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Abstract Mitral regurgitation (MR) is associated with morphological and functional alterations of left atrium (LA) and ventricle (LV), possibly inducing LA–LV misalignment. We aimed to: (1) characterize angulation between LA and mitral annulus from conventional cine MRI data and feature-tracking (FT) contours, (2) assess their associations with functional capacity in MR patients, as assessed by oxygen consumption (peak-VO2) and minute ventilation to carbon dioxide production (VE/VCO2) slope, in comparison with MRI LA/LV strain indices. Thirty-two asymptomatic primary MR patients (56 [40; 66] years, 12 women) underwent cardiac MRI resulting in LA/LV conventional FT-derived strain indices. Then, end-diastolic angles were derived from FT LA contours: (1) α, centered on the LA centre of mass and defined by mitral valve extremities, (2) γ, centered on the mitral ring anterior/lateral side, and defined by LA centre and the other extremity of the mitral ring. Cardiopulmonary exercise testing with simultaneous echocardiography were also performed; peak-VO2 and VE/VCO2 slope were measured. While peak-VO2 and VE/VCO2 slope were not correlated to LA/LV strains, they were significantly associated with angles (α: r = 0.50, p = 0.003 and r = − 0.52, p = 0.003; γ: r = − 0.53, p = 0.002 and r = 0.52, p = 0.003; respectively), independently of age and gender (R2 ≥ 0.29, p ≤ 0.03). In primary MR, the new LA/mitral annulus angles, computed directly from standard-of-care MRI, are better correlated to exercise tolerance than conventional LA/LV strain.

Abstract Background Coupling between left ventricle (LV) and left atrium (LA) plays a central role in the process of cardiac remodeling during aging and development of cardiac disease. The hydraulic force (HyF) is related to variation in size between LV and LA. The objectives of this study were to: (1) derive an estimate of left atrioventricular HyF using cine- Magnetic Resonance Imaging (MRI) in healthy subjects with a wide age range, and (2) study its relationship with age and conventional diastolic function parameters, as estimated by reference echocardiography. Methods We studied 119 healthy volunteers (mean age 44 ± 17 years, 58 women) who underwent Doppler echocardiography and MRI on the same day. Conventional transmitral flow early (E) and late (A) LV filling peak velocities as well as mitral annulus diastolic longitudinal peak velocity (E’) were derived from echocardiography. MRI cine SSFP images in longitudinal two and four chamber views were acquired, and analyzed using feature tracking (FT) software. In addition to conventional LV and LA strain measurements, FT-derived LV and LA contours were further used to calculate chamber cross-sectional areas. HyF was approximated as the difference between the LV and LA maximal cross-sectional areas in the diastasis phase corresponding to the lowest LV-LA pressure gradient. Univariate and multivariate analyses while adjusting for appropriate variables were used to study the associations between HyF and age as well as diastolic function and strain indices. Results HyF decreased significantly with age (R²=0.34, p

Introduction Without accounting for the underlying need for Special Educational Needs (SEN) provision, pupils with SEN in England have been shown to have higher rates of unauthorised absences. Objectives and Approach Our objective was to understand the impact of SEN provision on unauthorised absences in children with an expected need for SEN, those born with Cleft Lip and/or Palate. We used linked health and educational records to investigate the relationship between three categories of SEN provision (No Provision versus SEN Support versus Education and Healthcare Plan (EHCP)) and unauthorised absences. We aimed to causally estimate the incident rate ratio (IRR) of SEN Support vs No Provision and EHCP vs SEN support on unauthorised absences between years one and six of primary education. Combining sociodemographic, educational and clinical variables from linked data, we used propensity-score based methods to adjust for non-randomised assignment to these categories of treatment. Conclusions Between academic years 2009 to 2019, we found common support between comparison groups No provision (n = 4350) and SEN support (n = 2009) only for children with Cleft lip and palate and only reported on these comparisons. Unadjusted estimates demonstrate a 22% increase in absences in children with SEN support over No Support (IRR: 1.22 95%CI: 1.10-1.34). Reweighting for need using data from linked health and education records demonstrated a 14% reduction in unauthorised absences (IRR: 0.86 95%CI: 0.76-0.97). Implication Contrary to prior findings, by carefully matching on detailed linked health and education characteristics, we find SEN provision reduces unauthorised absences

Objective and Approach We explored variation in special educational needs (SEN) provision between local authorities (LAs) in England by focussing on children born preterm (24-

Objectives: The importance of SARS-CoV-2 transmission via the eyes is unknown, with previous studies mainly focusing on protective eyewear in healthcare settings. This study aimed to test the hypothesis that wearing eyeglasses is associated with a lower risk of COVID-19. Methods: Participants from the Virus Watch prospective community cohort study responded to a questionnaire on the use of eyeglasses and contact lenses. Infection was confirmed through data linkage, self-reported positive results, and, for a subgroup, monthly capillary antibody testing. Multivariable logistic regression models, controlling for age, sex, income, and occupation, were used to identify the odds of infection depending on frequency and purpose of eyeglasses or contact lenses use. Results: A total of 19,166 participants responded to the questionnaire, with 13,681 (71.3%, CI 70.7-72.0) reporting they wore eyeglasses. Multivariable logistic regression model showed a 15% lower odds of infection for those who reported using eyeglasses always for general use (odds ratio [OR] 0.85, 95% 0.77-0.95, P = 0.002) compared to those who never wore eyeglasses. The protective effect was reduced for those who said wearing eyeglasses interfered with mask-wearing and was absent for contact lens wearers. Conclusions: People who wear eyeglasses have a moderate reduction in risk of COVID-19 infection, highlighting that eye protection may make a valuable contribution to the reduction of transmission in community and healthcare settings.

Abstract Research question Are live birth rates affected in frozen embryo transfer cycles that develop transient endometrial cavity fluid that resolves by day of embryo transfer? Design The first frozen blastocyst transfer cycle between January 1st, 2016 and December 31st, 2019 were included in this retrospective cohort study at an academic fertility center. The presence or absence of endometrial cavity fluid (ECF) detected on initial ultrasound and at time of transfer was recorded. Patients who had persistent ECF at time of transfer were excluded from the study. The primary outcome was live birth rate in the group with resolved ECF relative to the group without ECF. Results A total of 1034 frozen blastocyst transfer cycles were included, 54 with resolved ECF and 980 without ECF. Adjusted analyses were performed using a log-binomial regression model. Live birth rates were 35.2% and 34.2%, adjusted risk ratio 1.00 [95% CI 0.70-1.50] in the two groups, respectively. Conclusion Live birth rates in frozen embryo transfer cycles are equivalent between patients with resolved endometrial cavity fluid compared to those who never had endometrial cavity fluid. Our findings suggest that the presence of endometrial cavity fluid is likely not detrimental to live birth rates if the fluid spontaneously resolves by the time of embryo transfer.

Abstract Respiratory viruses that were suppressed through previous lockdowns during the COVID-19 pandemic have recently started to co-circulate with SARS-CoV-2. Understanding the clinical characteristics and symptomatology of different respiratory viral infections can help address the challenges related to the identification of cases and the understanding of SARS-CoV-2 variants' evolutionary patterns. Flu Watch (2006–2011) and Virus Watch (2020–2022) are household community cohort studies monitoring the epidemiology of influenza, respiratory syncytial virus, rhinovirus, seasonal coronavirus, and SARS-CoV-2, in England and Wales. This study describes and compares the proportion of symptoms reported during illnesses infected by common respiratory viruses. The SARS-CoV-2 symptom profile increasingly resembles that of other respiratory viruses as new strains emerge. Increased cough, sore throat, runny nose, and sneezing are associated with the emergence of the Omicron strains. As SARS-CoV-2 becomes endemic, monitoring the evolution of its symptomatology associated with new variants will be critical for clinical surveillance.

OBJECTIVES: COVID-19 mitigations have had a profound impact on workplaces, however, multisectoral comparisons of how work-related mitigations were applied are limited. This study aimed to investigate (i) occupational differences in the usage of key work-related mitigations over time and (ii) workers’ perceptions of these mitigations.METHODS: Employed/self-employed Virus Watch study participants (N=6279) responded to a mitigation-related online survey covering the periods of December 2020–February 2022. Logistic regression was used to investigate occupation- and time-related differences in the usage of work-related mitigation methods. Participants’ perceptions of mitigation methods were investigated descriptively using proportions.RESULTS: Usage of work-related mitigation methods differed between occupations and over time, likely reflecting variation in job roles, workplace environments, legislation and guidance. Healthcare workers had the highest predicted probabilities for several mitigations, including reporting frequent hand hygiene [predicted probability across all survey periods 0.61 (95% CI 0.56–0.66)] and always wearing face coverings [predicted probability range 0.71 (95% CI 0.66–0.75) – 0.80 (95% CI 0.76–0.84) across survey periods]. There were significant cross-occupational trends towards reduced mitigations during periods of less stringent national restrictions. The majority of participants across occupations (55–88%) agreed that most mitigations were reasonable and worthwhile even after the relaxation of national restrictions; agreement was lower for physical distancing (39–44%).CONCLUSIONS: While usage of work-related mitigations appeared to vary alongside stringency of national restrictions, agreement that most mitigations were reasonable and worthwhile remained substantial. Further investigation into the factors underlying between-occupational differences could assist pandemic planning and prevention of workplace COVID-19 transmission.

Abstract Takotsubo cardiomyopathy is a stress-induced cardiovascular disease with symptoms comparable to those of an acute coronary syndrome but without coronary obstruction. Takotsubo was initially considered spontaneously reversible, but epidemiological studies revealed significant long-term morbidity and mortality, the reason for which is unknown. Here, we show in a female rodent model that a single pharmacological challenge creates a stress-induced cardiomyopathy similar to Takotsubo. The acute response involves changes in blood and tissue biomarkers and in cardiac in vivo imaging acquired with ultrasound, magnetic resonance and positron emission tomography. Longitudinal follow up using in vivo imaging, histochemistry, protein and proteomics analyses evidences a continued metabolic reprogramming of the heart towards metabolic malfunction, eventually leading to irreversible damage in cardiac function and structure. The results combat the supposed reversibility of Takotsubo, point to dysregulation of glucose metabolic pathways as a main cause of long-term cardiac disease and support early therapeutic management of Takotsubo.

Abstract Background Workers across different occupations vary in their risk of SARS-CoV-2 infection, but the direct contribution of occupation to this relationship is unclear. This study aimed to investigate how infection risk differed across occupational groups in England and Wales up to April 2022, after adjustment for potential confounding and stratification by pandemic phase. Methods Data from 15,190 employed/self-employed participants in the Virus Watch prospective cohort study were used to generate risk ratios for virologically- or serologically-confirmed SARS-CoV-2 infection using robust Poisson regression, adjusting for socio-demographic and health-related factors and non-work public activities. We calculated attributable fractions (AF) amongst the exposed for belonging to each occupational group based on adjusted risk ratios (aRR). Results Increased risk was seen in nurses (aRR = 1.44, 1.25–1.65; AF = 30%, 20–39%), doctors (aRR = 1.33, 1.08–1.65; AF = 25%, 7–39%), carers (1.45, 1.19–1.76; AF = 31%, 16–43%), primary school teachers (aRR = 1.67, 1.42- 1.96; AF = 40%, 30–49%), secondary school teachers (aRR = 1.48, 1.26–1.72; AF = 32%, 21–42%), and teaching support occupations (aRR = 1.42, 1.23–1.64; AF = 29%, 18–39%) compared to office-based professional occupations. Differential risk was apparent in the earlier phases (Feb 2020—May 2021) and attenuated later (June—October 2021) for most groups, although teachers and teaching support workers demonstrated persistently elevated risk across waves. Conclusions Occupational differences in SARS-CoV-2 infection risk vary over time and are robust to adjustment for socio-demographic, health-related, and non-workplace activity-related potential confounders. Direct investigation into workplace factors underlying elevated risk and how these change over time is needed to inform occupational health interventions.

Introduction One third of children in English primary schools have additional learning support called special educational needs (SEN) provision, but children born preterm are more likely to have SEN than those born at term. We aim to assess the impact of SEN provision on health and education outcomes in children grouped by gestational age at birth. Methods We will analyse linked administrative data for England using the Education and Child Health Insights from Linked Data (ECHILD) database. A target trial emulation approach will be used to specify data extraction from ECHILD, comparisons of interest and our analysis plan. Our target population is all children enrolled in year one of state-funded primary school in England who were born in an NHS hospital in England between 2003 and 2008, grouped by gestational age at birth (extremely preterm (24-

Introduction One-third of children in England have special educational needs (SEN) provision recorded during their school career. The proportion of children with SEN provision varies between schools and demographic groups, which may reflect variation in need, inequitable provision and/or systemic factors. There is scant evidence on whether SEN provision improves health and education outcomes.Methods The Health Outcomes of young People in Education (HOPE) research programme uses administrative data from the Education and Child Health Insights from Linked Data—ECHILD—which contains data from all state schools, and contacts with National Health Service hospitals in England, to explore variation in SEN provision and its impact on health and education outcomes. This umbrella protocol sets out analyses across four work packages (WP). WP1 defined a range of ‘health phenotypes’, that is health conditions expected to need SEN provision in primary school. Next, we describe health and education outcomes (WP1) and individual, school-level and area-level factors affecting variation in SEN provision across different phenotypes (WP2). WP3 assesses the impact of SEN provision on health and education outcomes for specific health phenotypes using a range of causal inference methods to account for confounding factors and possible selection bias. In WP4 we review local policies and synthesise findings from surveys, interviews and focus groups of service users and providers to understand factors associated with variation in and experiences of identification, assessment and provision for SEN. Triangulation of findings on outcomes, variation and impact of SEN provision for different health phenotypes in ECHILD, with experiences of SEN provision will inform interpretation of findings for policy, practice and families and methods for future evaluation.Ethics and dissemination Research ethics committees have approved the use of the ECHILD database and, separately, the survey, interviews and focus groups of young people, parents and service providers. These stakeholders will contribute to the design, interpretation and communication of findings.

Background Special educational needs (SEN) provision is designed to help pupils with additional educational, behavioural or health needs; for example, pupils with cleft lip and/or palate may be offered SEN provision to improve their speech and language skills. Our aim is to contribute to the literature and assess the impact of SEN provision on health and educational outcomes for a well-defined population. Methods We will use the ECHILD database, which links educational and health records across England. Our target population consists of children identified within ECHILD to have a specific congenital anomaly: isolated cleft lip and/or palate. We will apply a trial emulation framework to reduce biases in design and analysis of observational data to investigate the causal impact of SEN provision (including none) by the start of compulsory education (Year One – age five year on entry) on the number of unplanned hospital utilisation and school absences by the end of primary education (Year Six – age ten/eleven). We will use propensity score-based estimators (inverse probability weighting (IPW) and IPW regression adjustment IPW) to compare categories of SEN provision in terms of these outcomes and to triangulate results obtained using complementary estimation methods (Naïve estimator, multivariable regression, parametric g-formula, and if possible, instrumental variables), targeting a variety of causal contrasts (average treatment effect/in the treated/in the not treated) of SEN provision. Conclusions This study will evaluate the impact of reasonable adjustments at the start of compulsory education on health and educational outcomes in the isolated cleft lip and palate population by triangulating complementary methods under a target-trial framework.

Background: Individuals living in deprived areas in England and Wales undertook essential activities more frequently and experienced higher rates of SARS-CoV-2 infection than less deprived communities during periods of restrictions aimed at controlling the Alpha (B.1.1.7) variant. We aimed to understand whether these deprivation-related differences changed once restrictions were lifted. Methods: Among 11,231 adult Virus Watch Community Cohort Study participants multivariable logistic regressions were used to estimate the relationships between deprivation and self-reported activities and deprivation and infection (self-reported lateral flow or PCR tests and linkage to National Testing data and Second Generation Surveillance System (SGSS)) between August – December 2021, following the lifting of national public health restrictions. Results: Those living in areas of greatest deprivation were more likely to undertake essential activities (leaving home for work (aOR 1.56 (1.33 – 1.83)), using public transport (aOR 1.33 (1.13 – 1.57)) but less likely to undertake non-essential activities (indoor hospitality (aOR 0.82 (0.70 – 0.96)), outdoor hospitality (aOR 0.56 (0.48 – 0.66)), indoor leisure (aOR 0.63 (0.54 – 0.74)), outdoor leisure (aOR 0.64 (0.46 – 0.88)), or visit a hairdresser (aOR 0.72 (0.61 – 0.85))). No statistical association was observed between deprivation and infection (P=0.5745), with those living in areas of greatest deprivation no more likely to become infected with SARS-CoV-2 (aOR 1.25 (0.87 – 1.79). Conclusion: The lack of association between deprivation and infection is likely due to the increased engagement in non-essential activities among the least deprived balancing the increased work-related exposure among the most deprived. The differences in activities highlight stark disparities in an individuals’ ability to choose how to limit infection exposure.

Background: The serial interval is a key epidemiological measure that quantifies the time between the onset of symptoms in an infector-infectee pair. It indicates how quickly new generations of cases appear, thus informing on the speed of an epidemic. Estimating the serial interval requires to identify pairs of infectors and infectees. Yet, most studies fail to assess the direction of transmission between cases and assume that the order of infections - and thus transmissions - strictly follows the order of symptom onsets, thereby imposing serial intervals to be positive. Because of the long and highly variable incubation period of SARS-CoV-2, this may not always be true (i.e an infectee may show symptoms before their infector) and negative serial intervals may occur. This study aims to estimate the serial interval of different SARS-CoV-2 variants whilst accounting for negative serial intervals. Methods: This analysis included 5 842 symptomatic individuals with confirmed SARS-CoV-2 infection amongst 2 579 households from September 2020 to August 2022 across England & Wales. We used a Bayesian framework to infer who infected whom by exploring all transmission trees compatible with the observed dates of symptoms, based on a wide range of incubation period and generation time distributions compatible with estimates reported in the literature. Serial intervals were derived from the reconstructed transmission pairs, stratified by variants. Results: We estimated that 22% (95% credible interval (CrI) 8–32%) of serial interval values are negative across all VOC. The mean serial interval was shortest for Omicron BA5 (2.02 days, 1.26–2.84) and longest for Alpha (3.37 days, 2.52–4.04). Conclusions: This study highlights the large proportion of negative serial intervals across SARS-CoV-2 variants. Because the serial interval is widely used to estimate transmissibility and forecast cases, these results may have critical implications for epidemic control.

Vaccination can provide reliable and long-lasting protection against COVID-19, however the immune response to vaccination can vary between individuals and can decline over time, leading to differences in protective effects. Here the authors assess the immune response to COVID-19 vaccination across a large cohort of previously uninfected adults and demonstrate lower post-vaccination antibody levels amongst those with immune-suppressing conditions and medications, as well as those with several other more common chronic conditions.

Objectives: Seroprevalence studies can provide a measure of SARS-CoV-2 cumulative incidence, but a better understanding of spike and nucleocapsid (anti-N) antibody dynamics following infection is needed to assess the longevity of detectability. Methods: Adults aged ≥18 years, from households enrolled in the Virus Watch prospective community cohort study in England and Wales, provided monthly capillary blood samples, which were tested for spike antibody and anti-N. Participants self-reported vaccination dates and past medical history. Previous polymerase chain reaction (PCR) swabs were obtained through Second Generation Surveillance System linkage data. The primary outcome variables were seropositivity and total anti-N and spike antibody levels after PCR-confirmed infection. Results: A total of 13,802 eligible individuals provided 58,770 capillary blood samples. A total of 537 of these had a previous positive PCR-confirmed SARS-CoV-2 infection within 0-269 days of antibody sample date, among them 432 (80.45%) having a positive anti-N result. Median anti-N levels peaked between days 90 and 119 after PCR results and then began to decline. There is evidence of anti-N waning from 120 days onwards, with earlier waning for females and younger age categories. Conclusion: Our findings suggest that anti-N has around 80% sensitivity for identifying previous COVID-19 infection, and the duration of detectability is affected by sex and age.

Here the authors provide data from a sub-cohort of the Virus Watch study (19,556 adults) who completed at-home capillary blood sampling on a monthly basis and describe an association between anti-spike antibody levels and risk of SARS-CoV-2 infection.

Maple syrup urine disease (MSUD) is a rare inborn error of metabolism, which is currently treated with life-long low-protein diet that can be challenging to maintain. Here the authors develop an AAV8-directed gene therapy providing sustainable disease rescue in a mouse model of MSUD.

BackgroundEvidence suggests that individuals may change adherence to public health policies aimed at reducing the contact, transmission, and spread of the SARS-CoV-2 virus after they receive their first SARS-CoV-2 vaccination when they are not fully vaccinated. ObjectiveWe aimed to estimate changes in median daily travel distance of our cohort from their registered addresses before and after receiving a SARS-CoV-2 vaccine. MethodsParticipants were recruited into Virus Watch starting in June 2020. Weekly surveys were sent out to participants, and vaccination status was collected from January 2021 onward. Between September 2020 and February 2021, we invited 13,120 adult Virus Watch participants to contribute toward our tracker subcohort, which uses the GPS via a smartphone app to collect data on movement. We used segmented linear regression to estimate the median daily travel distance before and after the first self-reported SARS-CoV-2 vaccine dose. ResultsWe analyzed the daily travel distance of 249 vaccinated adults. From 157 days prior to vaccination until the day before vaccination, the median daily travel distance was 9.05 (IQR 8.06-10.09) km. From the day of vaccination to 105 days after vaccination, the median daily travel distance was 10.08 (IQR 8.60-12.42) km. From 157 days prior to vaccination until the vaccination date, there was a daily median decrease in mobility of 40.09 m (95% CI –50.08 to –31.10; P

Wearable smart glasses are an emerging technology gaining popularity in the assistive technologies industry. Smart glasses aids typically leverage computer vision and other sensory information to translate the wearer's surrounding into computer-synthesized speech. In this work, we explored the potential of a new technique known as "acoustic touch" to provide a wearable spatial audio solution for assisting people who are blind in finding objects. In contrast to traditional systems, this technique uses smart glasses to sonify objects into distinct sound auditory icons when the object enters the device's field of view. We developed a wearable Foveated Audio Device to study the efficacy and usability of using acoustic touch to search, memorize, and reach items. Our evaluation study involved 14 participants, 7 blind or low-visioned and 7 blindfolded sighted (as a control group) participants. We compared the wearable device to two idealized conditions, a verbal clock face description and a sequential audio presentation through external speakers. We found that the wearable device can effectively aid the recognition and reaching of an object. We also observed that the device does not significantly increase the user's cognitive workload. These promising results suggest that acoustic touch can provide a wearable and effective method of sensory augmentation.

Abstract Background An Informatics Consult has been proposed in which clinicians request novel evidence from large scale health data resources, tailored to the treatment of a specific patient. However, the availability of such consultations is lacking. We seek to provide an Informatics Consult for a situation where a treatment indication and contraindication coexist in the same patient, i.e., anti-coagulation use for stroke prevention in a patient with both atrial fibrillation (AF) and liver cirrhosis. Methods We examined four sources of evidence for the effect of warfarin on stroke risk or all-cause mortality from: (1) randomised controlled trials (RCTs), (2) meta-analysis of prior observational studies, (3) trial emulation (using population electronic health records (N = 3,854,710) and (4) genetic evidence (Mendelian randomisation). We developed prototype forms to request an Informatics Consult and return of results in electronic health record systems. Results We found 0 RCT reports and 0 trials recruiting for patients with AF and cirrhosis. We found broad concordance across the three new sources of evidence we generated. Meta-analysis of prior observational studies showed that warfarin use was associated with lower stroke risk (hazard ratio [HR] = 0.71, CI 0.39–1.29). In a target trial emulation, warfarin was associated with lower all-cause mortality (HR = 0.61, CI 0.49–0.76) and ischaemic stroke (HR = 0.27, CI 0.08–0.91). Mendelian randomisation served as a drug target validation where we found that lower levels of vitamin K1 (warfarin is a vitamin K1 antagonist) are associated with lower stroke risk. A pilot survey with an independent sample of 34 clinicians revealed that 85% of clinicians found information on prognosis useful and that 79% thought that they should have access to the Informatics Consult as a service within their healthcare systems. We identified candidate steps for automation to scale evidence generation and to accelerate the return of results. Conclusion We performed a proof-of-concept Informatics Consult for evidence generation, which may inform treatment decisions in situations where there is dearth of randomised trials. Patients are surprised to know that their clinicians are currently not able to learn in clinic from data on ‘patients like me’. We identify the key challenges in offering such an Informatics Consult as a service.

Introduction and objectives: Liver resection is the only curative therapeutic option for large hepatocellular carcinoma (> 5 cm), but survival is worse than in smaller tumours, mostly due to the high recurrence rate. There is currently no proper tool for stratifying relapse risk. Herein, we investigated prognostic factors before hepatectomy in patients with a single large hepatocellular carcinoma (HCC). Material and methods: We retrospectively identified 119 patients who underwent liver resection for a single large HCC in 2 tertiary academic French centres and collected pre- and post-operative clinical, biological and radiological features. The primary outcome was overall survival at five years. Secondary outcomes were recurrence-free survival at five years and prognostic factors for recurrence. Results: A total of 84% of the patients were male, and the median age was 66 years old (IQR 58–74). Thirty-nine (33%) had Child–Pugh A cirrhosis, and the mean Model for End-Stage Liver Disease (MELD) score was 6 (6–6). The aetiology of liver disease was predominantly alcohol-related (48%), followed by nonalcoholic steatohepatitis (22%), hepatitis B (18%) and hepatitis C (10%). The mean tumour size was 70 mm (55–110). The median overall survival was 72.5 months (IC 95%: 56.2-88.7), and the five-year overall survival was 55.1 ± 5.5%. The median recurrence-free survival was 26.6 months (95% CI: 16.0-37.1), and the five-year recurrence-free survival rate was 37.8 ± 5%. In multivariate analysis, preoperative prognostic factors for recurrence were baseline alpha-fetoprotein (AFP) > 7 ng/mL (p

ObjectiveSince the outbreak of COVID-19, public health and social measures to contain its transmission (e.g., social distancing and lockdowns) have dramatically changed people's lives in rural and urban areas globally. To facilitate future management of the pandemic, it is important to understand how different socio-demographic groups adhere to such demands. This study aims to evaluate the influences of restriction policies on human mobility variations associated with socio-demographic groups in England, UK.MethodsUsing mobile phone global positioning system (GPS) trajectory data, we measured variations in human mobility across socio-demographic groups during different restriction periods from Oct 14, 2020 to Sep 15, 2021. The six restriction periods which varied in degree of mobility restriction policies, denoted as “Three-tier Restriction,” “Second National Lockdown,” “Four-tier Restriction,” “Third National Lockdown,” “Steps out of Lockdown,” and “Post-restriction,” respectively. Individual human mobility was measured with respect to the time period people stayed at home, visited places outside the home, and traveled long distances. We compared these indicators across the six restriction periods and across socio-demographic groups.ResultsAll human mobility indicators significantly differed across the six restriction periods, and the influences of restriction policies on individual mobility behaviors are correlated with socio-demographic groups. In particular, influences relating to mobility behaviors are stronger in younger and low-income groups in the second and third national lockdowns.ConclusionsThis study enhances our understanding of the influences of COVID-19 pandemic restriction policies on human mobility behaviors within different social groups in England. The findings can be usefully extended to support policy-making by investigating human mobility and differences in policy effects across not only age and income groups, but also across geographical regions.

Summary: Background: How international migrants access and use primary care in England is poorly understood. We aimed to compare primary care consultation rates between international migrants and non-migrants in England before and during the COVID–19 pandemic (2015–2020). Methods: Using data from the Clinical Practice Research Datalink (CPRD) GOLD, we identified migrants using country-of-birth, visa-status or other codes indicating international migration. We linked CPRD to Office for National Statistics deprivation data and ran a controlled interrupted time series (ITS) using negative binomial regression to compare rates before and during the pandemic. Findings: In 262,644 individuals, pre-pandemic consultation rates per person-year were 4.35 (4.34–4.36) for migrants and 4.60 (4.59–4.60) for non-migrants (RR:0.94 [0.92–0.96]). Between 29 March and 26 December 2020, rates reduced to 3.54 (3.52–3.57) for migrants and 4.2 (4.17–4.23) for non-migrants (RR:0.84 [0.8–0.88]). The first year of the pandemic was associated with a widening of the gap in consultation rates between migrants and non-migrants to 0.89 (95% CI 0.84–0.94) times the ratio before the pandemic. This widening in ratios was greater for children, individuals whose first language was not English, and individuals of White British, White non-British and Black/African/Caribbean/Black British ethnicities. It was also greater in the case of telephone consultations, particularly in London. Interpretation: Migrants were less likely to use primary care than non-migrants before the pandemic and the first year of the pandemic exacerbated this difference. As GP practices retain remote and hybrid models of service delivery, they must improve services and ensure primary care is accessible and responsive to migrants’ healthcare needs. Funding: This study was funded by the Medical Research Council (MC_PC 19070 and MR/V028375/1) and a Wellcome Clinical Research Career Development Fellowship (206602).

Background: “Lockdowns” to control serious respiratory virus pandemics were widely used during the coronavirus disease 2019 (COVID-19) pandemic. However, there is limited information to understand the settings in which most transmission occurs during lockdowns, to support refinement of similar policies for future pandemics. Methods: Among Virus Watch household cohort participants we identified those infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outside the household. Using survey activity data, we undertook multivariable logistic regressions assessing the contribution of activities on non-household infection risk. We calculated adjusted population attributable fractions (APAF) to estimate which activity accounted for the greatest proportion of non-household infections during the pandemic’s second wave. Results: Among 10,858 adults, 18% of cases were likely due to household transmission. Among 10,475 participants (household-acquired cases excluded), including 874 non-household-acquired infections, infection was associated with: leaving home for work or education (AOR 1.20 (1.02 – 1.42), APAF 6.9%); public transport (more than once per week AOR 1.82 (1.49 – 2.23), public transport APAF 12.42%); and shopping (more than once per week AOR 1.69 (1.29 – 2.21), shopping APAF 34.56%). Other non-household activities were rare and not significantly associated with infection. Conclusions: During lockdown, going to work and using public or shared transport independently increased infection risk, however only a minority did these activities. Most participants visited shops, accounting for one-third of non-household transmission. Transmission in restricted hospitality and leisure settings was minimal suggesting these restrictions were effective. If future respiratory infection pandemics emerge these findings highlight the value of working from home, using forms of transport that minimise exposure to others, minimising exposure to shops and restricting non-essential activities.

9′-cis-norbixin (norbixin/BIO201) protects RPE cells against phototoxicity induced by blue light and N-retinylidene-N-retinylethanolamine (A2E) in vitro and preserves visual functions in animal models of age-related macular degeneration (AMD) in vivo. The purpose of this study was to examine the mode of action and the in vitro and in vivo effects of BIO203, a novel norbixin amide conjugate. Compared to norbixin, BIO203 displays improved stability at all temperatures tested for up to 18 months. In vitro, BIO203 and norbixin share a similar mode of action involving the inhibition of PPARs, NF-κB, and AP-1 transactivations. The two compounds also reduce IL-6, IL-8, and VEGF expression induced by A2E. In vivo, ocular maximal concentration and BIO203 plasma exposure are increased compared to those of norbixin. Moreover, BIO203 administered systemically protects visual functions and retinal structure in albino rats subjected to blue-light illumination and in the retinal degeneration model of Abca4−/− Rdh8−/− double knock-out mice following 6 months of oral complementation. In conclusion, we report here that BIO203 and norbixin share similar modes of action and protective effects in vitro and in vivo. BIO203, with its improved pharmacokinetic and stability properties, could be developed for the treatment of retinal degenerative diseases such as AMD.

Abstract Background Finding relevant literature is crucial for many biomedical research activities and in the practice of evidence-based medicine. Search engines such as PubMed provide a means to search and retrieve published literature, given a query. However, they are limited in how users can control the processing of queries and articles—or as we call them documents—by the search engine. To give this control to both biomedical researchers and computer scientists working in biomedical information retrieval, we introduce a public online tool for searching over biomedical literature. Our setup is guided by the NIST setup of the relevant TREC evaluation tasks in genomics, clinical decision support, and precision medicine. Results To provide benchmark results for some of the most common biomedical information retrieval strategies, such as querying MeSH subject headings with a specific weight or querying over the title of the articles only, we present our evaluations on public datasets. Our experiments report well-known information retrieval metrics such as precision at a cutoff of ranked documents. Conclusions We introduce the A2A search and benchmarking tool which is publicly available for the researchers who want to explore different search strategies over published biomedical literature. We outline several query formulation strategies and present their evaluations with known human judgements for a large pool of topics, from genomics to precision medicine.

Background: Understanding symptomatology and accuracy of clinical case definitions for community COVID-19 cases is important for Test, Trace and Isolate (TTI) and future targeting of early antiviral treatment. Methods: Community cohort participants prospectively recorded daily symptoms and swab results (mainly undertaken through the UK TTI system). We compared symptom frequency, severity, timing, and duration in test positive and negative illnesses. We compared the test performance of the current UK TTI case definition (cough, high temperature, or loss of or altered sense of smell or taste) with a wider definition adding muscle aches, chills, headache, or loss of appetite. Results: Among 9706 swabbed illnesses, including 973 SARS-CoV-2 positives, symptoms were more common, severe and longer lasting in swab positive than negative illnesses. Cough, headache, fatigue, and muscle aches were the most common symptoms in positive illnesses but also common in negative illnesses. Conversely, high temperature, loss or altered sense of smell or taste and loss of appetite were less frequent in positive illnesses, but comparatively even less frequent in negative illnesses. The current UK definition had 81% sensitivity and 47% specificity versus 93% and 27% respectively for the broader definition. 1.7-fold more illnesses met the broader case definition than the current definition. Conclusions: Symptoms alone cannot reliably distinguish COVID-19 from other respiratory illnesses. Adding additional symptoms to case definitions could identify more infections, but with a large increase in the number needing testing and the number of unwell individuals and contacts self-isolating whilst awaiting results.

Background: Household overcrowding is associated with increased risk of infectious diseases across contexts and countries. Limited data exist linking household overcrowding and risk of COVID-19. We used data collected from the Virus Watch cohort to examine the association between overcrowded households and SARS-CoV-2. Methods: The Virus Watch study is a household community cohort of acute respiratory infections in England and Wales. We calculated overcrowding using the measure of persons per room for each household. We considered two primary outcomes: PCR-confirmed positive SARS-CoV-2 antigen tests and laboratory-confirmed SARS-CoV-2 antibodies. We used mixed-effects logistic regression models that accounted for household structure to estimate the association between household overcrowding and SARS-CoV-2 infection. Results: 26,367 participants were included in our analyses. The proportion of participants with a positive SARS-CoV-2 PCR result was highest in the overcrowded group (9.0%; 99/1,100) and lowest in the under-occupied group (4.2%; 980/23,196). In a mixed-effects logistic regression model, we found strong evidence of an increased odds of a positive PCR SARS-CoV-2 antigen result (odds ratio 2.45; 95% CI:1.43–4.19; p-value=0.001) and increased odds of a positive SARS-CoV-2 antibody result in individuals living in overcrowded houses (3.32; 95% CI:1.54–7.15; p-value

Introduction: Increased transmissibility of B.1.1.7 variant of concern (VOC) in the UK may explain its rapid emergence and global spread. We analysed data from putative household infector - infectee pairs in the Virus Watch Community cohort study to assess the serial interval of COVID-19 and whether this was affected by emergence of the B.1.1.7 variant. Methods: The Virus Watch study is an online, prospective, community cohort study following up entire households in England and Wales during the COVID-19 pandemic. Putative household infector-infectee pairs were identified where more than one person in the household had a positive swab matched to an illness episode. Data on whether or not individual infections were caused by the B.1.1.7 variant were not available. We therefore developed a classification system based on the percentage of cases estimated to be due to B.1.1.7 in national surveillance data for different English regions and study weeks. Results: Out of 24,887 illnesses reported, 915 tested positive for SARS-CoV-2 and 186 likely ‘infector-infectee’ pairs in 186 households amongst 372 individuals were identified. The mean COVID-19 serial interval was 3.18 (95%CI: 2.55 - 3.81) days. There was no significant difference (p=0.267) between the mean serial interval for VOC hotspots (mean = 3.64 days, (95%CI: 2.55 – 4.73)) days and non-VOC hotspots, (mean = 2.72 days, (95%CI: 1.48 – 3.96)). Conclusions: Our estimates of the average serial interval of COVID-19 are broadly similar to estimates from previous studies and we find no evidence that B.1.1.7 is associated with a change in serial intervals. Alternative explanations such as increased viral load, longer period of viral shedding or improved receptor binding may instead explain the increased transmissibility and rapid spread and should undergo further investigation.

Introduction The coronavirus (COVID-19) pandemic has caused significant global mortality and impacted lives around the world. Virus Watch aims to provide evidence on which public health approaches are most likely to be effective in reducing transmission and impact of the virus, and will investigate community incidence, symptom profiles and transmission of COVID-19 in relation to population movement and behaviours.Methods and analysis Virus Watch is a household community cohort study of acute respiratory infections in England and Wales and will run from June 2020 to August 2021. The study aims to recruit 50 000 people, including 12 500 from minority ethnic backgrounds, for an online survey cohort and monthly antibody testing using home fingerprick test kits. Nested within this larger study will be a subcohort of 10 000 individuals, including 3000 people from minority ethnic backgrounds. This cohort of 10 000 people will have full blood serology taken between October 2020 and January 2021 and repeat serology between May 2021 and August 2021. Participants will also post self-administered nasal swabs for PCR assays of SARS-CoV-2 and will follow one of three different PCR testing schedules based on symptoms.Ethics and dissemination This study has been approved by the Hampstead National Health Service (NHS) Health Research Authority Ethics Committee (ethics approval number 20/HRA/2320). We are monitoring participant queries and using these to refine methodology where necessary, and are providing summaries and policy briefings of our preliminary findings to inform public health action by working through our partnerships with our study advisory group, Public Health England, NHS and government scientific advisory panels.

Background: Diagnostic testing forms a major part of the UK’s response to the current coronavirus disease 2019 (COVID-19) pandemic with tests offered to anyone with a continuous cough, high temperature or anosmia. Testing capacity must be sufficient during the winter respiratory season when levels of cough and fever are high due to non-COVID-19 causes. This study aims to make predictions about the contribution of baseline cough or fever to future testing demand in the UK. Methods: In this analysis of the Bug Watch community cohort study, we estimated the incidence of cough or fever in England in 2018-2019. We then estimated the COVID-19 diagnostic testing rates required in the UK for baseline cough or fever cases for the period July 2020-June 2021. This was explored for different rates of the population requesting tests, four COVID-19 second wave scenarios and high and low baseline cough or fever incidence scenarios. Results: Under the high baseline cough or fever scenario, incidence in the UK is expected to rise rapidly from 250,708 (95%CI 181,095 - 347,080) cases per day in September to a peak of 444,660 (95%CI 353,084 - 559,988) in December. If 80% of these cases request tests, testing demand would exceed 1.4 million tests per week for five consecutive months. Demand was significantly lower in the low cough or fever incidence scenario, with 129,115 (95%CI 111,596 - 151,679) tests per day in January 2021, compared to 340,921 (95%CI 276,039 - 424,491) tests per day in the higher incidence scenario. Conclusions: Our results show that national COVID-19 testing demand is highly dependent on background cough or fever incidence. This study highlights that the UK’s response to the COVID-19 pandemic must ensure that a high proportion of people with symptoms request tests, and that testing capacity is sufficient to meet the high predicted demand.

Metal nanoparticle catalysts functionalized with small, well-defined organic ligands are important because such systems can provide a spatial control in the catalyst-substrate interactions. This article describes the synthesis, stability, and catalytic property evaluations of four different Pd nanoparticles capped with constitutional isomers of pentanethiolate ligands that have either a straight chain or an alkyl chain with one methyl group at different locations (α, β, or γ from the surface-bound sulfur). The structure and composition analyses of Pd nanoparticles confirm that they have similar average core sizes and organic ligand contents. The presence of methyl group at α position is found to lower the capping ability of short ligands and thus make Pd nanoparticles to lose their colloidal stability during the catalytic reactions. The overall activity and selectivity for hydrogenation and isomerization of pentene and allylbenzene derivatives are investigated for each combination of ligand and substrate. Catalysis results indicate that steric interactions between the ligands on the metal catalyst surface and the alkene substrates are a factor in controlling the activity of Pd nanoparticles. In particular, Pd nanoparticles capped with pentanethiolate isomer having a methyl group at α position exhibit poor and inconsistent catalytic activity due to its low colloidal stability. The presence of a methyl group at β position mildly interferes the adsorption of alkene group on the nanoparticle surface resulting in lower conversion yields. Interestingly, a methyl group at γ position only has a minimal effect on the catalytic property of Pd nanoparticles exhibiting similar catalysis results with Pd nanoparticles capped with straight chain pentanethiolate ligands. This indicates the proximity of steric group at the reactive site controls the nanoparticle activity for surface oriented reactions, such as hydrogenation and isomerization of alkenes in addition to their colloidal stability.

Though bladder urothelial carcinoma is the most common form of bladder cancer, advances in its diagnosis and treatment have been modest in the past few decades. To evaluate miRNAs as putative disease markers for bladder urothelial carcinoma, this study develops a process to identify dysregulated miRNAs in cancer patients and potentially stratify patients based on the association of their microRNAome phenotype to genomic alterations. Using RNA sequencing data for 409 patients from the Cancer Genome Atlas, we examined miRNA differential expression between cancer and normal tissues and associated differentially expressed miRNAs with patient survival and clinical variables. We then correlated miRNA expressions with genomic alterations using the Wilcoxon test and REVEALER. We found a panel of six miRNAs dysregulated in bladder cancer and exhibited correlations to patient survival. We also performed differential expression analysis and clinical variable correlations to identify miRNAs associated with tobacco smoking, the most important risk factor for bladder cancer. Two miRNAs, miR-323a and miR-431, were differentially expressed in smoking patients compared to nonsmoking patients and were associated with primary tumor size. Functional studies of these miRNAs and the genomic features we identified for potential stratification may reveal underlying mechanisms of bladder cancer carcinogenesis and further diagnosis and treatment methods for urothelial bladder carcinoma.