Study protocol: azithromycin therapy for chronic lung disease of prematurity (AZTEC) - a randomised, placebo-controlled trial of azithromycin for the prevention of chronic lung disease of prematurity in preterm infants

Introduction Chronic lung disease of prematurity (CLD), also known as bronchopulmonary dysplasia (BPD), is a cause of significant respiratory morbidity in childhood and beyond. Coupled with lung immaturity, infections (especially by Ureaplasma spp) are implicated in the pathogenesis of CLD through promotion of pulmonary inflammation. Azithromycin, which is a highly effective against Ureaplasma spp also has potent anti-inflammatory properties. Thus, azithromycin therapy may improve respiratory outcomes by targeting infective and inflammatory pathways. Previous trials using macrolides have not been sufficiently powered to definitively assess CLD rates. To address this, the azithromycin therapy for chronic lung disease of prematurity (AZTEC) trial aims to determine if a 10-day early course of intravenous azithromycin improves rates of survival without CLD when compared with placebo with an appropriately powered study. Methods and analysis 796 infants born at less than 30 weeks’ gestational age who require at least 2 hours of continuous respiratory support within the first 72 hours following birth are being enrolled by neonatal units in the UK. They are being randomised to receive a double-blind, once daily dose of intravenous azithromycin (20 mg/kg for 3 days, followed by 10 mg/kg for a further 7 days), or placebo. CLD is being assessed at 36 weeks’ PMA. Whether colonisation with Ureaplasma spp prior to randomisation modifies the treatment effect of azithromycin compared with placebo will also be investigated. Secondary outcomes include necrotising enterocolitis, intraventricular/cerebral haemorrhage, retinopathy of prematurity and nosocomial infections, development of antibiotic resistance and adverse reactions will be monitored. Ethics and dissemination Ethics permission has been granted by Wales Research Ethics Committee 2 (Ref 18/WA/0199), and regulatory permission by the Medicines and Healthcare Products Regulatory Agency (Clinical Trials Authorisation reference 21323/0050/001–0001). The study is registered on ISRCTN (ISRCTN11650227). The study is overseen by an independent Data Monitoring Committee and an independent Trial Steering Committee. We shall disseminate our findings via national and international peer-reviewed journals, and conferences. A summary of the findings will also be posted on the trial website

Circadian oscillations of cytosolic free calcium regulate the Arabidopsis circadian clock

In the last decade, the view of circadian oscillators has expanded from transcriptional feedback to incorporate post-transcriptional, post-translational, metabolic processes and ionic signalling. In plants and animals, there are circadian oscillations in the concentration of cytosolic-free Ca2+ ([Ca2+]cyt), though their purpose has not been fully characterised. We investigated whether circadian oscillations of [Ca2+] cyt regulate the circadian oscillator of Arabidopsis thaliana. We report that in Arabidopsis, [Ca2+]cyt circadian oscillations can regulate circadian clock function through the Ca2+-dependent action of CALMODULIN-LIKE24 (CML24). Genetic analyses demonstrate a linkage between CML24 and the circadian oscillator, through pathways involving the circadian oscillator gene TIMING OF CAB2 EXPRESSION1 (TOC1).Supported by BBSRC UK research grants BBSRC BB/D010381/1 (A.N.D.), BB/D017904/1 (F.R.) BB/M00113X/1 (H.J.H.) awarded to (A.A.R.W.), Research Studentship (K.H.) and BBSRC Industrial Case (T.H.). A Swiss Science Foundation Award (PBZHP3-123289) and the Isaac Newton Trust Cambridge (M.C.M.R. and S.A.), 678 the National Science Foundation under Grant No. MCB 0817976 (Y-C.T. and J.B.), a Royal Society Grant RG081257 and Corpus Christi College, Cambridge Junior Research Fellowship (M.J.G.), a Cordenadoria de Apoio ao Ensino Superior Brazil 25681 studentship (C.T.H.), IEF Marrie Curie (Project No. 272186) (M.C.M.R.), a Broodbank Fellowship (M.C.M.R.), a Malaysian Government Studentship (N.I.M-H.)

Azithromycin therapy for prevention of chronic lung disease of prematurity (AZTEC): a multicentre, double-blind, randomised, placebo-controlled trial

Background Systematic reviews have reported conflicting evidence on whether macrolide antibiotics reduce rates of chronic lung disease of prematurity (CLD) in at-risk preterm infants born at less than 30 weeks’ gestation, including in those colonised with pulmonary Ureaplasma spp. Since an adequately powered trial has been lacking, we aimed to assess if the macrolide azithromycin improved survival without the development of physiologically defined moderate or severe CLD in preterm infants. Methods AZTEC was a multicentre, double-blind, randomised, placebo-controlled trial conducted in 28 tertiary neonatal intensive care units in the UK. Infants were eligible if they were born at less than 30 weeks’ gestation and had received at least 2 h of either non-invasive (continuous positive airway pressure or humidified high flow nasal cannula therapy) or invasive respiratory support (via endotracheal tube) within 72 h of birth. Eligible infants were randomly allocated in a 1:1 ratio using random permuted blocks of four to receive either intravenous azithromycin at 20 mg/kg per day for 3 days followed by 10 mg/kg for 7 days, or to placebo. Allocation was stratified by centre and gestational age at birth (<28 weeks vs ≥28 weeks). Azithromycin and placebo vials were encased in tamper-evident custom cardboard cartons to ensure masking for clinicians, parents, and the research team. The primary outcome was survival without development of physiologically defined moderate or severe CLD at 36 weeks’ postmenstrual age. Outcomes and safety were analysed on an intention-to-treat basis (all randomly allocated infants, regardless of any post-randomisation events). The study was registered with ISRCRN (11650227) and is closed. Findings Infants were recruited between Oct 9, 2019, and March 22, 2022. 799 (53·1%) of 1505 eligible infants underwent random allocation; three infants were withdrawn, including consent to use their data, leaving 796 infants for analysis. Survival without moderate or severe CLD occurred in 166 (42%) of 394 infants in the intervention group and 179 (45%) of 402 in the placebo group (three-level adjusted OR [aOR] 0·84, 95% CI 0·55–1·29, p=0·43). Pulmonary Ureaplasma spp colonisation did not influence treatment effect. Overall, seven serious adverse events were reported for the azithromycin group (five graded as severe, two as moderate), and six serious adverse events were reported in the placebo group (two severe, two moderate, and two mild), as assessed by the local principal investigators. Interpretation Since prophylactic use of azithromycin did not improve survival without development of physiologically-defined CLD, regardless of Ureaplasma spp colonisation, it cannot be recommended in clinical practice

The Consensus Coding Sequence (Ccds) Project: Identifying a Common Protein-Coding Gene Set for the Human and Mouse Genomes

Effective use of the human and mouse genomes requires reliable identification of genes and their products. Although multiple public resources provide annotation, different methods are used that can result in similar but not identical representation of genes, transcripts, and proteins. The collaborative consensus coding sequence (CCDS) project tracks identical protein annotations on the reference mouse and human genomes with a stable identifier (CCDS ID), and ensures that they are consistently represented on the NCBI, Ensembl, and UCSC Genome Browsers. Importantly, the project coordinates on manually reviewing inconsistent protein annotations between sites, as well as annotations for which new evidence suggests a revision is needed, to progressively converge on a complete protein-coding set for the human and mouse reference genomes, while maintaining a high standard of reliability and biological accuracy. To date, the project has identified 20,159 human and 17,707 mouse consensus coding regions from 17,052 human and 16,893 mouse genes. Three evaluation methods indicate that the entries in the CCDS set are highly likely to represent real proteins, more so than annotations from contributing groups not included in CCDS. The CCDS database thus centralizes the function of identifying well-supported, identically-annotated, protein-coding regions.National Human Genome Research Institute (U.S.) (Grant number 1U54HG004555-01)Wellcome Trust (London, England) (Grant number WT062023)Wellcome Trust (London, England) (Grant number WT077198

Collaborating with consumer and community representatives in health and medical research in Australia: results from an evaluation

<p>Abstract</p> <p>Objective</p> <p>To collaborate with consumer and community representatives in the <it>Alcohol and Pregnancy Project </it>from 2006-2008 <url>http://www.ichr.uwa.edu.au/alcoholandpregnancy</url> and evaluate researchers' and consumer and community representatives' perceptions of the process, context and impact of consumer and community participation in the project.</p> <p>Methods</p> <p>We formed two reference groups and sought consumer and community representatives' perspectives on all aspects of the project over a three year period. We developed an evaluation framework and asked consumer and community representatives and researchers to complete a self-administered questionnaire at the end of the project.</p> <p>Results</p> <p>Fifteen researchers (93.8%) and seven (53.8%) consumer and community representatives completed a questionnaire. Most consumer and community representatives agreed that the process and context measures of their participation had been achieved. Both researchers and consumer and community representatives identified areas for improvement and offered suggestions how these could be improved for future research. Researchers thought consumer and community participation contributed to project outputs and outcomes by enhancing scientific and ethical standards, providing legitimacy and authority, and increasing the project's credibility and participation. They saw it was fundamental to the research process and acknowledged consumer and community representatives for their excellent contribution. Consumer and community representatives were able to directly influence decisions about the research. They thought that consumer and community participation had significant influence on the success of project outputs and outcomes.</p> <p>Conclusions</p> <p>Consumer and community participation is an essential component of good research practice and contributed to the <it>Alcohol and Pregnancy Project </it>by enhancing research processes, outputs and outcomes, and this participation was valued by community and consumer representatives and researchers. The National Health and Medical Research Council in Australia expects researchers to work in partnership and involve consumer and community representatives in health and medical research, and to evaluate community and consumer participation. It is important to demonstrate whether consumer and community participation makes a difference to health and medical research.</p

2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines

A healthy lifestyle is important in the prevention of CVD, the leading cause of morbidity and mortality worldwide. The intent of the Lifestyle Work Group (Work Group) was to evaluate evidence that particular dietary patterns, nutrient intake, and levels and types of physical activity can play a major role in CVD prevention and treatment through effects on modifiable CVD risk factors (ie, blood pressure [BP] and lipids). These ESs and recommendations may be used as appropriate in the management of hypercholesterolemia and hypertension. The target audience of the report is primary care providers

2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines

A healthy lifestyle is important in the prevention of CVD, the leading cause of morbidity and mortality worldwide. The intent of the Lifestyle Work Group (Work Group) was to evaluate evidence that particular dietary patterns, nutrient intake, and levels and types of physical activity can play a major role in CVD prevention and treatment through effects on modifiable CVD risk factors (ie, blood pressure [BP] and lipids). These ESs and recommendations may be used as appropriate in the management of hypercholesterolemia and hypertension. The target audience of the report is primary care providers

Genome-wide ultraconserved elements exhibit higher phylogenetic informativeness than traditional gene markers in percomorph fishes

Ultraconserved elements (UCEs) have become popular markers in phylogenetic studies because of their cost effectiveness in phylogenomic analyses and because of their potential to resolve problematic phylogenetic questions such as interspecific relationships within the rayfinned fishes. Although UCE datasets typically contain a much larger number of loci and sites than more traditional datasets of PCR-amplified, single-copy, protein coding genes, a fraction of UCE sites are expected to be part of a nearly invariant core, and the relative performance of UCE datasets versus protein coding gene datasets is poorly understood. Here we use phylogenetic informativeness (PI) to compare the resolving power of multi-locus and UCE datasets in a sample of percomorph fishes with sequenced genomes (genome-enabled). We compare three data sets: UCE core regions, flanking sequence adjacent to the UCE core and a set of ten protein coding genes commonly used in fish systematics. We found the net informativeness of UCE core and flank regions to be roughly ten-fold and 100-fold more informative than that of the protein coding genes. On a per locus basis UCEs and protein coding genes exhibited similar levels of phylogenetic informativeness. Our results suggest that UCEs offer enormous potential for resolving relationships across the percomorph tree of life

Human and mouse essentiality screens as a resource for disease gene discovery

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery. Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery

AWZ1066S, a highly specific anti-Wolbachia drug candidate for a short-course treatment of filariasis

Onchocerciasis and lymphatic filariasis are two neglected tropical diseases that together affect ∼157 million people and inflict severe disability. Both diseases are caused by parasitic filarial nematodes with elimination efforts constrained by the lack of a safe drug that can kill the adult filaria (macrofilaricide). Previous proof-of-concept human trials have demonstrated that depleting >90% of the essential nematode endosymbiont bacterium, Wolbachia, using antibiotics, can lead to permanent sterilization of adult female parasites and a safe macrofilaricidal outcome. AWZ1066S is a highly specific anti-Wolbachia candidate selected through a lead optimization program focused on balancing efficacy, safety and drug metabolism/pharmacokinetic (DMPK) features of a thienopyrimidine/quinazoline scaffold derived from phenotypic screening. AWZ1066S shows superior efficacy to existing anti-Wolbachia therapies in validated preclinical models of infection and has DMPK characteristics that are compatible with a short therapeutic regimen of 7 days or less. This candidate molecule is well-positioned for onward development and has the potential to make a significant impact on communities affected by filariasis