Single dose oral dexamethasone versus multi-dose prednisolone in the treatment of acute exacerbations of asthma in children who attend the emergency department: study protocol for a randomized controlled trial.

BACKGROUND: Asthma is a major cause of pediatric morbidity and mortality. In acute exacerbations of asthma, corticosteroids reduce relapses, subsequent hospital admission and the need for ß2-agonist therapy. Prednisolone is relatively short-acting with a half-life of 12 to 36 hours, thereby requiring daily dosing. Prolonged treatment course, vomiting and a bitter taste may reduce patient compliance with prednisolone. Dexamethasone is a long-acting corticosteroid with a half-life of 36 to 72 hours. It is used frequently in children with croup and bacterial meningitis, and is well absorbed orally. The purpose of this trial is to examine whether a single dose of oral dexamethasone (0.3 mg/kg) is clinically non-inferior to prednisolone (1 mg/kg/day for three days) in the treatment of exacerbations of asthma in children who attend the Emergency Department. METHODS/DESIGN: This is a randomized, non-inferiority, open-label clinical trial. After informed consent with or without assent, patients will be randomized to either oral dexamethasone 0.3 mg/kg stat or prednisolone 1 mg/kg/day for three days. The primary outcome measure is the comparison between the Pediatric Respiratory Assessment Measure (PRAM) across both groups on Day 4. The PRAM score, a validated, responsive and reliable tool to determine asthma severity in children aged 2 to 16 years, will be performed by a clinician blinded to treatment allocation. Secondary outcomes include relapse, hospital admission and requirement for further steroid therapy. Data will be analyzed on an intention-to-treat and a per protocol basis. With a sample size of 232 subjects (105 in each group with an estimated 10% loss to follow-up), we will be able to reject the null hypothesis - that the population means of the experimental and control groups are equal with a probability (power) of 0.9. The Type I error probability associated with this test (of the null hypothesis) is 0.05. DISCUSSION: This clinical trial may provide evidence that a shorter steroid course using dexamethasone can be used in the treatment of acute pediatric asthma, thus eliminating the issue of compliance to treatment. REGISTRATION: ISRCTN26944158 and EudraCT Number 2010-022001-18

Intranasal fentanyl versus intravenous morphine in the emergency department treatment of severe painful sickle cell crises in children: study protocol for a randomised controlled trial.

BACKGROUND: Children with sickle cell disease (SCD) frequently and unpredictably present to the emergency department (ED) with pain. The painful event is the hallmark acute clinical manifestation of SCD, characterised by sudden onset and is usually bony in origin. This study aims to establish if 1.5mcg/kg of intranasal fentanyl (INF; administered via a Mucosal Atomiser Device, MAD™) is non-inferior to intravenous morphine 0.1 mg/kg in severe SCD-associated pain. METHODS/DESIGN: This study is a randomised,double-blind, double-dummy active control trial of children (weighing more than 10 kg) between 1 year and 21 years of age with severe painful sickle cell crisis. Severe pain is defined as rated seven or greater on a 0 to 10 age-appropriate numeric pain scale or equivalent. The trial will be conducted in a single tertiary urban paediatric ED in Dublin, Ireland. Each patient will receive a single active agent and a single placebo via the intravenous and intranasal routes. All clinical and research staff, patients and parents will be blinded to the treatment allocation. The primary endpoint is severity of pain scored at 10 min from administration of the study medications. Secondary endpoints include pain severity measured at 0, 5, 15, 20, 30, 60 and 120 min after the administration of analgesia, proportion of patients requiring rescue analgesia and incidence of adverse events. The trial ends at 120 min after the administration of the study drugs. A clinically meaningful difference in validated pain scores has been defined as 13 mm. Setting the permitted threshold to 50% of this limit (6 mm) and assuming both treatments are on average equal, a sample size of 30 patients (15 per group) will provide at least 80% power to demonstrate that INF is non-inferior to IV morphine with a level of significance of 0.05. DISCUSSION: This clinical trial will inform of the role of INF 1.5mcg/kg via MAD in the acute treatment of severe painful sickle cell crisis in children in the ED setting. TRIAL REGISTRATION: Current Controlled Trials ISRCTN67469672 and EudraCT no. 2011-005161-20

Maternal selection of human embryos in early gestation : insights from recurrent miscarriage

Compared to most mammals, human pregnancy is unusual in that it involves chromosomally diverse embryos, cyclical breakdown and regeneration of the uterine mucosa, and intimate integration of fetal and maternal cells at the uteroplacental interface. Not surprisingly, pregnancy often falters in early gestation. Whether these losses result in clinical miscarriages depends on the origins and impacts of chromosomal errors on fetal development and the ability of the decidualizing endometrium to engage in embryo biosensing and selection. Aneuploidy originating in oocytes during meiosis drives the age-related risk of miscarriage. By contrast, the frequency of endometrial cycles with an impaired decidual response may account for the stepwise increase in miscarriage rates with each pregnancy loss independently of maternal age. Additional physiological mechanisms operate in early gestation to ensure that most failing pregnancies are lost before vascular maternal-fetal connections are established by the end of the first trimester. Here, we summarise how investigations into the mechanisms that cause miscarriage led to new insights into the processes that govern maternal selection of human embryos in early gestation

Commercial Immunoglobulin Products Contain Neutralizing Antibodies Against Severe Acute Respiratory Syndrome Coronavirus 2 Spike Protein

BACKGROUND: Patients with antibody deficiency respond poorly to COVID-19 vaccination and are at risk of severe or prolonged infection. They are given long-term immunoglobulin replacement therapy (IRT) prepared from healthy donor plasma to confer passive immunity against infection. Following widespread COVID-19 vaccination alongside natural exposure, we hypothesised that immunoglobulin preparations will now contain neutralising SARS-CoV-2 spike antibodies which confer protection against COVID-19 disease and may help to treat chronic infection. METHODS: We evaluated anti-SARS-CoV-2 spike antibody in a cohort of patients before and after immunoglobulin infusion. Neutralising capacity of patient samples and immunoglobulin products was assessed using in vitro pseudo-virus and live-virus neutralisation assays, the latter investigating multiple batches against current circulating omicron variants. We describe the clinical course of nine patients started on IRT during treatment of COVID-19. RESULTS: In 35 individuals with antibody deficiency established on IRT, median anti-spike antibody titre increased from 2123 to 10600 U/ml post-infusion, with corresponding increase in pseudo-virus neutralisation titres to levels comparable to healthy donors. Testing immunoglobulin products directly in the live-virus assay confirmed neutralisation, including of BQ1.1 and XBB variants, but with variation between immunoglobulin products and batches.Initiation of IRT alongside Remdesivir in patients with antibody deficiency and prolonged COVID-19 infection (median 189 days, maximum over 900 days with an ancestral viral strain) resulted in clearance of SARS-CoV-2 virus at a median of 20 days. CONCLUSIONS: Immunoglobulin preparations now contain neutralising anti-SARS-CoV-2 antibodies which are transmitted to patients and help to treat COVID-19 in individuals with failure of humoral immunity

The use of propofol for procedural sedation in emergency departments

There is increasing evidence that propofol is efficacious and safe for procedural sedation (PS) in the emergency department (ED) setting. However, propofol has a narrow therapeutic window and lacks of a reversal agent. The aim of this review was to cohere the evidence base regarding the efficacy and safety profile of propofol when used in the ED setting for PS.To identify and evaluate all randomized controlled trials (RCTs) comparing propofol with alternative drugs (benzodiazepines, barbiturates, etomidate and ketamine) used in the ED setting for PS.We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 9), MEDLINE (1950 to September week 2 2013) and EMBASE (1980 to week 2 2013). We searched the Current Controlled Trials metaRegister of Clinical Trials (compiled by Current Science) (September 2013). We checked the reference lists of trials and contacted trial authors. We imposed no language restriction. We re-ran the search in February 2015. We will deal with the one study awaiting classification when we update the review.RCTs comparing propofol to alternative drugs (benzodiazepines, barbiturates, etomidate and ketamine) used in the ED setting for PS in participants of all ages.Two authors independently performed data extraction. Two authors performed trial quality assessment. We used mean difference (MD), odds ratio (OR) and 95% confidence intervals (CI) to measure effect sizes. Two authors independently assessed and rated the methodological quality of each trial using The Cochrane Collaboration tool for assessing risk of bias.Ten studies (813 participants) met the inclusion criteria. Two studies only included participants 18 years and younger; six studies only included participants 18 years and older; one study included participants between 16 and 65 years of age and one study included only adults but did not specify the age range. Eight of the included studies had a high risk of bias. The included studies were clinically heterogeneous. We undertook no meta-analysis.The primary outcome measures of this review were: adverse effects (as defined by the study authors) and participant satisfaction (as defined by the study authors). In one study comparing propofol/fentanyl with ketamine/midazolam, delayed adverse reactions (nightmares and behavioural change) were noted in 10% of the ketamine/midazolam group and none in the propofol/fentanyl group. Seven individual studies reported no evidence of a difference in adverse effects between intravenous propofol, with and without adjunctive analgesic agents, and alternative interventions. Three individual studies reported no evidence of a difference in pain at the injection site between intravenous propofol and alternative interventions. Four individual studies reported no evidence of a difference in participant satisfaction between intravenous propofol, with and without adjunctive analgesic agents, and alternative interventions (ketamine, etomidate, midazolam). All the studies employed propofol without the use of an adjunctive analgesic and all, except one, were small (fewer than 100 participants) studies. The quality of evidence for the adverse effects and participant satisfaction outcomes was very low.Nine included studies (eight comparisons) reported all the secondary outcome measures of the review except mortality. It was not possible to pool the results of the included studies for any of the secondary outcome measures because the comparator interventions were different and the measures were reported in different ways. Seven individual studies reported no evidence of difference in incidence of hypoxia between intravenous propofol, with and without adjunctive analgesic agents, and alternative interventions.No firm conclusions can be drawn concerning the comparative effects of administering intravenous propofol, with or without an adjunctive analgesic agent, with alternative interventions in participants undergoing PS in the ED setting on adverse effects (including pain at the injection site) and participant satisfaction. The review was limited because no two included studies employed the same comparator interventions, and because the number of participants in eight of the included studies were small (fewer than 100 participants)

PU_RACE_R2.fastq

V781-PG9 engineered Ramos cells after HIV C108 SOSIP enrichment followed by subsequent passage without further selection, passaged unselected (PU). Immunoglobulin heavy and light chain variable regions amplified from cDNA made by RACE with barcoded 5' template switch adapters. NEBnext amplicon sequenced using 400x100 paired end reads on the Illumina MiSeq. This is read 2 (R2

D3_nonengineered_R2.fastq

Donor 3 control primary B cells 13 days post nucleofection. Immunoglobulin heavy chain variable regions amplified from cDNA made by RACE with barcoded 5' template switch adapters. NEBnext amplicon sequenced using 400x100 paired end reads on the Illumina MiSeq. This is read 2 (R2)

D2_nonengineered_R1.fastq

Donor 2 control primary B cells 13 days post nucleofection. Immunoglobulin heavy chain variable regions amplified from cDNA made by RACE with barcoded 5' template switch adapters. NEBnext amplicon sequenced using 400x100 paired end reads on the Illumina MiSeq. This is read 1