436 research outputs found

    Additional file 1 of Identifying individual, household and environmental risk factors for malaria infection on Bioko Island to inform interventions

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    Additional file 1: Table S1. Odds ratios estimated from regression models of all risk factors for malaria transmission on Bioko Island and 95% confidence intervals, stratified by rural and urban settings and malaria annual indicator survey year, 2015 and 2018

    Type II Diabetes Mellitus Causes Extracellular Matrix Alterations in the Posterior Cornea That Increase Graft Thickness and Rigidity.

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    PurposeThere is a pressing need to investigate the impact of type II diabetes mellitus on the posterior cornea in donor tissues given its increasing prevalence and potential impact on endothelial keratoplasty surgical outcomes.MethodsImmortalized human cultured corneal endothelial cells (CECs; HCEC-B4G12) were grown in hyperglycemic media for 2 weeks. Extracellular matrix (ECM) adhesive glycoprotein expression and advanced glycation end products (AGEs) in cultured cells and corneoscleral donor tissues, as well as the elastic modulus for the Descemet membrane (DMs) and CECs of diabetic and nondiabetic donor corneas, were measured.ResultsIn CEC cultures, increasing hyperglycemia resulted in increased transforming growth factor beta-induced (TGFBI) protein expression and colocalization with AGEs in the ECM. In donor corneas, the thicknesses of the DM and the interfacial matrix (IFM) between the DM and stroma both increased from 8.42 ¬Ī 1.35 ¬Ķm and 0.504 ¬Ī 0.13 ¬Ķm in normal corneas, respectively, to 11.13 ¬Ī 2.91 ¬Ķm (DM) and 0.681 ¬Ī 0.24 ¬Ķm (IFM) in non-advanced diabetes (P = 0.013 and P = 0.075, respectively) and 11.31 ¬Ī 1.76 ¬Ķm (DM) and 0.744 ¬Ī 0.18 ¬Ķm (IFM) in advanced diabetes (AD; P = 0.0002 and P = 0.003, respectively). Immunofluorescence in AD tissues versus controls showed increased AGEs (P < 0.001) and markedly increased labeling intensity for adhesive glycoproteins, including TGFBI, that colocalized with AGEs. The elastic modulus significantly increased between AD and control tissues for the DMs (P < 0.0001) and CECs (P < 0.0001).ConclusionsDiabetes and hyperglycemia alter human CEC ECM structure and composition, likely contributing to previously documented complications of endothelial keratoplasty using diabetic donor tissue, including tearing during graft preparation and reduced graft survival. AGE accumulation in the DM and IFM may be a useful biomarker for determining diabetic impact on posterior corneal tissue

    Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants.

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    The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P‚ÄČ=‚ÄČ0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups

    Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

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    Background: The EMPA-KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1¬∑73 m2, or 45 to less than 90 mL/min per 1¬∑73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ‚Č•40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1¬∑73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2¬∑0 years (IQR 1¬∑5-2¬∑4). Prespecified subgroupings by primary kidney disease included 2057 (31¬∑1%) participants with diabetic kidney disease, 1669 (25¬∑3%) with glomerular disease, 1445 (21¬∑9%) with hypertensive or renovascular disease, and 1438 (21¬∑8%) with other or unknown causes. Kidney disease progression occurred in 384 (11¬∑6%) of 3304 patients in the empagliflozin group and 504 (15¬∑2%) of 3305 patients in the placebo group (hazard ratio 0¬∑71 [95% CI 0¬∑62-0¬∑81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0¬∑62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1¬∑37 mL/min per 1¬∑73 m2 per year (95% CI 1¬∑16-1¬∑59), representing a 50% (42-58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0¬∑1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

    Effects of empagliflozin on progression of chronic kidney disease: a prespecified secondary analysis from the empa-kidney trial

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    Background: Sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce progression of chronic kidney disease and the risk of cardiovascular morbidity and mortality in a wide range of patients. However, their effects on kidney disease progression in some patients with chronic kidney disease are unclear because few clinical kidney outcomes occurred among such patients in the completed trials. In particular, some guidelines stratify their level of recommendation about who should be treated with SGLT2 inhibitors based on diabetes status and albuminuria. We aimed to assess the effects of empagliflozin on progression of chronic kidney disease both overall and among specific types of participants in the EMPA-KIDNEY trial. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA), and included individuals aged 18 years or older with an estimated glomerular filtration rate (eGFR) of 20 to less than 45 mL/min per 1¬∑73 m2, or with an eGFR of 45 to less than 90 mL/min per 1¬∑73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher. We explored the effects of 10 mg oral empagliflozin once daily versus placebo on the annualised rate of change in estimated glomerular filtration rate (eGFR slope), a tertiary outcome. We studied the acute slope (from randomisation to 2 months) and chronic slope (from 2 months onwards) separately, using shared parameter models to estimate the latter. Analyses were done in all randomly assigned participants by intention to treat. EMPA-KIDNEY is registered at ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and then followed up for a median of 2¬∑0 years (IQR 1¬∑5-2¬∑4). Prespecified subgroups of eGFR included 2282 (34¬∑5%) participants with an eGFR of less than 30 mL/min per 1¬∑73 m2, 2928 (44¬∑3%) with an eGFR of 30 to less than 45 mL/min per 1¬∑73 m2, and 1399 (21¬∑2%) with an eGFR 45 mL/min per 1¬∑73 m2 or higher. Prespecified subgroups of uACR included 1328 (20¬∑1%) with a uACR of less than 30 mg/g, 1864 (28¬∑2%) with a uACR of 30 to 300 mg/g, and 3417 (51¬∑7%) with a uACR of more than 300 mg/g. Overall, allocation to empagliflozin caused an acute 2¬∑12 mL/min per 1¬∑73 m2 (95% CI 1¬∑83-2¬∑41) reduction in eGFR, equivalent to a 6% (5-6) dip in the first 2 months. After this, it halved the chronic slope from -2¬∑75 to -1¬∑37 mL/min per 1¬∑73 m2 per year (relative difference 50%, 95% CI 42-58). The absolute and relative benefits of empagliflozin on the magnitude of the chronic slope varied significantly depending on diabetes status and baseline levels of eGFR and uACR. In particular, the absolute difference in chronic slopes was lower in patients with lower baseline uACR, but because this group progressed more slowly than those with higher uACR, this translated to a larger relative difference in chronic slopes in this group (86% [36-136] reduction in the chronic slope among those with baseline uACR <30 mg/g compared with a 29% [19-38] reduction for those with baseline uACR ‚Č•2000 mg/g; ptrend<0¬∑0001). Interpretation: Empagliflozin slowed the rate of progression of chronic kidney disease among all types of participant in the EMPA-KIDNEY trial, including those with little albuminuria. Albuminuria alone should not be used to determine whether to treat with an SGLT2 inhibitor. Funding: Boehringer Ingelheim and Eli Lilly

    Empagliflozin in Patients with Chronic Kidney Disease