Large libraries of single-chain trimer peptide-MHCs enable antigen-specific CD8+ T cell discovery and analysis.

The discovery and characterization of antigen-specific CD8+ T cell clonotypes typically involves the labor-intensive synthesis and construction of peptide-MHC tetramers. We adapt single-chain trimer (SCT) technologies into a high throughput platform for pMHC library generation, showing that hundreds can be rapidly prepared across multiple Class I HLA alleles. We use this platform to explore the impact of peptide and SCT template mutations on protein expression yield, thermal stability, and functionality. SCT libraries were an efficient tool for identifying T cells recognizing commonly reported viral epitopes. We then construct SCT libraries to capture SARS-CoV-2 specific CD8+ T cells from COVID-19 participants and healthy donors. The immunogenicity of these epitopes is validated by functional assays of T cells with cloned TCRs captured using SCT libraries. These technologies should enable the rapid analyses of peptide-based T cell responses across several contexts, including autoimmunity, cancer, or infectious disease.

The outcomes of same-day discharge following holmium laser enucleation of the prostate (HoLEP) surgeries: our experience during the COVID-19 pandemic.

OBJECTIVE: To describe the outcomes of Same-Day Discharge (SDD) following Holmium Laser Enucleation of the Prostate (HoLEP) in patients during the COVID-19 pandemic. METHODS: A retrospective review of HoLEP surgeries at a single institution between January 2021 and March 2022 was performed. Patient demographic and operative data were collected, and postoperative outcomes were evaluated in terms of safety and efficacy and compared in both groups using a t-test and chi-square test. Logistic regression was also performed to identify factors that correlate with the failure of SDD. RESULTS: A total of 155 patients were identified; 135 patients were successfully discharged on the same day and 20 were admitted (87% SDD rate). Admitted HoLEP patients had a significantly higher median prostate-specific antigen (5.7 vs 3.9 ng/dL, P < 0.001), prostate volume (152.3 vs 100.6 mL, P < 0.001), and enucleated tissue weight (90.3 vs 56.9 g, P = 0.04) compared to the SDD group. The SDD group had a 2.9% (n = 4) readmission rate and a 5.2% (n = 7) Emergency Department (ED) visit rate. There was no significant difference in the rate of postoperative ED visits (P = 0.64), readmissions (P = 0.98), complications, and catheterization time (P = 0.98) between both groups. Preoperative predictors of SDD failure included prostate gland volume > 150 mL (OR = 7.17; CI 2.01-25.67; P < 0.01) and history of antiplatelet/anticoagulation use (OR = 6.59; CI 2.00-21.67; P < 0.01). CONCLUSION: Same-day discharge following HoLEP is a safe and effective approach that can be performed in most patients using a liberal discharge criteria and relying on postoperative findings only.

Diminished cell proliferation promotes natural killer cell adaptive-like phenotype by limiting FcεRIγ expression.

Human adaptive-like natural killer (NK) cells express low levels of FcεRIγ (FcRγ-/low) and are reported to accumulate during COVID-19 infection; however, the mechanism underlying and regulating FcRγ expression in NK cells has yet to be fully defined. We observed lower FcRγ protein expression in NK cell subsets from lung transplant patients during rapamycin treatment, suggesting a link with reduced mTOR activity. Further, FcRγ-/low NK cell subsets from healthy donors displayed reduced mTOR activity. We discovered that FcRγ upregulation is dependent on cell proliferation progression mediated by IL-2, IL-15, or IL-12, is sensitive to mTOR suppression, and is inhibited by TGFß or IFNα. Accordingly, the accumulation of adaptive-like FcRγ-/low NK cells in COVID-19 patients corresponded to increased TGFß and IFNα levels and disease severity. Our results show that an adaptive-like NK cell phenotype is induced by diminished cell proliferation and has an early prognostic value for increased TGFß and IFNα levels in COVID-19 infection associated with disease severity.

Reinfection with SARS-CoV-2 and Waning Humoral Immunity: A Case Report.

Recovery from COVID-19 is associated with production of anti-SARS-CoV-2 antibodies, but it is uncertain whether these confer immunity. We describe viral RNA shedding duration in hospitalized patients and identify patients with recurrent shedding. We sequenced viruses from two distinct episodes of symptomatic COVID-19 separated by 144 days in a single patient, to conclusively describe reinfection with a different strain harboring the spike variant D614G. This case of reinfection was one of the first cases of reinfection reported in 2020. With antibody, B cell and T cell analytics, we show correlates of adaptive immunity at reinfection, including a differential response in neutralizing antibodies to a D614G pseudovirus. Finally, we discuss implications for vaccine programs and begin to define benchmarks for protection against reinfection from SARS-CoV-2.

The impact of COVID-19 and rapid policy exemptions expanding on access to medication for opioid use disorder (MOUD): A nationwide Veterans Health Administration cohort study.

BACKGROUND: In March 2020, Veterans Health Administration (VHA) enacted policies to expand treatment for Veterans with opioid use disorder (OUD) during COVID-19. In this study, we evaluate whether COVID-19 and subsequent OUD treatment policies impacted receipt of therapy/counseling and medication for OUD (MOUD). METHODS: Using VHA's nationwide electronic health record data, we compared outcomes between a comparison cohort derived using data from prior to COVID-19 (October 2017-December 2019) and a pandemic-exposed cohort (January 2019-March 2021). Primary outcomes included receipt of therapy/counseling or any MOUD (any/none); secondary outcomes included the number of therapy/counseling sessions attended, and the average percentage of days covered (PDC) by, and months prescribed, each MOUD in a year. RESULTS: Veterans were less likely to receive therapy/counseling over time, especially post-pandemic onset, and despite substantial increases in teletherapy. The likelihood of receiving buprenorphine, methadone, and naltrexone was reduced post-pandemic onset. PDC on MOUD generally decreased over time, especially methadone PDC post-pandemic onset, whereas buprenorphine PDC was less impacted during COVID-19. The number of months prescribed methadone and buprenorphine represented relative improvements compared to prior years. We observed important disparities across Veteran demographics. CONCLUSION: Receipt of treatment was negatively impacted during the pandemic. However, there was some evidence that coverage on methadone and buprenorphine may have improved among some veterans who received them. These medication effects are consistent with expected COVID-19 treatment disruptions, while improvements regarding access to therapy/counseling via telehealth, as well as coverage on MOUD during the pandemic, are consistent with the aims of MOUD policy exemptions.

Tobacco control measures in COVID-19 recovery: an opportune time to restore equity and planetary health.

Tobacco intersects with the COVID-19 pandemic not only in terms of health consequences, but also environmental change and planetary health. Tobacco use exacerbates inequalities, causes catastrophic environmental degradation and climate change and adds burdens to COVID-19-related mortality, which are major challenges to recovery from the COVID-19 pandemic. However, the pandemic has provided a chance to combat tobacco use and accelerate efforts to alleviate these challenges in response. The MPOWER measures introduced by the World Health Organization Framework Convention on Tobacco Control (WHO FCTC) can play a crucial role in COVID-19 recovery to fight tobacco use and contribute to sustainable and equitable development. To accelerate recovery, it is critical to call for actions for governments and policy-makers to strengthen synergies and coordinate policy actions emphasising tobacco control and cessation across equity, public health, and climate actions as global authorities pledge to achieve the Sustainable Development Goals (SDGs) and net zero emissions targets as part of the Climate Change Conference 2021 (COP26).

Multiple early factors anticipate post-acute COVID-19 sequelae.

Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific auto-antibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes, exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time, leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.

Babesiosis as a Cause of Atraumatic Splenic Injury: Two Case Reports and a Review of Literature.

We present two cases of Babesia-induced splenic injury at a single institution. In the late summer, two patients presented with left-sided abdominal pain radiating to the shoulder. They were both found to have hemolytic anemia, thrombocytopenia, and acute splenic infarction on imaging. Blood smears showed intracellular ring forms consistent with Babesia spp. and low parasitemia (<1%). Diagnosis was confirmed by PCR for Babesia microti. Both patients improved with azithromycin and atovaquone, without blood products or surgical intervention. Several weeks following treatment, repeat blood smears revealed no parasites. Splenic infarct and hemorrhage have been previously reported as rare complications of babesiosis. However, given the steady rise in Babesia microti cases in the USA, even these rare complications will become more prevalent. We review both the diagnosis and management of Babesia-induced splenic complications, which can be challenging in patients with low-level parasitemia. Clinicians should consider babesiosis as a cause of atraumatic splenic injury.

COVID-19 within families amplifies the prosociality gap between adolescents of high and low socioeconomic status.

COVID-19 has had worse health, education, and labor market effects on groups with low socioeconomic status (SES) than on those with high SES. Little is known, however, about whether COVID-19 has also had differential effects on noncognitive skills that are important for life outcomes. Using panel data from before and during the pandemic, we show that COVID-19 affects one key noncognitive skill, that is, prosociality. While prosociality is already lower for low-SES students prior to the pandemic, we show that COVID-19 infections within families amplify the prosociality gap between French high school students of high and low SES by almost tripling its size in comparison to pre-COVID-19 levels.

Early IFN-α signatures and persistent dysfunction are distinguishing features of NK cells in severe COVID-19.

Longitudinal analyses of the innate immune system, including the earliest time points, are essential to understand the immunopathogenesis and clinical course of coronavirus disease (COVID-19). Here, we performed a detailed characterization of natural killer (NK) cells in 205 patients (403 samples; days 2 to 41 after symptom onset) from four independent cohorts using single-cell transcriptomics and proteomics together with functional studies. We found elevated interferon (IFN)-α plasma levels in early severe COVD-19 alongside increased NK cell expression of IFN-stimulated genes (ISGs) and genes involved in IFN-α signaling, while upregulation of tumor necrosis factor (TNF)-induced genes was observed in moderate diseases. NK cells exert anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) activity but are functionally impaired in severe COVID-19. Further, NK cell dysfunction may be relevant for the development of fibrotic lung disease in severe COVID-19, as NK cells exhibited impaired anti-fibrotic activity. Our study indicates preferential IFN-α and TNF responses in severe and moderate COVID-19, respectively, and associates a prolonged IFN-α-induced NK cell response with poorer disease outcome.

Integrated analysis of plasma and single immune cells uncovers metabolic changes in individuals with COVID-19.

A better understanding of the metabolic alterations in immune cells during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may elucidate the wide diversity of clinical symptoms experienced by individuals with coronavirus disease 2019 (COVID-19). Here, we report the metabolic changes associated with the peripheral immune response of 198 individuals with COVID-19 through an integrated analysis of plasma metabolite and protein levels as well as single-cell multiomics analyses from serial blood draws collected during the first week after clinical diagnosis. We document the emergence of rare but metabolically dominant T cell subpopulations and find that increasing disease severity correlates with a bifurcation of monocytes into two metabolically distinct subsets. This integrated analysis reveals a robust interplay between plasma metabolites and cell-type-specific metabolic reprogramming networks that is associated with disease severity and could predict survival.

Association of Jail Decarceration and Anticontagion Policies With COVID-19 Case Growth Rates in US Counties.

Importance: Mass incarceration is known to foster infectious disease outbreaks, amplification of infectious diseases in surrounding communities, and exacerbation of health disparities in disproportionately policed communities. To date, however, policy interventions intended to achieve epidemic mitigation in US communities have neglected to account for decarceration as a possible means of protecting public health and safety. Objective: To evaluate the association of jail decarceration and government anticontagion policies with reductions in the spread of SARS-CoV-2. Design, Setting, and Participants: This cohort study used county-level data from January to November 2020 to analyze COVID-19 cases, jail populations, and anticontagion policies in a panel regression model to estimate the association of jail decarceration and anticontagion policies with COVID-19 growth rates. A total of 1605 counties with data available on both jail population and COVID-19 cases were included in the analysis. This sample represents approximately 51% of US counties, 72% of the US population, and 60% of the US jail population. Exposures: Changes to jail populations and implementation of 10 anticontagion policies: nursing home visitation bans, school closures, mask mandates, prison visitation bans, stay-at-home orders, and closure of nonessential businesses, gyms, bars, movie theaters, and restaurants. Main Outcomes and Measures: Daily COVID-19 case growth rates. Results: In the 1605 counties included in this study, the mean (SD) prison population was 283.38 (657.78) individuals, and the mean (SD) population was 315.24 (2151.01) persons per square mile. An estimated 80% reduction in US jail populations, achievable through noncarceral management of nonviolent alleged offenses and in line with average international incarceration rates, would have been associated with a 2.0% (95% CI, 0.8%-3.1%) reduction in daily COVID-19 case growth rates. Jail decarceration was associated with 8 times larger reductions in COVID-19 growth rates in counties with above-median population density (4.6%; 95% CI, 2.2%- 7.1%) relative to those below this median (0.5%; 95% CI, 0.1%-0.9%). Nursing home visitation bans were associated with a 7.3% (95% CI, 5.8%-8.9%) reduction in COVID-19 case growth rates, followed by school closures (4.3%; 95% CI, 2.0%-6.6%), mask mandates (2.5%; 95% CI, 1.7%-3.3%), prison visitation bans (1.2%; 95% CI, 0.2%-2.2%), and stay-at-home orders (0.8%; 95% CI, 0.1%-1.6%). Conclusions and Relevance: Although many studies have documented that high incarceration rates are associated with communitywide health harms, this study is, to date, the first to show that decarceration is associated with population-level public health benefits. Its findings suggest that, among other anticontagion interventions, large-scale decarceration and changes to pretrial detention policies are likely to be important for improving US public health, biosecurity, and pandemic preparedness.

Carceral-community epidemiology, structural racism, and COVID-19 disparities.

Black and Hispanic communities are disproportionately affected by both incarceration and COVID-19. The epidemiological relationship between carceral facilities and community health during the COVID-19 pandemic, however, remains largely unexamined. Using data from Cook County Jail, we examine temporal patterns in the relationship between jail cycling (i.e., arrest and processing of individuals through jails before release) and community cases of COVID-19 in Chicago ZIP codes. We use multivariate regression analyses and a machine-learning tool, elastic regression, with 1,706 demographic control variables. We find that for each arrested individual cycled through Cook County Jail in March 2020, five additional cases of COVID-19 in their ZIP code of residence are independently attributable to the jail as of August. A total 86% of this additional disease burden is borne by majority-Black and/or -Hispanic ZIPs, accounting for 17% of cumulative COVID-19 cases in these ZIPs, 6% in majority-White ZIPs, and 13% across all ZIPs. Jail cycling in March alone can independently account for 21% of racial COVID-19 disparities in Chicago as of August 2020. Relative to all demographic variables in our analysis, jail cycling is the strongest predictor of COVID-19 rates, considerably exceeding poverty, race, and population density, for example. Arrest and incarceration policies appear to be increasing COVID-19 incidence in communities. Our data suggest that jails function as infectious disease multipliers and epidemiological pumps that are especially affecting marginalized communities. Given disproportionate policing and incarceration of racialized residents nationally, the criminal punishment system may explain a large proportion of racial COVID-19 disparities noted across the United States.

Inequality-Related Health and Social Factors and Their Impact on Well-Being during the COVID-19 Pandemic: Findings from a National Survey in the UK.

Background: Lower socioeconomic groups and disadvantaged populations across the world suffer disproportionately from the coronavirus disease 2019 (COVID-19) pandemic. This study aimed to examine the impact of health- and social-inequality-related factors on well-being in order to further distinguish each of their effects during the pandemic. Methods: A nationally-representative sample of 5077 UK respondents aged 18 years or older was recruited through an online survey panel during the COVID-19 pandemic. Their subjective well-being was measured using the 11-point Cantril Ladder of Life Scale. The impact of inequality-related health and social factors (pre-existing medical conditions, household size and occupation), as well as COVID-19-related risk factors (symptoms, confirmed infections, and social distancing behaviours) on well-being were analysed using multiple linear regression models. The associations between the COVID-19-related risk factors and well-being according to the respondents' household size and occupation were modelled in order to test the differences by their socioeconomic profile. Results: We identified inverted V-shaped associations between household size and subjective well-being during the COVID-19 pandemic. Compared to single-person households, respondents from households of two to four persons showed better well-being (ß = 0.57; CI (0.44, 0.72)), whereas living in crowded households of five persons or more was associated with decreased well-being (ß = -0.48; CI (-0.71, -0.25)). Furthermore, lower-skilled occupations (elementary occupations: ß = -0.31; CI (-0.58, -0.03); logistics and transport services: ß = -0.37; CI (-0.74, -0.01)) and chronic medical conditions (cardiometabolic or respiratory diseases: ß = -0.25; CI (-0.41, -0.1); and mental health conditions: ß = -1.12; CI (-1.28, -0.96)) were factors associated with reduced well-being during the pandemic. Interactions between a positive COVID-19 diagnosis, symptoms, and crowded households were identified (ß = -0.95; CI (-1.76, -0.14) and ß = -4.74; CI (-9.87, -1.61), respectively). Conclusions: In a national sample, the levels of general subjective well-being during the COVID-19 pandemic and lockdowns were disproportionately distributed across different groups within society. Preventive policies should explicitly focus on reaching lower socioeconomic groups; more emphasis should be placed on the coordination of multisectoral support in order to tackle existing health and social inequalities.

Multi-Omics Resolves a Sharp Disease-State Shift between Mild and Moderate COVID-19.

We present an integrated analysis of the clinical measurements, immune cells, and plasma multi-omics of 139 COVID-19 patients representing all levels of disease severity, from serial blood draws collected during the first week of infection following diagnosis. We identify a major shift between mild and moderate disease, at which point elevated inflammatory signaling is accompanied by the loss of specific classes of metabolites and metabolic processes. Within this stressed plasma environment at moderate disease, multiple unusual immune cell phenotypes emerge and amplify with increasing disease severity. We condensed over 120,000 immune features into a single axis to capture how different immune cell classes coordinate in response to SARS-CoV-2. This immune-response axis independently aligns with the major plasma composition changes, with clinical metrics of blood clotting, and with the sharp transition between mild and moderate disease. This study suggests that moderate disease may provide the most effective setting for therapeutic intervention.

The psychosocial impact of the COVID-19 pandemic on changes in smoking behavior: Evidence from a nationwide survey in the UK.

INTRODUCTION: The stress and anxiety during this unprecedented public health crisis may lead current smokers to increase tobacco use or former smokers to relapse. Thus, this study aims to provide epidemiological evidence of the changes in smoking behavior among British smokers in response to the COVID-19 pandemic and assess the impact of psychosocial factors on these behaviors. METHODS: A nationwide survey of a representative sample of 4075 UK respondents aged >16 years was conducted between 27 April and 24 May 2020 during the COVID-19 pandemic. Psychosocial and demographic variables between different smoking behavior groups were compared using Pearson's χ2 test and Cramer's V. RESULTS: Among current smokers (n=329), one-quarter (25.2%, n=86) reported smoking more than usual, 50.9% (n=174) reported smoking the same amount, and 20.2% (n=69) reported smoking less. Significant associations were observed between different smoking behavior groups and psychosocial factors. Pearson's χ2 test revealed significant differences between different smoking behavior groups in their concerns about mental health (p<0.001), anxiety (p<0.001) and stress (p<0.001), state of low mood (p=0.012), in the Patient Health Questionnaire (PHQ) score (p=0.018) and ranking on the Cantril Ladder scale (p<0.001). Many respondents expressed that the pandemic had a more negative impact on their mental health and the impact was more pronounced among those who smoked more. CONCLUSIONS: Deterioration of mental health and psychosocial well-being were linked to increased smoking. Public health authorities should take proactive measures to provide mental healthcare and smoking cessation support as preventive measures to tackle the pandemic.

Incarceration And Its Disseminations: COVID-19 Pandemic Lessons From Chicago's Cook County Jail.

Jails and prisons are major sites of novel coronavirus (SARS-CoV-2) infection. Many jurisdictions in the United States have therefore accelerated the release of low-risk offenders. Early release, however, does not address how arrest and pretrial detention practices may be contributing to disease spread. Using data from Cook County Jail-one of the largest known nodes of SARS-CoV-2 spread in the United States-in Chicago, Illinois, we analyzed the relationship between jailing practices and community infections at the ZIP code level. We found that jail-community cycling was a significant predictor of cases of coronavirus disease 2019 (COVID-19), accounting for 55 percent of the variance in case rates across ZIP codes in Chicago and 37 percent of the variance in all of Illinois. Jail-community cycling far exceeds race, poverty, public transit use, and population density as a predictor of variance. The data suggest that cycling people through Cook County Jail alone is associated with 15.7 percent of all documented COVID-19 cases in Illinois and 15.9 percent of all documented cases in Chicago as of April 19, 2020. Our findings support arguments for reduced reliance on incarceration and for related justice reforms both as emergency measures during the present pandemic and as sustained structural changes vital for future pandemic preparedness and public health.