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

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Precision Measurement of the Bs−B‾s0B_s-\kern0.18em\overline{\kern -0.18em B}{}^0_s Oscillation Frequency Δms\Delta m_s with Bs→Ds−π+B_s\to D_s^-\pi^+ Decays at LHCb

Decays of $B^0_s \to D_s^- \pi^+$ allow to determine the oscillation frequency $\Delta m_s$ between the $B^0_s$ particle and $\kern0.18em\overline{\kern -0.18em B}{}^0_s$ antiparticle states with high precision. It is a crucial input to constrain the CKM matrix and a manifestation of the quantum nature of physics. A new measurement of this frequency is presented, using a dataset corresponding to $6\,\mathrm{fb}^{-1}$ of $pp$ collisions, recorded by LHCb at a centre-of-mass energy of $13\,\mathrm{TeV}$. The oscillation frequency is determined to be $\Delta m_s = 17.7683\pm0.0051(\mathrm{stat.})\pm0.0032(\mathrm{syst.})\,\mathrm{ps}^{-1}$ and a combination with previous LHCb measurements yields $\Delta m_s^\mathrm{LHCb} = 17.7656\pm0.0057\,\mathrm{ps}^{-1}$.Decays of $B^0_s \to D_s^- \pi^+$ allow to determine the oscillation frequency $\Delta m_s$ between the $B^0_s$ particle and $\kern0.18em\overline{\kern -0.18em B}{}^0_s$ antiparticle states with high precision. It is a crucial input to constrain the CKM matrix and a manifestation of the quantum nature of physics. A new measurement of this frequency is presented, using a dataset corresponding to $6\,\mathrm{fb}^{-1}$ of $pp$ collisions, recorded by LHCb at a centre-of-mass energy of $13\,\mathrm{TeV}$. The oscillation frequency is determined to be $\Delta m_s = 17.7683\pm0.0051(\mathrm{stat.})\pm0.0032(\mathrm{syst.})\,\mathrm{ps}^{-1}$ and a combination with previous LHCb measurements yields $\Delta m_s^\mathrm{LHCb} = 17.7656\pm0.0057\,\mathrm{ps}^{-1}$

Studies of Top-Quark-Pair Kinematic Reconstructions in the Dilepton-channel

This project aims to improve the understanding of the neutrino-weighting method for reconstruction of dilepton-events at the ATLAS experiment by implementing such a method and testing it with events produced in leading order of the strong coupling using a QCD calculation based on SHERPA monte carlo

Optimization of Flavour Tagging Algorithms for the LHCb Experiment

Studies of $C\!P$ violation can be used to test the Standard Model and might give insight into New Physics. Therefore, a wide range of $C\!P$ measurements, including time-dependent decay rate measurements, are performed with the LHCb Experiment. Many of these are subject to mixing of neutral $B$ meson states with their antiparticles. The knowledge of the initial $B$ flavour is essential in these cases which is why several Flavour Tagging algorithms are used to deduce this information from the available event properties. These algorithms must be adjusted to changes in the shape of the event properties, resulting from an upgrade of the LHC centre-of-mass energy to $\sqrt{s} = 13\,\mathrm{TeV}$. To simplify this process, the Flavour Tagging software is re-implemented. The tagging power of the muon, electron and kaon tagger is measured based on $B^+ \to J\!/\!\psi K^+$ data, which is processed within the new framework. It is found to be $(0.782 ± 0.018)\%$, $(0.243 ± 0.011)\%$ and $(0.649 ± 0.020)\%$ for Run 1 data, respectively, and $(0.67 ± 0.05)\%$, $(0.134 ± 0.019)\%$ and $(0.54 ± 0.04)\%$ for Run 2 data. Furthermore a new inclusive strategy for the muon tagger is implemented that improves its tagging power to $\varepsilon_\text{eff} = (1.09 ± 0.04)\%$ on Run 1 data and $\varepsilon_\text{eff} = (0.83 ± 0.06)\%$ on Run 2 data