Faculty Bibliography

BACKGROUND:Black men are disproportionately affected by prostate cancer, the most common non-cutaneous malignancy among men in the USA. The United States Preventive Services Task Force (USPSTF) encourages prostate-specific antigen (PSA) testing decisions to be based on shared decision-making (SDM) clinician professional judgment, and patient preferences. However, evidence suggests that SDM is underutilized in clinical practice, especially among the most vulnerable patients. The purpose of this study is to evaluate the efficacy of a community health worker (CHW)-led decision-coaching program to facilitate SDM for prostate cancer screening among Black men in the primary care setting, with the ultimate aim of improving/optimizing decision quality. METHODS:We proposed a CHW-led decision-coaching program to facilitate SDM for prostate cancer screening discussions in Black men at a primary care FQHC. This study enrolled Black men who were patients at the participating clinical site and up to 15 providers who cared for them. We estimated to recruit 228 participants, ages 40-69 to be randomized to either (1) a decision aid along with decision coaching on PSA screening from a CHW or (2) receiving a decision aid along with CHW-led interaction on modifying dietary and lifestyle to serve as an attention control. The independent randomization process was implemented within each provider and we controlled for age by dividing patients into two strata: 40-54 years and 55-69 years. This sample size sufficiently powered the detection differences in the primary study outcomes: knowledge, indicative of decision quality, and differences in PSA screening rates. Primary outcome measures for patients will be decision quality and decision regarding whether to undergo PSA screening. Primary outcome measures for providers will be acceptability and feasibility of the intervention. We will examine how decision coaching about prostate cancer screening impact patient-provider communication. These outcomes will be analyzed quantitatively through objective, validated scales and qualitatively through semi-structured, in-depth interviews, and thematic analysis of clinical encounters. Through a conceptual model combining elements of the Preventative Health Care Model (PHM) and Informed Decision-Making Model, we hypothesize that the prostate cancer screening decision coaching intervention will result in a preference-congruent decision and decisional satisfaction. We also hypothesize that this intervention will improve physician satisfaction with counseling patients about prostate cancer screening. DISCUSSION/CONCLUSIONS:Decision coaching is an evidence-based approach to improve decision quality in many clinical contexts, but its efficacy is incompletely explored for PSA screening among Black men in primary care. Our proposal to evaluate a CHW-led decision-coaching program for PSA screening has high potential for scalability and public health impact. Our results will determine the efficacy, cost-effectiveness, and sustainability of a CHW intervention in a community clinic setting in order to inform subsequent widespread dissemination, a critical research area highlighted by USPSTF. TRIAL REGISTRATION/BACKGROUND:The trial was registered prospectively with the National Institute of Health registry ( www.clinicaltrials.gov ), registration number NCT03726320 , on October 31, 2018.

In lung cancer, enrichment of the lower airway microbiota with oral commensals commonly occurs and ex vivo models support that some of these bacteria can trigger host transcriptomic signatures associated with carcinogenesis. Here, we show that this lower airway dysbiotic signature was more prevalent in group IIIB-IV TNM stage lung cancer and is associated with poor prognosis, as shown by decreased survival among subjects with early stage disease (I-IIIA) and worse tumor progression as measured by RECIST scores among subjects with IIIB-IV stage disease. In addition, this lower airway microbiota signature was associated with upregulation of IL-17, PI3K, MAPK and ERK pathways in airway transcriptome, and we identified Veillonella parvula as the most abundant taxon driving this association. In a KP lung cancer model, lower airway dysbiosis with V. parvula led to decreased survival, increased tumor burden, IL-17 inflammatory phenotype and activation of checkpoint inhibitor markers.

INTRODUCTION/BACKGROUND:Epidemiological studies that investigate alterations in the gut microbial composition associated with smoking are lacking. This study examined the composition of the gut microbiome in smokers compared with non-smokers. METHODS:Stool samples were collected in a cross-sectional study of 249 participants selected from the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh. Microbial DNA was extracted from the fecal samples and sequenced by 16S rRNA gene sequencing. The associations of smoking status and intensity of smoking with the relative abundance or the absence and presence of individual bacterial taxon from phylum to genus levels were examined. RESULTS:The relative abundance of bacterial taxa along the Erysipelotrichi-to-Catenibacterium lineage was significantly higher in current smokers compared to never smokers. The odds ratio comparing the mean relative abundance in current smokers with that in never smokers was 1.91 (95% confidence interval [CI] = 1.36 to 2.69) for the genus Catenibacterium and 1.89 (95% CI = 1.39 to 2.56) for the family Erysipelotrichaceae, the order Erysipelotrichale, and the class Erysipelotrichi ((FDR-adjusted p-values = 0.0008 to 0.01). A dose-response association was observed for each of these bacterial taxa. The presence of Alphaproteobacteria was significantly greater comparing current with never smokers (OR = 4.85, FDR-adjusted p-values = 0.04). CONCLUSIONS:Our data in a Bangladeshi population are consistent with evidence of an association between smoking status and dosage with change in the gut bacterial composition. IMPLICATIONS/CONCLUSIONS:This study for the first time examined the relationship between smoking and the gut microbiome composition. The data suggest that smoking status may play an important role in the composition of the gut microbiome, especially among individuals with higher levels of tobacco exposure.

Despite advances in lipid-lowering therapies, people with diabetes continue to experience more limited cardiovascular benefits. In diabetes, hyperglycemia sustains inflammation and preempts vascular repair. We tested the hypothesis that the receptor for advanced glycation end-products (RAGE) contributes to these maladaptive processes. We report that transplantation of aortic arches from diabetic, Western diet-fed Ldlr-/- mice into diabetic Ager-/- (Ager, the gene encoding RAGE) versus WT diabetic recipient mice accelerated regression of atherosclerosis. RNA-sequencing experiments traced RAGE-dependent mechanisms principally to the recipient macrophages and linked RAGE to interferon signaling. Specifically, deletion of Ager in the regressing diabetic plaques downregulated interferon regulatory factor 7 (Irf7) in macrophages. Immunohistochemistry studies colocalized IRF7 and macrophages in both murine and human atherosclerotic plaques. In bone marrow-derived macrophages (BMDMs), RAGE ligands upregulated expression of Irf7, and in BMDMs immersed in a cholesterol-rich environment, knockdown of Irf7 triggered a switch from pro- to antiinflammatory gene expression and regulated a host of genes linked to cholesterol efflux and homeostasis. Collectively, this work adds a new dimension to the immunometabolic sphere of perturbations that impair regression of established diabetic atherosclerosis and suggests that targeting RAGE and IRF7 may facilitate vascular repair in diabetes.

MOTIVATION/BACKGROUND:Recent microbiome association studies have revealed important associations between microbiome and disease/health status. Such findings encourage scientists to dive deeper to uncover the causal role of microbiome in the underlying biological mechanism, and have led to applying statistical models to quantify causal microbiome effects and to identify the specific microbial agents. However, there are no existing causal mediation methods specifically designed to handle high dimensional and compositional microbiome data. RESULTS:We propose a rigorous Sparse Microbial Causal Mediation Model (SparseMCMM) specifically designed for the high dimensional and compositional microbiome data in a typical three-factor (treatment, microbiome and outcome) causal study design. In particular, linear log-contrast regression model and Dirichlet regression model are proposed to estimate the causal direct effect of treatment and the causal mediation effects of microbiome at both the community and individual taxon levels. Regularization techniques are used to perform the variable selection in the proposed model framework to identify signature causal microbes. Two hypothesis tests on the overall mediation effect are proposed and their statistical significance is estimated by permutation procedures. Extensive simulated scenarios show that SparseMCMM has excellent performance in estimation and hypothesis testing. Finally, we showcase the utility of the proposed SparseMCMM method in a study which the murine microbiome has been manipulated by providing a clear and sensible causal path among antibiotic treatment, microbiome composition and mouse weight. AVAILABILITY/BACKGROUND:https://sites.google.com/site/huilinli09/software and https://github.com/chanw0/SparseMCMM. SUPPLEMENTARY INFORMATION/BACKGROUND:Supplementary data are available at Bioinformatics online.

Over the past decade, there has been a change in the epidemiology of oral cavity squamous cell cancer (OC-SCC). Many new cases of OC-SCC lack the recognized risk factors of smoking, alcohol and human papilloma virus. The aim of this study was to determine if the oral microbiome may be associated with OC-SCC in nonsmoking HPV negative patients. We compared the oral microbiome of HPV-negative nonsmoker OC-SCC( n=18), premalignant lesions(PML) (n=8) and normal control patients (n=12). Their oral microbiome was sampled by oral wash and defined by 16S rRNA gene sequencing. We report that the periodontal pathogens Fusobacterium, Prevotella, Alloprevotella were enriched while commensal Streptococcus depleted in OC-SCC. Based on the four genera plus a marker genus Veillonella for PML, we classified the oral microbiome into two types. Gene/pathway analysis revealed a progressive increase of genes encoding HSP90 and ligands for TLRs 1, 2 and 4 along the controls→PML→OC-SCC progression sequence. Our findings suggest an association between periodontal pathogens and OC-SCC in non smoking HPV negative patients.

Background/UNASSIGNED:(the gene encoding RAGE), have been reported to be associated with T2D and its complications, we tested for potential relationships between these factors and T2D status in Emirati subjects. Methods/UNASSIGNED:In a case-control study, we recruited Emirati subjects with T2D and controls from the Sheikh Khalifa Medical City in Abu Dhabi. Anthropomorphic characteristics, levels of plasma sRAGE and esRAGE, and routine chemistry variables were measured. Results/UNASSIGNED: = 0.01, after adjustment for age and sex). Conclusion/discussion/UNASSIGNED:Levels of sRAGE, but not esRAGE, were associated with T2D status in Abu Dhabi, but not after correction for eGFR. Elevated levels of plasma insulin in both control and T2D subjects suggests the presence of metabolic dysfunction, even in subjects without diabetes.

Objectives/UNASSIGNED:Hemoglobin A1c (HbA1c) is associated with hypertension in prediabetes (PD) and type 2 diabetes (T2D), both of which are associated with increased cardiovascular disease (CVD) risk. Traditionally, HbA1c is the standard approach to assessing glycemic status, however, glycemic variability (GV)-the daily fluctuations in blood glucose concentrations-may be more predictive of CVD. Little is known regarding the relationship between GV and blood pressure (BP). Therefore, we examined GV and HbA1c and their associations with BP in overweight adults with PD and early stage T2D enrolled in a weight loss study. Methods/UNASSIGNED:Participants had a history of PD or T2D treated with lifestyle alone or lifestyle and metformin. Data for this report were obtained at baseline and included sociodemographics, height, weight, BP, and HbA1c. Up to two weeks of continuous glucose monitoring data were collected using the Abbott Freestyle Libre Pro, and mean amplitude of glycemic excursions (MAGE) was computed using EasyGV. Linear mixed models were used to test the associations of MAGE and HbA1c with BP, with adjustment for sociodemographic characteristics, as well as to compare MAGE on weekdays versus weekends. Repeated measures ANOVA was used to investigate the within-subject and between-subject variation of MAGE. All analyses were performed using R software. Results/UNASSIGNED:Â =Â 0.03). Conclusions/UNASSIGNED:Among overweight adults with PD and early-stage T2D, MAGE was found to be associated with SBP. This suggests that a measure of daily GV may be a good alternative measure of metabolic health outcomes in this population. Funding Sources/UNASSIGNED:This work was funded by the American Heart Association.

Our objective was to investigate the relationship between the gut microbiota and anthropometric measurements among 248 participants from the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh. Our cohort represents a unique population that allows for the investigation of the gut microbiota and anthropometric measurements in lean individuals. We measured height, weight, arm, thigh, hip, and waist circumferences, and collected fecal samples. Microbial DNA was extracted from the stool samples and sequenced by 16S rRNA gene sequencing. We examined associations between relative abundance of individual bacterial taxa from phylum to genus levels and anthropometric measurements. We found that higher BMI, mid-upper arm circumference, waist circumference, and waist-to-hip ratio were associated with a lower alpha diversity of fecal bacteria. Relative abundance of the genus Oscillospira and the family S24-7 were inversely related to all measurements after correction for multiple testing. Relative abundance of genus Acidaminococcus and family Ruminococcaceae were also associated with several measurements. The positive associations of the genus Acidaminococcus with BMI, as well as waist and hip circumferences, were stronger in women than in men. Our data in this lean Bangladeshi population found a correlation between Oscillospira and leanness, as measured using multiple anthropometric measures.