Faculty Bibliography

Limiting the metabolic competition in the tumor microenvironment (TME) may increase the effectiveness of immunotherapy. Because of its critical role in glucose metabolism of activated T cells, CD28 signaling has been proposed as a T-cell metabolic biosensor¹. Conversely, CTLA-4 engagement has been shown to down-regulate T-cell glycolysis¹. Here, we investigated the impact of CTLA-4 blockade on the metabolic fitness of intra-tumor T cells in relationship to the tumor glycolytic capacity. We found that CTLA-4 blockade promotes immune cell infiltration and metabolic fitness especially in glycolysis-low tumors. Accordingly, anti-CTLA-4 achieved better therapeutic outcomes in mice bearing glycolysis-defective tumors. Intriguingly, tumor-specific CD8⁺ T-cell responses correlated with phenotypic and functional destabilization of tumor-infiltrating regulatory T cells (Tregs) toward IFN-γ- and TNF-α-producing cells in glycolysis-defective tumors. By mimicking the highly and poorly glycolytic TME in vitro, we show that the effect of CTLA-4 blockade to promote Treg destabilization is dependent on Treg glycolysis and CD28 signaling. These findings indicate that decreasing tumor competition for glucose may facilitate the therapeutic activity of CTLA-4 blockade, thus supporting its combination with inhibitors of tumor glycolysis. Moreover, these results reveal a new mechanism through which anti-CTLA-4 interferes with Treg function in the presence of glucose.

BACKGROUND:Little is known about long-term recovery from severe COVID-19 disease. Here, we characterize overall health, physical health, and mental health of patients 1 month after discharge for severe COVID-19. METHODS:This was a prospective single health system observational cohort study of patients ≥ 18 years hospitalized with laboratory-confirmed COVID-19 disease who required at least 6 l of oxygen during admission, had intact baseline cognitive and functional status, and were discharged alive. Participants were enrolled between 30 and 40 days after discharge. Outcomes were elicited through validated survey instruments: the PROMIS® Dyspnea Characteristics and PROMIS® Global Health-10. RESULTS:A total of 161 patients (40.6% of eligible) were enrolled; 152 (38.3%) completed the survey. Median age was 62 years (interquartile range [IQR], 50-67); 57 (37%) were female. Overall, 113/152 (74%) participants reported shortness of breath within the prior week (median score 3 out of 10 [IQR 0-5]), vs 47/152 (31%) pre-COVID-19 infection (0, IQR 0-1), p < 0.001. Participants also rated their physical health and mental health as worse in their post-COVID state (43.8, standard deviation 9.3; mental health 47.3, SD 9.3) compared to their pre-COVID state, (54.3, SD 9.3; 54.3, SD 7.8, respectively), both p < 0.001. Physical and mental health means in the general US population are 50 (SD 10). A total of 52/148 (35.1%) patients without pre-COVID oxygen requirements needed home oxygen after hospital discharge; 20/148 (13.5%) reported still using oxygen at time of survey. CONCLUSIONS:Patients with severe COVID-19 disease typically experience sequelae affecting their respiratory status, physical health, and mental health for at least several weeks after hospital discharge.

BACKGROUND:Coronary calcium is a marker of coronary atherosclerosis and established predictor of cardiovascular risk in general populations; however, there are limited studies examining its prognostic value among older adults (≥75 years) and even less regarding its utility in older males compared with females. Accordingly, we sought to examine the prognostic significance of both absolute and percentile coronary calcium scores among older adults. METHODS:The multicenter Coronary Artery Calcium Consortium consists of 66,636 asymptomatic patients without cardiovascular disease. Participants ages ≥75 were included in this study and stratified by sex. Multivariable Cox regression models were constructed to assess cardiovascular and all-cause mortality risk by Agatston coronary calcium scores and percentiles. RESULTS:Among 2,474 asymptomatic patients (mean age 79 years, 10.4-year follow-up), prevalence of coronary artery calcium was 92%. For both sexes, but in females more so than males, higher coronary calcium score and percentiles were associated with increased cardiovascular and all-cause mortality risk. Those at the lowest coronary calcium categories (0-9 and <25 percentile) had significantly lower risk of cardiovascular and all-cause mortality relative to the rest of the population. Multivariable analyses of traditional cardiovascular risk factors and coronary artery calcium variables revealed that age and coronary calcium were the strongest independent predictors for adverse outcomes. CONCLUSIONS:Both coronary artery calcium scores and percentiles are strongly predictive of cardiovascular and all-cause mortality among older adults, with greater risk-stratification among females than males. Both low coronary artery calcium scores 0-9 and <25th percentile define relatively low risk older adults.

Objectives/UNASSIGNED:The aim of this study was to test the mediating role of perceived discrimination and stress on associations between perceived neighborhood social environment (PNSE) and TV viewing. Methods/UNASSIGNED:Baseline data were used for 4716 participants (mean age = 55.1 y; 63.4% female) in the Jackson Heart Study (JHS), a large prospective cohort study of African Americans in Jackson, Mississippi. One binary TV viewing outcome was created: ≥4 h/day versus <4 h/day. PNSE variables included neighborhood violence, problems (higher value = more violence/problems), and social cohesion (higher value = more cohesion). Mediators included perceived lifetime discrimination, daily discrimination, and chronic stress (higher value = greater discrimination/stress). Multivariable regression was used with bootstrap-generated 95% bias-corrected confidence intervals (BC CIs) to test for mediation adjusting for demographics, health-related and psychosocial factors, and population density. Results/UNASSIGNED: = 1.01, 1.10, respectively). Daily discrimination was neither directly nor indirectly associated with TV viewing. Conclusions/UNASSIGNED:Each PNSE variable was indirectly associated with TV viewing via lifetime discrimination and perceived stress, but not with daily discrimination among JHS participants. Unexpected directionality of mediating effects of lifetime discrimination and chronic stress should be replicated in future studies. Further research is also needed to pinpoint effective community efforts and physical environmental policies (e.g., installing bright street lights, community policing) to reduce adverse neighborhood conditions and psychosocial factors, and decrease TV viewing and subsequent cardiovascular disease risk.

New therapies offer hope for a cure to millions of persons living with hepatitis C virus (HCV) infection. HCV elimination is a global goal that will be difficult to achieve using the traditional paradigms of diagnosis and care. The current standard has evolved toward universal HCV screening and treatment, to achieve elimination goals. There are several steps between HCV diagnosis and cure with major barriers along the way. Innovative models of care can address barriers to better serve hardly reached populations and scale national efforts in the United States and abroad. Herein, we highlight innovative models of HCV care that aid in our progress toward HCV elimination.

BACKGROUND:Child maltreatment is a leading cause of pediatric morbidity and mortality. We previously reported on development and implementation of a child abuse clinical decision support system (CA-CDSS) in the Cerner electronic health record (EHR). Our objective was to develop a CA-CDSS in two different EHRs. METHODS:Using the CA-CDSS in Cerner as a template, CA-CDSSs were developed for use in four hospitals in the Northwell Health system who use Allscripts and two hospitals in the University of Wisconsin health system who use Epic. Each system had a combination of triggers, alerts and child abuse-specific order sets. Usability evaluation was done prior to launch of the CA-CDSS. RESULTS:Over an 18-month period, a CA-CDSS was embedded into Epic and Allscripts at two hospital systems. The CA-CDSSs vary significantly from each other in terms of the type of triggers which were able to be used, the type of alert, the ability of the alert to link directly to child abuse-specific order sets and the order sets themselves. CONCLUSIONS:Dissemination of CA-CDSS from one EHR into the EHR in other health care systems is possible but time-consuming and needs to be adapted to the strengths and limitations of the specific EHR. Site-specific usability evaluation, buy-in of multiple stakeholder groups and significant information technology support are needed. These barriers limit scalability and widespread dissemination of CA-CDSS.

BACKGROUND & AIMS:Chronic liver disease (CLD) and cirrhosis are associated with immune dysregulation, leading to concerns that affected patients may be at risk of adverse outcomes following SARS-CoV-2 infection. We aimed to determine the impact of COVID-19 on patients with pre-existing liver disease, which currently remains ill-defined. METHODS:Between 25th March and 8th July 2020, data on 745 patients with CLD and SARS-CoV-2 (including 386 with and 359 without cirrhosis) were collected by 2 international registries and compared to data on non-CLD patients with SARS-CoV-2 from a UK hospital network. RESULTS:Mortality was 32% in patients with cirrhosis compared to 8% in those without (p <0.001). Mortality in patients with cirrhosis increased according to Child-Pugh class (A [19%], B [35%], C [51%]) and the main cause of death was from respiratory failure (71%). After adjusting for baseline characteristics, factors associated with death in the total CLD cohort were age (odds ratio [OR] 1.02; 1.01-1.04), Child-Pugh A (OR 1.90; 1.03-3.52), B (OR 4.14; 2.4-7.65), or C (OR 9.32; 4.80-18.08) cirrhosis and alcohol-related liver disease (OR 1.79; 1.03-3.13). Compared to patients without CLD (n = 620), propensity-score-matched analysis revealed significant increases in mortality in those with Child-Pugh B (+20.0% [8.8%-31.3%]) and C (+38.1% [27.1%-49.2%]) cirrhosis. Acute hepatic decompensation occurred in 46% of patients with cirrhosis, of whom 21% had no respiratory symptoms. Half of those with hepatic decompensation had acute-on-chronic liver failure. CONCLUSIONS:In the largest such cohort to date, we demonstrate that baseline liver disease stage and alcohol-related liver disease are independent risk factors for death from COVID-19. These data have important implications for the risk stratification of patients with CLD across the globe during the COVID-19 pandemic. LAY SUMMARY:This international registry study demonstrates that patients with cirrhosis are at increased risk of death from COVID-19. Mortality from COVID-19 was particularly high among patients with more advanced cirrhosis and those with alcohol-related liver disease.