Faculty Bibliography

BACKGROUND:Decisions involving the purchase of procedural equipment at the health system level require balancing efficacy, safety, physician preference, and cost. The application of efficient and low-cost pragmatic study designs has the potential to rapidly generate data to inform health system operations. METHODS:The aim of the pragmatic RAISE-EMR study is to determine physician preference between two commercially available radial artery introducer sheaths, one of which has a higher acquisition cost, to guide inventory selection in the hospital system's catheterization laboratories. Patients undergoing coronary angiography using 6-French radial artery access were prospectively identified and randomized through the health system's electronic medical record (EMR). Among 1696 eligible unique patients, 554 patients (32.7%) were randomized over 37 days across three hospitals. Randomization took place through the EMR after the attending interventional cardiologist signed a mandated pre-procedure note. The study was deemed non-human subject research and approved by the NYU Langone Health Quality Improvement Oversight Committee. The primary endpoint, a physician satisfaction score, will be ascertained by a mandated semi-quantitative survey within the electronic procedure note. All data, including co-variables and clinical outcomes, will be ascertained using structured data within the EMR. CONCLUSIONS:The RAISE-EMR study is designed to determine physician preference of two commercially available radial artery introducer sheaths and potentially reduce supply costs using an entirely EMR-based randomized study design. Pragmatic study designs leveraging structured data within an EMR can be used to rapidly provide data to inform operational decision-making and have implications for the future of evidence generation.

The American Heart Association's PREVENT equations estimate risk of total cardiovascular disease (CVD), atherosclerotic CVD (ASCVD), and heart failure (HF) to guide lipid and blood pressure-lowering therapy in people ages 30 to 79 years in the United States. The SCORE2 risk algorithm is used to estimate CVD risk for similar purposes in people ages 40 and older in Europe. Neither set of equations has been comprehensively validated in global observational cohorts and randomized trials. Here, in 44 observational cohorts and 18 randomized trials, we assessed discrimination and calibration of the two risk algorithms across geographical regions (North America, Europe, Asia/other, multi-region trials). We also created scaling factors for risk prediction over 1-9 years using the PREVENT equations, enabling shorter-term risk prediction for research purposes or to facilitate clinical trial enrolment. Over 5.1 years of mean follow-up, 293,737 PREVENT total CVD events (fatal and non-fatal ASCVD or HF) and 258,086 SCORE2 CVD events (myocardial infarction, stroke, or cardiovascular death) were observed among 6,422,714 and 5,437,384 individuals, respectively. Despite differences in CVD outcome definitions, target populations and predictor variables, overall discrimination and calibration were similar for both equations, with generally good performance across regions, including in multi-regional randomized trials. These findings lend support for adoption of PREVENT or SCORE2 for cardiovascular risk stratification across diverse settings.

OBJECTIVES/OBJECTIVE:Given the known link between maternal and child mental health, it is likely that children whose mothers experienced more distress because of the COVID-19 pandemic were at greater risk for increased behavior problems. Yet research to date has not tested this hypothesis among families who were hit hardest by the pandemic-those with low incomes and from Black and Hispanic backgrounds. Research is also needed that focuses on young children and uses a longitudinal design. DESIGN/METHODS:We harmonized data from 4 cohorts originally designed to study pediatric parenting interventions with underresourced families in 2 US cities. We examined, first, whether maternal distress because of the pandemic was associated with change over the next 1 to 2 years in preschool-aged children's anxiety/depression and aggression, and second, whether such associations were moderated by maternal depression. RESULTS:Maternal pandemic-related distress predicted a small increase in child aggression but no change in anxiety/depression. There was no moderation by maternal depression. CONCLUSION/CONCLUSIONS:Among families at risk of the most severe health and financial hardships because of the pandemic, maternal pandemic-related distress was associated with increases in child aggression 1 to 2 years later. Maternal mental health must be made a priority in the future disasters not only in its own right but also because of possible spillover effects on young children.

Osteoarthritis, especially knee osteoarthritis, is a leading cause of disability and reduced quality of life. The etiology of pain in osteoarthritis is multifactorial, and one promising potential treatment approach involves targeting chemokine systems. The present study was a phase 2, multisite, multiperiod randomized crossover trial of CNTX-6970, a small molecule and selective oral cytokine chemokine receptor type 2 (CCR2) and CCR5 antagonist, in patients with painful knee osteoarthritis (OA). It represents the first trial performed within the National Institutes of Health's Early Phase Pain Investigation Clinical Network. The primary objectives were to evaluate the safety and efficacy of CNTX-6970, relative to placebo, for the treatment of moderate to severe pain related to knee OA. A total of 55 participants were randomized in this multiperiod crossover trial. Linear mixed effects models revealed no significant pain-related benefits of active medication; indeed, trial participants reported slightly higher knee pain intensity when taking the novel chemokine antagonist CNTX-6970 than when taking placebo. In addition, biomarker analysis revealed notably higher level of serum monocyte chemoattractant protein 1 levels when patients were on CNTX-6970 compared to placebo. Overall, although CNTX-6970 was safe and relatively well-tolerated, pharmacologic blockade of specific chemokine receptors with this compound was not effective in reducing moderate-to-severe knee osteoarthritis pain.

OBJECTIVE:Exposure to per- and polyfluoroalkyl substances (PFAS) may increase the risk of gestational diabetes mellitus (GDM), with adverse consequences for pregnant women and their offspring. However, epidemiologic studies have shown inconsistent results. We addressed this question in a large, pooled sample of U.S. women. RESEARCH DESIGN AND METHODS/METHODS:Participants (n = 5,229) from 16 cohorts had singleton pregnancies. PFAS were quantified in a single plasma or serum sample during pregnancy (1999-2021); six PFAS detected in ≥60% of participants were analyzed. The primary outcome was GDM diagnosis based on self-report or medical record documentation. The secondary outcome, among 1,213 participants, was fasting glucose. We estimated associations between each PFAS and GDM using generalized estimating equations models with Poisson distribution and robust variance, and estimated associations between each PFAS and fasting glucose using generalized estimating equations models for linear regression. Effect modification by prepregnancy BMI or race and ethnicity was evaluated via interaction terms and stratification. We quantified the combined effect of the PFAS mixture using quantile-based g-computation. RESULTS:Associations between individual PFAS and GDM were null or weakly inverse; the association with the six-PFAS mixture was negative (prevalence ratio [95% CI] per quartile increase: 0.75 [0.58, 0.96]). Certain PFAS were more strongly negatively associated with GDM among participants with BMI <25 kg/m2. Associations between PFAS and fasting glucose were largely null, although both positive and negative associations were observed in specific race and ethnicity strata. CONCLUSIONS:In a large, pooled sample of U.S. pregnant women, greater concentrations of PFAS were not associated with higher prevalence of GDM.

PURPOSE/UNASSIGNED:Keratoconus (KC) is a common eye disease characterized by progressive corneal thinning and steepening. Despite multiple treatment options, there is no definitive cure for KC. Previously we identified loss and dysregulation of nuclear factor erythroid 2-related factor 2 (NRF2) mediated antioxidant functions in stromal cells and extracellular matrix (ECM) in KC. Here we used tear fluid samples and cell culture models to investigate oxidative stress in KC. METHODS/UNASSIGNED:Primary human KC and donor (DN) stromal fibroblasts were exposed to hydrogen peroxide (H2O2) to induce oxidative stress and treated with sulforaphane (SFN) for antioxidant rescue. The fibroblasts were then assessed for NRF2 activation and apoptosis by measuring TXNRD1, HMOX1, NRF2, and GPX3 expression and caspase-3/7 activity. ML385 was used to inhibit NRF2 functions in DN fibroblast cultures followed by measurements of cell death (Caspase 3/7), proliferation (BrdU and Ki-67 labeling) and ECM deposition by immunohistology. Oxidative stress was directly assessed in KC and non-KC subjects by measuring malondialdehyde (MDA) and glutathione peroxidase 3 (GPX3) levels in the tear fluid. RESULTS/UNASSIGNED:H2O2-stressed KC fibroblasts displayed increased apoptosis and suboptimal NRF2 activation, which could be rescued with SFN. Conversely, DN fibroblasts treated with ML385 elicited KC-like cellular phenotypes, including decreased antioxidant response, reduced cell growth, myofibroblastic changes and poor ECM deposition. Compared to unaffected controls, KC patient tear fluid exhibited elevated levels of GPX3 and MDA, a byproduct of lipid peroxidation. CONCLUSIONS/UNASSIGNED:NRF2-mediated anti-oxidative functions are dysregulated in KC. In the future SFN antioxidant treatments may be therapeutic in KC, while MDA and GPX3 may lead to promising biomarkers for diagnosis and severity predictions.

BACKGROUND:Self-reported smoking may not fully capture individualized risk of smoking-related cancer. Circulating proteins may reflect biological consequences of smoking. Thus, we developed a score from smoking-related proteins and evaluated its association with smoking-related cancer. METHODS:This prospective cohort study included 10,563 participants aged 47-70 years in the Atherosclerosis Risk in Communities study. Plasma proteins were measured by SomaScan. The score was constructed from proteins associated with current smoking, packyears, and/or recent quitting identified by linear regression and elastic net regression. Cox regression was used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI). We confirmed the association in a case-cohort study in the European Prospective Investigation into Cancer and Nutrition (EPIC). RESULTS:aHRs comparing score quartiles Q4 to Q1 for total incidence and mortality of 13 smoking-related cancers were 3.89 (95% CI 3.06-4.96) and 5.73 (95% CI 4.08-8.06) before, and 2.28 (95% CI 1.65-3.15) and 2.07 (95% CI 1.74-4.10) after adjusting for self-reported smoking. aHRs for lung cancer were 12.1 (95% CI 7.11-20.6) and 14.2 (95% CI 7.58-26.8) before, 3.04 (95% CI 1.59-5.81) and 4.12 (95% CI 1.99-8.53) after adjusting. In EPIC, aHRs for lung cancer were 9.47 (95% CI 6.82-13.15) before and 2.23 (95% CI 1.48-3.35) after adjusting. CONCLUSION/CONCLUSIONS:The smoking-related protein score provided relative risk information for smoking-associated cancers beyond self-reported smoking, which was confirmed in an independent cohort. Such a score may be considered for use in risk stratification for prevention and cancer screening in settings in which detailed smoking history cannot be obtained.