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BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

Purpose To define the burden of morbidity and mortality arising from COVID-19 in individuals with primary (PID) and secondary immunodeficiency (SID) in the United Kingdom. Methods In March 2020, the United Kingdom Primary Immunodeficiency Network (UKPIN) established a registry of cases to collate the outcomes of individuals with PID and SID following SARS-CoV-2 infection and treatment. Anonymised demographic data, pre-SARS-CoV-2 infection lymphocyte counts, co-morbidities, targeted treatments and outcomes were collected. Three groups were analysed in further detail: individuals with common variable immunodeficiency (CVID), individuals with any PID, including CVID, receiving immunoglobulin replacement therapy (IgRT) and individuals with secondary immunodeficiency. Results A total of 310 cases of SARS-CoV-2 infection in individuals with PID or SID have now been reported in the UK. The overall mortality within the cohort was 17.7% (n = 55/310). Individuals with CVID demonstrated an infection fatality rate (IFR) of 18.3% (n = 17/93), individuals with PID receiving IgRT had an IFR of 16.3% (n = 26/159) and individuals with SID, an IFR of 27.2% (n = 25/92). Individuals with PID and SID, had higher inpatient mortality and died at a younger age than the general population. Increasing age, low pre-SARS-CoV-2 infection lymphocyte count and the presence of common co-morbidities increased the risk of mortality in PID. Access to specific COVID-19 treatments in this cohort was limited: only 22.9% (n = 33/144) of patients admitted to hospital received dexamethasone, remdesivir, an anti-SARS-CoV-2 antibody-based therapeutic (e.g. REGN-COV2 or convalescent plasma) or tocilizumab as a monotherapy or in combination. Dexamethasone, remdesivir and anti-SARS-CoV-2 antibody-based therapeutics appeared efficacious in PID and SID. Conclusion Compared to the general population, individuals with PID or SID are at high risk of mortality following SARS-CoV-2 infection. Increasing age, low baseline lymphocyte count and the presence of co-morbidities are additional risk factors for poor outcome in this cohort.

Introduction In early 2020, at first surge of the coronavirus disease 2019 (COVID-19) pandemic, many health care workers (HCW) were re-deployed to critical care environments to support intensive care teams looking after patients with severe COVID-19. There was considerable anxiety of increased risk of COVID-19 for these staff. To determine whether critical care HCW were at increased risk of hospital acquired infection, we explored the relationship between workplace, patient facing role and evidence of immune exposure to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within a quaternary hospital providing a regional critical care response. Routine viral surveillance was not available at this time. Methods We screened over 500 HCW (25% of the total workforce) for history of clinical symptoms of possible COVID19, assigning a symptom severity score, and quantified SARS-CoV-2 serum antibodies as evidence of immune exposure to the virus. Results Whilst 45% of the cohort reported symptoms that they consider may have represented COVID-19, 14% had evidence of immune exposure. Staffs in patient facing critical care roles were least likely to be seropositive (9%) and staff working in non-patient facing roles most likely to be seropositive (22%). Anosmia and fever were the most discriminating symptoms for seropositive status. Older males presented with more severe symptoms. Of the 12 staff screened positive by nasal swab (10 symptomatic), 3 showed no evidence of seroconversion in convalescence. Conclusions Patient facing staff working in critical care do not appear to be at increased risk of hospital acquired infection however the risk of nosocomial infection from non-patient facing staff may be more significant than previous recognised. Most symptoms ascribed to possible COVID-19 were found to have no evidence of immune exposure however seroprevalence may underrepresent infection frequency. Older male staff were at the greatest risk of more severe symptoms.

Background: Elevated levels of interferon-gamma (IFNγ) have been found in COVID-19 infection, however its role in this setting remains poorly understood. Cases of non-tuberculous mycobacterium (NTM) infections due to anti-IFNγ autoantibodies (Ab) were first reported in 2004. NTM and COVID-19 co-infection in a patient with acquired IFNγ deficiency has not previously been described. The impact of anti-IFNγ Ab on the severity of COVID-19 has not been previously explored. Objective: We report a case of COVID-19 infection in a patient hospitalised with NTM infection due to acquired IFNγ deficiency caused by anti-IFNγ Ab. We also explore effects of IFNγ Ab on the severity of COVID-19 infection. Methods: Detailed immunological investigations were performed. Bio-rad, Bio-Plex methodology was used to detect anti-IFNγ Ab, titration, IFNγ recovery assay and SARS-CoV-2 serology. Anti-IFNγ Ab were tested in patients with severe (COV-Pat) and health care workers with mild/asymptomatic COVID-19 infection (COV-Asx). Results: Mycobacterium avium intracellulare was diagnosed following bone marrow examination and culture. High titre anti-IFNγ Ab were detected in patient’s serum. The autoantibodies neutralized both endogenously produced and exogenously administered IFNγ. SARS-COV-2 infection was identified during routine inpatient testing. Despite prolonged SARS-COV-2 infection the patient showed only minimal additional symptoms, never developed any significant inflammatory complications and eventually mounted an adequate IgG antibody response to the SARS-COV-2 trimeric S-protein. Elevated titres of anti-IFNγ Ab were detected in COV-Pat and COV-Asx, compared to non-infected healthy controls. The titres were broadly similar between COV-Pat and COV-Asx groups, but much lower compared to patients with acquired IFNγ Ab deficiency. Conclusion: IFN-γ is known to play a central role in hyperinflammatory disease states such as macrophage activation syndrome This study illustrates the potential value of inhibiting IFNγ to prevent pathological inflammatory response to COVID-19.

Background Increased understanding of whether individuals who have recovered from COVID-19 are protected from future SARS-CoV-2 infection is an urgent requirement. We aimed to investigate whether antibodies against SARS-CoV-2 were associated with a decreased risk of symptomatic and asymptomatic reinfection. Methods A large, multicentre, prospective cohort study was done, with participants recruited from publicly funded hospitals in all regions of England. All health-care workers, support staff, and administrative staff working at hospitals who could remain engaged in follow-up for 12 months were eligible to join The SARS-CoV-2 Immunity and Reinfection Evaluation study. Participants were excluded if they had no PCR tests after enrolment, enrolled after Dec 31, 2020, or had insufficient PCR and antibody data for cohort assignment. Participants attended regular SARS-CoV-2 PCR and antibody testing (every 2–4 weeks) and completed questionnaires every 2 weeks on symptoms and exposures. At enrolment, participants were assigned to either the positive cohort (antibody positive, or previous positive PCR or antibody test) or negative cohort (antibody negative, no previous positive PCR or antibody test). The primary outcome was a reinfection in the positive cohort or a primary infection in the negative cohort, determined by PCR tests. Potential reinfections were clinically reviewed and classified according to case definitions (confirmed, probable, or possible) and symptom-status, depending on the hierarchy of evidence. Primary infections in the negative cohort were defined as a first positive PCR test and seroconversions were excluded when not associated with a positive PCR test. A proportional hazards frailty model using a Poisson distribution was used to estimate incidence rate ratios (IRR) to compare infection rates in the two cohorts. Findings From June 18, 2020, to Dec 31, 2020, 30 625 participants were enrolled into the study. 51 participants withdrew from the study, 4913 were excluded, and 25 661 participants (with linked data on antibody and PCR testing) were included in the analysis. Data were extracted from all sources on Feb 5, 2021, and include data up to and including Jan 11, 2021. 155 infections were detected in the baseline positive cohort of 8278 participants, collectively contributing 2 047 113 person-days of follow-up. This compares with 1704 new PCR positive infections in the negative cohort of 17 383 participants, contributing 2 971 436 person-days of follow-up. The incidence density was 7·6 reinfections per 100 000 person-days in the positive cohort, compared with 57·3 primary infections per 100 000 person-days in the negative cohort, between June, 2020, and January, 2021. The adjusted IRR was 0·159 for all reinfections (95% CI 0·13–0·19) compared with PCR-confirmed primary infections. The median interval between primary infection and reinfection was more than 200 days. Interpretation A previous history of SARS-CoV-2 infection was associated with an 84% lower risk of infection, with median protective effect observed 7 months following primary infection. This time period is the minimum probable effect because seroconversions were not included. This study shows that previous infection with SARS-CoV-2 induces effective immunity to future infections in most individuals. Funding Department of Health and Social Care of the UK Government, Public Health England, The National Institute for Health Research, with contributions from the Scottish, Welsh and Northern Irish governments.

Background: Physical activity decreases the risk and development of many angiogenesis related health problems including atherosclerosis. Physiological influence of different physical activities on plasma endostatin concentration is contradictory. This study aimed to determine the effects of mild, moderate and vigorous exercise on the concentration of endostatin. Methodology: 22 participants, 16 males (age = 30.6 ± 7.8 years) and 6 females (age = 26.5 ± 5 years) were recruited. Weekly session of different intensities exercise based on predicted maximum heart (60% (low), 70% (moderate) and 80% (vigorous)] were carried out. One pre and two post exercise samples were taken at 10 and 60 minutes. Results: Low intensity exercise insignificantly decreased the endostatin concentration at 10 and 60 minutes (P = 0.5 and 0.8). However, moderate (P values = 0.022. 0.004) and vigorous intensities (P= < 0.001, 0.02) increased the endostatin concentrations significantly at both intervals respectively. The effects were not significantly influenced by gender, exercise mode (walking vs running), components of exercise (HR, Speed, Gradients, distance, duration) or metabolism during exercise (VO2 max, VCO2, RER, Energy expenditure). Conclusion: Low intensity exercises did not influence endostatin concentration. However, moderate to high intensity exercises significantly increase endostatin concentration and may have potential benefits.

Autoerotic asphyxiation (AEA) involves enhancing sexual arousal by deliberately self-inducing a reduction of oxygen to the brain. Most studies of AEA have focused on those who have expressed distress or who have died from the practice. The present study explores correlates of AEA-related distress in a community sample, focusing on self-reported measures of psychological distress, substance misuse, and sexual sensation seeking. Individuals who expressed an interest in AEA ( n = 165) participated in an online anonymous survey. Findings revealed a significant positive association between AEA-related distress and symptoms of depression, and a significant negative association between AEA-related distress and sexual sensation seeking. Both depression and sexual sensation seeking remained associated with AEA-related distress at the multivariate level. The findings are consistent with prior literature on AEA that suggests comorbidity with depression and highlights the importance of psychological screening when people present to clinicians due to AEA, particularly for depression. Contrary to our hypothesis, those with higher sexual sensation seeking reported lower levels of AEA-related distress. Future research on AEA-related distress may benefit from using a sexual sensation seeking measure that better assesses sexual dysregulation.

We describe a case of primary pneumococcal peritonitis which uncovered a family with compound heterozygous deficiency for complement factor I. Primary pneumococcal peritonitis has been described in women but has not been previously linked with complement disorders. We propose that unexplained pneumococcal peritonitis should be considered a “red flag” for primary immunodeficiency., Summary Primary pneumococcal peritonitis is a rare infection that has been described in women but has not been previously linked with immunodeficiency. The complement system plays a central role in immune defence against Streptococcus pneumoniae and, in order to evade complement attack, pneumococci have evolved a large number of mechanisms that limit complement‐mediated opsonization and subsequent phagocytosis. We investigated an apparently immunocompetent woman with primary pneumococcal peritonitis and identified a family with deficiency for complement factor I. Primary pneumococcal peritonitis should be considered a possible primary immunodeficiency presentation.

Background: Autoimmunity may play a role in idiopathic pulmonary arterial hypertension (IPAH). It is not clear if this is causative, or as a bystander of disease and if it carries any prognostic or treatment significance. Methods: Comprehensive immune phenotyping was performed in IPAH patients, utilising patient samples from the UK National cohort study of Idiopathic and Heritable PAH. Standardised flow cytometric analysis of peripheral blood mononuclear cell types was assessed in IPAH patients and healthy controls. Serum autoantibody biomarkers were assayed using a Protoplex™ autoimmune panel in 473 type I PAH patients and 946 matched controls. Finally, a GST-fusion human proteomic screen was undertaken to identify novel circulating autoantibodies in PAH, and 350 PAH sera samples ELISA assayed for a putative antibody to BMPR2. Findings: Flow cytometric immune profiling demonstrates IPAH is associated with a signature consistent with altered humoral immune response. Increased autoantibody positivity was detected in PAH and patient subgroups associated with worse haemodynamic parameters but better overall survival. We identify a small subset of PAH patients who demonstrate immunoglobulin reactivity to the extracellular domain of the TGFbeta superfamily receptor, BMPR2, a protein which is strongly associated with hereditary causes of the disease. Interpretation: This evidence strongly suggests a proportion of patients with IPAH have an autoimmune component to the disease and that the BMPR2 pathway may be a target. Future trials targeting inflammation need to consider biomarker stratification. Funding Information: NIHR BRC, The Dinosaur Trust, MRC (MC_UU_00002/4) and the Wellcome Trust [WT107881]. Declarations of Interest: Gerry Coghlan reports grants and personal fees for conference attendance from Johnson & Johnson, personal fees for lectures from GlaxoSmithKline, Bayer and MSD, outside the submitted work. Paul Corris reports grants and personal fees for lectures and consultations from Actelion and Bayer, and personal fees for lectures and consultations from MSD, outside the submitted work. Luke Howard reports grants, personal fees for lectures, steering committee and advisory board work, and non-financial support for meeting attendance from Actelion, personal fees for lectures and advisory board work from Bayer and MSD, personal fees for advisory board work from GSK, outside the submitted work. Martin Johnson reports grants and personal fees for meeting attendance, lectures, and advisory board work from Actelion and MSD, outside the submitted work. David Kiely reports grants, personal fees, and other support from Actelion, Bayer and GSK, and personal fees and other support from MSD, outside the submitted work. Allan Lawrie reports grants from British Heart Foundation and Medical Research Council, grants, personal fees, and travel support from Actelion Pharmaceuticals Ltd, grants and personal fees from GlaxoSmithKline, outside the submitted work. James Lordan has received modest honoraria from Actelion and modest support to attend conference from Merck Sharp & Dohme, outside the submitted work. Joanna Pepke Zaba received fees for research grant, support to travel to meetings and honoraria from Actelion, Bayer, GlaxoSmithKline and Merck Sharp & Dohme, outside the submitted work. S.John Wort has received modest honoraria from GlaxoSmithKline, Actelion and Bayer and has received significant research grants from Actelion and Bayer, outside the submitted work. Nicholas Morrell reports personal fees from GSK and Johnson & Johnson/Actelion, outside the submitted work. Mark Toshner reports personal fees from GSK, grants and personal fees from J&J/Actelion, grants from Merck and Bayer, outside the submitted work. All other authors have nothing to disclose Ethics Approval Statement: Ethical approval was obtained, and informed written consent was given. For collection and processing of samples for autoantibody analysis, including controls ethical approval was obtained (An integrated approach to dissect the determinants, risk factors and pathways of ageing in the immune system 15/EE/0327, IRAS # 188383 and Genetics and epidemiology of aging-associated conditions in the Sardinian population, ProgeNIA PROT 2171/CE).

BackgroundThe rise of SARS-CoV-2 variants has made the pursuit to define correlates of protection more troublesome, despite the availability of the World Health Organisation (WHO) International Standard for anti-SARS-CoV-2 Immunoglobulin sera, a key reagent used to standardise laboratory findings into an international unitage.MethodsUsing pseudotyped virus, we examine the capacity of convalescent sera, from a well-defined cohort of healthcare workers (HCW) and Patients infected during the first wave from a national critical care centre in the UK to neutralise B.1.1.298, variants of interest (VOI) B.1.617.1 (Kappa), and four VOCs, B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta), including the B.1.617.2 K417N, informally known as Delta Plus. We utilised the WHO International Standard for anti-SARS-CoV-2 Immunoglobulin to report neutralisation antibody levels in International Units per mL.FindingsOur data demonstrate a significant reduction in the ability of first wave convalescent sera to neutralise the VOCs. Patients and HCWs with more severe COVID-19 were found to have higher antibody titres and to neutralise the VOCs more effectively than individuals with milder symptoms. Using an estimated threshold for 50% protection, 54 IU/mL, we found most asymptomatic and mild cases did not produce titres above this threshold.InterpretationExpressing our data in IU/ml, we provide a benchmark pre-vaccine standardised dataset that compares disease severity with neutralising antibody titres. Our data may now be compared across multiple laboratories. The continued use and aggregation of standardised data will eventually assist in defining correlates of protection.FundingUKRI and NIHR; grant number G107217Research in contextEvidence before this studyDuring the first wave outbreak, much focus was placed on the role of neutralising antibodies and titres generated upon infection to ancestral SARS-CoV-2. Due to the large amounts of different assays used to elucidate the antibody-mediated immunity and laboratory to laboratory, large amounts of invaluable data could not be directly compared in order to define a correlate of protection, due to variability in the results. The WHO International Standard for anti-SARS-CoV-2 Immunoglobulin sera was made in order to standardise future data so that comparisons may take place.Added value of this studyOur study compares the neutralisation capacity of sera from patients and healthcare workers (HCWs) from the ancestral strain of SARS-CoV-2 against new variants, including the current variants of concern in circulation. We also provide data in International Units per mL, a standardised unitage, for infected individuals that have a clinical severity score, allowing us to assess levels of neutralising antibodies across different severities of COVID-19 disease. By providing a method to calibrate most of the variants of concern so that the WHO International Standard for anti-SARS-CoV-2 Immunoglobulin reagent could be used to standardise our results, therefore making them comparable to other laboratories who also standardised their data in an identical manner.Implications of all the available evidenceContinual use and accumulation of standardised data would eventually lead to defining the correlates of protection against SARS-CoV-2. This could help to inform medical staff to identify which individuals would be a greater risk of a potential reinfection to SARS-CoV-2.

With the first 2020 surge of the COVID-19 pandemic, many health care workers (HCW) were re-deployed to critical care environments to support intensive care teams to look after high numbers of patients with severe COVID-19. There was considerable anxiety of increased risk of COVID19 for staff working in these environments.Using a multiplex platform to assess serum IgG responses to SARS-CoV-2 N, S and RBD proteins, and detailed symptom reporting, we screened over 500 HCW (25% of the total workforce) in a quaternary level hospital to explore the relationship between workplace and evidence of exposure to SARS-CoV-2.Whilst 45% of the cohort reported symptoms that they consider may have represented COVID-19, overall seroprevalence was 14% with anosmia and fever being the most discriminating symptoms for seropositive status. There was a significant difference in seropositive status between staff working in clinical and non-clinical roles (9% patient facing critical care, 15% patient facing non-critical care, 22% nonpatient facing). In the seropositive cohort, symptom severity increased with age for men and not for women. In contrast, there was no relationship between symptom severity and age or sex in the seronegative cohort reporting possible COVID-19 symptoms. Of the 12 staff screened PCR positive (10 symptomatic), 3 showed no evidence of seroconversion in convalescence.ConclusionThe current approach to Personal Protective Equipment (PPE) appears highly effective in protecting staff from patient acquired infection in the critical care environment including protecting staff managing interhospital transfers of COVID-19 patients. The relationship between seroconversion and disease severity in different demographics warrants further investigation. Longitudinally paired virological and serological surveillance, with symptom reporting are urgently required to better understand the role of antibody in the outcome of HCW exposure during subsequent waves of COVID-19 in health care environments.

Precision monitoring of antibody responses during the COVID-19 pandemic is increasingly important during large scale vaccine rollout and rise in prevalence of Severe Acute Respiratory Syndrome-related Coronavirus-2 (SARS-CoV-2) variants of concern (VOC). Equally important is defining Correlates of Protection (CoP) for SARS-CoV-2 infection and COVID-19 disease. Data from epidemiological studies and vaccine trials identified virus neutralising antibodies (Nab) and SARS-CoV-2 antigen-specific (notably RBD and S) binding antibodies as candidate CoP. In this study, we used the World Health Organisation (WHO) international standard to benchmark neutralising antibody responses and a large panel of binding antibody assays to compare convalescent sera obtained from: a) COVID-19 patients; b) SARS-CoV-2 seropositive healthcare workers (HCW) and c) seronegative HCW. The ultimate aim of this study is to identify biomarkers of humoral immunity that could be used to differentiate severe from mild or asymptomatic SARS-CoV-2 infections. Some of these biomarkers could be used to define CoP in further serological studies using samples from vaccination breakthrough and/or re-infection cases. Whenever suitable, the antibody levels of the samples studied were expressed in International Units (IU) for virus neutralisation assays or in Binding Antibody Units (BAU) for ELISA tests. In this work we used commercial and non-commercial antibody binding assays; a lateral flow test for detection of SARS-CoV-2-specific IgG/IgM; a high throughput multiplexed particle flow cytometry assay for SARS-CoV-2 Spike (S), Nucleocapsid (N) and Receptor Binding Domain (RBD) proteins); a multiplex antigen semi-automated immuno-blotting assay measuring IgM, IgA and IgG; a pseudotyped microneutralisation test (pMN) and an electroporation-dependent neutralisation assay (EDNA). Our results indicate that overall, severe COVID-19 patients showed statistically significantly higher levels of SARS-CoV-2-specific neutralising antibodies (average 1029 IU/ml) than those observed in seropositive HCW with mild or asymptomatic infections (379 IU/ml) and that clinical severity scoring, based on WHO guidelines was tightly correlated with neutralisation and RBD/S antibodies. In addition, there was a positive correlation between severity, N-antibody assays and intracellular virus neutralisation.

Summary Background BNT162b2 mRNA and ChAdOx1 nCOV-19 adenoviral vector vaccines have been rapidly rolled out in the UK from December, 2020. We aimed to determine the factors associated with vaccine coverage for both vaccines and documented the vaccine effectiveness of the BNT162b2 mRNA vaccine in a cohort of health-care workers undergoing regular asymptomatic testing. Methods The SIREN study is a prospective cohort study among staff (aged ≥18 years) working in publicly-funded hospitals in the UK. Participants were assigned into either the positive cohort (antibody positive or history of infection [indicated by previous positivity of antibody or PCR tests]) or the negative cohort (antibody negative with no previous positive test) at the beginning of the follow-up period. Baseline risk factors were collected at enrolment, symptom status was collected every 2 weeks, and vaccination status was collected through linkage to the National Immunisations Management System and questionnaires. Participants had fortnightly asymptomatic SARS-CoV-2 PCR testing and monthly antibody testing, and all tests (including symptomatic testing) outside SIREN were captured. Data cutoff for this analysis was Feb 5, 2021. The follow-up period was Dec 7, 2020, to Feb 5, 2021. The primary outcomes were vaccinated participants (binary ever vacinated variable; indicated by at least one vaccine dose recorded by at least one of the two vaccination data sources) for the vaccine coverage analysis and SARS-CoV-2 infection confirmed by a PCR test for the vaccine effectiveness analysis. We did a mixed-effect logistic regression analysis to identify factors associated with vaccine coverage. We used a piecewise exponential hazard mixed-effects model (shared frailty-type model) using a Poisson distribution to calculate hazard ratios to compare time-to-infection in unvaccinated and vaccinated participants and estimate the impact of the BNT162b2 vaccine on all PCR-positive infections (asymptomatic and symptomatic). This study is registered with ISRCTN, number ISRCTN11041050, and is ongoing. Findings 23 324 participants from 104 sites (all in England) met the inclusion criteria for this analysis and were enrolled. Included participants had a median age of 46·1 years (IQR 36·0–54·1) and 19 692 (84%) were female; 8203 (35%) were assigned to the positive cohort at the start of the analysis period, and 15 121 (65%) assigned to the negative cohort. Total follow-up time was 2 calendar months and 1 106 905 person-days (396 318 vaccinated and 710 587 unvaccinated). Vaccine coverage was 89% on Feb 5, 2021, 94% of whom had BNT162b2 vaccine. Significantly lower coverage was associated with previous infection, gender, age, ethnicity, job role, and Index of Multiple Deprivation score. During follow-up, there were 977 new infections in the unvaccinated cohort, an incidence density of 14 infections per 10 000 person-days; the vaccinated cohort had 71 new infections 21 days or more after their first dose (incidence density of eight infections per 10 000 person-days) and nine infections 7 days after the second dose (incidence density four infections per 10 000 person-days). In the unvaccinated cohort, 543 (56%) participants had typical COVID-19 symptoms and 140 (14%) were asymptomatic on or 14 days before their PCR positive test date, compared with 29 (36%) with typical COVID-19 symptoms and 15 (19%) asymptomatic in the vaccinated cohort. A single dose of BNT162b2 vaccine showed vaccine effectiveness of 70% (95% CI 55–85) 21 days after first dose and 85% (74–96) 7 days after two doses in the study population. Interpretation Our findings show that the BNT162b2 vaccine can prevent both symptomatic and asymptomatic infection in working-age adults. This cohort was vaccinated when the dominant variant in circulation was B1.1.7 and shows effectiveness against this variant. Funding Public Health England, UK Department of Health and Social Care, and the National Institute for Health Research.

Patients with some types of immunodeficiency can experience chronic or relapsing infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This leads to morbidity and mortality, infection control challenges, and the risk of evolution of novel viral variants. The optimal treatment for chronic coronavirus disease 2019 (COVID-19) is unknown.Our aim was to characterize a cohort of patients with chronic or relapsing COVID-19 disease and record treatment response.We conducted a UK physician survey to collect data on underlying diagnosis and demographics, clinical features, and treatment response of immunodeficient patients with chronic (lasting ≥21 days) or relapsing (≥2 episodes) of COVID-19.We identified 31 patients (median age 49 years). Their underlying immunodeficiency was most commonly characterized by antibody deficiency with absent or profoundly reduced peripheral B-cell levels; prior anti-CD20 therapy, and X-linked agammaglobulinemia. Their clinical features of COVID-19 were similar to those of the general population, but their median duration of symptomatic disease was 64 days (maximum 300 days) and individual patients experienced up to 5 episodes of illness. Remdesivir monotherapy (including when given for prolonged courses of ≤20 days) was associated with sustained viral clearance in 7 of 23 clinical episodes (30.4%), whereas the combination of remdesivir with convalescent plasma or anti-SARS-CoV-2 mAbs resulted in viral clearance in 13 of 14 episodes (92.8%). Patients receiving no therapy did not clear SARS-CoV-2.COVID-19 can present as a chronic or relapsing disease in patients with antibody deficiency. Remdesivir monotherapy is frequently associated with treatment failure, but the combination of remdesivir with antibody-based therapeutics holds promise.

Background The impact of COVID-19 on physical and mental health and employment after hospitalisation with acute disease is not well understood. The aim of this study was to determine the effects of COVID-19-related hospitalisation on health and employment, to identify factors associated with recovery, and to describe recovery phenotypes. Methods The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a multicentre, long-term follow-up study of adults (aged ≥18 years) discharged from hospital in the UK with a clinical diagnosis of COVID-19, involving an assessment between 2 and 7 months after discharge, including detailed recording of symptoms, and physiological and biochemical testing. Multivariable logistic regression was done for the primary outcome of patient-perceived recovery, with age, sex, ethnicity, body-mass index, comorbidities, and severity of acute illness as covariates. A post-hoc cluster analysis of outcomes for breathlessness, fatigue, mental health, cognitive impairment, and physical performance was done using the clustering large applications k-medoids approach. The study is registered on the ISRCTN Registry (ISRCTN10980107). Findings We report findings for 1077 patients discharged from hospital between March 5 and Nov 30, 2020, who underwent assessment at a median of 5·9 months (IQR 4·9–6·5) after discharge. Participants had a mean age of 58 years (SD 13); 384 (36%) were female, 710 (69%) were of white ethnicity, 288 (27%) had received mechanical ventilation, and 540 (50%) had at least two comorbidities. At follow-up, only 239 (29%) of 830 participants felt fully recovered, 158 (20%) of 806 had a new disability (assessed by the Washington Group Short Set on Functioning), and 124 (19%) of 641 experienced a health-related change in occupation. Factors associated with not recovering were female sex, middle age (40–59 years), two or more comorbidities, and more severe acute illness. The magnitude of the persistent health burden was substantial but only weakly associated with the severity of acute illness. Four clusters were identified with different severities of mental and physical health impairment (n=767): very severe (131 patients, 17%), severe (159, 21%), moderate along with cognitive impairment (127, 17%), and mild (350, 46%). Of the outcomes used in the cluster analysis, all were closely related except for cognitive impairment. Three (3%) of 113 patients in the very severe cluster, nine (7%) of 129 in the severe cluster, 36 (36%) of 99 in the moderate cluster, and 114 (43%) of 267 in the mild cluster reported feeling fully recovered. Persistently elevated serum C-reactive protein was positively associated with cluster severity. Interpretation We identified factors related to not recovering after hospital admission with COVID-19 at 6 months after discharge (eg, female sex, middle age, two or more comorbidities, and more acute severe illness), and four different recovery phenotypes. The severity of physical and mental health impairments were closely related, whereas cognitive health impairments were independent. In clinical care, a proactive approach is needed across the acute severity spectrum, with interdisciplinary working, wide access to COVID-19 holistic clinical services, and the potential to stratify care. Funding UK Research and Innovation and National Institute for Health Research.

Supplemental Digital Content is available in the text., OBJECTIVES: To compare the performance of Sequential Organ Failure Assessment, systemic inflammatory response syndrome, Red Flag Sepsis, and National Institute of Clinical Excellence sepsis risk stratification tools in the identification of patients at greatest risk of mortality from sepsis in nonintensive care environments. DESIGN: Secondary analysis of three annual 24-hour point-prevalence study periods. SETTING: The general wards and emergency departments of 14 acute hospitals across Wales. Studies were conducted on the third Wednesday of October in 2017, 2018, and 2019. PATIENTS: We screened all patients presenting to the emergency department and on the general wards. MEASUREMENTS AND MAIN RESULTS: We recruited 1,271 patients, of which 724 (56.9%) had systemic inflammatory response syndrome greater than or equal to 2, 679 (53.4%) had Sequential Organ Failure Assessment greater than or equal to 2, and 977 (76.9%) had Red Flag Sepsis. When stratified according to National Institute of Clinical Excellence guidelines, 450 patients (35.4%) were in the “High risk” category in comparison with 665 (52.3%) in “Moderate to High risk” and 156 (12.3%) in “Low risk” category. In a planned sensitivity analysis, we found that none of the tools accurately predicted mortality at 90 days, and Sequential Organ Failure Assessment and National Institute of Clinical Excellence tools showed only moderate discriminatory power for mortality at 7 and 14 days. Furthermore, we could not find any significant correlation with any of the tools at any of the mortality time points. CONCLUSIONS: Our data suggest that the sepsis risk stratification tools currently utilized in emergency departments and on the general wards do not predict mortality adequately. This is illustrated by the disparity in mortality risk of the populations captured by each instrument, as well as the weak concordance between them. We propose that future studies on the development of sepsis identification tools should focus on identifying predicator values of both the short- and long-term outcomes of sepsis.

The virus SARS-CoV-2, responsible for the global COVID-19 pandemic, spread rapidly around the world causing high morbidity and mortality because humans have no pre-existing immunity. However, there are four known, endemic seasonal coronaviruses in humans (HCoVs) and whether antibodies for these HCoVs play a role in severity of COVID-19 disease has generated a lot of interest. Of these seasonal viruses NL63 is of particular interest as it uses the same cell entry receptor as SARS-CoV-2.We use functional, neutralising assays to investigate cross reactive antibodies and their relationship with COVID-19 severity. We analysed neutralisation of SARS-CoV-2, NL63, HKU1, and 229E in 38 COVID-19 patients and 62 healthcare workers, and a further 182 samples to specifically study the relationship between SARS-CoV-2 and NL63.We found that although HCoV neutralisation was very common there was little evidence that these antibodies neutralised SARS-CoV-2. Despite no evidence in cross neutralisation, levels of NL63 neutralisating antibodies become elevated after exposure to SARS-CoV-2 through infection or following vaccination.

For a single nano-optical material, it is difficult to possess high transmittance and adequately filter ultraviolet (UV) and infrared radiation (IR) simultaneously. Consequently, hybrid nano-optical materials comprising components of appropriate proportions for superimposing serviceable optical property are required. The design, optimization and processing of new composite blends with an aim to creating defect free thin films is far from a trivial endeavor. In this report, optimum composition and optical properties of hybrid nano-optical material has been determined and improved by crossover matching experiments and ball milling, respectively. Film preparation has been optimized to reduce defects expressed as cracks, tiny bubbles, strips, groove points, corrugation, and formation of acicular fibers by regulating proportion of polyvinyl butyral colloid and dry film processes. Two ameliorative processing conditions are exemplified where the resultant composite films possessed 86% maximum transmittance in the visible range and 90% and 50% blocking rate with respect to the IR and UV bands.

Autoerotic asphyxiation (AEA) is a sexual interest that involves heightening sexual arousal by deliberately self-inducing a reduced supply of oxygen to the brain. Most of the literature on AEA is comprised of case studies and research based on people who have died from the practice. The present study explored information about AEA practices and the degree of overlap between AEA and other paraphilias in community participants. Participants (n = 395) were recruited through different online platforms to complete an anonymous survey and 165 were classified as having AEA by reporting mild to strong sexual arousal in AEA. These individuals reported that their interest emerged in late adolescence, and many reported that they discovered AEA via the internet. Regarding safety precautions people take during their AEA practice, 19% of participants reported that they did not use safety precautions. Most people (> 80%) were not distressed by their AEA interest. Additionally, significant relationships were found between AEA interest and many paraphilic interests with masochism being the only paraphilia associated with AEA when considering other paraphilic interests. These results suggest that most individuals engage in less risky manifestations of AEA than what is reported in the clinical literature and that AEA is appropriately conceptualized as a subtype of masochism. The results underscore the importance of gathering information about alternative sexual practices in community samples.

This review examines the clinical and neuroradiological features of traumatic brain injury that are most frequently associated with persistent cognitive complaints. Neuropsychological outcomes do not depend solely on brain injury severity but result from a complex interplay between premorbid factors, the extent and nature of the underlying structural damage, the person’s neuropsychological reserve and the impact of non-neurological factors in the recovery process. Brain injury severity is only one of these factors and has limited prognostic significance with respect to neuropsychological outcome. We examine the preinjury and postinjury factors that interact with the severity of a traumatic brain injury to shape outcome trajectories. We aim to provide a practical base on which to build discussions with the patient and their family about what to expect following injury and also to plan appropriate neurorehabilitation.

The synthesis of the naturally occurring toxin pyocyanin has been realized in a short 4 step sequence. The key photochemical reaction and isolation of the final product has been facilitated by the use of flow chemistry techniques and immobilised reagents. Using these procedures gram quantities of pyocyanin were easily prepared in high yield and purity.

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.

RaTG13 is a close relative of SARS-CoV-2, the virus responsible for the Coronavirus Disease 2019 (COVID-19) pandemic, sharing 96% sequence similarity at the genome-wide level. The spike receptor binding domain (RBD) of RaTG13 contains a large number of amino acid substitutions when compared to SARS-CoV-2, likely impacting affinity for the ACE2 receptor. Antigenic differences between the viruses are less well understood, especially whether RaTG13 spike can be efficiently neutralised by antibodies generated from infection with, or vaccination against, SARS-CoV-2. Using RaTG13 and SARS-CoV-2 pseudotypes we compared neutralisation using convalescent sera from previously infected patients as well as vaccinated healthcare workers. Surprisingly, our results revealed that RaTG13 was more efficiently neutralised than SARS-CoV-2. In addition, neutralisation assays using spike chimeras and mutants harbouring single amino acid substitutions within the RBD demonstrated that both spike proteins can tolerate multiple changes without dramatically reducing how efficiently they are neutralised. Moreover, introducing the 484K mutation into RaTG13 resulted in increased neutralisation, in contrast to the same mutation in SARS-CoV-2 (E484K). This is despite E484K having a well-documented role in immune evasion in variants of concern (VOC) such as B.1.351 (Beta). These results indicate that the immune-escape mutations found in SARS-CoV-2 VOCs might be driven by strong antibody pressures, and that the future spill-over of RaTG13 and/or related sarbecoviruses could be mitigated using current SARS-CoV-2-based vaccination strategies.

The novel coronavirus SARS-CoV-2 is the seventh identified human coronavirus. Understanding the extent of pre-existing immunity induced by seropositivity to endemic seasonal coronaviruses and the impact of cross-reactivity on COVID-19 disease progression remains a key research question in immunity to SARS-CoV-2 and the immunopathology of COVID-2019 disease. This paper describes a panel of lentiviral pseudotypes bearing the spike (S) proteins for each of the seven human coronaviruses (HCoVs), generated under similar conditions optimized for high titre production allowing a high-throughput investigation of antibody neutralization breadth. Optimal production conditions and most readily available permissive target cell lines were determined for spike-mediated entry by each HCoV pseudotype: SARS-CoV-1, SARS-CoV-2 and HCoV-NL63 best transduced HEK293T/17 cells transfected with ACE2 and TMPRSS2, HCoV-229E and MERS-CoV preferentially entered HUH7 cells, and CHO cells were most permissive for the seasonal betacoronavirus HCoV-HKU1. Entry of ACE2 using pseudotypes was enhanced by ACE2 and TMPRSS2 expression in target cells, whilst TMPRSS2 transfection rendered HEK293T/17 cells permissive for HCoV-HKU1 and HCoV-OC43 entry. Additionally, pseudotype viruses were produced bearing additional coronavirus surface proteins, including the SARS-CoV-2 Envelope (E) and Membrane (M) proteins and HCoV-OC43/HCoV-HKU1 Haemagglutinin-Esterase (HE) proteins. This panel of lentiviral pseudotypes provides a safe, rapidly quantifiable and high-throughput tool for serological comparison of pan-coronavirus neutralizing responses, this can be used to elucidate antibody dynamics against individual coronaviruses and the effects of antibody cross-reactivity on clinical outcome following natural infection or vaccination.

The prefusion Spike protein of SARS-CoV2 binds advanced glycation end product (AGE) glycated human serum albumin (HSA) and a higher mass, hyperglycosylated/glycated, IgG3, as determined by matrix assisted laser desorption mass spectrometry (MALDI-ToF MS). We set out to investigate if the total blood plasma of patients who had recovered from acute respiratory distress as a result of COVID-19, contained more glycated HSA and higher mass (glycosylated/glycated) IgG3 than those with only clinically mild or asymptomatic infections. A direct dilution and disulphide bond reduction method was development and applied to plasma samples from SARS-CoV2 seronegative (N = 30) and seropositive (N = 31) healthcare workers and 38 convalescent plasma samples from patients who had been admitted with acute respiratory distress syndrome (ARDS) associated with COVID-19.Patients recovering from COVID-19 ARDS had significantly higher mass, AGE-glycated HSA and higher mass IgG3 levels. This would indicate that increased levels and/or ratios of hyper-glycosylation (probably terminal sialic acid) IgG3 and AGE glycated HSA may be predisposition markers for development of ARDS as a result of COVID-19 infection. Furthermore, rapid direct analysis of plasma samples by MALDI-ToF MS for such humoral immune correlates of COVID-19 presents a feasible screening technology for the most at risk; regardless of age or known health conditions.Abstract Figure

Understanding the levels of immunity in both the immunocompromised and general populations will facilitate the development of public health strategies to contain and prevent novel variants of interest or the emergence of vaccine-resistant variants that could threaten COVID-19 immunisation programmes.

SummaryBMP signalling is known to have a conserved function in development of the semicircular canal system of the vertebrate inner ear, but its regulation, target genes and effects on cell behaviour during otic morphogenesis are not fully understood. We have characterised the effects of mutations in the zebrafish gene bmper, which codes for a regulator of BMP signalling with both pro- and anti-BMP roles in different developmental contexts. The inner ears of bmper mutant embryos develop with truncations of the anterior and posterior semicircular canal ducts. To image the developing ear in live embryos, we have exploited a new transgenic line, Tg(smad6b:EGFP), which exhibits strong GFP expression in the otic epithelium. Morphometric analysis indicates defects in the bmper mutant ear from early stages of semicircular canal formation, correlating with a specific reduction in BMP signalling activity and specific loss of dlx5a expression in dorsal otic epithelium. Subsequent changes to cell shape occur at the truncation site and the dorsolateral septum. The bmper mutations that we describe are adult viable; truncation of the anterior and posterior semicircular canal ducts persists into adulthood. Our results argue against a major role for Bmper in specification of the pre-placodal region, induction of the otic placode, or development of the neural crest, processes in which Bmper function has previously been implicated. Instead, we conclude that a key requirement for Bmper function in the zebrafish is to promote BMP signalling during patterning and morphogenesis of the semicircular canal system.

The involvement of IgG3 in the humoral immune response to SARS-CoV2 infection has been implicated in the pathogenesis of ARDS in COVID-19. The exact molecular mechanism is unknown but may be due to the differential ability of IgG3 Fc region to fix complement and stimulate cytokine release. We examined convalescent patients antibodies binding to immobilised nucleocapsid and spike protein by MALDI-ToF mass spectrometry. IgG3 was a major immunoglobulin found in all samples. Differential analysis of the spectral signatures found for nucleocapsid versus spike protein demonstrated that the predominant humoral immune response to nucleocapsid was IgG3, whilst against spike it was IgG1. However, the spike protein displayed a strong affinity for IgG3 itself which it would bind from control plasma samples as well as from those previously infected with SARS-CoV2, much in the way Protein-G binds IgG1. Furthermore, detailed spectral analysis indicated a mass shift consistent with hyper-glycosylation or glycation was a characteristic of the IgG3 captured by the spike protein. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/21259077v2_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@181773eorg.highwire.dtl.DTLVardef@bb8d58org.highwire.dtl.DTLVardef@13cbe05org.highwire.dtl.DTLVardef@df579e_HPS_FORMAT_FIGEXP M_FIG C_FIG

A large portion of the UK general population has currently only received a single dose of a COVID-19 vaccination (either BNT162b2 (Pfizer) or AZD1222 (Vaxevria, AstraZeneca)), making it critical that we continue to track and understand the levels of protection against SARS-CoV-2 Variants of Concern (VOCs). We undertook a single-centre cross-sectional study in order to understand the variations in vaccine-induced immunity to the SARS-CoV-2 vaccine strain (B.1) and three major VOCs (B.1.1.7, B.1351 and P.1). We studied a cohort of outpatients with immunodeficiencies (IDPs) and health care workers (HCWs) based at the same critical care tertiary NHS Trust, following a single dose of either BNT162b2 or AZD1222 vaccines. Our serological data revealed either undetectable antibodies or low neutralising antibodies (nAbs) in IDPs, with only 5% and 3% showing detectable neutralisation of B.1.1.7 and B.1.351, respectively. Healthy HCWs without a prior SARS-CoV-2 infection demonstrated a wide range of nAb titres post-vaccination. However, their responses are significantly lower than HCWs with previous SARS-CoV-2 infection. Neutralisation of VOCs with the E484K mutation (B.1.351 and P.1) were consistently lower in HCWs in the absence of evidence of prior SARS-CoV-2 infection (p

Precision monitoring of antibody responses during the COVID-19 pandemic is increasingly important during large scale vaccine rollout and rise in prevalence of Severe Acute Respiratory Syndrome-related Coronavirus-2 (SARS-CoV-2) variants of concern (VOC). Equally important is defining Correlates of Protection (CoP) for SARS-CoV-2 infection and COVID-19 disease. Data from epidemiological studies and vaccine trials identified virus neutralising antibodies (Nab) and SARS-CoV-2 antigen-specific (notably RBD, and S) binding antibodies as candidate CoP. In this study, we used the World Health Organisation (WHO) international standard to benchmark neutralising antibody responses and a large panel of binding antibody assays to compare convalescent sera obtained from: a) COVID-19 patients; b) SARS-CoV-2 seropositive healthcare workers (HCW) and c) seronegative HCW. The ultimate aim of this study, was to identify biomarkers of humoral immunity that could be used as candidate CoP in internationally accepted unitage. Whenever suitable, the antibody levels of the samples studied were expressed in International Units (INU) for virus neutralisation assays or International Binding Antibody Units (BAU) for ELISA tests. In this work we used commercial and non-commercial antibody binding assays; a lateral flow test for detection of SARS-CoV-2-specific IgG / IgM; a high throughput multiplexed particle flow cytometry assay for SARS-CoV-2 Spike (S), Nucleocapsid (N) and Receptor Binding Domain (RBD) proteins); a multiplex antigen semi-automated immuno-blotting assay measuring IgM, IgA and IgG; a pseudotyped microneutralisation test (pMN) and electroporation-dependent neutralisation assay (EDNA). Our results indicate that overall, severe COVID-19 patients showed statistically significantly higher levels of SARS-CoV-2-specific neutralising antibodies (average 1029 IU/ml) than those observed in seropositive HCW with mild or asymptomatic infections (379 IU/ml) and that clinical severity scoring, based on WHO guidelines was tightly correlated with neutralisation and RBD / S binding assays. In addition, there was a positive correlation between severity, N-antibody assays and intracellular virus neutralisation.

BACKGROUND The natural history of traumatic glenohumeral dislocation is well-established in young adults, but it is less clear in pediatric patients. We aimed to determine the rate of recurrent instability and medium-term functional outcome following shoulder dislocation in patients aged 14 years or younger. METHODS All patients aged 14 years or younger who sustained a glenohumeral dislocation from 2008 to 2019 presenting to our regional health-board were identified. Patients who had subluxations associated with generalized laxity were excluded. Data was collected regarding further dislocations, stabilization surgery, sporting activity and patient-reported outcomes using the Western Ontario Shoulder Instability (WOSI) Index and Quick Disabilities of the Arm, Shoulder, and Hand score. RESULTS Forty-one patients with a radiologically confirmed traumatic glenohumeral dislocation were suitable for study inclusion [mean age at injury 12.3 y (range: 7.2 to 14.0 y), male sex 29 (70.7%), median 7.9 y follow-up]. The incidence rate of pediatric glenohumeral dislocation was 2.5 cases per 100,000 population (aged 0 to 14 y) per year. Recurrent dislocation occurred in 43.9% (n=18/41) at a median time of 14.7 months postinjury (range: 1 to 54 mo). Skeletal maturity was associated with significantly higher proportion of recurrent instability (immature 6/24 vs. mature 12/17, P=0.01). One in 5 patients required surgical intervention for recurrent instability [mean 8 (range: 1 to 14) dislocations before surgery]. Twenty-eight patients had completed outcome questionnaires. The median modified WOSI score was 87.1% [270 (interquartile range: 65 to 795)] and the median Quick Disabilities of the Arm, Shoulder, and Hand score was 3.4 (interquartile range: 0 to 9.7). Recurrent shoulder instability was significantly associated with poorer WOSI score (unstable 71.4% vs. stable 94.3%, 95% confidence interval of the difference 6.2-36.9, P=0.04). CONCLUSIONS Traumatic glenohumeral dislocation in patients aged 14 years or younger occurs rarely but is not a benign event. One in 2 patients experienced recurrent dislocation and 1 in 5 ultimately underwent surgical stabilization. LEVEL OF EVIDENCE Level IV.

Objective Problem gambling results from the complex interaction of neurological factors with psychological, demographic, and socioeconomical influences. The vulnerabilities of people with epilepsy to many of these influences may increase their susceptibility to developing problematic gambling behaviors. The aim of this study was to establish the frequency of gambling participation and the clinical correlates of problem gambling behaviors in people with epilepsy. Methods Lifestyle questions, including the Lie/Bet screening questionnaire were administered to 250 consecutive attendees at a neurology clinic. Valid data were available for 174 adults with epilepsy and 65 adults with other neurological conditions. Results With the exception of people with frontal lobe epilepsy (FLE), gambling participation rates in people with epilepsy and those with other neurological conditions were lower than those reported in the general population. While the overall levels of gambling participation were relatively low in this sample, the number of gamblers who responded positively to the lie/bet questionnaire was ten times higher than that seen in the general population, with one in three gamblers in our series reporting signs of escalation. All had epilepsy and were more likely to be taking Levetiracetam or Brivaracetam than the other gamblers in our series. While epilepsy classification was not related to gambling escalation, patients with FLE were overrepresented in this group due to their significantly higher baseline levels of participation in gambling. Conclusions People with FLE may have a heightened vulnerability to developing problem gambling behaviors. The role of the neurological consultation in managing these risks is discussed.

Objective Although group studies provide some support for the material-specific model of memory function, there are considerable individual variations in memory function in people with temporal lobe epilepsy, even in those with the same underlying pathology. In this proof-of-concept study, we examined the sensitivity and specificity of a single measure of an individual's relative strength for the encoding of verbal or visual learning. Methods Six hundred ninety-two patients with left hemisphere language dominance and unilateral hippocampal sclerosis completed verbal and visual encoding tasks with similar test structures as part of their presurgical evaluation. Three hundred one patients had right hippocampal sclerosis (RHS), and 391 patients had left hippocampal sclerosis (LHS). A memory specialization index (MSI) was calculated by subtracting the Visual Learning z-score from the Verbal Learning z-score. A positive value on the MSI indicates a relative strength in verbal learning. A negative score indicates a relative strength in visual learning. Results Employing cut-offs of ±1, the MSI had a positive predictive value of 71% (confidence interval [CI] 95% 0.64-0.77) for LHS and 64% (CI 95% 0.55-0.74) for RHS and was superior to the standalone z-scores from the verbal and visual tests in each respect. In the LHS group, the MSI was significantly correlated with age and duration of epilepsy. Older patients who had a longer duration of epilepsy were more likely to demonstrate a similar level of impairment in both verbal and visual learning, with a decreasing discrepancy between the scores on the two tasks over time. Significance Our MSI provides a measure with high specificity for RHS. The pattern of strengths and weaknesses in visual and verbal encoding may evolve with age and duration of epilepsy, and clinicians should be aware of these factors when interpreting the lateralizing significance of test scores, particularly in a presurgical setting.

To identify small molecules that shield mammalian sensory hair cells from the ototoxic side effects of aminoglycoside antibiotics we screened 10,240 compounds, selecting those that protected against neomycin and gentamicin in zebrafish lateral-line hair cells and, when retested in mouse cochlear cultures, prevented gentamicin-induced death of outer hair cells (OHCs). Of 64 compounds that protected zebrafish hair cells, 8 protect OHCs from gentamicin in vitro. These hits share structural features and all block, to varying degrees, the OHC’s mechano-electrical transducer (MET) channel, a known route of aminoglycoside entry into hair cells. Further characterisation of one of the strongest MET-channel blockers, UoS-7692, revealed it additionally protects against kanamycin and tobramycin, and does not abrogate the bactericidal activity of gentamicin. UoS-7692 behaves, like the aminoglycosides, as a permeant blocker of the MET channel, significantly reduces gentamicin-Texas Red loading into OHCs, and preserves lateral-line function in neomycin-treated zebrafish. Trans-tympanic injection of UoS-7692 protects mouse OHCs from furosemide-kanamycin exposure in vivo and partially preserves hearing. The results confirm the hair-cell MET channel as a viable target for the identification of compounds that protect the cochlea from aminoglycosides, and provide a series of hit compounds that will inform the design of future otoprotectants.

We report the presence of a rare cell type, the olfactory rod cell, in the developing zebrafish olfactory epithelium. These cells each bear a single actin-rich rod-like apical projection extending 5–10 μm from the epithelial surface. Live imaging with a ubiquitous Lifeact-RFP label indicates that the olfactory rods can oscillate. Olfactory rods arise within a few hours of the olfactory pit opening, increase in numbers and size during larval stages, and can develop in the absence of olfactory cilia. Olfactory rod cells differ in morphology from the known classes of olfactory sensory neuron, but express reporters driven by neuronal promoters. A sub-population of olfactory rod cells expresses a Lifeact-mRFPruby transgene driven by the sox10 promoter. Mosaic expression of this transgene reveals that olfactory rod cells have rounded cell bodies located apically in the olfactory epithelium and have no detectable axon. We offer speculation on the possible function of these cells in the Discussion. Agency for Science, Technology and Research (A*STAR) Nanyang Technological University Published version KYC was funded by an A∗STAR Research Attachment Programme Ph.D. studentship (ARAP-2019-01-0014). Research in Sheffield was supported by a BBSRC project grant (BB/S007008/1) to TW and SB. Imaging in Sheffield was carried out in the Sheffield Electron Microscopy Unit and Wolfson Light Microscopy Facility, with support from a BBSRC ALERT14 award (BB/M012522/1) to TW and SB for light-sheet microscopy. Work in the SJ lab was funded by a start-up grant from the Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.

Supplemental Digital Content is available in the text., Background: Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH, we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. Methods: We analyzed 13 037 participants enrolled in the NBR study (NIHR BioResource—Rare Diseases), of which 1148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension, we used the Bayesian rare variant association method BeviMed. Results: Heterozygous, high impact, likely loss-of-function variants in the kinase insert domain receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (posterior probability=0.989) and older age at diagnosis (posterior probability=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the 5 patients harboring these predicted deleterious variants in KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions: The Bayesian inference approach allowed us to independently validate KDR, which encodes for the VEGFR2 (vascular endothelial growth factor receptor 2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.

We report the presence of a rare cell type, the olfactory rod cell, in the developing zebrafish olfactory epithelium. These cells each bear a single actin-rich rod-like apical projection extending about 10 μm from the epithelial surface. Live imaging with a ubiquitous Lifeact-RFP label indicates that the rods can oscillate. Olfactory rods arise within a few hours of the olfactory pit opening, increase in numbers and size during larval stages, and can develop in the absence of olfactory cilia. Olfactory rod cells differ in morphology from the known classes of olfactory sensory neuron, but express reporters driven by neuronal promoters. The cells also differ from secondary sensory cells such as hair cells of the inner ear or lateral line, or sensory cells in the taste bud, as they are not associated with established synaptic terminals. A sub-population of olfactory rod cells expresses a Lifeact-mRFPruby transgene driven by thesox10promoter. Mosaic expression of this transgene reveals that olfactory rod cells have rounded cell bodies located apically in the olfactory epithelium.

Background Children with Social (Pragmatic) Communication Disorder (SPCD) have long-term needs in using and processing social language and have a high risk of later mental health difficulties. A manualised speech and language therapy programme, the Social Communication Intervention Programme (SCIP) provides therapy content for SPCD. A feasibility study is required to derive more precise estimates of key parameters for a future trial of SCIP. Aims To assess the feasibility of conducting a substantive randomized controlled trial of SCIP for children with SPCD. Methods A questionnaire was distributed to paediatric speech and language therapists in England. Survey questions addressed number of eligible children, routine intervention provision and trial recruitment factors. In the second phase, a single-arm intervention feasibility study was completed. Fifteen speech and language practitioners identified 24 children aged 5–11 years with SPCD. Practitioners received training/supervision to deliver 20 SCIP therapy sessions to each child. At time 1, parents of participating children provided three communication goals; expected steps in each goal were defined. After intervention, parents and practitioners independently rated each goal compared to baseline ability. Two research practitioners compared parent post-intervention commentaries with outcome scores to derive guidance about clinical significance. All practitioners recorded audio commentaries on therapy experiences. Post-intervention interviews were conducted with 6 practitioners and 6 parents. An expert panel completed a Delphi consultation on trial design. Results Routine practice for SPCD varies widely. Children tend to be embedded in autism provision. Participation in a future trial was well supported provided resources are available to services. Outcomes analysis indicated all children except one made some progress on parent ratings; all children made progress on practitioner ratings. A power analysis for a future trial was carried out using current outcome measure as putative primary endpoint. Practitioners’ audio-diaries provided suggestions for training and adaption in a future trial. Outcomes and therapy methods were acceptable to practitioners and parents. Conclusions The feasibility study evaluated a novel outcome measure of social communication skills in SPCD. A power calculation indicated a feasible framework for a trial within a realistic period of time. Recommendations for recruitment methods, adaptation of manual and training were supported by practitioners and an expert panel. Trial registration Title: Speech-language therapy for child social communication disorder Trial ID: ISRCTN48030419. Date registered: January 1, 2017. Registered retrospectively.

BackgroundThe first step in bundle design or implementation is to identify the problem being addressed. Several validated approaches are recommended to facilitate this. These include using systematic reviews, adverse event triggers and risk assessment tools. However, these methods do not fully take the local context into account, which will limit the effectiveness of the bundle.AimThis study explores the potential benefit of using a comprehensive audit to identify an organisation’s local context prior to designing and implementing a care bundle.MethodA comprehensive audit comprising observations of four patient journeys, interviews with 21 staff and clinical data was carried out at one large National Health Service trust in England. A patient warming care bundle was used as the exemplar.FindingsEach of the three data collection methods identified specific local practices which would be addressed within the planning and implementation stages of a care bundle. These practices would not have been identified through other recommended methods.ConclusionA comprehensive audit, comprising observations, interviews and clinical data is a successful method to identify local contextual issues prior to care bundle implementation.

International audience; OBJECTIVES:Cognitive problems, especially disturbances in episodic memory, and hippocampal sclerosis are common in temporal lobe epilepsy (TLE) but little is known about the relationship of hippocampal morphology with memory. We aimed to relate hippocampal surface-shape patterns to verbal and visual learning.METHODS:We analysed hippocampal surface shapes on high-resolution MRI images and the Adult Memory and Information Processing Battery in 145 unilateral refractory TLE patients undergoing epilepsy surgery, a validation set of 55 unilateral refractory TLE patients and 39 age- and sex-matched healthy volunteers.RESULTS:Both left (LTLE) and right (RTLE) TLE patients had lower verbal (LTLE 44 ± 11; RTLE 45 ± 10) and visual learning (LTLE 34 ± 8; RTLE 30 ± 8) scores than healthy controls (verbal 58 ± 8; visual 39 ± 6; p