Correlates of protection against SARS-CoV-2 infection and COVID-19 disease

Antibodies against epitopes in S1 give the most accurate CoP against infection by the SARS-CoV-2 coronavirus. Measurement of those antibodies by neutralization or binding assays both have predictive value, with binding antibody titers giving the highest statistical correlation. However, the protective functions of antibodies are multiple. Antibodies with multiple functions other than neutralization influence efficacy. The role of cellular responses can be discerned with respect to CD4+ T cells and their augmentation of antibodies, and with respect to CD8+ cells with regard to control of viral replication, particularly in the presence of insufficient antibody. More information is needed on mucosal responses

Triage for coronary artery bypass graft surgery in Canada: Do patients agree on who should come first?

<p>Abstract</p> <p>Background</p> <p>The extent to which clinical and non-clinical factors impact on the waiting-list prioritization preferences of patients in the queue is unknown. Using a series of hypothetical scenarios, the objective of this study was to examine the extent to which clinical and non-clinical factors impacted on how patients would prioritize others relative to themselves in the coronary artery bypass surgical queue.</p> <p>Methods</p> <p>Ninety-one consecutive eligible patients awaiting coronary artery bypass grafting surgery at Sunnybrook Health Sciences Centre (median waiting-time duration prior to survey of 8 weeks) were given a self-administered survey consisting of nine scenarios in which clinical and non-clinical characteristic profiles of hypothetical patients (also awaiting coronary artery bypass surgery) were varied. For each scenario, patients were asked where in the queue such hypothetical patients should be placed relative to themselves.</p> <p>Results</p> <p>The eligible response rate was 65% (59/91). Most respondents put themselves marginally ahead of a hypothetical patient with identical clinical and non-clinical characteristics as themselves. There was a strong tendency for respondents to place patients of higher clinical acuity ahead of themselves in the queue (P < 0.0001). Social independence among young individuals was a positively valued attribute (P < 0.0001), but neither age per se nor financial status, directly impacted on patients waiting-list priority preferences.</p> <p>Conclusion</p> <p>While patient perceptions generally reaffirmed a bypass surgical triage process based on principals of equity and clinical acuity, the valuation of social independence may justify further debate with regard to the inclusion of non-clinical factors in waiting-list prioritization management systems in Canada, as elsewhere.</p

Macrostate Data Clustering

We develop an effective nonhierarchical data clustering method using an analogy to the dynamic coarse graining of a stochastic system. Analyzing the eigensystem of an interitem transition matrix identifies fuzzy clusters corresponding to the metastable macroscopic states (macrostates) of a diffusive system. A "minimum uncertainty criterion" determines the linear transformation from eigenvectors to cluster-defining window functions. Eigenspectrum gap and cluster certainty conditions identify the proper number of clusters. The physically motivated fuzzy representation and associated uncertainty analysis distinguishes macrostate clustering from spectral partitioning methods. Macrostate data clustering solves a variety of test cases that challenge other methods.Comment: keywords: cluster analysis, clustering, pattern recognition, spectral graph theory, dynamic eigenvectors, machine learning, macrostates, classificatio

Effect of Cardiac and Noncardiac Conditions on Survival After Defibrillator Implantation

ObjectivesWe sought to examine outcomes in recipients of implantable cardioverter-defibrillators (ICDs) and the effect of age, gender, and comorbidities on survival.BackgroundAge, gender, and comorbidities may significantly affect outcomes in ICD recipients.MethodsWe examined factors associated with mortality in 2,467 ICD recipients in Ontario, Canada, using a province-wide database. Comorbidities were identified retrospectively by examining all diagnosis codes within the 3 years before implant.ResultsMean ages at ICD implant were 63.2 ± 12.5 years (1,944 men) and 59.8 ± 15.9 years (523 women). Mortality rates at one and 2 years were 7.8% and 14.0%. Older age at implant increased the risk of death with hazard ratios (HR) of 2.05 (95% confidence interval [CI] 1.70 to 2.47) and 3.00 (95% CI 2.43 to 3.71) for those 65 to 74 years and ≥75 years, respectively (both p < 0.001), but gender was not a predictor of death. Common noncardiac conditions associated with death included peripheral vascular disease (adjusted HR 1.50, 95% CI 1.18 to 1.91), pulmonary disease (adjusted HR 1.35, 95% CI 1.10 to 1.66), and renal disease (adjusted HR 1.57, 95% CI 1.25 to 1.99). Many ICD recipients had prior heart failure (46.2%) with an increased HR of 2.33 for death (95% CI 1.96 to 2.76; p < 0.001). Greater comorbidity burden conferred increased risk, with HRs adjusted for age, gender, and heart failure of 1.72 (95% CI 1.44 to 2.05), 2.79 (95% CI 2.15 to 3.62), and 2.98 (95% CI 1.74 to 5.10) for those with 1, 2, and 3 or more noncardiac comorbidities, respectively (all p < 0.001).ConclusionsAge, noncardiac comorbidities, and prior heart failure influence survival outcomes in ICD recipients. These factors should be considered in the care of ICD recipients

Hybrid immunity expands the functional humoral footprint of both mRNA and vector-based SARS-CoV-2 vaccines

Funding Information: We thank Nancy Zimmerman, Mark and Lisa Schwartz, an anonymous donor (financial support), Terry and Susan Ragon, and the SAMANA Kay MGH Research Scholars award for support. We acknowledge support from the Ragon Institute of Mass General, MIT, and Harvard (to G.A.) the Massachusetts Consortium on Pathogen Readiness (MassCPR) (to G.A.), and the National Institutes of Health ( 3R37AI080289-11S1 , R01AI146785 , U19AI42790–01 , U19AI135995–02 , U19AI42790-01 , 1U01CA260476 – 01 , and CIVIC75N93019C00052 ) (to G.A.). Publisher Copyright: © 2023Despite the successes of current coronavirus disease 2019 (COVID-19) vaccines, waning immunity, the emergence of variants of concern, and breakthrough infections among vaccinees have begun to highlight opportunities to improve vaccine platforms. Real-world vaccine efficacy studies have highlighted the reduced risk of breakthrough infections and diseases among individuals infected and vaccinated, referred to as hybrid immunity. Thus, we sought to define whether hybrid immunity shapes the humoral immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) following Pfizer/BNT162b2, Moderna mRNA-1273, ChadOx1/AZD1222, and Ad26.COV2.S vaccination. Each vaccine exhibits a unique functional humoral profile in vaccination only or hybrid immunity. However, hybrid immunity shows a unique augmentation of S2-domain-specific functional immunity that was poorly induced for the vaccination only. These data highlight the importance of natural infection in breaking the immunodominance away from the evolutionarily unstable S1 domain and potentially affording enhanced cross-variant protection by targeting the more highly conserved S2 domain of SARS-CoV-2.publishersversionPeer reviewe

Hybrid immunity expands the functional humoral footprint of both mRNA and vector-based SARS-CoV-2 vaccines

Despite the successes of current coronavirus disease 2019 (COVID-19) vaccines, waning immunity, the emergence of variants of concern, and breakthrough infections among vaccinees have begun to highlight opportunities to improve vaccine platforms. Real-world vaccine efficacy studies have highlighted the reduced risk of breakthrough infections and diseases among individuals infected and vaccinated, referred to as hybrid immunity. Thus, we sought to define whether hybrid immunity shapes the humoral immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) following Pfizer/BNT162b2, Moderna mRNA-1273, ChadOx1/AZD1222, and Ad26.COV2.S vaccination. Each vaccine exhibits a unique functional humoral profile in vaccination only or hybrid immunity. However, hybrid immunity shows a unique augmentation of S2-domain-specific functional immunity that was poorly induced for the vaccination only. These data highlight the importance of natural infection in breaking the immunodominance away from the evolutionarily unstable S1 domain and potentially affording enhanced cross-variant protection by targeting the more highly conserved S2 domain of SARS-CoV-2

Global State Measures of the Dentate Gyrus Gene Expression System Predict Antidepressant-Sensitive Behaviors

Background Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are the most common form of medication treatment for major depression. However, approximately 50% of depressed patients fail to achieve an effective treatment response. Understanding how gene expression systems respond to treatments may be critical for understanding antidepressant resistance. Methods We take a novel approach to this problem by demonstrating that the gene expression system of the dentate gyrus responds to fluoxetine (FLX), a commonly used antidepressant medication, in a stereotyped-manner involving changes in the expression levels of thousands of genes. The aggregate behavior of this large-scale systemic response was quantified with principal components analysis (PCA) yielding a single quantitative measure of the global gene expression system state. Results Quantitative measures of system state were highly correlated with variability in levels of antidepressant-sensitive behaviors in a mouse model of depression treated with fluoxetine. Analysis of dorsal and ventral dentate samples in the same mice indicated that system state co-varied across these regions despite their reported functional differences. Aggregate measures of gene expression system state were very robust and remained unchanged when different microarray data processing algorithms were used and even when completely different sets of gene expression levels were used for their calculation. Conclusions System state measures provide a robust method to quantify and relate global gene expression system state variability to behavior and treatment. State variability also suggests that the diversity of reported changes in gene expression levels in response to treatments such as fluoxetine may represent different perspectives on unified but noisy global gene expression system state level responses. Studying regulation of gene expression systems at the state level may be useful in guiding new approaches to augmentation of traditional antidepressant treatments

Self-Control in Cyberspace: Applying Dual Systems Theory to a Review of Digital Self-Control Tools

Many people struggle to control their use of digital devices. However, our understanding of the design mechanisms that support user self-control remains limited. In this paper, we make two contributions to HCI research in this space: first, we analyse 367 apps and browser extensions from the Google Play, Chrome Web, and Apple App stores to identify common core design features and intervention strategies afforded by current tools for digital self-control. Second, we adapt and apply an integrative dual systems model of self-regulation as a framework for organising and evaluating the design features found. Our analysis aims to help the design of better tools in two ways: (i) by identifying how, through a well-established model of self-regulation, current tools overlap and differ in how they support self-control; and (ii) by using the model to reveal underexplored cognitive mechanisms that could aid the design of new tools.Comment: 11.5 pages (excl. references), 6 figures, 1 tabl

The relationship between depressive symptoms, health service consumption, and prognosis after acute myocardial infarction: a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>The use of cardiovascular health services is greater among patients with depressive symptoms than among patients without. However, the extent to which such associations between depressive symptoms and health service utilization are attributable to variations in comorbidity and prognostic disease severity is unknown. This paper explores the relationship between depressive symptoms, health service cardiovascular consumption, and prognosis following acute myocardial infarction (AMI).</p> <p>Methods</p> <p>The study design was a prospective cohort study with follow-up telephone interviews of 1,941 patients 30 days following AMI discharged from 53 hospitals across Ontario, Canada between December 1999 and February, 2003. Outcome measures were post discharge use of cardiac and non-cardiac health care services. The service utilization outcomes were adjusted for age, sex, income, comorbidity, two validated measures of prognosis (cardiac functional capacity and risk adjustment severity index), cardiac procedures (CABG or PTCA) and drugs prescribed at discharge.</p> <p>Results</p> <p>Depressive symptoms were associated with a 24% (Adjusted RR:1.24; 95% CI:1.19–1.30, P < 0.001), 9% (Adjusted RR:1.09; 95% CI:1.02–1.16, P = 0.007) and 43% (Adjusted RR: 1.43; 95% CI:1.34–1.52, P < 0.001) increase in total, cardiac, and non-cardiac hospitalization days post-AMI respectively, after adjusting for baseline patient and hospital characteristics. Depressive-associated increases in cardiac health service consumption were significantly more pronounced among patients of lower than higher cardiac risk severity. Depressive symptoms were not associated with increased mortality after adjusting for baseline patient characteristics.</p> <p>Conclusion</p> <p>Depressive symptoms are associated with significantly higher cardiac and non-cardiac health service consumption following AMI despite adjustments for comorbidity and prognostic severity. The disproportionately higher cardiac health service consumption among lower-risk AMI depressive patients may suggest that health seeking behaviors are mediated by psychosocial factors more so than by objective measures of cardiovascular risk or necessity.</p

Phase II Study of Nivolumab and Salvage Nivolumab/Ipilimumab in Treatment-Naive Patients With Advanced Clear Cell Renal Cell Carcinoma (HCRN GU16-260-Cohort A)

PURPOSE To determine the value of tumor cell programmed death-ligand 1 (PD-L1) expression as a predictive biomarker of nivolumab monotherapy efficacy in treatment-naive patients with clear cell renal cell carcinoma (ccRCC) and the efficacy of salvage nivolumab/ipilimumab in patients with tumors unresponsive to nivolumab monotherapy. METHODS Eligible patients with treatment-naive ccRCC received nivolumab until progressive disease (PD), toxicity, or completing 96 treatment weeks (part A). Patients with PD before or stable disease at 48 weeks could receive salvage nivolumab/ipilimumab (part B). The primary end point was improvement in 1-year progression-free survival in patients with tumor PD-L1 expression > 20% versus 0%. RESULTS One hundred twenty-three patients were enrolled. The objective response rate (ORR) was 34.1% (95% CI, 25.8 to 43.2). ORR by International Metastatic RCC Database Consortium category was favorable-risk 57.1%, intermediate-risk/poor-risk 25.0%, and by sarcomatoid features 36.4%. The ORR was 26.9%, 50.0%, and 75.0% for patients with the tumor PD-L1 expression of 0, 1-20, or > 20%, respectively (trend test P value = .002). The median duration of response was 27.6 (19.3 to not reached) months, with 26 of 42 responders including 17 of 20 with favorable-risk disease remaining progression-free. The 1-year progression-free survival was 34.6% and 75.0% in the PD-L1 = 0% and > 20% categories, respectively (P = .050). Ninety-seven patients with PD or prolonged stable disease were potentially eligible for part B, and 35 were enrolled. The ORR for part B was 11.4%. Grade >= 3 treatment-related adverse events occurred in 35% of patients on nivolumab and 43% of those on salvage nivolumab/ipilimumab. CONCLUSION Nivolumab monotherapy is active in treatment-naive ccRCC. Although efficacy appears to be less than that of nivolumab/ipilimumab in patients with intermediate-risk/poor-risk disease, favorable-risk patients had notable benefit. Efficacy correlated with tumor PD-L1 status. Salvage nivolumab/ipilimumab was frequently not feasible and of limited benefit