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

Randomized Clinical Trial of Activated Protein C for the Treatment of Acute Lung Injury

Rationale: Microvascular injury, inflammation, and coagulation play critical roles in the pathogenesis of acute lung injury (ALI). Plasma protein C levels are decreased in patients with acute lung injury and are associated with higher mortality and fewer ventilator-free days

Safety Assessment of a Noninvasive Respiratory Protocol for Adults with COVID-19

As evidence emerged supporting noninvasive strategies for coronavirus disease 2019 (COVID-19)-related respiratory distress, we implemented a noninvasive COVID-19 respiratory protocol (NCRP) that encouraged high-flow nasal cannula (HFNC) and self-proning across our healthcare system. To assess safety, we conducted a retrospective chart review evaluating mortality and other patient safety outcomes after implementation of the NCRP protocol (April 3, 2020, to April 15, 2020) for adult patients hospitalized with COVID-19, compared with preimplementation outcomes (March 15, 2020, to April 2, 2020). During the study, there were 469 COVID-19 admissions. Fewer patients underwent intubation after implementation (10.7% [23 of 215]), compared with before implementation (25.2% [64 of 254]) (P \u3c .01). Overall, 26.2% of patients died (24% before implementation vs 28.8% after implementation; P = .14). In patients without a do not resuscitate/do not intubate order prior to admission, mortality was 21.8% before implementation vs 21.9% after implementation. Overall, we found no significant increase in mortality following implementation of a noninvasive respiratory protocol that decreased intubations in patients with COVID-19

Character and temporal evolution of apoptosis in acetaminophen-induced acute liver failure

OBJECTIVE: To evaluate the role of hepatocellular and extrahepatic apoptosis during the evolution of Acetaminophen-induced acute liver failure (AALF). DESIGN & SETTING: A prospective observational study in two tertiary liver transplant units. PATIENTS: 88 patients with AALF were recruited. Control groups included patients with non-AALF (n=13), non-hepatic multi-organ failure (MOF, n=28), chronic liver disease (CLD, n=19) and healthy controls (HC, n=11). MEASUREMENTS: Total and caspase-cleaved cytokeratin 18 (M65 and M30 measured on admission and sequentially on day 3, 7 and 10 following admission. Levels were also determined from hepatic, portal vein and systemic arterial blood in seven patients undergoing transplantation. Protein arrays of liver homogenates from AALF patients were assessed for apoptosis-associated proteins and histological assessment of liver tissue was performed. MAIN RESULTS: Admission M30 levels were significantly elevated in AALF and NALF patients compared to MOF, CLD and healthy controls. Admission M30 levels correlated with outcome with AUROC of 0.755 (0.639-0.885, p<0.001). Peak levels in ALF patients were seen on admission then fell significantly but did not normalize over ten days. A negative gradient of M30 from the portal to hepatic vein was demonstrated in AALF patients (p=0.042) at the time of liver transplant. Analysis of protein array data demonstrated lower apoptosis-associated protein and higher catalase concentrations in AALF liver compared to controls (p<0.05). Explant histological analysis revealed evidence of cellular proliferation with an absence of histological evidence of apoptosis. CONCLUSIONS: Hepatocellular apoptosis occurs in the early phases of human AALF, peaking on day 1 of hospital admission and correlates strongly with poor outcome. Hepatic regenerative/tissue repair responses prevail during the later stages of ALF where elevated levels of M30 are likely to reflect epithelial cell death in extra-hepatic organs

A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome.

BackgroundRenin-angiotensin system (RAS) signaling and angiotensin-converting enzyme 2 (ACE2) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). We postulated that repleting ACE2 using GSK2586881, a recombinant form of human angiotensin-converting enzyme 2 (rhACE2), could attenuate acute lung injury.MethodsWe conducted a two-part phase II trial comprising an open-label intrapatient dose escalation and a randomized, double-blind, placebo-controlled phase in ten intensive care units in North America. Patients were between the ages of 18 and 80&nbsp;years, had an American-European Consensus Criteria consensus diagnosis of ARDS, and had been mechanically ventilated for less than 72&nbsp;h. In part A, open-label GSK2586881 was administered at doses from 0.1&nbsp;mg/kg to 0.8&nbsp;mg/kg to assess safety, pharmacokinetics, and pharmacodynamics. Following review of data from part A, a randomized, double-blind, placebo-controlled investigation of twice-daily doses of GSK2586881 (0.4&nbsp;mg/kg) for 3&nbsp;days was conducted (part B). Biomarkers, physiological assessments, and clinical endpoints were collected over the dosing period and during follow-up.ResultsDose escalation in part A was well-tolerated without clinically significant hemodynamic changes. Part B was terminated after 39 of the planned 60 patients following a planned futility analysis. Angiotensin II levels decreased rapidly following infusion of GSK2586881, whereas angiotensin-(1-7) and angiotensin-(1-5) levels increased and remained elevated for 48&nbsp;h. Surfactant protein D concentrations were increased, whereas there was a trend for a decrease in interleukin-6 concentrations in rhACE2-treated subjects compared with placebo. No significant differences were noted in ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, oxygenation index, or Sequential Organ Failure Assessment score.ConclusionsGSK2586881 was well-tolerated in patients with ARDS, and the rapid modulation of RAS peptides suggests target engagement, although the study was not powered to detect changes in acute physiology or clinical outcomes.Trial registrationClinicalTrials.gov, NCT01597635 . Registered on 26 January 2012

Nonlinear Imputation of PaO2/FIO2 From SpO2/FIO2 Among Mechanically Ventilated Patients in the ICU: A Prospective, Observational Study.

OBJECTIVES: In the contemporary ICU, mechanically ventilated patients may not have arterial blood gas measurements available at relevant timepoints. Severity criteria often depend on arterial blood gas results. Retrospective studies suggest that nonlinear imputation of PaO2/FIO2 from SpO2/FIO2 is accurate, but this has not been established prospectively among mechanically ventilated ICU patients. The objective was to validate the superiority of nonlinear imputation of PaO2/FIO2 among mechanically ventilated patients and understand what factors influence the accuracy of imputation. DESIGN: Simultaneous SpO2, oximeter characteristics, receipt of vasopressors, and skin pigmentation were recorded at the time of a clinical arterial blood gas. Acute respiratory distress syndrome criteria were recorded. For each imputation method, we calculated both imputation error and the area under the curve for patients meeting criteria for acute respiratory distress syndrome (PaO2/FIO2 ≤ 300) and moderate-severe acute respiratory distress syndrome (PaO2/FIO2 ≤ 150). SETTING: Nine hospitals within the Prevention and Early Treatment of Acute Lung Injury network. PATIENTS: We prospectively enrolled 703 mechanically ventilated patients admitted to the emergency departments or ICUs of participating study hospitals. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We studied 1,034 arterial blood gases from 703 patients; 650 arterial blood gases were associated with SpO2 less than or equal to 96%. Nonlinear imputation had consistently lower error than other techniques. Among all patients, nonlinear had a lower error (p \u3c 0.001) and higher (p \u3c 0.001) area under the curve (0.87; 95% CI, 0.85-0.90) for PaO2/FIO2 less than or equal to 300 than linear/log-linear (0.80; 95% CI, 0.76-0.83) imputation. All imputation methods better identified moderate-severe acute respiratory distress syndrome (PaO2/FIO2 ≤ 150); nonlinear imputation remained superior (p \u3c 0.001). For PaO2/FIO2 less than or equal to 150, the sensitivity and specificity for nonlinear imputation were 0.87 (95% CI, 0.83-0.90) and 0.91 (95% CI, 0.88-0.93), respectively. Skin pigmentation and receipt of vasopressors were not associated with imputation accuracy. CONCLUSIONS: In mechanically ventilated patients, nonlinear imputation of PaO2/FIO2 from SpO2/FIO2 seems accurate, especially for moderate-severe hypoxemia. Linear and log-linear imputations cannot be recommended

Bayesian methods: a potential path forward for sepsis trials

BACKGROUND: Given the success of recent platform trials for COVID-19, Bayesian statistical methods have become an option for complex, heterogenous syndromes like sepsis. However, study design will require careful consideration of how statistical power varies using Bayesian methods across different choices for how historical data are incorporated through a prior distribution and how the analysis is ultimately conducted. Our objective with the current analysis is to assess how different uses of historical data through a prior distribution, and type of analysis influence results of a proposed trial that will be analyzed using Bayesian statistical methods. METHODS: We conducted a simulation study incorporating historical data from a published multicenter, randomized clinical trial in the US and Canada of polymyxin B hemadsorption for treatment of endotoxemic septic shock. Historical data come from a 179-patient subgroup of the previous trial of adult critically ill patients with septic shock, multiple organ failure and an endotoxin activity of 0.60-0.89. The trial intervention consisted of two polymyxin B hemoadsorption treatments (2 h each) completed within 24 h of enrollment. RESULTS: In our simulations for a new trial of 150 patients, a range of hypothetical results were observed. Across a range of baseline risks and treatment effects and four ways of including historical data, we demonstrate an increase in power with the use of clinically defensible incorporation of historical data. In one possible trial result, for example, with an observed reduction in risk of mortality from 44 to 37%, the probability of benefit is 96% with a fixed weight of 75% on prior data and 90% with a commensurate (adaptive-weighting) prior; the same data give an 80% probability of benefit if historical data are ignored. CONCLUSIONS: Using Bayesian methods and a biologically justifiable use of historical data in a prior distribution yields a study design with higher power than a conventional design that ignores relevant historical data. Bayesian methods may be a viable option for trials in critical care medicine where beneficial treatments have been elusive

A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome

Background: Renin-angiotensin system (RAS) signaling and angiotensin-converting enzyme 2 (ACE2) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). We postulated that repleting ACE2 using GSK2586881, a recombinant form of human angiotensin-converting enzyme 2 (rhACE2), could attenuate acute lung injury. Methods: We conducted a two-part phase II trial comprising an open-label intrapatient dose escalation and a randomized, double-blind, placebo-controlled phase in ten intensive care units in North America. Patients were between the ages of 18 and 80 years, had an American-European Consensus Criteria consensus diagnosis of ARDS, and had been mechanically ventilated for less than 72 h. In part A, open-label GSK2586881 was administered at doses from 0.1 mg/kg to 0.8 mg/kg to assess safety, pharmacokinetics, and pharmacodynamics. Following review of data from part A, a randomized, double-blind, placebo-controlled investigation of twice-daily doses of GSK2586881 (0.4 mg/kg) for 3 days was conducted (part B). Biomarkers, physiological assessments, and clinical endpoints were collected over the dosing period and during follow-up. Results: Dose escalation in part A was well-tolerated without clinically significant hemodynamic changes. Part B was terminated after 39 of the planned 60 patients following a planned futility analysis. Angiotensin II levels decreased rapidly following infusion of GSK2586881, whereas angiotensin-(1–7) and angiotensin-(1–5) levels increased and remained elevated for 48 h. Surfactant protein D concentrations were increased, whereas there was a trend for a decrease in interleukin-6 concentrations in rhACE2-treated subjects compared with placebo. No significant differences were noted in ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, oxygenation index, or Sequential Organ Failure Assessment score. Conclusions: GSK2586881 was well-tolerated in patients with ARDS, and the rapid modulation of RAS peptides suggests target engagement, although the study was not powered to detect changes in acute physiology or clinical outcomes. Trial registration ClinicalTrials.gov, NCT01597635 . Registered on 26 January 2012.Other UBCNon UBCReviewedFacult

A randomised trial of anti-GM-CSF otilimab in severe COVID-19 pneumonia (OSCAR).

BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) and dysregulated myeloid cell responses are implicated in the pathophysiology and severity of COVID-19. METHODS: In this randomised, sequential, multicentre, placebo-controlled, double-blind study, adults aged 18-79 years (Part 1) or ≥70 years (Part 2) with severe COVID-19, respiratory failure and systemic inflammation (elevated C-reactive protein/ferritin) received a single intravenous infusion of otilimab 90 mg (human anti-GM-CSF monoclonal antibody) plus standard care (NCT04376684). The primary outcome was the proportion of patients alive and free of respiratory failure at Day 28. RESULTS: In Part 1 (n=806 randomised 1:1 otilimab:placebo), 71% of otilimab-treated patients were alive and free of respiratory failure at Day 28 versus 67% who received placebo; the model-adjusted difference of 5.3% was not statistically significant (95% CI -0.8-11.4%, p=0.09). A nominally significant model-adjusted difference of 19.1% (95% CI 5.2-33.1%, p=0.009) was observed in the predefined 70-79 years subgroup, but this was not confirmed in Part 2 (n=350 randomised) where the model-adjusted difference was 0.9% (95% CI -9.3-11.2%, p=0.86). Compared with placebo, otilimab resulted in lower serum concentrations of key inflammatory markers, including the putative pharmacodynamic biomarker CC chemokine ligand 17, indicative of GM-CSF pathway blockade. Adverse events were comparable between groups and consistent with severe COVID-19. CONCLUSIONS: There was no significant difference in the proportion of patients alive and free of respiratory failure at Day 28. However, despite the lack of clinical benefit, a reduction in inflammatory markers was observed with otilimab, in addition to an acceptable safety profile