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The relationship between SARS-CoV-2-specific T cell responses and COVID-19 risk is incompletely understood, particularly after variant-adapted booster receipt. We assessed Spike-specific and Nucleocapsid-specific CD4+ and CD8+ T cell responses, measured by validated 27-color intracellular cytokine staining assay, as correlates of COVID-19 risk over 6 months in COVAIL recipients of a second SARS-CoV-2 booster on Day 1 (D1). Among one-dose mRNA recipients, D15 CD4+ T cell IFN-γ and/or IL-2 Spike BA.4/5 responses correlated inversely with COVID-19 risk for previously-infected (non-naïve) [hazard ratio (HR) = 0.62 (95% CI 0.39, 0.99) per 3-fold increase], but not SARS-CoV-2 naïve [HR = 1.03 (0.81, 1.32)], participants (22 non-naïve, 122 naïve cases). Spike-specific CD4+ T cells and neutralizing antibodies each independently predicted COVID-19 in non-naïve participants [Cox bivariate model HRs per standard deviation: D1 Spike CD4+ T cell 0.81 (0.68, 0.96), D15 titer 0.43 (0.27, 0.69), co-correlate p < 0.001]. Among non-naïve participants, high Spike-specific CD4+ T cell responses and neutralizing antibody titers marked low risk, as did polyfunctional Spike-specific CD4+ T cells expressing ≥ three cytokine(s)/markers. At the same high D15 CD4+ Spike-specific T cell levels, risk was lower for non-naïve vs. naïve participants, suggesting that these T cell responses are a proxy for unmeasured protective immune mechanism(s) operant post-SARS-CoV-2 infection.

Background: Patients taking direct oral anticoagulants (DOACs), warfarin, or dual antiplatelet therapy (DAPT) who present with acute Type A aortic dissection (ATAAD) are a unique challenge. Our objective was to investigate the surgical outcomes of this patient population. Methods: A retrospective cohort study was performed of 20,530 patients who underwent first-time sternotomy repair of ATAAD in the Society of Thoracic Surgeons Adult Cardiac Surgery Database from 2017 to 2022. Propensity score matching was used to pair each DOAC (n=625), warfarin (n=245), and DAPT (n=525) patient with 2 controls. Outcomes included operative mortality and reoperation for bleeding. Results: Compared to matched controls, mortality was higher for patients on DOACs (24.8% vs 17.9%, OR 1.50 [1.2,2.0], p<0.001), warfarin (26.7% vs 19.2%, OR 1.6 [1.1,2.4], p=0.02), or DAPT (27.4% vs 20.1%, OR 1.5 [1.2,2.0], p=0.001). Reoperation for bleeding was higher for DOACs (12.0% vs 7.0%, OR 1.8 [1.3,2.5], p=0.001) and DAPT (15.2% vs 7.3%, OR 2.2 [1.6,3.2], p<0.001), and trended that way for warfarin (11.4% vs 7.8%, OR 1.5 [0.9,2.6], p=0.11). Most DOAC (76.5% [478/625]) and DAPT (71.2% [374/525]) patients underwent surgery on the day of admission. While there was a non-significant difference toward lower mortality for DOAC patients who had surgery on day ≥1 (17.4% vs 25.0%, p=0.08), there was no difference for those on DAPT. Conclusions: Patients undergoing first-time surgery for ATAAD on DOACs, DAPT, or warfarin preoperatively had increased mortality and bleeding complications. For those on DOACs or DAPT, further study is required to investigate whether delaying surgery impacts outcomes.

T cell correlates of COVID-19 risk are poorly defined, particularly in people with HIV (PWH). CoVPN 3008 (NCT05168813) Part A was a prospective 14,002-participant cohort study that administered one or two doses of mRNA-1273 COVID-19 vaccine, depending on baseline SARS-CoV-2 serostatus, in participants (83% PWH) in sub-Saharan Africa. Participants self-monitored for prespecified COVID-19 symptoms, defined by Centers for Disease Control and Prevention symptom criteria. Previous work showed that protection from COVID-19 was superior for hybrid versus vaccine-induced immunity, and that neutralizing antibody titers inversely associated with COVID-19 risk. In the present work, we measured T cell responses to Spike and Nucleocapsid at baseline and 4 weeks post last-vaccination (Peak) in a case-cohort study and assessed them as correlates of risk. In Hybrid Group PWH (n = 22 cases), COVID-19 risk over 6 months decreased with increasing Peak Spike BA.4/5-specific CD4 + T cell responses, from 15.8%, 4.7%, and 0% risk at 0.1%, 0.2%, and 0.3% IFN-γ and/or IL-2 response magnitude, respectively. Including baseline Spike-specific neutralizing antibody titer and Peak CD4 + T cell functionality score in the same model increased the association’s strength (overall p < 0.001). Thus, CD4 + T cell responses are an independent correlate of COVID-19 risk among PWH with pre-existing SARS-CoV-2 immunity.

Background: Intraoperative transesophageal echocardiography (TEE) is used in approximately half of isolated coronary artery bypass grafting (CABG) procedures in the United States, yet its routine use remains unsupported by randomized evidence. Objectives: The objective of the study was to assess the feasibility and protocol adherence of routine vs selective intraoperative TEE strategies during isolated CABG surgery. Methods: We conducted a pragmatic, randomized feasibility trial at 2 tertiary-care hospitals within a single health system. Adults undergoing isolated CABG for whom both strategies were clinically acceptable were randomized 1:1 to TEE-by-default (routine use) or TEE-on-demand (selective use). In the selective group, TEE was performed as clinically indicated. Primary feasibility outcomes included enrollment, successful randomization, and protocol adherence. Exploratory outcomes included perioperative clinical events, patient-centered recovery measures, and TEE-related adverse events. Results: A total of 274 patients were screened and 72 were eligible. Of these, 46 (64%) consented, and 40 (56% of eligible; 87% of consented) were randomized following induction of anesthesia (20 per group). Protocol adherence was high (39/40; 98%) with 1 allocation error. In the TEE-on-demand arm, 3 of 20 patients (15%) underwent clinically triggered TEE. No deaths occurred within 90 days. Three serious adverse events were adjudicated as related to TEE exposure including 2 esophageal complications and 1 conversion to combined CABG and mitral valve replacement. Conclusions: In this pragmatic randomized feasibility trial, both TEE strategies were successfully implemented with high protocol adherence and preserved clinician and patient equipoise, supporting a multicenter randomized trial evaluating routine vs selective TEE during isolated CABG.

A key objective in vaccine studies is to evaluate vaccine-induced immunogenicity and determine whether participants have mounted a response to the vaccine. Cellular immune responses are essential for assessing vaccine-induced immunogenicity, and single-cell assays, such as intracellular cytokine staining (ICS) and B-cell phenotyping (BCP), are commonly employed to profile individual immune cell phenotypes and the cytokines they produce after stimulation. In this article, we introduce a novel statistical framework for identifying vaccine responders using ICS data collected before and after vaccination. This framework incorporates paired control data to account for potential unintended variations between assay runs, such as batch effects, that could lead to misclassification of participants as vaccine responders or non-responders. To formally integrate paired control data for accounting for assay variation across different time points (ie before and after vaccination), our proposed framework calculates and reports two values, both adjusting for paired control data but in distinct ways: (i) the maximally adjusted value, which applies the most conservative adjustment to the unadjusted value, ensuring validity over all plausible batch effects consistent with the paired control samples’ data, and (ii) the minimally adjusted value, which imposes only the minimal adjustment to the unadjusted value, such that the adjusted value cannot be falsified by the paired control samples’ data. Minimally and maximally adjusted values offer a balanced approach to managing Type I error rates and statistical power in the presence of batch effects. We apply this framework to analyze ICS data collected at baseline and 4 wks post-vaccination from the COVID-19 Prevention Network (CoVPN) 3008 study. Our analysis helps address two clinical questions: (i) which participants exhibited evidence of an incident Omicron infection between baseline and 4 wks after receiving the final dose of the primary vaccination series, and (ii) which participants showed vaccine-induced T cell responses against the Omicron BA.4/5 Spike protein.

In this cohort study of 1.26 million patients who underwent isolated CABG, intraoperative TEE was associated with survival benefits at low and medium surgical volume hospitals, particularly among patients with greater than 50% left-main coronary stenosis, 3 or more diseased vessels, or preoperative inotrope use. No survival benefit was observed at high surgical volume hospitals.These findings support a more individualized approach to TEE use during isolated CABG surgery and provide a rationale for future randomized evaluation.

In febrile comatose patients living in malaria-endemic areas, overlapping symptoms and limited laboratory capacity make it difficult to distinguish parasitic, bacterial, and viral central nervous system infections. We evaluated electroencephalography (EEG) as a biomarker to differentiate the microbiologic etiology of pediatric febrile coma at a major referral center in Malawi.This was a retrospective case-control study comparing EEG recordings of Malawian children with cerebral malaria to those with febrile coma of nonmalarial cause (bacterial meningitis, viral encephalitis, or unknown cause). Participants were admitted to Queen Elizabeth Central Hospital (Blantyre, Malawi) between 2013 and 2021. Inclusion criteria were fever, coma (Blantyre Coma Score ≤2), and coma etiology (malarial or nonmalarial) defined by laboratory testing. Four supervised machine learning algorithms were used to train a balanced ensemble classifier, SuperLearner, generating test characteristics of the diagnostic ability of EEG features.Two hundred three children with cerebral malaria and 87 children with nonmalarial coma were included. Univariate analysis of qualitative (visual) EEG interpretations revealed higher voltage, slower background frequency, more sleep elements, less variability, more abnormal organization, and less continuity in cerebral malaria. Quantitative waveform analysis showed greater power in cerebral malaria. Both quantitative and qualitative EEG interpretation distinguished coma etiology (area under the receiver operating characteristic curve [AUROC] = 0.85 and 0.86, respectively). Combining qualitative and quantitative interpretation methods, the test characteristic improved (AUROC = 0.90).EEG features distinguish malarial from nonmalarial coma in febrile Malawian children. This technology may aid in distinguishing the microbiologic etiology of febrile coma in malaria-endemic areas.

People with HIV (PWH) are understudied in COVID-19 vaccine trials, leaving knowledge gaps on whether the identified immune correlates of protection also hold in PWH. CoVPN 3008 (NCT05168813) enrolled predominantly PWH and reported lower COVID-19 incidence for a Hybrid vs. Vaccine Group (baseline SARS-CoV-2-positive and one mRNA-1273 dose vs. negative and two doses). Using case-cohort sampling, antibody markers at enrolment (M0) and four weeks post-final vaccination (Peak) are assessed as immune correlates of COVID-19. For the Hybrid Group [n = 287 (195 PWH)], all M0 markers inversely correlate with COVID-19 through 230 days post-Peak, with 50% inhibitory dilution BA.4/5 neutralizing antibody titer (nAb-ID50 BA.4/5) the strongest and only independent correlate (HR per 10-fold increase=0.46, 95% CI 0.28, 0.75; P = 0.002). For the Vaccine Group [n = 115 (86 PWH)], Peak nAb-ID50 BA.4/5 correlates with reduced COVID-19 risk (1.9%, 1.1%, and 0.3% at titers 10, 100, and 1000 AU/ml) through 92, but not 165, days post-Peak. Using multivariable Cox analysis of binding and nAb, nAb titers predict COVID-19 in PWH. Two doses of a 100-µg Ancestral strain mRNA vaccine in baseline-SARS-CoV-2-negative individuals elicit sufficient cross-reacting Omicron antibodies to reduce COVID-19 incidence for 90 days post-Peak, but viral evolution and waning antibodies abrogate this protection thereafter.

Covid-19 vaccines are updated to match circulating strains based on reasoning that better strain-matched immunogenicity should provide better protection. Randomized evidence with disease endpoints to support strain matching is lacking. We evaluated COVID-19 incidence among adults randomized to a second booster of Prototype or Omicron-based vaccines. COVAIL was a four-stage Phase 2 clinical trial; results from Stages 1 (mRNA-1273 [Moderna]) and 2 (BNT162b2 [Pfizer/BioNTech]) are described here. Adults who had received a primary series and one booster of an authorized COVID-19 vaccine were eligible. Participants received one dose of either Prototype vaccine or a monovalent or bivalent Omicron BA.1 vaccine. SARS-CoV-2 neutralization titers (ID50) were measured pre- and post-vaccination. Covariate-adjusted cumulative COVID-19 incidence and Cox regression analyses were conducted separately for each stage. 706 participants with pre- and day 15 post-vaccination ID50 titers (n = 503 in Stage 1, n = 203 in Stage 2) were included. Within stages, participant characteristics and baseline ID50 titers were similar between Prototype and Omicron-based arms. There was no difference in cumulative COVID-19 incidence for Prototype vs. Omicron-based vaccine in Stage 1 (RR 1.04, 95 % CI 0.73–1.48), while incidence was higher among Prototype recipients in Stage 2 (RR 2.56, 1.44–4.52). Cox regression analysis showed no difference in Stage 1 (HR 1.04, 0.68–1.58), but higher incidence for Prototype recipients in Stage 2 (HR 2.95, 1.52–5.72). Omicron-based vaccines as second boosters were more protective against COVID-19 relative to Prototype among those receiving BNT162b2 but not mRNA-1273. Differences between stages such as force of infection, antigen matching, and vaccine differences may explain this finding.