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Mass and heat rate dependant deposition of SiO2 vapour species by controlled thermal degradation of PDMS on solid substrates.

Author(s): Schneider, Ruth B; Myers, Taylor L; Rowbotham, Helen M; Luff, Marie K; Amodeo, Katherine; Sharma, Saloni; Wilson, Renee; Jensen-Roberts, Stella; Auinger, Peggy; McDermott, Michael P; Alcalay, Roy N; Biglan, Kevin; Kinel, Daniel; Tanner, Caroline; Winter-Evans, Reni; Augustine, Erika F; Cannon, Paul; 23andMe Research Team; Holloway, Robert G; Dorsey, E Ray | Abstract: BackgroundThe rise of direct-to-consumer genetic testing has enabled many to learn of their possible increased risk for rare diseases, some of which may be suitable for gene-targeted therapies. However, recruiting a large and representative population for rare diseases or genetically defined sub-populations of common diseases is slow, difficult, and expensive.ObjectiveTo assess the feasibility of recruiting and retaining a cohort of individuals who carry a genetic mutation linked to Parkinson's disease (G2019S variant of LRRK2); to characterize this cohort relative to the characteristics of traditional, in-person studies; and to evaluate this model's ability to create an engaged study cohort interested in future clinical trials of gene-directed therapies.MethodsThis single-site,3-year national longitudinal observational study will recruit between 250 to 350 LRRK2 carriers without Parkinson's disease and approximately 50 with the condition. Participants must have undergone genetic testing by the personal genetics company, 23andMe, Inc., have knowledge of their carrier status, and consent to be contacted for research studies. All participants undergo standardized assessments, including video-based cognitive and motor examination, and complete patient-reported outcomes on an annual basis.Results263 individuals living in 33 states have enrolled. The cohort has a mean (SD) age of 56.0 (15.9) years, 59% are female, and 76% are of Ashkenazi Jewish descent. 233 have completed the baseline visit: 47 with self-reported Parkinson's disease and 186 without.ConclusionsThis study establishes a promising model for developing a geographically dispersed and well-characterized cohort ready for participation in future clinical trials of gene-directed therapies.

Author(s): Chahine, Lana M; Chin, Iris; Caspell-Garcia, Chelsea; Standaert, David G; Brown, Ethan; Smolensky, Luba; Arnedo, Vanessa; Daeschler, Daisy; Riley, Lindsey; Korell, Monica; Dobkin, Roseanne; Amondikar, Ninad; Gradinscak, Stephen; Shoulson, Ira; Dean, Marissa; Kwok, Kevin; Cannon, Paul; Marek, Kenneth; Kopil, Catherine; Tanner, Caroline M; Marrason, Connie; behalf of the Fox Insight Study | Abstract: BackgroundOnline tools for data collection could be of value in patient-oriented research. The Fox Insight (FI) study collects data online from individuals with self-reported Parkinson's disease (PD). Comparing the FI cohort to other cohorts assessed through more traditional (in-person) observational research studies would inform the representativeness and utility of FI data.ObjectiveTo compare self-reported demographic characteristics, symptoms, medical history, and PD medication use of the FI PD cohort to other recent observational research study cohorts assessed with in-person visits.MethodsThe FI PD cohort (n = 12,654) was compared to 3 other cohorts, selected based on data accessibility and breadth of assessments: Parkinson's Progression Markers Initiative (PPMI; PD n = 422), Parkinson's Disease Biomarker Program (PDBP; n = 700), and PD participants in the LRRK2 consortium without LRRK2 mutations (n = 508). Demographics, motor and non-motor assessments, and medications were compared across cohorts. Where available, identical items on surveys and assessments were compared; otherwise, expert opinion was used to determine comparable definitions for a given variable.ResultsThe proportion of females was significantly higher in FI (45.56%) compared to PPMI (34.36%) and PDBP (35.71%). The FI cohort had greater educational attainment as compared to all other cohorts. Overall, prevalence of difficulties with motor experiences of daily living and non-motor symptoms in the FI cohort was similar to other cohorts, with only a few significant differences that were generally small in magnitude. Missing data were rare for the FI cohort, except on a few variables.DiscussionPatterns of responses to patient-reported assessments obtained online on the PD cohort of the FI study were similar to PD cohorts assessed in-person.

Objective: Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants. Methods: Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan–Meier survival analysis. Results: A 5′-region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5′ risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3′ of SNCA (OR = 1.32, p = 4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E-06). The known top PD-associated variant (3′ variant rs356182) had an opposite direction of effect in iRBD compared to PD. Interpretation: There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3′ of SNCA. Several 5′ SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584–598.

Background: Traditional in-person Parkinson’s disease (PD) research studies are often slow to recruit and place unnecessary burden on participants. The ongoing COVID-19 pandemic has added new impetus to the development of new research models. Objective: To compare recruitment processes and outcomes of three remote decentralized observational PD studies with video visits. Methods: We examined the number of participants recruited, speed of recruitment, geographic distribution of participants, and strategies used to enhance recruitment in FIVE, a cross-sectional study of Fox Insight participants with and without PD (n = 203); VALOR-PD, a longitudinal study of 23andMe, Inc. research participants carrying the LRRK2 G2019S variant with and without PD (n = 277); and AT-HOME PD, a longitudinal study of former phase III clinical trial participants with PD (n = 226). Results: Across the three studies, 706 participants from 45 U.S. states and Canada enrolled at a mean per study rate of 4.9 participants per week over an average of 51 weeks. The cohorts were demographically homogenous with regard to race (over 95%white) and level of education (over 90%with more than a high school education). The number of participants living in primary care Health Professional Shortage Areas in each study ranged from 30.3–42.9%. Participants reported interest in future observational (98.5–99.6%) and interventional (76.1–87.6%) research studies with remote video visits. Conclusion: Recruitment of large, geographically dispersed remote cohorts from a single location is feasible. Interest in participation in future remote decentralized PD studies is high. More work is needed to identify best practices for recruitment, particularly of diverse participants.

Background and ObjectivesTo recruit and characterize a national cohort of individuals who have a genetic variant (LRRK2 G2019S) that increases risk of Parkinson disease (PD), assess participant satisfaction with a decentralized, remote research model, and evaluate interest in future clinical trials.MethodsIn partnership with 23andMe, Inc., a personal genetics company, LRRK2 G2019S carriers with and without PD were recruited to participate in an ongoing 36-month decentralized, remote natural history study. We examined concordance between self-reported and clinician-determined PD diagnosis. We applied the Movement Disorder Society Prodromal Parkinson's Disease Criteria and asked investigators to identify concern for parkinsonism to distinguish participants with probable prodromal PD. We compared baseline characteristics of LRRK2 G2019S carriers with PD, with prodromal PD, and without PD.ResultsOver 15 months, we enrolled 277 LRRK2 G2019S carriers from 34 states. At baseline, 60 had self-reported PD (mean [SD] age 67.8 years [8.4], 98% White, 52% female, 80% Ashkenazi Jewish, and 67% with a family history of PD), and 217 did not (mean [SD] age 53.7 years [15.1], 95% White, 59% female, 73% Ashkenazi Jewish, and 57% with a family history of PD). Agreement between self-reported and clinician-determined PD status was excellent (κ = 0.94, 95% confidence interval 0.89–0.99). Twenty-four participants had prodromal PD; 9 met criteria for probable prodromal PD and investigators identified concern for parkinsonism in 20 cases. Compared with those without prodromal PD, participants with prodromal PD were older (63.9 years [9.0] vs 51.9 years [15.1], p < 0.001), had higher modified Movement Disorders Society-Unified Parkinson's Disease Rating Scale motor scores (5.7 [4.3] vs 0.8 [2.1], p < 0.001), and had higher Scale for Outcomes in PD for Autonomic Symptoms scores (11.5 [6.2] vs 6.9 [5.7], p = 0.002). Two-thirds of participants enrolled were new to research, 97% were satisfied with the overall study, and 94% of those without PD would participate in future preventive clinical trials.DiscussionAn entirely remote national cohort of LRRK2 G2019S carriers was recruited from a single site. This study will prospectively characterize a large LRRK2 G2019S cohort, refine a new model of clinical research, and engage new research participants willing to participate in future therapeutic trials.

BACKGROUND: Tobacco smoking and alcohol intake have been identified in observational studies as potentially protective factors against developing Parkinson's disease (PD); the impact of body mass index (BMI) on PD risk is debated. Whether such epidemiological associations are causal remains unclear. Mendelian randomsation (MR) uses genetic variants to explore the effects of exposures on outcomes; potentially reducing bias from residual confounding and reverse causation.OBJECTIVE: Using MR, we examined relationships between PD risk and three unhealthy behaviours: tobacco smoking, alcohol intake, and higher BMI.METHODS: 19,924 PD cases and 2,413,087 controls were included in the analysis. We performed genome-wide association studies to identify single nucleotide polymorphisms associated with tobacco smoking, alcohol intake, and BMI. MR analysis of the relationship between each exposure and PD was undertaken using a split-sample design.RESULTS: Ever-smoking reduced the risk of PD (OR 0.955; 95%confidence interval [CI] 0.921-0.991; p = 0.013). Higher daily alcohol intake increased the risk of PD (OR 1.125, 95%CI 1.025-1.235; p = 0.013) and a 1 kg/m2 higher BMI reduced the risk of PD (OR 0.988, 95%CI 0.979-0.997; p = 0.008). Sensitivity analyses did not suggest bias from horizontal pleiotropy or invalid instruments.CONCLUSION: Using split-sample MR in over 2.4 million participants, we observed a protective effect of smoking on risk of PD. In contrast to observational data, alcohol consumption appeared to increase the risk of PD. Higher BMI had a protective effect on PD, but the effect was small.

Rapid eye movement (REM) sleep behavior disorder (RBD), enactment of dreams during REM sleep, is an early clinical symptom of alpha-synucleinopathies. RBD also defines more severe forms of alpha-synucleinopathies. The genetic background of RBD and its underlying mechanisms are not well understood. Here, we performed the first genome-wide association study of RBD, identifying five RBD risk loci. Expression analyses highlight SNCA-AS1 and SCARB2 differential expression in different brain regions in RBD, with SNCA-AS1 further supported by colocalization analyses. Genetic risk score and other analyses provide further insights into RBD genetics, highlighting RBD as a unique subpopulation that will allow future early intervention.

Hypothesis Functionalized nanoparticles (NPs) offer diverse biomedical applications, but their synthesis is complex, costly, and labour-intensive, particularly when providing for additional functionalization requirements which are a key feature of biomedical applications. Pulsed laser ablation in liquids (PLAL) has previously allowed for the synthesis of metal and metal oxide nanoparticles using metal targets, which can then be surface functionalized during synthesis by the surrounding liquid species. Therefore, it should be possible to achieve biomolecule functionalization by ablating in biomolecular solutions. We explore a novel controlled recirculation PLAL scheme which should increase functionalization and productivity of functionalized nanoparticles. Experiments Traditional PLAL was performed by ablating a silicon target in a DNA solution. We have extended beyond traditional approaches by ablating the silicon target under novel flow conditions in a controlled recirculating loop of DNA solution. Findings Ablating in a DNA solution allows for high efficiency binding of DNA to silicon nanoparticles (SiNPs) in a single step process. By using SiNPs we are significantly reducing the overall cost of the process, when compared with the more traditional use of gold or silver; as well as, using a biocompatible material with an affinity for protein and nucleic acid binding. Reducing the laser shielding effects of particles and debris by removing them from the ablation site produces higher volumes and concentrations of functionalized colloid. Recirculating this liquid over the target has resulted in a 50% relative increase in binding efficiency, compared with static and single-pass flow conditions processing, achieving an average maximum binding efficiency of 78% in flow compared to 52% under static conditions. Furthermore, by reducing the initial DNA concentration, we were able to achieve 100% binding efficiency, which we believe to be the highest reported in literature to date.

Objective The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease. Methods We performed the first genome-wide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genome-wide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers. Results A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; P-value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genome-wide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these two proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: P-value = 1.1E-07; age-at-onset top variant: P-value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset. Interpretation This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. This article is protected by copyright. All rights reserved.

OBJECTIVE This work was undertaken in order to identify Parkinson's disease (PD) risk variants in a Latino cohort, to describe the overlap in the genetic architecture of PD in Latinos compared to European-ancestry subjects, and to increase the diversity in PD genome-wide association (GWAS) data. METHODS We genotyped and imputed 1,497 PD cases and controls recruited from nine clinical sites across South America. We performed a GWAS using logistic mixed models; variants with a p-value

Background: Patients who survive critical illness have well-defined physical, cognitive, emotional, and familial problems. However, the impact of these problems on survivors’ ability to return to w...

IntroductionImproving oral health and reducing oral health inequalities is an important global health priority. ‘Upstream interventions’ are a vital part of the collective effort to reduce oral disease burdens, however it is a rather nebulous term. Furthermore, there is little evidence on the effectiveness, impact and sustainability of upstream interventions that have focused on oral health and wider public health measures that impact on oral health. The aim of this scoping review is to systematically map and synthesise evidence on the effectiveness, impact and sustainability of upstream interventions on population oral health and reducing socioeconomic oral health inequalities.Methods and analysisThis scoping review will be conducted in accordance with the Joanna Briggs Institute methodology and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews checklist. A detailed search strategy will be used to conduct a comprehensive search of electronic databases: Scopus, Embase and MEDLINE, PsycINFO and CINAHL, ASSIA and Cochrane Database of Systematic Reviews. A search of grey literature will also be completed to identify relevant dissertations, governmental reports and evaluations of implemented policies. Identification and extraction of data will be performed by two pairs of reviewers. Oversight and feedback will be provided by an independent expert advisory group.Ethics and disseminationThis study will review published and available grey literature and does not require an ethics review. The scoping review protocol has been registered with the Open Science Framework. The final report will be circulated and disseminated through publication and feed into the work of the ongoing Lancet Commission on Oral Health. Due to the policy relevance of this work, discussions will take place with key stakeholders regarding the implications of the findings for future policy development.

IntroductionObservational studies have flagged smoking, alcohol and high body mass index (BMI) as potential protective factors against Parkinson’s disease (PD), however it is unclear whether such asso- ciations are causal. Mendelian randomisation (MR) uses gene variants to explore causal trait-outcome effects, minimising bias from observational studies. Using MR, we sought to determine the causal relation- ship between unhealthy traits (tobacco smoking, alcohol intake, and high BMI) and PD risk.MethodsWe used genome-wide association studies to find single nucleotide polymorphisms associated with each trait. Using split-sample MR, we used inverse weighted (IVW) methods to determine the effect of traits on PD. We used MR-Egger and weighted mean methods to check for bias in IVW analyses.ResultsEver-smoking and high BMI causally reduced PD risk (OR 0.96 95%CI 0.92–0.99 p=0.01; OR 0.99 95%CI 0.98–1.00 per 1 kg/m2 p=0.01, respectively). Alcohol causally increased PD risk (OR 1.13 95%CI 1.03–1.24 p=0.01). Sensitivity analyses did not reveal bias from pleiotropy or invalid instruments.ConclusionsMR analysis in over 2.4 million participants showed a protective effect of smoking on PD; war- ranting prioritisation of related therapeutic targets in clinical trials. Conversely, alcohol causally increased PD risk. Higher BMI protected against PD, but the effect was marginal.m.jensen@cantab.net

BackgroundSARS-CoV-2 infection, the causative agent of COVID-19, has resulted in over 2,500,000 deaths to date1. Although vaccines are becoming available, treatment options remain limited. Repurposing of compounds could reduce the time, cost, and risks associated with the development of new drugs and has been the focus of many clinical studies.Here, we summarise available evidence on 29 FDA-approved compounds, from in vitro results to clinical trials, focussing on remdesivir, galidesivir and favipiravir, and test 29 antiviral compounds’ activity in vitro.MethodsA comprehensive search strategy was used to retrieve trials and publications related to antiviral compounds with potential efficacy to treat coronaviruses. These data were used to prioritise testing of a panel of antiviral drugs in vitro against patient isolates of SARS-CoV-2. An in vitro screen was carried out to determine the activity of 29 FDA-approved compounds.Results625 clinical trials investigated 16 repurposed antiviral candidate compounds for the treatment of COVID-19. In vitro studies identified ten drug candidates with demonstrable anti-SARS-CoV-2 activity, including favipiravir, remdesivir, and galidesivir. To validate these findings, a drug screen was conducted using two cell lines and wildtype isolates of SARS-CoV-2 isolated from patients in the UK. While eight drugs with anti-SARS-CoV-2 activity were identified in vitro, activity in clinical trials has, as yet failed to demonstrate a strong effect on mortality.ConclusionsSo far, no repurposed antiviral has shown a strong effect on mortality in clinical studies. The urgent need for novel antivirals in this pandemic is clear, despite the costs and time associated with their development.Research in ContextEvidence before this studyRepurposing of existing compounds for the treatment of COVID-19 has been the focus of many in vitro studies and clinical trials, saving time, costs and risks associated with the research and development of new compounds.Added value of this studyWe reviewed the literature for 29 FDA-approved compounds with previously reported (or suspected) anti-SARS-CoV-2 activity and found 625 clinical trials that have been undertaken on 16 different drugs. We determined if repurposed antivirals are suitable for clinical trials based on previously published data, and conducted an additional in vitro screen using locally circulating strains in the UK (PHE2 and GLA1). We report the difference in IC50 from published data using Wuhan1/Wash1 strains with PHE2 and GLA1, including IC50 values below 100μM for galidesivir in wild-type virus. Given the limited success of repurposed compounds in the treatment of COVID-19, we comment on the urgent need for new antivirals specifically targeting SARS-CoV-2.Implications of all the available evidenceOur data show that most prospective compounds for repurposing show no anti-SARS-CoV-2 activity, and antiviral activity in vitro does not always translate to clinical benefit. So far, no repurposed compound has shown a strong effect on mortality in clinical studies. Drugs, including monoclonal antibody therapies, that have been developed to target SARS-CoV-2 virus itself have shown most promise.

Patients with acute coronary syndrome fall into two groups: those with unstable angina or non—ST segment elevation (formerly non—Q wave) myocardial infarction (NSTEMI) and those with acute ST segment elevation (formerly Q wave) myocardial infarction (STEMI). STEMI is the focus of this chapter. The epidemiology, pathophysiology, diagnosis, differential diagnosis, and complications of STEMI are elaborated. Reperfusion therapy (including time to reperfusion; diagnostic coronary angiography; primary, facilitated, rescue, and late percutaneous coronary intervention [PCI]; thrombolytic therapy and choice of thrombolytic agent; early invasive strategy; coronary artery bypass grafting; and therapeutic hypothermia), medical therapy (including aspirin, P2Y12 inhibitors, glycoprotein IIb/IIIa inhibitors, anticoagulants, nitrates, beta blockers, inhibition of the renin-angiotensin-aldosterone system, oxygen, analgesia, lipid-lowering therapy, prophylactic antiarrhythmics, and magnesium), risk stratification, secondary prevention, and post-STEMI care are also covered. Tables delineate classifications of MI as defined by proximal cause of myocardial ischemia, Killip classification of acute MI and mortality rates, differential diagnosis of ST segment elevation, contraindications for administering thrombolytic agents, and major recommendations for antithrombotic therapy in patients with STEMI treated with primary PCI and thrombolysis. Algorithms indicate a diagnostic approach to acute coronary syndromes and corresponding pathology and reperfusion strategies. Electrocardiogram changes in STEMI and corresponding territory of myocardium are depicted. A variety of graphs are included. This review contains 11 highly rendered figures, 6 tables, and 151 references.

Highlights • All RCTs on physical activity, fast-mimicking diet and psychological interventions with evaluated survival outcomes in all cancers were reviewed. • Long-term psychological therapies in primary and/or adjuvant treatment settings have demonstrated potential to improve survival. • The effects of fast-mimicking diet on cancer survival has not been evaluated to date. • Well-designed and sufficiently powered RCTs are needed to evaluate the survival benefits of physical activities and psychological and behavioural therapies in cancer., Background Health professionals are often asked if non-pharmacological interventions prolong life. This review aims to evaluate the effects of physical activity, fast-mimicking diet (FMD) and psychological interventions on survival in all cancers. Methods A systematic review and meta-analysis of randomized controlled trials (RCTs). Only RCTs of physical activity, FMD and psychological interventions (including counselling, cognitive and other psychotherapies) in cancer patients that reported survival outcomes were included. Data sources CENTRAL, MEDLINE, Embase, CINAHL, APA PsycINFO, Web of Science, ICTRP and ClinicalTrials.gov from inception to January 2020 were searched without language restrictions. The protocol was prospectively registered at PROSPERO (CRD42019160944). Results Thirty-one RCTs (9 on physical activity and 22 on psychological interventions) were included in the final analysis after evaluation of 60,207 records from our initial search. No eligible RCT on FMD was reported. RCTs on group psychological interventions (41.9 %) and in patients with breast cancer (38.7 %) were the most common. Most evaluated short-term interventions and in primary or adjuvant settings. Only one of 9 (11 %) RCTs on physical activity and 8 of 22 (36 %) RCTs on psychological interventions were associated with improved overall survival. Only group psychological interventions in breast cancer had adequate number of RCTs to allow a meta-analysis to be performed. It demonstrated a trend towards improved overall survival (HR -0.20, 95 %CI -0.49 to 0.10), particularly in RCTs that evaluated long-term (>6 months) therapies (HR -0.29, 95 %CI -0.59 to 0.01). Conclusion Longer term interventions starting early in the patients’ care journey in primary and adjuvant settings have shown the most promise for improving survival. Better designed RCTs including survival outcomes are particularly needed in non-breast cancers.

Objective: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease. Methods: We performed the first genome-wide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genome-wide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers. Results: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; P-value=2.5E-08, beta=1.27, SE=0.23, risk allele: C) met genome-wide significance for the penetrance model. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: P-value=1.1E-07; age-at-onset top variant: P-value=9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset. Interpretation: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations.

To date, over 90 Parkinson’s disease (PD) risk variants have been reported from genome-wide association studies (GWAS). However, these GWAS efforts have been limited to individuals of European and East Asian ancestry. We performed the first GWAS of Latino PD patients from South America, comparing 807 cases against 690 controls followed by association testing of suggestive loci in a replication cohort of 1,234 cases and 439,522 controls. We demonstrated that SNCA plays a significant role in PD etiology in a Latino cohort and identified a suggestive locus near NRROS on chromosome 3 that appeared to be driven by Peruvian subjects. We also characterized the overlap of PD genetic architecture between Europeans and Latinos with a replication of significant variants identified by Nalls et al. in their 2019 GWAS1, finding 80% concordance in direction of effect. We then leveraged the population history of Latinos via admixture mapping, identifying a significant locus on chromosome 14 in a joint test of ancestries, driven by the Native American ancestral background, and a significant locus on chromosome 6 in our test of African ancestry, containing the genes STXBP6 and RPS6KA2, respectively. Ultimately, our work reflects the most comprehensive characterization of PD genetic architecture in Latinos to date.

Post-traumatic joint contracture (PTJC) is a debilitating condition characterized by loss of joint motion following injury. Previous work in a rat model of elbow PTJC investigated disease etiology, progression and recovery in only male animals; this study explored sex-based differences. Rat elbows were subjected to a unilateral anterior capsulotomy and lateral collateral ligament transection followed by 42 days of immobilization and 42 days of free mobilization. Grip strength and gait were collected throughout the free mobilization period while joint mechanical testing, micro-computed tomography and histological analysis were performed post-mortem. Overall, few differences were seen between sexes in functional, mechanical and morphological outcomes with PTJC being similarly debilitating in male and female animals. Functional measures of grip strength and gait showed that, while some baseline differences existed between sexes, traumatic injury produced similar deficits that remained significantly different long-term when compared to control animals. Similarly, male and female animals both had significant reductions in joint range of motion due to injury. Ectopic calcification (EC), which had not been previously evaluated in this injury model, was present in all limbs on the lateral side. Injury caused increased EC volume but did not alter mineral density regardless of sex. Furthermore, histological analysis of the anterior capsule showed minor differences between sexes for inflammation and thickness but not for other histological parameters. A quantitative understanding of sex-based differences associated with this injury model will help inform future therapeutics aimed at reducing or preventing elbow PTJC.

Analysis of large genomic datasets, including gnomAD, reveals that partial LRRK2 loss of function is not strongly associated with diseases, serving as an example of how human genetics can be leveraged for target validation in drug discovery. Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes(1,2). Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson's disease(3,4), suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns(5-8), the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here, we systematically analyze pLoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)(9), 49,960 exome-sequenced individuals from the UK Biobank and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2. Experimental validation of three variants, combined with previous work(10), confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery.

ObjectiveTobacco smoking, alcohol intake, and high BMI have been identified in observational studies as potentially protective factors against developing Parkinson’s disease (PD). Because of the possibility of residual confounding and reverse causation, it is unclear whether such epidemiological associations are causal. Mendelian randomisation (MR) uses genetic variants to explore causal effects of exposures on outcomes; minimising these sources of bias. Using MR, this study sought to determine the causal relationship between tobacco smoking, alcohol intake, and high BMI, and the risk of PD.MethodsWe performed genome-wide association studies to identify single nucleotide polymorphisms associated with the exposures. MR analysis of the relationship between each exposure and PD was undertaken using a split-sample design. The inverse variance weighted (IVW) method was used to combine SNP-specific effect estimates.ResultsEver-smoking causally reduced risk of PD (OR 0.955; 95% confidence interval [CI] 0.921-0.991; p=0.013). An increase in daily alcohol intake causally increased risk of PD (OR 1.125, 95% CI 1.025-1.235; p=0.013) and a 1 kg/m2BMI causally reduced risk of PD (OR 0.988, 95% CI 0.979-0.997; p=0.008). Sensitivity analyses did not suggest bias from horizontal pleiotropy or invalid instruments.InterpretationUsing split-sample MR in over 2.4 million participants, we observed a protective effect of smoking on risk of PD, warranting the prioritisation of related therapeutic targets, such as nicotinic agonists, in prevention trials. In contrast to observational data, alcohol consumption causally increased risk of PD. Higher BMI had a protective effect on PD, but the effect was small.

Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes

Objective: Radiology has been espoused as an excellent tool for educating medical students since 1925. Advances in technology and PACS mean it has never been easier to demonstrate living anatomy and clinical pathology in exquisite detail to students. The aim of this study was to provide an overview of radiologic publications related to teaching medical students and its evolution through time. Methods A literature search was performed from inception to November 2018. The search strategies used both text words and relevant indexing related to “radiology”, “medical students” and “curriculum”. Results: 3589 records were identified of which 377 were included. There was a 100 fold increase in rate of publication over time—most were expository or surveys (60%), with few truly experimental articles. Radiology was used in clinical teaching (67%) and anatomy (33%). Almost half of radiologic anatomy teaching was conducted without the input of a Radiologist. Compulsory clinical clerkships/blocks in radiology was offered infrequently (35%). Female first authorship had increased in the last decade (47%). Conclusion: There is a significant increase in articles published on the role of radiology in medical student teaching in the last decade. Research in this area is required in order to investigate the role of radiology in improving the modern medical students’ education.

ObjectiveREM-sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants.MethodsFull sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n=1,076), Parkinson’s disease (PD, n=1,013), and dementia with Lewy bodies (DLB, n=415), and in control subjects (n=6,155). A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (cases n=1,782, controls n=131,250). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan-Meier survival analysis.ResultsA 5’-region SNCA variant (rs10005233) was associated with iRBD (OR=1.43, p=1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5’ risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3’ of SNCA (OR=1.32, p=4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR=5.74, p=2E-06). The known top PD-associated variant (3’ variant rs356182) had an opposite direction of effect in iRBD compared to PD.InterpretationThere is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3’ of SNCA. Several 5’ SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies, and may suggest a cognitive component to this region.

Introduction Following intravenous steroid use, salvage therapy for acute, severe Ulcerative Colitis consists of infliximab or ciclosporin. Conventional escalation therapy beyond this comprises referral to the surgeons for colectomy and this is our usual practice too. Previous studies where Infliximab or ciclosporin were given as third line therapy have suggested modest efficacy and highlighted potential adverse effects. We sought to review patients under our care who were treated with successive rescue therapy using Infliximab and ciclosporin or vice versa in steroid refractory UC Methods A retrospective review of case notes was undertaken at the Norfolk and Norwich University Hospital. Between February 2017 and June 2018 eight patients with steroid-refractory ulcerative colitis given ciclosporin and infliximab therapy in succession were identified. The success and safety of treatment was assessed alongside the biochemical changes during treatment. 12 month follow up was reviewed post treatment. Results Ages ranged from 17 to 41. One patient was known to have pancolitis, while seven had at least distal/left sided colitis. Six patients were switched from ciclosporin to infliximab (Cic-Ifx) and two patients were switched from infliximab to ciclosporin (Ifx-Cic). Reasons for switching included intolerance to treatment and concerns about fertility with future ileal pouch formation. Five out of eight patients responded to treatment and avoided surgical intervention during admission. The remaining three patients were referred for colectomy which they underwent without complications or a prolonged post-op stay. All five patients undergoing successive rescue therapy avoided colectomy up to 12 months post treatment. There were no deaths, or significant adverse events reported in all eight patients. Three patients were given intravenous antibiotics due to suspected bacterial translocation. Conclusions In this small case series colectomy avoidance was 62.5% in patients who were given alternative rescue treatment during admission and remained medically managed for at least 12 months following the intervention. In contrast to other studies there were no significant adverse outcomes encountered. Careful monitoring and selection of patient profile may help determine who benefits most from successive salvage therapies in acute, severe UC.

Post-traumatic joint contracture (PTJC) is a debilitating condition, particularly in the elbow. Previously, we established an animal model of elbow PTJC quantifying passive postmortem joint mechanics and histological changes temporally. These results showed persistent motion loss similar to what is experienced in humans. Functional assessment of PTJC in our model was not previously considered; however, these measures would provide a clinically relevant measure and would further validate our model by demonstrating persistently altered joint function. To this end, a custom bilateral grip strength device was developed, and a recently established open-source gait analysis system was used to quantify forelimb function in our unilateral injury model. In vivo joint function was shown to be altered long-term and never fully recover. Specifically, forelimb strength in the injured limbs showed persistent deficits at all time points; additionally, gait patterns remained imbalanced and asymmetric throughout the study (although a few gait parameters did return to near normal levels). A quantitative understanding of these longitudinal, functional disabilities further strengthens the clinical relevance of our rat PTJC model enabling assessment of the effectiveness of future interventions aimed at reducing or preventing PTJC.

In order to systematically describe the Parkinson’s disease phenome, we performed a series of 832 cross-sectional case-control analyses in a large database. Responses to 832 online survey-based phenotypes including diseases, medications, and environmental exposures were analyzed in 23andMe research participants. For each phenotype, survey respondents were used to construct a cohort of Parkinson’s disease cases and age-matched and sex-matched controls, and an association test was performed using logistic regression. Cohorts included a median of 3899 Parkinson’s disease cases and 49,808 controls, all of European ancestry. Highly correlated phenotypes were removed and the novelty of each significant association was systematically assessed (assigned to one of four categories: known, likely, unclear, or novel). Parkinson’s disease diagnosis was associated with 122 phenotypes. We replicated 27 known associations and found 23 associations with a strong a priori link to a known association. We discovered 42 associations that have not previously been reported. Migraine, obsessive-compulsive disorder, and seasonal allergies were associated with Parkinson’s disease and tend to occur decades before the typical age of diagnosis for Parkinson’s disease. The phenotypes that currently comprise the Parkinson’s disease phenome have mostly been explored in relatively small purpose-built studies. Using a single large dataset, we have successfully reproduced many of these established associations and have extended the Parkinson’s disease phenome by discovering novel associations. Our work paves the way for studies of these associated phenotypes that explore shared molecular mechanisms with Parkinson’s disease, infer causal relationships, and improve our ability to identify individuals at high-risk of Parkinson’s disease.

Background:The anteromedial (AM) bundle of the anterior cruciate ligament (ACL) has a higher modulus and failure stress than does the posterolateral (PL) bundle. However, it is unknown how these properties vary within each bundle.Purpose:To quantify mechanical and microstructural properties of samples within ACL bundles to elucidate any regional variation across the ligament. We hypothesized that there are no differences within each bundle in contrast to cross-bundle variation.Study Design:Descriptive laboratory study.Methods:Sixteen human ACLs were dissected into AM and PL bundles. Three samples were taken from each bundle in an ordered sequence from AM (region 1 AM bundle) to PL (region 6 PL bundle). Each sample was tested in uniaxial tension, using quantitative polarized light imaging (QPLI) to quantify collagen fiber alignment. After preconditioning, samples were subjected to a stress-relaxation (SR) test followed by quasistatic ramp-to-failure (RF). Peak and equilibrium stress values were computed from the SR test and modulus quantified in the toe- and linear-regions of the RF. QPLI values describing collagen orientation (angle of polarization [AoP]) and strength of alignment (degree of linear polarization [DoLP]) were computed for the SR test and at points corresponding to the zero, transition point, and linear region of the RF.Results:Toe- and linear-region modulus values decreased from region 1 to 6. Slopes of regression lines increased for the average DoLP during RF, with significance at higher strains. The standard deviation of AoP values decreased during RF, indicating tighter distribution of orientation angles, with significant correlations at all points of the RF. During SR, stress values uniformly decreased but did not show significant linear regression by region. DoLP and AoP values changed slightly during SR and demonstrated significant linear variation by region at both peak and equilibrium points.Conclusion:Most microstructural and material properties evaluated in this study appear to follow a linear gradient across the ACL, rather than varying by bundle.Clinical Relevance:This AM-to-PL variation provides a more accurate description of functional tissue anatomy and can be used to assess and guide techniques of ACL reconstruction.

International audience; Mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene were reported to be associated with Parkinson's disease and dementia with Lewy bodies. In the current study, we aimed to evaluate the role of SMPD1 variants in isolated rapid eye movement sleep behavior disorder (iRBD). SMPD1 and its untranslated regions were sequenced using targeted next-generation sequencing in 959 iRBD patients and 1287 controls from European descent. Our study reports no statistically significant association of SMPD1 variants and iRBD. It is hence unlikely that SMPD1 plays a major role in iRBD.

We show real-time measurement of error-free superchannel transmission over more than 10,500 km of large-area fiber at a spectral efficiency of 4.66 b/s/Hz, utilizing subcarrier based signal processing optimized at 5.4 GBd.

BackgroundObservational studies have begun to characterize the wide spectrum of phenotypes associated with Parkinson’s disease (PD), but recruiting large numbers of PD cases and assaying a diversity of phenotypes has often been difficult. Here, we set out to systematically describe the PD phenome using a cross-sectional case-control design in a large database.MethodsWe analyzed the association between PD and 840 phenotypes derived from online surveys. For each phenotype, we ran a logistic regression using an average of 5,141 PD cases and 65,459 age- and sex-matched controls. We selected uncorrelated phenotypes, determined statistical significance after correcting for multiple testing, and systematically assessed the novelty of each significant association. We tested whether significant phenotypes were also associated with disease duration in PD cases.FindingsPD diagnosis was associated with 149 independent phenotypes. We replicated 32 known associations and discovered 49 associations that have not previously been reported. We found that migraine, obsessive-compulsive disorder, seasonal allergies, and anemia were associated with PD, but were not significantly associated with PD duration, and tend to occur decades before the average age of diagnosis for PD. Further work is needed to determine whether these phenotypes are PD risk factors or whether they share common disease mechanisms.InterpretationWe used a systematic approach in a single large dataset to assess the spectrum of traits that were associated with PD. Some of these traits may be risk factors for PD, features of the pre-diagnostic phase of disease, or manifestations of PD pathology. The model outputs from all 840 logistic regressions are available to the research community and may be used to generate hypotheses regarding PD etiology.FundingThe Michael J. Fox Foundation, Parkinson’s UK, Barts Charity, National Institute on Aging, and 23andMe, Inc.Research in ContextEvidence before this studyWe used PubMed to perform a MEDLINE database search for review articles published up to January 21st, 2018 that contained the keywords “Parkinson” and “epidemiology” in the title or abstract. We performed additional MEDLINE searches for each phenotype that was significantly associated with PD. Although dozens of phenotypes have been tested for an association with PD, only a few associations have been consistently repeatable (e.g. pesticide exposure, coffee consumption).Added value of this studyWe systematically tested for an association between PD and 840 phenotypes using up to 13,546 cases and 1·3 million controls, making this one of the largest PD epidemiology studies ever conducted. We discovered 49 novel associations that will need to be replicated or validated. We found 44 associations for phenotypes that have previously been studied in relation to PD, but for which an association has not been consistently demonstrated.Implications of all the available evidenceTaken together with results from previous studies, this series of case-control analyses adds evidence for associations between PD and many phenotypes that are not currently thought to be part of the canonical PD phenome. This work paves the way for future studies to assess whether any of these phenotypes represent PD risk factors and whether any of these risk factors are modifiable.

Purpose The purpose of this paper is to examine the nature of professionalism within Library and Information Science (LIS) and in doing so draw comparisons with the education and medicine professions. Design/methodology/approach The paper provides a review of the extant literature from the three professions and gives a brief review of the theoretical constructs of professional knowledge using the work of Eisner and Eraut to explore knowledge types. It then relates these definitions to knowledge use within LIS, education and medicine, before examining the roles that professional associations have on the knowledge development of a profession. It concludes with a reflection on the future of professionalism within LIS. Findings The literature suggests a fragmented epistemological knowledge-base and threats to its practices from outside professions. It does, however, find opportunities to redefine its knowledge boundaries within the phronetic practices of LIS and in socio-cultural uses of knowledge. It finds strengths and weaknesses in professionalism within LIS and its practitioners. Originality/value This review provides a contemporary update to several earlier, related, works and provides useful context to current efforts to professionalise LIS by the Chartered Institute of Library and Information Professionals.

No abstract available.