Risk Factors for Tremor in a Population of Patients with Severe Mental Illness:An 18-year Prospective Study in a Geographically Representative Sample (The Curacao Extrapyramidal Syndromes Study XI)

BACKGROUND: The aim was to assess incidence, prevalence and risk factors of medication-induced tremor in African-Caribbean patients with severe mental illness (SMI).METHOD: A prospective study of SMI patients receiving care from the only mental health service of the previous Dutch Antilles. Eight clinical assessments, over 18 years, focused on movement disorders, medication use, and resting tremor (RT) and (postural) action tremor (AT). Risk factors were modeled with logistic regression for both current (having) tremor and for tremor at the next time point (developing). The latter used a time-lagged design to assess medication changes prior to a change in tremor state.RESULTS: Yearly tremor incidence rate was 2.9% and mean tremor point prevalence was 18.4%. Over a third of patients displayed tremor during the study. Of the patients, 5.2% had AT with 25% of cases persisting to the next time point, while 17.1% of patients had RT of which 65.3% persisted. When tremor data were examined in individual patients, they often had periods of tremor interspersed with periods of no tremor. Having RT was associated with age (OR=1.07 per year; 95% confidence interval 1.03-1.11), sex (OR=0.17 for males; 0.05-0.78), cocaine use (OR=10.53; 2.22-49.94), dyskinesia (OR=0.90; 0.83-0.97), and bradykinesia (OR=1.16; 1.09-1.22). Developing RT was strongly associated with previous measurement RT (OR=9.86; 3.80-25.63), with previous RT severity (OR=1.22; 1.05-1.41), and higher anticholinergic load (OR= 1.24; 1.08-1.43). Having AT was associated with tremor-inducing medication (OR= 4.54; 1.90-10.86), cocaine use (OR=14.04; 2.38-82.96), and bradykinesia (OR=1.07; 1.01-1.15). Developing AT was associated with, previous AT severity (OR=2.62 per unit; 1.64-4.18) and tremor reducing medication (OR=0.08; 0.01-0.55).CONCLUSIONS: Long-stay SMI patients are prone to developing tremors, which show a relapsing-remitting course. Differentiation between RT and AT is important as risk factors differ and they require different prevention and treatment strategies.</p

Prediction of Emerging Technologies Based on Analysis of the U.S. Patent Citation Network

The network of patents connected by citations is an evolving graph, which provides a representation of the innovation process. A patent citing another implies that the cited patent reflects a piece of previously existing knowledge that the citing patent builds upon. A methodology presented here (i) identifies actual clusters of patents: i.e. technological branches, and (ii) gives predictions about the temporal changes of the structure of the clusters. A predictor, called the {citation vector}, is defined for characterizing technological development to show how a patent cited by other patents belongs to various industrial fields. The clustering technique adopted is able to detect the new emerging recombinations, and predicts emerging new technology clusters. The predictive ability of our new method is illustrated on the example of USPTO subcategory 11, Agriculture, Food, Textiles. A cluster of patents is determined based on citation data up to 1991, which shows significant overlap of the class 442 formed at the beginning of 1997. These new tools of predictive analytics could support policy decision making processes in science and technology, and help formulate recommendations for action

A GWAS sequence variant for platelet volume marks an alternative DNM3 promoter in megakaryocytes near a MEIS1 binding site

We recently identified 68 genomic loci where common sequence variants are associated with platelet count and volume. Platelets are formed in the bone marrow by megakaryocytes, which are derived from hematopoietic stem cells by a process mainly controlled by transcription factors. The homeobox transcription factor MEIS1 is uniquely transcribed in megakaryocytes and not in the other lineage-committed blood cells. By ChIP-seq, we show that 5 of the 68 loci pinpoint a MEIS1 binding event within a group of 252 MK-overexpressed genes. In one such locus in DNM3, regulating platelet volume, the MEIS1 binding site falls within a region acting as an alternative promoter that is solely used in megakaryocytes, where allelic variation dictates different levels of a shorter transcript. The importance of dynamin activity to the latter stages of thrombopoiesis was confirmed by the observation that the inhibitor Dynasore reduced murine proplatelet for-mation in vitro

2019 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations : summary from the basic life support; advanced life support; pediatric life support; neonatal life support; education, implementation, and teams; and first aid task forces

The International Liaison Committee on Resuscitation has initiated a continuous review of new, peer-reviewed, published cardiopulmonary resuscitation science. This is the third annual summary of the International Liaison Committee on Resuscitation International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. It addresses the most recent published resuscitation evidence reviewed by International Liaison Committee on Resuscitation Task Force science experts. This summary addresses the role of cardiac arrest centers and dispatcher-assisted cardiopulmonary resuscitation, the role of extracorporeal cardiopulmonary resuscitation in adults and children, vasopressors in adults, advanced airway interventions in adults and children, targeted temperature management in children after cardiac arrest, initial oxygen concentration during resuscitation of newborns, and interventions for presyncope by first aid providers. Members from 6 International Liaison Committee on Resuscitation task forces have assessed, discussed, and debated the certainty of the evidence on the basis of the Grading of Recommendations, Assessment, Development, and Evaluation criteria, and their statements include consensus treatment recommendations. Insights into the deliberations of the task forces are provided in the Justification and Evidence to Decision Framework Highlights sections. The task forces also listed priority knowledge gaps for further research

Maps of Open Chromatin Guide the Functional Follow-Up of Genome-Wide Association Signals: Application to Hematological Traits

Turning genetic discoveries identified in genome-wide association (GWA) studies into biological mechanisms is an important challenge in human genetics. Many GWA signals map outside exons, suggesting that the associated variants may lie within regulatory regions. We applied the formaldehyde-assisted isolation of regulatory elements (FAIRE) method in a megakaryocytic and an erythroblastoid cell line to map active regulatory elements at known loci associated with hematological quantitative traits, coronary artery disease, and myocardial infarction. We showed that the two cell types exhibit distinct patterns of open chromatin and that cell-specific open chromatin can guide the finding of functional variants. We identified an open chromatin region at chromosome 7q22.3 in megakaryocytes but not erythroblasts, which harbors the common non-coding sequence variant rs342293 known to be associated with platelet volume and function. Resequencing of this open chromatin region in 643 individuals provided strong evidence that rs342293 is the only putative causative variant in this region. We demonstrated that the C- and G-alleles differentially bind the transcription factor EVI1 affecting PIK3CG gene expression in platelets and macrophages. A protein–protein interaction network including up- and down-regulated genes in Pik3cg knockout mice indicated that PIK3CG is associated with gene pathways with an established role in platelet membrane biogenesis and thrombus formation. Thus, rs342293 is the functional common variant at this locus; to the best of our knowledge this is the first such variant to be elucidated among the known platelet quantitative trait loci (QTLs). Our data suggested a molecular mechanism by which a non-coding GWA index SNP modulates platelet phenotype

Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities.

OBJECTIVES: The majority of people with suspected genetic dystonia remain undiagnosed after maximal investigation, implying that a number of causative genes have not yet been recognized. We aimed to investigate this paucity of diagnoses. METHODS: We undertook weighted burden analysis of whole-exome sequencing (WES) data from 138 individuals with unresolved generalized dystonia of suspected genetic etiology, followed by additional case-finding from international databases, first for the gene implicated by the burden analysis (VPS16), and then for other functionally related genes. Electron microscopy was performed on patient-derived cells. RESULTS: Analysis revealed a significant burden for VPS16 (Fisher's exact test p value, 6.9 × 109 ). VPS16 encodes a subunit of the homotypic fusion and vacuole protein sorting (HOPS) complex, which plays a key role in autophagosome-lysosome fusion. A total of 18 individuals harboring heterozygous loss-of-function VPS16 variants, and one with a microdeletion, were identified. These individuals experienced early onset progressive dystonia with predominant cervical, bulbar, orofacial, and upper limb involvement. Some patients had a more complex phenotype with additional neuropsychiatric and/or developmental comorbidities. We also identified biallelic loss-of-function variants in VPS41, another HOPS-complex encoding gene, in an individual with infantile-onset generalized dystonia. Electron microscopy of patient-derived lymphocytes and fibroblasts from both patients with VPS16 and VPS41 showed vacuolar abnormalities suggestive of impaired lysosomal function. INTERPRETATION: Our study strongly supports a role for HOPS complex dysfunction in the pathogenesis of dystonia, although variants in different subunits display different phenotypic and inheritance characteristics. ANN NEUROL 2020;88:867-877

A comparison of multidisciplinary team residential rehabilitation with conventional outpatient care for the treatment of non-arthritic intra-articular hip pain in UK Military personnel:a protocol for a randomised controlled trial

BACKGROUND: Non-arthritic hip disorders are defined as abnormalities of the articulating surfaces of the acetabulum and femur before the onset of osteoarthritis, including intra-articular structures such as the acetabular labrum and chondral surfaces. Abnormal femoroacetabular morphology is commonly seen in young men who constitute much of the UK military population. Residential multidisciplinary team (MDT) rehabilitation for patients with musculoskeletal injuries has a long tradition in the UK military, however, there are no studies presenting empirical data on the efficacy of a residential MDT approach compared with individualised conventional outpatient treatment. With no available data, the sustainability of this care pathway has been questioned. The purpose of this randomised controlled trial is to compare the effects of a residential multidisciplinary intervention, to usual outpatient care, on the clinical outcomes of young active adults undergoing treatment for non-arthritic intra-articular hip pain. METHODS/DESIGN: The trial will be conducted at the Defence Medical Rehabilitation Centre, Headley Court, UK. One hundred military male participants with clinical indicators of non-arthritic intra-articular hip pain will be randomly allocated to either: (1) 7-day residential multidisciplinary team intervention, n = 50; (2) 6-week physiotherapist-led outpatient intervention (conventional care), n = 50. Measurements will be taken at baseline, post-treatment (1-week MDT group; 6-weeks physiotherapy group), and 12-weeks. The primary outcome measures are the function in daily living sub-scale of the Copenhagen Hip and Groin Outcome Score (HAGOS), the physical function subscale of the Non-arthritic Hip Score (NAHS), and VAS pain scale. Secondary outcomes include objective measures of physical capacity and general health. An intention-to-treat analysis will be performed using linear and mixed models. DISCUSSION: This study will be the first to assess the efficacy of intensive MDT rehabilitation, versus conventional outpatient care, for the management of non-arthritic hip pain. The results from this study will add to the evidence-base and inform clinical practice for the management of intra-articular non-arthritic hip pain and femoroacetabular impingement in young active adults. TRIAL REGISTRATION: ISRCTN Reference: ISRCTN 59255714 dated 11-Nov-2015 ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12891-016-1309-z) contains supplementary material, which is available to authorized users