Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial

Item does not contain fulltextBACKGROUND: Platelet transfusion after acute spontaneous primary intracerebral haemorrhage in people taking antiplatelet therapy might reduce death or dependence by reducing the extent of the haemorrhage. We aimed to investigate whether platelet transfusion with standard care, compared with standard care alone, reduced death or dependence after intracerebral haemorrhage associated with antiplatelet therapy use. METHODS: We did this multicentre, open-label, masked-endpoint, randomised trial at 60 hospitals in the Netherlands, UK, and France. We enrolled adults within 6 h of supratentorial intracerebral haemorrhage symptom onset if they had used antiplatelet therapy for at least 7 days beforehand and had a Glasgow Coma Scale score of at least 8. With use of a secure web-based system that concealed allocation and used biased coin randomisation, study collaborators randomly assigned participants (1:1; stratified by hospital and type of antiplatelet therapy) to receive either standard care or standard care with platelet transfusion within 90 min of diagnostic brain imaging. Participants and local investigators giving interventions were not masked to treatment allocation, but allocation was concealed from outcome assessors and investigators analysing data. The primary outcome was shift towards death or dependence rated on the modified Rankin Scale (mRS) at 3 months, and analysed by ordinal logistic regression, adjusted for stratification variables and the Intracerebral Haemorrhage Score. The primary analysis was done in the intention-to-treat population and safety analyses were done in the intention-to-treat and as-treated populations. This trial is registered with the Netherlands Trial Register, number NTR1303, and is now closed. FINDINGS: Between Feb 4, 2009, and Oct 8, 2015, 41 sites enrolled 190 participants. 97 participants were randomly assigned to platelet transfusion and 93 to standard care. The odds of death or dependence at 3 months were higher in the platelet transfusion group than in the standard care group (adjusted common odds ratio 2.05, 95% CI 1.18-3.56; p=0.0114). 40 (42%) participants who received platelet transfusion had a serious adverse event during their hospital stay, as did 28 (29%) who received standard care. 23 (24%) participants assigned to platelet transfusion and 16 (17%) assigned to standard care died during hospital stay. INTERPRETATION: Platelet transfusion seems inferior to standard care for people taking antiplatelet therapy before intracerebral haemorrhage. Platelet transfusion cannot be recommended for this indication in clinical practice. FUNDING: The Netherlands Organisation for Health Research and Development, Sanquin Blood Supply, Chest Heart and Stroke Scotland, French Ministry of Health

Reliability and validity of the Infant and Toddler Quality of Life Questionnaire (ITQOL) in a general population and respiratory disease sample

Objective: To evaluate feasibility, internal consistency, test-retest reliability, and concurrent and discriminative validity of the Infant and Toddler Quality of Life Questionnaire (ITQOL) for parents of pre-school children with 12 scales (103-items) covering physical and psychosocial domains and impact of child health on parents, in comparison with the TNO-AZL Pre-school Children Quality of Life Questionnaire (TAPQOL). Methods: Parents of children from a random general population sample (2 months-4 years old; n = 500) and of an outpatient clinic sample of children with respiratory disease (5 months-51/2 years old; n = 217) were mailed ITQOL and TAPQOL questionnaires; a retest was sent after two weeks. Results: Feasibility: The response was ≥80% with few missing and non-unique ITQOL-answers (25% at maximum score). Internal consistency: All Cronbach's α >0.70. Test-retest Intraclass Correlation Coefficients (ICCs) were moderate or adequate (≥0.50; p < 0.01) for 10 ITQOL-scales. Validity: ITQOL-scales, with a few exceptions, correlated better with predefined parallel TAPQOL scales than with non-parallel scales. Five to eight ITQOL-scales discriminated clearly between children with few and with many parent-reported chronic conditions, between children with and without doctor-diagnosed respiratory disease and with a low and a high parent-reported medical consumption (p < 0.05). Conclusions: This study supported the evidence that the ITQOL is a feasible instrument with adequate psychometric properties. The study provided reference ITQOL scores for gender/age subgroups. We recommend repeated evaluations of the ITQOL in varied populations, especially among very young children, including repeated assessments of test-retest characteristics and evaluations of responsiveness to change. We recommend developing and evaluating a shortened ITQOL version

Maternal sensitivity and children’s sleep problems across early childhood

The current study aims to clarify the temporal associations between maternal sensitivity and children’s sleep problems across early childhood. This study comprised 942 Dutch mother–child dyads from the Generation R Study, a population-based prospective cohort study. Throughout early childhood, maternal sensitivity was observed in mother–child interactions and coded using Ainsworth’s 9-point rating scales (1.5 years) and the revised Erickson 7-point rating scales (3 and 4 years). Caregivers reported children’s sleep problems on the Sleep Problems Scale of the Child Behaviour Checklist 1½−5 at child ages 1.5, 3, and 6 years. Cross-lagged panel modelling revealed that higher levels of maternal sensitivity (3 years) were associated with fewer sleep problems (6 years); all other temporal associations between maternal sensitivity and children’s sleep problems were nonsignificant. In conclusion, some indication of an association of parenting with children’s sleep across early childhood was found, but there was no evidence for bidirectional associations over time

Genetic variation in GNB5 causes bradycardia by augmenting the cholinergic response via increased acetylcholine-activated potassium current (IK,ACh)

Mutations in GNB5, encoding the G-protein β5 subunit (Gβ5), have recently been linked to a multisystem disorder that includes severe bradycardia. Here, we investigated the mechanism underlying bradycardia caused by the recessive p.S81L Gβ5 variant. Using CRISPR/Cas9-based targeting, we generated an isogenic series of human induced pluripotent stem cell (hiPSC) lines that were either wild type, heterozygous or homozygous for the GNB5 p.S81L variant. These were differentiated into cardiomyocytes (hiPSC-CMs) that robustly expressed the acetylcholine-activated potassium channel [I(KACh); also known as IK,ACh]. Baseline electrophysiological properties of the lines did not differ. Upon application of carbachol (CCh), homozygous p.S81L hiPSC-CMs displayed an increased acetylcholine-activated potassium current (IK,ACh) density and a more pronounced decrease of spontaneous activity as compared to wild-type and heterozygous p.S81L hiPSC-CMs, explaining the bradycardia in homozygous carriers. Application of the specific I(KACh) blocker XEN-R0703 resulted in near-complete reversal of the phenotype. Our results provide mechanistic insights and proof of principle for potential therapy in patients carrying GNB5 mutations.This article has an associated First Person interview with the first author of the paper

Genetic variation in GNB5 causes bradycardia by augmenting the cholinergic response via increased acetylcholine-activated potassium current (I K,ACh)

Mutations in GNB5, encoding the G-protein β5 subunit (Gβ5), have recently been linked to a multisystem disorder that includes severe bradycardia. Here, we investigated the mechanism underlying bradycardia caused by the recessive p.S81L Gβ5 variant. Using CRISPR/Cas9-based targeting, we generated an isogenic series of human induced pluripotent stem cell (hiPSC) lines that were either wild type, heterozygous or homozygous for the GNB5 p.S81L variant. These were differentiated into cardiomyocytes (hiPSC-CMs) that robustly expressed the acetylcholine-activated potassium channel [I(KACh); also known as I K,ACh]. Baseline electrophysiological properties of the lines did not differ. Upon application of carbachol (CCh), homozygous p.S81L hiPSC-CMs displayed an increased acetylcholine-activated potassium current (I K,ACh) density and a more pronounced decrease of spontaneous activity as compared to wild-type and heterozygous p.S81L hiPSC-CMs, explaining the bradycardia in homozygous carriers. Application of the specific I(KACh) blocker XEN-R0703 resulted in near-complete reversal of the phenotype. Our results provide mechanistic insights and proof of principle for potential therapy in patients carrying GNB5 mutations

THE LIFE AND THOUGHT OF YEN HSI-CHAI (1635-1704)

Childhood, adolescent, and young adult (CAYA) cancer survivors may be at risk for a severe course of COVID-19. Little is known about the clinical course of COVID-19 in CAYA cancer survivors, or if additional preventive measures are warranted. We established a working group within the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) to summarize existing evidence and worldwide recommendations regarding evidence about factors/conditions associated with risk for a severe course of COVID-19 in CAYA cancer survivors, and to develop a consensus statement to provide guidance for healthcare practitioners and CAYA cancer survivors regarding COVID-19