Genome sequencing in persistently unsolved white matter disorders

Genetic white matter disorders have heterogeneous etiologies and overlapping clinical presentations. We performed a study of the diagnostic efficacy of genome sequencing in 41 unsolved cases with prior exome sequencing, resolving an additional 14 from an historical cohort (n = 191). Reanalysis in the context of novel disease-associated genes and improved variant curation and annotation resolved 64% of cases. The remaining diagnoses were directly attributable to genome sequencing, including cases with small and large copy number variants (CNVs) and variants in deep intronic and technically difficult regions. Genome sequencing, in combination with other methodologies, achieved a diagnostic yield of 85% in this retrospective cohort.Guy Helman, Bryan R. Lajoie, Joanna Crawford, Asako Takanohashi, Marzena Walkiewicz ... Stephen J. Bent ... et al

Assessing the relative importance of parameter and forcing uncertainty and their interactions in conceptual hydrological model simulations

Predictions of river flow dynamics provide vital information for many aspects of water management including water resource planning, climate adaptation, and flood and drought assessments. Many of the subjective choices that modellers make including model and criteria selection can have a significant impact on the magnitude and distribution of the output uncertainty. Hydrological modellers are tasked with understanding and minimising the uncertainty surrounding streamflow predictions before communicating the overall uncertainty to decision makers. Parameter uncertainty in conceptual rainfall-runoff models has been widely investigated, and model structural uncertainty and forcing data have been receiving increasing attention. This study aimed to assess uncertainties in streamflow predictions due to forcing data and the identification of behavioural parameter sets in 31 Irish catchments. By combining stochastic rainfall ensembles and multiple parameter sets for three conceptual rainfall-runoff models, an analysis of variance model was used to decompose the total uncertainty in streamflow simulations into contributions from (i) forcing data, (ii) identification of model parameters and (iii) interactions between the two. The analysis illustrates that, for our subjective choices, hydrological model selection had a greater contribution to overall uncertainty, while performance criteria selection influenced the relative intra-annual uncertainties in streamflow predictions. Uncertainties in streamflow predictions due to the method of determining parameters were relatively lower for wetter catchments, and more evenly distributed throughout the year when the Nash-Sutcliffe Efficiency of logarithmic values of flow (lnNSE) was the evaluation criterion

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Global Retinoblastoma Presentation and Analysis by National Income Level

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4) were female. Most patients (n = 3685 84.7%) were from low-and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 62.8%), followed by strabismus (n = 429 10.2%) and proptosis (n = 309 7.4%). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 95% CI, 12.94-24.80, and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 95% CI, 4.30-7.68). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs. © 2020 American Medical Association. All rights reserved

Validation of the Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) scale in the portuguese language Validação da escala ALSAQ-40 em pacientes com esclerose lateral amiotrófica para a língua portuguesa

The amyotrophic lateral sclerosis (ALS) is a degenerative neurological disorder that has a great impact in the quality of life of the patients. This study had the objective of validating the ALS Assessment Questionnaire in the Portuguese Language (ALSAQ-40/BR). The version of ALSAQ-40/BR, was adapted into the Portuguese language after the evaluation and re-evaluation of 20 patients with a defined ALS diagnosis. The demonstration of its reproducibility and reliability makes this instrument an additional and useful parameter which can be used in the evaluation of ALS for research or assistance.<br>Esclerose lateral amiotrófica, doença neurológica degenerativa, apresenta grande impacto na qualidade de vida dos pacientes. Este estudo teve como objetivo realizar a adaptação transcultural e validação da escala Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) nestes pacientes. Foi aplicada em 20 pacientes com reteste após 30 dias. A tradução para o português e sua adequação às condições socioeconômicas e culturais da nossa população, bem como a demonstração de sua reprodutibilidade e validade, tornam este instrumento um parâmetro adicional útil que pode ser utilizado na avaliação da ELA seja em nível de pesquisa ou assistencial

The Short Form 36 and older people:some problems encountered when using postal administration

OBJECTIVE: To explore some of the problems encountered in the postal administration of the Short-Form 36 (SF-36). Questions that seem to present particular difficulties for the group are identified. In addition some of the written comments from the questionnaires and people's responses to questions on how difficult they found the SF-36 are discussed. DESIGN: The study group were asked to complete a health questionnaire containing the SF-36 on three separate occasions (at zero, three, and six months). The first and final questionnaires were interviewer administered during a face to face interview. A shorter questionnaire containing only the SF-36 and another health status measure was sent by post to each patient in the interim. PARTICIPANTS: People aged 65 years or above who were new referrals to community based occupational therapy or physiotherapy services in three areas in north west England. MAIN RESULTS: Response and completion rates for the postal questionnaire were lower than expected, even though all the patients had already had a face to face interview and had therefore completed the SF-36 once. Only 34 of 56 respondents (60.7%) completed all the items on the SF-36. CONCLUSIONS: All those planning to use the SF-36 (and similar measures) with older populations should be sensitive to the problems of postal administration. Non-return of questionnaires, high levels of missing data on those that are received, and ambiguities in response may mean that other measures, or perhaps alternative research methods, are more appropriate

Explaining the Short- and Long-Term IPO Anomalies in the US by R&D

Financial scholars who research the initial underpricing and long-term underperformance of IPOs generally attribute these phenomena to information asymmetry and investors' misevaluations. Here, we identify, on a sample of 2,696 US IPOs issued during 1980-1995, a widespread source of information asymmetry and valuation uncertainty-the R&D activities of issuers-and document that these activities significantly affect both the initial underpricing of IPOs (R&D is positively correlated with underpricing) and their long-term performance (R&D is positively related to long-term performance). Given the pervasiveness and constant growth of firms' R&D activities in modern economies, our identification of R&D as a major factor affecting IPO's performance contributes to the understanding of this important economic and capital market phenomenon. Copyright Blackwell Publishers Ltd, 2006.