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1.
21st International Conference on Harmonisation within Atmospheric Dispersion Modelling for Regulatory Purposes, HARMO 2022 ; 2022.
Article in English | Scopus | ID: covidwho-2208004

ABSTRACT

An inversion system that uses a Bayesian approach to combine measurements and ADMS-Urban modelled data by adjusting individual source emissions, subject to estimated uncertainty in the measurements and emissions, has previously been applied to optimising road traffic emissions in Cambridge. In this study the system has been applied specifically to the impact of interventions, in particular the impact of COVID-19 lockdowns on NOX emissions from road traffic and other sources in London. The ADMS-Urban model was used to calculate a priori hourly NOX concentrations at 195 receptors in London representing 115 reference monitors and 80 Breathe London Network AQMesh sensors. Input data included hourly meteorological measurements from Heathrow Airport, hourly NOX concentrations from 4 rural background monitoring sites and buildings road centreline data from Ordnance Survey. A priori emissions were obtained from the London Atmospheric Emissions Inventory (LAEI) for 35 point sources, approximately 70,000 major road sources and 2,500 1km grid cells representing minor road, heating and other sources. The analysis period was 1 January 2020 to 30 April 2021. Estimated uncertainties of 4 and 12 µg/m3 were applied to reference and sensor measurements respectively, while emissions uncertainties of 100%, 50%, 20% were applied to road traffic, fuels and other emissions respectively. Road traffic emissions were assumed to have error covariance of 40% of their emissions uncertainty. Measured NOX concentrations in London reduced significantly during lockdown, with the greatest reduction (around 60%) at kerbside and roadside sites in Central London. However, poor dispersal conditions led to increased concentrations at times when restrictions were tightest. In contrast, inversion system results demonstrate that NOX emissions from road traffic dropped by around 60% in London compared with pre-lockdown levels and that this reduction occurred when the strictest lockdown measures were in force. The results also show that NOX road traffic emissions were still approximately 30% lower than pre-lockdown levels at the end of April 2021. This analysis demonstrates that lower cost sensors such as AQMesh can provide valuable insight into the effects of policy measures (in this case lockdown restrictions), if their increased uncertainty compared with reference monitors is accounted for. © British Crown Copyright (2022)

2.
Cureus ; 14(12):e32814, 2022.
Article in English | MEDLINE | ID: covidwho-2203431

ABSTRACT

Background Von Hippel-Lindau (VHL) disease is an autosomal dominant multisystem disorder caused by germline mutations at chromosome 3p25-26 in the VHLtumour suppressor gene. Retinal manifestations include capillary haemangiomas that develop in up to 80% of gene carriers. Lifelong retinal surveillance involves yearly assessment usually by fundoscopy and often as part of a VHL multidisciplinary clinic. Optos ultra-widefield retinal imaging is now becoming more widely used in virtual retinal screening clinics. We aimed to assess discrepancies in the pickup rate of angioma and angiomatous-associated disease between slit-lamp fundoscopy and Optos ultra-widefield imaging. Methodology A total of 49 patients had both Optos ultra-widefield retinal imaging and slit-lamp fundoscopy over 16 months in VHL retinal surveillance clinics at the John Radcliffe Hospital, Oxford, UK. Optos images were analysed for image quality and presence of angioma(s) by a Consultant Ophthalmologist who was masked to the fundoscopy findings. The pickup rate was compared between slit-lamp fundoscopy and Optos imaging. Results In total, data on 94 eyes were collected. Of the total Optos retinal images, 12.8% were positive for angiomas compared to 11.7% from the slit-lamp examination. There was a discrepancy of 1.1% (one value) where the Optos image analysis suggested a possible angioma, which was not identified on slit-lamp examination. Optos imaging identified all angiomas in this cohort. Conclusions Optos imaging was non-inferior to slit-lamp examination in this sample of 94 eyes. In the current COVID-19 climate, reducing clinician-patient interaction is important. This research supports providing retinal imaging as an acceptable alternative to the yearly slit-lamp fundus examination.

3.
Cureus ; 14(11):e31897, 2022.
Article in English | MEDLINE | ID: covidwho-2203348

ABSTRACT

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has disrupted the world since 2019, causing significant morbidity and mortality in developed and developing countries alike. Although substantial resources have been diverted to developing diagnostic, preventative, and treatment measures, disparities in the availability and efficacy of these tools vary across countries. We seek to assess the ability of commercial artificial intelligence (AI) technology to diagnose COVID-19 by analyzing chest radiographs.

4.
Frontiers in Immunology ; 13 (no pagination), 2022.
Article in English | EMBASE | ID: covidwho-2198900

ABSTRACT

Introduction: The effects of the SARS-CoV-2 virus on the body, and why the effects are more severe in certain patients, remain incompletely understood. One population of special interest is transplant recipients because of their immunosuppressed state. Understanding the pathophysiology of graft dysfunction in transplant patients with the COVID-19 viral syndrome is important for prognosticating the risk to the graft as well as understanding how best to prevent and, if necessary, treat graft injury in these patients. Method(s): We analyzed multiple types of solid organ transplant recipients (liver, kidney, heart or lung) at our institution who died from SARS-CoV-2 and underwent autopsy (n = 6) or whose grafts were biopsied during active SARS-CoV-2 infection (n = 8). Their serum inflammatory markers were examined together with the histological appearance, viral load, and TCR repertoire of their graft tissue and, for autopsy patients, several native tissues. Result(s): Histology and clinical lab results revealed a systemic inflammatory pattern that included elevated inflammatory markers and diffuse tissue damage regardless of graft rejection. Virus was detected throughout all tissues, although most abundant in lungs. The TCR repertoire was broadly similar throughout the tissues of each individual, with greater sharing of dominant clones associated with more rapid disease course. There was no difference in viral load or clonal distribution of overall, COVID-associated, or putative SARS-CoV-2-specific TCRs between allograft and native tissue. We further demonstrated that SARSCoV-2-specific TCR sequences in transplant patients lack a donor HLArestricted pattern, regardless of distribution in allograft or native tissues,suggesting that recognition of viral antigens on infiltrating recipient cells can effectively trigger host T cell anti-viral responses in both the host and graft. Discussion(s): Our findings suggest a systemic immune response to the SARS-CoV-2 virus in solid organ transplant patients that is not associated with rejection and consistent with a largely destructive effect of recipient HLA-restricted T cell clones that affects donor and native organs similarly. Copyright © 2022 Fu, Rust, Fang, Jiao, Lagana, Batal, Chen, Merl, Jones, Sykes and Weiner.

5.
Annals of Work Exposures And Health ; 13:13, 2022.
Article in English | MEDLINE | ID: covidwho-2160916

ABSTRACT

The COVID-19 pandemic spurred some regulators in the USA to require occupational health and safety programs to prevent COVID-19 transmission in workplaces. The objective of this study was to describe such state and federal regulations enacted between January 2020 and January 2022. Regulations, including emergency temporary standards (ETS) and permanent standards, were identified through a search of Nexis Uni and Bloomberg Law and review of US OSHA websites and the Federal Register. Full texts were reviewed for regulatory scope, hazard and exposure definitions, determination of exposure or risk levels, and control strategies. Four state (California, Michigan, Virginia, and Oregon) and two federal regulations were identified. All regulations described respiratory aerosols as the primary source of SARS-CoV-2 and recognized person-to-person transmission by droplet, airborne, and contact routes. Only the US OSHA ETS for healthcare explicitly stated that inhalation of respiratory particles was the most likely method of COVID-19 transmission. The Virginia, Michigan, and Oregon regulations described different categories of risk defined by exposure frequency and duration or specific workplace activities. California described exposure as places and times when employees come into contact or congregate with other people. The US OSHA ETS for healthcare described exposure as involving close contact with suspected or confirmed COVID-19 patients. While all of the state regulations required strategies from across the hierarchy, only the Virginia regulations specifically incorporated the hierarchy of controls. Only the California and Virginia regulations explicitly linked control strategies to the transmission route, while Virginia demarcated control strategies by risk level. Oregon linked risk level to occupancy levels and physical distancing requirements and referred to the use of a layered approach for transmission control. The US OSHA ETS for healthcare defined droplet and airborne precautions but made no mention of the hierarchy of controls or risk levels. Respirators were discussed in most of the regulations. The first Michigan regulation explicitly required respirators appropriate to exposure risk. The California regulations noted that respirators protect the wearer while face coverings protect people around the wearer. These regulations offer insights for a permanent US OSHA infectious disease regulation, such as the need to consider a range of transmission modes including near- and far-range aerosol inhalation, endemic and novel pathogens, workplaces beyond healthcare settings, factors that contribute to exposure and risk, the hierarchy of controls, the role of vaccination, and the importance of written exposure assessment and infection prevention plans.

6.
British Journal of Surgery ; 109(Supplement 7):vii9, 2022.
Article in English | EMBASE | ID: covidwho-2134967

ABSTRACT

Aim: Elective surgery services suffered significantly due to the COVID-19 pandemic. The aim of this study was to analyse the impact and outcomes of abdominal wall reconstruction (AWR) performed during the COVID-19 pandemic, assessing safety and sustainability. Material(s) and Method(s): A retrospective review of all patients undergoing AWR in a single NHS trust, multiple surgeons, between 23rd March 2020 and 22rd March 2022, the 2 years following U.K. Government imposed lockdown, was undertaken and compared with the pre-pandemic AWR activity. Procedures were initially undertaken at a cold site and when demonstrated to be safe, main site operating restarted. The primary outcome was 90 day mortality, secondary outcomes of COVID-19 infection within 7 days, length of stay, critical care requirement, and complication rate. Result(s): In the study period, 173 patients underwent AWR, compared with 99 cases in a single year preceding lockdown. 90 day mortality rate was zero. No patients returned positive COVID tests to the trust within 7 days of AWR, and no patients were readmitted for COVID related symptoms. Critical care admission was required in 7 patients, 3 of these were planned admissions pre-operatively. The surgical site occurrence rate was 9.8% (17), infection 5.8% (10), seroma 2.3% (4) and haematoma 1.7% (3). There were no recurrences reported, with follow up ranging between 1 and 18 months. Conclusion(s): Continuing AWR services during the COVID pandemic is feasible and safe. Peri-operative COVID infection rates are low, critical care requirements minimal, and there is no impact on patient morbidity or mortality.

7.
17th Annual ACM/IEEE International Conference on Human-Robot Interaction, HRI 2022 ; 2022-March:1095-1099, 2022.
Article in English | Scopus | ID: covidwho-2097604

ABSTRACT

Anthropomorphic robots may reduce loneliness in older people, however, acceptance is requisite for adoption. We collected the experiences of 10 people aged 80-92 who used a pre-market social robot, GenieConnect, for between 2 to 35 days during the COVID19 pandemic restrictions. GenieConnect is a table-top robot with a large face and animated eyes, designed for support and companionship. The robot asked 'how are you feeling, Name' each day and delivered lifestyle prompts such as medication reminders. We observed conflicting responses from participants - five expressed positive responses, three negative (two of these withdrew) and two neutral. Positive comments included 'feeling not alone';'having someone to talk to';and enjoying being asked 'how are you feeling'. Negative comments were mainly related to not liking the eyes. Design adaptations were made to increase acceptance. We conclude that robots like GenieConnect could reduce loneliness when a user-centred design approach is taken. © 2022 IEEE.

9.
European Eating Disorders Review ; 30(6):832, 2022.
Article in English | EMBASE | ID: covidwho-2094182

ABSTRACT

Introduction: Ward round is a key component in inpatient settings for treatment-related decision making. However, the meeting is often stressful and anxietyprovoking. Participating in ward round discussions is also little mentioned in clinical education in disciplines such as clinical psychology and nursing. Aim(s): This study aimed to explore and improve patients' experiences of the virtual clinical team meeting (CTM, historically known as ward round) in an eating disorders inpatient ward during COVID-19. Method(s): A mixed-method approach was used. Five clinical team meetings were observed, and six patients were interviewed through focus groups and video interviews. Former patients were involved in data analysis, improvement and dissemination. Result(s): The mean CTM duration was 14.3 min. Patients spoke roughly half of the time, followed by psychiatry colleagues. 'Request' was the most-spoken category. Thematic analysis identified (1) CTM is important but feels impersonal, (2) they generate a sense of palpable anxiety;and (3) the differing views of staff and patients. Using the findings, and co-produced with a former patient, the description of the CTM was revised in the admission induction booklet. A new CTM agenda sheet as well as guidance sheet for nurses were devised. Nursing staff and patients found them more helpful than the existing versions. Discussion(s): The findings and the co-produced guidance documents provided concrete contribution for nurses to improve patient's experiences despite the challenges brought by COVID-19. The ward's power hierarchy, culture and language use also need to be considered to facilitate shared decision-making.

10.
Journal of Gastroenterology and Hepatology ; 37(Supplement 1):97, 2022.
Article in English | EMBASE | ID: covidwho-2088254

ABSTRACT

Background and Aim: The COVID-19 pandemic has led to significant disruption to the delivery of health care worldwide. The impact of the pandemic on liver transplant (LT) services in Australia and New Zealand has not yet been established. In March 2020, the Transplantation Society of Australia and New Zealand COVID-19 Taskforce raised the minimum eligibility for LT to patients with high short-term mortality (i.e. Model for End-Stage Liver Disease [MELD] score > 20). This directive was later removed, but services continued to be affected by broader government and hospital pandemic responses. This study aimed to examine the impact of the various responses to the pandemic on LT services in Australia and New Zealand. Method(s): We performed a retrospective analysis of all LT activity on the Australia and New Zealand Liver and Intestinal Transplant Registry from 2012 to 2021. The primary outcome was delisting from the LT waitlist (WL) due to disease progression or death. Outcomes were assessed at the end of each year and categorized as transplanted, died, or delisted. Delisted patients were defined as those who were removed and not relisted onto the WL within 180 days. Additional registrations onto the WL for retransplantation in the same patient were considered separate events. Annual trends in LT and WL activity were observed for the entire study period, using interrupted time series analysis. Differences between the pandemic cohort (1 January 2020 to 31 December 2021) and a corresponding pre-pandemic cohort (1 January 2018 to 31 December 2019), were then analyzed using chi2 and Mann-Whitney U tests as appropriate. Additionally, organ donation rates were obtained from the publicly accessible Australia and New Zealand Organ Donation (ANZOD) registry. Result(s): From 2012 to 2021, there were 3219 LTs performed, 3920 WL registrations, and 416 patients who died or were delisted due to disease progression. On interrupted time series analysis, there was a predicted annual increase of 17 LTs from 2012 to 2019 (95% CI, 12-22;P < 0.001);however, in 2020-2021, there was an annual reduction of 43 LTs (95% CI, 38-48;P < 0.001) compared with 2018-2019 (Fig. 1a). Concurrently, there was a predicted annual increase of 12 new WL registrations (95% CI, 7-17;P = 0.001) before the pandemic, which reduced by 18 new registrations annually in 2020-2021 (95% CI, 14-24;P < 0.001) (Fig. 1b). The number of patients remaining on the WL at year's end remained stable. ANZOD donor data found a corresponding predicted annual reduction of 86 actual/intended donors (95% CI, 80-93;P < 0.001) in 2020-2021 compared with before COVID-19 (Fig. 1c). Compared with the pre-pandemic cohort, the pandemic cohort had more severe liver disease at listing (median MELD score, 18 [12-24] vs 17 [11-22];P = 0.020) but no other baseline differences. The Australian pandemic cohort had a higher proportion of death or delisting due to disease progression (8.6% vs 6.0%, P = 0.043) and a corresponding lower proportion transplanted (66.9% vs 72.6%, P = 0.011) compared with the pre-pandemic cohort. In contrast, New Zealand transplant activity and outcomes were unchanged. Overall WL numbers and median days on the WL were unchanged before and after the pandemic in both nations. Conclusion(s): Despite low community rates of COVID-19, the effects on LT in Australia were similar to those seen in nations with high COVID-19 prevalence. Reduced Australian LT activity corresponded with reduced donor numbers and was associated with more severe disease at WL, as well as higher rates of disease progression. In New Zealand, LT activity was less disrupted and outcomes were unchanged.

11.
British Journal of Social Work ; 52(7):3858-3880, 2022.
Article in English | Web of Science | ID: covidwho-2087746

ABSTRACT

This article reports on a quantitative study of the national datasets for adult social care in England. Building on recent analysis of trends in demand and expenditure, the aim of the study was to investigate the relationship between local authority (LA) characteristics, levels of demand for state-funded services and rates of short- and long-term provision. Publicly available data on short- and long-term activity and finances were collected for all LAs in England from 2016 to 2019 and combined with other indicators including population demographics and the Index of Multiple Deprivation. Correlation analysis was undertaken to investigate patterns of demand and provision and their link to contextual factors. Findings showed that variation between LAs was to some extent shaped by contextual factors such as deprivation and demographics, but was also subject to the effects of rationing and the impact of the self-funded market on levels of demand. Implications are discussed for efforts to reform the adult social system and address longstanding inequalities that have been both highlighted and exacerbated by the COVID-19 pandemic.

13.
Meteorological Applications ; 29(5), 2022.
Article in English | Web of Science | ID: covidwho-2082821

ABSTRACT

The Met Office held a testbed over winter 2020/2021 where a new numerical weather prediction (NWP) sub-km ensemble was set up on-demand in response to interesting weather phenomena in the United Kingdom. The domain for the model was chosen in real time by a community of Met Office Research Scientists and Operational Meteorologists and over a 4-month period the ensemble was triggered for nine events. The purpose of the testbed was to investigate whether a real-time weather regime-based enhancement in NWP capability was feasible, to understand what benefits a testbed environment might give, and to explore the practicalities of running such an event. Case studies from the testbed demonstrated that forecast ensembles at 2.2 km and 300 m grid spacing were able to capture observed winter weather, with greater spatial detail apparent, especially over complex orography, in the 300-m model. Ensemble spread appeared less influenced by resolution, potentially due to the size of the domains tested or the weather regimes of the case studies. The testbed also showcased underutilized observations and additional radiosonde ascents were conducted. All the testbed meetings were conducted virtually due to COVID-19 restrictions, and decisions were made about when to trigger the event using an online message board. The winter 2020/2021 testbed provides ideas for how on-demand weather-dependent testbeds might be conducted in the future. However, several recommendations are made that would enhance testbed benefits further, including more dedicated resource, stronger technology and data visualization and greater participation from both academia and weather information users.

14.
Archives of Disease in Childhood ; 107(Supplement 2):A346-A347, 2022.
Article in English | EMBASE | ID: covidwho-2064041

ABSTRACT

Aims Many paediatric emergency departments (PED) reported an unexpected increase in attendances during summer 2021;most of these children were stated to have minor illnesses and were discharged with reassurance. The primary objective of our questionnaire was to obtain parental perspective of how changes to local acute paediatric healthcare services in response to Covid-19 had impacted upon accessing care for their children. Additional objectives aimed to identify if parents were more worried about their child's health in view of the pandemic, understand parents' ideas of how children should be assessed when unwell, and explore how parents felt remote consultations could be improved. Methods A questionnaire comprised of Likert scale, multiple choice and free-text questions was developed to explore the study aiSeveral iterations of the questionnaire were test-run with parents prior to roll-out. The project was registered with the Trust's Quality Improvement team. A total of 88 families presenting to the paediatric emergency department and local urgent treatment centres completed the questionnaire between 26th October and 31st December 2021. Excluded were families for whom a translator was needed for their medical assessment. A thematic analysis was performed using NVivo, and quantitative analysis performed using PRISM statistical software. Results 68.2% of parents had sought medical advice outside of the PED prior to presentation, either in the community and/or online. 20.5% of respondents sought healthcare input from two or more sources prior to attending PED. Figure 1 outlines the responses to Likert-scale questions. Statistical analysis of the responses in relation to of age of child, number of children in the family and whether English was the family's first language was performed. Confidence of phone/video assessments and English/non-English as first language approached statistical significance (p=0.059). No other comparisons were statistically significant. Analysis of free-text responses identified key themes regarding the parental expectation of how children should be reviewed when unwell, and how parents thought remote consultations can be improved. An outline of the identified themes and a selection of responses are outlined in Figure 2. Conclusion The questionnaire identified that parents had still been able to access healthcare during the pandemic when they felt their child was unwell. Parents reported concerns of their children becoming sick with Covid-19, but still felt confident managing minor illnesses at home. The increasing volume of remote assessments in primary care was a necessary adjustment during the pandemic which is likely to be embraced as a more permanent model of service. Many parents recognised the benefit of remote consultations for non-urgent issues. However, a key theme from the questionnaire was the lack of parental confidence in remote (particularly phone) consultations;parents were more likely to still seek a face-to-face assessment in PED if they felt they couldn't communicate their child's signs and symptoms over the phone. As local networks embrace a more remote model of working to deliver some urgency and emergency care it is necessary to identify the cohorts of patients who may still attend PED, and plan how better to provide clinical reviews for them in the community.

15.
Am J Public Health ; 112(S3): S275-S278, 2022 06.
Article in English | MEDLINE | ID: covidwho-2054653

ABSTRACT

With Minneapolis, Minnesota, partners, we developed a community-based participatory intervention using a mobile health application to provide actionable data to communities. More than 550 participants completed the survey. Key messages included strengths in our homes, neighborhoods, and faith communities. Key challenges were related to substance use and sleeping. We jointly conducted virtual community meetings such as webinars, Facebook Live shows, and online newsletters to begin to shift the community narrative from deficits to whole-person health, including strengths. (Am J Public Health. 2022;112(S3):S275-S278. https://doi.org/10.2105/AJPH.2022.306852).


Subject(s)
Substance-Related Disorders , Telemedicine , Community Participation , Community-Based Participatory Research , Humans , Minnesota , Narration , United States
16.
Annals of Oncology ; 33:S1427-S1428, 2022.
Article in English | EMBASE | ID: covidwho-2041570

ABSTRACT

Background: AAP or ENZ added to ADT improves outcomes for mHSPC. Any benefit of combining ENZ & AAP in this disease setting is uncertain. Methods: STAMPEDE is a multi-arm, multi-stage (MAMS), platform protocol conducted at 117 sites in the UK & Switzerland. 2 trials with no overlapping controls randomised mHSPC patients (pts) 1:1 to ADT +/- AAP (1000mg od AA + 5mg od P) or AAP + ENZ (160mg od). Treatment was continued to progression. From Jan 2016 docetaxel 75mg/m2 3-weekly with P 10mg od was permitted + ADT. Using meta-analysis methods, we tested for evidence of a difference in OS and secondary outcomes (as described previously: failure-free, metastatic progression-free, progression-free & prostate cancer specific survival) across the 2 trials using data frozen 3 Jul 2022. All confidence intervals (CI) 95%. Restricted mean survival times (RMST) restricted to 84 months (m). Results: Between Nov 2011 & Jan 2014, 1003 pts were randomised ADT +/- AAP & between Jul 2014 & Mar 2016, 916 pts were randomised ADT +/- AAP + ENZ. Randomised groups were well balanced across both trials. Pt cohort: age, median 68 years (yr), IQR 63, 72;PSA prior to ADT, median 95.7 ng/ml, IQR 26.5, 346;de novo 94%, relapsed after radical treatment, 6%. In AAP + ENZ trial, 9% had docetaxel + ADT. OS benefit in AAP + ENZ trial, HR 0.65 (CI 0.55‒0.77) p = 1.4×10-6;in AAP trial, HR 0.62 (0.53, 0.73) p = 1.6×10-9. No evidence of a difference in treatment effect (interaction HR 1.05 CI 0.83‒1.32, p = 0.71) or between-trial heterogeneity (I2 p = 0.70). Same for secondary end-points. % (CI) of pts reporting grade 3-5 toxicity in 1st 5 yr: AAP trial, ADT: 38.5 (34.2-42.8), + AAP: 54.4 (50.0-58.8);AAP + ENZ trial, ADT: 45.2 (40.6 – 49.8), + AAP + ENZ: 67.9 (63.5 – 72.2);most frequently increased with AAP or AAP + ENZ = liver derangement, hypertension. At 7 yr in AAP trial (median follow-up: 95.8m), % (CI) pts alive with ADT: 30 (26, 34) versus with ADT + AAP: 48 (43, 52);RMST: ADT: 50.4m, ADT + AAP: 60.6m, p = 6.6 x 10-9. Conclusions: ENZ + AAP need not be combined for mHSPC. Clinically important improvements in OS when adding AAP to ADT are maintained at 7 yr. Clinical trial identification: NCT00268476. Legal entity responsible for the study: Medical Research Council Clinical Trials Unit at University College London. Funding: Cancer Research UK, Medical Research Council, Janssen, Astellas. Disclosure: G. Attard: Financial Interests, Personal, Invited Speaker: Janssen, Astellas, AstraZeneca;Financial Interests, Personal, Advisory Board: Janssen, Astellas, Novartis, Bayer, AstraZeneca, Pfizer, Sanofi, Sapience, Orion;Financial Interests, Personal, Royalties, Included in list of rewards to discoverers of abiraterone: Institute of Cancer Research;Financial Interests, Institutional, Research Grant: Janssen, Astellas;Non-Financial Interests, Principal Investigator: Janssen, Astellas;Non-Financial Interests, Advisory Role: Janssen, AstraZeneca. W.R. Cross: Financial Interests, Personal, Invited Speaker, Speaker fee: Myriad Genetics, Janssen, Astellas;Financial Interests, Personal, Advisory Board, Advisory Board fee: Bayer;Financial Interests, Institutional, Research Grant, Research grant: Myriad Genetics. S. Gillessen: Financial Interests, Personal, Advisory Board, 2018: Sanofi, Roche;Financial Interests, Personal, Advisory Board, 2018, 2019: Orion;Financial Interests, Personal, Invited Speaker, 2019 Speaker's Bureau: Janssen Cilag;Financial Interests, Personal, Advisory Board, 2020: Amgen;Financial Interests, Personal, Invited Speaker, 2020: ESMO;Financial Interests, Personal, Other, Travel Grant 2020: ProteoMEdiX;Financial Interests, Institutional, Advisory Board, 2018, 2019, 2022: Bayer;Financial Interests, Institutional, Advisory Board, 2020: Janssen Cilag, Roche, MSD Merck Sharp & Dohme, Pfizer;Financial Interests, Institutional, Advisory Board, 2018: AAA International, Menarini Silicon Biosystems;Financial Interests, Institutional, Advisory Board, 2019, 2020: Astellas Pharma;Financial Interests, Institutional, Advisory B ard, 2019: Tolero Pharmaceuticals;Financial Interests, Personal, Invited Speaker, 2021, 2022: SAKK, DESO;Financial Interests, Institutional, Advisory Board, 2021: Telixpharma, BMS, AAA International, Novartis, Modra Pharmaceuticas Holding B.V.;Financial Interests, Institutional, Other, Steering Committee 2021: Amgen;Financial Interests, Institutional, Advisory Board, 2021, 2022: Orion, Bayer;Financial Interests, Personal, Invited Speaker, 2021: SAKK, SAKK, SAMO - IBCSG (Swiss Academy of Multidisciplinary oncology);Financial Interests, Personal, Advisory Board, 2021: MSD Merck Sharp & Dhome;Financial Interests, Personal, 2021: RSI (Televisione Svizzera Italiana);Financial Interests, Institutional, Invited Speaker, 2021: Silvio Grasso Consulting;Financial Interests, Institutional, Other, Faculty activity 2022: WebMD-Medscape;Financial Interests, Institutional, Advisory Board, 2022: Myriad genetics, AstraZeneca;Financial Interests, Institutional, Invited Speaker, 2022: TOLREMO;Financial Interests, Personal, Other, Travel support 2022: AstraZeneca;Financial Interests, Institutional, Funding, 2021, Unrestricted grant for a Covid related study as co-investigator: Astellas;Non-Financial Interests, Advisory Role, 2019: Menarini Silicon Biosystems, Aranda;Non-Financial Interests, Advisory Role, Continuing: ProteoMediX. C. Pezaro: Financial Interests, Personal, Advisory Board, Ad board Dec 2020: Advanced Accelerator Applications;Financial Interests, Personal, Advisory Board, Aug 2021: Astellas;Financial Interests, Personal, Advisory Board, Oct 2021: Bayer;Financial Interests, Personal, Invited Speaker, Sept-Oct 2020: AstraZeneca;Financial Interests, Personal, Invited Speaker, Oct 2020: Janssen;Financial Interests, Personal, Advisory Board, July-Sept 2022: Pfizer. Z. Malik: Financial Interests, Personal, Advisory Board, advisry board for new hormonal therapy for breast cancer: sanofi;Financial Interests, Institutional, Invited Speaker, research grant for CHROME study: sanofi;Other, Other, support to attend meetings or advisory boards in the past: Astellas,Jaansen,Bayer;Other, Other, Sponsorship to attend ASCO meeting 2022: Bayer. M.R. Sydes: Financial Interests, Personal, Invited Speaker, Speaker fees at clinical trial statistics training sessions for clinicians (no discussion of particular drugs): Janssen;Financial Interests, Personal, Invited Speaker, Speaker fees at clinical trial statistics training session for clinicians (no discussion of particular drugs): Eli Lilly;Financial Interests, Institutional, Research Grant, Educational grant and drug for STAMPEDE trial: Astellas, Janssen, Novartis, Pfizer, Sanofi;Financial Interests, Institutional, Research Grant, Educational grant and biomarker costs for STAMPEDE trial: Clovis Oncology. L.C. brown: Financial Interests, Institutional, Research Grant, £170k educational grant for the FOCUS4-C Trial from June 2017 to Dec 2021: AstraZeneca;Financial Interests, Institutional, Funding, Various grants awarded to my institution for work undertaken as part of the STAMPEDE Trial: janssen pharmaceuticals;Non-Financial Interests, Other, I am a member of the CRUK CERP funding advisory panel and my Institution also receive grant funding from CRUK for the STAMPEDE and FOCUS4 trials: Cancer Research UK. M.K. Parmar: Financial Interests, Institutional, Full or part-time Employment, Director at MRC Clinical Trials Unit at UCL: Medical Research Council Clinical Trials Unit at UCL;Financial Interests, Institutional, Research Grant: AstraZeneca, Astellas, Janssen, Clovis;Non-Financial Interests, Advisory Role, Euro Ewing Consortium: University College London;Non-Financial Interests, Advisory Role, rEECur: University of Birmingham;Non-Financial Interests, Advisory Role, CompARE Trial: University of Birmingham. N.D. James: Financial Interests, Personal, Advisory Board, Advice around PARP inhibitors: AstraZeneca;Financial Interests, Personal, Advisory Board, Prostate cancer therapies: Janssen, Clovis, Novartis;Financial Interests, Institutional, Expert Testimony, Assisted with submissions regarding licencing for abiraterone: Janssen;Financial Interests, Personal, Advisory Board, Docetaxel: Sanofi;Financial Interests, Institutional, Expert Testimony, Providing STAMPEDE trial data to facilitate licence extensions internationally for docetaxel: Sanofi;Financial Interests, Personal, Advisory Board, Bladder cancer therapy: Merck;Financial Interests, Personal, Advisory Board, Advice around novel hormone therapies for prostate cancer: Bayer;Financial Interests, Personal, Invited Speaker, Lecture tour in Brazil August 2022 - speaking on therapy for advanced prostate cancer: Merck Sharp & Dohme (UK) Limited;Financial Interests, Institutional, Invited Speaker, Funding for STAMPEDE trial: Janssen, Astellas;Financial Interests, Institutional, Invited Speaker, Funding for RADIO trial bladder cancer: AstraZeneca. All other authors have declared no conflicts of interest.

17.
Proc Natl Acad Sci U S A ; 119(41): e2209042119, 2022 10 11.
Article in English | MEDLINE | ID: covidwho-2037058

ABSTRACT

Viruses employ a variety of strategies to escape or counteract immune responses, including depletion of cell surface major histocompatibility complex class I (MHC-I), that would ordinarily present viral peptides to CD8+ cytotoxic T cells. As part of a screen to elucidate biological activities associated with individual severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) viral proteins, we found that ORF7a reduced cell surface MHC-I levels by approximately fivefold. Nevertheless, in cells infected with SARS-CoV-2, surface MHC-I levels were reduced even in the absence of ORF7a, suggesting additional mechanisms of MHC-I down-regulation. ORF7a proteins from a sample of sarbecoviruses varied in their ability to induce MHC-I down-regulation and, unlike SARS-CoV-2, the ORF7a protein from SARS-CoV lacked MHC-I downregulating activity. A single amino acid at position 59 (T/F) that is variable among sarbecovirus ORF7a proteins governed the difference in MHC-I downregulating activity. SARS-CoV-2 ORF7a physically associated with the MHC-I heavy chain and inhibited the presentation of expressed antigen to CD8+ T cells. Specifically, ORF7a prevented the assembly of the MHC-I peptide loading complex and caused retention of MHC-I in the endoplasmic reticulum. The differential ability of ORF7a proteins to function in this way might affect sarbecovirus dissemination and persistence in human populations, particularly those with infection- or vaccine-elicited immunity.


Subject(s)
Antigen Presentation , CD8-Positive T-Lymphocytes , COVID-19 , Histocompatibility Antigens Class I , Viral Proteins , Amino Acids , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Histocompatibility Antigens Class I/immunology , Humans , Major Histocompatibility Complex , Peptides , SARS-CoV-2 , Viral Proteins/immunology
19.
Gut ; 71:A167-A168, 2022.
Article in English | EMBASE | ID: covidwho-2005391

ABSTRACT

Introduction With secondary care services transitioning into virtual and telephone consultations our aim was to minimise face to face routine appointments during the Covid 19 pandemic for patients with stable ulcerative proctitis. We assessed patient satisfaction of the guided self-management leaflet and whether this can be adopted long term for this patient group. Methods From our IBD database we identified all patients with a coded diagnosis of 'proctitis'. Clinical portal notes and previous colonoscopies were reviewed to ensure correct diagnosis. Only patients with stable disease - minimal contact with IBD nurses, no recent admissions, infrequent flares were included. Identified patients were sent a Guided Self-Management leaflet in the post and a follow-on response questionnaire was sent around 6 months later. For non-responders a second questionnaire and/or telephone was arranged. Results 37 Patients were identified. We received responses (via post, phone or email) from 28/37 patients (76%). 10/28 (36%) didn't receive or do not recall receiving the leaflet.18/ 28 received the leaflet (64%). of those who received the leaflet, 16/18 felt it was easy to understand and contained enough information to confidently manage their symptoms. 2 patients had 1 flare and 3 patients had more than 3 flares since receiving the leaflet. of those with flares 2 patients were able to self-manage their proctitis using the leaflet provided. 2 patients had to contact the IBD nurses. These patients were called back within 24 hours and received useful advice. One patient had forgotten to use the leaflet. No one required rescue steroids or admission to hospital. Overall, 17/18 (94%) felt the service was good or excellent compared to previous clinic review systems. Conculsions The above results suggest the Self Guided Management Leaflets in this low symptom burden proctitis group are safe and easy to use. Overall feedback of the leaflet was positive and allowed the vast majority of patients to selfmanage their symptoms without the input of the IBD nurses. The main limitations of this study were leaflet distribution and questionnaire response. Issues included: wrong patient address, the leaflet being thrown away and patients forgetting to use it during a flare. We therefore suggest all patients identified have a Face-to-Face appointment at point of diagnosis or subsequently with an IBD nurse to issue and discuss leaflet. This will ensure each patient receives the leaflet and hopefully improve engagement with self-managing flares. We plan to repeat the survey in 6-12 months with a larger patient group.

20.
Nat Commun ; 13(1): 4888, 2022 08 19.
Article in English | MEDLINE | ID: covidwho-2000886

ABSTRACT

Efforts to cure HIV have focused on reactivating latent proviruses to enable elimination by CD8+ cytotoxic T-cells. Clinical studies of latency reversing agents (LRA) in antiretroviral therapy (ART)-treated individuals have shown increases in HIV transcription, but without reductions in virologic measures, or evidence that HIV-specific CD8+ T-cells were productively engaged. Here, we show that the SARS-CoV-2 mRNA vaccine BNT162b2 activates the RIG-I/TLR - TNF - NFκb axis, resulting in transcription of HIV proviruses with minimal perturbations of T-cell activation and host transcription. T-cells specific for the early gene-product HIV-Nef uniquely increased in frequency and acquired effector function (granzyme-B) in ART-treated individuals following SARS-CoV-2 mRNA vaccination. These parameters of CD8+ T-cell induction correlated with significant decreases in cell-associated HIV mRNA, suggesting killing or suppression of cells transcribing HIV. Thus, we report the observation of an intervention-induced reduction in a measure of HIV persistence, accompanied by precise immune correlates, in ART-suppressed individuals. However, we did not observe significant depletions of intact proviruses, underscoring challenges to achieving (or measuring) HIV reservoir reductions. Overall, our results support prioritizing the measurement of granzyme-B-producing Nef-specific responses in latency reversal studies and add impetus to developing HIV-targeted mRNA therapeutic vaccines that leverage built-in LRA activity.


Subject(s)
CD8-Positive T-Lymphocytes , COVID-19 Vaccines , COVID-19 , HIV Infections , HIV-1 , BNT162 Vaccine , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Granzymes , HIV Infections/immunology , Humans , RNA, Messenger/genetics , RNA, Messenger/therapeutic use , SARS-CoV-2 , Vaccination , Vaccines, Synthetic , Virus Latency , mRNA Vaccines , nef Gene Products, Human Immunodeficiency Virus/genetics
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