Genome-wide association meta-analysis for early age-related macular degeneration highlights novel loci and insights for advanced disease

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Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Abstract: Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Publisher Copyright: © 2019, The Author(s).Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.Peer reviewe

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria

Cognitive Remediation in Psychiatric Disorders: State of the Evidence, Future Perspectives, and Some Bold Ideas

Many people with psychiatric disorders experience impairments in cognition. These deficits have a significant impact on daily functioning and sometimes even on the further course of their disease. Cognitive remediation (CR) is used as an umbrella term for behavioral training interventions to ameliorate these deficits. In most but not all studies, CR has proven effective in improving cognition and enhancing everyday functional outcomes. In this paper, after quickly summarizing the empirical evidence, practical advice to optimize the effects of CR interventions is provided. We advocate that CR interventions should be as fun and motivating as possible, and therapists should at least consider using positively toned emotional stimuli instead of neutral stimuli. Participants should be screened for basic processing deficits, which should be trained before CR of higher-order cognitive domains. CR should stimulate metacognition and utilize natural settings to invoke social cognition. Wherever possible, CR tasks should link to tasks that participants face in their everyday life. Therapists should consider that participants might also benefit from positive side effects on symptomatology. Finally, the CR approach might even be utilized in settings where the treatment of cognitive impairments is not a primary target

Association of sleep-disordered breathing with diabetes-associated kidney disease

Introduction: Diabetes-associated kidney disease is characterized by impairment of renal function and albuminuria. The aim of the present study was to assess whether sleep-disordered breathing is associated with decreased estimated glomerular filtration rate or increased urine-albumin- to-creatinine-ratio independently from known modulators of diabetes-associated kidney disease. Material and methods: Estimated glomerular filtration rate and urine-albumin-to-creatinine-ratio were determined in the baseline survey of the DIACORE-SDB substudy, a prospectively planned study of Diabetes mellitus 2 patients. As a measure of the severity of sleep-disordered breathing, the apnea-hypopnea-index was assessed using a 2-channel ambulatory SDB-monitoring device. Results: A total of 679 patients (mean age 66 years, men 61%, mean body-mass-index 31.2 kg/m(2)) were analyzed. In multivariable linear regression models adjusting for known modulators of diabetes-associated kidney disease, such as sex, age, body-mass-index, systolic blood pressure, duration of diabetes and HbA1c, apnea-hypopnea-index [beta-estimate -0.2 ml/min/1.73 m(2), 95% CI (-0.3; -0.1), p = .004], duration of diabetes and age were associated with estimated glomerular filtration rate. Apnea-hypopnea-index [beta-estimate 0.01mg/g, 95% CI (0.00; 0.02), p = .009], duration of diabetes, HbA1c and systolic blood pressure were associated with ln(urine-albumin-to-creatinine-ratio). Conclusion: In patients with diabetes mellitus type 2, more severe sleep-disordered breathing is significantly associated with lower estimated glomerular filtration rate and increased albuminuria, independent of known modulators of diabetes-associated kidney disease

Is laparoscopic major hepatectomy feasible and safe in Swiss cantonal hospitals?

BACKGROUND: The number of laparoscopic liver resections is increasing worldwide, including in Switzerland. However, laparoscopy is mostly used for minor resections. Little is known about indications for and outcomes of major liver resections performed laparoscopically. The aim of this study was to compare the clinical outcome of open and laparoscopic major liver resection cohorts in two Swiss centres. METHODS: Patients undergoing open or laparoscopic major hepatectomy (>3 segments) in two cantonal hospitals from January 2015 to December 2019 were analysed. All disease types except perihilar cholangiocarcinomas, rare malignancies and resections with biliary reconstruction were included. The primary outcome was the number of complications incurred. Operation time, blood loss, hospital stay and 90-day mortality were secondary outcomes investigated. A separate analysis was performed for colorectal liver metastases, the most common indication. Potential risk factors for major complications were evaluated in a multivariate analysis. RESULTS: A total of 88 patients were identified. Among those, 34 patients underwent laparoscopic major hepatectomy (LAPH) and 54 patients open major hepatectomy (OH). The two groups did not differ in demographics. The most common indication was malignancy (LAPH 94% vs OH 98%), mainly colorectal liver metastases (LAPH 53% vs OH 59%). There was no significant difference in major complications (21% vs 15%, p = 0.565). Median operation time (LAPH 433 minutes, interquartile range [IQR 351–482  vs OH 397 minutes, IQR 296–446; p = 0.222), blood loss (325 ml, IQR 200–575 vs 475 ml, IQR 300–800; p = 0.150) and hospital stay (9 days, IQR 8–14 vs 11 days, IQR 9–14; p = 0.441) were comparable between the two cohorts. There was no significant difference in 90-day mortality (3% vs 7%, p = 0.881). The laparoscopic technique was not identified as a risk factor for major complications in a multivariate analysis. CONCLUSION: This first report from Switzerland evaluating outcomes of laparoscopic major hepatectomies showed no difference in complications and clinical non-inferiority compared with open major hepatectomy

Daytime napping and diabetes-associated kidney disease

Background: Diabetes-associated Kidney Disease (DKD) is a common comorbidity in patients with type 2 diabetes. The present study investigates whether daytime sleeping duration in patients, ill with type 2 diabetes, is associated with DKD. Methods: A total of 733 outpatients of the cross-sectional baseline survey of the DIACORE study were analyzed with respect to their self-reported daytime sleeping duration, assessed by a standardized questionnaire. DKD was defined as eGFR 30 mg/g. Results: Mean daytime sleeping duration was 17 +/- 27 min. With increasing daytime sleeping duration a statistically significant decrease in eGFR (p = 0.002) and increase in UACR (p < 0.001) were found, respectively. Prevalence of DKD was significantly higher in patients with longer daytime sleeping duration (31% in patients not napping, 40% in patients napping less than 30 min, 47% in patients napping 30-60 min, 56% in patients napping 60 min or more; p = 0.001). After accounting for known modulators (Age, sex, BMI, waist-hip-ratio, systolic and diastolic blood pressure, physical activity, diabetes duration, HbA1c, homeostasis model assessment (HOMA-Index), nighttime sleeping duration, apnea-hypopnea-index (AHI), Epworth Sleepiness Scale (ESS)), longer daytime sleeping duration was significantly associated with impaired eGFR [B (95% CI) = -0.05 (-0.09; 0.00), p = 0.044] and increased UACR [B (95% CI) = 0.01 (0.01; 0.02), p < 0.001], respectively. Conclusion: Increased daytime sleeping duration is significantly associated with reduced eGFR and higher UACR, independent of known modulators of DKD. The direction of this relationship remains unclear. (c) 2018 Elsevier B.V. All rights reserved