A repeated cross-sectional study of nurses immediately before and during the COVID-19 pandemic: Implications for action.

BACKGROUND: The shortage of nursing care in US hospitals has become a national concern. PURPOSE: The purpose of this manuscript was to determine whether hospital nursing care shortages are primarily due to the pandemic and thus likely to subside or due to hospital nurse understaffing and poor working conditions that predated it. METHODS: This study used a repeated cross-sectional design before and during the pandemic of 151,335 registered nurses in New York and Illinois, and a subset of 40,674 staff nurses employed in 357 hospitals. FINDINGS: No evidence was found that large numbers of nurses left health care or hospital practice in the first 18 months of the pandemic. Nurses working in hospitals with better nurse staffing and more favorable work environments prior to the pandemic reported significantly better outcomes during the pandemic. DISCUSSION: Policies that prevent chronic hospital nurse understaffing have the greatest potential to stabilize the hospital nurse workforce at levels supporting good care and clinician wellbeing.

SARS-CoV-2 Infection of Young Infants during the Omicron Wave: A Case Series

We describe the clinical course of 4 infants infected with severe acute respiratory syndrome coronavirus 2. All were admitted to our tertiary care neonatal intensive care unit during the Omicron variant wave in our region. All 4 infants, who were less than 3 months of age, including three born prematurely, presented with critical illness. However, their clinical presentation varied considerably. Of them, two infants presented with apnea, one with respiratory distress, and one with gastrointestinal manifestation. Our experience with these four infants provides evidence for a severe form of disease and varied clinical presentation in neonates and young infants speculated to be infected with Omicron variant.

Workplace Violence and the Mental Health of Public Health Workers During COVID-19.

INTRODUCTION: During the COVID-19 pandemic, public health workers were at an increased risk for violence and harassment due to their public health work and experienced adverse mental health conditions. This article quantifies the prevalence of job-related threats, harassment, and discrimination against public health workers and measures the association of these incidents with mental health symptoms during the COVID-19 pandemic. METHODS: A nonprobability convenience sample of state, local, and tribal public health workers completed a self-administered, online survey in April 2021. The survey link was emailed to members of national public health associations and included questions on workplace violence, demographics, workplace factors, and mental health symptoms. Mental health symptoms were measured using standardized, validated tools to assess depression, anxiety, post-traumatic stress disorder, and suicidal ideation. Multivariable Poisson models calculated adjusted prevalence ratios of mental health symptoms, with workplace violence as the primary risk factor. Analyses were conducted in 2021-2022. RESULTS: Experiencing any type or combination of workplace violence was significantly associated with an increased likelihood of reporting depression symptoms (prevalence ratio=1.21, 95% CI=1.15, 1.27), anxiety (prevalence ratio=1.21, 95% CI=1.15, 1.27), post-traumatic stress disorder (prevalence ratio=1.31, 95% CI=1.25, 1.37), and suicidal ideation (prevalence ratio=1.26, 95% CI=1.14, 1.38), after adjusting for confounders. A dose‒response relationship was found between the number of workplace violence events experienced by a public health worker and the likelihood of reporting mental health symptoms. CONCLUSIONS: Violence targeted at the public health workforce is detrimental to workers and their communities. Ongoing training, workplace support, and increased communication after a workplace violence incident may be helpful. Efforts to strengthen public health capacities and support the public health workforce are also needed.

SARS-CoV-2 down-regulates ACE2 through lysosomal degradation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes its Spike (S) glycoprotein to bind to the angiotensin-converting enzyme 2 (ACE2) receptor for cellular entry. ACE2 is a critical negative regulator of the renin-angiotensin system and plays a protective role in preventing tissue injury. Expression of ACE2 has been shown to decrease upon infection by SARS-CoV. However, whether SARS-CoV-2 down-regulates ACE2 and the underlying mechanism and biological impact of this down-regulation have not been well defined. Here we show that the SARS-CoV-2 infection down-regulates ACE2 in vivo in an animal model, and in cultured cells in vitro, by inducing clathrin- and AP2-dependent endocytosis, leading to its degradation in the lysosome. SARS-CoV-2 S-treated cells and ACE2 knockdown cells exhibit similar alterations in downstream gene expression, with a pattern indicative of activated cytokine signaling that is associated with respiratory distress and inflammatory diseases often observed in COVID-19 patients. Finally, we have identified a soluble ACE2 fragment with a stronger binding to SARS-CoV-2 S that can efficiently block ACE2 down-regulation and viral infection. Thus, our study suggests that ACE2 down-regulation represents an important mechanism underlying SARS-CoV-2-associated pathology, and blocking this process could be a promising therapeutic strategy.

SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF-ß signaling.

Severe COVID-19 is associated with epithelial and endothelial barrier dysfunction within the lung as well as in distal organs. While it is appreciated that an exaggerated inflammatory response is associated with barrier dysfunction, the triggers of vascular leak are unclear. Here, we report that cell-intrinsic interactions between the Spike (S) glycoprotein of SARS-CoV-2 and epithelial/endothelial cells are sufficient to induce barrier dysfunction in vitro and vascular leak in vivo, independently of viral replication and the ACE2 receptor. We identify an S-triggered transcriptional response associated with extracellular matrix reorganization and TGF-ß signaling. Using genetic knockouts and specific inhibitors, we demonstrate that glycosaminoglycans, integrins, and the TGF-ß signaling axis are required for S-mediated barrier dysfunction. Notably, we show that SARS-CoV-2 infection caused leak in vivo, which was reduced by inhibiting integrins. Our findings offer mechanistic insight into SARS-CoV-2-triggered vascular leak, providing a starting point for development of therapies targeting COVID-19.

Effect of Wearing a Face Mask on Hand-to-Face Contact by Children in a Simulated School Environment: The Back-to-School COVID-19 Simulation Randomized Clinical Trial.

Importance: Wearing a face mask in school can reduce SARS-CoV-2 transmission but it may also lead to increased hand-to-face contact, which in turn could increase infection risk through self-inoculation. Objective: To evaluate the effect of wearing a face mask on hand-to-face contact by children while at school. Design, Setting, and Participants: This prospective randomized clinical trial randomized students from junior kindergarten to grade 12 at 2 schools in Toronto, Ontario, Canada, during August 2020 in a 1:1 ratio to either a mask or control class during a 2-day school simulation. Classes were video recorded from 4 angles to accurately capture outcomes. Interventions: Participants in the mask arm were instructed to bring their own mask and wear it at all times. Students assigned to control classes were not required to mask at any time (grade 4 and lower) or in the classroom where physical distancing could be maintained (grade 5 and up). Main Outcomes and Measures: The primary outcome was the number of hand-to-face contacts per student per hour on day 2 of the simulation. Secondary outcomes included hand-to-mucosa contacts and hand-to-nonmucosa contacts. A mixed Poisson regression model was used to derive rate ratios (RRs), adjusted for age and sex with a random intercept for class with bootstrapped 95% CIs. Results: A total of 174 students underwent randomization and 171 students (mask group, 50.6% male; control group, 52.4% male) attended school on day 2. The rate of hand-to-face contacts did not differ significantly between the mask and the control groups (88.2 vs 88.7 events per student per hour; RR, 1.00; 95% CI, 0.78-1.28; P = >.99). When compared with the control group, the rate of hand-to-mucosa contacts was significantly lower in the mask group (RR, 0.12; 95% CI, 0.07-0.21), while the rate of hand-to-nonmucosa contacts was higher (RR, 1.40; 95% CI, 1.08-1.82). Conclusions and Relevance: In this clinical trial of simulated school attendance, hand-to-face contacts did not differ among students required to wear face masks vs students not required to wear face masks; however, hand-to-mucosa contracts were lower in the face mask group. This suggests that mask wearing is unlikely to increase infection risk through self-inoculation. Trial Registration: ClinicalTrials.gov Identifier: NCT04531254.

Charlson comorbidity index, neutrophil-to-lymphocyte ratio and undertreatment with renin-angiotensin-aldosterone system inhibitors predict in-hospital mortality of hospitalized COVID-19 patients during the omicron dominant period.

Purpose: To investigate the clinical predictors of in-hospital mortality in hospitalized patients with Coronavirus disease 2019 (COVID-19) infection during the Omicron period. Methods: All consecutive hospitalized laboratory-confirmed COVID-19 patients between January and May 2022 were retrospectively analyzed. All patients underwent accurate physical, laboratory, radiographic and echocardiographic examination. Primary endpoint was in-hospital mortality. Results: 74 consecutive COVID-19 patients (80.0 ± 12.6 yrs, 45.9% males) were included. Patients who died during hospitalization (27%) and those who were discharged alive (73%) were separately analyzed. Compared to patients discharged alive, those who died were significantly older, with higher comorbidity burden and greater prevalence of laboratory, radiographic and echographic signs of pulmonary and systemic congestion. Charlson comorbidity index (CCI) (OR 1.76, 95%CI 1.07-2.92), neutrophil-to-lymphocyte ratio (NLR) (OR 1.24, 95%CI 1.10-1.39) and absence of angiotensin-converting enzyme inhibitors (ACEI)/angiotensin II receptor blockers (ARBs) therapy (OR 0.01, 95%CI 0.00-0.22) independently predicted the primary endpoint. CCI ≥7 and NLR ≥9 were the best cut-off values for predicting mortality. The mortality risk for patients with CCI ≥7, NLR ≥9 and not in ACEI/ARBs therapy was high (86%); for patients with CCI <7, NLR ≥9, with (16.6%) or without (25%) ACEI/ARBs therapy was intermediate; for patients with CCI <7, NLR <9 and in ACEI/ARBs therapy was of 0%. Conclusions: High comorbidity burden, high levels of NLR and the undertreatment with ACEI/ARBs were the main prognostic indicators of in-hospital mortality. The risk stratification of COVID-19 patients at hospital admission would help the clinicians to take care of the high-risk patients and reduce the mortality.

Internet-Enabled Behaviors in Older Adults During the Pandemic: Patterns of Use, Psychosocial Impacts, and Plans for Continued Utilization

In response to social distancing measures during the COVID-19 pandemic, there was a need to increase the frequency of internet enabled behaviors (IEBs). To date, little is known about how the pandemic impacted IEBs in older adults, a population that has historically been linked to lower digital literacy and utilization. We administered an online survey between April and July 2021 to 298 adults who were over age 50 (mean age = 73 years;93.5% non-Hispanic white;94% smart phone owners;83.5% retired). Older adults self-reported IEBs for social, shopping, medical, and leisure activities during the pandemic, plans for continued use of these behaviors, and completed measures of psychosocial functioning. 66.8% of respondents reported an overall increase in IEBs during the pandemic, most notably for online meeting attendance. More frequent online meeting use was associated with less depression (r = -0.12, p = .04) and less loneliness (r = -0.14, p = .02). With regard to plans for continued use, 82.5% of the sample reported at least one IEB (M = 2.18, SD = 1.65) that they increased during the pandemic and planned to maintain over time (e.g., online shopping for household goods). Plans for continued use were more likely in participants who used IEBs more overall during the pandemic (r = 0.56, p < .001), and who frequently sought technical support on search engines (r = 0.22, p < .001), or online video sites (r = 0.16, p = .006). In summary, IEBs during the pandemic were associated with favorable psychosocial functioning and expectations for continued use in this sample of predominantly white older adults who had some baseline technological familiarity.

A workplace organisational intervention to improve hospital nurses' and physicians' mental health: study protocol for the Magnet4Europe wait list cluster randomised controlled trial.

INTRODUCTION: The increasing burden of mental distress reported by healthcare professionals is a matter of serious concern and there is a growing recognition of the role of the workplace in creating this problem. Magnet hospitals, a model shown to attract and retain staff in US research, creates positive work environments that aim to support the well-being of healthcare professionals. METHODS AND ANALYSIS: Magnet4Europe is a cluster randomised controlled trial, with wait list controls, designed to evaluate the effects of organisational redesign, based on the Magnet model, on nurses' and physicians' well-being in general acute care hospitals, using a multicomponent implementation strategy. The study will be conducted in more than 60 general acute care hospitals in Belgium, England, Germany, Ireland, Norway and Sweden. The primary outcome is burnout among nurses and physicians, assessed in longitudinal surveys of nurses and physicians at participating hospitals. Additional data will be collected from them on perceived work environments, patient safety and patient quality of care and will be triangulated with data from medical records, including case mix-adjusted in-hospital mortality. The process of implementation will be evaluated using qualitative data from focus group and key informant interviews. ETHICS AND DISSEMINATION: This study was approved by the Ethics Committee Research UZ/KU Leuven, Belgium; additionally, ethics approval is obtained in all other participating countries either through a central or decentral authority. Findings will be disseminated at conferences, through peer-reviewed manuscripts and via social media. TRIAL REGISTRATION NUMBER: ISRCTN10196901.

The Microalgal Diatoxanthin Inflects the Cytokine Storm in SARS-CoV-2 Stimulated ACE2 Overexpressing Lung Cells.

Contact between SARS-CoV-2 and human lung cells involves the viral spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptor on epithelial cells, the latter being strongly involved in the regulation of inflammation as well as blood pressure homeostasis. SARS-CoV-2 infection is characterized by a strong inflammatory response defined as a "cytokine storm". Among recent therapeutic approaches against SARS-CoV-2 targeting the dramatic inflammatory reaction, some natural products are promising. Diatoms are microalgae able to produce bioactive secondary metabolites, such as the xanthophyll diatoxanthin (Dt). The aim of this study is to demonstrate the anti-inflammatory effects of Dt on the A549-hACE2 lung cell line, exploring its interaction with the ACE2 receptor, as well as depicting its role in inhibiting a cytokine storm induced by the SARS-CoV-2 spike glycoprotein. Results showed that Dt enhanced the cell metabolism, e.g., the percent of metabolically active cells, as well as the ACE2 enzymatic activity. Moreover, Dt strongly affected the response of the SARS-CoV-2 spike glycoprotein-exposed A549-hACE2 cells in decreasing the interleukin-6 production and increasing the interleukin-10 release. Moreover, Dt upregulated genes encoding for the interferon pathway related to antiviral defense and enhanced proteins belonging to the innate immunity response. The potential interest of Dt as a new therapeutic agent in the treatment and/or prevention of the severe inflammatory syndrome related to SARS-CoV-2 infection is postulated.

Genome-wide bidirectional CRISPR screens identify mucins as host factors modulating SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a range of symptoms in infected individuals, from mild respiratory illness to acute respiratory distress syndrome. A systematic understanding of host factors influencing viral infection is critical to elucidate SARS-CoV-2-host interactions and the progression of Coronavirus disease 2019 (COVID-19). Here, we conducted genome-wide CRISPR knockout and activation screens in human lung epithelial cells with endogenous expression of the SARS-CoV-2 entry factors ACE2 and TMPRSS2. We uncovered proviral and antiviral factors across highly interconnected host pathways, including clathrin transport, inflammatory signaling, cell-cycle regulation, and transcriptional and epigenetic regulation. We further identified mucins, a family of high molecular weight glycoproteins, as a prominent viral restriction network that inhibits SARS-CoV-2 infection in vitro and in murine models. These mucins also inhibit infection of diverse respiratory viruses. This functional landscape of SARS-CoV-2 host factors provides a physiologically relevant starting point for new host-directed therapeutics and highlights airway mucins as a host defense mechanism.

Platelet proteome reveals features of cell death, antiviral response and viral replication in covid-19.

Coronavirus disease 2019 (COVID-19) has affected over 400 million people worldwide, leading to 6 million deaths. Among the complex symptomatology of COVID-19, hypercoagulation and thrombosis have been described to directly contribute to lethality, pointing out platelets as an important SARS-CoV-2 target. In this work, we explored the platelet proteome of COVID-19 patients through a label-free shotgun proteomics approach to identify platelet responses to infection, as well as validation experiments in a larger patient cohort. Exclusively detected proteins (EPs) and differentially expressed proteins (DEPs) were identified in the proteomic dataset and thus classified into biological processes to map pathways correlated with pathogenesis. Significant changes in the expression of proteins related to platelet activation, cell death, and antiviral response through interferon type-I were found in all patients. Since the outcome of COVID-19 varies highly among individuals, we also performed a cross-comparison of proteins found in survivors and nonsurvivors. Proteins belonging to the translation pathway were strongly highlighted in the nonsurvivor group. Moreover, the SARS-CoV-2 genome was fully sequenced in platelets from five patients, indicating viral internalization and preprocessing, with CD147 as a potential entry route. In summary, platelets play a significant role in COVID-19 pathogenesis via platelet activation, antiviral response, and disease severity.

Persistence of Transitional Cell State Without Senescence or Fibrosis During Alveolar Epithelial Regeneration in Human Acute Respiratory Distress Syndrome

RATIONALE: Acute respiratory distress syndrome (ARDS) results from injury to the alveolar epithelial cell (AEC) barrier leading to pulmonary edema;recovery requires epithelial regeneration. However, the specific defect resulting in ongoing barrier permeability in fatal early ARDS is unknown. In mouse models of ARDS, we found that AEC2s assume a transitional state characterized by transient cell cycle arrest during differentiation towards AEC1s. Transitional cells persist and are senescent in human idiopathic pulmonary fibrosis (IPF), leading some to speculate that persistence of transitional cells is pathognomonic of fibrosis in humans. We hypothesized that transitional cells also arise early in human ARDS and that incomplete AEC1 differentiation from the transitional state underlies barrier permeability and death from respiratory failure in early ARDS. We speculated that in contrast to IPF, transitional cells in early ARDS are in transient cell cycle arrest but not senescent and maintain capacity for an AEC1 fate. METHODS AND RESULTS: Lung tissue was obtained from patients who died within two weeks of hospitalization of ARDS due to COVID-19 or other etiologies, and from patients with IPF. Histology revealed diffuse alveolar damage without fibrosis in patients with ARDS. Immunostaining demonstrated AEC damage and abundant transitional cells in both ARDS and IPF. In ARDS, transitional cells existed in a monolayer on alveolar septa, filling gaps denuded of AEC1s and displaying spread morphologies without AEC1 marker expression, suggesting ongoing but incomplete differentiation. In fibrosis, transitional cells existed on a background of architectural distortion and fibrosis. Meta-analysis of single cell RNA sequencing (scRNAseq) datasets demonstrated that transitional cells were transcriptionally highly similar. However, the senescence marker p16 was expressed in transitional cells in human IPF but not in mouse models. Immunostaining confirmed that transitional cells in IPF but not human ARDS expressed p16. CONCLUSION: We conclude that transitional cells arise in early human ARDS without fibrosis. We propose that incomplete AEC1 differentiation from the transitional state is the specific defect in epithelial regeneration underlying barrier permeability and respiratory failure. We speculate that in early human ARDS, as in mouse models, transitional cells retain the capacity to differentiate into AEC1s, restoring alveolar architecture without fibrosis. However, in IPF and fibroproliferative ARDS, transitional cells become senescent, lose capacity for AEC1 differentiation, and fibrosis ensues. Evolution of transitional cells from a transient cell cycle arrest to a permanent cell cycle arrest (senescence) may be the key defect driving the pathogenesis of fibrosis after injury.

PROTOCOL: Digital interventions to reduce social isolation and loneliness in older adults: An evidence and gap map.

This is the protocol for a Campbell systematic review. The objectives are as follows: the aim is to map available evidence on the effects of digital interventions to mitigate social isolation and/or loneliness in older adults in all settings except hospital settings.

A Case of Acute Pericarditis After COVID-19 Vaccination.

A two-dose regimen of Pfizer-BioNTech COVID-19 vaccination confers 95% protection against COronaVIrus Disease 19 (COVID-19) and the safety profile is adequate. To the submission date, there were no reports in literature of acute pericarditis after BNT162b2 vaccination. However, pericarditis has been reported as a rare event associated with COVID-19 infection, which could be due to the pro-inflammatory effects of the spike protein. Recent evidence of post-vaccine myocarditis has been published. Herein we describe the case of a middle-aged healthy women who developed symptoms and signs of acute pericarditis 7-10 days after the second dose of Pfizer-BioNTech COVID-19 vaccination. Although a direct effect cannot be stated, it is important to report a potential adverse vaccine reaction effect that could be associated with the expression of SARS-CoV-2 spike protein induced from the mRNA of the vaccine.

Establishing a COVID-secure site for elective surgery during the COVID pandemic: An observational study.

INTRODUCTION: Maintaining timely and safe delivery of major elective surgery during the COVID-19 pandemic is essential to manage cancer and time-critical surgical conditions. Our NHS Trust established a COVID-secure elective site with a level 2 Post Anaesthetic Care Unit (PACU) facility. Patients requiring level 3 Intensive Care Unit admission were transferred to a non-COVID-secure site. We investigated the relationship between perioperative anaesthetic care and outcomes. MATERIALS AND METHODS: All consecutive patients undergoing major surgery at the COVID-secure site between June and November 2020 were included. Patient demographics, operative interventions and 30-day outcomes were recorded. Multivariate logistic regression was used to determine the odds ratio of outcomes according to PACU length of stay and the use of spinal or epidural anaesthesia, with age, sex, malignancy status and American Society of Anesthesiologists grade as independent co-variables. RESULTS: There were 280 patients. PACU length of stay >23h was associated with increased 30-day complications. Epidural anaesthesia was associated with PACU length of stay >23h, increased total length of stay, increase hospital transfer and 30-day complications. Two patients acquired nosocomial COVID-19 following hospital transfer. DISCUSSION: Establishing a separate COVID-secure site has facilitated delivery of major elective surgery during the COVID-19 pandemic. Choice of perioperative anaesthesia and utilisation of PACU appear likely to affect the risk of adverse outcomes.

Improving access to research among individuals from under-represented racial and ethnic minority communities: The Strengthening Research In Diverse Enrollment (STRIDE) Study

INTRODUCTION Under-representation in health-related research is one of a multitude of factors that contribute to cancer disparities experienced by African American and Latinx communities. Barriers to research participation stem from historical social injustices, are multi-faceted and include factors specific to the research process, research team members and community experiences and expectations about research participation. Informed consent is a longitudinal process and represents an opportunity to address these barriers and potentially improve access to research by individuals from underrepresented groups. The purpose of the Strengthening Translational Research in Diverse Enrollment (STRIDE) study was to develop and test an integrated, literacy- and culturally-sensitive, multi-component intervention that addresses barriers to research participation during the informed consent process. METHODS A multi-pronged community engaged approach was used to inform the development the three components of the STRIDE intervention. At each of the three study sites, Community Investigators, local community members of diverse racial/ethnic backgrounds, contribute to intervention development, pilot testing and dissemination activities. Community engagement studios provided a semi-structured opportunity to solicit feedback from community experts in a facilitated group regarding the relevance, usability and understandability of the STRIDE intervention components. Additionally, component-specific approaches to obtaining community input were utilized. RESULTS The three components were developed and refined with community input. The STRIDE intervention includes: (1) an electronic consent (eConsent) framework within the REDCap software platform that incorporates tools designed to facilitate material comprehension and relevance, (2) a storytelling intervention in which prior research participants from diverse backgrounds share their experiences, and (3) a simulation-based training program for research assistants that emphasizes cultural competency and communication skills for assisting in the informed consent process. CONCLUSIONS The STRIDE project had produced an integrated set of interventions that are available to support researchers across the CTSA hubs and beyond in efforts to enhance diversity in clinical research. Early dissemination of STRIDE intervention components include utilization in national COVID-19 trials and research networks.