Covid and the common good: In-group out-group dynamics and Covid-19 vaccination in Wales and the United States.

Vaccination is a social act, where benefits spill-over to third parties. How we approach such social decisions is influenced by whether likely beneficiaries share salient social identities with us. This study explores these dynamics using representative survey data from two contexts: national identity groups in Wales (N = 4187) and political partisans in America (N = 4864). In both cases, those in the minority in their local area were less likely to be vaccinated. In Wales, respondents who did not identify as Welsh were less likely to be vaccinated the greater the proportion of residents of their local area identified as Welsh. In America, the vaccination rate of Biden voters fell off more steeply than that of Trump voters as the proportion of Trump voters in their county increased. Results are robust to controlling for likely confounds and sensitivity analyses. In-group out-group dynamics help to shape important health decisions.

Novel machine-learning analysis of SARS-CoV-2 infection in a subclinical nonhuman primate model using radiomics and blood biomarkers.

Detection of the physiological response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is challenging in the absence of overt clinical signs but remains necessary to understand a full subclinical disease spectrum. In this study, our objective was to use radiomics (from computed tomography images) and blood biomarkers to predict SARS-CoV-2 infection in a nonhuman primate model (NHP) with inapparent clinical disease. To accomplish this aim, we built machine-learning models to predict SARS-CoV-2 infection in a NHP model of subclinical disease using baseline-normalized radiomic and blood sample analyses data from SARS-CoV-2-exposed and control (mock-exposed) crab-eating macaques. We applied a novel adaptation of the minimum redundancy maximum relevance (mRMR) feature-selection technique, called mRMR-permute, for statistically-thresholded and unbiased feature selection. Through performance comparison of eight machine-learning models trained on 14 feature sets, we demonstrated that a logistic regression model trained on the mRMR-permute feature set can predict SARS-CoV-2 infection with very high accuracy. Eighty-nine percent of mRMR-permute selected features had strong and significant class effects. Through this work, we identified a key set of radiomic and blood biomarkers that can be used to predict infection status even in the absence of clinical signs. Furthermore, we proposed and demonstrated the utility of a novel feature-selection technique called mRMR-permute. This work lays the foundation for the prediction and classification of SARS-CoV-2 disease severity.

Covid and the coalfield: Covid-19 vaccine hesitance in Wales and Appalachia.

BACKGROUND: Vaccine hesitancy is a barrier to Covid-19 vaccine uptake and displays a social gradient, compounding health disparities. While social gradients are a vital concept in health, they flatten distinctions between types of disadvantaged community. This paper focuses on vaccine hesitance in post-industrial and de-industrialising coalfields. The social consequences of the decline of coal mining may present barriers to vaccine uptake. METHODS: We ran parallel surveys in Wales (N = 4187) and US states overlapping with central Appalachia (N = 4864), to examine whether vaccine attitudes and uptake varied between areas with different coal mining histories. These surveys were accompanied by qualitative interviews of 36 residents of these coalfields to explore vaccination decisions and triangulate with survey data. RESULTS: Factor analysis identified four axes of attitudes in the survey data: vaccine confidence, covid scepticism, vaccine individualism, and concerned confusion. These themes were echoed in the interviews. Vaccine confidence was lower; and covid scepticism, vaccine individualism, and concerned confusion higher, in residents of areas of Wales with greater mining extent and where pits closed during certain periods. Residents of former US coal counties had lower vaccine confidence and higher covid scepticism, while those in current coal counties had greater vaccine individualism and concerned confusion. In former US coal counties and Welsh areas where pits closed since 1980, vaccine uptake was lower. Differences could not be explained by respondents' income and education. In the interviews, norms of social solidarity were often invoked by vaccinated respondents, while unvaccinated respondents did not frame decisions in the context of the industrial history of their areas. DISCUSSION: The legacy of coal-mining's decline presents barriers to public health campaigns. We show evidence of this across two historically significant coalfields. Attention is needed to avert negative public health consequences of global energy transition.

Clinical and Immunologic Correlates of Vasodilatory Shock Among Ebola Virus-Infected Nonhuman Primates in a Critical Care Model.

BACKGROUND: Existing models of Ebola virus infection have not fully characterized the pathophysiology of shock in connection with daily virologic, clinical, and immunologic parameters. We implemented a nonhuman primate critical care model to investigate these associations. METHODS: Two rhesus macaques received a target dose of 1000 plaque-forming units of Ebola virus intramuscularly with supportive care initiated on day 3. High-dimensional spectral cytometry was used to phenotype neutrophils and peripheral blood mononuclear cells daily. RESULTS: We observed progressive vasodilatory shock with preserved cardiac function following viremia onset on day 5. Multiorgan dysfunction began on day 6 coincident with the nadir of circulating neutrophils. Consumptive coagulopathy and anemia occurred on days 7 to 8 along with irreversible shock, followed by death. The monocyte repertoire began shifting on day 4 with a decline in classical and expansion of double-negative monocytes. A selective loss of CXCR3-positive B and T cells, expansion of naive B cells, and activation of natural killer cells followed viremia onset. CONCLUSIONS: Our model allows for high-fidelity characterization of the pathophysiology of acute Ebola virus infection with host innate and adaptive immune responses, which may advance host-targeted therapy design and evaluation for use after the onset of multiorgan failure.

Ebola Virus Disease Features Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome in the Rhesus Macaque Model.

BACKGROUND: Ebola virus (EBOV) disease (EVD) is one of the most severe and fatal viral hemorrhagic fevers and appears to mimic many clinical and laboratory manifestations of hemophagocytic lymphohistiocytosis syndrome (HLS), also known as macrophage activation syndrome. However, a clear association is yet to be firmly established for effective host-targeted, immunomodulatory therapeutic approaches to improve outcomes in patients with severe EVD. METHODS: Twenty-four rhesus monkeys were exposed intramuscularly to the EBOV Kikwit isolate and euthanized at prescheduled time points or when they reached the end-stage disease criteria. Three additional monkeys were mock-exposed and used as uninfected controls. RESULTS: EBOV-exposed monkeys presented with clinicopathologic features of HLS, including fever, multiple organomegaly, pancytopenia, hemophagocytosis, hyperfibrinogenemia with disseminated intravascular coagulation, hypertriglyceridemia, hypercytokinemia, increased concentrations of soluble CD163 and CD25 in serum, and the loss of activated natural killer cells. CONCLUSIONS: Our data suggest that EVD in the rhesus macaque model mimics pathophysiologic features of HLS/macrophage activation syndrome. Hence, regulating inflammation and immune function might provide an effective treatment for controlling the pathogenesis of acute EVD.

Association Between Fuchs Endothelial Corneal Dystrophy, Diabetes Mellitus, and Multimorbidity.

PURPOSE: The aim of this study was to assess risk for demographic variables and other health conditions that are associated with Fuchs endothelial corneal dystrophy (FECD). METHODS: We developed a FECD case-control algorithm based on structured electronic health record data and confirmed accuracy by individual review of charts at 3 Veterans Affairs (VA) Medical Centers. This algorithm was applied to the Department of VA Million Veteran Program cohort from whom sex, genetic ancestry, comorbidities, diagnostic phecodes, and laboratory values were extracted. Single-variable and multiple variable logistic regression models were used to determine the association of these risk factors with FECD diagnosis. RESULTS: Being a FECD case was associated with female sex, European genetic ancestry, and a greater number of comorbidities. Of 1417 diagnostic phecodes evaluated, 213 had a significant association with FECD, falling in both ocular and nonocular conditions, including diabetes mellitus (DM). Five of 69 laboratory values were associated with FECD, with the direction of change for 4 being consistent with DM. Insulin dependency and type 1 DM raised risk to a greater degree than type 2 DM, like other microvascular diabetic complications. CONCLUSIONS: Female sex, European ancestry, and multimorbidity increased FECD risk. Endocrine/metabolic clinic encounter codes and altered patterns of laboratory values support DM increasing FECD risk. Our results evoke a threshold model in which the FECD phenotype is intensified by DM and potentially other health conditions that alter corneal physiology. Further studies to better understand the relationship between FECD and DM are indicated and may help identify opportunities for slowing FECD progression.

Longitudinal analyses using 18F-Fluorodeoxyglucose positron emission tomography with computed tomography as a measure of COVID-19 severity in the aged, young, and humanized ACE2 SARS-CoV-2 hamster models.

This study compared disease progression of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in three different models of golden hamsters: aged (≈60 weeks old) wild-type (WT), young (6 weeks old) WT, and adult (14-22 weeks old) hamsters expressing the human-angiotensin-converting enzyme 2 (hACE2) receptor. After intranasal (IN) exposure to the SARS-CoV-2 Washington isolate (WA01/2020), 2-deoxy-2-[fluorine-18]fluoro-D-glucose positron emission tomography with computed tomography (18F-FDG PET/CT) was used to monitor disease progression in near real time and animals were euthanized at pre-determined time points to directly compare imaging findings with other disease parameters associated with coronavirus disease 2019 (COVID-19). Consistent with histopathology, 18F-FDG-PET/CT demonstrated that aged WT hamsters exposed to 105 plaque forming units (PFU) developed more severe and protracted pneumonia than young WT hamsters exposed to the same (or lower) dose or hACE2 hamsters exposed to a uniformly lethal dose of virus. Specifically, aged WT hamsters presented with a severe interstitial pneumonia through 8 d post-exposure (PE), while pulmonary regeneration was observed in young WT hamsters at that time. hACE2 hamsters exposed to 100 or 10 PFU virus presented with a minimal to mild hemorrhagic pneumonia but succumbed to SARS-CoV-2-related meningoencephalitis by 6 d PE, suggesting that this model might allow assessment of SARS-CoV-2 infection on the central nervous system (CNS). Our group is the first to use (18F-FDG) PET/CT to differentiate respiratory disease severity ranging from mild to severe in three COVID-19 hamster models. The non-invasive, serial measure of disease progression provided by PET/CT makes it a valuable tool for animal model characterization.

Diversity is key for cross-ancestry transferability of glaucoma genetic risk scores in Hispanic Veterans in the Million Veteran Program.

A major goal of precision medicine is to stratify patients based on their genetic risk for a disease to inform future screening and intervention strategies. For conditions like primary open-angle glaucoma (POAG), the genetic risk architecture is complicated with multiple variants contributing small effects on risk. Following the tepid success of genome-wide association studies for high-effect disease risk variant discovery, genetic risk scores (GRS), which collate effects from multiple genetic variants into a single measure, have shown promise for disease risk stratification. We assessed the application of GRS for POAG risk stratification in Hispanic-descent (HIS) and European-descent (EUR) Veterans in the Million Veteran Program. Unweighted and cross-ancestry meta-weighted GRS were calculated based on 127 genomic variants identified in the most recent report of cross-ancestry POAG meta-analyses. We found that both GRS types were associated with POAG case-control status and performed similarly in HIS and EUR Veterans. This trend was also seen in our subset analysis of HIS Veterans with less than 50% EUR global genetic ancestry. Our findings highlight the importance of evaluating GRS based on known POAG risk variants in different ancestry groups and emphasize the need for more multi-ancestry POAG genetic studies.

Operational Insights into Analysing Team and Player Performance in Elite Rugby League: A Narrative Review with Case Examples.

In professional team sports, like Rugby League, performance analysis has become an integral part of operational practices. This has helped practitioners gain deeper insight into phenomena like team and athlete behaviour and understanding how such behaviour may be influenced by various contextual factors. This information can then be used by coaches to design representative practice tasks, inform game principles and opposition strategies, and even support team recruitment practices. At the elite level, the constant evolution of sports technology (both hardware and software) has enabled greater access to information, making the role of the performance analyst even more valuable. However, this increase in information can create challenges regarding which variables to use to help guide decision-making, and how to present it in ways that can be utilised by coaches and other support staff. While there are published works exploring aspects of performance analysis in team sports like Rugby League, there is yet to be a perspective that explores the various operational uses of performance analysis in Rugby League, the addition of which could help guide the practices of emerging performance analysts in elite organisations like the Australian National Rugby League and the European Super League. Thus, this narrative review-with accompanying case examples-explores the various ways performance analysis can help address pertinent operational questions commonly encountered when working in high-performance sport.

Persistent intraocular Ebola virus RNA is associated with severe uveitis in a convalescent rhesus monkey.

Despite increasing evidence that uveitis is common and consequential in survivors of Ebola virus disease (EVD), the host-pathogen determinants of the clinical phenotype are undefined, including the pathogenetic role of persistent viral antigen, ocular tissue-specific immune responses, and histopathologic characterization. Absent sampling of human intraocular fluids and tissues, these questions might be investigated in animal models of disease; however, challenges intrinsic to the nonhuman primate model and the animal biosafety level 4 setting have historically limited inquiry. In a rhesus monkey survivor of experimental Ebola virus (EBOV) infection, we observed and documented the clinical, virologic, immunologic, and histopathologic features of severe uveitis. Here we show the clinical natural history, resultant ocular pathology, intraocular antigen-specific antibody detection, and persistent intraocular EBOV RNA detected long after clinical resolution. The association of persistent EBOV RNA as a potential driver of severe immunopathology has pathophysiologic implications for understanding, preventing, and mitigating vision-threatening uveitis in EVD survivors.

Effects of the COVID-19 pandemic on hospital admissions and inpatient mortality in Kenya

BackgroundThe impact of COVID-19 in Africa remains poorly defined. We sought to describe trends in hospitalisation due to all medical causes, pneumonia-specific admissions, and inpatient mortality in Kenya before and during the first five waves of the COVID-19 pandemic in Kenya. MethodsWe conducted a hospital-based, multi-site, longitudinal observational study of patients admitted to 13 public referral facilities in Kenya from January 2018 to December 2021. The pre-COVID population included patients admitted before 1 March 2020. We fitted time series models to compare observed and predicted trends for each outcome. To estimate the impact of the COVID-19 pandemic, we calculated incidence rate ratios (IRR) and corresponding 95% confidence intervals (CI) from negative binomial mixed-effects models. ResultsOut of 302,703 patients hospitalised across the 13 surveillance sites (range 11547 to 57011), 117642 (39%) were admitted to adult wards. Compared with the pre-COVID period, hospitalisations declined markedly among adult (IRR 0.68, 95% CI 0.63 to 0.73) and paediatric (IRR 0.67, 95% CI 0.62 to 0.73) patients. Adjusted in-hospital mortality also declined among both adult (IRR 0.83, 95% CI 0.77 to 0.89) and paediatric (IRR 0.85, 95% CI 0.77 to 0.94) admissions. Pneumonia-specific admissions among adults increased during the pandemic (IRR 1.75, 95% CI 1.18 to 2.59). Paediatric pneumonia cases were lower than pre-pandemic levels in the first year of the pandemic and elevated in late 2021 (IRR 0.78, 95% CI 0.51 to 1.20). ConclusionsContrary to initial predictions, the COVID-19 pandemic was associated with lower hospitalisation rates and in-hospital mortality, despite increased pneumonia admissions among adults. These trends were sustained after the withdrawal of containment measures that disrupted essential health services, suggesting a role for additional factors that warrant further investigation.

Impact of COVID-19 on mortality in coastal Kenya: a longitudinal open cohort study

BackgroundThere is uncertainty about the mortality impact of the COVID-19 pandemic in Africa because of poor ascertainment of cases and limited national civil vital registration. We analysed excess mortality from 1st January 2020-5th May 2022 in a Health and Demographic Surveillance Study in Coastal Kenya where the SARS-CoV-2 seroprevalence reached 75% among adults in March 2022 despite vaccine uptake of only 17%. MethodsWe modelled expected mortality in 2020-2022 among a population of 306,000 from baseline surveillance data between 2010-2019. We calculated excess mortality as the ratio of observed/expected deaths in 5 age strata for each month and for each national wave of the pandemic. We estimated cumulative mortality risks as the total number of excess deaths in the pandemic per 100,000 population. We investigated observed deaths using verbal autopsy. FindingWe observed 16,236 deaths among 3,410,800 person years between 1st January 2010 and 5th May 2022. Across 5 waves of COVID-19 cases during 1st April 2020-16th April 2022, population excess mortality was 4.1% (95% PI -0.2%, 7.9%). Mortality was elevated among those aged [≥]65 years at 14.3% (95% PI 7.4%, 21.6%); excess deaths coincided with wave 2 (wild-type), wave 4 (Delta) and wave 5 (Omicron BA1). Among children aged 1-14 years there was negative excess mortality of -20.3% (95% PI -29.8%, -8.1%). Verbal autopsy data showed a transient reduction in deaths from acute respiratory infections in 2020 at all ages. For comparison with other studies, cumulative excess mortality risk for January 2020-December 2021, age-standardized to the Kenyan population, was 47.5/100,000. InterpretationNet excess mortality during the pandemic was substantially lower in Coastal Kenya than in many high income countries. However, adults, aged [≥]65 years, experienced substantial excess mortality suggesting that targeted COVID-19 vaccination of older persons may limit further COVID-19 deaths by protecting the residual pool of naive individuals. FundingWellcome Trust

Methods to evaluate the impact of SARS-CoV-2 nucleocapsid mutations on antigen detection by rapid diagnostic tests.

Mutations in the nucleocapsid of SARS-CoV-2 may interfere with antigen detection by diagnostic tests. We used several methods to evaluate the effect of various SARS-CoV-2 nucleocapsid mutations on the performance of the Panbio™ and BinaxNOW™ lateral flow rapid antigen tests and a prototype high-throughput immunoassay that utilizes Panbio antibodies. Variant detection was also evaluated by immunoblot and BIAcore™ assay. A panel of 23 recombinant nucleocapsid antigens (rAgs) were produced that included mutations found in circulating SARS-CoV-2 variants, including variants of concern. All mutant rAgs were detected by all assays, at a sensitivity equivalent to wild-type control (Wuhan strain). Thus, using a rAg approach, we found that the SARS-CoV-2 nucleocapsid mutations examined do not directly impact antigen detection or antigen assay performance.

Glaucoma Genetic Risk Scores in the Million Veteran Program.

PURPOSE: Primary open-angle glaucoma (POAG) is a degenerative eye disease for which early treatment is critical to mitigate visual impairment and irreversible blindness. POAG-associated loci individually confer incremental risk. Genetic risk score(s) (GRS) could enable POAG risk stratification. Despite significantly higher POAG burden among individuals of African ancestry (AFR), GRS are limited in this population. A recent large-scale, multi-ancestry meta-analysis identified 127 POAG-associated loci and calculated cross-ancestry and ancestry-specific effect estimates, including in European ancestry (EUR) and AFR individuals. We assessed the utility of the 127-variant GRS for POAG risk stratification in EUR and AFR Veterans in the Million Veteran Program (MVP). We also explored the association between GRS and documented invasive glaucoma surgery (IGS). DESIGN: Cross-sectional study. PARTICIPANTS: MVP Veterans with imputed genetic data, including 5830 POAG cases (445 with IGS documented in the electronic health record) and 64 476 controls. METHODS: We tested unweighted and weighted GRS of 127 published risk variants in EUR (3382 cases and 58 811 controls) and AFR (2448 cases and 5665 controls) Veterans in the MVP. Weighted GRS were calculated using effect estimates from the most recently published report of cross-ancestry and ancestry-specific meta-analyses. We also evaluated GRS in POAG cases with documented IGS. MAIN OUTCOME MEASURES: Performance of 127-variant GRS in EUR and AFR Veterans for POAG risk stratification and association with documented IGS. RESULTS: GRS were significantly associated with POAG (P < 5 × 10-5) in both groups; a higher proportion of EUR compared with AFR were consistently categorized in the top GRS decile (21.9%-23.6% and 12.9%-14.5%, respectively). Only GRS weighted by ancestry-specific effect estimates were associated with IGS documentation in AFR cases; all GRS types were associated with IGS in EUR cases. CONCLUSIONS: Varied performance of the GRS for POAG risk stratification and documented IGS association in EUR and AFR Veterans highlights (1) the complex risk architecture of POAG, (2) the importance of diverse representation in genomics studies that inform GRS construction and evaluation, and (3) the necessity of expanding diverse POAG-related genomic data so that GRS can equitably aid in screening individuals at high risk of POAG and who may require more aggressive treatment.

Impact of the COVID-19 epidemic on mortality in rural coastal Kenya

BackgroundThe impact of COVID-19 on all-cause mortality in sub-Saharan Africa remains unknown. MethodsWe monitored mortality among 306,000 residents of Kilifi Health and Demographic Surveillance System, Kenya, through four COVID-19 waves from April 2020-September 2021. We calculated expected deaths using negative binomial regression fitted to baseline mortality data (2010-2019) and calculated excess mortality as observed-minus-expected deaths. We excluded deaths in infancy because of under-ascertainment of births during lockdown. In February 2021, after two waves of wild-type COVID-19, adult seroprevalence of anti-SARS-CoV-2 was 25.1%. We predicted COVID-19-attributable deaths as the product of age-specific seroprevalence, population size and global infection fatality ratios (IFR). We examined changes in cause of death by Verbal Autopsy (VA). ResultsBetween April 2020 and February 2021, we observed 1,000 deaths against 1,012 expected deaths (excess mortality -1.2%, 95% PI -6.6%, 5.8%). Based on SARS-CoV-2 seroprevalence, we predicted 306 COVID-19-attributable deaths (a predicted excess mortality of 30.6%) within this period. Monthly mortality analyses showed a significant excess among adults aged [≥]45 years in only two months, July-August 2021, coinciding with the fourth (Delta) wave of COVID-19. By September 2021, overall excess mortality was 3.2% (95% PI -0.6%, 8.1%) and cumulative excess mortality risk was 18.7/100,000. By VA, there was a transient reduction in deaths attributable to acute respiratory infections in 2020. ConclusionsNormal mortality rates during extensive transmission of wild-type SARS-CoV-2 through February 2021 suggests that the IFR for this variant is lower in Kenya than elsewhere. We found excess mortality associated with the Delta variant but the cumulative excess mortality risk remains low in coastal Kenya compared to global estimates.

Cocktail party: Low-dose antibody combinations deliver pan-ebolavirus protection.

Recent outbreaks of Ebola have brought to the forefront the need for focused therapeutic treatments. In this issue of Cell, Milligan and colleagues build on previous studies of antibody treatments for Ebola virus disease, uncovering broad synergistic protective immunity when administered in combination (as antibody cocktails).

An observational study of the association between COVID-19 vaccination rates and participation in a vaccine lottery

ObjectivesTo examine the association between financial incentives from entry into a vaccine competition with the probability of vaccination for COVID-19. DesignA cross-sectional study with adjustment for covariates using logistic regression SettingOctober and November 2021, Australia. Participants2,375 respondents of the Taking the Pulse of the Nation Survey Primary and secondary outcome measuresThe proportion of respondents who had any vaccination, a first dose only, or second dose after the competition opened. ResultsThose who entered the competition were 2.27 (95% CI 1.73 to 2.99) times more likely to be vaccinated after the competition opened on October 1st than those who did not enter--an increase in the probability of having any dose of 0.16 (95 % CI 0.10 to 0.21) percentage points. This increase was mostly driven by those receiving second doses. Entrants were 2.39 (95% CI 1.80 to 3.17) times more likely to receive their second dose after the competition opened. ConclusionsThose who entered the Million Dollar Vax competition were more likely to receive a vaccination after the competition opened compared to those who did not enter the competition, with this effect dominated by those receiving second doses. Strengths and limitations of this studyO_LIWe use a nationally representative sample of individual self-reported vaccination status and timings. C_LIO_LIWe distinguish between the association between competition entry and first and second doses. C_LIO_LIWe adjust for a rich set of individual characteristics associated with vaccination status, and examine the factors influencing competition entry C_LIO_LIThe strong association for second dose vaccinations may reflect some individuals who had already scheduled their second dose after the competition opened, potentially leading to an overestimate of the association. C_LI

Development and Evaluation of a Rules-based Algorithm for Primary Open-Angle Glaucoma in the VA Million Veteran Program.

The availability of electronic health record (EHR)-linked biobank data for research presents opportunities to better understand complex ocular diseases. Developing accurate computable phenotypes for ocular diseases for which gold standard diagnosis includes imaging remains inaccessible in most biobank-linked EHRs. The objective of this study was to develop and validate a computable phenotype to identify primary open-angle glaucoma (POAG) through accessing the Department of Veterans Affairs (VA) Computerized Patient Record System (CPRS) and Million Veteran Program (MVP) biobank. Accessing CPRS clinical ophthalmology data from VA Medical Center Eye Clinic (VAMCEC) patients, we developed and iteratively refined POAG case and control algorithms based on clinical, prescription, and structured diagnosis data (ICD-CM codes). Refinement was performed via detailed chart review, initially at a single VAMCEC (n = 200) and validated at two additional VAMCECs (n = 100 each). Positive and negative predictive values (PPV, NPV) were computed as the proportion of CPRS patients correctly classified with POAG or without POAG, respectively, by the algorithms, validated by ophthalmologists and optometrists with access to gold-standard clinical diagnosis data. The final algorithms performed better than previously reported approaches in assuring the accuracy and reproducibility of POAG classification (PPV >83% and NPV >97%) with consistent performance in Black or African American and in White Veterans. Applied to the MVP to identify cases and controls, genetic analysis of a known POAG-associated locus further validated the algorithms. We conclude that ours is a viable approach to use combined EHR-genetic data to study patients with complex diseases that require imaging confirmation.

Expeditious recruitment of circulating memory CD8 T cells to the liver facilitates control of malaria.

Circulating memory CD8 T cell trafficking and protective capacity during liver-stage malaria infection remains undefined. We find that effector memory CD8 T cells (Tem) infiltrate the liver within 6 hours after malarial or bacterial infections and mediate pathogen clearance. Tem recruitment coincides with rapid transcriptional upregulation of inflammatory genes in Plasmodium-infected livers. Recruitment requires CD8 T cell-intrinsic LFA-1 expression and the presence of liver phagocytes. Rapid Tem liver infiltration is distinct from recruitment to other non-lymphoid tissues in that it occurs both in the absence of liver tissue resident memory "sensing-and-alarm" function and ∼42 hours earlier than in lung infection by influenza virus. These data demonstrate relevance for Tem in protection against malaria and provide generalizable mechanistic insights germane to control of liver infections.

Severity of Sepsis Determines the Degree of Impairment Observed in Circulatory and Tissue-Resident Memory CD8 T Cell Populations.

Sepsis reduces the number and function of memory CD8 T cells within the host, contributing to the long-lasting state of immunoparalysis. Interestingly, the relative susceptibility of memory CD8 T cell subsets to quantitative/qualitative changes differ after cecal ligation and puncture (CLP)-induced sepsis. Compared with circulatory memory CD8 T cells (TCIRCM), moderate sepsis (0-10% mortality) does not result in numerical decline of CD8 tissue-resident memory T cells (TRM), which retain their "sensing and alarm" IFN-γ-mediated effector function. To interrogate this biologically important dichotomy, vaccinia virus-immune C57BL/6 (B6) mice containing CD8 TCIRCM and skin TRM underwent moderate or severe (∼50% mortality) sepsis. Severe sepsis led to increased morbidity and mortality characterized by increased inflammation compared with moderate CLP or sham controls. Severe CLP mice also displayed increased vascular permeability in the ears. Interestingly, skin CD103+ CD8 TRM, detected by i.v. exclusion or two-photon microscopy, underwent apoptosis and subsequent numerical loss following severe sepsis, which was not observed in mice that experienced moderate CLP or sham surgeries. Consequently, severe septic mice showed diminished CD8 T cell-mediated protection to localized skin reinfection. Finally, the relationship between severity of sepsis and demise in circulatory versus tissue-embedded memory CD8 T cell populations was confirmed by examining tumor-infiltrating and nonspecific CD8 T cells in B16 melanoma tumors. Thus, sepsis can differentially affect the presence and function of Ag-specific CD8 T cells that reside inside tissues/tumors depending on the severity of the insult, a notion with direct relevance to sepsis survivors and their ability to mount protective memory CD8 T cell-dependent responses to localized Ag re-encounter.