Unique Differentiation and Homing Features of T Cells in Individuals with Long Covid

Background: A significant portion of individuals experience persistent symptoms months after SARS-CoV-2 infection, broadly referred to as Long COVID (LC). Although the frequencies of subsets of SARS-CoV-2-specific T cells have been shown to differ in individuals with LC relative to those with complete recovery, a deep dive into phenotypic and functional features of total and SARSCoV- 2-specific T cells from individuals with LC has yet to be performed. Method(s): Here, we used CyTOF to characterize the phenotypes and effector functions of T cells from LIINC cohort. The median age was 46, the cohort was 55.8% female, and 9/43 had been hospitalized. Participants were reported a median of 7 LC symptoms at 8 months. SARS-CoV-2-specific total antibody levels were also measured in concurrent sera. Manual gating was used to define T cell subsets, SPICE analyses for polyfunctionality, T cell clustering for phenotypic features, and linear regression for correlation. Permutation tests, Student's t tests, and Welch's t test were used for statistical analysis. Result(s): SARS-CoV-2 total antibody responses were elevated in the LC group (p=0.043), and correlated with frequencies of SARS-CoV-2-specific T cells in those without LC (r=0.776, p< 0.001) but not those with LC. While the frequencies of total SARS-CoV-2-specific CD4+ and CD8+ T cells were similar between individuals with and without LC, those from individuals without LC tended to be more polyfunctional (co-expressing IFNgamma, TNFalpha, IL2, and/or MIP1beta). CD4+ T cells from individuals with LC harbored higher frequencies of Tcm (p=0.003), Tfh (p=0.037), and Treg subsets (p=0.0412), and preferentially expressed a variety of tissue homing receptors including CXCR4 and CXCR5 (p=0.037). SARS-CoV-2-specific CD4+ T cells producing IL6, albeit rare, were observed exclusively among those with LC (p=0.016). In addition, participants with LC harbored significantly higher frequencies of SARS-CoV-2-specific CD8+ T cells co-expressing exhaustion markers PD1 and CTLA4 (p=0.018). Conclusion(s): Long COVID is characterized by global phenotypic differences in the CD4+ T cell compartment in ways suggesting preferential migration of these cells to inflamed mucosal tissues. Individuals with LC also harbor higher numbers of exhausted SARS-CoV-2-specific CD8+ T cells, potentially implicating viral persistence. Finally, our data additionally suggest that individuals with LC may uniquely exhibit an uncoordinated T cell and antibody response during COVID-19 convalescence.

PLASMA-BASED ANTIGEN PERSISTENCE IN THE POST-ACUTE PHASE OF SARS-CoV-2 INFECTION

Background: There is mounting evidence regarding the frequency and spectrum of post-acute sequelae of SARS-CoV-2 infection (PASC), but a search for causes has been elusive. Recently, a plasma-based assay for SARS-CoV-2 antigen has been developed, which in initial use revealed that a high fraction of severely affected patients with PASC had circulating antigen. It is unknown whether detectable SARS-CoV-2 antigen is specific for PASC or how the assay performs in a broader clinical spectrum of patients with PASC. Method(s): We evaluated a cohort of patients with RNA-confirmed SARS-CoV-2 infection enrolled >=3 weeks following initial symptoms. Participants, both with and without PASC at enrollment, were identified via facility- and communitybased advertising and examined every 4 months. An interviewer-administered questionnaire ascertained presence of 30 different symptoms (new or worse compared to pre-COVID) in the prior 2 days at each exam. Using the single molecule array (Simoa) assay, we measured spike, S1, and nucleocapsid SARSCoV- 2 antigens in plasma collected at time of symptom assessment. Result(s): We examined 172 participants (50% men, 46% non-white, median age 46 years) who contributed 667 timepoints from 0.7 to 15.4 months following infection, at which 66% featured report of >=1 symptom. Sixty-one of 667 timepoints (9.1%) representing 24% of persons had >=1 detectable SARSCoV- 2 antigen. Among the 437 timepoints at which >=1 symptom was present, 9.8% had >=1 detectable antigen;this compares to 7.8% of timepoints at which symptoms were absent. In comparison to those without symptoms, individuals with several specific symptom complexes (gastrointestinal, musculoskeletal, and central neurologic) more commonly had detectable antigen (Figure). Hospitalization during acute COVID-19 was strongly related to antigen detection. Conclusion(s): Among a diverse group of SARS-CoV-2-infected persons in the post-acute phase of infection, SARS-CoV-2 antigen is detectable in plasma in both those with and without symptoms but more commonly in those with gastrointestinal, musculoskeletal, and central neurologic complaints. The findings indicate that antigen persists in at least some persons and suggest (but do not prove) that antigen is causally related to symptoms. That antigen is found in only a fraction of those with PASC indicates either that not all symptoms are driven by antigen, current plasma antigen detection is insensitive relative to tissue, or nominal PASC symptoms are sometimes unrelated to SARS-CoV-2. (Figure Presented).

Post-acute sequelae of SARS-CoV-2 among previously hospitalised individuals with COVID-19: a systematic literature review and meta-analysis

Introduction: Many individuals hospitalised with COVID-19 experience persistent symptoms following acute infection, known as long COVID or post-acute sequelae of COVID-19 (PASC). Objective(s): To conduct a de novo SLR and meta-analysis to identify PASC-associated symptoms in patients that required hospitalisation, and to determine frequency and temporal nature of PASC. Method(s): Searches of MEDLINE, Embase, the Cochrane Library (from 2019-2021), WHO ICTRP and reference lists were performed. Articles were assessed by two reviewers against eligibility criteria and a risk-of-bias tool. Symptom data were synthesised by random-effects meta-analyses. Result(s): Of 6,942 records found, 52 studies with >100 patients were included in this analysis, ~70% of which were Europe-based. Most collected data from the first wave of the pandemic. PASC symptoms were analysed from 28 days to 1 year after hospital discharge. At 1-4 months post-acute COVID, the most frequent symptoms were fatigue (29%;95% CI: 20-41) and dyspnea (20%;13-29). Symptom burden persisted at 4-8 and 8-12 months (Fig 1). Conclusion(s): Lasting symptoms of COVID-19 can result in clinical and societal burden long after acute infection. Further research with longer follow-up is needed to better define the duration of PASC and whether factors such as vaccination, hospitalisation status and prior treatments have an impact on PASC.

The effects of department of Veterans Affairs medical centers on socio-economic outcomes: Evidence from the Paycheck Protection Program.

Do medical facilities also help advance improvements in socio-economic outcomes? We focus on Veterans, a vulnerable group over the COVID-19 pandemic who have access to a comprehensive healthcare network, and the receipt of funds from the Paycheck Protection Program (PPP) between April and June as a source of variation. First, we find that Veterans received 3.5% more loans and 6.8% larger loans than their counterparts (p < 0.01), controlling for a wide array of zipcode characteristics. Second, we develop models to predict the number of PPP loans awarded to Veterans, finding that the inclusion of local VA medical center characteristics adds almost as much explanatory power as the industry and occupational composition in an area and even more than the education, race, and age distribution combined. Our results suggest that VA medical centers can play an important role in helping Veterans thrive even beyond addressing their direct medical needs.

Plasma Markers of Neurologic Injury and Inflammation in People With Self-Reported Neurologic Postacute Sequelae of SARS-CoV-2 Infection.

BACKGROUND AND OBJECTIVES: The biologic mechanisms underlying neurologic postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) are incompletely understood. METHODS: We measured markers of neurologic injury (glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL]) and soluble markers of inflammation among a cohort of people with prior confirmed SARS-CoV-2 infection at early and late recovery after the initial illness (defined as less than and greater than 90 days, respectively). The primary clinical outcome was the presence of self-reported CNS PASC symptoms during the late recovery time point. We compared fold changes in marker values between those with and without CNS PASC symptoms using linear mixed-effects models and examined relationships between neurologic and immunologic markers using rank linear correlations. RESULTS: Of 121 individuals, 52 reported CNS PASC symptoms. During early recovery, those who went on to report CNS PASC symptoms had elevations in GFAP (1.3-fold higher mean ratio, 95% CI 1.04-1.63, p = 0.02), but not NfL (1.06-fold higher mean ratio, 95% CI 0.89-1.26, p = 0.54). During late recovery, neither GFAP nor NfL levels were elevated among those with CNS PASC symptoms. Although absolute levels of NfL did not differ, those who reported CNS PASC symptoms demonstrated a stronger downward trend over time in comparison with those who did not report CNS PASC symptoms (p = 0.041). Those who went on to report CNS PASC also exhibited elevations in interleukin 6 (48% higher during early recovery and 38% higher during late recovery), monocyte chemoattractant protein 1 (19% higher during early recovery), and tumor necrosis factor α (19% higher during early recovery and 13% higher during late recovery). GFAP and NfL correlated with levels of several immune activation markers during early recovery; these correlations were attenuated during late recovery. DISCUSSION: Self-reported neurologic symptoms present approximately 4 months after SARS-CoV-2 infection are associated with elevations in markers of neurologic injury and inflammation at earlier time points. Some inflammatory pathways seem to be involved months after acute infection. Additional work will be needed to better characterize these processes and to identify interventions to prevent or treat this condition.

NEUROLOGIC and IMMUNOLOGIC BIOMARKERS ASSOCIATED with POST-COVID NEUROLOGIC SYMPTOMS

Background: The biologic mechanisms underlying neurologic post-acute-sequelae of SARS-CoV-2 infection (PASC) are incompletely understood. We measured plasma markers of neuronal injury (glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL]) and inflammation among a cohort of people with prior confirmed SARS-CoV-2 infection at early and late recovery following the initial illness (defined as < and > 90 days since COVID-19 onset, respectively). We hypothesized that those experiencing persistent neurologic symptoms would have elevations in these markers. Methods: The primary clinical outcome was the presence of self-reported central nervous system (CNS) PASC symptoms during the late recovery timepoint. We compared fold-changes in marker values between those with and without CNS PASC symptoms using linear mixed effects models and examined relationships between neurologic and immunologic markers using rank linear correlations. Results: Of 121 individuals, 52 reported CNS PASC symptoms. During early recovery, those who went on to report CNS PASC symptoms had elevations in GFAP (1.3-fold higher mean ratio, 95% CI 1.04-1.63, p=0.02), but not NfL (1.06-fold higher mean ratio, 95% CI 0.89-1.26, p=0.54). During late recovery, neither GFAP nor NfL levels were elevated among those with CNS PASC symptoms. Although absolute levels of NfL did not differ, those who reported CNS PASC symptoms demonstrated a stronger downward trend over time in comparison to those who did not report CNS PASC symptoms (p=0.041). Those who went on to report CNS PASC also exhibited elevations in IL-6 (48% higher during early recovery and 38% higher during late recovery), MCP-1 (19% higher during early recovery), and TNF-alpha (19% higher during early recovery and 13% higher during late recovery). GFAP and NfL correlated with levels of several immune markers during early recovery (MCP-1, IL-6, TNF-a, IFN-g);these correlations were attenuated during late recovery. Conclusion: Self-reported neurologic symptoms present approximately four months following SARS-CoV-2 infection are associated with elevations in markers of neurologic injury and inflammation at early recovery timepoints, suggesting that early injury can result in long-term disease. The correlation of GFAP and NfL with markers of systemic immune activation suggests one possible mechanism that might contribute to these symptoms. Additional work will be needed to better characterize these processes and to identify interventions to prevent or treat this condition.

Complementarities of part-time and full-time postgraduates in process systems engineering (PSE): when industry and academia merges

Academia is an arena where practitioners from industry are integrated to theoreticians. Such alliance has been intensified by the industry 4.0 (I4) age from which these counterparts are seeking to merge efforts towards society 5.0 (S5), enabling next generations to easily accept novelties and changes in well-established operations, process-of-work, behaviours, etc. In educational centres, such a pace into the I4-S5 state pushes new ways of adopting (or adapting current) sharing of work among peers since this may potentially become a tool for an efficient process-of-research. Thus, we particularly cover postgraduate centres with part-time (PT) and full-time (FT) students in the fields of process system engineering (PSE) and we are widely relying on computer aided process engineering (CAPE) tools, algorithms, software, packages, etc. A collaborative research and development of PSE-CAPE systems may a) involve PT and FT postgraduates in multi-disciplinary fields of science and engineering and b) go across physics, math, and technologies to include social sciences, public policies, and beyond. The proposition is to analyse PT-FT synergies considering their experiences, accessibility of data to validate models, viability to handle CAPE tools, etc. An example of collaboration between PT and FT students, involving a university, a research center, a consulting company, and a medical corporation, is highlighted to optimise healthcare treatment systems for social progress and sustainable development amid COVID-19. © 2021 Elsevier B.V.

Components of a safe cystectomy service during coronavirus disease 2019 in a high-volume centre

Objective: Delivery of a safe cystectomy service is a multidisciplinary exercise. In this article, we detail the measures implemented at our institution to deliver a cystectomy service for bladder cancer patients during coronavirus disease 2019 (COVID-19). Methods: A ‘one-stop’ enhanced recovery clinic had been established at our hospital, consisting of an anaesthetist, an exercise testing service, urinary diversion nurses, clinical nurse specialists and surgeons. During COVID-19, we modified these processes in order to continue to provide urgent cystectomy safely for bladder cancer. We collected patients’ outcomes prospectively measuring demographic characteristics, oncological and perioperative outcomes, the presence of COVID-19 symptoms and confirmed COVID-19 test results. Results: From March to May 2020, 25 patients underwent radical cystectomy for bladder cancer. Twenty-four procedures were performed with robotic assistance and one open as part of a research trial. We instituted modifications at various multidisciplinary steps, including patient selection, preoperative optimisation, enhanced recovery protocols, patient counselling and perioperative protocols. Thirty-day mortality was 0%. The 30-day rate of Clavien ⩾3 complications was 8%. Postoperatively, none of the patients developed COVID-19 based on World Health Organization criteria and testing. Conclusion: We safely delivered a complex cystectomy service during the peak of the COVID-19 pandemic without any COVID-19-related morbidity or mortality. Level of evidence: Level 2b.