Positive COVID-19 Diagnosis Following Primary Elective Total Joint Arthroplasty: Increased Complication and Mortality Rates.

BACKGROUND: This study analyzed complication rates following primary elective total joint arthroplasty (TJA) in patients who subsequently contracted COVID-19. METHODS: A large national database was queried for adult patients who underwent primary elective TJA in 2020. Patients who contracted COVID-19 after total knee arthroplasty (TKA) or total hip arthroplasty (THA) underwent 1:6 matching (age [±6 years], sex, month of surgery, COVID-19-related comorbidities) to patients who did not. Differences between groups were assessed using univariate and multivariate analyses. Overall, 712 COVID-19 patients were matched to 4,272 controls (average time to diagnosis: 128-117 days [range, 0-351]). RESULTS: Of patients diagnosed <90 days postoperatively, 32.5%-33.6% required COVID-19-driven readmission. Discharge to a skilled nursing facility (adjusted odds ratio [aOR] 1.72, P = .003) or acute rehabilitation unit (aOR 4.93, P < .001) and Black race (aOR 2.28, P < .001) were associated with readmission after TKA. Similar results were associated with THA. COVID-19 patients were at increased risk of pulmonary embolism (aOR 4.09, P = .001) after TKA and also periprosthetic joint infection (aOR 4.65, P < .001) and sepsis (aOR 11.11, P < .001) after THA. The mortality rate was 3.51% in COVID-19 patients and 7.94% in readmitted COVID-19 patients compared to 0.09% in controls, representing a 38.7 OR and 91.8 OR of death, respectively. Similar results were observed for TKA and THA separately. CONCLUSION: Patients who contracted COVID-19 following TJA were at greater risk of numerous complications, including death. These patients represent a high-risk cohort who may require more aggressive medical interventions. Given the potential limitations presently, prospectively collected data may be warranted to validate these findings.

Associations between depression, stress, and e-cigarette use among OEF/OIF veterans.

The COVID-19 pandemic has had profound mental and behavioral health implications for the general U.S. population. However, little is known regarding outcomes for U.S. veterans, who represent a population with high rates of depression, stress, and e-cigarette use. One month prior to the pandemic-related closures (February 2020), 1230 OEF/OIF veterans (ages 18-40) completed an online baseline survey. Six months later, participants completed a follow-up survey (83% retention rate). Hierarchical negative binomial regressions were used to examine the relationship between baseline depression and past 30-day e-cigarette use at follow-up and whether baseline stress moderated this relationship. Veterans who screened positive for depression or who endorsed higher stress levels reported greater e-cigarette use at follow-up. Stress also moderated the relationship between depression and e-cigarette use, such that regardless of stress levels, a positive depression screen was associated with greater rates of later e-cigarette use. However, for those with a negative depression screen, higher stress levels were associated with greater e-cigarette use relative to lower stress levels. Veterans with pre-pandemic depression and stress may be at highest risk for e-cigarette use. Ongoing assessment and treatment for depression and promoting stress management skills for veterans in e-cigarette use prevention and intervention programs may be valuable.

Divalent siRNAs are bioavailable in the lung and efficiently block SARS-CoV-2 infection.

The continuous evolution of SARS-CoV-2 variants complicates efforts to combat the ongoing pandemic, underscoring the need for a dynamic platform for the rapid development of pan-viral variant therapeutics. Oligonucleotide therapeutics are enhancing the treatment of numerous diseases with unprecedented potency, duration of effect, and safety. Through the systematic screening of hundreds of oligonucleotide sequences, we identified fully chemically stabilized siRNAs and ASOs that target regions of the SARS-CoV-2 genome conserved in all variants of concern, including delta and omicron. We successively evaluated candidates in cellular reporter assays, followed by viral inhibition in cell culture, with eventual testing of leads for in vivo antiviral activity in the lung. Previous attempts to deliver therapeutic oligonucleotides to the lung have met with only modest success. Here, we report the development of a platform for identifying and generating potent, chemically modified multimeric siRNAs bioavailable in the lung after local intranasal and intratracheal delivery. The optimized divalent siRNAs showed robust antiviral activity in human cells and mouse models of SARS-CoV-2 infection and represent a new paradigm for antiviral therapeutic development for current and future pandemics.

Clinical outcomes and immune responses to SARS-CoV-2 vaccination in severe aplastic anaemia.

Patients with severe aplastic anaemia (SAA) are often not vaccinated against viruses due to concerns of ineffective protective antibody response and potential for pathogenic global immune system activation, leading to relapse. We evaluated the impact of COVID-19 vaccination on haematological indices and disease status and characterized the humoural and cellular responses to vaccination in 50 SAA patients, who were previously treated with immunosuppressive therapy (IST). There was no significant difference in haemoglobin (p = 0.52), platelet count (p = 0.67), absolute lymphocyte (p = 0.42) and neutrophil (p = 0.98) counts prior to and after completion of vaccination series. Relapse after vaccination, defined as a progressive decline in counts requiring treatment, occurred in three patients (6%). Humoural response was detectable in 90% (28/31) of cases by reduction in an in-vitro Angiotensin II Converting Enzyme (ACE2) binding and neutralization assay, even in patients receiving ciclosporin (10/11, 90.1%). Comparison of spike-specific T-cell responses in 27 SAA patients and 10 control subjects revealed qualitatively similar CD4+ Th1-dominant responses to vaccination. There was no difference in CD4+ (p = 0.77) or CD8+ (p = 0.74) T-cell responses between patients on or off ciclosporin therapy at the time of vaccination. Our data highlight appropriate humoural and cellular responses in SAA previously treated with IST and true relapse after vaccination is rare.

The Persistent Effects of the COVID-19 Pandemic on Total Joint Arthroplasty Changes in Practice Patterns in the United States From 2020 to 2021.

BACKGROUND: The SARS-CoV-2 (COVID-19) pandemic has dramatically disrupted orthopaedic surgery practice patterns. This study aimed to examine differences between patients who underwent total joint arthroplasty (TJA) before the pandemic compared to 2020 and 2021. METHODS: A retrospective cohort study was performed on all patients who underwent elective inpatient TJA from January 2017 to December 2021 using a national large database. Descriptive statistics were utilized to trend length of stay (LOS) and patient age. Patient demographics, discharge destinations, and rates of medical comorbidities were assessed for patients undergoing TJA in 2020 and 2021 compared to patients from prepandemic years (2017 to 2019). Overall, 1,173,366 TJAs were identified (2017 to 2019: 810,268 TJAs, average 270,089 cases/year; 2020: 175,185 TJAs; 2021: 187,627 TJAs). There was a 35.3% and 30.5% decrease in 2020 and 2021, respectively, when compared to the prepandemic annual average. RESULTS: Average LOS decreased from 1.6 days in January 2020 to 0.9 days by December 2021. Same-day discharges increased from 6.2% of cases in 2019 to 30.5% in 2021. Discharge to skilled nursing facilities (SNF) reduced from 11.3% in 2017 to 2019 to 4.3% and 4.5% in 2020 and 2021, respectively. Patients ≥70 years old undergoing elective TJA decreased from 39.6% in 2017 to 2019 to 29.2% in April 2020. CONCLUSION: In response to the COVID-19 pandemic, same-day discharges following primary elective TJA increased markedly, the average LOS decreased, discharges to SNFs decreased, and a preferential shift toward younger patients was observed. LEVEL OF EVIDENCE: Therapeutic Level III.

Immune correlates analysis of the ENSEMBLE single Ad26.COV2.S dose vaccine efficacy clinical trial.

Measuring immune correlates of disease acquisition and protection in the context of a clinical trial is a prerequisite for improved vaccine design. We analysed binding and neutralizing antibody measurements 4 weeks post vaccination as correlates of risk of moderate to severe-critical COVID-19 through 83 d post vaccination in the phase 3, double-blind placebo-controlled phase of ENSEMBLE, an international randomized efficacy trial of a single dose of Ad26.COV2.S. We also evaluated correlates of protection in the trial cohort. Of the three antibody immune markers we measured, we found most support for 50% inhibitory dilution (ID50) neutralizing antibody titre as a correlate of risk and of protection. The outcome hazard ratio was 0.49 (95% confidence interval 0.29, 0.81; P = 0.006) per 10-fold increase in ID50; vaccine efficacy was 60% (43%, 72%) at non-quantifiable ID50 (<2.7 IU50 ml-1) and increased to 89% (78%, 96%) at ID50 = 96.3 IU50 ml-1. Comparison of the vaccine efficacy by ID50 titre curves for ENSEMBLE-US, the COVE trial of the mRNA-1273 vaccine and the COV002-UK trial of the AZD1222 vaccine supported the ID50 titre as a correlate of protection across trials and vaccine types.

Primary exposure to SARS-CoV-2 variants elicits convergent epitope specificities, immunoglobulin V gene usage and public B cell clones.

An important consequence of infection with a SARS-CoV-2 variant is protective humoral immunity against other variants. However, the basis for such cross-protection at the molecular level is incompletely understood. Here, we characterized the repertoire and epitope specificity of antibodies elicited by infection with the Beta, Gamma and WA1 ancestral variants and assessed their cross-reactivity to these and the more recent Delta and Omicron variants. We developed a method to obtain immunoglobulin sequences with concurrent rapid production and functional assessment of monoclonal antibodies from hundreds of single B cells sorted by flow cytometry. Infection with any variant elicited similar cross-binding antibody responses exhibiting a conserved hierarchy of epitope immunodominance. Furthermore, convergent V gene usage and similar public B cell clones were elicited regardless of infecting variant. These convergent responses despite antigenic variation may account for the continued efficacy of vaccines based on a single ancestral variant.

Anti-SARS-CoV-2 Activity of Adamantanes In Vitro and in Animal Models of Infection.

Coronavirus disease 2019 (COVID-19) has had devastating effects worldwide, with particularly high morbidity and mortality in outbreaks on residential care facilities. Amantadine, originally licensed as an antiviral agent for therapy and prophylaxis against influenza A virus, has beneficial effects on patients with Parkinson's disease and is used for treatment of Parkinson's disease, multiple sclerosis, acquired brain injury, and various other neurological disorders. Recent observational data suggest an inverse relationship between the use of amantadine and COVID-19. Adamantanes, including amantadine and rimantadine, are reported to have in vitro activity against severe acute respiratory syndrome coronavirus (SARS-CoV) and, more recently, SARS-CoV-2. We hypothesized that adamantanes have antiviral activity against SARS-CoV-2, including variant strains. To assess the activity of adamantanes against SARS-CoV-2, we used in vitro and in vivo models of infection. We established that amantadine, rimantadine, and tromantadine inhibit the growth of SARS-CoV-2 in vitro in cultured human epithelial cells. While neither rimantadine nor amantadine reduces lung viral titers in mice infected with mouse-adapted SARS-CoV-2, rimantadine significantly reduces viral titers in the lungs in golden Syrian hamsters infected with SARS-CoV-2. In summary, rimantadine has antiviral activity against SARS-CoV-2 in human alveolar epithelial cells and in the hamster model of SARS-CoV-2 lung infection. The evaluation of amantadine or rimantadine in human randomized controlled trials can definitively address applications for the treatment or prevention of COVID-19.

Substance Use, Financial Stress, Employment Disruptions, and Anxiety among Veterans during the COVID-19 Pandemic.

The COVID-19 pandemic has resulted in financial, employment, and mental health challenges. In general, American veterans report high rates of substance use, which may be influenced by the COVID-19 pandemic. Those with pre-existing mental health problems, employment disruptions, or financial stress may be particularly vulnerable. We examined the relationships between pre-existing self-report screens for a probable anxiety disorder, COVID-19-related financial stress, employment disruption (e.g., lost job, reduced hours), and alcohol, cannabis, and cigarette use during the pandemic among 1230 veterans (Mage = 34.5; 89% male). Participants were recruited through various social media sites and completed an online survey 1 month prior to implementation of the nationwide physical distancing guidelines in the United States (February 2020). Six months later (August 2020), they completed a follow-up survey. Compared to veterans who screened negative for anxiety prior to the pandemic, veterans who screened positive reported consuming more drinks per week (b = 3.05), were more likely to use cannabis (OR = 6.53), and smoked more cigarettes (b = 2.06) during the first 6 months of the pandemic. Financial stress was positively associated with alcohol (b = 1.09) and cannabis use (OR = 1.90). Alcohol use was heaviest among veterans with a positive pre-existing anxiety screen and high financial stress. Moreover, veterans who experienced employment disruption due to the pandemic consumed less alcohol but were more likely to use cannabis during the pandemic. Veterans with pre-pandemic anxiety and pandemic-related financial stress may be using substances at higher rates and may benefit from intervention to mitigate negative substance use-related outcomes. Findings also enhance our understanding of veteran substance use behaviors following disruptions in employment due to the pandemic.

Elective Inpatient Total Joint Arthroplasty Case Volume in the United States in 2020: Effects of the COVID-19 Pandemic.

BACKGROUND: Despite known surgical volume reductions in 2020 during the height of the COVID-19 pandemic, no study has fully quantified the impact of the pandemic on the number of elective inpatient total hip (THA) and total knee arthroplasty (TKA) cases. The purpose of the present study was to analyze THA and TKA case volumes in the United States during the COVID-19 pandemic. METHODS: The Premier Healthcare Database was utilized to identify adults undergoing primary elective THA or TKA from January 2017 to December 2020. The National Inpatient Sample was cross-referenced to provide nationwide representative sampling weights. Patients undergoing revision total joint arthroplasty (TJA) or non-elective surgery were excluded. Two quantitative models were created from both databases to estimate TJA case volume in 2020. Descriptive statistics were utilized to report monthly changes in elective TJA utilization throughout 2020. Univariate analyses were performed to compare differences between subgroups. RESULTS: From 2017 to 2019, it was estimated that 1,006,000 elective inpatient TJAs (64.2% TKA and 35.8% THA) were performed annually. In 2020, an estimated 526,000 to 538,000 cases (62.0% TKA and 38.0% THA) were performed, representing a 46.5% to 47.7% decrease in nationwide volume from the prior 3-year average. Moreover, the elective TJA case volume for April 2020 was 1.9% of the average for that month from 2017 through 2019. Subsequently, case volumes for May and June increased compared with the volumes for those months from 2017 through 2019. There was then a decrease in cases for July, corresponding with the "second wave" of COVID-19, followed by an additional steady monthly decline through December, corresponding with the "third wave." Finally, the elective TJA cases for December 2020 represented only 41.0% of the average case volume for that month from 2017 through 2019. CONCLUSIONS: In the midst of the 2020 COVID-19 pandemic, approximately 526,000 to 538,000 elective inpatient TJA cases were performed, representing a 46.5% to 47.7% decrease compared with the 3 previous years. The effects of the COVID-19 pandemic persisted through the end of that year, with decreased case volume through December 2020.

US201 Study: A Phase 2, Randomized Proof-of-Concept Trial of Favipiravir for the Treatment of COVID-19.

BACKGROUND: Favipiravir is used to treat influenza, and studies demonstrate that it has antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We performed a randomized, open-label, multicenter, phase 2 proof-of-concept trial of favipiravir in hospitalized adult patients with polymerase chain reaction (PCR)-positive coronavirus disease 2019 (COVID-19). Patients were randomized to standard of care (SOC) or favipiravir treatment (1800mg per os twice a day [b.i.d.] on day 1, followed by 1000mg b.i.d. for 13 days). The primary end point was time to viral clearance on day 29. RESULTS: Fifty patients were enrolled and stratified by disease severity (critical disease, severe disease, or mild to moderate disease). Nineteen patients were censored from the event of viral clearance based on being SARS-CoV-2 PCR-negative at the study outset, being PCR-positive at day 29, or because of loss to follow-up. Data from the 31 remaining patients who achieved viral clearance show enhanced viral clearance in the favipiravir group compared with the SOC group by day 29, with 72% of the favipiravir group and 52% of the SOC group being evaluable for viral clearance through day 29. The median time to viral clearance was 16.0 days (90% CI, 12.0 to 29.0) in the favipiravir group and 30.0 days (90% CI, 12.0 to 31.0) in the SOC group. A post hoc analysis revealed an effect in the subgroup of patients who were neutralizing antibody-negative at randomization. Treatment-emergent adverse events were equally distributed between the groups. CONCLUSIONS: We demonstrate that favipiravir can be safely administered to hospitalized adults with COVID-19 and believe that further studies are warranted. CLINICALTRIALSGOV REGISTRATION: NCT04358549.

Human nasal wash RNA-Seq reveals distinct cell-specific innate immune responses in influenza versus SARS-CoV-2.

BACKGROUNDInfluenza A virus (IAV) and SARS-CoV-2 are pandemic viruses causing millions of deaths, yet their clinical manifestations are distinctly different.METHODSWith the hypothesis that upper airway immune and epithelial cell responses are also distinct, we performed single-cell RNA sequencing (scRNA-Seq) on nasal wash cells freshly collected from adults with either acute COVID-19 or influenza or from healthy controls. We focused on major cell types and subtypes in a subset of donor samples.ResultsNasal wash cells were enriched for macrophages and neutrophils for both individuals with influenza and those with COVID-19 compared with healthy controls. Hillock-like epithelial cells, M2-like macrophages, and age-dependent B cells were enriched in COVID-19 samples. A global decrease in IFN-associated transcripts in neutrophils, macrophages, and epithelial cells was apparent in COVID-19 samples compared with influenza samples. The innate immune response to SARS-CoV-2 appears to be maintained in macrophages, despite evidence for limited epithelial cell immune sensing. Cell-to-cell interaction analyses revealed a decrease in epithelial cell interactions in COVID-19 and highlighted differences in macrophage-macrophage interactions for COVID-19 and influenza.ConclusionsOur study demonstrates that scRNA-Seq can define host and viral transcriptional activity at the site of infection and reveal distinct local epithelial and immune cell responses for COVID-19 and influenza that may contribute to their divergent disease courses.FundingMassachusetts Consortium on Pathogen Readiness, the Mathers Foundation, and the Department of Defense (W81XWH2110029) "COVID-19 Expansion for AIRe Program."

SARS-CoV-2 Initiates Programmed Cell Death in Platelets.

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The Mount Sinai Hospital Institute for critical care medicine response to the COVID-19 pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic resulted in a surge of critically ill patients. This was especially true in New York City. We present a roadmap for hospitals and healthcare systems to prepare for a Pandemic. METHODS: This was a retrospective review of how Mount Sinai Hospital (MSH) was able to rapidly prepare to handle the pandemic. MSH, the largest academic hospital within the Mount Sinai Health System, rapidly expanded the intensive care unit (ICU) bed capacity, including creating new ICU beds, expanded the workforce, and created guidelines. RESULTS: MSH a 1,139-bed quaternary care academic referral hospital with 104 ICU beds expanded to 1,453 beds (27.5% increase) with 235 ICU beds (126% increase) during the pandemic peak in the first week of April 2020. From March to June 2020, with follow-up through October 2020, MSH admitted 2,591 COVID-19-positive patients, 614 to ICUs. Most admitted patients received noninvasive support including a non-rebreather mask, high flow nasal cannula, and noninvasive positive pressure ventilation. Among ICU patients, 68.4% (n=420) received mechanical ventilation; among the admitted ICU patients, 42.8% (n=263) died, and 47.8% (n=294) were discharged alive. CONCLUSIONS: Flexible bed management initiatives; teamwork across multiple disciplines; and development and implementation of guidelines were critical accommodating the surge of critically ill patients. Non-ICU services and staff were deployed to augment the critical care work force and open new critical care units. This approach to rapidly expand bed availability and staffing across the system helped provide the best care for the patients and saved lives.

Substance use, depression, and loneliness among American veterans during the COVID-19 pandemic.

BACKGROUND AND OBJECTIVES: Behavioral health issues, such as substance use, depression, and social isolation, are of grave concern during COVID-19, especially for vulnerable populations. One such population is US veterans, who have high rates of pre-existing behavioral health conditions and may thus be at-risk for poorer outcomes. The current study aimed to investigate substance use among US veterans during COVID-19 as a function of pre-existing depression, loneliness, and social support. METHODS: We investigated the relationship between pre-pandemic depression and substance use during COVID-19 using linear (alcohol) and logistic (cannabis) regression among a large sample of US veterans (N = 1230). We then tested if loneliness and social support moderated these effects. RESULTS: Though there was a decrease in alcohol and cannabis use among the overall sample, veterans who screened for depression prior to the pandemic exhibited higher levels of substance use after the pandemic's onset. Loneliness compounded the effects of depression on rates of alcohol use. Social support was not protective for the effects of depression on either alcohol or cannabis use. DISCUSSION AND CONCLUSIONS: Veterans with pre-existing depression may be in need of attention for substance use behaviors. Interventions aimed at alleviating loneliness among veterans may be useful in mitigating alcohol use, but not cannabis use, amid COVID-19. SCIENTIFIC SIGNIFICANCE: Our findings are among the first to report tangible behavioral health outcomes experienced by US veterans as a result of COVID-19. Results can help inform treatment efforts for veterans who are struggling with substance use during and post-pandemic.

Head and neck surgical oncology in the time of a pandemic: Subsite-specific triage guidelines during the COVID-19 pandemic.

BACKGROUND: COVID-19 pandemic has strained human and material resources around the world. Practices in surgical oncology had to change in response to these resource limitations, triaging based on acuity, expected oncologic outcomes, availability of supportive resources, and safety of health care personnel. METHODS: The MD Anderson Head and Neck Surgery Treatment Guidelines Consortium devised the following to provide guidance on triaging head and neck cancer (HNC) surgeries based on multidisciplinary consensus. HNC subsites considered included aerodigestive tract mucosa, sinonasal, salivary, endocrine, cutaneous, and ocular. RECOMMENDATIONS: Each subsite is presented separately with disease-specific recommendations. Options for alternative treatment modalities are provided if surgical treatment needs to be deferred. CONCLUSION: These guidelines are intended to help clinicians caring for patients with HNC appropriately allocate resources during a health care crisis, such as the COVID-19 pandemic. We continue to advocate for individual consideration of cases in a multidisciplinary fashion based on individual patient circumstances and resource availability.

Endocrine Surgery in the Coronavirus Disease 2019 Pandemic

Abstract Background In the face of the COVID-19 pandemic, cancer care has had to adapt rapidly given the Centers for Disease Control and Prevention (CDC) and the American College of Surgeons (ACS) issuing recommendations to postpone non-urgent surgeries. Methods An institutional multidisciplinary group of Head and Neck Surgical Oncology, Surgical Endocrinology, and Medical Endocrinology devised Surgical Triaging Guidelines for Endocrine Surgery during COVID-19, aligned with phases of care published by the ACS. Results Phases of care with examples of corresponding endocrine cases are outlined. Most cases can be safely postponed with active surveillance, including most differentiated and medullary thyroid cancers. During the most acute phase, all endocrine surgeries are deferred except thyroid tumors requiring acute airway management. Conclusions These guidelines provide context for endocrine surgery within the spectrum of surgical oncology, with the goal of optimal individualized multidisciplinary patient care, and the expectation of significant resource diversion to care for COVID-19 patients. This article is protected by copyright. All rights reserved.