The experience of falls and balance impairment for people with Charcot-Marie-Tooth disease

People with Charcot Marie Tooth disease (CMT) have impairments of balance and may fall more frequently than those without the condition. This qualitative study aimed to explore the experiences of falling and poor balance through focus group interviews. Participants were recruited through local and national meetings of the CMT United Kingdom support group. Three focus groups took place, including 25 adults with CMT in total. Thematic analysis revealed five main themes: frequent falling; cognitive burden of walking; environmental issues; external support; getting off the floor; perception of others. Participants described the physical issues of poor balance and falling, such as frequency, challenging physical environments and difficulty getting up after a fall. In addition, fear and embarrassment were discussed along with the impact on daily activities and participation. Physical and psychological factors need to be considered when designing falls management interventions for this group

Effects of superficial heating and insulation on walking speed in people with hereditary and spontaneous spastic paraparesis: A randomised crossover study.

OBJECTIVES: Cooling of the lower limb in people with Hereditary and Spontaneous Spastic Paraparesis (pwHSSP) has been shown to affect walking speed and neuromuscular impairments. The investigation of practical strategies, which may help to alleviate these problems is important. The potential of superficial heat to improve walking speed has not been explored in pwHSSP. Primary objective was to explore whether the application of superficial heat (hot packs) to lower limbs in pwHSSP improves walking speed. Secondary objective was to explore whether wearing insulation after heating would prolong any benefits. METHODS: A randomised crossover study design with 21 pwHSSP. On two separate occasions two hot packs and an insulating wrap (Neo-G™) were applied for 30minutes to the lower limbs of pwHSSP. On one occasion the insulating wrap was maintained for a further 30minutes and on the other occasion it was removed. Measures of temperature (skin, room and core), walking speed (10 metre timed walk) and co-ordination (foot tap time) were taken at baseline (T1), after 30 mins (T2) and at one hour (T3). RESULTS: All 21 pwHSSP reported increased lower limb stiffness and decreased walking ability when their legs were cold. After thirty minutes of heating, improvements were seen in walking speed (12.2%, P0.001) in both conditions. CONCLUSIONS: Application of 30minutes superficial heating moderately improved walking speed in pwHSSP with effects maintained at 1hour. The use of hot packs applied to lower limbs should be the focus of further research for the clinical management of pwHSSP who report increased stiffness of limbs in cold weather and do not have sensory deficits

An observational study to assess validity and reliability of smartphone sensor-based gait and balance assessments in multiple sclerosis: Floodlight GaitLab protocol

Background Gait and balance impairments are often present in people with multiple sclerosis (PwMS) and have a significant impact on quality of life and independence. Gold-standard quantitative tools for assessing gait and balance such as motion capture systems and force plates usually require complex technical setups. Wearable sensors, including those integrated into smartphones, offer a more frequent, convenient, and minimally burdensome assessment of functional disability in a home environment. We developed a novel smartphone sensor-based application (Floodlight) that is being used in multiple research and clinical contexts, but a complete validation of this technology is still lacking. Methods This protocol describes an observational study designed to evaluate the analytical and clinical validity of Floodlight gait and balance tests. Approximately 100 PwMS and 35 healthy controls will perform multiple gait and balance tasks in both laboratory-based and real-world environments in order to explore the following properties: (a) concurrent validity of the Floodlight gait and balance tests against gold-standard assessments; (b) reliability of Floodlight digital measures derived under different controlled gait and balance conditions, and different on-body sensor locations; (c) ecological validity of the tests; and (d) construct validity compared with clinician- and patient-reported assessments. Conclusions The Floodlight GaitLab study (ISRCTN15993728) represents a critical step in the technical validation of Floodlight technology to measure gait and balance in PwMS, and will also allow the development of new test designs and algorithms

Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets

Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations. Through the temporal dissection of aberrations, we identified driver mutations specifically associated with steps in the progression of prostate cancer, establishing, for example, loss of CHD1 and BRCA2 as early events in cancer development of ETS fusion-negative cancers. Computational chemogenomic (canSAR) analysis of prostate cancer mutations identified 11 targets of approved drugs, 7 targets of investigational drugs, and 62 targets of compounds that may be active and should be considered candidates for future clinical trials

Measurement of the W-boson mass in pp collisions at √s=7 TeV with the ATLAS detector

A measurement of the mass of the W boson is presented based on proton–proton collision data recorded in 2011 at a centre-of-mass energy of 7 TeV with the ATLAS detector at the LHC, and corresponding to 4.6 fb−1 of integrated luminosity. The selected data sample consists of 7.8×106 candidates in the W→μν channel and 5.9×106 candidates in the W→eν channel. The W-boson mass is obtained from template fits to the reconstructed distributions of the charged lepton transverse momentum and of the W boson transverse mass in the electron and muon decay channels, yielding mW=80370±7 (stat.)±11(exp. syst.) ±14(mod. syst.) MeV =80370±19MeV, where the first uncertainty is statistical, the second corresponds to the experimental systematic uncertainty, and the third to the physics-modelling systematic uncertainty. A measurement of the mass difference between the W+ and W−bosons yields mW+−mW−=−29±28 MeV

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead