Antipsychotics and Torsadogenic Risk: Signals Emerging from the US FDA Adverse Event Reporting System Database

Background: Drug-induced torsades de pointes (TdP) and related clinical entities represent a current regulatory and clinical burden. Objective: As part of the FP7 ARITMO (Arrhythmogenic Potential of Drugs) project, we explored the publicly available US FDA Adverse Event Reporting System (FAERS) database to detect signals of torsadogenicity for antipsychotics (APs). Methods: Four groups of events in decreasing order of drug-attributable risk were identified: (1) TdP, (2) QT-interval abnormalities, (3) ventricular fibrillation/tachycardia, and (4) sudden cardiac death. The reporting odds ratio (ROR) with 95 % confidence interval (CI) was calculated through a cumulative analysis from group 1 to 4. For groups 1+2, ROR was adjusted for age, gender, and concomitant drugs (e.g., antiarrhythmics) and stratified for AZCERT drugs, lists I and II (http://www.azcert.org, as of June 2011). A potential signal of torsadogenicity was defined if a drug met all the following criteria: (a) four or more cases in group 1+2; (b) significant ROR in group 1+2 that persists through the cumulative approach; (c) significant adjusted ROR for group 1+2 in the stratum without AZCERT drugs; (d) not included in AZCERT lists (as of June 2011). Results: Over the 7-year period, 37 APs were reported in 4,794 cases of arrhythmia: 140 (group 1), 883 (group 2), 1,651 (group 3), and 2,120 (group 4). Based on our criteria, the following potential signals of torsadogenicity were found: amisulpride (25 cases; adjusted ROR in the stratum without AZCERT drugs = 43.94, 95 % CI 22.82-84.60), cyamemazine (11; 15.48, 6.87-34.91), and olanzapine (189; 7.74, 6.45-9.30). Conclusions: This pharmacovigilance analysis on the FAERS found 3 potential signals of torsadogenicity for drugs previously unknown for this risk

Selective Removal of Alkali Metal Cations from Multiply-Charged Ions via Gas-Phase Ion/Ion Reactions Using Weakly Coordinating Anions

Selective removal of alkali metal cations from mixed cation multiply-charged peptide ions is demonstrated here using gas-phase ion/ion reactions with a series of weakly coordinating anions (WCAs), including hexafluorophosphate (PF6 (-)), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (BARF), tetrakis(pentafluorophenyl)borate (TPPB), and carborane (CHB11Cl11 (-)). In all cases, a long-lived complex is generated by dication/anion condensation followed by ion activation to compare proton transfer with alkali ion transfer from the peptide to the anion. The carborane anion was the only anion studied to undergo dissociation exclusively through loss of the metallated anion, regardless of the studied metal adduct. All other anions studied yield varying abundances of protonated and metallated peptide depending on the peptide sequence and the metal identity. Density functional theory calculations suggest that for the WCAs studied, metal ion transfer is most strongly favored thermodynamically, which is consistent with the experimental results. The carborane anion is demonstrated to be a robust reagent for the selective removal of alkali metal cations from peptide cations with mixtures of excess protons and metal cations

Somatosensory processing in neurodevelopmental disorders

The purpose of this article is to review the role of somatosensory perception in typical development, its aberration in a range of neurodevelopmental disorders, and the potential relations between tactile processing abnormalities and central features of each disorder such as motor, communication, and social development. Neurodevelopmental disorders that represent a range of symptoms and etiologies, and for which multiple peer-reviewed articles on somatosensory differences have been published, were chosen to include in the review. Relevant studies in animal models, as well as conditions of early sensory deprivation, are also included. Somatosensory processing plays an important, yet often overlooked, role in typical development and is aberrant in various neurodevelopmental disorders. This is demonstrated in studies of behavior, sensory thresholds, neuroanatomy, and neurophysiology in samples of children with Fragile X syndrome, autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), and cerebral palsy (CP). Impaired somatosensory processing is found in a range of neurodevelopmental disorders and is associated with deficits in communication, motor ability, and social skills in these disorders. Given the central role of touch in early development, both experimental and clinical approaches should take into consideration the role of somatosensory processing in the etiology and treatment of neurodevelopmental disorders

Identifying associations between diabetes and acute respiratory distress syndrome in patients with acute hypoxemic respiratory failure: an analysis of the LUNG SAFE database

Background: Diabetes mellitus is a common co-existing disease in the critically ill. Diabetes mellitus may reduce the risk of acute respiratory distress syndrome (ARDS), but data from previous studies are conflicting. The objective of this study was to evaluate associations between pre-existing diabetes mellitus and ARDS in critically ill patients with acute hypoxemic respiratory failure (AHRF). Methods: An ancillary analysis of a global, multi-centre prospective observational study (LUNG SAFE) was undertaken. LUNG SAFE evaluated all patients admitted to an intensive care unit (ICU) over a 4-week period, that required mechanical ventilation and met AHRF criteria. Patients who had their AHRF fully explained by cardiac failure were excluded. Important clinical characteristics were included in a stepwise selection approach (forward and backward selection combined with a significance level of 0.05) to identify a set of independent variables associated with having ARDS at any time, developing ARDS (defined as ARDS occurring after day 2 from meeting AHRF criteria) and with hospital mortality. Furthermore, propensity score analysis was undertaken to account for the differences in baseline characteristics between patients with and without diabetes mellitus, and the association between diabetes mellitus and outcomes of interest was assessed on matched samples. Results: Of the 4107 patients with AHRF included in this study, 3022 (73.6%) patients fulfilled ARDS criteria at admission or developed ARDS during their ICU stay. Diabetes mellitus was a pre-existing co-morbidity in 913 patients (22.2% of patients with AHRF). In multivariable analysis, there was no association between diabetes mellitus and having ARDS (OR 0.93 (0.78-1.11); p = 0.39), developing ARDS late (OR 0.79 (0.54-1.15); p = 0.22), or hospital mortality in patients with ARDS (1.15 (0.93-1.42); p = 0.19). In a matched sample of patients, there was no association between diabetes mellitus and outcomes of interest. Conclusions: In a large, global observational study of patients with AHRF, no association was found between diabetes mellitus and having ARDS, developing ARDS, or outcomes from ARDS. Trial registration: NCT02010073. Registered on 12 December 2013

Spontaneous Breathing in Early Acute Respiratory Distress Syndrome: Insights From the Large Observational Study to UNderstand the Global Impact of Severe Acute Respiratory FailurE Study

OBJECTIVES: To describe the characteristics and outcomes of patients with acute respiratory distress syndrome with or without spontaneous breathing and to investigate whether the effects of spontaneous breathing on outcome depend on acute respiratory distress syndrome severity. DESIGN: Planned secondary analysis of a prospective, observational, multicentre cohort study. SETTING: International sample of 459 ICUs from 50 countries. PATIENTS: Patients with acute respiratory distress syndrome and at least 2 days of invasive mechanical ventilation and available data for the mode of mechanical ventilation and respiratory rate for the 2 first days. INTERVENTIONS: Analysis of patients with and without spontaneous breathing, defined by the mode of mechanical ventilation and by actual respiratory rate compared with set respiratory rate during the first 48 hours of mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Spontaneous breathing was present in 67% of patients with mild acute respiratory distress syndrome, 58% of patients with moderate acute respiratory distress syndrome, and 46% of patients with severe acute respiratory distress syndrome. Patients with spontaneous breathing were older and had lower acute respiratory distress syndrome severity, Sequential Organ Failure Assessment scores, ICU and hospital mortality, and were less likely to be diagnosed with acute respiratory distress syndrome by clinicians. In adjusted analysis, spontaneous breathing during the first 2 days was not associated with an effect on ICU or hospital mortality (33% vs 37%; odds ratio, 1.18 [0.92-1.51]; p = 0.19 and 37% vs 41%; odds ratio, 1.18 [0.93-1.50]; p = 0.196, respectively ). Spontaneous breathing was associated with increased ventilator-free days (13 [0-22] vs 8 [0-20]; p = 0.014) and shorter duration of ICU stay (11 [6-20] vs 12 [7-22]; p = 0.04). CONCLUSIONS: Spontaneous breathing is common in patients with acute respiratory distress syndrome during the first 48 hours of mechanical ventilation. Spontaneous breathing is not associated with worse outcomes and may hasten liberation from the ventilator and from ICU. Although these results support the use of spontaneous breathing in patients with acute respiratory distress syndrome independent of acute respiratory distress syndrome severity, the use of controlled ventilation indicates a bias toward use in patients with higher disease severity. In addition, because the lack of reliable data on inspiratory effort in our study, prospective studies incorporating the magnitude of inspiratory effort and adjusting for all potential severity confounders are required

Epidemiology and patterns of tracheostomy practice in patients with acute respiratory distress syndrome in ICUs across 50 countries

Background: To better understand the epidemiology and patterns of tracheostomy practice for patients with acute respiratory distress syndrome (ARDS), we investigated the current usage of tracheostomy in patients with ARDS recruited into the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG-SAFE) study. Methods: This is a secondary analysis of LUNG-SAFE, an international, multicenter, prospective cohort study of patients receiving invasive or noninvasive ventilation in 50 countries spanning 5 continents. The study was carried out over 4 weeks consecutively in the winter of 2014, and 459 ICUs participated. We evaluated the clinical characteristics, management and outcomes of patients that received tracheostomy, in the cohort of patients that developed ARDS on day 1-2 of acute hypoxemic respiratory failure, and in a subsequent propensity-matched cohort. Results: Of the 2377 patients with ARDS that fulfilled the inclusion criteria, 309 (13.0%) underwent tracheostomy during their ICU stay. Patients from high-income European countries (n = 198/1263) more frequently underwent tracheostomy compared to patients from non-European high-income countries (n = 63/649) or patients from middle-income countries (n = 48/465). Only 86/309 (27.8%) underwent tracheostomy on or before day 7, while the median timing of tracheostomy was 14 (Q1-Q3, 7-21) days after onset of ARDS. In the subsample matched by propensity score, ICU and hospital stay were longer in patients with tracheostomy. While patients with tracheostomy had the highest survival probability, there was no difference in 60-day or 90-day mortality in either the patient subgroup that survived for at least 5 days in ICU, or in the propensity-matched subsample. Conclusions: Most patients that receive tracheostomy do so after the first week of critical illness. Tracheostomy may prolong patient survival but does not reduce 60-day or 90-day mortality. Trial registration: ClinicalTrials.gov, NCT02010073. Registered on 12 December 2013

Determinants of recovery from post-COVID-19 dyspnoea: analysis of UK prospective cohorts of hospitalised COVID-19 patients and community-based controls

Background The risk factors for recovery from COVID-19 dyspnoea are poorly understood. We investigated determinants of recovery from dyspnoea in adults with COVID-19 and compared these to determinants of recovery from non-COVID-19 dyspnoea. Methods We used data from two prospective cohort studies: PHOSP-COVID (patients hospitalised between March 2020 and April 2021 with COVID-19) and COVIDENCE UK (community cohort studied over the same time period). PHOSP-COVID data were collected during hospitalisation and at 5-month and 1-year follow-up visits. COVIDENCE UK data were obtained through baseline and monthly online questionnaires. Dyspnoea was measured in both cohorts with the Medical Research Council Dyspnoea Scale. We used multivariable logistic regression to identify determinants associated with a reduction in dyspnoea between 5-month and 1-year follow-up. Findings We included 990 PHOSP-COVID and 3309 COVIDENCE UK participants. We observed higher odds of improvement between 5-month and 1-year follow-up among PHOSP-COVID participants who were younger (odds ratio 1.02 per year, 95% CI 1.01–1.03), male (1.54, 1.16–2.04), neither obese nor severely obese (1.82, 1.06–3.13 and 4.19, 2.14–8.19, respectively), had no pre-existing anxiety or depression (1.56, 1.09–2.22) or cardiovascular disease (1.33, 1.00–1.79), and shorter hospital admission (1.01 per day, 1.00–1.02). Similar associations were found in those recovering from non-COVID-19 dyspnoea, excluding age (and length of hospital admission). Interpretation Factors associated with dyspnoea recovery at 1-year post-discharge among patients hospitalised with COVID-19 were similar to those among community controls without COVID-19. Funding PHOSP-COVID is supported by a grant from the MRC-UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research (NIHR) rapid response panel to tackle COVID-19. The views expressed in the publication are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health and Social Care. COVIDENCE UK is supported by the UK Research and Innovation, the National Institute for Health Research, and Barts Charity. The views expressed are those of the authors and not necessarily those of the funders