Hepatitis A vaccination coverage among people with chronic liver disease in England (HEALD): protocol for a retrospective cohort study

Background: Hepatitis A outbreaks in the United Kingdom are uncommon. Most people develop mild to moderate symptoms that resolve, without sequelae, within months. However, in high-risk groups, including those with underlying chronic liver disease (CLD), hepatitis A infection can be severe, with a higher risk of mortality and morbidity. The Health Security Agency and the National Institute of Health and Care Excellence recommend preexposure hepatitis A vaccination given in 2 doses to people with CLD, regardless of its cause. There are currently no published reports of vaccination coverage for people with CLD in England or internationally. Objective: This study aims to describe hepatitis A vaccination coverage in adults with CLD in a UK primary care setting and compare liver disease etiology, sociodemographic characteristics, and comorbidities in people who are and are not exposed to the hepatitis A vaccine. Methods: We will conduct a retrospective cohort study with data from the Primary Care Sentinel Cohort of the Oxford-Royal College of General Practitioners Clinical Informatics Digital Hub database, which is nationally representative of the English population. We will include people aged 18 years and older who have been registered in general practices in the Research and Surveillance Centre network and have a record of CLD between January 1, 2012, and December 31, 2022, including those with alcohol-related liver disease, chronic hepatitis B, chronic hepatitis C, nonalcohol fatty liver disease, Wilson disease, hemochromatosis, and autoimmune hepatitis. We will carefully curate variables using the Systematized Nomenclature of Medicine Clinical Terms. We will report the sociodemographic characteristics of those who are vaccinated. These include age, gender, ethnicity, population density, region, socioeconomic status (measured using the index of multiple deprivation), obesity, alcohol consumption, and smoking. Hepatitis A vaccination coverage for 1 and 2 doses will be calculated using an estimate of the CLD population as the denominator. We will analyze the baseline characteristics using descriptive statistics, including measures of dispersion. Pairwise comparisons of case-mix characteristics, comorbidities, and complications will be reported according to vaccination status. A multistate survival model will be fitted to estimate the transition probabilities among four states: (1) diagnosed with CLD, (2) first dose of hepatitis A vaccination, (3) second dose of hepatitis A vaccination, and (4) death. This will identify any potential disparities in how people with CLD get vaccinated. Results: The Research and Surveillance Centre population comprises over 8 million people. The reported incidence of CLD is 20.7 cases per 100,000. International estimates of hepatitis A vaccine coverage vary between 10% and 50% in this group. Conclusions: This study will describe the uptake of the hepatitis A vaccine in people with CLD and report any disparities or differences in the characteristics of the vaccinated population. International Registered Report Identifier (IRRID): PRR1-10.2196/5186

Adverse Drug Reactions in Children—A Systematic Review

Adverse drug reactions in children are an important public health problem. We have undertaken a systematic review of observational studies in children in three settings: causing admission to hospital, occurring during hospital stay and occurring in the community. We were particularly interested in understanding how ADRs might be better detected, assessed and avoided

Bi-allelic loss-of-function CACNA1B mutations in progressive epilepsy-dyskinesia

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment

Higher or Lower Hemoglobin Transfusion Thresholds for Preterm Infants

Background: Limited data suggest that higher hemoglobin thresholds for red-cell transfusions may reduce the risk of cognitive delay among extremely-low-birth-weight infants with anemia. Methods: We performed an open, multicenter trial in which infants with a birth weight of 1000 g or less and a gestational age between 22 weeks 0 days and 28 weeks 6 days were randomly assigned within 48 hours after delivery to receive red-cell transfusions at higher or lower hemoglobin thresholds until 36 weeks of postmenstrual age or discharge, whichever occurred first. The primary outcome was a composite of death or neurodevelopmental impairment (cognitive delay, cerebral palsy, or hearing or vision loss) at 22 to 26 months of age, corrected for prematurity. Results: A total of 1824 infants (mean birth weight, 756 g; mean gestational age, 25.9 weeks) underwent randomization. There was a between-group difference of 1.9 g per deciliter (19 g per liter) in the pretransfusion mean hemoglobin levels throughout the treatment period. Primary outcome data were available for 1692 infants (92.8%). Of 845 infants in the higher-threshold group, 423 (50.1%) died or survived with neurodevelopmental impairment, as compared with 422 of 847 infants (49.8%) in the lower-threshold group (relative risk adjusted for birth-weight stratum and center, 1.00; 95% confidence interval [CI], 0.92 to 1.10; P = 0.93). At 2 years, the higher- and lower-threshold groups had similar incidences of death (16.2% and 15.0%, respectively) and neurodevelopmental impairment (39.6% and 40.3%, respectively). At discharge from the hospital, the incidences of survival without severe complications were 28.5% and 30.9%, respectively. Serious adverse events occurred in 22.7% and 21.7%, respectively. Conclusions: In extremely-low-birth-weight infants, a higher hemoglobin threshold for red-cell transfusion did not improve survival without neurodevelopmental impairment at 22 to 26 months of age, corrected for prematurity

Inshore and offshore marine migration pathways of Atlantic salmon post-smolts from multiple rivers in Scotland, England, Northern Ireland, and Ireland

The migratory behavior of Atlantic salmon (Salmo salar) post-smolts in coastal waters is poorly understood. In this collaborative study, 1914 smolts, from 25 rivers, in four countries were tagged with acoustic transmitters during a single seasonal migration. In total, 1105 post-smolts entered the marine study areas and 438 (39.6%) were detected on a network of 414 marine acoustic receivers and an autonomous underwater vehicle. Migration pathways (defined as the shortest distance between two detections) of up to 575 km and over 100 days at sea were described for all 25 populations. Post-smolts from different rivers, as well as individuals from the same river, used different pathways in coastal waters. Although difficult to generalize to all rivers, at least during the year of this study, no tagged post-smolts from rivers draining into the Irish Sea were detected entering the areas of sea between the Hebrides and mainland Scotland, which is associated with a high density of finfish aquaculture. An important outcome of this study is that a high proportion of post-smolts crossed through multiple legislative jurisdictions and boundaries during their migration. This study provides the basis for spatially explicit assessment of the impact risk of coastal pressures on salmon during their first migration to sea

Large-scale evaluation of outcomes after a genetic diagnosis in children with severe developmental disorders

Purpose We sought to evaluate outcomes for clinical management after a genetic diagnosis from the Deciphering Developmental Disorders study. Methods Individuals in the Deciphering Developmental Disorders study who had a pathogenic/likely pathogenic genotype in the DECIPHER database were selected for inclusion (n = 5010). Clinical notes from regional clinical genetics services notes were reviewed to assess predefined clinical outcomes relating to interventions, prenatal choices, and information provision. Results Outcomes were recorded for 4237 diagnosed probands (85% of those eligible) from all 24 recruiting centers across the United Kingdom and Ireland. Clinical management was reported to have changed in 28% of affected individuals. Where individual-level interventions were recorded, additional diagnostic or screening tests were started in 903 (21%) probands through referral to a range of different clinical specialties, and stopped or avoided in a further 26 (0.6%). Disease-specific treatment was started in 85 (2%) probands, including seizure-control medications and dietary supplements, and contra-indicated medications were stopped or avoided in a further 20 (0.5%). The option of prenatal/preimplantation genetic testing was discussed with 1204 (28%) families, despite the relatively advanced age of the parents at the time of diagnosis. Importantly, condition-specific information or literature was given to 3214 (76%) families, and 880 (21%) were involved in family support groups. In the most common condition (KBG syndrome; 79 [2%] probands), clinical interventions only partially reflected the temporal development of phenotypes, highlighting the importance of consensus management guidelines and patient support groups. Conclusion Our results underscore the importance of achieving a clinico-molecular diagnosis to ensure timely onward referral of patients, enabling appropriate care and anticipatory surveillance, and for accessing relevant patient support groups

TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport

The analysis of individuals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating thoracic dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas, accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions.Peer reviewe

Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants.Peer reviewe

The UK10K project identifies rare variants in health and disease.

The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes