Early, robust mucosal secretory IgA but not IgG response to SARS-CoV-2 spike in oral fluid is associated with faster viral clearance and COVID-19 symptom resolution (preprint)

High priority efforts are under way to support the development of novel mucosal COVID-19 vaccines, such as the US Governments Project NextGen and the Center for Epidemic Preparedness Innovations (CEPI) goal to respond to the next pandemic with a new vaccine in 100 days. However, there is limited consensus about the complementary role of mucosal immunity in disease progression and how the immunogenicity of mucosal vaccines will be evaluated. This study investigated the role of oral mucosal antibody responses in viral clearance and in COVID-19 symptom duration. Participants with PCR-confirmed SARS-CoV-2 infection provided oral fluid for testing with SARS-CoV-2 antibody multiplex assays, nasal swabs for RT-PCR and symptom information at up to eight follow-ups from April 2020 to February 2022. High and moderate oral fluid anti-spike (S) SIgA post infection was associated with significantly higher likelihood of viral clearance and of COVID-19 symptom resolution across age groups. Those with high and moderate anti-S SIgA cleared the virus and recovered 14 days (95% CI: 10-18 days) and 9-10 days (95% CI: 6-14 days) earlier, respectively. Delayed but higher oral fluid anti-S IgG was associated with significantly longer time to viral clearance and recovery. The effect size of moderate or high SIgA was equivalent to prior COVID-19 vaccine immunity, which was also associated with faster clearance and recovery. Unvaccinated adults with prolonged COVID-19 symptoms had significantly lower anti-RBD SIgA 15-30 days after infection onset (p<0.001). Robust mucosal SIgA early post infection appears to support faster clearance of SARS-CoV-2 and recovery from COVID-19 symptoms. This research underscores the importance of harmonizing mucosal immune response assays to evaluate new vaccines that can boost local mucosal immunity. DisclaimerThe findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Plasma proteomic evidence for increased Alzheimer's disease-related brain pathology after SARS-CoV-2 infection (preprint)

Viral infections have been linked to an increased risk for dementia. We investigated whether SARS-CoV-2 infection increases preclinical brain pathology associated with Alzheimer's disease (AD) by comparing changes in plasma biomarkers in UK Biobank participants with and without prior SARS-CoV-2 infection. We discovered an association between SARS-CoV-2 infection and reduced plasma A{beta}42:A{beta}40 concentration ratio. In older participants, SARS-CoV-2 infection was associated with both lower plasma A{beta}42 and higher plasma pTau-181. These biomarker changes, which have been associated with beta-amyloid accumulation and prodromal AD, were associated with increased brain imaging signatures of AD, poorer cognitive scores, and worse assessments of overall health and appeared to be greater in participants who had been hospitalised with COVID-19. Protein biomarker risk scores for other diseases were also raised among individuals who had past SARS-CoV-2 infections. Our data provide support for the hypothesis that viral infections can accelerate prodromal AD pathology and highlight biomarker profiles indicative of an increased risk of dementia and systemic diseases after SARS-CoV-2 infection, particularly in older people.

A Saliva-Based Serological and Behavioral Analysis of SARS-CoV-2 Antibody Prevalence in Howard County, Maryland.

The objective of the study was to estimate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence in the Howard County, Maryland, general population and demographic subpopulations attributable to natural infection or coronavirus disease 2019 (COVID-19) vaccination and to identify self-reported social behaviors that may affect the likelihood of recent or past SARS-CoV-2 infection. A cross-sectional, saliva-based serological study of 2,880 residents of Howard County, Maryland, was carried out from July through September 2021. Natural SARS-CoV-2 infection prevalence was estimated by inferring infections among individuals according to anti-nucleocapsid immunoglobin G levels and calculating averages weighted by sample proportions of various demographics. Antibody levels between BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) recipients were compared. Antibody decay rate was calculated by fitting exponential decay curves to cross-sectional indirect immunoassay data. Regression analysis was carried out to identify demographic factors, social behaviors, and attitudes that may be linked to an increased likelihood of natural infection. The estimated overall prevalence of natural infection in Howard County, Maryland, was 11.9% (95% confidence interval, 9.2% to 15.1%), compared with 7% reported COVID-19 cases. Antibody prevalence indicating natural infection was highest among Hispanic and non-Hispanic Black participants and lowest among non-Hispanic White and non-Hispanic Asian participants. Participants from census tracts with lower average household income also had higher natural infection rates. After accounting for multiple comparisons and correlations between participants, none of the behavior or attitude factors had significant effects on natural infection. At the same time, recipients of the mRNA-1273 vaccine had higher antibody levels than those of BNT162b2 vaccine recipients. Older study participants had overall lower antibody levels compared with younger study participants. The true prevalence of SARS-CoV-2 infection is higher than the number of reported COVID-19 cases in Howard County, Maryland. A disproportionate impact of infection-induced SARS-CoV-2 positivity was observed across different ethnic/racial subpopulations and incomes, and differences in antibody levels across different demographics were identified. Taken together, this information may inform public health policy to protect vulnerable populations. IMPORTANCE We employed a highly innovative noninvasive multiplex oral fluid SARS-CoV-2 IgG assay to ascertain our seroprevalence estimates. This laboratory-developed test has been applied in NCI's SeroNet consortium, possesses high sensitivity and specificity according to FDA Emergency Use Authorization guidelines, correlates strongly with SARS-CoV-2 neutralizing antibody responses, and is Clinical Laboratory Improvement Amendments-approved by the Johns Hopkins Hospital Department of Pathology. It represents a broadly scalable public health tool to improve understanding of recent and past SARS-CoV-2 exposure and infection without drawing any blood. To our knowledge, this is the first application of a high-performance salivary SARS-CoV-2 IgG assay to estimate population-level seroprevalence, including identifying COVID-19 disparities. We also are the first to report differences in SARS-CoV-2 IgG responses by COVID-19 vaccine manufacturers (BNT162b2 [Pfizer-BioNTech] and mRNA-1273 [Moderna]). Our findings demonstrate remarkable consistency with those of blood-based SARS-CoV-2 IgG assays in terms of differences in the magnitude of SARS-CoV-2 IgG responses between COVID-19 vaccines.

Severe Acute Respiratory Syndrome Coronavirus 2 Neutralizing Antibody Responses After Community Infections in Children and Adults.

Background: We compared postinfection severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibody (nAb) responses among children and adults while the D614G-like strain and Alpha, Iota, and Delta variants circulated. Methods: During August 2020-October 2021, households with adults and children were enrolled and followed in Utah, New York City, and Maryland. Participants collected weekly respiratory swabs that were tested for SARS-CoV-2 and had sera collected during enrollment and follow-up. Sera were tested for SARS-CoV-2 nAb by pseudovirus assay. Postinfection titers were characterized with biexponential decay models. Results: Eighty participants had SARS-CoV-2 infection during the study (47 with D614G-like virus, 17 with B.1.1.7, and 8 each with B.1.617.2 and B.1.526 virus). Homologous nAb geometric mean titers (GMTs) trended higher in adults (GMT = 2320) versus children 0-4 (GMT = 425, P = .33) and 5-17 years (GMT = 396, P = .31) at 1-5 weeks postinfection but were similar from 6 weeks. Timing of peak titers was similar by age. Results were consistent when participants with self-reported infection before enrollment were included (n = 178). Conclusions: The SARS-CoV-2 nAb titers differed in children compared to adults early after infection but were similar by 6 weeks postinfection. If postvaccination nAb kinetics have similar trends, vaccine immunobridging studies may need to compare nAb responses in adults and children 6 weeks or more after vaccination.

Public transport access to drug treatment before and during COVID-19: Implications for the opioid epidemic.

Public transport disruptions caused by the COVID-19 pandemic had wide-ranging impacts on the ability of individuals to access health care. Individuals with opioid use disorder represent an especially vulnerable population due to the necessity of frequent, supervised doses of opioid agonists. Focused on Toronto, a major Canadian city suffering from the opioid epidemic, this analysis uses novel realistic routing methodologies to quantify how travel times to individuals\220 nearest clinics changed due to public transport disruptions from 2019 to 2020. Individuals seeking opioid agonist treatment face very constrained windows of access due to the need to manage work and other essential activities. We find that thousands of households in the most materially and socially deprived neighbourhoods crossed 30 and 20-minute travel time thresholds to their nearest clinic. As even small changes to travel times can lead to missed appointments and heighten the chances of overdose and death, understanding the distribution of those most impacted can help inform future policy measures to ensure adequate access to care.

The Impact of Socioeconomic Factors on the 2022 Plastic Surgery Match.

BACKGROUND: In 2022, the plastic and reconstructive surgery (PRS) match faced unprecedented system-wide transitions that have redefined conventional measures of applicant success. This challenges the equitable assessment of student competitiveness and diversity in the field. METHODS: A survey of demography, application content, and 2022 match outcomes was distributed to applicants to a single PRS residency program. Comparative statistics and regression models were performed to assess the predictive value of factors in match success and quality. RESULTS: A total of 151 respondents (response rate 49.7%) were analyzed. Although step 1 and step 2 CK scores were significantly higher among matched applicants, neither examination predicted match success. Most respondents (52.3%) were women, although gender was also not significantly associated with match success. Underrepresented in medicine applicants made up 19.2% of responses and 16.7% of matches, and the plurality of respondents (22.5%) were raised with a household income ≥$300,000. Both Black race and household income ≤$100,000 were associated with lower odds of scoring above a 240 on either step 1 or step 2 CK (Black: OR, 0.03 and 0.06; P < 0.05 and P < 0.001; income: OR, 0.07-0.47 and 0.1 to 0.8, among income subgroups), receiving interview offers (OR, -9.4; P < 0.05; OR, -11.0 to -5.4), and matching into PRS (OR, 0.2; P < 0.05; OR, 0.2 to 0.5), compared with White and high-income applicants, respectively. CONCLUSIONS: Systemic inequities in the match process disadvantage underrepresented in medicine candidates and those from lower household incomes. As the residency match continues to evolve, programs must understand and mitigate the impacts of bias in various application components.

The 'omics of obesity in B-cell acute lymphoblastic leukemia.

The obesity pandemic currently affects more than 70 million Americans and more than 650 million individuals worldwide. In addition to increasing susceptibility to pathogenic infections (eg, SARS-CoV-2), obesity promotes the development of many cancer subtypes and increases mortality rates in most cases. We and others have demonstrated that, in the context of B-cell acute lymphoblastic leukemia (B-ALL), adipocytes promote multidrug chemoresistance. Furthermore, others have demonstrated that B-ALL cells exposed to the adipocyte secretome alter their metabolic states to circumvent chemotherapy-mediated cytotoxicity. To better understand how adipocytes impact the function of human B-ALL cells, we used a multi-omic RNA-sequencing (single-cell and bulk transcriptomic) and mass spectroscopy (metabolomic and proteomic) approaches to define adipocyte-induced changes in normal and malignant B cells. These analyses revealed that the adipocyte secretome directly modulates programs in human B-ALL cells associated with metabolism, protection from oxidative stress, increased survival, B-cell development, and drivers of chemoresistance. Single-cell RNA sequencing analysis of mice on low- and high-fat diets revealed that obesity suppresses an immunologically active B-cell subpopulation and that the loss of this transcriptomic signature in patients with B-ALL is associated with poor survival outcomes. Analyses of sera and plasma samples from healthy donors and those with B-ALL revealed that obesity is associated with higher circulating levels of immunoglobulin-associated proteins, which support observations in obese mice of altered immunological homeostasis. In all, our multi-omics approach increases our understanding of pathways that may promote chemoresistance in human B-ALL and highlight a novel B-cell-specific signature in patients associated with survival outcomes.

Prior metabolic surgery reduced COVID-19 severity: Systematic analysis from year one of the COVID-19 pandemic

Background Obesity is a risk factor for COVID-19 severity. Recent studies suggest that prior metabolic surgery (MS) modifies the risk of COVID-19 severity. Methods COVID-19 outcomes were compared between patients with MS (n = 287) and a matched cohort of unoperated patients (n = 861). Multiple logistic regression was used to identify predictors of hospitalization. A systematic literature review and pooled analysis was conducted to provide overall evidence of the influence of prior metabolic surgery on COVID-19 outcomes. Results COVID-19 patients with MS had less hospitalization (9.8% versus 14.3%, p = 0.049). Age 70+, higher BMI, and low weight regain after MS were associated with more hospitalization after COVID-19. A systematic review of 7 studies confirmed that MS reduced the risk of post-COVID-19 hospitalization (OR = 0.71, 95%CI = [0.61–0.83], p < 0.0001) and death (OR = 0.44, 95%CI = [0.30–0.65], p < 0.0001). Conclusion MS favorably modifies the risks of severe COVID-19 infection. Older age and higher BMI are major risk factors for severity of COVID-19 infection.

Past Relational Experiences and Social Interaction: Direct, Moderated, and Mediated Associations Between Relational Difficulty, Communication, and Perception in Two Samples

This study examined the relationship between perceptions of relational history, namely, past relational challenges, and everyday social interaction experiences. In efforts to build upon and extend previous research, hypotheses directed toward replication and extension were tested in two experience sampling datasets (N = 120 and 220). Consistent support was found for the idea that people with a history of relational difficulties tend to perceive less interaction partner responsiveness, lower well-being, and higher stress during social interactions. Support was also found in a sample of adults for a multilevel mediation model whereby negative relations with others negatively predicted partner responsiveness through stress and partner liking. Results are interpreted based on affection-, appraisal-, and resource-based theories and potential differences in relational experiences at unique life stages and phases of the COVID-19 pandemic. [ FROM AUTHOR] Copyright of Communication Research is the property of Sage Publications Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Discovery of Highly Potent Small Molecule Pan-Coronavirus Fusion Inhibitors.

The unprecedented pandemic of COVID-19, caused by a novel coronavirus, SARS-CoV-2, and its highly transmissible variants, led to massive human suffering, death, and economic devastation worldwide. Recently, antibody-evasive SARS-CoV-2 subvariants, BQ and XBB, have been reported. Therefore, the continued development of novel drugs with pan-coronavirus inhibition is critical to treat and prevent infection of COVID-19 and any new pandemics that may emerge. We report the discovery of several highly potent small-molecule inhibitors. One of which, NBCoV63, showed low nM potency against SARS-CoV-2 (IC50: 55 nM), SARS-CoV-1 (IC50: 59 nM), and MERS-CoV (IC50: 75 nM) in pseudovirus-based assays with excellent selectivity indices (SI > 900), suggesting its pan-coronavirus inhibition. NBCoV63 showed equally effective antiviral potency against SARS-CoV-2 mutant (D614G) and several variants of concerns (VOCs) such as B.1.617.2 (Delta), B.1.1.529/BA.1 and BA.4/BA.5 (Omicron), and K417T/E484K/N501Y (Gamma). NBCoV63 also showed similar efficacy profiles to Remdesivir against authentic SARS-CoV-2 (Hong Kong strain) and two of its variants (Delta and Omicron), SARS-CoV-1, and MERS-CoV by plaque reduction in Calu-3 cells. Additionally, we show that NBCoV63 inhibits virus-mediated cell-to-cell fusion in a dose-dependent manner. Furthermore, the absorption, distribution, metabolism, and excretion (ADME) data of NBCoV63 demonstrated drug-like properties.

Effect of a ketogenic diet versus Mediterranean diet on glycated hemoglobin in individuals with prediabetes and type 2 diabetes mellitus: The interventional Keto-Med randomized crossover trial.

BACKGROUND: Consensus has not been reached on what constitutes an optimal diet in individuals with prediabetes and type 2 diabetes mellitus (T2DM), especially between low-carbohydrate options. OBJECTIVES: We compared 2 low-carbohydrate diets with 3 key similarities (incorporating nonstarchy vegetables and avoiding added sugars and refined grains) and 3 key differences (incorporating compared with avoiding legumes, fruits, and whole, intact grains) for their effects on glucose control and cardiometabolic risk factors in individuals with prediabetes and T2DM. METHODS: Keto-Med was a randomized, crossover, interventional trial. Forty participants aged ≥18 years with prediabetes or T2DM followed the well-formulated ketogenic diet (WFKD) and the Mediterranean-plus diet (Med-Plus) for 12 weeks each, in random order. The diets shared the 3 key similarities noted above. The Med-Plus incorporated legumes, fruits, and whole, intact grains, while the WFKD avoided them. The primary outcome was the percentage change in glycated hemoglobin (HbA1c) after 12 weeks on each diet. Secondary and exploratory outcomes included percentage changes in body weight, fasting insulin, glucose, and blood lipids; average glucose from continuous glucose monitor (CGM), and nutrient intake. RESULTS: The primary analysis was of 33 participants with complete data. The HbA1c values did not differ between diets at 12 weeks. Triglycerides decreased more for the WFKD [percentage changes, -16% (SEM, 4%) compared with -5% (SEM, 6%) for the Med-Plus; P = 0.02] and LDL cholesterol was higher for the WFKD [percentage changes, +10% (SEM, 4%) compared with -5% (SEM, 5%) for the Med-Plus; P = 0.01]. Weight decreased 8% (SEM, 1%) compared with 7% (SEM, 1%) and HDL cholesterol increased 11% (SEM, 2%) compared with 7% (SEM, 3%) for the WFKD compared with the Med-Plus, respectively; however, there was a significant interaction of diet × order for both. Participants had lower intakes of fiber and 3 nutrients on the WFKD compared with the Med-Plus. Twelve-week follow-up data suggest the Med-Plus is more sustainable. CONCLUSIONS: HbA1c values were not different between diet phases after 12 weeks, but improved from baseline on both diets, likely due to several shared dietary aspects. The WFKD led to a greater decrease in triglycerides, but also had potential untoward risks from elevated LDL cholesterol and lower nutrient intakes from avoiding legumes, fruits, and whole, intact grains, as well as being less sustainable. This trial was registered at clinicaltrials.gov as NCT03810378.

Impact of post-COVID-19 lung damage on Respiratory function and HRQOL in Indians

Background: In people recovering from COVID-19, there is concern regarding potential long-term pulmonary sequelae and associated impairment of functional capacity. This study was designed to assess this. Method(s): 207 subjects with mean age of 48.7 years were assessed after 63 days(mean), from symptom onset. Clinical symptoms, St George's Respiratory questionnaire(SGRQ), pulmonary function testing, 6-minute walk test(6MWT) and chest radiography were evaluated. Details pertaining to the COVID-19 illness and hospitalisation, WHO disease severity categories(asymptomatic, mild, moderate, severe and critical) and baseline laboratory biomarkers were retrieved from the hospital records. 'Mild COVID'(WHO mild category) was compared with 'COVID pneumonia'(WHO moderate, severe & critical) and further, moderate was compared with the severe/critical. Result(s): In all,35% had restrictive defect(TLC< 80%), 8.3% had obstructive defect(FEV1/FVC<70%) and 44.4% had impaired diffusing capacity(DLCO<80%). The 'COVID pneumonia'group, compared to 'mild COVID' had lower FVC(2.4vs2.9;P=0.0002), FVC%(77.85vs88.18;P=0.001), FEV1(2.0vs2.36;P=0.0014), TLC% (79.48vs87.91;P=0.0002), DLCO(6.80vs8.30;P=0.0004), DLCO%(75.30vs89.20;P<0.0001), DLCO/VA(2.0vs2.2;P=0.004) and DLCO/VA%(105.6vs111.8;P=0.032), lower minimum oxygen saturation(94.89vs97.73;P<0.0001) and drop in saturation >=4% in more subjects(21.69%vs4.84%;P=0.001) during 6MWT, higher mean total SGRQ score(29.2vs11.0;P<0.0001) and domain scores: Symptom(37.2vs12.9;P<0.0001), Activity(49.1vs13.2;P<0.0001) and Impact(12.7vs2.0;P<0.0001). Conclusion(s): In an Indian cohort, post-COVID-19 lung damage results in significant impairment of lung function, effort tolerance and quality of life.

Seroprevalence of COVID-19 among out patients with chronic respiratory disease in a tertiary care hospital in India

Background: Unexpectedly, COVID-19 was less prevalent in Chronic Respiratory Disease(CRD) than in the general population (Gupta N et al. Lung India. 2021;38(5):454-9). The vaccine and infection-related immune status of CRD patients is unknown. Aims and Objectives: Our primary objective was to study the cross sectional seroprevalence among chronic respiratory disease patients attending the Pulmonary medicine outpatients service and comparing it with the national seroprevalence data. Method(s): Consecutive subjects with CRD were recruited. History of past COVID 19 infection and other relevant information was obtained. Blood sample was taken for Roche Elecsys SARS-CoV-2 assay to detect anti-N and anti-S antibodies. Result(s): We recruited 364 patients(Asthma & COPD-100 each, Bronchiectasis, ILD & PTB-sequelae- 50 each and other restrictive diseases-14). The overall seroprevalence in CRD(Anti-S) was 85.16%, which was significantly higher than the 4th national serosurvey seroprevalence of 67.60%(p=0.001) (ICMR, Ministry of Health and Family Welfare;2021). Asthma had the highest seroprevalence, which was higher than COPD [93% vs 78%, p=0.027] and bronchiectasis [93% vs 80%, p=0.018]. Seroprevalence dropped with increasing age: <40 yrs: 93%, 41-60 yrs: 87% and >= 61 yrs: 77% (p=0.004). Patients on inhaled-steroids had higher seroprevalence than those without (89% vs 80%;p=0.026) and those on inhaled-anticholinergics (89% VS 79%;p=0.013). Conclusion(s): COVID-19 seroprevalence is higher in CRD than in the general population. Asthmatics had the highest prevalence and the seroprevalence dropped with increasing age.

Dyspnoea in patients presenting post-COVID-19 respiratory clinic not fully explained by lung function impairment and chest radiography abnormalities

Introduction: Patients who have recovered from acute COVID-19 continue to have persistent respiratory symptoms and we established Post-COVID respiratory clinic (PCRC) to evaluate them. Method(s): This is a retrospective study of patients who had presented to the PCRC. Full pulmonary function test and chest radiography were done and the images were scored for severity using radiographic assessment of lung edema(RALE) & Yasin score. Result(s): One hundred patients presented after a mean duration of 9 weeks after the acute illness. The most common symptom was dyspnoea in 55% of the patients. There was good correlation of Chest Xray scores with the lung function. Comparison of clinical, radiologic and lung function parameters showed that more patients presenting in PCR clinic with dyspnoea had dyspnoea during acute COVID-19 compared to those without dyspnoea. There was no correlation of dyspnoea with lung function parameters and Chest Xray scores. Conclusion(s): Dyspnoea is the commonest symptom in post-COVID-19 patients and it has no correlation to lung function parameters and Chest Xray abnormalities.

Treatment of COVID-19 ARDS with a tabletop NIV device in a Respiratory Intermediate Care Unit

Background: Non-invasive ventilation (NIV) has been tried in COVID-19 ARDS (CARDS), and its role is being increasingly recognised. If proven, it could be a game-changer in resource limited settings. We report our experience with administration of respiratory support using a tabletop NIV device in a respiratory intermediate care unit (RIMCU). Methodology: We retrospectively studied a cohort of hospitalised COVID-19 patients, who received protocolised management with positive airway pressure using a tabletop NIV device in the RIMCU as a step-up rescue therapy for deterioration despite low flow oxygen support. Treatment was commenced with continuous positive airway pressure (CPAP) mode up to a pressure of 10 cm H2O and if required inspiratory pressures were added with the bilevel positive airway pressure (BPAP) mode. Success was defined as weaning from NIV and stepping down to the ward. Failure was defined as escalation to the intensive care unit (ICU) or need for intubation or death. Result(s): In all, 246 patients were treated in the RIMCU during the study period. Of these, 168 received respiratory support via tabletop NIV device as a step-up rescue therapy. Their mean age was 54 years, and 83% were males. Diabetes Mellitus (78%) and hypertension (44%) were the commonest comorbidities. Treatment was successful with tabletop NIV in 77%;of this, 41% was on CPAP alone and 36% after receiving increased inspiratory pressures on BPAP mode. Conclusion(s): Respiratory support using a tabletop NIV device is an effective, and economical treatment for CARDS. Further studies are required to assess the appropriate time of initiation for maximal benefit and judicious resource utilisation.

Dual mechanism: Epigenetic inhibitor apabetalone reduces SARS-CoV-2 Delta and Omicron variant spike binding and attenuates SARS-CoV-2 RNA induced inflammation.

The SARS-CoV-2 virus initiates infection via interactions between the viral spike protein and the ACE2 receptors on host cells. Variants of concern have mutations in the spike protein that enhance ACE2 binding affinity, leading to increased virulence and transmission. Viral RNAs released after entry into host cells trigger interferon-I (IFN-I) mediated inflammatory responses for viral clearance and resolution of infection. However, overreactive host IFN-I responses and pro-inflammatory signals drive COVID-19 pathophysiology and disease severity during acute infection. These immune abnormalities also lead to the development of post-COVID syndrome if persistent. Novel therapeutics are urgently required to reduce short- and long-term pathologic consequences associated with SARS-CoV-2 infection. Apabetalone, an inhibitor of epigenetic regulators of the BET protein family, is a candidate for COVID-19 treatment via a dual mechanism of action. In vitro, apabetalone downregulates ACE2 gene expression to limit SARS-CoV-2 entry and propagation. In pre-clinical models and patients treated for cardiovascular disease, apabetalone inhibits expression of inflammatory mediators involved in the pathologic cytokine storm (CS) stimulated by various cytokines. Here we show apabetalone treatment of human lung epithelial cells reduces binding of viral spike protein regardless of mutations found in the highly contagious Delta variant and heavily mutated Omicron. Additionally, we demonstrate that apabetalone counters expression of pro-inflammatory factors with roles in CS and IFN-I signaling in lung cells stimulated with SARS-CoV-2 RNA. Our results support clinical evaluation of apabetalone to treat COVID-19 and post-COVID syndrome regardless of the SARS-CoV-2 variant.

Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma.

BACKGROUND: Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown. METHODS: In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated. RESULTS: At a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group. CONCLUSIONS: Among patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.).