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Abstract Thyroid hormones play a critical role in regulation of multiple physiological functions and thyroid dysfunction is associated with substantial morbidity. Here, we use electronic health records to undertake a genome-wide association study of thyroid-stimulating hormone (TSH) levels, with a total sample size of 247,107. We identify 158 novel genetic associations, more than doubling the number of known associations with TSH, and implicate 112 putative causal genes, of which 76 are not previously implicated. A polygenic score for TSH is associated with TSH levels in African, South Asian, East Asian, Middle Eastern and admixed American ancestries, and associated with hypothyroidism and other thyroid disease in South Asians. In Europeans, the TSH polygenic score is associated with thyroid disease, including thyroid cancer and age-of-onset of hypothyroidism and hyperthyroidism. We develop pathway-specific genetic risk scores for TSH levels and use these in phenome-wide association studies to identify potential consequences of pathway perturbation. Together, these findings demonstrate the potential utility of genetic associations to inform future therapeutics and risk prediction for thyroid diseases.

Background: Globally, respiratory infections contribute to significant morbidity and mortality. However, genetic determinants of respiratory infections are understudied and remain poorly understood. Methods: We conducted a genome-wide association study in 19,459 hospitalised respiratory infection cases and 101,438 controls from UK Biobank (Stage 1). We followed-up well-imputed top signals from our Stage 1 analysis in 50,912 respiratory infection cases and 150,442 controls from 11 cohorts (Stage 2). We aggregated effect estimates across studies using inverse variance-weighted meta-analyses. Additionally, we investigated the function of the top signals in order to gain understanding of the underlying biological mechanisms. Results: From our Stage 1 analysis, we report 56 signals at P

Abstract Background Air pollution is a global, public health emergency. The effect of living in areas with very poor air quality on adolescents’ physical health is largely unknown. The aim of this study was to investigate the prevalence of adverse respiratory health outcomes among adolescents living in a known air pollution hotspot in South Africa. Methods Ambient air quality data from 2005 to 2019 for the two areas, Secunda and eMbalenhle, in the Highveld Air Pollution Priority Area in Mpumalanga province, South Africa were gathered and compared against national ambient air pollution standards and the World Health Organization Air Quality Guidelines. In 2019, adolescents attending schools in the areas completed a self-administered questionnaire investigating individual demographics, socio-economic status, health, medical history, and fuel type used in homes. Respiratory health illnesses assessed were doctor-diagnosed hay fever, allergies, frequent cough, wheezing, bronchitis, pneumonia and asthma. The relationship between presence (at least one) or absence (none) of self-reported respiratory illness and risk factors, e.g., fuel use at home, was explored. Logistic regression was used to estimate the odds ratio and 95% confidence interval (CI) of risk factors associated with respiratory illness adjusted for body mass index (measured by field assistants), gender, education level of both parents / guardians and socio-economic status. Results Particulate matter and ozone were the two pollutants most frequently exceeding national annual air quality standards in the study area. All 233 adolescent participants were between 13 and 17 years of age. Prevalence of self-reported respiratory symptoms among the participants ranged from 2% for ‘ever’ doctor-diagnosed bronchitis and pneumonia to 42% ever experiencing allergies; wheezing chest was the second most reported symptom (39%). Half (52%) of the adolescents who had respiratory illness were exposed to environmental tobacco smoke in the dwelling. There was a statistically significant difference between the presence or absence of self-reported respiratory illness based on the number of years lived in Secunda or eMbalenhle (p = 0.02). For a one-unit change in the number of years lived in an area, the odds of reporting a respiratory illness increased by a factor of 1.08 (p = 0.025, 95% CI = 1.01–1.16). This association was still statistically significant when the model was adjusted for confounders (p = 0.037). Conclusions Adolescents living in air polluted areas experience adverse health impacts Future research should interrogate long-term exposure and health outcomes among adolescents living in the air polluted environment.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is a complex trait with an estimated prevalence of 25% globally. We aimed to identify the genetic variant underlying a four-generation family with progressive NAFLD leading to cirrhosis, decompensation, and development of hepatocellular carcinoma in the absence of common risk factors such as obesity and type 2 diabetes. Methods: Exome sequencing and genome comparisons were used to identify the likely causal variant. We extensively characterised the clinical phenotype and post-prandial metabolic responses of family members with the identified novel variant in comparison with healthy non-carriers and wild-type patients with NAFLD. Variant-expressing hepatocyte-like cells (HLCs) were derived from human-induced pluripotent stem cells generated from homozygous donor skin fibroblasts and restored to wild-type using CRISPR-Cas9. The phenotype was assessed using imaging, targeted RNA analysis, and molecular expression arrays. Results: We identified a rare causal variant c.1691T>C p.I564T (rs745447480) in MTTP, encoding microsomal triglyceride transfer protein (MTP), associated with progressive NAFLD, unrelated to metabolic syndrome and without characteristic features of abetalipoproteinaemia. HLCs derived from a homozygote donor had significantly lower MTP activity and lower lipoprotein ApoB secretion than wild-type cells, while having similar levels of MTP mRNA and protein. Cytoplasmic triglyceride accumulation in HLCs triggered endoplasmic reticulum stress, secretion of pro-inflammatory mediators, and production of reactive oxygen species. Conclusions: We have identified and characterised a rare causal variant in MTTP, and homozygosity for MTTP p.I564T is associated with progressive NAFLD without any other manifestations of abetalipoproteinaemia. Our findings provide insights into mechanisms driving progressive NAFLD. Impact and Implications: A rare genetic variant in the gene MTTP has been identified as responsible for the development of severe non-alcoholic fatty liver disease in a four-generation family with no typical disease risk factors. A cell line culture created harbouring this variant gene was characterised to understand how this genetic variation leads to a defect in liver cells, which results in accumulation of fat and processes that promote disease. This is now a useful model for studying the disease pathways and to discover new ways to treat common types of fatty liver disease.

Abstract Background Healthcare workers (HCWs) are at high risk of SARS-CoV-2 infection. Effective use of personal protective equipment (PPE) reduces this risk. We sought to determine the prevalence and predictors of self-reported access to appropriate PPE (aPPE) for HCWs in the UK during the COVID-19 pandemic. Methods We conducted cross sectional analyses using data from a nationwide questionnaire-based cohort study administered between December 2020-February 2021. The outcome was a binary measure of self-reported aPPE (access all of the time vs access most of the time or less frequently) at two timepoints: the first national lockdown in the UK in March 2020 (primary analysis) and at the time of questionnaire response (secondary analysis). Results Ten thousand five hundred eight HCWs were included in the primary analysis, and 12,252 in the secondary analysis. 35.2% of HCWs reported aPPE at all times in the primary analysis; 83.9% reported aPPE at all times in the secondary analysis. In the primary analysis, after adjustment (for age, sex, ethnicity, migration status, occupation, aerosol generating procedure exposure, work sector and region, working hours, night shift frequency and trust in employing organisation), older HCWs and those working in Intensive Care Units were more likely to report aPPE at all times. Asian HCWs (aOR:0.77, 95%CI 0.67–0.89 [vs White]), those in allied health professional and dental roles (vs those in medical roles), and those who saw a higher number of COVID-19 patients compared to those who saw none (≥ 21 patients/week 0.74, 0.61–0.90) were less likely to report aPPE at all times. Those who trusted their employing organisation to deal with concerns about unsafe clinical practice, compared to those who did not, were twice as likely to report aPPE at all times. Significant predictors were largely unchanged in the secondary analysis. Conclusions Only a third of HCWs in the UK reported aPPE at all times during the first lockdown and that aPPE had improved later in the pandemic. We also identified key determinants of aPPE during the first UK lockdown, which have mostly persisted since lockdown was eased. These findings have important implications for the safe delivery of healthcare during the pandemic.

Objectives The complexities of the informed consent process for participating in cohort-based medical studies are well-recognised, and the pandemic presented specific challenges related to this. Our response in EXCEED was to build and deploy a local secure eConsent system that was simple to use, provided advanced functionality and improved data linkage. Approach The eConsent system is integrated into a web app (https://exceed.org.uk/) which was written in Python using the Django framework. A unique profile provides participant access to elements of the study, including two-way linkage to REDCap-based surveys and internal bespoke pages (for example an occupation questionnaire backed by a well-established classification) and access to consent to take part in sub-studies. This allowed participants to see which items have been completed or they have taken part in. Administrator tools were also built to enable advanced management and search functionality for dealing with participants queries or data quality issues. Results In 2020, backed by the new eConsent system, and driven by the COVID-19 pandemic, EXCEED undertook both a new wave of recruitment, and re-contacted existing participants to encourage them to take part in COVID related research. Profile registration and management of pre-2020 participants was also enabled by importing their contact details and consent data from legacy tools. Approximately 1000 EXCEED participants gave informed consent using the new system, while ~1000 existing participants registered. Facilitated by improved data quality using the eConsent system, we correctly linked 93% of consented participants to primary care health care records. This high level of data linkage enables research on the causes and consequences of COVID-19 infection, studies of the genomics of disease onset and progression and recall studies. Conclusion We developed a novel eConsent system, which as well as providing online participant registration and improved administration of participants has improved data linkage. Furthermore, the success of the approach has led it to be implemented in other studies with similar requirements.

Abstract Background Airway bacterial dysbiosis is a feature of chronic obstructive pulmonary disease (COPD). However, there is limited comparative data of the lung microbiome between healthy smokers, non-smokers and COPD. Methods We compared the 16S rRNA gene-based sputum microbiome generated from pair-ended Illumina sequencing of 124 healthy subjects (28 smokers and 96 non-smokers with normal lung function), with single stable samples from 218 COPD subjects collected from three UK clinical centres as part of the COPDMAP consortium. Results In healthy subjects Firmicutes, Bacteroidetes and Actinobacteria were the major phyla constituting 88% of the total reads, and Streptococcus, Veillonella, Prevotella, Actinomyces and Rothia were the dominant genera. Haemophilus formed only 3% of the healthy microbiome. In contrast, Proteobacteria was the most dominant phylum accounting for 50% of the microbiome in COPD subjects, with Haemophilus and Moraxella at genus level contributing 25 and 3% respectively. There were no differences in the microbiome profile within healthy and COPD subgroups when stratified based on smoking history. Principal coordinate analysis on operational taxonomic units showed two distinct clusters, representative of healthy and COPD subjects (PERMANOVA, p = 0·001). Conclusion The healthy and COPD sputum microbiomes are distinct and independent of smoking history. Our results underline the important role for Gammaproteobacteria in COPD.

BackgroundHealthcare workers (HCWs), particularly those from ethnic minority groups, have been shown to be at disproportionately higher risk of infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) compared to the general population. However, there is insufficient evidence on how demographic and occupational factors influence infection risk among ethnic minority HCWs.Methods and findingsWe conducted a cross-sectional analysis using data from the baseline questionnaire of the United Kingdom Research study into Ethnicity and Coronavirus Disease 2019 (COVID-19) Outcomes in Healthcare workers (UK-REACH) cohort study, administered between December 2020 and March 2021. We used logistic regression to examine associations of demographic, household, and occupational risk factors with SARS-CoV-2 infection (defined by polymerase chain reaction (PCR), serology, or suspected COVID-19) in a diverse group of HCWs. The primary exposure of interest was self-reported ethnicity. Among 10,772 HCWs who worked during the first UK national lockdown in March 2020, the median age was 45 (interquartile range [IQR] 35 to 54), 75.1% were female and 29.6% were from ethnic minority groups. A total of 2,496 (23.2%) reported previous SARS-CoV-2 infection. The fully adjusted model contained the following dependent variables: demographic factors (age, sex, ethnicity, migration status, deprivation, religiosity), household factors (living with key workers, shared spaces in accommodation, number of people in household), health factors (presence/absence of diabetes or immunosuppression, smoking history, shielding status, SARS-CoV-2 vaccination status), the extent of social mixing outside of the household, and occupational factors (job role, the area in which a participant worked, use of public transport to work, exposure to confirmed suspected COVID-19 patients, personal protective equipment [PPE] access, aerosol generating procedure exposure, night shift pattern, and the UK region of workplace). After adjustment, demographic and household factors associated with increased odds of infection included younger age, living with other key workers, and higher religiosity. Important occupational risk factors associated with increased odds of infection included attending to a higher number of COVID-19 positive patients (aOR 2.59, 95% CI 2.11 to 3.18 for ≥21 patients per week versus none), working in a nursing or midwifery role (1.30, 1.11 to 1.53, compared to doctors), reporting a lack of access to PPE (1.29, 1.17 to 1.43), and working in an ambulance (2.00, 1.56 to 2.58) or hospital inpatient setting (1.55, 1.38 to 1.75). Those who worked in intensive care units were less likely to have been infected (0.76, 0.64 to 0.92) than those who did not. Black HCWs were more likely to have been infected than their White colleagues, an effect which attenuated after adjustment for other known risk factors. This study is limited by self-selection bias and the cross sectional nature of the study means we cannot infer the direction of causality.ConclusionsWe identified key sociodemographic and occupational risk factors associated with SARS-CoV-2 infection among UK HCWs, and have determined factors that might contribute to a disproportionate odds of infection in HCWs from Black ethnic groups. These findings demonstrate the importance of social and occupational factors in driving ethnic disparities in COVID-19 outcomes, and should inform policies, including targeted vaccination strategies and risk assessments aimed at protecting HCWs in future waves of the COVID-19 pandemic.Trial registrationThe study was prospectively registered at ISRCTN (reference number: ISRCTN11811602).

Summary: Background: Several countries now have mandatory SARS-CoV-2 vaccination for healthcare workers (HCWs) or the general population. HCWs’ views on this are largely unknown. Using data from the nationwide UK-REACH study we aimed to understand UK HCW's views on improving SARS-CoV-2 vaccination coverage, including mandatory vaccination. Methods: Between 21st April and 26th June 2021, we administered an online questionnaire via email to 17 891 UK HCWs recruited as part of a longitudinal cohort from across the UK who had previously responded to a baseline questionnaire (primarily recruited through email) as part of the United Kingdom Research study into Ethnicity And COVID-19 outcomes in Healthcare workers (UK-REACH) nationwide prospective cohort study. We categorised responses to a free-text question “What should society do if people do not get vaccinated against COVID-19?” using qualitative content analysis. We collapsed categories into a binary variable: favours mandatory vaccination or not, using logistic regression to calculate its demographic predictors, and its occupational, health, and attitudinal predictors adjusted for demographics. Findings: Of 5633 questionnaire respondents, 3235 answered the free text question. Median age of free text responders was 47 years (IQR 36–56) and 2705 (74.3%) were female. 18% (n = 578) favoured mandatory vaccination (201 [6%] participants for HCWs and others working with vulnerable populations; 377 [12%] for the general population), but the most frequent suggestion was education (32%, n = 1047). Older HCWs (OR 1.84; 95% CI 1.44–2.34 [≥55 years vs 16 years to

Background: New data collection in established longitudinal population studies provides an opportunity for studying the risk factors and sequelae of the novel coronavirus disease 2019 (COVID-19), plus the indirect impacts of the COVID-19 pandemic on wellbeing. The Extended Cohort for E-health, Environment and DNA (EXCEED) cohort is a population-based cohort (N>11,000), recruited from 2013 in Leicester, Leicestershire and Rutland. EXCEED includes consent for electronic healthcare record (EHR) linkage, spirometry, genomic data, and questionnaire data. Methods: Between May 2020 and July 2021, a new questionnaire was deployed in EXCEED, which captured COVID-19 symptoms, general physical and mental health, plus socioeconomic and environmental factors during the pandemic. An online system was developed to invite new participants to join EXCEED, with informed consent being provided online. New and existing participants then completed the COVID-19 questionnaire online. A subset of the new questionnaire respondents were invited to participate in COVID-19 serology substudies, using home antibody testing kits. Results: In total, 3,693 participants provided COVID-19 infection status (median age 62.9 (IQR 54.7-69.2), 58.9% female). Trends of monthly incidence proportions of COVID-19 in EXCEED (self-report or symptom-predicted) approximated local and national figures. Regression analysis of 2,768 participants with linked EHR data showed no obvious monotonic relationship between number of chronic diseases (of 16 pre-specified diseases) and COVID-19 infection. There were 2,144 participants with valid results from a kit allowing differentiation between antibodies due to vaccination or infection. Of these, 8.5% had results consistent with previous COVID-19 infection, and 85.9% had evidence of COVID-19 vaccination, but without evidence of infection. Conclusions: Enriching EXCEED with a new COVID-19 questionnaire and serology data may improve understanding of the risk factors, clinical sequelae and broader impacts of the COVID-19 pandemic in the general population. Controlled access to these data for bona fide researchers is via application to the EXCEED study.

Introduction The COVID-19 pandemic has resulted in significant morbidity and mortality and devastated economies globally. Among groups at increased risk are healthcare workers (HCWs) and ethnic minority groups. Emerging evidence suggests that HCWs from ethnic minority groups are at increased risk of adverse COVID-19-related outcomes. To date, there has been no large-scale analysis of these risks in UK HCWs or ancillary workers in healthcare settings, stratified by ethnicity or occupation, and adjusted for confounders. This paper reports the protocol for a prospective longitudinal questionnaire study of UK HCWs, as part of the UK-REACH programme (The United Kingdom Research study into Ethnicity And COVID-19 outcomes in Healthcare workers).Methods and analysis A baseline questionnaire will be administered to a national cohort of UK HCWs and ancillary workers in healthcare settings, and those registered with UK healthcare regulators, with follow-up questionnaires administered at 4 and 8 months. With consent, questionnaire data will be linked to health records with 25-year follow-up. Univariate associations between ethnicity and clinical COVID-19 outcomes, physical and mental health, and key confounders/explanatory variables will be tested. Multivariable analyses will test for associations between ethnicity and key outcomes adjusted for the confounder/explanatory variables. We will model changes over time by ethnic group, facilitating understanding of absolute and relative risks in different ethnic groups, and generalisability of findings.Ethics and dissemination The study is approved by Health Research Authority (reference 20/HRA/4718), and carries minimal risk. We aim to manage the small risk of participant distress about questions on sensitive topics by clearly participant information that the questionnaire covers sensitive topics and there is no obligation to answer these or any other questions, and by providing support organisation links. Results will be disseminated with reports to Government and papers submitted to pre-print servers and peer reviewed journals.Trial registration number ISRCTN11811602; Pre-results.

Introduction COVID-19 has spread rapidly worldwide, causing significant morbidity and mortality. People from ethnic minorities, particularly those working in healthcare settings, have been disproportionately affected. Current evidence of the association between ethnicity and COVID-19 outcomes in people working in healthcare settings is insufficient to inform plans to address health inequalities.Methods and analysis This study combines anonymised human resource databases with professional registration and National Health Service data sets to assess associations between ethnicity and COVID-19 diagnosis, hospitalisation and death in healthcare workers in the UK. Adverse COVID-19 outcomes will be assessed between 1 February 2020 (date following first confirmed COVID-19 case in UK) and study end date (31 January 2021), allowing 1-year of follow-up. Planned analyses include multivariable Poisson, logistic and flexible parametric time-to-event regression within each country, adjusting for core predictors, followed by meta-analysis of country-specific results to produce combined effect estimates for the UK. Mediation analysis methods will be explored to examine the direct, indirect and mediated interactive effects between ethnicity, occupational group and COVID-19 outcomes.Ethics and dissemination Ethical approval for the UK-REACH programme has been obtained via the expedited HRA COVID-19 processes (REC ref: 20/HRA/4718, IRAS ID: 288316). Research information will be anonymised via the Secure Anonymised Information Linkage Databank before release to researchers. Study results will be submitted for publication in an open access peer-reviewed journal and made available on our dedicated website (https://uk-reach.org/).Trial registration number ISRCTN11811602.

Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P

Homozygosity for the SERPINA1 Z allele causes α1-antitrypsin deficiency, a rare condition that can cause lung and liver disease. However, the effects of Z allele heterozygosity on nonrespiratory phenotypes, and on lung function in the general population, remain unclear. We conducted a large, population-based study to determine Z allele effects on >2400 phenotypes in the UK Biobank (N=303 353). Z allele heterozygosity was strongly associated with increased height (β=1.02 cm, p=3.91×10−68), and with other nonrespiratory phenotypes including increased risk of gall bladder disease, reduced risk of heart disease and lower blood pressure, reduced risk of osteoarthritis and reduced bone mineral density, increased risk of headache and enlarged prostate, as well as with blood biomarkers of liver function. Heterozygosity was associated with higher height-adjusted forced expiratory volume in 1 s (FEV1) (β=19.36 mL, p=9.21×10−4) and FEV1/forced vital capacity (β=0.0031, p=1.22×10−5) in nonsmokers, whereas in smokers, this protective effect was abolished. Furthermore, we show for the first time that sex modifies the association of the Z allele on lung function. We conclude that Z allele heterozygosity and homozygosity exhibit opposing effects on lung function in the UK population, and that these associations are modified by smoking and sex. In exploratory analyses, heterozygosity for the Z allele also showed pleiotropic associations with nonrespiratory health-related traits and disease risk.

Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P

Recall-by-Genotype (RbG) is an approach to recall participants from genetic studies based on their specific genotype for further, more extensive phenotyping. Here, the authors discuss examples of RbG as well as practical and ethical considerations and provide an online tool to aid in designing RbG studies.

Cervical decidual reaction in pregnancy is a common finding. In rare cases, these changes can mimic the appearance of invasive cervical cancers.We are presenting a case of a pregnant woman with a large cervical mass. Whilst magnetic resonance imaging (MRI) supported a diagnosis of cervical cancer, cervical tissue biopsies showed decidual reaction and no invasion. Cervical appearance postpartum reverted back to normal. Importantly, cervical biopsies were obtained in a fully equipped theatre attended by multiple specialities in case of life-threatening haemorrhage during pregnancy.

Background: We examined the feasibility and outcomes of Artificial Intelligence (AI) as a virtual coach in guided self-help (GSH-AI) compared to pure self-help (PSH). Method: Participants (N = 85 undergraduate university students; M age = 20.65 years [SD = 2.38]; 84 % female) were randomised to PSH (N = 42) or GSH-AI (N = 43). The intervention was a brief 11-module online cognitive behaviour therapy for perfectionism intervention completed over 4-weeks. GSH-AI participants were given suggested questions to ask AI for guidance in completing the intervention. Data were collected at baseline, 4- and 8-weeks post-randomisation. Results: Engagement was good, only one person in each group did not use any modules; module completion was equivalent across conditions (6.67, SD = 3.22 and 6.18, SD = 3.42 respectively). Between baseline and post-intervention people in the GSH-AI condition showed an almost 3.5 times increase in preferring support to be received from AI versus other modes of support. Only 52 % and 22 % of participants completed 4- and 8-week post-randomisation surveys, with no differences in psychological outcomes between the PSH and GSH-AI groups. Main effects of time indicated moderate to large within-group effect size improvements for disordered eating, stress, anxiety, and perfectionism. Conclusions: Qualitative feedback indicated that AI was initially acceptable as a guide and became even more acceptable after it had been experienced. Fully powered trials are required to determine the impact of AI guidance on outcomes, and whether type of AI platform (customised versus generic) and type of mental health disorder interact with its effects.

Propionic acid (PPA), an anti-fungal agent and common food additive, has been shown to induce atypical neurodevelopment in mice, accompanied by gastrointestinal dysfunction potentially resulting from gut dysbiosis. A putative association between dietary PPA exposure and gut dysbiosis is suggested but has not been explored directly. Here, we investigated PPA-associated alteration in gut microbial composition that may result in dysbiosis. Using long-read metagenomic sequencing, gut microbiomes of mice fed an untreated (n=9) or PPA-rich (n=13) diet were sequenced to assess differences in microbial composition and bacterial metabolic pathways. Dietary PPA was associated with an increased abundance of notable taxa, including several species of Bacteroides, Prevotella, and Ruminococcus, whose member species have previously been associated with PPA production. Microbiomes of PPA exposed mice also possessed a greater abundance of pathways related to lipid metabolism and steroid hormone biosynthesis. Our findings demonstrate PPA’s effect in altering the gut microbiota and associated metabolic pathways. These observed changes highlight how preservatives listed as safe for consumption may affect gut microbiome composition with implications for one’s health.

The continual evolution of SARS-CoV-2 has significantly influenced the global response to the COVID-19 pandemic, with the emergence of highly transmissible and immune-evasive variants posing persistent challenges. The Omicron variant, first identified in November 2021, rapidly replaced the Delta variant, becoming the predominant strain worldwide. In Florida, Omicron was first detected in December 2021, leading to an unprecedented surge in cases that surpassed all prior waves, despite extensive vaccination efforts. This study investigates the molecular evolution and transmission dynamics of the Omicron lineages during Florida’s Omicron waves, supported by a robust dataset of over 1000 sequenced genomes. Through phylogenetic and phylodynamic analyses, we capture the rapid diversification of the Omicron lineages, identifying significant importation events, predominantly from California, Texas, and New York, and exportation to North America, Europe, and South America. Variants such as BA.1, BA.2, BA.4, and BA.5 exhibited distinct transmission patterns, with BA.2 showing the ability to reinfect individuals previously infected with BA.1. Despite the high transmissibility and immune evasion of the Omicron sub-lineages, the plateauing of cases by late 2022 suggests increasing population immunity from prior infection and vaccination. Our findings underscore the importance of continuous genomic surveillance in identifying variant introductions, mapping transmission pathways, and guiding public health interventions to mitigate current and future pandemic risks.

The Coastal and Marine Ecological Classification Standard (CMECS) was applied to four portions of Acadia National Park, USA, focusing on intertidal rocky and tidal flat habitats. Side-scan sonar coupled with multi-phase echo sounder bathymetry are the primary data sources used to map the seafloor, coupled with underwater video imagery and surface grab samples for grain size and macrofaunal analysis. The CMECS Substrate, Geoform, and Biotic components were effective in describing the study areas. However, integrating the CMECS components to define Biotopes was more challenging due to the limited number of grab samples available and because the dominant species within a given map unit is largely inconsistent. While Biotopes ultimately could not be defined in this study, working within the CMECS framework to create statistically significant biotopes revealed the complexity of these study areas that may otherwise have been overlooked. This study demonstrates the effectiveness of the CMECS classification, including the framework’s ability to be flexible in communicating information.

Medical imaging allows for the visualization of spinal cord compression sites; however, it is impossible to assess the impact of visible stenotic sites on neuronal functioning, which is crucial information to formulate a correct prognosis and install targeted therapy. It is hypothesized that with the transcranial electrical stimulation (TES) technique, neurological impairment can be reliably diagnosed.ObjectiveTo evaluate the ability of the TES technique to assess neuronal functional integrity in ataxic horses by recording TES-induced muscular evoked potentials (MEPs) in three different muscles and to structurally involve multiple ancillary diagnostic techniques, such as clinical neurological examination, plain radiography (RX) with ratio assessment, contrast myelography, and post-mortem gross and histopathological examination.MethodsNine ataxic horses, showing combined fore and hindlimb ataxia (grades 2–4), were involved, together with 12 healthy horses. TES-induced MEPs were recorded bilaterally at the level of the trapezius (TR), the extensor carpi radialis (ECR), and tibialis cranialis (TC) muscles. Two Board-certified radiologists evaluated intra- and inter-sagittal diameter ratios on RX, reductions of dorsal contrast columns, and dural diameters (range skull-T1). Post-mortem gross pathological and segmental histopathological examination was also performed by a Board-certified pathologist.ResultsTES-MEP latencies were significantly prolonged in both ECR and TC in all ataxic horses as opposed to the healthy horses. The TR showed a mixed pattern of normal and prolonged latency times. TES-MEP amplitudes were the least discriminative between healthy and ataxic horses. Youden’s cutoff latencies for ataxic horses were 24.6 ms for the ECR and 45.5 ms for the TC (sensitivity and specificity of 100%). For healthy horses, maximum latency values were 22 and 37 ms, respectively. RX revealed spinal cord compression in 8 out of 9 involved ataxic horses with positive predictive values of 0–100%. All ataxic horses showed multi-segmental Wallerian degeneration. All pathological changes recorded in the white matter of the spinal cord were widely dispersed across all cervical segments, whereas gray matter damage was more localized at the specific segmental level.ConclusionTES-MEP latencies are highly sensitive to detect impairment of spinal cord motor functions for mild-to-severe ataxia (grades 2–4).

Perfectionism is a transdiagnostic process associated with a range of psychological disorders. Cognitive Behaviour Therapy for Perfectionism (CBT-P) has been demonstrated as efficacious across guided and unguided internet delivered interventions in reducing perfectionism and psychopathology. The aim of this pilot study was to understand perceptions and acceptability of an artificial intelligence supplemented CBT-P intervention (AI-CBT-P) in young people with lived experience of anxiety and depression (n = 8; age range 19–29 years, M = 24 years, SD = 3.77; 50 % female, 38 % male, 12 % non-binary). Young people reported that they were frequent users of artificial intelligence for study, work and general information, were positive about the intervention and using artificial intelligence for guidance in a self-help intervention, but also noted several concerns. Young people perceived numerous benefits to AI-CBT-P, including ease of access, low cost, lack of stigma and benefits for individuals with social anxiety. Overall, young people appear to be interested in, and have a positive view of, AI-CBT-P. Further research is now required to examine the feasibility and acceptability of the intervention.

Abstract Viral genomic surveillance has been integral in the global response to the SARS-CoV-2 pandemic. Surveillance efforts rely on the availability of representative clinical specimens from ongoing testing activities. However, testing practices have recently shifted due to the widespread availability and use of rapid antigen tests, which could lead to gaps in future monitoring efforts. As such, genomic surveillance strategies must adapt to include laboratory workflows that are robust to sample type. To that end, we compare the results of RT-qPCR and viral genome sequencing using samples from positive BinaxNOW COVID-19 Antigen Card swabs (N = 555) to those obtained from nasopharyngeal (NP) swabs used for nucleic acid amplification testing (N = 135). We show that swabs obtained from antigen cards are comparable in performance to samples from NP swabs, providing a viable alternative and allowing for the potential expansion of viral genomic surveillance to outpatient clinic as well as other settings where rapid antigen tests are often used.

Abstract Background Oesophageal and gastrooesophageal junction (GOJ) carcinoma frequently present with dysphagia and de novo metastatic disease. There is scope to improve treatment paradigms to both address symptoms and improve survival. One method is integrating immune checkpoint inhibition with novel treatment combinations. Methods PALEO is a single arm, phase II clinical trial in patients with previously untreated, oligometastatic or locoregionally advanced oesophageal or GOJ carcinoma and dysphagia. PALEO is sponsored by the Australasian Gastro-Intestinal Trials Group (AGITG). Participants receive 2 weeks of therapy with concurrent hypofractionated radiotherapy of 30Gy in 10 fractions to the primary tumour, weekly carboplatin AUC2, weekly paclitaxel 50 mg/m2 and durvalumab 1500 mg q4 weekly, followed by durvalumab monotherapy continuing at 1500 mg q4weekly until disease progression, unacceptable toxicity or 24 months of therapy. A single metastasis is treated with stereotactic radiotherapy of 24Gy in 3 fractions in week 7. The trial primary endpoint is the progression free survival rate at 6 months. Secondary endpoints include duration of dysphagia relief, nutritional status change, quality of life, response rate, toxicity, progression free survival and overall survival. The tertiary endpoint is prediction of outcome based on biomarkers identified from patient serial blood samples collected pre- and post-radiotherapy. Discussion This unique investigator-initiated clinical trial is designed to simultaneously address the clinically relevant problems of dysphagia and distant disease control. The overarching aims are to improve patient nutrition, quality of life and survival with low toxicity therapy. AGITG PALEO is a multidisciplinary collaboration and will add to the understanding of the relationship between radiotherapy and the anti-tumour immune response. Trial registration Australian and New Zealand Clinical Trials Registry: ACTRN12619001371189 , registered 8 October 2019.

Metagenomic sequencing analysis is central to investigating microbial communities in clinical and environmental studies. Short-read sequencing remains the primary approach for metagenomic research; however, long-read sequencing may offer advantages of improved metagenomic assembly and resolved taxonomic identification. To compare the relative performance for metagenomic studies, we simulated short- and long-read datasets using increasingly complex metagenomes comprising 10, 20, and 50 microbial taxa. Additionally, we used an empirical dataset of paired short- and long-read data generated from mouse fecal pellets to assess real-world performance. We compared metagenomic assembly quality, taxonomic classification, and metagenome-assembled genome (MAG) recovery rates. We show that long-read sequencing data significantly improve taxonomic classification and assembly quality. Metagenomic assemblies using simulated long reads were more complete and more contiguous with higher rates of MAG recovery. This resulted in more precise taxonomic classifications. Principal component analysis of empirical data demonstrated that sequencing technology affects compositional results as samples clustered by sequence type, not sample type. Overall, we highlight strengths of long-read metagenomic sequencing for microbiome studies, including improving the accuracy of classification and relative abundance estimates. These results will aid researchers when considering which sequencing approaches to use for metagenomic projects.

Plain English summary Many people with eating disorders (EDs) either do not access treatment, access it well after symptoms first start, or drop out of treatment. This study evaluated ways to improve early access to the best treatments for those with EDs in regional Australia. Links were formed between general medical practitioners and treatment providers (such as psychologists and dietitians) who received ongoing training, feedback and support. This approach achieved completion rates and outcomes equivalent to those found in specialised clinical trials of ED treatments. A key finding was the benefit of a care coordinator to connect users to services and help navigate barriers to ongoing treatment.

Abstract The Martian bow shock stands as the first defense against the solar wind and shapes the Martian magnetosphere. Previous studies showed the correlation between the Martian bow shock location and solar wind parameters. Here we present direct evidence of solar wind effects on the Martian bow shock by analyzing Tianwen‐1 and MAVEN data. We examined three cases where Tianwen‐1 data show rapid oscillations of the bow shock, while MAVEN data record changes in solar wind plasma and magnetic field. The results indicate that the bow shock is rapidly compressed and then expanded during the dynamic pressure pulse in the solar wind, and is also oscillated during the IMF rotation. The superposition of variations in multiple solar wind parameters leads to more intensive bow shock oscillation. This study emphasizes the importance of joint observations by Tianwen‐1 and MAVEN for studying the real‐time response of the Martian magnetosphere to the solar wind.

Abstract Background teen Mental Health First Aid (tMHFA) is a universal mental health literacy, stigma reduction, help-seeking, and suicide prevention program designed for adolescents in Years 10–12 of secondary school (16–18 years). tMHFA is delivered by trained instructors, in a regular classroom setting, to increase the knowledge, attitudes and behaviours that adolescents’ require to better support peers with mental health problems or mental health crises. Methods To explore the efficacy of tMHFA, a cluster crossover randomised controlled trial was conducted with Year 10 students in four schools in Victoria, Australia, using physical first aid training as the control intervention. Of the 1942 eligible students, 1,624 completed baseline and 894 completed follow-up surveys. Online surveys, administered one week before training and again 12-months later, included vignettes depicting peers John (depression and suicide risk) and Jeanie (social anxiety/phobia), measures of mental health first aid (quality of first aid intentions, confidence, first aid behaviours provided, and first aid behaviours received), mental health literacy (beliefs about adult help, help-seeking intentions), and stigma (social distance, weak-not-sick, dangerous/unpredictable, and would not tell anyone). Results The primary outcome—quality of first aid intentions towards the John vignette—showed statistically significant group x time interactions, with tMHFA students reporting more helpful and less unhelpful first aid intentions, than PFA students did over time. Confidence in providing first aid also showed significant interactions. First aid behaviours—both those provided to a peer with a mental health problem and those received from a peer—showed null results. Ratings of both beliefs about adult help and help-seeking intentions were found to be significantly improved among tMHFA students at follow-up. A group x time interaction was found on one stigma scale (would not tell anyone). Conclusions This trial showed that, one year after training, tMHFA improves first aid intentions towards peers with depression and suicide risk, confidence in helping peers with mental health problems, willingness to tell someone and seek help from an adult or health professional if experiencing a mental health problem. Trial registration This research was registered with Australia New Zealand Clinical Trials Registry: ACTRN12614000061639 .

It has been estimated that in the next decade, IHD prevalence, DALYs and deaths will increase more significantly in EMR than in any other region of the world. This study aims to provide a comprehensive description of the trends in the burden of ischemic heart disease (IHD) across the countries of the Eastern Mediterranean Region (EMR) from 1990 to 2019. Data on IHD prevalence, disability-adjusted life years (DALYs), mortality, DALYs attributable to risk factors, healthcare access and quality index (HAQ), and universal health coverage (UHC) were extracted from the Global Burden of Disease (GBD) database for EMR countries. The data were stratified based on the social demographic index (SDI). Information on cardiac rehabilitation was obtained from publications by the International Council of Cardiovascular Prevention and Rehabilitation (ICCPR), and additional country-specific data were obtained through advanced search methods. Age standardization was performed using the direct method, applying the estimated age structure of the global population from 2019. Uncertainty intervals were calculated through 1000 iterations, and the 2.5th and 97.5th percentiles were derived from these calculations. The age-standardized prevalence of IHD in the EMR increased from 5.0% to 5.5% between 1990 and 2019, while it decreased at the global level. In the EMR, the age-standardized rates of IHD mortality and DALYs decreased by 11.4% and 15.4%, respectively, during the study period, although both rates remained higher than the global rates. The burden of IHD was found to be higher in males compared to females. Bahrain exhibited the highest decrease in age-standardized prevalence (-3.7%), mortality (-65.0%), and DALYs (-69.1%) rates among the EMR countries. Conversely, Oman experienced the highest increase in prevalence (14.5%), while Pakistan had the greatest increase in mortality (30.0%) and DALYs (32.0%) rates. The top three risk factors contributing to IHD DALYs in the EMR in 2019 were high systolic blood pressure, high low-density lipoprotein cholesterol, and particulate matter pollution. The trend analysis over the 29-year period (1990-2019) revealed that high fasting plasma glucose (64.0%) and high body mass index (23.4%) exhibited increasing trends as attributed risk factors for IHD DALYs in the EMR. Our findings indicate an increasing trend in the prevalence of IHD and a decrease in mortality and DALYs in the EMR. These results emphasize the need for well-planned prevention and treatment strategies to address the risk factors associated with IHD. It is crucial for the countries in this region to prioritize the development and implementation of programs focused on health promotion, education, prevention, and medical care.

Abstract White‐nose syndrome (WNS) is a disease caused by the fungus Pseudogymnoascus destructans which has resulted in the deaths of millions of bats across eastern North America. To date, hibernacula counts have been the predominant means of tracking the spread and impact of this disease on bat populations. However, an understanding of the impacts of WNS on demographic parameters outside the winter season is critical to conservation and recovery of bat populations impacted by this disease. We used long‐term monitoring data to examine WNS‐related impacts to summer populations in West Virginia, where WNS has been documented since 2009. Using capture data from 290 mist‐net sites surveyed from 2003 to 2019 on the Monongahela National Forest, we estimated temporal patterns in presence and relative abundance for each bat species. For species that exhibited a population‐level response to WNS, we investigated post‐WNS changes in adult female reproductive state and body mass. Myotis lucifugus (little brown bat), M. septentrionalis (northern long‐eared bat), and Perimyotis subflavus (tri‐colored bat) all showed significant decreases in presence and relative abundance during and following the introduction of WNS, while Eptesicus fuscus (big brown bat) and Lasiurus borealis (eastern red bat) responded positively during the WNS invasion. Probability of being reproductively active was not significantly different for any species, though a shift to earlier reproduction was estimated for E. fuscus and M. septentrionalis. For some species, body mass appeared to be influenced by the WNS invasion, but the response differed by species and reproductive state. Results suggest that continued long‐term monitoring studies, additional research into impacts of this disease on the fitness of WNS survivors, and a focus on providing optimal nonwintering habitat may be valuable strategies for assessing and promoting recovery of WNS‐affected bat populations.

Antibiotic resistance is a significant global health concern that affects both human and animal populations. The One Health approach acknowledges the interconnectedness of human health, animal health, and the environment. It emphasizes the importance of collaboration and coordination across these sectors to tackle complex health challenges such as antibiotic resistance. In the context of One Health, antibiotic resistance refers to the ability of bacteria to withstand the efficacy of antibiotics, rendering them less effective or completely ineffective in treating infections. The emergence and spread of antibiotic-resistant bacteria pose a threat to human and animal health, as well as to the effectiveness of medical treatments and veterinary interventions. In particular, One Health recognizes that antibiotic use in human medicine, animal agriculture, and the environment are interconnected factors contributing to the development and spread of antibiotic resistance. For example, the misuse and overuse of antibiotics in human healthcare, including inappropriate prescribing and patient non-compliance, can contribute to the selection and spread of resistant bacteria. Similarly, the use of antibiotics in livestock production for growth promotion and disease prevention can contribute to the development of antibiotic resistance in animals and subsequent transmission to humans through the food chain. Addressing antibiotic resistance requires a collaborative One Health approach that involves multiple participants, including healthcare professionals, veterinarians, researchers, and policymakers.

Neurocognitive consequences of blast-induced traumatic brain injury (bTBI) pose significant concerns for military service members and veterans with the majority of “invisible injury.” However, the underlying mechanism of such mild bTBI by low-intensity blast (LIB) exposure for long-term cognitive and mental deficits remains elusive. Our previous studies have shown that mice exposed to LIB result in nanoscale ultrastructural abnormalities in the absence of gross or apparent cellular damage in the brain. Here we tested the hypothesis that glutamatergic hyperexcitability may contribute to long-term learning deficits. Using brain slice electrophysiological recordings, we found an increase in averaged frequencies with a burst pattern of miniature excitatory postsynaptic currents (mEPSCs) in hippocampal CA3 neurons in LIB-exposed mice at 1- and 7-days post injury, which was blocked by a specific NMDA receptor antagonist AP5. In addition, cognitive function assessed at 3-months post LIB exposure by automated home-cage monitoring showed deficits in dynamic patterns of discrimination learning and cognitive flexibility in LIB-exposed mice. Collected hippocampal tissue was further processed for quantitative global-proteomic analysis. Advanced data-independent acquisition for quantitative tandem mass spectrometry analysis identified altered expression of proteins involved in synaptic plasticity and serine protease inhibitors in LIB-exposed mice. Some were correlated with the ability of discrimination learning and cognitive flexibility. These findings show that acute glutamatergic hyperexcitability in the hippocampus induced by LIB may contribute to long-term cognitive dysfunction and protein alterations. Studies using this military-relevant mouse model of mild bTBI provide valuable insights into developing a potential therapeutic strategy to ameliorate hyperexcitability-modulated LIB injuries.

Reason for Performing StudySo far, only transcranial motor evoked potentials (MEP) of the extensor carpi radialis and tibialis cranialis have been documented for diagnostic evaluation in horses. These allow for differentiating whether lesions are located in either the thoraco-lumbar region or in the cervical myelum and/or brain. Transcranial trapezius MEPs further enable to distinguish between spinal and supraspinal located lesions. No normative data are available. It is unclear whether transcranial electrical stimulation (TES) and transcranial magnetic stimulation (TMS) are interchangeable modalities.ObjectivesTo provide normative data for trapezius MEP parameters in horses for TES and TMS and to discern direct and indirect conduction routes by neurophysiological models that use anatomical geometric characteristics to relate latency times with peripheral (PCV) and central conduction velocities (CCV).MethodsTranscranial electrical stimulation-induced trapezius MEPs were obtained from twelve horses. TES and TMS-MEPs (subgroup 5 horses) were compared intra-individually. Trapezius MEPs were measured bilaterally twice at 5 intensity steps. Motoneurons were localized using nerve conduction models of the cervical and spinal accessory nerves (SAN). Predicted CCVs were verified by multifidus MEP data from two horses referred for neurophysiological assessment.ResultsMean MEP latencies revealed for TES: 13.5 (11.1–16.0)ms and TMS: 19.7 (12–29.5)ms, comprising ∼100% direct routes and for TMS mixed direct/indirect routes of L:23/50; R:14/50. Left/right latency decreases over 10 > 50 V for TES were: –1.4/–1.8 ms and over 10 > 50% for TMS: –1.7/–3.5 ms. Direct route TMS-TES latency differences were 1.88–4.30 ms. 95% MEP amplitudes ranges for TES were: L:0.26–22 mV; R:0.5–15 mV and TMS: L:0.9 – 9.1 mV; R:1.1–7.9 mV.ConclusionThis is the first study to report normative data characterizing TES and TMS induced- trapezius MEPs in horses. The complex trapezius innervation leaves TES as the only reliable stimulation modality. Differences in latency times along the SAN route permit for estimation of the location of active motoneurons, which is of importance for clinical diagnostic purpose. SAN route lengths and latency times are governed by anatomical locations of motoneurons across C2-C5 segments. TES intensity-dependent reductions of trapezius MEP latencies are similar to limb muscles while MEP amplitudes between sides and between TES and TMS are not different. CCVs may reach 180 m/s.

Abstract Pulmonary arterial hypertension (PAH) is characterized by increased resistance in the pulmonary arterioles as a result of remodeled blood vessels. We sought all available epidemiologic data on population‐based prevalence, incidence, and 1‐year survival of PAH as part of the Global Burden of Disease Study. We performed a systematic review searching Global Index Medicus (GIM) for keywords related to PAH between 1980 and 2021 and identified population‐representative sources of prevalence, incidence, and mortality for clinically diagnosed PAH. Of 6772 articles identified we found 65 with population‐level data: 17 for prevalence, 17 for incidence, and 58 reporting case fatality. Reported prevalence ranged from 0.37 cases/100,000 persons in a referral center of French children to 15 cases/100,000 persons in an Australian study. Reported incidence ranged from 0.008 cases/100,000 person‐years in Finland, to 1.4 cases/100,000 person‐years in a retrospective chart review at a clinic in Utah, United States. Reported 1‐year survival ranged from 67% to 99%. All studies with sex‐specific estimates of prevalence or incidence reported higher levels in females than males. Studies varied in their size, study design, diagnostic criteria, and sampling procedures. Reported PAH prevalence, incidence, and mortality varied by location and study. Prevalence ranged from 0.4 to 1.4 per 100,000 persons. Harmonization of methods for PAH registries would improve efforts at disease surveillance. Results of this search contribute to ongoing efforts to quantify the global burden of PAH.