Identification of a Druggable Site on GRP78 at the GRP78-SARS-CoV-2 Interface and Compounds to Disrupt that Interface (preprint)

SARS-CoV-2, the virus that causes COVID-19, led to a global health emergency that claimed the lives of millions. Despite the widespread availability of vaccines, the virus continues to exist in the population in an endemic state which allows for the continued emergence of new variants. Most of the current vaccines target the spike glycoprotein interface of SARS-CoV-2, creating a selection pressure favoring viral immune evasion. Antivirals targeting other molecular interactions of SARS-CoV-2 can help slow viral evolution by providing orthogonal selection pressures on the virus. GRP78 is a host auxiliary factor that mediates binding of the SARS-CoV- 2 spike protein to human cellular ACE2, the primary pathway of cell infection. As GRP78 forms a ternary complex with SARS-CoV-2 spike protein and ACE2, disrupting the formation of this complex is expected to hinder viral entry into host cells. Here, we developed a model of the GRP78-spike protein-ACE2 complex. We then used that model together with hot spot mapping of the GRP78 structure to identify the putative binding site for spike protein on GRP78. Next, we performed structure-based virtual screening of known drug/candidate drug libraries to identify binders to GRP78 that are expected to disrupt spike protein binding to the GRP78, and thereby preventing viral entry to the host cell. A subset of these compounds have previously been shown to have some activity against SARS-CoV-2. The identified hits are starting points for the further development of novel SARS-CoV-2 therapeutics, potentially serving as proof-of-concept for GRP78 as a potential drug target for other viruses.

Mixed Reality Enhanced Otolaryngology Case-Based Learning: A Randomized Educational Study.

INTRODUCTION: The COVID-19 pandemic has caused unprecedented disruptions to medical education. Education in medical specialties, such as otolaryngology faces multiple challenges, including reduced bedside and "hands-on" training opportunities at all levels. Educators are turning to technological advancements to deliver effective remote medical education. This study investigated the value of enhancing traditional remote case-based teaching with the HoloLens2™. METHODS: We present a randomized educational design study. All educational content, media, and learning outcomes were identical. Primary outcome measures included student performance as measured with pre- and post-intervention quizzes and student engagement as measured by a tally-mark system. Secondary outcome measures, collected using feedback questionnaires, included perceived enjoyment, engagement, and opinions regarding the educational role of this technology. RESULTS: The undergraduate medical students were randomized to either conventional or HoloLens2™ enhanced remote case-based teaching (n = 56). HoloLens2™ enhanced teaching improved student performance by an average of 3 marks of 15% (p < 0.001). It was engaging and encouraged questions 4-fold per session (p < 0.05) when compared to conventional remote case-based teaching. There was no significant difference in overall objective measurements of engagement. Students taught using HoloLens2™ agreed that the teaching was enjoyable, effective in concept demonstration, and encouraged engagement. CONCLUSIONS: Remote teaching has allowed for the continuation of medical education in uncertain times. Beyond COVID-19, we predict that there will be a paradigm shift toward remote learning as new technological advancements emerges. These novel technologies may prove invaluable in the future potentially enabling education to be delivered between different hospitals, universities, and even overseas. LEVEL OF EVIDENCE: NA Laryngoscope, 2022.

Coronavirus disease 2019 (COVID-19) vaccination rates and staffing shortages among healthcare personnel in nursing homes before, during, and after implementation of mandates for COVID-19 vaccination among 15 US jurisdictions, National Healthcare Safety Network, June 2021-January 2022.

OBJECTIVE: To examine temporal changes in coverage with a complete primary series of coronavirus disease 2019 (COVID-19) vaccination and staffing shortages among healthcare personnel (HCP) working in nursing homes in the United States before, during, and after the implementation of jurisdiction-based COVID-19 vaccination mandates for HCP. SAMPLE AND SETTING: HCP in nursing homes from 15 US jurisdictions. DESIGN: We analyzed weekly COVID-19 vaccination data reported to the Centers for Disease Control and Prevention's National Healthcare Safety Network from June 7, 2021, through January 2, 2022. We assessed 3 periods (preintervention, intervention, and postintervention) based on the announcement of vaccination mandates for HCP in 15 jurisdictions. We used interrupted time-series models to estimate the weekly percentage change in vaccination with complete primary series and the odds of reporting a staffing shortage for each period. RESULTS: Complete primary series vaccination among HCP increased from 66.7% at baseline to 94.3% at the end of the study period and increased at the fastest rate during the intervention period for 12 of 15 jurisdictions. The odds of reporting a staffing shortage were lowest after the intervention. CONCLUSIONS: These findings demonstrate that COVID-19 vaccination mandates may be an effective strategy for improving HCP vaccination coverage in nursing homes without exacerbating staffing shortages. These data suggest that mandates can be considered to improve COVID-19 coverage among HCP in nursing homes to protect both HCP and vulnerable nursing home residents.

Overcoming your inner goblin.

A rise in antisocial behaviour indicates covid-19 lockdowns disrupted our cultural evolution, says Jonathan R. Goodman.

Longitudinal analyses using 18F-Fluorodeoxyglucose positron emission tomography with computed tomography as a measure of COVID-19 severity in the aged, young, and humanized ACE2 SARS-CoV-2 hamster models.

This study compared disease progression of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in three different models of golden hamsters: aged (≈60 weeks old) wild-type (WT), young (6 weeks old) WT, and adult (14-22 weeks old) hamsters expressing the human-angiotensin-converting enzyme 2 (hACE2) receptor. After intranasal (IN) exposure to the SARS-CoV-2 Washington isolate (WA01/2020), 2-deoxy-2-[fluorine-18]fluoro-D-glucose positron emission tomography with computed tomography (18F-FDG PET/CT) was used to monitor disease progression in near real time and animals were euthanized at pre-determined time points to directly compare imaging findings with other disease parameters associated with coronavirus disease 2019 (COVID-19). Consistent with histopathology, 18F-FDG-PET/CT demonstrated that aged WT hamsters exposed to 105 plaque forming units (PFU) developed more severe and protracted pneumonia than young WT hamsters exposed to the same (or lower) dose or hACE2 hamsters exposed to a uniformly lethal dose of virus. Specifically, aged WT hamsters presented with a severe interstitial pneumonia through 8 d post-exposure (PE), while pulmonary regeneration was observed in young WT hamsters at that time. hACE2 hamsters exposed to 100 or 10 PFU virus presented with a minimal to mild hemorrhagic pneumonia but succumbed to SARS-CoV-2-related meningoencephalitis by 6 d PE, suggesting that this model might allow assessment of SARS-CoV-2 infection on the central nervous system (CNS). Our group is the first to use (18F-FDG) PET/CT to differentiate respiratory disease severity ranging from mild to severe in three COVID-19 hamster models. The non-invasive, serial measure of disease progression provided by PET/CT makes it a valuable tool for animal model characterization.

Telecytology Makes Significant Contribution in ROSE with Great Accuracy - Experience During the COVID-19 Pandemic at Stony Brook University Hospital

Introduction: Telecytology (TC) has been used in rapid onsite evaluation (ROSE) of touch preparations (TPs) from core biopsies and smears from fine-needle aspiration (FNA) procedures. Although TC was established at our institution in 2010, utilization has fluctuated. The COVID-19 pandemic highlighted the value of TC for maintaining high-quality patient care with the advantages of minimizing contact with hospital personnel and patients, conserving personal protective equipment (PPE), and saving cytopathologists' time. However, the accuracy of TC compared to on site evaluation by cytopathologists has been a concern. This study aimed to address this question. Material(s) and Method(s): 697 ROSEs were identified from our quality assurance (QA) data base in 2021 (Q2-Q4) including 1) TC;2) onsite cytopathologist (OC);and 3) onsite cytotechnologistonly (OCT). Discrepancy rates between ROSE and final diagnoses were compared between TC and OC groups. A student T-test was performed to determine the statistical significance of the discrepancy rate between TC and OC. Result(s): Results are summarized in Table 1. On average, there were 26% FNA and 74% Cores by TP. The difference in discrepancy rates between TC and OC during the 3 quarters in 2021 is not statistically significant (p=0.5012). The type of discrepancy for TC was all minor while 17% major and 83% minor for OC. Conclusion(s): The value of TC for ROSE was highlighted during the pandemic, allowing cytopathologists to participate in ROSE while minimizing interpersonal contact at procedures, conserving PPE, and saving cytopathologists' time. TC provides as high quality as OC for ROSE service with statistically insignificant minor discrepancies with the final diagnosis. Although pandemic-related restrictions are easing, we anticipate that TC will continue to play a major role in ROSE.

A 3-year analysis of the impact of COVID-19 pandemic on NSTEMI incidence, clinical characteristics, management, and outcomes.

OBJECTIVE: The COVID-19 pandemic has been associated with decreased incidence of acute coronary syndrome with worsened outcomes. Few studies have addressed the effects beyond the initial phases of the pandemic. This study elucidated the incidence, clinical characteristics, management, and outcomes of NSTEMI at a tertiary referral center from sample time periods of 2019-2022. METHODS: This study included consecutive NSTEMI patients from March 14-May 9, 2019-2022. Variables included baseline characteristics, clinical features on arrival, management strategy, time parameters, and adverse outcomes. The primary outcome was defined as death, heart failure requiring diuretics, and/or sustained ventricular arrhythmia. RESULTS: This study comprised 250 patients of whom 181 who were admitted during the COVID-19 outbreak. Baseline characteristics were similar among groups. There was a reduction in door-to-angiography time from 29 h in 2019 to 19 h in 2020 [p = 0.01] and 20 h in 2021 [p = 0.02]. PCI intervention increased from 31.8% in 2019% to 50.0% in 2020 [p = 0.05] and 54.7% in 2021 [p < 0.01]. Median length-of-stay (LOS) was reduced from 3 days in 2019 to 2 days in 2020 [p = 0.03]. There was no significant change in outcomes in COVID-19 cohorts compared to control year. CONCLUSIONS: NSTEMI patients during the first 2 years of the COVID-19 pandemic were associated with reduced door-to-angiography times and increased percutaneous coronary intervention (PCI), and patients in year one were associated with reduced LOS. This study suggests that NSTEMI may be managed more efficiently thus reducing hospital bed utilization and potential costs.

SARS-CoV-2 Main Protease Targets Host Selenoproteins and Glutathione Biosynthesis for Knockdown via Proteolysis, Potentially Disrupting the Thioredoxin and Glutaredoxin Redox Cycles.

Associations between dietary selenium status and the clinical outcome of many viral infections, including SARS-CoV-2, are well established. Multiple independent studies have documented a significant inverse correlation between selenium status and the incidence and mortality of COVID-19. At the molecular level, SARS-CoV-2 infection has been shown to decrease the expression of certain selenoproteins, both in vitro and in COVID-19 patients. Using computational methods, our group previously identified a set of six host proteins that contain potential SARS-CoV-2 main protease (Mpro) cleavage sites. Here we show experimentally that Mpro can cleave four of the six predicted target sites, including those from three selenoproteins: thioredoxin reductase 1 (TXNRD1), selenoprotein F, and selenoprotein P, as well as the rate-limiting enzyme in glutathione synthesis, glutamate-cysteine ligase catalytic subunit (GCLC). Cleavage was assessed by incubating recombinant SARS-CoV-2 Mpro with synthetic peptides spanning the proposed cleavage sites, and analyzing the products via UPLC-MS. Furthermore, upon incubation of a recombinant Sec498Ser mutant of the full TXNRD1 protein with SARS-CoV-2 Mpro, the predicted cleavage was observed, destroying the TXNRD1 C-terminal redox center. Mechanistically, proteolytic knockdown of both TXNRD1 and GCLC is consistent with a viral strategy to inhibit DNA synthesis, conserving the pool of ribonucleotides for increased virion production. Viral infectivity could also be enhanced by GCLC knockdown, given the ability of glutathione to disrupt the structure of the viral spike protein via disulfide bond reduction. These findings shed new light on the importance of dietary factors like selenium and glutathione in COVID-19 prevention and treatment.

Factors associated with enrolment into a national COVID-19 pulse oximetry remote monitoring programme in England: a retrospective observational study.

BACKGROUND: Hypoxaemia is an important predictor of severity in individuals with COVID-19 and can present without symptoms. The COVID Oximetry @home (CO@h) programme was implemented across England in November, 2020, providing pulse oximeters to higher-risk people with COVID-19 to enable early detection of deterioration and the need for escalation of care. We aimed to describe the clinical and demographic characteristics of individuals enrolled onto the programme and to assess whether there were any inequalities in enrolment. METHODS: This retrospective observational study was based on data from a cohort of people resident in England recorded as having a positive COVID-19 test between Oct 1, 2020, and May 3, 2021. The proportion of participants enrolled onto the CO@h programmes in the 7 days before and 28 days after a positive COVID-19 test was calculated for each clinical commissioning group (CCG) in England. Two-level hierarchical multivariable logistic regression with random intercepts for each CCG was run to identify factors predictive of being enrolled onto the CO@h programme. FINDINGS: CO@h programme sites were reported by NHS England as becoming operational between Nov 21 and Dec 31, 2020. 1 227 405 people resident in 72 CCGs had a positive COVID-19 test between the date of programme implementation and May 3, 2021, of whom 19 932 (1·6%) were enrolled onto the CO@h programme. Of those enrolled, 14 441 (72·5%) were aged 50 years or older or were identified as clinically extremely vulnerable (ie, having a high-risk medical condition). Higher odds of enrolment onto the CO@h programme were found in older individuals (adjusted odds ratio 2·21 [95% CI 2·19-2·23], p<0·001, for those aged 50-64 years; 3·48 [3·33-3·63], p<0·001, for those aged 65-79 years; and 2·50 [2·34-2·68], p<0·001, for those aged ≥80 years), in individuals of non-White ethnicity (1·35 [1·28-1·43], p<0·001, for Asian individuals; 1·13 [1·04-1·22], p=0·005, for Black individuals; and 1·17 [1·03-1·32], p=0·015, for those of mixed ethnicity), in those who were overweight (1·31 [1·26-1·37], p<0·001) or obese (1·69 [1·63-1·77], p<0·001), or in those identified as clinically extremely vulnerable (1·58 [1·51-1·65], p<0·001), and lower odds were reported in those from the least socioeconomically deprived areas compared with those from the most socioeconomically deprived areas (0·75 [0·69-0·81]; p<0·001). INTERPRETATION: Nationally, uptake of the CO@h programme was low, with clinical judgment used to determine eligibility. Preferential enrolment onto the pulse oximetry monitoring programme was observed in people known to be at the highest risk of developing severe COVID-19. FUNDING: NHS England, National Institute for Health Research, and The Wellcome Trust.

Efficacy, Safety, and Molecular Response Predictors of Oral Ixazomib and Short-Course Rituximab in Untreated iNHL.

Indolent B-cell non-Hodgkin lymphoma (iNHL) patients generally require treatment but experience normal survival, emphasizing the need for simpler, safer therapies. Proteasome inhibitors target aberrant signaling pathways within iNHL and have manageable toxicities. We evaluated the oral proteasome inhibitor ixazomib as initial monotherapy, and combined with rituximab, for first-line treatment of iNHL. Treatment-naïve iNHL patients needing therapy received oral ixazomib 4 mg weekly until progressive disease or unacceptable adverse events. A 4-week course of rituximab was added during month 7. The primary endpoint was overall response rate (ORR) during the ixazomib monotherapy window. Correlates included gene expression profiling and response to SARS-CoV-2 vaccination. Thirty-three patients with follicular lymphoma (FL) (n=20), marginal zone lymphoma (n=7), and other iNHL were treated with median follow-up of 30.3 months. During the 6-month ixazomib window the ORR was 24%, including 35% in FL. Best ORR over the entire study period was 52% overall and 65% in FL; CR was achieved in 33% and 45%, respectively. The median duration of response was 25.8 months (range, 0 - 49.7), and the 24-month progression-free and overall survival were 51% (95% CI 32-67%) and 91% (95% CI 74-97%). Ixazomib was well-tolerated. Baseline downregulation of proteasome genes PSMB9 (P = 0.03) and PSMB8 (P = 0.007) were associated with response. All evaluated patients generated anti-S antibodies to SARS-CoV-2 vaccination, median 254.9 BAU/mL. Ixazomib demonstrated efficacy alone and with short course rituximab in untreated iNHL while exhibiting favorable toxicity, convenience, and retention of B-cell immune response. This trial is registered at www.clinicaltrials.gov as NCT02339922.

Empagliflozin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial (preprint)

Background: Empagliflozin has been proposed as a treatment for COVID-19 on the basis of its anti-inflammatory, metabolic and haemodynamic effects. Methods: In this randomised, controlled, open-label trial, several possible treatments are compared with usual care in patients hospitalised with COVID-19. Eligible and consenting adults were randomly allocated in a 1:1 ratio to either usual standard of care alone or usual standard of care plus empagliflozin 10mg once daily for 28 days or until discharge using web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was 28-day mortality. On 3 March the independent data monitoring committee recommended that the investigators review the data and recruitment was consequently stopped on 7 March. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). Findings: Between 8 July 2021 and 6 March 2023, 4271 patients were randomly allocated to receive either empagliflozin (2113 patients) or usual care alone (2158 patients). Overall, 289 (14%) patients allocated to empagliflozin and 307 (14%) patients allocated to usual care died within 28 days (rate ratio 0.96; 95% confidence interval [CI] 0.82-1.13; p=0.64). There was no evidence of significant differences in duration of hospitalisation (median 8 days vs. 8 days) or the proportion of patients discharged from hospital alive within 28 days (79% vs. 78%; rate ratio 1.03; 95% CI 0.96-1.10; p=0.44). Among those not on invasive mechanical ventilation at baseline, there was no evidence of a significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (16% vs. 17%; risk ratio 0.95; 95% CI 0.84-1.08; p=0.44). Interpretation: In adults hospitalised with COVID-19, empagliflozin was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death.

The importance of collaboration between medical and exercise professionals in addressing patient physical inactivity.

Physical activity has declined further during the coronavirus disease 2019 (COVID-19) pandemic. Physicians are at the front lines of proactively educating and promoting physical activity to patients; however, physicians do not feel confident and face numerous barriers in prescribing exercise to patients. Exercise referral schemes, comprising collaborations with qualified exercise professionals, represent a fruitful option for supporting physicians hoping to promote physical activity to more patients. Herein, we provide practical suggestions for establishing and creating a successful referral scheme. Ultimately, exercise referral schemes offer an alternative to help physician burnout and mitigate patient physical inactivity during and beyond the COVID-19 pandemic.

Editor's Choice - Outcomes of Surgery for Patients with Peripheral Arterial Disease During the COVID-19 Pandemic in the United Kingdom: A Population Based Study.

OBJECTIVE: There is limited information on changes in the patterns of care and outcomes for patients who had vascular procedures after the first wave of the COVID-19 pandemic. The aim of this population based study was to examine the patterns of care and outcomes for vascular lower limb procedures in the UK during the COVID-19 pandemic. METHODS: Lower limb revascularisations and major amputations performed from January 2019 to April 2021 in the UK and entered in the National Vascular Registry were included in the study. The primary outcome was in hospital post-operative death and secondary outcomes were complications and re-interventions. The study was divided into Pre-pandemic (1 January 2019 - 29 February 2020), Wave 1 (1 March - 30 June 2020), Respite (1 July - 31 October 2020), Wave 2/3 (1 November 2020 - 30 April 2021). RESULTS: The study included 36 938 procedures (7 245 major amputations, 16 712 endovascular, 12 981 open revascularisations), with 15 501 procedures after March 2020, a 27.7% reduction compared with pre-pandemic. The proportion of open surgical procedures performed under general anaesthetic was lower in Wave 1 and after compared with pre-pandemic (76.7% vs. 81.9%, p < .001). Only 4.6% of patients in the cohort had SARS-CoV-2 infection (n = 708), but their in hospital post-operative mortality rate was 25.0% (n = 177), six times higher than patients without SARS-CoV-2 (adjusted odds ratio 5.88; 95% CI 4.80 - 7.21, p < .001). The in hospital mortality rate was higher during the pandemic than pre-pandemic after elective open and endovascular revascularisation (respectively 1.6% vs. 1.1%, p = .033, and 0.9% vs. 0.5%, p = .005) and after major amputations (10.4% during Wave 2/3 vs. 7.7% pre-pandemic, p = .022). CONCLUSION: There was excess post-operative mortality rate for patients undergoing lower limb vascular procedures during the pandemic, which was associated with SARS-CoV-2 infections. Further research should be conducted on long term outcomes of patients operated on during the COVID-19 pandemic period.

COVID-19 risk, attitudes and behaviour study (CRAB study): A knowledge, attitudes, and practise qualitative study of COVID-19 in the Royal Navy.

Introduction: Outbreaks of SARS-CoV-2 onboard maritime platforms spread rapidly and have high attack rates. The aim of the COVID-19 Risk, Attitudes and Behaviour (CRAB) study was to investigate the knowledge, attitudes, and practises in the Royal Navy in relation to COVID-19 prevention. Methods: The CRAB study was a cross-sectional survey, using a census sampling method, conducted in May and June 2021. An online questionnaire was distributed to all serving Royal Navy regular personnel using either the MyNavy application or via a QR code through email for a continuous 14 day period. The questionnaire was based on an existing validated questionnaire used for avian influenza epidemics. Questions investigated individual perceptions of COVID-19 seriousness, compliance with prevention methods, explored vaccination intention and vaccine hesitancy (unvaccinated individuals who declined or were unsure about receiving a COVID-19 vaccine). The chi-squared test of best fit was used to compare the demographic responses against the whole organisation, with p-value < 0.05 deemed significant. Odds ratios were used to investigate associations between demographic groups and responses to questions, with an odds ratio crossing 1.0 deemed non-significant. Results: The response rate was 6% (2,080/33,200), with 315 responses collated in the pilot phase and 1,765 in the main study phase. Male participants were less likely to rate COVID-19 as serious (OR 0.34; 95% CI: 0.23-0.49). BAME ethnicity (OR 2.41; 95% CI: 1.12-5.17) rated it as more serious. At the time of the study 62% of respondents had received one dose of a COVID-19 vaccine. In the 797 unvaccinated personnel, vaccine hesitancy accounted for 24.2% (193/797), of whom 136 were white males. Those who had a higher COVID-19 serious rating, the most significant factor for non-adherence to COVID-19 prevention measures in both vaccinated (OR 1.61 [95%CI: 1.20-2.17]) and vaccine-hesitant (OR 3.24 [95%CI: 1.63-6.41]) individuals was colleagues' non-adherence. The most trusted source of information on vaccines was provided by the Defence Medical Services (77.2% [1,606/2,080]). Conclusion: This study has identified reasons for COVID-19 protective measure adherence, sources of information trusted by respondents and vaccine hesitancy, in the Royal Navy. The questionnaire can be used to investigate attitudes and behaviours in future emerging infectious diseases.

COVID-19 risk, attitudes and behaviour study (CRAB study): A knowledge, attitudes, and practise qualitative study of COVID-19 in the Royal Navy

Introduction Outbreaks of SARS-CoV-2 onboard maritime platforms spread rapidly and have high attack rates. The aim of the COVID-19 Risk, Attitudes and Behaviour (CRAB) study was to investigate the knowledge, attitudes, and practises in the Royal Navy in relation to COVID-19 prevention. Methods The CRAB study was a cross-sectional survey, using a census sampling method, conducted in May and June 2021. An online questionnaire was distributed to all serving Royal Navy regular personnel using either the MyNavy application or via a QR code through email for a continuous 14 day period. The questionnaire was based on an existing validated questionnaire used for avian influenza epidemics. Questions investigated individual perceptions of COVID-19 seriousness, compliance with prevention methods, explored vaccination intention and vaccine hesitancy (unvaccinated individuals who declined or were unsure about receiving a COVID-19 vaccine). The chi-squared test of best fit was used to compare the demographic responses against the whole organisation, with p-value < 0.05 deemed significant. Odds ratios were used to investigate associations between demographic groups and responses to questions, with an odds ratio crossing 1.0 deemed non-significant. Results The response rate was 6% (2,080/33,200), with 315 responses collated in the pilot phase and 1,765 in the main study phase. Male participants were less likely to rate COVID-19 as serious (OR 0.34;95% CI: 0.23–0.49). BAME ethnicity (OR 2.41;95% CI: 1.12–5.17) rated it as more serious. At the time of the study 62% of respondents had received one dose of a COVID-19 vaccine. In the 797 unvaccinated personnel, vaccine hesitancy accounted for 24.2% (193/797), of whom 136 were white males. Those who had a higher COVID-19 serious rating, the most significant factor for non-adherence to COVID-19 prevention measures in both vaccinated (OR 1.61 [95%CI: 1.20–2.17]) and vaccine-hesitant (OR 3.24 [95%CI: 1.63–6.41]) individuals was colleagues' non-adherence. The most trusted source of information on vaccines was provided by the Defence Medical Services (77.2% [1,606/2,080]). Conclusion This study has identified reasons for COVID-19 protective measure adherence, sources of information trusted by respondents and vaccine hesitancy, in the Royal Navy. The questionnaire can be used to investigate attitudes and behaviours in future emerging infectious diseases.

Laboratory-Confirmed COVID-19 Case Incidence Rates Among Residents in Nursing Homes by Up-to-Date Vaccination Status - United States, October 10, 2022-January 8, 2023.

Nursing home residents have been disproportionately affected by COVID-19; older age, comorbidities, and the congregate nature of nursing homes place residents at higher risk for infection and severe COVID-19-associated outcomes, including death (1). Studies have demonstrated that receipt of a primary COVID-19 mRNA vaccination series (2) and monovalent booster doses (3) is effective in reducing COVID-19-related morbidity and mortality in this population. Public health recommendations for staying up to date with COVID-19 vaccination have been revised throughout the pandemic response, most recently to include an updated (bivalent) booster dose, which protects against both the ancestral strain of SARS-CoV-2 and recent Omicron variants BA.4 and BA.5 (4). However, data on the effectiveness of staying up to date, including with bivalent booster doses, are lacking among nursing home residents. CDC's National Healthcare Safety Network (NHSN) analyzed surveillance data to examine weekly incidence rates of COVID-19 among nursing home residents by up-to-date vaccination status (receipt of a bivalent booster dose or completion of a primary series or receipt of a monovalent booster dose within the previous 2 months [i.e., not yet eligible to receive a bivalent booster dose]).* Up-to-date vaccination status among nursing home residents remained low throughout the study period, increasing to 48.9% by the week ending January 8, 2023. During October 10, 2022-January 8, 2023, the COVID-19 weekly incidence rates (new cases per 1,000 nursing home residents) among residents who were not up to date with COVID-19 vaccination were consistently higher than those among residents who were up to date. Moreover, the weekly incidence rate ratios (IRRs) indicated that residents who were not up to date with COVID-19 vaccines had a higher risk for acquiring SARS-CoV-2 than their up-to-date counterparts (IRR range = 1.3-1.5). It is critical that nursing home residents stay up to date with COVID-19 vaccines and receive a bivalent booster dose to maximize protection against COVID-19.

Hospital-onset bacteremia and fungemia: An evaluation of predictors and feasibility of benchmarking comparing two risk-adjusted models among 267 hospitals.

OBJECTIVES: To evaluate the prevalence of hospital-onset bacteremia and fungemia (HOB), identify hospital-level predictors, and to evaluate the feasibility of an HOB metric. METHODS: We analyzed 9,202,650 admissions from 267 hospitals during 2015-2020. An HOB event was defined as the first positive blood-culture pathogen on day 3 of admission or later. We used the generalized linear model method via negative binomial regression to identify variables and risk markers for HOB. Standardized infection ratios (SIRs) were calculated based on 2 risk-adjusted models: a simple model using descriptive variables and a complex model using descriptive variables plus additional measures of blood-culture testing practices. Performance of each model was compared against the unadjusted rate of HOB. RESULTS: Overall median rate of HOB per 100 admissions was 0.124 (interquartile range, 0.00-0.22). Facility-level predictors included bed size, sex, ICU admissions, community-onset (CO) blood culture testing intensity, and hospital-onset (HO) testing intensity, and prevalence (all P < .001). In the complex model, CO bacteremia prevalence, HO testing intensity, and HO testing prevalence were the predictors most associated with HOB. The complex model demonstrated better model performance; 55% of hospitals that ranked in the highest quartile based on their raw rate shifted to a lower quartile when the SIR from the complex model was applied. CONCLUSIONS: Hospital descriptors, aggregate patient characteristics, community bacteremia and/or fungemia burden, and clinical blood-culture testing practices influence rates of HOB. Benchmarking an HOB metric is feasible and should endeavor to include both facility and clinical variables.

Impact of coronavirus disease 2019 on pediatric intestinal intussusception in the United States.

BACKGROUND: Masking and social distancing to mitigate the spread of the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) virus curbed the spread of other viruses. Given a potential link between viral illnesses and ileocolic intussusception, the purpose of this study is to characterize trends in incidence, diagnosis and management of pediatric intussusception in the United States in the context of the coronavirus disease 2019 (COVID-19) pandemic. MATERIALS AND METHODS: This cross-sectional retrospective study used the Pediatric Hospital Information System and included children (ages 0-17 years) with a primary diagnosis of intussusception (ICD-10 [International Classification of Diseases, Tenth Revision]: K56.1) from January 2018 to December 2021. Descriptive statistics and chi-square analyses were used to characterize and compare proportions pre-COVID (2018 and 2019) to 2020 and 2021. RESULTS: Eight thousand one hundred forty-three encounters met inclusion criteria. Intussusception diagnoses declined in 2020 (n = 1,480) compared to 2019 (n = 2,321) and 2018 (n = 2,171) but returned to pre-COVID levels in 2021 (n = 2,171). Patient age was similar across years (mean age in years: 2018: 2.3; 2019: 2.1; 2020: 2.3; 2021: 2.3). There was no significant change in the proportion of patients who underwent imaging in 2020 (96% [1,415/1,480]) compared to the other years in the study (2018: 96% [2,093/2,171], P = 0.21; 2019: 97% [2,253/2,321], P = 0.80; 2021: 96% [1,415/1,480], P = 0.85). There was a statistically significant but minimal increase in the proportion of cases treated with surgery in 2020 compared to 2019 (2020: 17.8% vs. 2019: 15%, P = 0.02); however, this was not replicated in the pairwise comparison of 2020 to 2018 (2020: 17.8% vs. 2018: 16.4%, P = 0.23). There was a statistically significant increase in the proportion of cases treated with surgery in 2020 compared to 2021 (2020: 17.8% vs. 2021: 14%, P = 0.001). CONCLUSION: Pediatric intussusception diagnoses decreased at a national level in 2020 compared to previous years, with a rebound increase in 2021. This may reflect a secondary benefit of public health interventions imposed to curb the spread of COVID-19.

Molecular basis for antiviral activity of two pediatric neutralizing antibodies targeting SARS-CoV-2 Spike RBD.

Neutralizing antibodies (NAbs) hold great promise for clinical interventions against SARS-CoV-2 variants of concern (VOCs). Understanding NAb epitope-dependent antiviral mechanisms is crucial for developing vaccines and therapeutics against VOCs. Here we characterized two potent NAbs, EH3 and EH8, isolated from an unvaccinated pediatric patient with exceptional plasma neutralization activity. EH3 and EH8 cross-neutralize the early VOCs and mediate strong Fc-dependent effector activity in vitro. Structural analyses of EH3 and EH8 in complex with the receptor-binding domain (RBD) revealed the molecular determinants of the epitope-driven protection and VOC evasion. While EH3 represents the prevalent IGHV3-53 NAb whose epitope substantially overlaps with the ACE2 binding site, EH8 recognizes a narrow epitope exposed in both RBD-up and RBD-down conformations. When tested in vivo, a single-dose prophylactic administration of EH3 fully protected stringent K18-hACE2 mice from lethal challenge with Delta VOC. Our study demonstrates that protective NAbs responses converge in pediatric and adult SARS-CoV-2 patients.