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Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) antibody measurements can be used to estimate the proportion of a population exposed or infected and may be informative about the risk of future infection. Previous estimates of the duration of antibody responses vary. Methods We present 6 months of data from a longitudinal seroprevalence study of 3276 UK healthcare workers (HCWs). Serial measurements of SARS-CoV-2 anti-nucleocapsid and anti-spike IgG were obtained. Interval censored survival analysis was used to investigate the duration of detectable responses. Additionally, Bayesian mixed linear models were used to investigate anti-nucleocapsid waning. Results Anti-spike IgG levels remained stably detected after a positive result, for example, in 94% (95% credibility interval [CrI] 91–96%) of HCWs at 180 days. Anti-nucleocapsid IgG levels rose to a peak at 24 (95% CrI 19–31) days post first polymerase chain reaction (PCR)-positive test, before beginning to fall. Considering 452 anti-nucleocapsid seropositive HCWs over a median of 121 days from their maximum positive IgG titer, the mean estimated antibody half-life was 85 (95% CrI 81–90) days. Higher maximum observed anti-nucleocapsid titers were associated with longer estimated antibody half-lives. Increasing age, Asian ethnicity, and prior self-reported symptoms were independently associated with higher maximum anti-nucleocapsid levels and increasing age and a positive PCR test undertaken for symptoms with longer anti-nucleocapsid half-lives. Conclusions SARS-CoV-2 anti-nucleocapsid antibodies wane within months and fall faster in younger adults and those without symptoms. However, anti-spike IgG remains stably detected. Ongoing longitudinal studies are required to track the long-term duration of antibody levels and their association with immunity to SARS-CoV-2 reinfection.

Background: Progressive familial intrahepatic cholestasis (PFIC) is an ultra-rare disease with a considerable burden on pediatric patients and their caregivers, impacting quality of life (QoL). The mortality rates highlight a significant need for efficacious treatments. Real-world data on associated costs and QoL are needed to gauge the potential impact of new pharmacological treatments. Methods: Clinical and socio-economic burden of PFIC on patients/caregivers, health systems, and society will be assessed. Patient/caregiver- and physician-level retrospective cross-sectional data will be collected from the US, UK, France, and Germany, for PFIC types 1, 2, 3. A representative sample of physicians will provide clinical and resource utilization information using an electronic Case Report Form (eCRF). Patient/caregiver surveys will collect socio-economic and QoL data, enabling assessment of PFIC impact on QoL. Mean costs (direct medical/non-medical, indirect) will be calculated. The study materials were reviewed by medical professionals and patient representatives and received ethical approval from the University of Chester. Discussion: The study aims to reveal the unmet medical need, disease burden, resource utilization, and costs of PFIC, to raise awareness with policymakers and healthcare professionals, and provide support for the patient/caregiver community. As novel PFIC therapies recently emerged, this study will yield quantifiable data for health technology assessments.

We conducted voluntary Covid-19 testing programmes for symptomatic and asymptomatic staff at a UK teaching hospital using naso-/oro-pharyngeal PCR testing and immunoassays for IgG antibodies. 1128/10,034 (11.2%) staff had evidence of Covid-19 at some time. Using questionnaire data provided on potential risk-factors, staff with a confirmed household contact were at greatest risk (adjusted odds ratio [aOR] 4.82 [95%CI 3.45–6.72]). Higher rates of Covid-19 were seen in staff working in Covid-19-facing areas (22.6% vs. 8.6% elsewhere) (aOR 2.47 [1.99–3.08]). Controlling for Covid-19-facing status, risks were heterogenous across the hospital, with higher rates in acute medicine (1.52 [1.07–2.16]) and sporadic outbreaks in areas with few or no Covid-19 patients. Covid-19 intensive care unit staff were relatively protected (0.44 [0.28–0.69]), likely by a bundle of PPE-related measures. Positive results were more likely in Black (1.66 [1.25–2.21]) and Asian (1.51 [1.28–1.77]) staff, independent of role or working location, and in porters and cleaners (2.06 [1.34–3.15]).

Introduction Diabetes mellitus (DM) is an important risk factor for atrial fibrillation (AF) – the most common heart rhythm disorder. However, the mechanisms underlying this association are poorly understood. In addition, patients with DM often have comorbidities, such as obesity, hypertension, dyslipidaemia, that are also independently associated with increased risk for AF. The aim of this project was to explore whether prolonged hyperglycaemia alone is sufficient to increase the risk of AF. Methods Multiple low-dose (50 mg/kg over 5 days) intraperitoneal injections of streptozotocin were used to induce DM in C57BL/6 mice. After 12 weeks of DM, left ventricular (LV) systolic and diastolic function was characterised using echocardiography. In vivo atrial electrophysiological properties and arrhythmia inducibility were assessed using transoesophageal atrial pacing. Atrial conduction time and action potential duration (APD) and conduction velocity were measured by optical mapping of isolated atria. Results Diabetic mice had significantly higher probability of in vivo AF induction (15±3% vs. 6±1%, in controls, p=0.005, n=24–26/group), atrial ECG conduction abnormalities (longer PQ interval in diabetic mice: 44±1 ms vs. 39±1 ms in controls, p=0.001, n=24–26/group), but without any changes in the P wave duration, RR, QRS or QT intervals. Diabetic mice developed modest LV diastolic dysfunction (tissue Doppler E’/A’ 1.02±0.05 vs. 1.20±0.06 in controls, p=0.04, n=11–12/group), but no LV systolic dysfunction. In addition, diabetic mice also had larger relative LA size (LA area/body weight 0.28±0.01 mm2/g vs. 0.23±0.01 mm2/g in controls, p=0.001, n=11–12/group). Optical mapping revealed a two-fold greater conduction time in diabetic left atria (LA) (39±3 ms vs. 22±2 ms in controls, p=0.0006, n=6/group), without differences in the right atrial (RA) conduction time. The APD was not significantly different in RA or LA. The regional analysis of optical mapping recordings demonstrated a significant decrease in the conduction velocity in the medial part of the RA resulting in increased conduction wavefront roughness in the LA. Finally, the medial part of the diabetic RA also had a significantly higher total collagen content (5.5±0.5 µg/mg vs. 9.1±0.6 µg/mg in controls, p=0.0002, n=9–11/group), and a decrease in the connexin 43 levels (0.92±0.05 vs. 0.66±0.4 in controls, p=0.001, n=7–8/group), with no significant changes in other parts of the atria. Conclusions Prolonged hyperglycaemia alone is sufficient to cause pathological remodelling making atria more susceptible for AF. Diabetic hearts also have modest LV diastolic dysfunction, relative LA enlargement, but no LV systolic dysfunction. In this study, we provide evidence of a novel mechanism where localized (rather than global) atrial fibrosis in a critical area causes a focal conduction defect and predisposes diabetic mice to AF.

Objectives Glucagon-like peptide-1 (GLP-1) is secreted from enteroendocrine cells and exerts a broad number of metabolic actions through activation of a single GLP-1 receptor (GLP-1R). The cardiovascular actions of GLP-1 have garnered increasing attention as GLP-1R agonists are used to treat human subjects with diabetes and obesity that may be at increased risk for development of heart disease. Here we studied mechanisms linking GLP-1R activation to control of heart rate (HR) in mice. Methods The actions of GLP-1R agonists were examined on the control of HR in wild type mice (WT) and in mice with cardiomyocyte-selective disruption of the GLP-1R (Glp1rCM−/−). Complimentary studies examined the effects of GLP-1R agonists in mice co-administered propranolol or atropine. The direct effects of GLP-1R agonism on HR and ventricular developed pressure were examined in isolated perfused mouse hearts ex vivo, and atrial depolarization was quantified in mouse hearts following direct application of liraglutide to perfused atrial preparations ex vivo. Results Doses of liraglutide and lixisenatide that were equipotent for acute glucose control rapidly increased HR in WT and Glp1rCM−/− mice in vivo. The actions of liraglutide to increase HR were more sustained relative to lixisenatide, and diminished in Glp1rCM−/− mice. The acute chronotropic actions of GLP-1R agonists were attenuated by propranolol but not atropine. Neither native GLP-1 nor lixisenatide increased HR or developed pressure in perfused hearts ex vivo. Moreover, liraglutide had no direct effect on sinoatrial node firing rate in mouse atrial preparations ex vivo. Despite co-localization of HCN4 and GLP-1R in primate hearts, HCN4-directed Cre expression did not attenuate levels of Glp1r mRNA transcripts, but did reduce atrial Gcgr expression in the mouse heart. Conclusions GLP-1R agonists increase HR through multiple mechanisms, including regulation of autonomic nervous system function, and activation of the atrial GLP-1R. Surprisingly, the isolated atrial GLP-1R does not transduce a direct chronotropic effect following exposure to GLP-1R agonists in the intact heart, or isolated atrium, ex vivo. Hence, cardiac GLP-1R circuits controlling HR require neural inputs and do not function in a heart-autonomous manner., Graphical abstract Image 1, Highlights • GLP-1 controls heart rate (HR) through the autonomic nervous system and the cardiac GLP-1R in mice. • The acute induction of HR by GLP-1R agonists is sensitive to propranolol. • GLP-1R agonists do not directly increase HR in isolated perfused mouse hearts ex vivo. • The GLP-1R agonist liraglutide does not directly enhance sinoatrial activity ex vivo. • GLP-1 does not increase heart rate in a heart autonomous manner.

Background Lateral flow device (LFD) viral antigen immunoassays have been developed around the world as diagnostic tests for SARS-CoV-2 infection. They have been proposed to deliver an infrastructure-light, cost-economical solution giving results within half an hour. Methods LFDs were initially reviewed by a Department of Health and Social Care team, part of the UK government, from which 64 were selected for further evaluation from 1st August to 15th December 2020. Standardised laboratory evaluations, and for those that met the published criteria, field testing in the Falcon-C19 research study and UK pilots were performed (UK COVID-19 testing centres, hospital, schools, armed forces). Findings 4/64 LFDs so far have desirable performance characteristics (orient Gene, Deepblue, Abbott and Innova SARS-CoV-2 Antigen Rapid Qualitative Test). All these LFDs have a viral antigen detection of >90% at 100,000 RNA copies/ml. 8951 Innova LFD tests were performed with a kit failure rate of 5.6% (502/8951, 95% CI: 5.1–6.1), false positive rate of 0.32% (22/6954, 95% CI: 0.20–0.48). Viral antigen detection/sensitivity across the sampling cohort when performed by laboratory scientists was 78.8% (156/198, 95% CI 72.4–84.3). Interpretation Our results suggest LFDs have promising performance characteristics for mass population testing and can be used to identify infectious positive individuals. The Innova LFD shows good viral antigen detection/sensitivity with excellent specificity, although kit failure rates and the impact of training are potential issues. These results support the expanded evaluation of LFDs, and assessment of greater access to testing on COVID-19 transmission. Funding Department of Health and Social Care. University of Oxford. Public Health England Porton Down, Manchester University NHS Foundation Trust, National Institute of Health Research.

ObjectivesTo systematically review and quantify the effect of motor vehicle crashes (MVCs) in pregnancy on maternal and offspring outcomes.DesignSystematic review and meta-analysis of observational data searched from inception until 1 July 2018. Searching was from June to August 2018 in Medline, Embase, Web of Science, Scopus, Latin-American and Caribbean System on Health Sciences Information, Scientific Electronic Library Online, TRANSPORT, International Road Research Documentation, European Conference of Ministers of Transportation Databases, Cochrane Database of Systematic Reviews and Cochrane Central Register.ParticipantsStudies were selected if they focused on the effects of exposure MVC during pregnancy versus non-exposure, with follow-up to verify outcomes in various settings, including secondary care, collision and emergency, and inpatient care.Data synthesisFor incidence data, we calculated a pooled estimate per 1000 women. For comparison of outcomes between women involved and those not involved in MVC, we calculated ORs with 95% CIs. Where possible, we statistically pooled the data using the random-effects model. The quality of studies used in the comparative analysis was assessed with Newcastle–Ottawa Scale.ResultsWe included 19 studies (3 222 066 women) of which the majority was carried out in high-income countries (18/19). In population-level studies of women involved in MVC, maternal death occurred in 3.6 per 1000 (95% CI 0.25–10.42; 3 studies, 12 000 women; Tau=1.77), and fetal death or stillbirth in 6.6 per 1000 (95% CI 3.81–10.12; 8 studies, 47 992 women; I2=92.6%). Pooled incidence of complications per 1000 women involved in MVC was labour induction (276.43), preterm delivery (191.90) and caesarean section (166.65). Compared with women not involved in MVC, those involved had increased odds of placental abruption (OR 1.43, 95% CI 1.27–1.63; 3 studies, 1 500 825 women) and maternal death (OR 202.27; 95% CI 110.60–369.95; 1 study, 1 094 559 women).ConclusionPregnant women involved in MVC were at higher risk of maternal death and complications than those not involved.PROSPERO registration numberCRD42018100788.

Objectives: The goal of this study was to assess mechanisms underlying atrial fibrillation (AF) promotion by exercise training in an animal model.Background: High-level exercise training promotes A...

Atrial fibrillation, NADPH oxidases, ryanodine receptor Background Gp91-containing NADPH oxidases (NOX2) are a significant source of reactive oxygen species (ROS) in the human atrial myocardium. An increase in NOX2 activity accompanies atrial fibrillation (AF) induction and electrical remodelling in animal models and predicts incident AF in humans; however, whether an increase in atrial NOX2 activity is necessary to create a substrate for AF remains to be demonstrated. The purpose of this study is to determine whether an increase in NOX2-derived ROS directly contributes to the development of AF and to identify the molecular changes that occur downstream of NOX2 activation in atrial myocytes. Methods and Results Mice with myocardial NOX2 overexpression (NOX2-Tg) showed a 2-fold increase in NADPH-stimulated superoxide production (2-hydroxyethidium by HPLC) in both the left and right atria, without any other electrophysiological or structural abnormalities (assessed by surface ECG and echocardiography); however, AF susceptibility assessed in vivo by transesophageal pacing was significantly higher in NOX2-Tg mice compared with their wild-type (WT) littermate controls (AF probability: 16.9±1.8% vs. 10.2±1.6% respectively, n=25–26/genotype, p Conclusions Myocardial NOX2 overexpression and related increase in NADPH-stimulated ROS production are associated with increased AF susceptibility in vivo and reduced RyR phosphorylation at Ser2814. These findings suggest increased NOX2 ROS may promote arrhythmogenesis by modulating atrial calcium handling.

Neurotransmitters released from sympathetic and parasympathetic nerve terminals in the SAN exert their effects via G-protein-coupled receptors. Integration of these different G-protein signals within pacemaker cells of the sinoatrial node (SAN) is critical for proper regulation of heart rate and function. For example, excessive parasympathetic signaling can be associated with sinus node dysfunction and supraventricular arrhythmias. Our previous work has shown that one member of the regulator of G-protein signaling (RGS) protein family, RGS4, is highly and selectively expressed in pacemaker cells of the SAN. Consistent with its role as an inhibitor of parasympathetic signaling, RGS4-knockout mice have reduced basal heart rates and enhanced negative chronotropic responses to parasympathetic agonists. Moreover, RGS4 appears to be an important part of SA nodal myocyte signaling pathways that mediate G protein-coupled inwardly-rectifying potassium channel (GIRK) channel activation/deactivation and desensitization. Since RGS4 acts immediately downstream of M2 muscarinic receptors, it is tempting to speculate that RGS4 functions as a master regulator of parasympathetic signaling upstream of GIRKs, HCNs and L-type Ca2+ channels in the SAN. Thus, loss of RGS4 function may lead to increased susceptibility to conditions associated with increased parasympathetic signaling, including bradyarrhythmia, sinus node dysfunction, and atrial fibrillation.