👤 Geisinger-Regeneron DiscovEHR Collaboration

An accurate understanding of prognosis in Parkinson's disease (PD) is important for patient information provision, personalized treatment, and clinical trial design, but most previous research has been biased towards younger, healthier patients. To describe key clinical outcomes longitudinally and identify baseline prognostic factors (predictors) for these outcomes using population-representative PD cohorts. We meta-analyzed individual patient data from six incidence cohorts in Western Europe (Norway, Sweden, and UK). Each cohort aimed to recruit and follow up all newly diagnosed cases in defined population/incidence periods (between 2000 and 2011). We described postural instability (Hoehn & Yahr Stage 3), functional dependency (needing help with daily activities), dementia, and death with up to 12 years' follow-up and investigated clinical and genetic predictors using frailty Cox models. In 883 population-based incident patients, median age at motor symptom onset was 69.2 years. Median time to postural instability and functional dependency was 7.4 years. Dementia affected 49.6% by 10 years and 54.7% had died by 12 years (median survival 9.4 years). Older age, higher Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III) score, and lower Mini-Mental State Examination (MMSE) were significantly associated with all outcomes; cognitive symptoms and GBA polymorphisms with each outcome except mortality; and APOE ε4 with increased mortality and dementia. This first individual patient data meta-analysis of population-based incidence cohorts provides robust prognostic data, with fewer selection biases than previous PD studies, for informing people with PD about prognosis. In incidence cohorts, overall PD prognosis is worse than previously suggested, with key outcomes often occurring early. Further work should develop validated prognostic models for objective stratification of prognostic risk and for personalized medicine. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. Show less

Guidelines recommend low-dose colchicine for secondary prevention in cardiovascular disease, but uncertainty remains concerning its efficacy for stroke, efficacy in key subgroups and about uncommon but serious safety outcomes. In this trial-level meta-analysis, we searched bibliographic databases and trial registries form inception to May 16, 2024. We included randomised trials of colchicine for secondary prevention of ischaemic stroke and major adverse cardiovascular events (MACE: ischaemic stroke, myocardial infarction, coronary revascularisation, or cardiovascular death). Secondary outcomes were serious safety outcomes and mortality. A fixed-effect inverse-variance model was used to generate a pooled estimate of relative risk (RR) with 95% confidence intervals (CI). This study is registered with PROSPERO, CRD42024540320. Six trials involving 14,934 patients with prior stroke or coronary disease were included. In all patients, colchicine compared with placebo or no colchicine reduced the risk for ischaemic stroke by 27% (132 [1.8%] events versus 186 [2.5%] events, RR 0.73 [95% CI 0.58-0.90]) and MACE by 27% (505 [6.8%] events versus 693 [9.4%] events, with RR 0.73 [0.65-0.81]). Efficacy was consistent in key subgroups (females versus males, age below versus above 70, with versus without diabetes, statin versus non-statin users). Colchicine was not associated with an increase in serious safety outcomes: hospitalisation for pneumonia (109 [1.5%] versus 106 [1.5%], RR 0.99 [0.76-1.30]), cancer (247 [3.5%] versus 255 [3.6%], RR 0.97 [0.82-1.15]), and gastro-intestinal events (153 [2.1%] versus 135 [1.9%]), RR 1.15 [0.91-1.44]. There was no difference in all-cause death (201 [2.7%] versus 181 [2.4%], RR 1.09 [0.89-1.33]), cardiovascular death (70 [0.9%] versus 80 [1.1%], RR 0.89 [0.65-1.23]), or non-cardiovascular death (131 [1.8%] versus 101 [1.4%], RR 1.26 [0.98-1.64]). In patients with prior stroke or coronary disease, colchicine reduced ischaemic stroke and MACE, with consistent treatment effect in key subgroups, and did not increase serious safety events or death. There was no funding source for this study. Show less

Monte Carlo modelling of SPECT imaging in Molecular Radiotherapy can improve activity quantification. Until now, SPECT modelling with GATE only considered circular orbit (CO) acquisitions. This cannot reproduce auto-contour acquisitions, where the detector head moves close to the patient to improve image resolution. The aim of this work is to develop and validate an auto-contouring step-and-shoot acquisition mode for GATE SPECT modelling. Experimental and simulated SPECT images were compared using the gamma index, and were in good agreement with gamma index passing rate (GIPR) and gamma This work thereby justifies the need for auto-contouring modelling for isotopes with high septal penetration. Show less

Large-scale human exome sequencing can identify rare protein-coding variants with a large impact on complex traits such as body adiposity. We sequenced the exomes of 645,626 individuals from the United Kingdom, the United States, and Mexico and estimated associations of rare coding variants with body mass index (BMI). We identified 16 genes with an exome-wide significant association with BMI, including those encoding five brain-expressed G protein-coupled receptors ( Show less

The Million Veteran Program (MVP) was established in 2011 as a national research initiative to determine how genetic variation influences the health of US military veterans. Here we genotyped 312,571 MVP participants using a custom biobank array and linked the genetic data to laboratory and clinical phenotypes extracted from electronic health records covering a median of 10.0 years of follow-up. Among 297,626 veterans with at least one blood lipid measurement, including 57,332 black and 24,743 Hispanic participants, we tested up to around 32 million variants for association with lipid levels and identified 118 novel genome-wide significant loci after meta-analysis with data from the Global Lipids Genetics Consortium (total n > 600,000). Through a focus on mutations predicted to result in a loss of gene function and a phenome-wide association study, we propose novel indications for pharmaceutical inhibitors targeting PCSK9 (abdominal aortic aneurysm), ANGPTL4 (type 2 diabetes) and PDE3B (triglycerides and coronary disease). Show less

Whether triglyceride-mediated pathways are causally relevant to coronary heart disease is uncertain. We studied a genetic variant that regulates triglyceride concentration to help judge likelihood of causality. We assessed the -1131T>C (rs662799) promoter polymorphism of the apolipoprotein A5 (APOA5) gene in relation to triglyceride concentration, several other risk factors, and risk of coronary heart disease. We compared disease risk for genetically-raised triglyceride concentration (20,842 patients with coronary heart disease, 35,206 controls) with that recorded for equivalent differences in circulating triglyceride concentration in prospective studies (302 430 participants with no history of cardiovascular disease; 12,785 incident cases of coronary heart disease during 2.79 million person-years at risk). We analysed -1131T>C in 1795 people without a history of cardiovascular disease who had information about lipoprotein concentration and diameter obtained by nuclear magnetic resonance spectroscopy. The minor allele frequency of -1131T>C was 8% (95% CI 7-9). -1131T>C was not significantly associated with several non-lipid risk factors or LDL cholesterol, and it was modestly associated with lower HDL cholesterol (mean difference per C allele 3.5% [95% CI 2.6-4.6]; 0.053 mmol/L [0.039-0.068]), lower apolipoprotein AI (1.3% [0.3-2.3]; 0.023 g/L [0.005-0.041]), and higher apolipoprotein B (3.2% [1.3-5.1]; 0.027 g/L [0.011-0.043]). By contrast, for every C allele inherited, mean triglyceride concentration was 16.0% (95% CI 12.9-18.7), or 0.25 mmol/L (0.20-0.29), higher (p=4.4x10(-24)). The odds ratio for coronary heart disease was 1.18 (95% CI 1.11-1.26; p=2.6x10(-7)) per C allele, which was concordant with the hazard ratio of 1.10 (95% CI 1.08-1.12) per 16% higher triglyceride concentration recorded in prospective studies. -1131T>C was significantly associated with higher VLDL particle concentration (mean difference per C allele 12.2 nmol/L [95% CI 7.7-16.7]; p=9.3x10(-8)) and smaller HDL particle size (0.14 nm [0.08-0.20]; p=7.0x10(-5)), factors that could mediate the effects of triglyceride. These data are consistent with a causal association between triglyceride-mediated pathways and coronary heart disease. British Heart Foundation, UK Medical Research Council, Novartis. Show less