.69 [95% CI: 1.18-2.43]), as was edentulism: HFpEF (HR: 2.00 [95% CI: 1.37-2.93]), HFrEF (HR: 2.19 [95% CI: 1.43-3.36]). Edentulism was associated with unfavorable change in CRP and NT-proBNP, whereas PD was associated only with CRP., Conclusions: Periodontal status was associated with incident HF, HFpEF, and HFrEF, as well as unfavorable changes in CRP and NT-proBNP., Competing Interests: Funding Support and Author Disclosures The ARIC study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract numbers (75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, 75N92022D00005). Ms Molinsky was supported by institutional training grant T32HL007779 from the National Institutes of Health, and Dr Lutsey was supported by K24 HL 159246. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Acute heart failure (HF) is associated with muscle mass loss, potentially leading to overestimation of kidney function using serum creatinine-based estimated glomerular filtration rate (eGFR sCr ). Cystatin C-based eGFR (eGFR CysC ) is less muscle mass dependent. Changes in the difference between eGFR CysC and eGFR sCr may reflect muscle mass loss. We investigated the difference between eGFR CysC and eGFR sCr and its association with clinical outcomes in acute HF patients., Methods and Results: A post hoc analysis was performed in 841 patients enrolled in three trials: Diuretic Optimization Strategy Evaluation (DOSE), Renal Optimization Strategies Evaluation (ROSE), and Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF). Intra-individual differences between eGFRs (eGFR diff ) were calculated as eGFR CysC -eGFR sCr at serial time points during HF admission. We investigated associations of (i) change in eGFR diff between baseline and day 3 or 4 with readmission-free survival up to day 60; (ii) index hospitalization length of stay (LOS) and readmission with eGFR diff at day 60. eGFR CysC reclassified 40% of samples to more advanced kidney dysfunction. Median eGFR diff was -4 [-11 to 1.5] mL/min/1.73 m 2 at baseline, became more negative during admission and remained significantly different at day 60. The change in eGFR diff between baseline and day 3 or 4 was associated with readmission-free survival (adjusted hazard ratio per standard deviation decrease in eGFR diff : 1.14, P = 0.035). Longer index hospitalization LOS and readmission were associated with more negative eGFR diff at day 60 (both P ≤ 0.026 in adjusted models)., Conclusions: In acute HF, a marked difference between eGFR CysC and eGFR sCr is present at baseline, becomes more pronounced during hospitalization, and is sustained at 60 day follow-up. The change in eGFR diff during HF admission and eGFR diff at day 60 are associated with clinical outcomes., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: The majority of healthcare workers (HCW) in the US report being fully vaccinated against COVID-19, yet little is known about vaccine decision-making for their household members, including children., Methods: Cross-sectional survey July-August 2021 of HCW and their household members in Minnesota., Results: 94 % of eligible participants were vaccinated with the most common reasons being wanting to protect oneself, family and loved ones. Safety concerns were the most commonly reported reasons for not being vaccinated; a significantly higher proportion of unvaccinated compared to vaccinated HCW (58 % vs 12 %, p = 0.0035) and household adults (25 % vs 5 %, p = 0.03) reported prior SARS-CoV-2 infection. Nearly half of unvaccinated adults and two-thirds of unvaccinated children would be vaccinated if a vaccine mandate were in place., Conclusions: Despite high COVID-19 vaccine acceptance among HCWs, more research is required to identify and address the needs and concerns of healthcare workers who decline COVID-19 vaccination despite availability., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors reports financial support was provided by Minnesota Department of Health. All authors reports financial support was provided by Centers for Disease Control and Prevention., (Copyright © 2022. Published by Elsevier Ltd.)

Study Objective: Mycophenolate mofetil (MMF) is the gold-standard immunosuppressive agent in heart transplantation (HT), but dose-dependent toxicities (e.g., neutropenia) are frequent. Gut bacteria β-d-glucuronidases (GUS) modulate MMF bioavailability, and changes in the intestinal flora may influence the pharmacokinetics of MMF. The objective of this study was to evaluate the safety and efficacy of MMF 1.5 g every 12 h (q12) [high-dose, HD] versus 1 g q12 [low-dose, LD] and explore the association between neutropenia and GUS., Measurements: We compared the incidence of acute cellular rejection (ACR) and neutropenia during the first 6 months post-HT. The association between neutropenia and GUS was investigated in an exploratory analysis on a subset of patients with prospectively collected stool data. Stool samples were analyzed using 16S rRNA sequencing., Main Results: A total of 168 patients (120 MMF-HD, 48 MMF-LD; mean age 55.7 years, 79% male) were studied. Neutropenia occurred in 38.6% of patients at a median of 106 [64-143] days. Freedom from neutropenia was lower in MMF-HD compared with MMF-LD (57% vs. 73%, p = 0.03). ACR (≥1R/1B) occurred in 37.5% of patients at a median of 20 [10-96] days, while high-grade ACR (≥2R/3A) occurred in 11.3% at a median of 14 [9-89] days. Freedom from ACR was similar between groups. MMF-LD was associated with more high-grade ACR (hazard ratio [HR] 3.47, 95% confidence interval [CI] 1.09-11.08, p = 0.03) during the first month, but less neutropenia (HR 0.54, 95% CI 0.29-1.00, p = 0.05) between 1 and 6 months. GUS-producing bacteria were more abundant in neutropenic patients., Conclusions: MMF-LD was associated with higher rates of early high-grade ACR and lower rates of later neutropenia. Further studies are warranted to test whether temporal MMF dose adjustments and gut microbial composition could improve clinical outcomes post-HT., (© 2022 Pharmacotherapy Publications, Inc.)

Background: Genome-wide association studies have identified six genetic variants associated with severe COVID-19, yet the mechanisms through which they may affect disease remains unclear. We investigated proteomic signatures related to COVID-19 risk variants rs657152 (ABO), rs10735079 (OAS1/OAS2/OAS3), rs2109069 (DPP9), rs74956615 (TYK2), rs2236757 (IFNAR2) and rs11385942 (SLC6A20/LZTFL1/CCR9/FYCO1/CXCR6/XCR1) as well as their corresponding downstream pathways that may promote severe COVID-19 in risk allele carriers and their potential relevancies to other infection outcomes., Methods: A DNA aptamer-based array measured 4870 plasma proteins among 11 471 participants. Linear regression estimated associations between the COVID-19 risk variants and proteins with correction for multiple comparisons, and canonical pathway analysis was conducted. Cox regression assessed associations between proteins identified in the main analysis and risk of incident hospitalized respiratory infections (2570 events) over a 20.7-year follow-up., Results: The ABO variant rs657152 was associated with 84 proteins in 7241 white participants with 24 replicated in 1671 Black participants. The TYK2 variant rs74956615 was associated with ICAM-1 and -5 in white participants with ICAM-5 replicated in Black participants. Of the 84 proteins identified in the main analysis, seven were significantly associated with incident hospitalized respiratory infections including Ephrin type-A receptor 4 (hazard ratio (HR): 0.87; P = 2.3 × 10-11) and von Willebrand factor type A (HR: 1.17; P = 1.6x10-13)., Conclusions: Novel proteomics signatures and pathways for COVID-19-related risk variants TYK2 and ABO were identified. A subset of these proteins predicted greater risk of incident hospitalized pneumonia and respiratory infections. Further studies to examine these proteins in COVID-19 patients are warranted., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: The association of periodontal disease with atherosclerotic cardiovascular diseases is well known, but not specifically with incident peripheral artery disease (PAD). Therefore, we studied the associations of periodontal disease with incident PAD in a population-based setting., Methods: Among 9,793 participants (aged 53-75 years) without prevalent PAD, self-reported history of periodontal disease was ascertained. Of these, 5,872 participants underwent full-mouth examinations from which periodontal status was defined using the US Centers for Disease Control and Prevention-American Academy of Periodontology (CDC-AAP) definition. We quantified the association of periodontal disease with incident PAD (defined by hospital admission diagnosis or procedures) using multivariable Cox regression models., Results: During a median follow-up of 20.1 years, 360 participants (3.6%) developed PAD. In models accounting for potential confounders including diabetes and smoking pack-years, there was higher hazard of PAD in participants with self-reported tooth loss because of periodontal disease (hazard ratio:1.54 [95% CI:1.20-1.98]), history of periodontal disease treatment (1.37 [1.05-1.80]), and periodontal disease diagnosis (1.38 [1.09-1.74]), compared to their respective counterparts. The clinical measure of periodontal disease (n = 5,872) was not significantly associated with incident PAD in the fully adjusted model (e.g., 1.53 [0.94-2.50] in CDC-AAP-defined severe periodontal disease versus no disease)., Conclusion: We observed a modest association of self-reported periodontal disease, especially when resulting in tooth loss, with incident PAD in the general population. Nonetheless, a larger study with the clinical measure of periodontal disease is warranted., (© 2021 American Academy of Periodontology.)

The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults comprising 14 established US prospective cohort studies. Starting as early as 1971, investigators in the C4R cohort studies have collected data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R links this pre-coronavirus disease 2019 (COVID-19) phenotyping to information on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and acute and postacute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and reflects the racial, ethnic, socioeconomic, and geographic diversity of the United States. C4R ascertains SARS-CoV-2 infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey conducted via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations and high-quality event surveillance. Extensive prepandemic data minimize referral, survival, and recall bias. Data are harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these data will be pooled and shared widely to expedite collaboration and scientific findings. This resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including postacute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term health trajectories., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Introduction: Using body mass index (BMI) as a proxy, previous Mendelian randomization (MR) studies found total causal effects of general obesity on polycystic ovarian syndrome (PCOS). Hitherto, total and direct causal effects of general- and central obesity on PCOS have not been comprehensively analyzed., Objectives: To investigate the causality of central- and general obesity on PCOS using surrogate anthropometric markers., Methods: Summary GWAS data of female-only, large-sample cohorts of European ancestry were retrieved for anthropometric markers of central obesity (waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR)) and general obesity (BMI and its constituent variables-weight and height), from the IEU Open GWAS Project. As the outcome, we acquired summary data from a large-sample GWAS (118870 samples; 642 cases and 118228 controls) within the FinnGen cohort. Total causal effects were assessed via univariable two-sample Mendelian randomization (2SMR). Genetic architectures underlying causal associations were explored. Direct causal effects were analyzed by multivariable MR modelling., Results: Instrumental variables demonstrated no weak instrument bias (F > 10). Four anthropometric exposures, namely, weight (2.69-77.05), BMI (OR: 2.90-4.06), WC (OR: 6.22-20.27), and HC (OR: 6.22-20.27) demonstrated total causal effects as per univariable 2SMR models. We uncovered shared and non-shared genetic architectures underlying causal associations. Direct causal effects of WC and HC on PCOS were revealed by two multivariable MR models containing exclusively the anthropometric markers of central obesity. Other multivariable MR models containing anthropometric markers of both central- and general obesity showed no direct causal effects on PCOS., Conclusions: Both and general- and central obesity yield total causal effects on PCOS. Findings also indicated potential direct causal effects of normal weight-central obesity and more complex causal mechanisms when both central- and general obesity are present. Results underscore the importance of addressing both central- and general obesity for optimizing PCOS care., Competing Interests: The authors have declared that no competing interests exist.