Faculty Bibliography

Background As tumor genomes are shaped by their interaction with the immune system, a phenomenon known as immunoediting, it is critical to understand how immunotherapies impact this process. Checkpoint inhibitors directly influence T cells responding to neoantigens, as such, these therapies drastically affect the genomes of surviving tumor clones. Similar to the concept of immune camouflage, observed in infectious diseases, where genomes of pathogens evolve in a way to avoid immune detection, we hypothesized that tumor clones surviving checkpoint inhibition therapy harbor mutations more prone to immune avoidance. Methods We analyzed a cohort of nivolumab-treated melanoma patients (n=41) for which tumor samples were collected from the same site prior (Pre samples) and during (On samples) nivolumab therapy.1 The immunogenic and tolerance potential of mutations from the Pre and On samples were evaluated with the Ancer neoantigen screening platform,2 which includes the EpiMatrix algorithm to identify HLA-I and HLA-II neoepitopes and the JanusMatrix algorithm to evaluate neoepitopes homology with self. Prior work with JanusMatrix showed epitopes highly homologous to self can be inhibitory.3 Matching Pre and On therapy samples were compared to identify mutations deleted (unique to the Pre samples), maintained (found in both the Pre and On samples), and induced while on therapy (unique to the On samples). Results Mutations from the On therapy samples had a lower immunogenic potential than mutations found in the Pre therapy samples (figure 1A, Mann-Whitney test, p=0.0001). After further distinguishing mutations deleted, maintained, and induced while on therapy, we observed that newly induced mutations had a significantly lower immunogenic potential compared to other mutations (Kruskal-Wallis test, p<0.0001). In addition, newly induced mutations were more homologous to self than other mutations (figure 1B, Kruskal-Wallis test, p<0.0001), indicating a greater likelihood for these new mutations to be tolerated by the immune system. In summary, we showed that mutations generated after nivolumab therapy are less immunogenic and more tolerated than mutations found prior to therapy. Abstract 313 Figure 1 Immunogenicity (A) and tolerance (B) potentials of mutations found in matching melanoma tumor samples collected before (Pre) and during (On) nivolumab therapy. Conclusions Our Ancer analysis suggests that nivolumab therapy affects the immunogenicity and tolerance profiles of newly generated mutations in a manner that is consistent with the concepts of immunoediting and immune camouflaging. Mutations induced after therapy appear less immunogenic and more self-like, illustrating a potential mechanism tumors employ to avoid immune surveillance. Furthermore, our approach highlights in silico tools can distinguish effector from tolerance inducing neoepitopes, a critical feature for designing novel neoantigen-based precision immunotherapies

As they age, people living with HIV (PLWH) experience greater rates of inflammation-related health conditions compared to their HIV-negative peers. Because early life adversity can exaggerate proinflammatory effects of later physiological challenges, inflammation may be higher among PLWH with these combined risks, which could inform intervention approaches to mitigate multimorbidity. In this cross-sectional analysis, we investigated individual and combined effects of childhood sexual abuse (CSA) history and physiological burden (Veterans Aging Cohort Study Index scores) on serum cytokine and C-reactive protein (CRP) levels among PLWH. Participants (n ​= ​131; age 54 and older) were patients at an outpatient HIV clinic who completed a psychosocial survey and biomedical research visit as part of a larger study. 93% were virally suppressed, and 40% reported experiencing sexual abuse in childhood. Composite cytokine levels (summarizing IL-6, TNF-α, IFN-γ), CRP, and disease burden did not differ significantly between those who had a history of CSA and those who did not. Participants with greater disease burden had higher composite cytokine levels (r ​= ​0.29, p ​= ​0.001). The disease burden by CSA interaction effect was a significant predictor of composite cytokine levels (but not CRP), and remained significant after controlling for age, sex, race, BMI, anti-inflammatory medication use, selective serotonin reuptake inhibitor use, depressive symptoms, and smoking status (F(1, 114) ​= ​5.68, p ​= ​0.02). In follow-up simple slopes analysis, greater disease burden was associated with higher cytokine levels among those with CSA history (b ​= ​0.03, SE ​= ​0.008, p<0.001), but not among those without CSA history. Further, in the context of greater disease burden, individuals with a CSA history tended to have higher cytokine levels than those without a CSA history (b ​= ​0.38, SE ​= ​0.21, p ​= ​0.07). These data suggest that the physiological sequelae of childhood trauma may persist into older age among those with HIV. Specifically, links between physiological burden and inflammation were stronger among survivors of CSA in this study. The combined presence of CSA history and higher disease burden may signal a greater need for and potential benefit from interventions to reduce inflammation, an area for future work.

OBJECTIVE:This population-based, matched cohort study aimed to evaluate utilization of health care services by mothers of children with major congenital anomalies (MCAs), compared to mothers of children without MCAs over a 20-year post-birth time horizon in Denmark. METHODS:Our analytic sample included mothers who gave birth to an infant with a MCA (n = 23,927) and a cohort of mothers matched to them by maternal age, parity and infant's year of birth (n = 239,076). Primary outcomes were period prevalence and mothers' quantity of health care utilization (primary, inpatient, outpatient, surgical, and psychiatric services) stratified by their child's age (i.e., ages 0-6 = before school, ages 7-13 = pre-school + primary education, and ages 14-18 = secondary education or higher). The secondary outcome measure was length of hospital stays. Outcome measures were adjusted for maternal age at delivery, parity, marital status, income quartile, level of education in the year prior to the index birth, previous spontaneous abortions, maternal pregnancy complications, maternal diabetes, hypertension, alcohol-related diseases, and maternal smoking. RESULTS:In both cohorts the majority of mothers were between 26 and 35 years of age, married, and employed, and 47% were primiparous. Mothers of infants with anomalies had greater utilization of outpatient, inpatient, surgical, and psychiatric services, compared with mothers in the matched cohort. Inpatient service utilization was greater in the exposed cohort up to 13 years after a child's birth, with the highest risk in the first six years after birth [adjusted risk ratio, 1.13; 95% confidence interval (CI), 1.12-1.14], with a decrease over time. Regarding the quantity of health care utilization, the greatest difference between the two groups was in inpatient service utilization, with a 39% increased rate in the exposed cohort during the first six years after birth (adjusted rate ratio, 1.39; 95% CI, 1.37-1.42). During the first 6 years after birth, mothers of children with anomalies stayed a median of 6 days (interquartile range [IQR], 3-13) in hospital overall, while the comparison cohort stayed a median of 4 days (IQR, 2-7) in hospital overall. Rates of utilization of outpatient clinics (adjusted rate ratio, 1.36; 95% CI, 1.29-1.42), as well as inpatient (adjusted rate ratio, 1.77; 95% CI, 1.68-1.87), and surgical services (adjusted rate ratio, 1.33; 95% CI, 1.26-1.41) was higher in mothers of children with multiple-organ MCAs during 0 to 6 years after birth. Among mothers at the lowest income levels, utilization of psychiatric clinic services increased to 59% and when their child was 7 to 13 years of age (adjusted rate ratio, 1.59; 95% CI, 1.24-2.03). CONCLUSION:Mothers of infants with a major congenital anomaly had greater health care utilization across services. Health care utilization decreased over time or remained stable for outpatient, inpatient, and surgical care services, whereas psychiatric utilization increased for up to 13 years after an affected child's birth. Healthcare utilization was significantly elevated among mothers of children with multiple MCAs and among those at the lowest income levels.

BACKGROUND AND AIMS/OBJECTIVE:Rates of obesity are rising in patients with inflammatory bowel disease [IBD]. We conducted a US population-based study to determine the effects of obesity on outcomes in hospitalised patients with IBD. METHODS:We searched the Nationwide Readmissions Database 2016-2017 to identify all adult patients hospitalised for IBD, using ICD-10 codes. We compared obese (body mass index [BMI] ≥ 30) vs non-obese [BMI < 30] patients with IBD to evaluate the independent effects of obesity on readmission, mortality, and other hospital outcomes. Multivariate regression and propensity matching were performed. RESULTS:We identified 143 190 patients with IBD, of whom 9.1% were obese. Obesity was independently associated with higher all-cause readmission at 30 days {18% vs 13% (adjusted odds ratio [aOR] 1.16, p = 0.005)} and 90 days (29% vs 21% [aOR 1.27, p < 0.0001]), as compared with non-obese patients, with similar findings upon a propensity-matched sensitivity analysis. Obese and non-obese patients had similar risks of mortality on index admission [0.24% vs 0.31%, p = 0.18] and readmission [1.5% vs 1.8% p = 0.3]. Obese patients had longer [5.3 vs 4.9 days] and more expensive [USD12,195 vs USD11,154] hospitalisations on index admission. Obesity did not affect the risk of intestinal surgery or bowel obstruction. Compared with index admissions, readmissions were characterised by increased mortality [6-fold], health care use, and bowel obstruction [3-fold] [all p < 0.0001]. CONCLUSIONS:Obesity in IBD appears to be associated with increased early readmission, characterised by a higher burden, despite the introduction of weight-based therapeutics. Prevention of obesity should be a focus in the treatment of IBD to decrease readmission and health care burden.

BACKGROUND:Diabetes and hypertension disparities are pronounced among South Asians. There is regional variation in the prevalence of diabetes and hypertension in the US, but it is unknown whether there is variation among South Asians living in the US. The objective of this study was to compare the burden of diabetes and hypertension between South Asian patients receiving care in the health systems of two US cities. METHODS:Cross-sectional analyses were performed using electronic health records (EHR) for 90,137 South Asians receiving care at New York University Langone in New York City (NYC) and 28,868 South Asians receiving care at Emory University (Atlanta). Diabetes was defined as having 2 + encounters with a diagnosis of diabetes, having a diabetes medication prescribed (excluding Acarbose/Metformin), or having 2 + abnormal A1C levels (≥ 6.5%) and 1 + encounter with a diagnosis of diabetes. Hypertension was defined as having 3 + BP readings of systolic BP ≥ 130 mmHg or diastolic BP ≥ 80 mmHg, 2 + encounters with a diagnosis of hypertension, or having an anti-hypertensive medication prescribed. RESULTS:Among South Asian patients at these two large, private health systems, age-adjusted diabetes burden was 10.7% in NYC compared to 6.7% in Atlanta. Age-adjusted hypertension burden was 20.9% in NYC compared to 24.7% in Atlanta. In Atlanta, 75.6% of those with diabetes had comorbid hypertension compared to 46.2% in NYC. CONCLUSIONS:These findings suggest differences by region and sex in diabetes and hypertension risk. Additionally, these results call for better characterization of race/ethnicity in EHRs to identify ethnic subgroup variation, as well as intervention studies to reduce lifestyle exposures that underlie the elevated risk for type 2 diabetes and hypertension development in South Asians.

The United States Centers for Disease Control and Prevention (CDC) recommends HIV pre-exposure prophylaxis (PrEP) be considered for all patients diagnosed with a sexually transmitted infection (STI). Emergency departments (EDs) are an important site for diagnosis and treatment of STIs for under-served populations. Consequently, we identified 377 patients diagnosed with a bacterial sexually transmitted infection (gonorrhea, chlamydia, and/or syphilis) at a major New York City emergency department between 1/1/2014 and 7/30/2017 to examine associations between key sociodemographic characteristics and missed opportunities for PrEP provision. In this sample, 299 (79%) emergency department patients missed their medical follow-up 90 days after STI diagnosis, as recommended. Results from adjusted generalized estimating equation regression models indicate that patients >45 yo (aOR = 2.2, 95% CI 1.2-3.9) and those with a primary care provider in the hospital system (aOR = 6.8, 95% CI 3.8-12.0) were more likely to return for follow-up visits, whereas Black patients (aOR = 0.44, 95% CI 0.25-0.77) were less likely to return for follow-up visits. These findings indicate that lack of STI treatment follow-up visits are significantly missed opportunities for PrEP provision and comprehensive human immunodeficiency virus prevention care.