Faculty Bibliography

INTRODUCTION:The USA has the highest rate of community gun violence of any developed democracy. There is an urgent need to develop feasible, scalable and community-led interventions that mitigate incident gun violence and its associated health impacts. Our community-academic research team received National Institutes of Health funding to design a community-led intervention that mitigates the health impacts of living in communities with high rates of gun violence. METHODS AND ANALYSIS:We adapted 'Building Resilience to Disasters', a conceptual framework for natural disaster preparedness, to guide actions of multiple sectors and the broader community to respond to the man-made disaster of gun violence. Using this framework, we will identify existing community assets to be building blocks of future community-led interventions. To identify existing community assets, we will conduct social network and spatial analyses of the gun violence episodes in our community and use these analyses to identify people and neighbourhood blocks that have been successful in avoiding gun violence. We will conduct qualitative interviews among a sample of individuals in the network that have avoided violence (n=45) and those living or working on blocks that have not been a location of victimisation (n=45) to identify existing assets. Lastly, we will use community-based system dynamics modelling processes to create a computer simulation of the community-level contributors and mitigators of the effects of gun violence that incorporates local population-based based data for calibration. We will engage a multistakeholder group and use themes from the qualitative interviews and the computer simulation to identify feasible community-led interventions. ETHICS AND DISSEMINATION:The Human Investigation Committee at Yale University School of Medicine (#2000022360) granted study approval. We will disseminate study findings through peer-reviewed publications and academic and community presentations. The qualitative interview guides, system dynamics model and group model building scripts will be shared broadly.

INTRODUCTION/BACKGROUND:Obstructive sleep apnea (OSA) is associated with Alzheimer's disease (AD) biomarkers in cognitively normal (CN) and mild cognitive impaired (MCI) participants. However, independent and combined effects of OSA, amyloid beta (Aβ) and tau-accumulation on AD time-dependent progression risk is unclear. METHODS:Study participants grouped by biomarker profile, as described by the A/T/N scheme, where "A" refers to aggregated Aβ, "T" aggregated tau, and "N" to neurodegeneration, included 258 CN (OSA-positive [OSA+] [A+TN+ n = 10, A+/TN- n = 6, A-/TN+ n = 10, A-/TN- n = 6 and OSA-negative [OSA-] [A+TN+ n = 84, A+/TN- n = 11, A-/TN+ n = 96, A-/TN- n = 36]) and 785 MCI (OSA+ [A+TN+ n = 35, A+/TN- n = 15, A-/TN+ n = 25, A-/TN- n = 16] and OSA- [A+TN+ n = 388, A+/TN- n = 28, A-/TN+ n = 164, A-/TN- n = 114]) older-adults from the Alzheimer's Disease Neuroimaging Initiative cohort. Cox proportional hazards regression models estimated the relative hazard of progression from CN-to-MCI and MCI-to-AD, among baseline OSA CN and MCI patients, respectively. Multi-level logistic mixed-effects models with random intercept and slope investigated the synergistic associations of self-reported OSA, Aβ, and tau burden with prospective cognitive decline. RESULTS:Independent of TN-status (CN and MCI), OSA+/Aβ+ participants were approximately two to four times more likely to progress to MCI/AD (P < .001) and progressed 6 to 18 months earlier (P < .001), compared to other participants combined (ie, OSA+/Aβ-, OSA-/Aβ+, and OSA-/Aβ-). Notably, OSA+/Aβ- versus OSA-/Aβ- (CN and MCI) and OSA+/TN- versus OSA-/TN- (CN) participants showed no difference in the risk and time-to-MCI/AD progression. Mixed effects models demonstrated OSA synergism with Aβ (CN and MCI [β = 1.13, 95% confidence interval (CI), 0.74 to 1.52, and β = 1.18, 95%CI, 0.82 to 1.54]) respectively, and with tau (MCI [β = 1.31, 95% CI, 0.87 to 1.47]), P < .001 for all. DISCUSSION/CONCLUSIONS:OSA acts in synergism with Aβ and with tau, and all three acting together result in synergistic neurodegenerative mechanisms especially as Aβ and tau accumulation becomes increasingly abnormal, thus leading to shorter progression time to MCI/AD in CN and MCI-OSA patients, respectively.

BACKGROUND:Physician shortage is a major barrier to hypertension (HTN) control in Ghana, with only one physician to 10,000 patients in 2015, thus limiting its capacity for HTN control at the primary care level such as the Community Health Planning and Services (CHPS) compounds, where most Ghanaians receive care. A Task-Shifting Strategy for HTN control (TASSH) based on the WHO Cardiovascular (CV) Risk Package is an evidence-based strategy for mitigating provider- and systems-level barriers to optimal HTN control. Despite its effectiveness, TASSH remains untested in CHPS zones. Additionally, primary care practices in low- and middle-income countries (LMICs) lack resources and expertise needed to coordinate multilevel system changes without assistance. The proposed study will evaluate the effectiveness of practice facilitation (PF) as a quality improvement strategy for implementing TASSH within CHPS zones in Ghana. METHODS:Guided by the Consolidated Framework for Implementation Research and the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework, we will evaluate, in a hybrid clinical effectiveness-implementation design, the effect of PF on the uptake of an evidence-based TASSH, among 700 adults who present to 70 CHPS zones with uncontrolled HTN. Components of the PF strategy include (a) an advisory board that provides leadership support for implementing the intervention within the CHPS zones and (b) trained task-strengthening facilitators (TSFs) who serve as practice coaches to provide training, and performance feedback to community health officers (CHOs) who will deliver TASSH at the CHPS zones. For this purpose, the TSFs are trained to identify, counsel, and refer adults with uncontrolled HTN to community health centers in Bono East Region of Ghana. DISCUSSION/CONCLUSIONS:Uptake of community-based evidence-supported interventions for hypertension control in Ghana is urgently needed to address the CVD epidemic and its associated morbidity, mortality, and societal costs. Findings from this study will provide policymakers and other stakeholders the "how to do it" empirical literature on the uptake of evidence-based task-strengthening interventions for HTN control in Ghana and will serve as a model for similar action in other low, middle-income countries. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov, NCT03490695 . Registered on 6 April 2018. PROTOCOL VERSION AND DATE/UNASSIGNED:Version 1, date: 21 August, 2019.

: As coronavirus disease 2019 (Covid-19) restrictions upend the community bonds that have enabled African communities to thrive in the face of numerous challenges, it is vital that the gains made in community-based healthcare are preserved by adapting our approaches. Instead of reversing the many gains made through locally driven development partnerships with international funding agencies for other viral diseases like HIV, we must use this opportunity to adapt the many lessons learned to address the burden of Covid-19. Programs like the Academic Model Providing Access to Healthcare are currently leveraging widely available technologies in Africa to prevent patients from experiencing significant interruptions in care as the healthcare system adjusts to the challenges presented by Covid-19. These approaches are designed to preserve social contact while incorporating physical distancing. The gains and successes made through approaches like group-based medical care must not only continue but can help expand upon the extraordinary success of programs like President's Emergency Plan for AIDS Relief.

BACKGROUND:Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies (GWAS) in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. METHODS:To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study (TWAS) in Europeans using three approaches, FUSION, MetaXcan and SMulTiXcan. We integrated GWAS summary statistics from 9,040 pancreatic cancer cases and 12,496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics, LTG (n = 95) and Genotype-Tissue Expression, GTEx v7 (n = 174) datasets), and data from 48 different tissues (GTEx v7, n = 74-421 samples). RESULTS:We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (FDR < 0.05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12:, PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at 6 known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci, and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1 and BCAR1 at known loci) remained statistically significant after Bonferroni correction. CONCLUSIONS:By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

The destruction of the World Trade Center (WTC) towers on 11 September 2001 released many tons of aerosolized dust and smoke with potential for carcinogenic exposures to community members as well as responders. The WTC Environmental Health Center (WTC EHC) is a surveillance and treatment program for a diverse population of community members ("Survivors"), including local residents and workers, present in the NYC disaster area on 9/11 or in the days or weeks following. We report a case series of cancers identified in the WTC EHC as of 31 December 2019. Descriptive characteristics are presented for 2561 cancer patients (excluding non-melanoma skin cancer) and 5377 non-cancer WTC-EHC participants who signed informed consent. We identified a total of 2999 cancer diagnoses in 2561 patients: 2534 solid tumors (84.5%) and 465 lymphoid and hematopoietic tissue cancers (15.5%) with forty-one different cancer types. We describe the distribution, frequency, median age of cancer diagnosis and median latency from 9/11 by cancer site. In addition to common cancer types, rare cancers, including male breast cancers and mesotheliomas have been identified. The current study is the first report on cancer characteristics of enrollees at WTC EHC, a federally designated treatment and surveillance program for local community members affected by the 9/11 terrorist attack on the WTC.

OBJECTIVE:Increasingly, patients are seeking same-day care at urgent care (UC) facilities. Little is known about the health care utilization patterns of patients who visit UC facilities for headache and migraine. We examined the frequency of headache and migraine visits and revisits at UC facilities. METHODS:We conducted a retrospective cohort study of headache not otherwise specified (NOS) and migraine visits from 67 NYC UC facilities over an eight-month period. We report descriptive analyses, the frequency of headache NOS revisits, and the elapsed time to revisits. RESULTS:There were 10,240 patients who visited UC facilities for headache NOS or migraine within the eight-month period. The majority of patients, 6,994 (68.3%), were female, and the mean age (SD) was 35.1 (15.0) years. Most (93.9%) patients (N = 9,613) lived within 60 miles of NYC; 5.5% (N = 564) had at least one revisit, and among re-visitors, there was an average (SD) of 2.2 (0.7) visits to UC facilities during the study period and an average time to revisit (SD) of 61.3 (55.2) days. CONCLUSIONS:In just eight months, there were >10,000 headache NOS and migraine visits to UC facilities in NYC, with half of revisits occurring within 90 days. Future work should examine headache management in UC facilities.

Background/UNASSIGNED:Chronic kidney disease (CKD) measures (estimated glomerular filtration rate [eGFR] and albuminuria) are frequently assessed in clinical practice and improve the prediction of incident cardiovascular disease (CVD), yet most major clinical guidelines do not have a standardized approach for incorporating these measures into CVD risk prediction. "CKD Patch" is a validated method to calibrate and improve the predicted risk from established equations according to CKD measures. Methods/UNASSIGNED:Utilizing data from 4,143,535 adults from 35 datasets, we developed several "CKD Patches" incorporating eGFR and albuminuria, to enhance prediction of risk of atherosclerotic CVD (ASCVD) by the Pooled Cohort Equation (PCE) and CVD mortality by Systematic COronary Risk Evaluation (SCORE). The risk enhancement by CKD Patch was determined by the deviation between individual CKD measures and the values expected from their traditional CVD risk factors and the hazard ratios for eGFR and albuminuria. We then validated this approach among 4,932,824 adults from 37 independent datasets, comparing the original PCE and SCORE equations (recalibrated in each dataset) to those with addition of CKD Patch. Findings/UNASSIGNED:with albuminuria 30-299 mg/g), indicating considerable risk underestimation in CKD with SCORE. The corresponding estimates for ASCVD with PCE were 1.55 (1.37-1.81), 1.24 (1.10-1.54), and 1.21 (0.98-1.46). Interpretation/UNASSIGNED:The "CKD Patch" can be used to quantitatively enhance ASCVD and CVD mortality risk prediction equations recommended in major US and European guidelines according to CKD measures, when available. Funding/UNASSIGNED:US National Kidney Foundation and the NIDDK.

PURPOSE/UNASSIGNED:Biobanks usually do not collect transgender and gender-diverse (TGD) demographic information, hindering research on cancer risk and biological effects related to gender-affirming interventions. METHODS/UNASSIGNED:In August 2019, 172 scientists involved in biobanking research at a single institution (H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL) were invited to complete a survey measuring knowledge and attitudes about TGD health and research practices. Quantitative and qualitative analyses were performed. RESULTS/UNASSIGNED:< .001). Qualitative analysis of open-ended questions indicated overall support of TGD data inclusion in biobanks along with perceived barriers to inclusion of such data in biobanks. CONCLUSION/UNASSIGNED:To our knowledge, this was the first study of researchers to assess knowledge, attitudes, and research practices regarding TGD patients. Overall, there was limited knowledge about TGD health and cancer needs and low rates of TGD demographic data collection but a high interest in receiving education regarding this community.

Some chronic pain conditions and comorbidities suppress the hypothalamic-pituitary-adrenal (HPA) axis and response to dynamic testing. We measured HPA axis responses to corticotropin-releasing hormone (CRH) administration in relation to chronic pelvic pain and endometriosis. In a cross-sectional study of women (n = 54) with endometriosis-associated chronic pelvic pain (n = 22), chronic pelvic pain alone (n = 12), or healthy volunteers (n = 20), adrenocorticotropic-releasing hormone (ACTH) and cortisol levels were measured at 0, 15, 30, and 45 min after intravenous ovine CRH administration. ACTH and cortisol delta (peak-baseline) and area under the curve (AUC) were compared by study group and assessed for association with race and menstrual and non-menstrual pain severity. HPA axis responses did not differ among the racially diverse groups or in those with pain compared with healthy volunteers. However, when stratified by race, ACTH delta (129.9 ± 130.7 vs. 52.5 ± 66.0 pg/mL; p = 0.003), ACTH AUC (4813 ± 4707 vs. 2290 ± 2900 min*pg/mL; p = 0.013), and cortisol delta (26.3 ± 21.5 vs. 13.2 ± 9.7 μg/mL; p = 0.005) were significantly higher in black (n = 10) than predominately white (non-black) subjects (n = 44; 39/44 white). In analyses among primarily white (non-black) women, greater menstrual pain severity was associated with blunted ACTH delta (p = 0.015) and cortisol delta (p = 0.023), and greater non-menstrual pain severity with blunted cortisol delta (p = 0.017). Neuroendocrine abnormalities in women with chronic pelvic pain may differ by pain manifestations and may vary by race. The higher HPA axis response in black women merits investigation in pelvic pain studies stratified by race. In white (non-black) women experiencing pain, a blunted response was related to pain severity suggesting pain affects women independently of endometriosis lesions.