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BackgroundAlthough diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown.MethodsTo identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function.ResultsOur GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition (BMP7) or renal biology (COLEC11 and DDR1).ConclusionsThe 16 diabetic kidney disease–associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.

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Arterial stiffness is established as an independent predictor of cardiovascular morbidity and mortality. The objective was to prospectively evaluate association of aortic calcification burden with progression of arterial stiffness in population-based samples of healthy middle-aged men from ERA JUMP cohort. Men (n=635) aged 40–49 (207 White American, 45 African American, 142 Japanese American and 241 Japanese in Japan) were examined at baseline and 4–7 years later. Aortic calcification was evaluated from level of aortic arch to iliac bifurcation. Arterial stiffness progression was measured as annual change in brachial-ankle pulse wave velocity. Multivariable-adjusted general linear models were applied to investigate associations of longitudinal change in aortic calcification with arterial stiffness progression in participants overall, as well as in subgroups without or with prevalent aortic calcification at baseline. Annual change in aortic calcification was positively and significantly associated with arterial stiffness progression. In participants with annual changes in aortic calcium score of <=0, 1–10, 11–100, and > 100, the adjusted mean (standard deviation) for the annual change in baPWV was 3.8 (2.2), 7.2 (2.2), 12.2 (1.8) and 15.6 (2.6) cm/sec, respectively (P for trend < 0.01) adjusted for baseline aortic calcification, arterial stiffness and standard cardiovascular risk factors. Arterial stiffness was associated with incidence of aortic calcification over the follow-up period among participants without aortic calcification (n=297) and with an increase in aortic calcification among participants with prevalent aortic calcification at baseline (n=388). Our findings suggest aortic calcification may be causally linked to arterial stiffness.

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Background Preclinical studies have suggested potential beneficial effects of newer glucose‐lowering drugs (GLDs) including dipeptidyl peptidase (DPP)‐4 inhibitors, glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), and sodium glucose co‐transporter‐2 (SGLT2) inhibitors, in protecting humans against cognitive decline and dementia. However, population studies aiming to demonstrate such cognitive benefits from newer GLDs have produced mixed findings. This meta‐analysis aimed to evaluate the association between newer GLDs and risk of dementia in adults with type 2 diabetes (T2D). Methods Electronic databases were searched up to March 11, 2022 to include observational studies that examined the association between DPP‐4 inhibitors, GLP‐1RAs, and SGLT2 inhibitors and risk of dementia (including all‐cause dementia, Alzheimer's disease [AD], and vascular dementia [VD]) in people with T2D. We conducted a random‐effects meta‐analysis to calculate the relative risk (RR) with 95% confidence interval (CI) for each class of newer GLD. Results Ten studies (from nine articles) involving 819,511 individuals with T2D were included. Three studies found that SGLT2 inhibitor users had a lower risk of all‐cause dementia than non‐SGLT2 inhibitor users (RR, 0.62; 95% CI, 0.39–0.97). Five studies found that users versus nonusers of GLP‐1RAs were associated with a significant reduction in the risk of all‐cause dementia (RR, 0.72; 95% CI, 0.54–0.97). However, a meta‐analysis for AD and VD was unavailable for SGLT2 inhibitors and GLP‐1RAs because only one study was included for each drug. In seven studies, users vs. nonusers of DPP‐4 inhibitors were significantly associated with a decreased risk of all‐cause dementia (RR, 0.84; 95% CI, 0.74–0.94) and VD (RR, 0.59; 95% CI, 0.47–0.75) but not AD (RR, 0.82; 95% CI, 0.63–1.08). Conclusion Newer GLDs were associated with a decreased risk of all‐cause dementia in people with T2D. Because of the observational nature and significant heterogeneity between studies, the results should be interpreted with caution. Further research is warranted to confirm our findings.

Background The US Centers for Disease Control and Prevention has repeatedly called for Coronavirus Disease 2019 (COVID-19) vaccine equity. The objective our study was to measure equity in the early distribution of COVID-19 vaccines to healthcare facilities across the US. Specifically, we tested whether the likelihood of a healthcare facility administering COVID-19 vaccines in May 2021 differed by county-level racial composition and degree of urbanicity. Methods and findings The outcome was whether an eligible vaccination facility actually administered COVID-19 vaccines as of May 2021, and was defined by spatially matching locations of eligible and actual COVID-19 vaccine administration locations. The outcome was regressed against county-level measures for racial/ethnic composition, urbanicity, income, social vulnerability index, COVID-19 mortality, 2020 election results, and availability of nontraditional vaccination locations using generalized estimating equations. Across the US, 61.4% of eligible healthcare facilities and 76.0% of eligible pharmacies provided COVID-19 vaccinations as of May 2021. Facilities in counties with >42.2% non-Hispanic Black population (i.e., > 95th county percentile of Black race composition) were less likely to serve as COVID-19 vaccine administration locations compared to facilities in counties with <12.5% non-Hispanic Black population (i.e., lower than US average), with OR 0.83; 95% CI, 0.70 to 0.98, p = 0.030. Location of a facility in a rural county (OR 0.82; 95% CI, 0.75 to 0.90, p < 0.001, versus metropolitan county) or in a county in the top quintile of COVID-19 mortality (OR 0.83; 95% CI, 0.75 to 0.93, p = 0.001, versus bottom 4 quintiles) was associated with decreased odds of serving as a COVID-19 vaccine administration location. There was a significant interaction of urbanicity and racial/ethnic composition: In metropolitan counties, facilities in counties with >42.2% non-Hispanic Black population (i.e., >95th county percentile of Black race composition) had 32% (95% CI 14% to 47%, p = 0.001) lower odds of serving as COVID administration facility compared to facilities in counties with below US average Black population. This association between Black composition and odds of a facility serving as vaccine administration facility was not observed in rural or suburban counties. In rural counties, facilities in counties with above US average Hispanic population had 26% (95% CI 11% to 38%, p = 0.002) lower odds of serving as vaccine administration facility compared to facilities in counties with below US average Hispanic population. This association between Hispanic ethnicity and odds of a facility serving as vaccine administration facility was not observed in metropolitan or suburban counties. Our analyses did not include nontraditional vaccination sites and are based on data as of May 2021, thus they represent the early distribution of COVID-19 vaccines. Our results based on this cross-sectional analysis may not be generalizable to later phases of the COVID-19 vaccine distribution process. Conclusions Healthcare facilities in counties with higher Black composition, in rural areas, and in hardest-hit communities were less likely to serve as COVID-19 vaccine administration locations in May 2021. The lower uptake of COVID-19 vaccinations among minority populations and rural areas has been attributed to vaccine hesitancy; however, decreased access to vaccination sites may be an additional overlooked barrier.

AIMThe aim of the study was to assess ticagrelor's effects on inhibition of platelet aggregation (IPA), P2Y 12 reaction units (PRU, measure of platelet P2Y 12 receptor blockade), pharmacokinetic (PK) parameters and safety in Chinese patients with stable coronary artery disease (CAD). METHODSThis was an open label, single centre, randomized study. Thirty-six patients on low dose aspirin (75-100 mg day -1 ) received ticagrelor 45, 60 or 90 mg (single dose, days 1 and 7; twice daily, days 3-6). IPA (final extent), PRU and ticagrelor and AR-C124910XX plasma concentrations were determined. RESULTSOn day 1, peak IPA >80% occurred 2-6 h post-dose (all doses). PRU was markedly reduced at 1 h vs. baseline (all doses). With ticagrelor 45 and 90 mg twice daily, maximum IPA (mean, SD) was 91% (13%), and 99% (3%), and maximum PRU reduction from baseline (mean, SD) was 82% (17%) and 92% (9%) CONCLUSIONSIn Chinese patients with CAD, ticagrelor (45, 60 and 90 mg) markedly reduced platelet aggregation. The IPA and PRU magnitude increased generally with increasing doses. However, the mean pharmacodynamic differences between 45 and 60 mg doses were small. Following single and multiple doses, the mean C max and AUC values of ticagrelor and AR-C124910XX increased approximately dose proportionally between 45 and 90 mg doses. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Ticagrelor (an oral, direct acting, reversibly binding P2Y 12 receptor antagonist) is approved for preventing atherothrombotic events in patients with acute coronary syndromes.• Ticagrelor bioavailability is~40% higher in Asians than Caucasians.• Pharmacodynamics, pharmacokinetics and safety of ticagrelor have not been evaluated previously in Chinese patients with stable coronary artery disease. WHAT THIS STUDY ADDS• In Chinese patients with coronary artery disease, ticagrelor (45, 60 or 90 mg twice daily) markedly inhibited platelet aggregation.• Dose-related changes in pharmacodynamic/pharmacokinetic parameters occurred with ticagrelor.• Ticagrelor exposure was consistent with previous Asian studies and higher than in Caucasian studies.