Faculty Bibliography

BACKGROUND:Intrahepatic cholangiocarcinoma (ICC) arises from cholangiocytes in the intrahepatic bile duct and is the second most common type of liver cancer. Cholangiocytes express both oestrogen receptor-α and -β, and oestrogens positively modulate cholangiocyte proliferation. Studies in women and men have reported higher circulating oestradiol is associated with increased ICC risk, further supporting a hormonal aetiology. However, no observational studies have examined the associations between exogenous hormone use and reproductive factors, as proxies of endogenous hormone levels, and risk of ICC. METHODS:We harmonised data from 1,107,498 women who enroled in 12 North American-based cohort studies (in the Liver Cancer Pooling Project, LCPP) and the UK Biobank between 1980-1998 and 2006-2010, respectively. Cox proportional hazards regression models were used to generate hazard ratios (HR) and 95% confidence internals (CI). Then, meta-analytic techniques were used to combine the estimates from the LCPP (n = 180 cases) and the UK Biobank (n = 57 cases). RESULTS:Hysterectomy was associated with a doubling of ICC risk (HR = 1.98, 95% CI: 1.27-3.09), compared to women aged 50-54 at natural menopause. Long-term oral contraceptive use (9+ years) was associated with a 62% increased ICC risk (HR = 1.62, 95% CI: 1.03-2.55). There was no association between ICC risk and other exogenous hormone use or reproductive factors. CONCLUSIONS:This study suggests that hysterectomy and long-term oral contraceptive use may be associated with an increased ICC risk.

BACKGROUND:There is concern about the potential of an increased risk related to medications that act on the renin-angiotensin-aldosterone system in patients exposed to coronavirus disease 2019 (Covid-19), because the viral receptor is angiotensin-converting enzyme 2 (ACE2). METHODS:We assessed the relation between previous treatment with ACE inhibitors, angiotensin-receptor blockers, beta-blockers, calcium-channel blockers, or thiazide diuretics and the likelihood of a positive or negative result on Covid-19 testing as well as the likelihood of severe illness (defined as intensive care, mechanical ventilation, or death) among patients who tested positive. Using Bayesian methods, we compared outcomes in patients who had been treated with these medications and in untreated patients, overall and in those with hypertension, after propensity-score matching for receipt of each medication class. A difference of at least 10 percentage points was prespecified as a substantial difference. RESULTS:Among 12,594 patients who were tested for Covid-19, a total of 5894 (46.8%) were positive; 1002 of these patients (17.0%) had severe illness. A history of hypertension was present in 4357 patients (34.6%), among whom 2573 (59.1%) had a positive test; 634 of these patients (24.6%) had severe illness. There was no association between any single medication class and an increased likelihood of a positive test. None of the medications examined was associated with a substantial increase in the risk of severe illness among patients who tested positive. CONCLUSIONS:We found no substantial increase in the likelihood of a positive test for Covid-19 or in the risk of severe Covid-19 among patients who tested positive in association with five common classes of antihypertensive medications.

Gastric cancer represents one of the leading causes of cancer deaths worldwide. Helicobacter pylori (H. pylori) infection is the strongest risk factor associated with gastric cancer. Due to new molecular techniques allowing greater identification of stomach microbes, investigators are beginning to examine the role that bacteria other than H. pylori play in gastric cancer development. Recently, researchers have investigated how the composition of the gastric microbiota varies among individuals with various stages of gastric disease. Specific microbes residing in the stomach have been preferentially associated with gastric cancer patients compared to individuals with a healthy gastric mucosa. Studies conducted on the insulin-gastrin (INS-GAS) transgenic mouse model have provided additional insight into the association between the gastric microbiota and gastric cancer. The purpose of this article is to review the current state of literature on the relationship between the gastric microbiota and gastric cancer based on clinical studies performed to date.

BACKGROUND:Studies demonstrate that children with type 1 diabetes may not be meeting exercise recommendations. This, coupled with the lack of data on the determinants of exercise promotion in youth, may indicate a need for additional focus on exercise guidelines and promotion in youth with type 1 diabetes. OBJECTIVE:The objective of this study is to understand provider perspectives regarding exercise promotion in children with type 1 diabetes. SUBJECTS AND METHODS/METHODS:An online survey regarding perspectives on exercise was emailed to Pediatric Endocrine Society members. RESULTS:Of the 84 respondents, 85.5% believe counseling regarding exercise recommendations is a priority. However, 87.8% did not identify Office of Disease Prevention and Health Promotion (ODPHP) guidelines correctly and 79.3% did not identify American Diabetes Association (ADA) guidelines correctly. Providers who exercised regularly (p = 0.009) and providers who identified ODPHP guidelines correctly (p = 0.004) were more likely to identify ADA guidelines correctly. Providers who identified ADA guidelines correctly were 4.21 times (OR 4.21; 95% CI 1.30-13.7) more likely to make good recommendations and those who discussed recommendations at diagnosis were 6.10 times (OR 6.10; 95% CI 1.76-21.2) more likely to make good recommendations. CONCLUSION/CONCLUSIONS:To our knowledge, this study is the first to investigate provider perspectives of exercise promotion in children with type 1 diabetes. We found provider recommendations were not consistent with ADA exercise guidelines and most providers were not fully aware of the recommendations. Future research should address increasing provider education regarding exercise guidelines and developing exercise promotion tools. This article is protected by copyright. All rights reserved.

The aims of the NYU Children's Health and Environment Study (CHES) are to evaluate influences of prenatal non-persistent chemical exposures on fetal and postnatal growth and pool our data with the US National Institutes of Health Environmental influences on Child Health Outcomes (ECHO) Program to answer collaborative research questions on the impact of the preconceptual, prenatal, and postnatal environment on childhood obesity, neurodevelopment, pre/peri/postnatal outcomes, upper and lower airway outcomes, and positive health. Eligible women were ≥ 18 years old, < 18 weeks pregnant, had a pregnancy that is not medically threatened, and planned to deliver at NYU Langone Hospital-Manhattan, Bellevue Hospital, or NYU Langone Hospital-Brooklyn. Between March 22, 2016 and April 15, 2019, we recruited 2469 pregnant women, from whom 2193 completed an initial questionnaire and continued into NYU CHES. Of the 2193, 88 miscarried, 28 terminated, and 20 experienced stillbirth, while 57 were lost to follow up. We report here demographic and other characteristics of the 2000 live deliveries (2037 children), from whom 1624 (80%) consented to postnatal follow-up. Data collection in pregnancy was nested in clinical care, with questionnaire and specimen collection conducted during routine prenatal visits at < 18, 18-25, and > 25 weeks gestation. These have been followed by questionnaire and specimen collection at birth and regular postpartum intervals.

PURPOSE/OBJECTIVE:Metastatic castration-resistant prostate cancer (mCRPC) with low androgen receptor (AR) and without neuroendocrine signaling, termed double-negative prostate cancer (DNPC), is increasingly prevalent in patients treated with AR signaling inhibitors and is in need of new biomarkers and therapeutic targets. METHODS:Candidate genes enriched in DNPC were determined using differential gene expression analysis of discovery and validation cohorts of mCRPC biopsies. Laboratory studies were carried out in human mCRPC organoid cultures, prostate cancer (PCa) cell lines, and mouse xenograft models. Epigenetic studies were carried out in a rapid autopsy cohort. RESULTS:< .0005). Growth inhibition of the human PCa model PC3 by the anti-DKK1 monoclonal antibody DKN-01 depends on the presence of NK cells in a severe combined immunodeficient xenograft mouse model. CONCLUSION/CONCLUSIONS:These results support DKK1 as a contributor to the immunosuppressive tumor microenvironment of DNPC. These data have provided the rationale for a clinical trial targeting DKK1 in mCRPC (ClinicalTrials.gov identifier: NCT03837353).

Arsenic, a class I human carcinogen, is ubiquitously found throughout the environment and around the globe, posing a great public health concern. Notably, Bangladesh and regions of West Bengal have been found to have high levels (0.5-4600 μg/L) of arsenic drinking water contamination, and approximately 50 million of the world's 200 million people chronically exposed to arsenic in Bangladesh alone. This study was carried out to examine genome-wide gene expression changes in individuals chronically exposed to arsenic-contaminated drinking water. Our study population includes twenty-nine Bangladeshi female participants with urinary arsenic levels ranging from 22.32 to 1828.12 μg/g creatinine. RNA extracted from peripheral blood mononuclear cells (PBMCs) were evaluated using RNA-Sequencing analysis. Our results indicate that a total of 1,054 genes were significantly associated with increasing urinary arsenic levels (FDR p < 0.05), which include 418 down-regulated and 636 up-regulated genes. Further Ingenuity Pathway Analysis revealed potential target genes (DAPK1, EGR2, APP), microRNAs (miR-155, -338, -210) and pathways (NOTCH signaling pathway) related to arsenic carcinogenesis. The selection of female-only participants provides a homogenous study population since arsenic has significant sex dependent effects, and the wide exposure range provides new insight for key gene expression changes that correlate with increasing urinary arsenic levels.

BACKGROUND:Tobacco and alcohol are well-established risk factors for numerous cancers, yet their relationship to biliary tract cancers remains unclear. METHODS:We pooled data from 26 prospective studies to evaluate associations of cigarette smoking and alcohol consumption with biliary tract cancer risk. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with smoking and alcohol consumption were calculated. Random effects meta-analysis produced summary estimates. All statistical tests were two-sided. RESULTS:Over a period of 38,369,156 person-years of follow-up, 1,391 gallbladder, 758 intrahepatic bile duct, 1,208 extrahepatic bile duct, and 623 ampulla of Vater cancer cases were identified. Ever, former, and current smoking were associated with increased extrahepatic bile duct and ampulla of Vater cancers risk (e.g., current versus never smokers hazard ratio [HR] = 1.69, 95% confidence interval [CI] = 1.34 to 2.13 and 2.22, 95%CI = 1.69 to 2.92, respectively), with dose-response effects for smoking pack-years, duration, and intensity (all P-trend<0.01). Current smoking and smoking intensity were also associated with intrahepatic bile duct cancer (e.g., >40 cigarettes/day versus never smokers HR = 2.15, 95%CI: 1.15 to 4.00; P-trend=0.001). No convincing association was observed between smoking and gallbladder cancer. Alcohol consumption was only associated with intrahepatic bile duct cancer, with increased risk for individuals consuming ≥5 versus 0 drinks/day (HR = 2.35, 95%CI = 1.46 to 3.78; P-trend=0.04). There was evidence of statistical heterogeneity between several cancer sites, particularly between gallbladder cancer and the other biliary tract cancers. CONCLUSIONS:Smoking appears to increase the risk of developing all biliary tract cancers except gallbladder cancer. Alcohol may increase the risk of intrahepatic bile duct cancer. Findings highlight etiologic heterogeneity across the biliary tract.

OBJECTIVES/OBJECTIVE:Evidence of the association between inorganic arsenic (As) exposure, especially early-life exposure, and blood pressure (BP) in adolescence is limited. We examined the association of As exposure during early childhood, childhood, and adolescence with BP in adolescence. METHODS:We conducted a cross-sectional study of 726 adolescents aged 14-17 (mean 14.75) years whose mothers were participants in the Bangladesh Health Effects of Arsenic Longitudinal Study (HEALS). Adolescents' BP was measured at the time of their recruitment between December 2012 and December 2016. We considered maternal urinary As (UAs), repeatedly measured during childhood, as proxy measures of early childhood (<5 years old, A1) and childhood (5-12 years old, A2) exposure. Adolescents' current UAs was collected at the time of recruitment (14-17 years of age, A3). RESULTS:) than those with a BMI below the median (P for interaction = 0.03 and 0.03, respectively). There was no significant association between any of the exposure measures and DBP. The Weighted Quantile Sum (WQS) regression confirmed that adolescents' UAs at A3 and maternal UAs at A1 contributed the most to the overall effect of As exposure at three life stages on SBP. Mixture analyses using Bayesian Kernel Machine Regression identified UAs at A3 as a significant contributor to SBP and DBP independent of other concurrent blood levels of cadmium, lead, manganese, and selenium. CONCLUSION/CONCLUSIONS:Our findings suggest an association of current exposure and early childhood exposure to As with higher BP in adolescents, which may be exacerbated by higher BMI at adolescence.

Background/UNASSIGNED:Psoriasis is an inflammatory skin disease associated with atherosclerotic cardiovascular disease (ASCVD) risk factors and vascular disease. The relative impact of psoriasis on vascular disease is the strongest in young patients with psoriasis, yet data are lacking on how sex differences influence cardiovascular risk factors and vascular disease in these patients. Objective/UNASSIGNED:This observational study aimed to identify the burden of cardiovascular risk factors and vascular disease in patients with psoriasis and to explore whether this burden is different between men and women age < 35 years. Methods/UNASSIGNED:Young (age ≥ 20 and < 35 years) hospitalized patients with psoriasis from the United States National Inpatient Sample were compared with those matched patients without psoriasis. Vascular disease was defined as ASCVD and/or venous thromboembolic disease. Multivariable logistic regression was used to determine the associations between psoriasis, sex, ASCVD risk factors, and vascular disease. Results/UNASSIGNED:Overall, patients with psoriasis (n = 18,353) were more often obese (16% vs. 6%); smokers (31% vs. 17%); and diagnosed with diabetes mellitus (10% vs. 6%), hypertension (16% vs. 8%), hyperlipidemia (6% vs. 2%), ASCVD (2.2% vs. 1.6%), and deep vein thrombosis (6% vs. 4%; all p < .001) compared with patients without psoriasis (n = 55,059; matched by age, sex, and race). When stratified by sex, women with psoriasis were more likely to have multiple cardiovascular risk factors and ASCVD (odds ratio: 2.6; 95% confidence interval [2.1-3.1]) compared with men with psoriasis (odds ratio: 1.2; 95% confidence interval [0.9-1.4]; interaction p < .01). The association between psoriasis and ASCVD in women remained unchanged after multivariable adjustment for traditional cardiovascular risk factors. Conclusion/UNASSIGNED:Psoriasis was associated with cardiovascular disease and risk factors in young hospitalized patients, with stronger associations among women than among men.