Genomic Investigations of Acute Hepatitis of Unknown Aetiology in Children (preprint)

Since the first reports of hepatitis of unknown aetiology occurring in UK children, over 1000 cases have been reported worldwide, including 268 cases in the UK, with the majority younger than 6 years old. Using genomic, proteomic and immunohistochemical methods, we undertook extensive investigation of 28 cases and 136 control subjects. In five cases who underwent liver transplantation, we detected high levels of adeno-associated virus 2 (AAV2) in the explanted livers. AAV2 was also detected at high levels in blood from 10/11 non-transplanted cases. Low levels of Adenovirus (HAdV) and Human Herpesvirus 6B (HHV-6B), both of which enable AAV2 lytic replication, were also found in the five explanted livers and blood from 15/17 and 6/9 respectively, of the 23 non-transplant cases tested. In contrast, AAV2 was detected at low titre in 6/100 whole bloods from child controls from cohorts with presence or absence of hepatitis and/or adenovirus infection. Our data show an association of AAV2 at high titre in blood or liver tissue, with unexplained hepatitis in children infected in the recent HAdV-F41 outbreak. We were unable to find evidence by electron microscopy, immunohistochemistry or proteomics of HAdV or AAV2 viral particles or proteins in explanted livers, suggesting that hepatic pathology is not due to direct lytic infection by either virus. The potential that AAV2, although not previously associated with disease, may, together with HAdV-F41 and/or HHV-6, be causally implicated in the outbreak of unexplained hepatitis, requires further investigation.

An ACAT inhibitor regulates SARS-CoV-2 replication and antiviral T cell activity (preprint)

The severity of disease following infection with SARS-CoV-2 is determined by viral replication kinetics and host immunity, with early T cell responses and/or suppression of viraemia driving a favourable outcome. Recent studies have uncovered a role for cholesterol metabolism in the SARS-CoV-2 life cycle and in T cell function. Here we show that blockade of the enzyme Acyl-CoA:cholesterol acyltransferase (ACAT) with Avasimibe inhibits SARS-CoV-2 entry and fusion independent of transmembrane protease serine 2 expression in multiple cell types. We also demonstrate a role for ACAT in regulating SARS-CoV-2 RNA replication in primary bronchial epithelial cells. Furthermore, Avasimibe boosts the expansion of functional SARS-CoV-2-specific T cells from the blood of patients sampled in the acute phase of infection. Thus, re-purposing of available ACAT inhibitors provides a compelling therapeutic strategy for the treatment of COVID-19 to achieve both antiviral and immunomodulatory effects.

High Burden of COVID-19 among Unvaccinated Law Enforcement Officers and Firefighters (preprint)

Law Enforcement Officers (LEOs), firefighters, and other first responders are at increased risk of SARS-CoV-2 infection compared to healthcare personnel but have relatively low COVID-19 vaccine uptake. Resistance to COVID-19 vaccine mandates among first responders has the potential to disrupt essential public services and threaten public health and safety. Using data from the HEROES-RECOVER prospective cohorts, we report on the increased illness burden of COVID-19 among unvaccinated first responders. From January to September 2021, first responders contributed to weekly active surveillance for COVID-19-like illness (CLI). Self-collected respiratory specimens collected weekly, irrespective of symptoms, and at the onset CLI were tested by Reverse Transcription Polymerase Chain Reaction (RT-PCR) assay for SARS-CoV-2. Among 1415 first responders, 17% were LEOs, 68% firefighters, and 15% had other first responder occupations. Unvaccinated (41%) compared to fully vaccinated (59%) first responders were less likely to believe COVID-19 vaccines are very or extremely effective (17% versus 54%) or very or extremely safe (15% versus 54%). From January through September 2021, among unvaccinated LEOs, the incidence of COVID-19 was 11.9 per 1,000 person-weeks (95%CI=7.0-20.1) compared to only 0.6 (95%CI=0.2-2.5) among vaccinated LEOs. Incidence of COVID-19 was also higher among unvaccinated firefighters (9.0 per 1,000 person-weeks; 95%CI=6.4-12.7) compared to those vaccinated (1.8 per 1,000; 95%CI=1.1-2.8). Once they had laboratory-confirmed COVID-19, unvaccinated first responders were sick for a mean+/-SD of 14.7+/-21.7 days and missed a mean of 38.0+/-46.0 hours of work. These findings suggest that state and local governments with large numbers of unvaccinated first responders may face major disruptions in their workforce due to COVID-19 illness.

Adaptive leadership & managing change in breast cancer services during the Covid-19 pandemic

COVID-19 pandemic evolved rapidly and necessitated rapid, dynamic service reorganisation.Utilisation and distribution of our individual team members’ skillsets demonstrates our adaptive leadership across all aspects of the service.We adhered to the Association of Breast Surgeons guidelines for breast cancer care to downsize activity and resources.Objective of strategy was to maintain a consistent high standard of care, without compromising on NHS targets or cancer outcomes.Face-to-face appointments (FA) were minimised to reduce the risk of COVID-19 infection.A novel Vetting System stratified patients’ symptom into High Risk of cancer (FA) or Low Risk (Telephone Consultation, TC).Detailed patient spreadsheets were created, accessible on a shared drive as a real time dashboard - monitoring patient flow, recording triage decisions & outcomes.We redesigned patient spaces with an ‘in car’ waiting room, single direction flow and patient-only admittance for clinic safety.We suspended non-essential services: to preserve hospital resources;reducing non-essential attendances and allowing re-deployment of staff to acute areas.Data comparison over same period the previous year was used to gain an idea of the impact of activity changes and to anticipate additional workload post-lockdown.March 23 to May 1st, 2020:45 cancer surgery296 new breast clinics531 follow-ups (104 elected to postpone) 427 (331 TC, 96 FA)26 breast screeningMarch 25 to May 3rd, 2019:53 cancer surgery507 new breast clinics674 follow-ups32 breast screeningShortfall in new patients was related to reduced GP activity/patient reluctance to seek medical help.Shortfall in follow ups due to postponements.Subsequently clinical evaluation with patient experience questionnaires confirmed no cancer missed, no delays to treatment and no harm caused.Adaptive leadership was essential in a time of unprecedented challenges.

Leading change & the evolution of the breast clinic through the Covid-19 pandemic and into the future

The high transmissibility rate of Covid, obliged us to adapt and transform our symptomatic clinic to be able to continue diagnosing and treat breast cancer and at the same time protect patients and staff.Prior analysis of clinical activity suggests at least 80 per cent of patient attending breast clinics are either healthy or found to have benign conditions, identification of this group of patients ahead of time would allow assess and treat them safely with a telephone clinic consultation insteadOn this tenet we worked, in compliance to new and emerging guidance about breast cancer care during the pandemic from the Association of Breast Surgeons and the National Institute for Clinical Excellence, to devise a novel vetting system for stratifying and prioritizing all new referral to out-patient clinics.All changes were discussed at MDTS. Adjustments and refinements were made as necessary due to the dynamic and evolving situation;changing guidance and staff availability due to illness, need for self-isolation and those shielding at home.Patients were stratified according to their history and symptoms and their likely cancer risk,.Patients with high risk of cancer were offered face-to-face consultation, those at low risk were offered telephone consultation.From 23rd March to 1st May 2020, we moved all possible patients to phone consultations. 299 new patients were vetted: 149 allocated phone appointment, 150 attended face-to-face clinics, of these 62 were diagnosed with breast cancer.Initial phone contact appears safe with low risk patients. This will maximize available resources and reduce the pressures imposed by two week waiting list clinics on the breast services.Covid-19 gave us the opportunity of demonstrating the strong, shared leadership existing in our group. The entire team proved able to adapt to different ways of working and embrace change, whilst continuing to innovate and thrive.