Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation

Validation of Human Telomere Length Multi-Ancestry Meta-Analysis Association Signals Identifies POP5 and KBTBD6 as Human Telomere Length Regulation Genes

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation

Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value OBFC1indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated our TL polygenic trait scores (PTS) were associated with increased risk of cancer-related phenotypes

Real-World Six-Year National Cost-Minimization Analysis of IncobotulinumtoxinA and OnabotulinumtoxinA in the VA/DoD Healthcare Systems.

PURPOSE: This study sought to perform a real-world, long-term cost-minimization analysis for incobotulinumtoxinA (Xeomin®) versus onabotulinumtoxinA (Botox®), given the established non-inferiority when utilized at similar doses. METHODS: The Department of Veterans Affairs (VA) and Department of Defense (DoD) national healthcare systems were included in this analysis. Real-world purchase data for incobotulinumtoxinA were used to estimate the direct drug costs between calendar years 2014 and 2019. Publicly available federal pharmaceutical prices (Federal Supply Schedule and Big 4) were used. The primary outcome was the difference in total direct costs nationally for incobotulinumtoxinA (real-world) versus having hypothetically utilized onabotulinumtoxinA (projected) for similar utilization. Sites utilizing ≥100 vials (of 100 Unit equivalents) of incobotulinumtoxinA annually were categorized as major adopters. IncobotulinumtoxinA 50 Unit vials were assumed to be an alternative to a 100 Unit vial of onabotulinumtoxinA for 50% of such vial purchases in the base case scenario to account for differences in wastage. RESULTS: Over the six-year study time frame, 156 sites (76.8%) utilized incobotulinumtoxinA of the 203 total VA healthcare systems and DoD medical centers. Of these sites, 67 were major adopters for at least one year, with a mean of 3.4 years spent as a major adopter over the study period. Average annual savings per major adopter was $105,782. IncobotulinumtoxinA costs for all VA/DoD sites was$46.39 million for the six-year period versus a projected $71.92 million onabotulinumtoxinA cost-a total savings of$25.53 million (35.5% relative reduction). Approximately, 82.8% of savings stemmed from lower drug acquisition cost ($21.14 million) and 17.2$4.39 million) was related to reduced wastage. It was estimated that a total of 9958 extra onabotulinumtoxinA 100 Unit vials would have been wasted during the six-year period, translating to the need for a 5.9% increase in vial purchases versus incobotulinumtoxinA. CONCLUSION: Meaningful cost savings were realized related to incobotulinumtoxinA adoption over a long-term time frame in the VA/DoD healthcare systems

REINSTATEMENT OF SAGITTARIA MACROCARPA (ALISMATACEAE)

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Clinical progression in Parkinson's disease with features of REM sleep behavior disorder: A population-based longitudinal study

INTRODUCTION:Rapid Eye Movement (REM) sleep behavior disorder (RBD) is characterized by dream enactment and is associated with incidence of neurodegenerative disorders, especially Parkinson's disease (PD). Whether PD with RBD constitutes a distinct subtype with unique progression is unknown. Here, we investigated motor and cognitive symptom progression in patients with self-reported RBD features in adult life. METHODS:We screened for RBD in a cohort of 776 PD patients whom we ascertained using a population-based strategy. Among participants with at least one follow-up (60%), we compared those with and without probable RBD (pRBD) estimating hazard rate ratios for progression events UPDRS-III≥ 35 and MMSE≤ 24. RESULTS:Prevalence of pRBD at baseline was 21%. In adjusted Cox regression models among patients with a Postural Instability and Gait Dysfunction (PIGD) phenotype, those with pRBD progressed faster to a UPDRS-III≥ 35 (HR = 1.92, 95% CI = 1.12; 3.27). Also, all patients with pRBD progressed twice as fast to a MMSE score≤ 24 (HR = 2.04, 95% CI = 1.13; 3.69). In sensitivity analyses, using alternative definition of pRBD and accounting for bias due to loss to follow-up results remained similar. DISCUSSION:Employing data from one of the largest population-based studies of PD, in which movement disorder specialists assessed patients, we confirm evidence that pRBD features are a clinical marker for faster cognitive decline and possibly also motor progression in PD patients, the latter for patients with a PIGD subtype early in disease

The association between lifestyle factors and Parkinson's disease progression and mortality

BackgroundLifestyle factors may contribute to the development of Parkinson's disease, but little is known about factors that influence progression. The objective of the current study was to examine whether caffeine or alcohol consumption, physical activity, or cigarette smoking is associated with progression and survival among PD patients.MethodsWe assessed lifelong coffee, tea, and alcohol consumption, smoking, and physical activity in a prospective community-based cohort (n = 360). All patients were passively followed for mortality (2001-2016); 244 were actively followed on average ± SD 5.3 ± 2.1 years (2007-2014). Movement disorder specialists repeatedly assessed motor function (Hoehn & Yahr) and cognition (Mini-Mental State Exam). We used Cox proportional hazards models and inverse probability weights to account for censoring.ResultsCoffee, caffeinated tea, moderate alcohol consumption, and physical activity were protective against at least 1 outcome. Smoking and heavy alcohol consumption were associated with increased risks. Coffee was protective against time to Hoehn & Yahr stage 3 (hazard ratio, 0.52; 95% confidence interval, 0.28-1.01), cognitive decline (hazard ratio, 0.23; 95% confidence interval, 0.11, 0.48), and mortality (hazard ratio, 0.47; 95% confidence interval, 0.32-0.69). Relative to moderate drinkers, those who never drank liquor and those who drank more heavily were at an increased risk of Hoehn & Yahr 3 (hazard ratio, 3.48; 95% confidence interval, 1.90-6.38; and hazard ratio, 2.16; 95% confidence interval, 1.03, 4.54, respectively). A history of competitive sports was protective against cognitive decline (hazard ratio, 0.46; 95% confidence interval, 0.22-0.96) and Hoehn & Yahr 3 (hazard ratio, 0.42; 95% confidence interval, 0.23-0.79), as was physical activity measured by metabolic-equivalent hours. Current cigarette smoking was associated with faster cognitive decline (hazard ratio, 3.20; 95% confidence interval, 1.02-10.01).ConclusionsThis population-based study suggests that lifestyle factors influence PD progression and mortality. © 2019 International Parkinson and Movement Disorder Society

Education Research: Evaluation of curriculum to teach resilience skills to neurology residents.

ObjectiveTo evaluate feasibility and acceptability of a health professional resilience skills training program with neurology residents.MethodsThe curriculum consists of five 1-hour-long modules that included the following skills: reflective narrative practices, emotion regulation, communication with highly distressed individuals, boundary management, and the identification of depression and trauma. Using a web-based survey tool, we administered the Brief Resilience Scale (BRS) and Abbreviated Maslach Burnout Inventory (aMBI) at baseline, in addition to a pre- and post-survey assessing change in beliefs and self-efficacy, as well as satisfaction with the intervention. Means were compared using the Wilcoxon rank-sum and signed rank tests.ResultsTwenty-two residents representing each year of training completed the pre-survey; 41% were women. Subscale scores on the aMBI revealed that 50% had moderate or high emotional exhaustion, 41% had moderate depersonalization, and 37% had moderate or low personal accomplishment, though 77.3% reported high career satisfaction. Female residents had lower scores on the BRS (mean 3.26 vs 3.88, p < 0.05), though scores on aMBI subscales did not differ by sex. Scores did not differ by year of training. Sixteen residents completed both the pre- and post-survey. Significant increases were detected in 4 of 9 self-efficacy statements. Seventy-one percent of residents were satisfied or extremely satisfied with the training.ConclusionsResidents were satisfied with the curriculum and reported improved ability to identify and cope with work-related stress. Further study is needed to evaluate the influence of skills adoption and practice on resilience and burnout

Amyloid-β-related angiitis: a report of 2 cases with unusual presentations.

Amyloid-β-related angiitis (ABRA) is a rare complication of cerebral amyloid angiopathy in which amyloid-β deposition in the leptomeningeal and cortical vessels is associated with vasculitis characterized by transmural lymphohistiocytic, often granulomatous, inflammation. Patients usually present with acute to subacute cognitive dysfunction, headaches, and focal neurologic deficits. We report 2 cases of ABRA with unusual clinical presentations, including one case with fatal cerebral edema leading to herniation and Duret hemorrhages, and another associated with both lobar and deep parenchymal hemorrhages with intraventricular extension as well as hypercoagulability. Both showed extensive vascular amyloid-β deposition associated with granulomatous angiitis and foreign body-type multinucleated giant cells. One of our cases demonstrates the likely effects of ABRA on impairment of fluid regulation leading to severe cerebral edema, which is an uncommon manifestation of ABRA, and may be a result of impaired blood-brain barrier function or malfunction of the neurovascular unit