Defining the causes of sporadic Parkinson's disease in the global Parkinson's genetics program (GP2)

The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia

Multi-ancestry genome-wide association meta-analysis of Parkinson?s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations

A Comprehensive Coordinator Supported Hepatitis C Virus Testing and Linkage to Treatment Program at Kaiser Permanente Mid-Atlantic States

Since 2020, the US Preventive Services Taskforce has recommended expanding hepatitis C virus (HCV) screening to include ages 18−79, in addition to baby boomers (born 1945−1965) and those at-risk for hepatitis C virus. This retrospective cohort analysis compared patients (18 years and above) tested for HCV through usual care versus a coordinator-supported program (HCV pathway) during 2015−2018 within Kaiser Permanente Mid-Atlantic States (KPMAS). In total, 131,176 patients were tested through the HCV pathway and 128,311 through usual care (non-standardized testing). Of those tested, 1.6% (HCV pathway) and 0.5% (usual care) had chronic HCV. Of those with chronic HCV, more patients tested within the HCV pathway completed hepatic transient elastography (82.6% HCV pathway vs. 45.6% usual care; p < 0.001) and a gastroenterology visit (72.2% HCV pathway vs. 46.5% usual care; p < 0.001), and had filled prescriptions for treatment (56.5% HCV pathway vs. 40.3% usual care; p < 0.001). The median time to complete each step was shorter for those tested through the HCV pathway (hepatic transient elastography (26 vs. 118 days), gastroenterology visit (63 vs. 131 days), and prescription fill (222 vs. 326 days)). More patients tested through a coordinator-supported, standardized testing pathway completed the necessary testing steps, in less time, compared to usual care. These findings may inform institutions seeking to create effective population-wide testing programs for HCV and other conditions

A Comprehensive Coordinator Supported Hepatitis C Virus Testing and Linkage to Treatment Program at Kaiser Permanente Mid-Atlantic States

Since 2020, the US Preventive Services Taskforce has recommended expanding hepatitis C virus (HCV) screening to include ages 18−79, in addition to baby boomers (born 1945−1965) and those at-risk for hepatitis C virus. This retrospective cohort analysis compared patients (18 years and above) tested for HCV through usual care versus a coordinator-supported program (HCV pathway) during 2015−2018 within Kaiser Permanente Mid-Atlantic States (KPMAS). In total, 131,176 patients were tested through the HCV pathway and 128,311 through usual care (non-standardized testing). Of those tested, 1.6% (HCV pathway) and 0.5% (usual care) had chronic HCV. Of those with chronic HCV, more patients tested within the HCV pathway completed hepatic transient elastography (82.6% HCV pathway vs. 45.6% usual care; p p p < 0.001). The median time to complete each step was shorter for those tested through the HCV pathway (hepatic transient elastography (26 vs. 118 days), gastroenterology visit (63 vs. 131 days), and prescription fill (222 vs. 326 days)). More patients tested through a coordinator-supported, standardized testing pathway completed the necessary testing steps, in less time, compared to usual care. These findings may inform institutions seeking to create effective population-wide testing programs for HCV and other conditions

A care coordination program to support patients with hepatitis B virus at Kaiser Permanente Mid-Atlantic States

Abstract Background Eliminating hepatitis B virus (HBV) is a significant worldwide challenge requiring innovative approaches for vaccination, screening, disease management, and the prevention of related conditions. Programs that support patients in accessing needed clinical services can help optimize access to preventive services and treatment resources for hepatitis B. Methods Here, we outline a coordinator-supported program (HBV Pathway) that connects patients infected with HBV to laboratory testing, imaging, and specialty care for treatment initiation and/or liver cancer surveillance (screening of high-risk patients for liver cancer). This study describes the HBV Pathway steps and reports sociodemographic factors of patients by initiation and completion. Results Results showed a 72.5% completion rate (defined as completing all Pathway steps including the final specialty visit) among patients who initiated the Pathway. Differences in completion were observed by age, race, ethnicity, and service area, with higher rates for younger ages, Asian race, non-Hispanic ethnicity, and lower rates for patients within one service area. Of those who completed the specialty visit, 59.5% were referred for hepatocellular carcinoma surveillance. Conclusions The HBV Pathway offers dual benefits– care coordination support for patients to promote Pathway completion and a standardized testing and referral program to reduce physician burden. This program provides an easy and reliable process for patients and physicians to obtain updated clinical information and initiate treatment and/or liver cancer screening if needed

A reversible form of lysine acetylation in the ER and Golgi lumen controls the molecular stabilization of BACE1

The lipid second messenger ceramide regulates the rate of β cleavage of the Alzheimer's disease APP (amyloid precursor protein) by affecting the molecular stability of the β secretase BACE1 (β-site APP cleaving enzyme 1). Such an event is stimulated in the brain by the normal process of aging, and is under the control of the general aging programme mediated by the insulin-like growth factor 1 receptor. In the present study we report that BACE1 is acetylated on seven lysine residues of the N-terminal portion of the nascent protein. This process involves lysine acetylation in the lumen of the ER (endoplasmic reticulum) and is followed by deacetylation in the lumen of the Golgi apparatus, once the protein is fully mature. We also show that specific enzymatic activities acetylate (in the ER) and deacetylate (in the Golgi apparatus) the lysine residues. This process requires carrier-mediated translocation of acetyl-CoA into the ER lumen and is stimulated by ceramide. Site-directed mutagenesis indicates that lysine acetylation is necessary for nascent BACE1 to leave the ER and move ahead in the secretory pathway, and for the molecular stabilization of the protein