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Background: Individuals living with HIV are at increased risk of morbidity and mortality from COVID-19. Furthermore, SARS-CoV-2 infection in immunocompromised HIV infected individuals poses a risk to prolonged infection and viral shedding and the emergence of new variants of concern (VOCs). Using the SIV macaque model for AIDS, we are investigating the hypothesis that immune dysfunction during HIV infection will prolong SARSCoV- 2 viral infection, promote enhanced COVID-19 disease, and accelerate viral evolution. Here, we report the impact of SIV-CoV-2 co-infection on immune responses and pathogenesis. Method(s): Eight female rhesus macaques (aged 7-15 years, 5.5-9.9kg) were infected with SIVmac251 via low dose intravaginal challenge and then inoculated with 6.5x105 TCID50/mL SARS-CoV-2 (WA-1) at 17-34 weeks post-SIV infection via combined intranasal and intratracheal routes. Blood, bronchoalveolar lavage (BAL), stool, and nasal, oral, and rectal swabs were collected pre-infection through 14 days post-infection (DPI) to measure immune responses and viremia. ELISAs, ELISPOT, qRT-PCR, lung pathology, cytokine multiplex, and virus neutralization assays were performed to measure viral loads, pathogenesis, and immune responses. Result(s): Three days post-SARS-CoV-2 infection, we observed a transient decrease in CD4 counts, but there were no changes in clinical symptoms or plasma SIV viral loads. However, SARS-CoV-2 replication persisted in the upper respiratory tract, but not the lower respiratory tract. In addition, SARS-CoV-2 IgG seroconversion was delayed and antigen-specific T-cell responses were dampened. Notably, viral RNA levels in nasal swabs were significantly higher 7-14 DPI in SIV+ compared to previously published results using the same SARS-CoV-2 challenge virus in SIV- rhesus (PMCID: PMC8462335, PMC8829873). In addition, SIV/CoV-2 co-infected animals exhibited elevated levels of myeloperoxidase (MPO), a marker of neutrophil activation and increased lung inflammation. Conclusion(s): Here we provide evidence for the utility of the rhesus macaque in modeling human HIV-SARS-CoV-2 co-infection. Our results suggest that immunosuppression during SIV infection impairs de novo generation of anti-SARS-CoV-2 immunity, that may contribute to prolonged SARS-CoV-2 viral shedding, increased transmission windows, altered disease pathogenesis, and lower protection against subsequent SARS-CoV-2 exposures. Studies in progress will determine if SARS-CoV-2 viral evolution is accelerated in SIV-infected macaques.
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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.
ABSTRACT
RATIONALE: SARS-CoV-2, a novel coronavirus, is the third coronavirus with an associated severe acute respiratory syndrome since SARS-CoV [1]. Patients with severe COVID-19 suffer from immune hyperactivity, also referred to as a cytokine storm, which causes increased vascular permeability and multiorgan dysfunction and is a significant source of morbidity and mortality.1 Because Bruton's Tyrosine Kinase (BTK) activity is thought to play a role in the cytokine storm, with elevated activity found in monocytes, it has been explored as a target for intervention for COVID- 19.2 METHODS : This observational, case-control study included 49 hospitalized patients with severe COVID-19. Of the 49 patients, 11 patients received off-label Acalabrutinib between May 2020 through June 2020. The purpose of the study is the assess the use of Acalabrutinib as a potential strategy for management of COVID-19 patients. Bivariate and Multivariate logistic regression models were used to analyze the data. The response variable was patient outcome (remission discharge or death). The main predictor of interest was the administration of Acalabrutinib on patients (Yes/No). For the multivariate analysis the covariates included were age, gender, change in CRP levels (Discharge CRP - Admission CRP), hypertension, COPD, and comorbidities status (Yes/No). Stata Version 17.0 (Stata Corp, College Station, Texas USA) was used in all analyses. RESULTS : The median age of patients was 58 with a majority being male (51%). The average length of hospitalization was 17 days with 23 (46.9%) patients receiving mechanical ventilation. Bivariate analysis revealed that acalabrutinib was protective against death from COVID-19. However, these results were nonsignificant (OR 0.36, 95 CI [0.04, 2.87], P=0.31). The multivariate analysis supported the results of the bivariate analysis. However, we did not observe a significant association between outcome and acalabrutinib when adjusted for the study covariates (OR 0.32, 95% CI [0.03, 3.79], P=0.37). CONCLUSION: Acalabrutinib did not significantly reduce morbidity or mortality on severe COVID-19 patients. Further studies are warranted to assess the efficacy of BTK inhibitors for COVID-19 in a larger clinical trial. (Table Presented).
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Steven Pinker’s recent Enlightenment Now (2018) aside, Enlightenment values have been in for a rough ride of late. Following Max Horkheimer and Theodor Adorno’s critique of Enlightenment as the source of fascism, recent studies, amplified by Black Lives Matter, have laid bare the ugly economic underbelly of Enlightenment. The pros-perity that enabled intellectuals to scrutinize speculative truths in eighteenth-century Paris salons relied on the slave trade and surplus value extracted from slave labor on sugar plantations and in other areas Europeans controlled. Indeed, deprived of its ugly economic underbelly, Enlightenment was barely conceivable;furthermore, its reliance on surplus value extraction from oppressed labor was accompanied by a racism that, with the exception of the thought of Jean-Jacques Rousseau and a few other thinkers, was arguably inherent to Enlightenment. However, I am not proposing yet another revelation of Enlightenment’s complicity in exploitation of, or disregard for, the Other. Rather, I want to highlight the damage being done today by an insidious strategy of labelling as “pseudo-science” entire do-mains of non-Western knowledge such as Chinese medicine and Ayurveda, thereby rendering them no-go zones for serious minds. Even though the term pseudo-science had yet to be coined, the beginnings of this tendency are already evident in Enlighten-ment-era works such as Jean-Baptiste Du Halde’s Description … de la Chine (1735). The perpetuation of this dismissive treatment of non-Western natural knowledge creates a significant obstacle to superseding a “scientific revolution” whose confines have long been burst: it is increasingly recognized that traditional/indigenous knowledge affords a vast reservoir of materials, skills and insights of which the world has desperate need, no more urgently than in response to the covid-19 pandemic. © 2022, Polish Academy of Sciences - Institute of Philosophy and Sociology. All rights reserved.
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Introduction: The treatment of congenital heart disease (CHD) is complex and often requires a personalised approach involving several surgical interventions. Despite advancements in imaging, understandingCHDin 3D can still be a major challenge, especially for atypical cases spanning multiple pathologies. Virtual reality (VR) is a rapidly growing technology allowing the user to be completely immersed within a simulated environment. At our centre, we pioneered the use of VR for CHD to: (i) aid surgical planning (ii) enhance teaching and (iii) improve patient communication. Methods: A VR application has been designed in house specifically to meet these aims over the last year at our centre. The VR software allows the user to import multiple models of patient-specific anatomies reconstructed from medical images. The application uses a commercial headset with controllers to allow the user to interact with the virtual heart. Different tools were implemented to help the planning (measuring, cutting, device interaction), improve teaching (labelling, ultrasound simulators, multi-user experiences) and patient engagement (labelling, colours, splitting). The development was a collaborative process between clinicans, engineers and educators, allowing for tailored tools to be developed to address the clinical/educational needs. Results: In clinical practice, our VR app was successfully used for planning more than 20 cases, including: (i) double-outlet right ventricle repairs (ii) aortic root replacements for Marfan syndrome (iii) percutaneous pulmonary valve implantations (iv) stenting of pulmonary arteries. In an educational setting, VR has been routinely added to a specialised cardiac morphology course for healthcare professionals, over 90% of whom found it “extremely/very useful” in aiding their understanding of CHD. In addition, it was implemented in an undergraduate course during COVID- 19 to support remote learning, with the use of online multi-user teaching. Over the course of two years, more than 100 students were taught using VR. Finally, our app was found to be particularly engaging by patients and their families in understanding the complexity of CHD during public events held at our Centre. Conclusions: Our preliminary research with in-house developed VR software showed how this can be used in facilitating the understanding of CHD for treatment planning, education and communication.
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The COVID pandemic has highlighted the need for universities to be innovative and inclusive in their response to changing circumstances and to develop high quality courses in a completely online environment. In Semester 1, 2020, the team redeveloped a large undergraduate English and Chinese translation course at an Australian university in flipped mode while shifting the course to fully online delivery. The authors found that although student attitudes towards online flipped learning were initially mixed, levels of student engagement were similar to previous semesters. By the second semester of implementation, student evaluations of the course were significantly higher than in pre-flipped, pre-online semesters. This experience demonstrates that it is possible to develop a flipped university translation course that is interactive and engaging and challenges students academically. With appropriate scaffolding and the judicious use of technology, flipped learning offers a very positive learning experience and can be a key element of effective course design in fully online mode. © 2021, IGI Global.
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INTRODUCTION: At the beginning of the COVID-19 pandemic, the French government implemented its first national lockdown between March and May 2020 in order to limit the dissemination of the virus. This historic measure affected patients' daily lives and transportation, resulting in changes in the delivery of medical care, particularly emergency care. This study aimed to assess the impact of this restriction policy on the number and severity of ophthalmic emergencies seen in an ophthalmology emergency department. METHODS: This retrospective study conducted at the regional university Hospital of Tours included all patients presenting to the ophthalmology emergency department over four periods: lockdown (03/16/2020 to 05/10/2020), post-lockdown (05/11/2020 to 06/12/2020) and the two corresponding periods in 2019. The following data were recorded: sex, age, time of visit, reason for visit, diagnosis, severity of emergency graded on the BaSe SCOrE, time from first symptoms until visit, existence of a work-related injury, and referral source (ophthalmologist or other). RESULTS: A total of 1186 and 1905 patients were respectively included during the 2020 lockdown period and the corresponding period in 2019. The study populations for the 2019 and 2020 post-lockdown periods consisted of 1242 and 1086 patients respectively. During the lockdown, the number of consultations decreased significantly (-37.7%), affecting mild and severe emergencies similarly. During the post-lockdown period, the number of emergencies gradually increased but did not reach the level of the corresponding period in 2019 (-12.6%). CONCLUSION: The first French lockdown resulted in a significant decrease in ophthalmic emergency visits, similar for all levels of severity. All age groups were impacted similarly, without the expected exaggerated decrease for patients over 50 years of age, who are considered to be at greater risk for developing a severe form of COVID-19. The post-lockdown period showed a gradual increase in ophthalmic emergency visits, although these remained fewer than the previous year.
Subject(s)
COVID-19 , COVID-19/epidemiology , Communicable Disease Control , Emergencies , Emergency Service, Hospital , Hospitals, University , Humans , Middle Aged , Pandemics , Retrospective Studies , SARS-CoV-2ABSTRACT
Background. Casirivimab and imdevimab (CAS/IMDEV) is authorized for emergency use in the US for outpatients with COVID-19. We present results from patient cohorts receiving low flow or no supplemental oxygen at baseline from a phase 1/2/3, randomized, double-blinded, placebo (PBO)-controlled trial of CAS/IMDEV in hospitalized patients (pts) with COVID-19. Methods. Hospitalized COVID-19 pts were randomized 1:1:1 to 2.4 g or 8.0 g of IV CAS/IMDEV (co-administered) or PBO. Primary endpoints were time-weighted average (TWA) change in viral load from baseline (Day 1) to Day 7;proportion of pts who died or went on mechanical ventilation (MV) through Day 29. Safety was evaluated through Day 57. The study was terminated early due to low enrollment (no safety concerns). Results. Analysis was performed in pooled cohorts (low flow or no supplemental oxygen) as well as combined treatment doses (2.4 g and 8.0 g). The prespecified primary virologic analysis was in seronegative (seroneg) pts (combined dose group n=360;PBO n=160), where treatment with CAS/IMDEV led to a significant reduction in viral load from Day 1-7 (TWA change: LS mean (SE): -0.28 (0.12);95% CI: -0.51, -0.05;P=0.0172;Fig. 1). The primary clinical analysis had a strong positive trend, though it did not reach statistical significance (P=0.2048), and 4/6 clinical endpoints prespecified for hypothesis testing were nominally significant (Table 1). In seroneg pts, there was a 47.0% relative risk reduction (RRR) in the proportion of pts who died or went on MV from Day 1-29 (10.3% treated vs 19.4% PBO;nominal P=0.0061;Fig. 2). There was a 55.6% (6.7% treated vs 15.0% PBO;nominal P=0.0032) and 35.9% (7.3% treated vs 11.5% PBO;nominal P=0.0178) RRR in the prespecified secondary endpoint of mortality by Day 29 in seroneg pts and the overall population, respectively (Fig. 2). No harm was seen in seropositive patients, and no safety events of concern were identified. Conclusion. Co-administration of CAS/IMDEV led to a significant reduction in viral load in hospitalized, seroneg pts requiring low flow or no supplemental oxygen. In seroneg pts and the overall population, treatment also demonstrated clinically meaningful, nominally significant reductions in 28-day mortality and proportion of pts dying or requiring MV.
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Clinical manifestations of infection with the novel SARS-CoV-2 in humans are widely varied, ranging from asymptomatic to COVID-19 respiratory failure and multiorgan damage. Profound inflammation is the hallmark of severe COVID-19 disease, and commonly does not occur until the second week of infection. Although risk factors for this late hyperinflammatory disease have been identified, most notably age and pre-existing co-morbidities, even within high-risk groups the specific factors leading to severe COVID-19 illness remain elusive. Acquired somatic mutations in hematopoietic stem and progenitor cells (HSPCs), termed clonal hematopoiesis (CH), are associated with advanced age, and loss of function (LOF) mutations in certain genes, most commonly DNMT3A and TET2, have been linked to a marked hyperinflammatory phenotype as well as clonal expansion of mutant HSPCs. Given the similar age range of frequent CH and severe COVID-19 disease, the presence of CH could impact the risk of severe COVID-19. Several human cohort studies have suggested this relationship may exist, but results to date are conflicting. Rhesus macaques (RM) have been established as a model for SARS-CoV infection and are being utilized to test therapies and vaccine development, but up to now, macaques have not been reported to develop late hyperinflammatory COVID-19 disease. We have created a robust RM model of CH by introducing LOF TET2 mutations into young adult HSPC via CRISPR/Cas9 followed by autologous transplantation, recapitulating the clonal expansion and hyperinflammatory phenotype. Thus, we hypothesized that macaques with CH could develop severe late COVID-19 disease and be utilized as a model to study disease pathophysiology or test therapeutic approaches. Macaques with either engineered (n=2) or natural CH (n=1) along with age-matched transplanted controls (n=3) were inoculated with SARS-CoV-2 and monitored clinically and via laboratory studies until 12 days post-inoculation (dpi). Macaques normally clear infection and symptoms within 3-5 days of infection. No significant differences in clinical symptoms and blood counts were noted, however, an aged animal with natural DNMT3A CH died on 10 dpi. IL-6 levels were somewhat higher in sera of the CH animals until 12 dpi, and in BAL, mean concentrations of MCP-1, IL-6, IL-8 and MIP-1b were consistently higher in CH macaques compared to controls. Interestingly, we found the median copy number of subgenomic SARS-CoV-2 RNA was higher at every timepoint in the CH group as compared with the control group, in both upper and lower respiratory samples. Lung sections from euthanasia at 10 or 12 dpi showed evidence of mild inflammation in all animals. However, in the immunohistochemical analysis, the viral antigen was detected in the lung tissues of all three animals in the CH group even at the time of autopsy, whereas only one animal of three controls had detectable viral antigen. Although the striking inflammation and serious disease have not been observed, data so far provide evidence of potential pathophysiological differences with or without CH upon SARS-CoV-2 infection. We continue to expand sample size and conduct further analyses to draw a solid conclusion, but we believe this model may be of benefit to understand the relationship between COVID-19 disease and CH. Disclosures: No relevant conflicts of interest to declare.
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[Figure: see text].
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Background: Patients (pts) with high-risk M0 PCa are treated with ADT and when indicated, local radiotherapy (RT). Intensifying hormone treatment with AAP, ENZ or apalutamide continuous to progression improves outcomes of metastatic PCa but its efficacy in M0 PCa starting ADT is unknown. Methods: STAMPEDE is a multi-arm, multi-stage trial that, as part of 2 separate comparisons randomised PCa pts with M0 node positive or high-risk node negative (>1 T3/4, PSA ≥40ng/ml, Gleason 8-10 or relapsing) 1:1 to ADT (control) vs ADT with AAP (1000mg AA + 5mg P od) or ADT vs ADT with AAP + ENZ (160mg od) for 2 years (y), unless RT was omitted when treatment could be to progression. The primary end-point was metastasis-free survival (MFS, time to death or distant metastases). The sub-group of pts who received ADT +/- AAP was partially reported with metastatic pts in 2017 so one-sided type 1 error rate was set to 1.25%. All analyses were pre-specified, pooled using meta-analyses methods and stratified as described previously. Data frozen 3rd August 2021. Results: 1974 M0 pts at 113 sites in UK & Switzerland were randomised, 914 (Nov 2011 to Jan 2014) to ADT +/- AAP & 1060 (Mar 2016 to Jul 2014) to ADT +/- AAP + ENZ. Groups were well balanced: median age 68 y, range 43-86;median PSA 34 ng/ml, range 0.4-2773;Gleason 8-10, 79%;node positive 39%;planned for RT 85%. Median months to stopping AAP, 23.7 (IQR: 17.6-24.1);AAP when given with ENZ, 20.7 (IQR: 4.4-24);ENZ, 23.2 (IQR: 6.3-24). 180 MFS events occurred in the research group and 306 in the control group. AAP-based therapy improved MFS (HR 0.53, 95% CI 0.44-0.64, P=2.9×10- 11) & survival (HR 0.60, 95% CI 0.48-0.73, P=9.3×10-7): 6-y MFS from 69% to 82%, 6-y survival from 77% to 86%. Treatment effect was consistent in major subgroups and between AAP & AAP + ENZ randomisation periods (MFS HR=0.54, 95% CI 0.43-0.68;HR=0.53, 95% CI 0.39-0.71 respectively;interaction HR = 1.02, 95% CI: 0.70-1.50, p=0.908). Conclusions: 2 y of AAP-based therapy significantly improves MFS & survival of high-risk M0 PCa starting ADT and should be considered a new standard of care. 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, Astellas, Janssen. Disclosure: G. Attard: Financial Interests, Personal, Invited Speaker: Janssen;Financial Interests, Personal, Advisory Board: Janssen;Financial Interests, Personal, Invited Speaker: Astellas;Financial Interests, Personal, Advisory Board: Astellas;Financial Interests, Personal, Advisory Board: Novartis;Financial Interests, Personal, Advisory Board: Bayer;Financial Interests, Personal, Invited Speaker: AstraZeneca;Financial Interests, Personal, Advisory Board: AstraZeneca;Financial Interests, Personal, Advisory Board: Pfizer;Financial Interests, Personal, Advisory Board: Sanofi;Financial Interests, Personal, Advisory Board: Sapience;Financial Interests, Personal, Advisory Board: Orion;Financial Interests, Personal, Royalties: Janssen;Financial Interests, Institutional, Research Grant: Janssen;Financial Interests, Institutional, Research Grant: Astellas;Non-Financial Interests, Principal Investigator: Janssen;Non-Financial Interests, Advisory Role: Janssen;Non-Financial Interests, Advisory Role: AstraZeneca;Non-Financial Interests, Principal Investigator: Astellas. L.C. Brown: Financial Interests, Institutional, Research Grant, FOCUS4-C Trial from June 2017 to Dec 2021: AstraZeneca. N. Clarke: Financial Interests, Personal, Invited Speaker: Astellas;Financial Interests, Personal, Invited Speaker: AstraZeneca;Financial Interests, Personal, Invited Speaker: Ferring;Financial Interests, Personal, Invited Speaker: Janssen;Financial Interests, Personal, Advisory Board: Astellas;Financial Interests, Personal, Advisory Board: AstraZeneca;Financial Interests, Personal, Advisory Board: Ferring;Financial Interests, Personal, Advisory Board: Janssen;Financial Interests, Inst tutional, Research Grant: AstraZeneca. W. Cross: Financial Interests, Personal, Invited Speaker, Speaker fee: Myriad Genetics;Financial Interests, Personal, Invited Speaker, Speaker fee: Janssen;Financial Interests, Personal, Advisory Board, Advisory Board fee: Bayer;Financial Interests, Personal, Invited Speaker, Speaker fee: Astellas;Financial Interests, Institutional, Research Grant, Research grant: Myriad Genetics. R. Jones: Financial Interests, Personal, Advisory Board, advisory board attendance: AstraZeneca;Financial Interests, Personal, Advisory Board, advisory board attendance: Astellas;Financial Interests, Personal, Invited Speaker, Honoraria for speaking: Astellas;Financial Interests, Personal, Advisory Board: Bayer;Financial Interests, Personal, Invited Speaker: Bayer;Financial Interests, Personal, Advisory Board: Clovis;Financial Interests, Personal, Advisory Board: Exelixis;Financial Interests, Personal, Advisory Board: Ipsen;Financial Interests, Personal, Invited Speaker: Ipsen;Financial Interests, Personal, Advisory Board: Bristol Myers Squipp;Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb;Financial Interests, Personal, Advisory Board: Merck Serono;Financial Interests, Personal, Invited Speaker: Merck Serono;Financial Interests, Personal, Advisory Board: Merck Sharpe Dome;Financial Interests, Personal, Invited Speaker: Merck Sharpe Dome;Financial Interests, Personal, Invited Speaker: Pfizer;Financial Interests, Personal, Advisory Board: Roche;Financial Interests, Institutional, Other, IDMC membership: Roche;Financial Interests, Personal, Invited Speaker: Roche;Financial Interests, Personal, Advisory Board: Janssen;Financial Interests, Personal, Invited Speaker: Janssen;Financial Interests, Institutional, Other, IDMC member: Stab;Financial Interests, Personal, Advisory Board: Novartis / AAA;Financial Interests, Institutional, Invited Speaker: Janssen;Financial Interests, Institutional, Invited Speaker: Pfizer;Financial Interests, Institutional, Invited Speaker: Tail;Financial Interests, Institutional, Invited Speaker: AstraZeneca;Financial Interests, Institutional, Invited Speaker: BioXcel;Financial Interests, Institutional, Invited Speaker: Bristol Myers Squibb;Financial Interests, Institutional, Invited Speaker: Novartis / AAA;Financial Interests, Institutional, Invited Speaker: Roche;Financial Interests, Institutional, Invited Speaker: MSK. S. Gillessen: Financial Interests, Personal, Advisory Board, 2018: Sanofi;Financial Interests, Personal, Advisory Board, 2018, 2019: Orion;Financial Interests, Personal, Advisory Board, 2018: Roche;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: Bayer;Financial Interests, Institutional, Advisory Board, 2020: Janssen Cilag;Financial Interests, Institutional, Advisory Board, 2020: Roche;Financial Interests, Institutional, Advisory Board, 2018: AAA International;Financial Interests, Institutional, Advisory Board, 2018: Menarini Silicon Biosystems;Financial Interests, Institutional, Advisory Board, 2019, 2020: Astellas Pharma;Financial Interests, Institutional, Advisory Board, 2019: Tolero Pharmaceuticals;Financial Interests, Institutional, Advisory Board, 2020: MSD Merck Sharp & Dohme;Financial Interests, Institutional, Advisory Board, 2020: Pfizer;Financial Interests, Personal, Invited Speaker, 2021: SAKK;Financial Interests, Institutional, Advisory Board, 2021: Telixpharma;Financial Interests, Institutional, Other, Steering Committee 2021: Amgen;Financial Interests, Institutional, Invited Speaker, 2021: DESO;Financial Interests, Institutional, Advisory Board, 2021: BMS;Financial Interests, Institutional, Advisory Board, 2021: AAA International;Financial Interests, Institutional, Advisory Board, 2021: Orion;F nancial Interests, Personal, Invited Speaker, 2021: SAKK;Financial Interests, Personal, Invited Speaker, 2021: SAKK;Financial Interests, Institutional, Advisory Board, 2021: Bayer;Financial Interests, Personal, Advisory Board, 2021: MSD Merck Sharp & Dhome;Financial Interests, Personal, Other, 2021: RSI (Televisione Svizzera Italiana);Financial Interests, Personal, Invited Speaker, 2021: SAMO - IBCSG;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;Non-Financial Interests, Advisory Role, 2019: Aranda;Non-Financial Interests, Advisory Role, Continuing: ProteoMediX. S. Chowdhury: Financial Interests, Personal, Advisory Board: Astellas;Financial Interests, Personal, Advisory Board: Janssen;Financial Interests, Personal, Invited Speaker: Janssen;Financial Interests, Personal, Advisory Board: Huma;Financial Interests, Personal, Invited Speaker: AstraZeneca;Financial Interests, Personal, Advisory Board: Bayer;Financial Interests, Personal, Invited Speaker: Bayer;Financial Interests, Personal, Advisory Board: Novartis/AAA;Financial Interests, Personal, Advisory Board: Beigene;Financial Interests, Personal, Advisory Board: Remedy Bio;Financial Interests, Personal, Advisory Board: Athenex;Financial Interests, Personal, Advisory Board: Telix;Financial Interests, Personal, Advisory Board: Clovis Oncology;Financial Interests, Personal, Stocks/Shares: Curve Life;Financial Interests, Institutional, Research Grant: Clovis Oncology;Non-Financial Interests, Advisory Role, Non-compensated advice: NHS England;Non-Financial Interests, Advisory Role: NICE NHS England. Z. Malik: Financial Interests, Personal, Advisory Board, advisry board for new hormonal therapy for breast cancer:Sanofi;Other, support to attend meetings or advisory boards in the past: Astellas, Jaansen, Bayer. C. Parker: Financial Interests, Personal, Advisory Board, Education Steering Committee: Bayer;Financial Interests, Personal, Invited Speaker, Speaker at prostate cancer educational events: Janssen;Financial Interests, Personal, Advisory Board, Advisory board on apalutamide: Janssen;Financial Interests, Personal, Advisory Board, Advisory board: Clarity Pharmaceuticals;Financial Interests, Personal, Advisory Board, Advisory board on relugolix: Myovant;Financial Interests, Personal, Advisory Board, Advisory board: ITM Oncologics. 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;Financial Interests, Institutional, Research Grant, Educational grant and biomarker costs for STAMPEDE trial: Clovis Oncology;Financial Interests, Institutional, Research Grant, Educational grant and drug for STAMPEDE trial: Janssen;Financial Interests, Institutional, Research Grant, Educational grant and drug for STAMPEDE trial: Novartis;Financial Interests, Institutional, Research Grant, Educational grant and drug for STAMPEDE trial: Pfizer;Financial Interests, Institutional, Research Grant, Educational grant and drug for STAMPEDE trial: Sanofi. M.K. Parmar: Financial Interests, Institutional, Research Grant: AstraZeneca, Astellas, Janssen, Clovis. N.D. James: Financial Interests, Personal, Advisory Board, Advice around PARP inhibitors: AstraZeneca;Financial Interests, Personal, Advisory Board, Prostate cancer therapies: Janssen;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 facili ate licence extensions internationally for docetaxel: Sanofi;Financial Interests, Personal, Advisory Board, Prostate cancer therapies: Clovis;Financial Interests, Personal, Advisory Board, Prostate cancer therapies: Novartis;Financial Interests, Personal, Advisory Board, Bladder cancer therapy: Merck;Financial Interests, Institutional, Invited Speaker, Funding for STAMPEDE trial: Janssen;Financial Interests, Institutional, Invited Speaker, Funding for STAMPEDE trial: Astellas;Financial Interests, Institutional, Invited Speaker, Funding for RADIO trial bladder cancer: AstraZeneca. All other authors have declared no conflicts of interest.
ABSTRACT
INTRODUCTION: The COVID-19 pandemic has affected the world for more than a year, with multiple waves of infections resulting in morbidity, mortality and disruption to the economy and society. Response measures employed to control it have generally been effective but are unlikely to be sustainable over the long term. METHODS: We examined the evidence for a vaccine-driven COVID-19 exit strategy including academic papers, governmental reports and epidemiological data, and discuss the shift from the current pandemic footing to an endemic approach similar to influenza and other respiratory infectious diseases. RESULTS: A desired endemic state is characterised by a baseline prevalence of infections with a generally mild disease profile that can be sustainably managed by the healthcare system, together with the resumption of near normalcy in human activities. Such an endemic state is attainable for COVID-19 given the promising data around vaccine efficacy, although uncertainty remains around vaccine immunity escape in emergent variants of concern. Maintenance of non-pharmaceutical interventions remains crucial until high vaccination coverage is attained to avoid runaway outbreaks. It may also be worthwhile to de-escalate measures in phases, before standing down most measures for an endemic state. If a variant that substantially evades immunity emerges, it will need to be managed akin to a new disease threat, with pandemic preparedness and response plans. CONCLUSION: An endemic state for COVID-19, characterised by sustainable disease control measures, is likely attainable through vaccination.
ABSTRACT
The coronavirus disease 2019 (COVID-19) pandemic had caused a severe depletion of the worldwide supply of N95 respirators. The development of methods to effectively decontaminate N95 respirators while maintaining their integrity is crucial for respirator regeneration and reuse. In this study, we systematically evaluated five respirator decontamination methods using vaporized hydrogen peroxide (VHP) or ultraviolet (254 nm wavelength, UVC) radiation. Through testing the bioburden, filtration, fluid resistance, and fit (shape) of the decontaminated respirators, we found that the decontamination methods using BioQuell VHP, custom VHP container, Steris VHP, and Sterrad VHP effectively inactivated Cardiovirus (3-log10 reduction) and bacteria (6-log10 reduction) without compromising the respirator integrity after 2-15 cycles. Hope UVC system was capable of inactivating Cardiovirus (3-log10 reduction) but exhibited relatively poorer bactericidal activity. These methods are capable of decontaminating 10-1000 respirators per batch with varied decontamination times (10-200 min). Our findings show that N95 respirators treated by the previously mentioned decontamination methods are safe and effective for reuse by industry, laboratories, and hospitals.
ABSTRACT
Dental care professionals (DCPs) are thought to be at enhanced risk of occupational exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, robust data to support this from large-scale seroepidemiological studies are lacking. We report a longitudinal seroprevalence analysis of antibodies to SARS-CoV-2 spike glycoprotein, with baseline sampling prior to large-scale practice reopening in July 2020 and follow-up postimplementation of new public health guidance on infection prevention control (IPC) and enhanced personal protective equipment (PPE). In total, 1,507 West Midlands DCPs were recruited into this study in June 2020. Baseline seroprevalence was determined using a combined IgGAM enzyme-linked immunosorbent assay and the cohort followed longitudinally for 6 mo until January/February 2021 through the second wave of the coronavirus disease 2019 pandemic in the United Kingdom and vaccination commencement. Baseline seroprevalence was 16.3%, compared to estimates in the regional population of 6% to 7%. Seropositivity was retained in over 70% of participants at 3- and 6-mo follow-up and conferred a 75% reduced risk of infection. Nonwhite ethnicity and living in areas of greater deprivation were associated with increased baseline seroprevalence. During follow-up, no polymerase chain reaction-proven infections occurred in individuals with a baseline anti-SARS-CoV-2 IgG level greater than 147.6 IU/ml with respect to the World Health Organization international standard 20-136. After vaccination, antibody responses were more rapid and of higher magnitude in those individuals who were seropositive at baseline. Natural infection with SARS-CoV-2 prior to enhanced PPE was significantly higher in DCPs than the regional population. Natural infection leads to a serological response that remains detectable in over 70% of individuals 6 mo after initial sampling and 9 mo from the peak of the first wave of the pandemic. This response is associated with protection from future infection. Even if serological responses wane, a single dose of the Pfizer-BioNTech 162b vaccine is associated with an antibody response indicative of immunological memory.
Subject(s)
COVID-19 , Vaccines , Dental Care , Humans , SARS-CoV-2 , Seroepidemiologic Studies , United Kingdom/epidemiologyABSTRACT
BACKGROUND: Frequently SARS-CoV-2 results in mild or moderate disease with potentially lower concentrations of antibodies compared to those that are hospitalised. Here, we validated an ELISA using SARS-CoV-2 trimeric spike glycoprotein, with targeted detection of IgG, IgA and IgM (IgGAM) using serum and dried blood spots (DBS) from adults with mild or moderate disease. METHODS: Targeting the SARS-CoV-2 trimeric spike, a combined anti-IgG, IgA and IgM serology ELISA assay was developed using 62 PCR-confirmed non-hospitalised, mild or moderate COVID-19 samples, ≥14 days post symptom onset and 624 COVID-19 negative samples. The assay was validated using 73 PCR-confirmed non-hospitalised, mild or moderate COVID-19 samples, ≥14 days post symptom onset and 359 COVID-19 negative serum samples with an additional 81 DBSs. The assay was further validated in 226 PCR-confirmed non-hospitalised, mild or moderate COVID-19 samples, ≥14 days post symptom onset and 426 COVID-19 negative clinical samples. RESULTS: A sensitivity and specificity of 98.6% (95% CI, 92.6-100.0), 98.3% (95% CI, 96.4-99.4), respectively, was observed following validation of the SARS-CoV-2 ELISA. No cross-reactivities with endemic coronaviruses or other human viruses were observed, and no change in results were recorded for interfering substances. The assay was stable at temperature extremes and components were stable for 15 days once opened. A matrix comparison showed DBS to correlate with serum results. Clinical validation of the assay reported a sensitivity of 94.7% (95% CI, 90.9-97.2%) and a specificity of 98.4% (95% CI, 96.6-99.3%). CONCLUSIONS: The human anti-IgGAM SARS-CoV-2 ELISA provides accurate and sensitive detection of SARS-CoV-2 antibodies in non-hospitalised adults with mild or moderate disease. The use of dried blood spots makes the assay accessible to the wider community.