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Background: After surviving Coronavirus Disease 2019 (COVID-19), some people develop symptoms known as post-acute sequelae of COVID-19 (PASC). PASC is an emerging phenomenon yet to be fully understood, and identifying risk factors has been challenging. This study investigated the association between the number of COVID-19 episodes and the incidence of PASC among essential workers., Methods: We analyzed data from 2511 essential workers, mainly first responders, with confirmed polymerase chain reaction, antibody, or antigen-positive test results for SARS-CoV-2 infection from March 2020 to February 2024. Data were collected through in-person questionnaires and surveys sent via text and email, internal medical records, follow-up calls, and external medical records. Participants who reported continuation or the development of new symptoms three months after the initial SARS-CoV-2 infection, with symptoms lasting for at least two months, were categorized as having PASC, while those without any COVID-19 or whose symptoms resolved were classified as non-PASC. PASC was common in this cohort so we used a Poisson regression model to compute multivariable-adjusted Relative Risk (RR) for the association between risk of PASC and SARS-CoV-2 re-infection, severity, and vaccination status at first infection., Findings: A total of 475 (prevalence = 18.9%, [95% confidence interval] = [17.4-20.5]) PASC patients were identified. The mean (standard deviation (SD)) age of participants who experienced PASC (54.8 (7.2) years) was similar to those who did not (54.2 (7.4) years). There were 403 (16.1% [14.6-17.5]) participants who experienced multiple instances of COVID-19. After adjusting for relevant demographic, lifestyle, and clinical variables, we found a significant association between the risk of experiencing PASC and multiple SARS-COV-2 infections (RR = 1.41 [1.14-1.74]), severe COVID-19 (RR = 3.17 [2.41-4.16]), and being unvaccinated at first infection (RR = 3.29 [2.46-4.41])., Interpretation: Although the pathogenetic mechanism for PASC remains unclear, identifying risk factors such as lack of vaccination or re-infection can assist in better understanding and managing the condition., Funding: National Institute on Aging (NIH/NIA R01 AG049953) and Centers for Disease Control and Prevention (CDC/NIOSH U01 OH011864) and (CDC/NIOSH U01 OH012275)., Competing Interests: We declare no competing interests., (© 2024 The Author(s).)

Background: Research into COVID-19-related cognitive decline has focused on individuals who are cognitively impaired following hospitalization for COVID-19. Our objective was to determine whether cognitive decline emerged after the onset of COVID-19 and was more pronounced in patients with postacute sequelae of SARS-CoV-2 infection (PASC)., Methods: We analyzed longitudinal cognitive data collected during a cohort study of essential workers at midlife that continued through the COVID-19 pandemic. We used longitudinal discontinuity models, a form of causal modeling, to examine the change in cognitive performance among 276 participants with COVID-19 in comparison to contemporaneously-collected information from 217 participants who did not have COVID-19. Cognitive performance across four domains was measured before and after the pandemic. Eligible study participants were those with validated COVID-19 diagnoses who were observed before having a verified COVID-19 infection who survived their initial infection, and for whom post-COVID-19 information was also available., Results: The mean age of the COVID-19 group was 56.0 ± 6.6 years old, while the control group was 58.1 ± 7.3 years old. Longitudinal models indicated a significant decline in cognitive throughput (β = -0.168, P = .001) following COVID-19, after adjustment for pre-COVID-19 functioning, demographics, and medical factors. Associations were larger in those with more severe COVID-19 and those who reported PASC. Observed changes in throughput were equivalent to 10.6 years of normal aging., Conclusion: Findings from this longitudinal causal modeling study revealed that COVID-19 and PASC appeared to cause clincially relevant cognitive deterioration., Competing Interests: We have no financial conflicts of interest to disclose., (© 2024 The Author(s).)

Symptoms of coronavirus disease 2019 (COVID-19) can persist for months or years after infection, a condition called Post-Acute Sequelae of COVID-19 (PASC). Whole-brain white matter and cortical gray matter health were assessed using multi-shell diffusion tensor imaging. Correlational tractography was utilized to dissect the nature and extent of white matter changes. In this study of 42 male essential workers, the most common symptoms of Neurological PASC (n = 24) included fatigue (n = 19) and headache (n = 17). Participants with neurological PASC demonstrated alterations to whole-brain white matter health when compared to controls made up of uninfected, asymptomatic, or mildly infected controls (n = 18). Large differences were evident between PASC and controls in measures of fractional anisotropy (Cohen's D=-0.54, P = 0.001) and cortical isotropic diffusion (Cohen's D = 0.50, P = 0.002). Symptoms were associated with white matter fractional anisotropy (fatigue: rho = -0.62, P< 0.001; headache: rho = -0.66, P < 0.001), as well as nine other measures of white and gray matter health. Brain fog was associated with improved cerebral functioning including improved white matter isotropic diffusion and quantitative anisotropy. This study identified changes across measures of white and gray matter connectivity, neuroinflammation, and cerebral atrophy that were interrelated and associated with differences in symptoms of PASC. These results provide insights into the long-term cerebral implications of COVID-19., Competing Interests: Additional Declarations: The authors have declared there is NO conflict of interest to disclose

Background: Cognitive impairment is the most common and disabling manifestation of post-acute sequelae of SARS-CoV-2. There is an urgent need for the application of more stringent methods for evaluating cognitive outcomes in research studies., Objective: To determine whether cognitive decline emerges with the onset of COVID-19 and whether it is more pronounced in patients with Post-Acute Sequelae of SARS-CoV-2 or severe COVID-19., Methods: This longitudinal cohort study compared the cognitive performance of 276 patients with COVID-19 to that of 217 controls across four neuroinflammation or vascular disease-sensitive domains of cognition using data collected both before and after the pandemic starting in 2015., Results: The mean age of the COVID-19 group was 56.04±6.6 years, while that of the control group was 58.1±7.3 years. Longitudinal models indicated a significant decline in cognitive throughput (( β =-0.168, P =.001) following COVID-19, after adjustment for pre-COVID-19 functioning, demographics, and medical factors. The effect sizes were large; the observed changes in throughput were equivalent to 10.6 years of normal aging and a 59.8% increase in the burden of mild cognitive impairment. Cognitive decline worsened with coronavirus disease 2019 severity and was concentrated in participants reporting post-acute sequelae of SARS-CoV-2., Conclusion: COVID-19 was most likely associated with the observed cognitive decline, which was worse among patients with PASC or severe COVID-19. Monitoring patients with post-acute sequelae of SARS-CoV-2 for declines in the domains of processing speed and visual working memory and determining the long-term prognosis of this decline are therefore warranted.

Programmed cell death protein 1 (PD-1) ligation delimits immunogenic responses in T cells. However, the consequences of programmed cell death 1 ligand 1 (PD-L1) ligation in T cells are uncertain. We found that T cell expression of PD-L1 in cancer was regulated by tumor antigen and sterile inflammatory cues. PD-L1 + T cells exerted tumor-promoting tolerance via three distinct mechanisms: (1) binding of PD-L1 induced STAT3-dependent 'back-signaling' in CD4 + T cells, which prevented activation, reduced T H 1-polarization and directed T H 17-differentiation. PD-L1 signaling also induced an anergic T-bet - IFN-γ - phenotype in CD8 + T cells and was equally suppressive compared to PD-1 signaling; (2) PD-L1 + T cells restrained effector T cells via the canonical PD-L1-PD-1 axis and were sufficient to accelerate tumorigenesis, even in the absence of endogenous PD-L1; (3) PD-L1 + T cells engaged PD-1 + macrophages, inducing an alternative M2-like program, which had crippling effects on adaptive antitumor immunity. Collectively, we demonstrate that PD-L1 + T cells have diverse tolerogenic effects on tumor immunity.

The drivers and the specification of CD4 + T cell differentiation in the tumor microenvironment and their contributions to tumor immunity or tolerance are incompletely understood. Using models of pancreatic ductal adenocarcinoma (PDA), we show that a distinct subset of tumor-infiltrating dendritic cells (DC) promotes PDA growth by directing a unique T H -program. Specifically, CD11b + CD103 - DC predominate in PDA, express high IL-23 and TGF-β, and induce FoxP3 neg tumor-promoting IL-10 + IL-17 + IFNγ +  regulatory CD4 + T cells. The balance between this distinctive T H program and canonical FoxP3 +  T REGS is unaffected by pattern recognition receptor ligation and is modulated by DC expression of retinoic acid. This T H -signature is mimicked in human PDA where it is associated with immune-tolerance and diminished patient survival. Our data suggest that CD11b + CD103 - DC promote CD4 + T cell tolerance in PDA which may underscore its resistance to immunotherapy.

Introduction: Liver transplantation is the most effective treatment for hepatocellular carcinoma (HCC) in eligible patients, but is not accessed equally by all. We explored the effects of race and socioeconomic factors on transplantation for HCC while controlling for stage, resection status, and transplant candidacy., Patients and Methods: All HCC patients, 2003-2013, were retrospectively analyzed using multivariate analysis to explore differences in transplantation rates among cohorts., Results: Of 3078 HCC patients, 754 (24%) were considered transplant eligible. Odds of transplantation were significantly higher for those with commercial insurance (OR = 1.99, 95% CI [1.42, 2.79]) and lower for black patients (OR = 0.55, 95% CI [0.33, 0.91]). Asians were more likely to be resected than white patients with similarly staged tumors and transplant criteria (p < 0.001). Patients not listed for transplantation for non-medical reasons were more likely to be government-insured (p = 0.02) and not white (p = 0.05). No step along the transplantation pathway was identified as the dominant hurdle., Discussion: Patients who are black or government-insured are significantly less likely to undergo transplantation for HCC despite controlling for tumor stage, resection status, and transplant eligibility. Asian patients have higher rates of hepatic resection, but also appear to have lower transplantation rates beyond this effect., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)