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Goodrum, F.; Lowen, A.; Lakdawala, S.; Alwine, J.; Casadevall, A.; Imperiale, M.; Atwood, W.; Avgousti, D.; Baines, J.; Banfield, B.; Banks, L.; Bhaduri-McIntosh, S.; Bhattacharya, D.; Blanco-Melo, D.; Bloom, D.; Boon, A.; Boulant, S.; Brandt, C.; Broadbent, A.; Brooke, C.; Cameron, C.; Campos, S.; Caposio, P.; Chan, G.; Cliffe, A.; Coffin, J.; Collins, K.; Damania, B.; Daugherty, M.; Debbink, K.; DeCaprio, J.; Dermody, T.; Dikeakos, J.; DiMaio, D.; Dinglasan, R.; Duprex, W. P.; Dutch, R.; Elde, N.; Emerman, M.; Enquist, L.; Fane, B.; Fernandez-Sesma, A.; Flenniken, M.; Frappier, L.; Frieman, M.; Frueh, K.; Gack, M.; Gaglia, M.; Gallagher, T.; Galloway, D.; Garcia-Sastre, A.; Geballe, A.; Glaunsinger, B.; Goff, S.; Greninger, A.; Hancock, M.; Harris, E.; Heaton, N.; Heise, M.; Heldwein, E.; Hogue, B.; Horner, S.; Hutchinson, E.; Hyser, J.; Jackson, W.; Kalejta, R.; Kamil, J.; Karst, S.; Kirchhoff, F.; Knipe, D.; Kowalik, T.; Lagunoff, M.; Laimins, L.; Langlois, R.; Lauring, A.; Lee, B.; Leib, D.; Liu, S. L.; Longnecker, R.; Lopez, C.; Luftig, M.; Lund, J.; Manicassamy, B.; McFadden, G.; McIntosh, M.; Mehle, A.; Miller, W. A.; Mohr, I.; Moody, C.; Moorman, N.; Moscona, A.; Mounce, B.; Munger, J.; Munger, K.; Murphy, E.; Naghavi, M.; Nelson, J.; Neufeldt, C.; Nikolich, J.; O'Connor, C.; Ono, A.; Orenstein, W.; Ornelles, D.; Ou, J. H.; Parker, J.; Parrish, C.; Pekosz, A.; Pellett, P.; Pfeiffer, J.; Plemper, R.; Polyak, S.; Purdy, J.; Pyeon, D.; Quinones-Mateu, M.; Renne, R.; Rice, C.; Schoggins, J.; Roller, R.; Russell, C.; Sandri-Goldin, R.; Sapp, M.; Schang, L.; Schmid, S.; Schultz-Cherry, S.; Semler, B.; Shenk, T.; Silvestri, G.; Simon, V.; Smith, G.; Smith, J.; Spindler, K.; Stanifer, M.; Subbarao, K.; Sundquist, W.; Suthar, M.; Sutton, T.; Tai, A.; Tarakanova, V.; tenOever, B.; Tibbetts, S.; Tompkins, S.; Toth, Z.; van Doorslaer, K.; Vignuzzi, M.; Wallace, N.; Walsh, D.; Weekes, M.; Weinberg, J.; Weitzman, M.; Weller, S.; Whelan, S.; White, E.; Williams, B.; Wobus, C.; Wong, S.; Yurochko, A..
Msphere ; : e0003423, 2023.
Article in English | MEDLINE | ID: covidwho-2213885

ABSTRACT

Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns - conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the possible origins of SARS-CoV-2 and outline current regulatory structures that provide oversight for virological research in the United States. By offering our expertise, we - a broad group of working virologists - seek to aid policy makers in navigating these controversial issues. Balanced, evidence-based discourse is essential to addressing public concern while maintaining and expanding much-needed research in virology.

3.
HemaSphere ; 6:1985-1987, 2022.
Article in English | EMBASE | ID: covidwho-2032163

ABSTRACT

Background: Ibrutinib (IBR) is an oral covalent Bruton tyrosine kinase inhibitor (BTKi), licensed for treatment of relapsed or refractory mantle cell lymphoma (MCL). Under NHS interim Covid-19 agreements in England, IBR with or without rituximab (R) was approved for the frontline treatment for MCL patients (pts) as a safer alternative to conventional immunochemotherapy. Although recent phase 2 studies have reported high response rates in low-risk patients for this combination in the frontline setting, randomised phase 3 and real-world data are currently lacking. Aims: To describe the real-world response rates (overall response rate (ORR), complete response (CR) rate) and toxicity profile of IBR +/-R in adult patients with previously untreated MCL. Methods: Following institutional approval, adults commencing IBR +/-R for untreated MCL under interim Covid-19 arrangements were prospectively identified by contributing centres. Hospital records were interrogated for demographic, pathology, response, toxicity and survival data. ORR/CR were assessed per local investigator according to the Lugano criteria using CT and/or PET-CT. Results: Data were available for 66 pts (72.7% male, median age 71 years, range 41-89). Baseline demographic and clinical features are summarised in Table 1. 23/66 pts (34.8%) had high-risk disease (defined as presence of TP53 mutation/deletion, blastoid or pleomorphic variant MCL, or Ki67%/MiB-1 ≥30%). IBR starting dose was 560mg in 56/62 pts (90%) and was given with R in 22/64 pts (34%). At a median follow up of 8.7 months (m) (range 0-18.6), pts had received a median of 7 cycles of IBR. 19/60 pts (32%) required a dose reduction or delay in IBR treatment. New atrial fibrillation and grade ≥3 any-cause toxicity occurred in 3/59 pts (5.8%) and 8/57 (14.0%) respectively. For the whole population and high-risk pts only, ORR was 74.4% and 64.7% respectively (p=0.2379), with a median time to response of 3.8m, coinciding with the first response assessment scan. Seven pts (16.7%), of whom 2 had highrisk disease, attained CR at a median of 6.0m. ORR for pts receiving vs not receiving R were 84.2% and 66.7% respectively (p=0.1904). IBR was discontinued in 20/61 pts (32.8%) at a median time to discontinuation of 4.1m, due to progressive disease (PD, 19.7%), toxicity (4.9%), death (3.3%;1 pt each of Covid-19 and E. coli infection), pt choice (3.3%) and other unspecified reasons (1.6%). 15/66 pts (22.7%) overall and 7/23 (30.4%) with high-risk disease progressed on IBR at a median time to PD of 4.0m. No pts underwent autologous stem cell transplantation consolidation during the study period. 12/57 pts (21.1%) received second line treatment (R-chemotherapy n=7, Nordic MCL protocol n=2, VR-CAP n=2, pirtobrutinib n=1). Response to second line treatment was CR in 4/11 pts, PD in 7/11. Of the 2 Nordic-treated patients, 1 had CR after cycle 2 and 1 PD. Fourteen pts (21.2%) died during the follow up period, due to MCL (n=11), Covid-19 (n=2) and congestive cardiac failure (n=1). Overall survival was lower for patients with high-risk disease (HR 0.55, p=0.038). Image: Summary/Conclusion: In this real-world UK cohort of pts receiving first-line IBR +/-R for MCL, including older and high-risk pts, we report high ORR rates in a similar range to the phase II Geltamo IMCL-2015 study of combination IBR-R in an exclusively low-risk population. Documented CR rates were lower, possibly reflecting a low usage of rituximab in the Covid-19 pandemic as well as CT assessment of response. Treatment was generally well tolerated, with low rates of toxicityrelated treatment discontinuation. The study is ongoing.

4.
BMJ Supportive and Palliative Care ; 12:A21, 2022.
Article in English | EMBASE | ID: covidwho-2005499

ABSTRACT

Introduction The COVID-19 pandemic created new challenges due to the high numbers and the high symptom burden of end-of-life patients on respiratory support. Methods We conducted an audit of end-of-life patients on the respiratory HDU wards at Whipps Cross Hospital between 17/09/2020-30/01/2021. Results 84 patients receiving respiratory support (in the form of CPAP and HFNT) died during that time at a mean age of 77 (95% CI 67-87) and median of 79 years. All but one death, which followed a cardiac arrest, were expected. The most common clinical indicator for a patient approaching end-of-life was hypoxia on respiratory support, which was documented in 36 (43%) patients, followed by terminal agitation in 27 (32%) patients. Objections to the medical assessment of terminal illness were raised by 3 families and in 1 case the patient had conflicting wishes. The average time between recognition of a terminal deterioration and death was 1.4 days with a median of 2 days. 29 (35%) patients did not have a specialist palliative care review primarily due to the rapid patient deterioration. 25 (30%) patients were not visited by a relative due to the infection risk. 72 (86%) patients were weaned off respiratory support and those who continued did so due to a medical or patient decision. Despite most patients (82%) receiving continuous subcutaneous infusions with an opiate and benzodiazepine most patients had persistent terminal symptoms: 51 (74%) on infusions had agitation and 38 (55%) were persistently breathlessness. Discussion This data highlights some of the major difficulties faced in caring for patients with COVID on respiratory support and approaching end of life. With the inevitably persisting nature of this pandemic and the possibility of future pandemics still present, it is vital to be able to offer guidance and multidisciplinary input to ensure comfort and dignity for these patients.

5.
Heart Lung and Circulation ; 31:S33, 2022.
Article in English | EMBASE | ID: covidwho-2004114

ABSTRACT

Background: Transoesophegeal echocardiogram (TOE) is the gold standard imaging modality to evaluate the left atrial appendage (LAA) prior to direct current cardioversion (DCCV) for atrial arrhythmia. TOE is an aerosol generating procedure, with the potential for transmission of COVID-19 infection. This study describes our experience of utilising cardiac computed tomography (CT) as an alternative imaging modality, to exclude LAA thrombus prior to DCCV in patients with atrial arrhythmias at Middlemore Hospital from 1st September 2020 until 30th September 2021 during the COVID-19 pandemic. Method: Patients with atrial arrhythmia requiring DCCV who underwent cardiac CT were identified from ANZACS-QI linked cardiac CT registry database. Patients without thrombus on cardiac CT proceeded to DCCV. Patients with slow flow or thrombus in the left atrium (LA) or LAA on CT were considered for TOE. Results: Eighty-five cardiac CT scans were performed in eighty patients (male 68.8%, mean age 59.3±14 years, body mass index 33.4±8). Sixty-seven patients (87%) had no LAA thrombus, and 65 patients proceeded safely to DCCV with no periprocedural stroke. Thirteen patients (16%) had slow flow or possible thrombus in the LA or LAA and one patient had definite thrombus. Six patients with slow flow or possible thrombus underwent TOE none had LA or LAA thrombus. Conclusion: In the majority of patients with atrial arrhythmia requiring DCCV, cardiac CT is a safe and useful alternative to TOE.

6.
Emerg Microbes Infect ; 11(1): 1103-1114, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1764462

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a pandemic. As immunity to endemic human coronaviruses (i.e. NL63 or OC43) wanes leading to re-infection, it was unknown if SARS-CoV-2 immunity would also decline permitting repeat infections. Recent case reports confirm previously infected individuals can become re-infected; however, re-infection may be due to heterogeneity in the initial infection or the host immune response, or may be the result of infection with a variant strain that escapes pre-existing immunity. To control these variables, we utilized the Syrian hamster model to evaluate the duration of immunity and susceptibility to re-infection with SARS-CoV-2. Hamsters were given a primary mock or SARS-CoV-2 infection (culture media or 105 TCID50 USA/WA1/2020 isolate, respectively). Mock and SARS-CoV-2 infected hamsters were then given a secondary SARS-CoV-2 infection at 1, 2, 4, or 6 months post-primary infection (n = 14/time point/group). After the primary SARS-CoV-2 infection, hamsters developed anti-spike protein IgG, IgA, and neutralizing antibodies, and these antibodies were maintained for at least 6 months. Upon secondary SARS-CoV-2 challenge, previously SARS-CoV-2 infected animals were protected from weight loss, while all previously mock-infected animals became infected and lost weight. Importantly, despite having high titres of antibodies, one SARS-CoV-2 infected animal re-challenged at 4 months had a breakthrough infection with replicating virus in the upper and lower respiratory tract. These studies demonstrate immunity to SARS-CoV-2 is maintained for 6 months; however, protection may be incomplete and, even in the presence of high antibody titres, previously infected hosts may become re-infected.


Subject(s)
COVID-19 , Animals , Antibodies, Neutralizing , Antibodies, Viral , Cricetinae , Mesocricetus , Reinfection , SARS-CoV-2
8.
Thorax ; 76(Suppl 2):A187, 2021.
Article in English | ProQuest Central | ID: covidwho-1506525

ABSTRACT

IntroductionThe COVID-19 pandemic has seen an unprecedented number of adults receiving non-invasive respiratory support (NIRS) with such patients having a high mortality rate.MethodsAs part of better elucidating the challenges of end of life care delivery in the COVID era, we conducted an audit of our respiratory HDU ward at Whipps Cross Hospital focusing on a 19-week period between 17/09/2020–30/01/2021 and on patients who did not survive their admission. We excluded patients that were transferred to ITU.ResultsOf a total of 309 patients receiving NIRS on our ward, 84 died during that time at a mean age of 77 (95% CI 67–87) and median of 79 years. 63 patients received CPAP, 67 received HFNT and 42 were first started on HFNT and converted to CPAP. The average length of stay was 10 days (4–16). The mean day of symptoms on presentation to hospital was 11.5 days (1.7–21.3). Average duration of symptoms prior to admission to our ward was 19.7 (9.1–30.3) days.One death was unexpected and followed a cardiac arrest. The most common indicator for a patient approaching end-of-life was hypoxia on NIRS, which was documented in 36 (43%) patients, followed by terminal agitation in 27 (32%) patients. The average time between recognising end-of-life and death was 1.4 days with a median of 2 days. 72 (86%) patients were weaned off NIRS and those who continued did so due to a medical or patient decision. Despite the vast majority (82% of patients) being on syringe drivers with an opiate and benzodiazepine most patients had persistent terminal symptoms: 51 (74%) had agitation and 38 (55%) were persistently breathlessness. Interestingly, no patient opted to rest in the prone position.DiscussionThis data primarily suggests the challenging nature of managing end-of-life care for COVID patients deteriorating on NIRS due to the high symptom load and the short time there is to achieve comfort for these individuals. Clinicians need to conduct frequent comfort reviews for such patients, consider subcutaneous infusions, as well as potentially an increase in medication doses, in conjunction with specialist palliative care input, in order to achieve comfort.

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