Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

High-Entropy Perovskite Thin Film in the Gd-Nd-Sm-La-Y-Co System: Deposition, Structure and Optoelectronic Properties

Multicomponent equimolar perovskite oxides (ME-POs) have recently emerged as a highly promising class of materials with unique synergistic effects, making them well-suited for applications in such areas as photovoltaics and micro- and nanoelectronics. High-entropy perovskite oxide thin film in the (Gd0.2Nd0.2La0.2Sm0.2Y0.2)CoO3 (RECO, where RE = Gd0.2Nd0.2La0.2Sm0.2Y0.2, C = Co, and O = O3) system was synthesized via pulsed laser deposition. The crystalline growth in an amorphous fused quartz substrate and single-phase composition of the synthesized film was confirmed by X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). Surface conductivity and activation energy were determined using a novel technique implementing atomic force microscopy (AFM) in combination with current mapping. The optoelectronic properties of the deposited RECO thin film were characterized using UV/VIS spectroscopy. The energy gap and nature of optical transitions were calculated using the Inverse Logarithmic Derivative (ILD) and four-point resistance method, suggesting direct allowed transitions with altered dispersions. The narrow energy gap of RECO, along with its relatively high absorption properties in the visible spectrum, positions it as a promising candidate for further exploration in the domains of low-energy infrared optics and electrocatalysis

How dry is dry? Molecular mobility in relation to thallus water content in a lichen

The increasing demand for nanoscale magnetic devices requires development of 3D magnetic nanostructures. In this regard, focused electron beam induced deposition (FEBID) is a technique of choice for direct-writing of complex nano-architectures with applications in nanomagnetism, magnon spintronics, and superconducting electronics. However, intrinsic properties of nanomagnets are often poorly known and can hardly be assessed by local optical probe techniques. Here, an original spatially resolved approach is demonstrated for spin-wave spectroscopy of individual circular magnetic elements with sample volumes down to about 10(-3) mu m(3). The key component of the setup is a coplanar waveguide whose microsized central part is placed over a movable substrate with well-separated CoFe-FEBID nanodisks which exhibit standing spin-wave resonances. The circular symmetry of the disks allows for the deduction of the saturation magnetization and the exchange stiffness of the material using an analytical theory. A good correspondence between the results of analytical calculations and micromagnetic simulations is revealed, indicating a validity of the used analytical model going beyond the initial thin-disk approximation used in the theoretical derivation. The presented approach is especially valuable for the characterization of direct-write magnetic elements opening new horizons for 3D nanomagnetism and magnonics.This work was supported by the European Commission in the framework of the Horizon 2020 Marie Sklodowska-Curie program-Research and Innovation Staff Exchange (MSCA-RISE) under grant agreement no. 644348 (MagIC). Further, support by the European Cooperation in Science and Technology via COST Action CA16218 (NANOCOHYBRI) is acknowledged. The Austrian team acknowledges support by the Austrian Science Fund (FWF) under grant no. I 4889 (CurviMag). The Portuguese team acknowledges the Network of Extreme Conditions Laboratories-NECL and Portuguese Foundation of Science and Technology (FCT) support through project no. NORTE-01-0145-FEDER-022096, POCI-0145-FEDER-030085 (NOVAMAG), and EXPL/IF/00541/2015. D. N. acknowledges the Spanish Ministry for Science, Innovation and Universities, for funding through the "Ramon y Cajal" program RYC-2017-22820. A. V. C. acknowledges support within the ERC Starting grant no. 678309 MagnonCircuits. M. K. and P. G. acknowledge support of National Science Center Poland under the project UMO-2018/30/Q/ST3/00416. K. Y. G. acknowledges support by IKERBASQUE (the Basque Foundation for Science) and by the Spanish Ministry of Economy and Competitiveness under the project FIS2016-78591-C3-3-R. Support through the Frankfurt Center of Electron Microscopy (FCEM) is gratefully acknowledged. Open access funding has been provided by the University of Vienn

The impact of frailty on ICU and 30-day mortality and the level of care in very elderly patients (≥ 80 years)

Purpose: Very old critical ill patients are a rapid expanding group in the ICU. Indications for admission, triage criteria and level of care are frequently discussed for such patients. However, most relevant outcome studies in this group frequently find an increased mortality and a reduced quality of life in survivors. The main objective was to study the impact of frailty compared with other variables with regards to short-term outcome in the very old ICU population. Methods: A transnational prospective cohort study from October 2016 to May 2017 with 30 days follow-up was set up by the European Society of Intensive Care Medicine. In total 311 ICUs from 21 European countries participated. The ICUs included the first consecutive 20 very old (≥ 80 years) patients admitted to the ICU within a 3-month inclusion period. Frailty, SOFA score and therapeutic procedures were registered, in addition to limitations of care. For measurement of frailty the Clinical Frailty Scale was used at ICU admission. The main outcomes were ICU and 30-day mortality and survival at 30 days. Results: A total of 5021 patients with a median age of 84 years (IQR 81–86 years) were included in the final analysis, 2404 (47.9%) were women. Admission was classified as acute in 4215 (83.9%) of the patients. Overall ICU and 30-day mortality rates were 22.1% and 32.6%. During ICU stay 23.8% of the patients did not receive specific ICU procedures: ventilation, vasoactive drugs or renal replacement therapy. Frailty (values ≥ 5) was found in 43.1% and was independently related to 30-day survival (HR 1.54; 95% CI 1.38–1.73) for frail versus non-frail. Conclusions: Among very old patients (≥ 80 years) admitted to the ICU, the consecutive classes in Clinical Frailty Scale were inversely associated with short-term survival. The scale had a very low number of missing data. These findings provide support to add frailty to the clinical assessment in this patient group. Trial registration: ClinicalTrials.gov (ID: NCT03134807)

The impact of frailty on ICU and 30-day mortality and the level of care in very elderly patients (≥ 80 years)

Purpose: Very old critical ill patients are a rapid expanding group in the ICU. Indications for admission, triage criteria and level of care are frequently discussed for such patients. However, most relevant outcome studies in this group frequently find an increased mortality and a reduced quality of life in survivors. The main objective was to study the impact of frailty compared with other variables with regards to short-term outcome in the very old ICU population. Methods: A transnational prospective cohort study from October 2016 to May 2017 with 30 days follow-up was set up by the European Society of Intensive Care Medicine. In total 311 ICUs from 21 European countries participated. The ICUs included the first consecutive 20 very old (≥ 80 years) patients admitted to the ICU within a 3-month inclusion period. Frailty, SOFA score and therapeutic procedures were registered, in addition to limitations of care. For measurement of frailty the Clinical Frailty Scale was used at ICU admission. The main outcomes were ICU and 30-day mortality and survival at 30 days. Results: A total of 5021 patients with a median age of 84 years (IQR 81–86 years) were included in the final analysis, 2404 (47.9%) were women. Admission was classified as acute in 4215 (83.9%) of the patients. Overall ICU and 30-day mortality rates were 22.1% and 32.6%. During ICU stay 23.8% of the patients did not receive specific ICU procedures: ventilation, vasoactive drugs or renal replacement therapy. Frailty (values ≥ 5) was found in 43.1% and was independently related to 30-day survival (HR 1.54; 95% CI 1.38–1.73) for frail versus non-frail. Conclusions: Among very old patients (≥ 80 years) admitted to the ICU, the consecutive classes in Clinical Frailty Scale were inversely associated with short-term survival. The scale had a very low number of missing data. These findings provide support to add frailty to the clinical assessment in this patient group. Trial registration: ClinicalTrials.gov (ID: NCT03134807)