Faculty Bibliography

PURPOSE/OBJECTIVE:To present the results of a survey of the Zoster Eye Disease Study (ZEDS) investigators regarding barriers to the enrollment of study participants and approaches to overcome them. METHODS:ZEDS is a multicenter randomized clinical trial supported by the National Eye Institute to determine whether prolonged suppressive valacyclovir reduces the complications of herpes zoster ophthalmicus (HZO), relative to placebo. Enrollment of study participants is currently far below expectations. An institutional review board-approved anonymous internet survey was conducted of ZEDS investigators to study their experiences and opinions regarding barriers to enrollment and various approaches to overcome them. RESULTS:The overall survey response rate was 54% (79/145). Only 29% (23/79) agreed that it is easy to enroll study participants. Regarding patient barriers, 69% (55/79) agreed that HZO patients want to be treated with antiviral medication and 69% (54/78) agreed that HZO patients on antivirals do not want to be randomized. Regarding personal barriers facing investigators, 91% (72/79) agreed that antivirals are effective and 100% that the research questions ZEDS is designed to answer are very important. Fewer than 30% of respondents believed that steps taken to increase enrollment have been very helpful. Over half (54%, 42/78) believed that advertising on social media would be moderately or very effective. CONCLUSIONS:Belief among ZEDS investigators that antivirals are effective, and the preference of patients to be treated with antivirals rather than be randomized in ZEDS, are major barriers to enrollment. New approaches to overcoming barriers are necessary to develop an evidence-based standard of care for treatment of HZO.

Behavioral interventions involving electronic devices, financial incentives, gamification, and specially trained staff to encourage healthy behaviors are becoming increasingly prevalent and important in health innovation and improvement efforts. Although considerations of cost are key to their wider adoption, cost information is lacking because the resources required cannot be costed using standard administrative billing data. Pragmatic clinical trials that test behavioral interventions are potentially the best and often only source of cost information but rarely incorporate costing studies. This article provides a guide for researchers to help them collect and analyze, during the trial and with little additional effort, the information needed to inform potential adopters of the costs of adopting a behavioral intervention. A key challenge in using trial data is the separation of implementation costs, the costs an adopter would incur, from research costs. Based on experience with 3 randomized clinical trials of behavioral interventions, this article explains how to frame the costing problem, including how to think about costs associated with the control group, and describes methods for collecting data on individual costs: specifications for costing a technology platform that supports the specialized functions required, how to set up a time log to collect data on the time staff spend on implementation, and issues in getting data on device, overhead, and financial incentive costs.

INTRODUCTION/BACKGROUND:In a five-arm randomized clinical trial (RCT) with stratified randomization across 54 sites, we encountered low primary outcome event proportions, resulting in multiple sites with zero events either overall or in one or more study arms. In this paper, we systematically evaluated different statistical methods of accounting for center in settings with low outcome event proportions. METHODS:We conducted a simulation study and a reanalysis of a completed RCT to compare five popular methods of estimating an odds ratio for multicenter trials with stratified randomization by center: (i) no center adjustment, (ii) random intercept model, (iii) Mantel-Haenszel model, (iv) generalized estimating equation (GEE) with an exchangeable correlation structure, and (v) GEE with small sample correction (GEE-small sample correction). We varied the number of total participants (200, 500, 1000, 5000), number of centers (5, 50, 100), control group outcome percentage (2%, 5%, 10%), true odds ratio (1, > 1), intra-class correlation coefficient (ICC) (0.025, 0.075), and distribution of participants across the centers (balanced, skewed). RESULTS:Mantel-Haenszel methods generally performed poorly in terms of power and bias and led to the exclusion of participants from the analysis because some centers had no events. Failure to account for center in the analysis generally led to lower power and type I error rates than other methods, particularly with ICC = 0.075. GEE had an inflated type I error rate except in some settings with a large number of centers. GEE-small sample correction maintained the type I error rate at the nominal level but suffered from reduced power and convergence issues in some settings when the number of centers was small. Random intercept models generally performed well in most scenarios, except with a low event rate (i.e., 2% scenario) and small total sample size (n ≤ 500), when all methods had issues. DISCUSSION/CONCLUSIONS:Random intercept models generally performed best across most scenarios. GEE-small sample correction performed well when the number of centers was large. We do not recommend the use of Mantel-Haenszel, GEE, or models that do not account for center. When the expected event rate is low, we suggest that the statistical analysis plan specify an alternative method in the case of non-convergence of the primary method.

To determine the impact of tocilizumab, a monoclonal antibody against the interleukin 6 receptor, on survival in patients with coronavirus disease 2019.

BACKGROUND:Intensive glycemic control is of unclear benefit and carries increased risk for older adults with diabetes. The American Geriatrics Society's (AGS) Choosing Wisely (CW) guideline promotes less aggressive glycemic targets and reduction in pharmacologic therapy for older adults with type II diabetes. Meanwhile, behavioral economic (BE) approaches offer promise in influencing hard-to-change behavior, and previous studies have shown the benefits of using electronic health record (EHR) technology to encourage guideline adherence. OBJECTIVE:This study aimed to develop and pilot test an intervention that leverages BE with EHR technology to promote appropriate diabetes management in older adults. DESIGN/METHODS:A pilot study within the New York University Langone Health (NYULH) EHR and Epic system to deliver BE-inspired nudges at five NYULH clinics at varying time points from July 12, 2018, through October 31, 2019. PARTICIPANTS/METHODS:Clinicians across five practices in the NYULH system whose patients were older adults (age 76 and older) with type II diabetes. INTERVENTIONS/METHODS:A BE-EHR module comprising six nudges was developed through a series of design workshops, interviews, user-testing sessions, and clinic visits. BE principles utilized in the nudges include framing, social norming, accountable justification, defaults, affirmation, and gamification. MAIN MEASURES/METHODS:Patient-level CW compliance. KEY RESULTS/RESULTS:CW compliance increased 5.1% from a 16-week interval at baseline to a 16-week interval post intervention. From February 14 to June 5, 2018 (prior to the first nudge launch in Vanguard clinics), CW compliance for 1278 patients was mean (95% CI)-16.1% (14.1%, 18.1%). From July 3 to October 22, 2019 (after BE-EHR module launch at all five clinics), CW compliance for 680 patients was 21.2% (18.1%, 24.3%). CONCLUSIONS:The BE-EHR module shows promise for promoting the AGS CW guideline and improving diabetes management in older adults. A randomized controlled trial will commence to test the effectiveness of the intervention across 66 NYULH clinics. NIH TRIAL REGISTRY NUMBER/UNASSIGNED:NCT03409523.

Background: Zinc impairs replication of RNA viruses such as SARS-CoV-1, and may be effective against SARS-CoV-2. However, to achieve adequate intracellular zinc levels, administration with an ionophore, which increases intracellular zinc levels, may be necessary. We evaluated the impact of zinc with an ionophore (Zn+ionophore) on COVID-19 in-hospital mortality rates. Methods: A multicenter cohort study was conducted of 3,473 adult hospitalized patients with reverse-transcriptase-polymerase-chain-reaction (RT-PCR) positive SARS-CoV-2 infection admitted to four New York City hospitals between March 10 through May 20, 2020. Exclusion criteria were: death or discharge within 24h, comfort-care status, clinical trial enrollment, treatment with an IL-6 inhibitor or remdesivir. Patients who received Zn+ionophore were compared to patients who did not using multivariable time-dependent cox proportional hazards models for time to in-hospital death adjusting for confounders including age, sex, race, BMI, diabetes, week of admission, hospital location, sequential organ failure assessment (SOFA) score, intubation, acute renal failure, neurological events, treatment with corticosteroids, azithromycin or lopinavir/ritonavir and the propensity score of receiving Zn+ionophore. A sensitivity analysis was performed using a propensity score-matched cohort of patients who did or did not receive Zn+ionophore matched by age, sex and ventilator status. Results: Among 3,473 patients (median age 64, 1947 [56%] male, 522 [15%] ventilated, 545[16%] died), 1,006 (29%) received Zn+ionophore. Zn+ionophore was associated with a 24% reduced risk of in-hospital mortality (12% of those who received Zn+ionophore died versus 17% who did not; adjusted Hazard Ratio [aHR] 0.76, 95% CI 0.60-0.96, P=0.023). More patients who received Zn+ionophore were discharged home (72% Zn+ionophore vs 67% no Zn+ionophore, P=0.003) Neither Zn nor the ionophore alone were associated with decreased mortality rates. Propensity score-matched sensitivity analysis (N=1356) validated these results (Zn+ionophore aHR for mortality 0.63, 95%CI 0.44-0.91, P=0.015). There were no significant interactions for Zn+ionophore with other COVID-19 specific medications. Conclusions: Zinc with an ionophore was associated with increased rates of discharge home and a 24% reduced risk of in-hospital mortality among COVID-19 patients, while neither zinc alone nor the ionophore alone reduced mortality. Further randomized trials are warranted.

BACKGROUND:Targeted therapies and checkpoint blockade therapy (CBT) have shown efficacy for patients with Hodgkin lymphoma (HL) in the relapsed and refractory (R/R) setting, but once discontinued owing to progression or side effects, it is unclear how successful further therapies will be. Moreover, there are no data on optimal sequencing of these treatments with standard therapies and other novel agents. In a multicenter, retrospective analysis, we investigated whether exposure to CBT could sensitize HL to subsequent therapy. MATERIALS AND METHODS/METHODS:Seventeen centers across the U.S. and Canada retrospectively queried medical records for eligible patients. The primary aim was to evaluate the overall response rate (ORR) to post-CBT treatment using the Lugano criteria. Secondary aims included progression-free survival (PFS), duration of response, and overall survival (OS). RESULTS:Eighty-one patients were included. Seventy-two percent had stage III-IV disease, and the population was heavily pretreated with a median of four therapies before CBT. Most patients (65%) discontinued CBT owing to progression. The ORR to post-CBT therapy was 62%, with a median PFS of 6.3 months and median OS of 21 months. Post-CBT treatment regimens consisted of chemotherapy (44%), targeted agents (19%), immunotherapy (15%), transplant conditioning (14%), chemotherapy/targeted combination (7%), and clinical trials (1%). No significant difference in OS was found when stratified by post-CBT regimen. CONCLUSION/CONCLUSIONS:In a heavily pretreated R/R HL population, CBT may sensitize patients to subsequent treatment, even after progression on CBT. Post-CBT regimen category did not impact OS. This may be a novel treatment strategy, which warrants further investigation in prospective clinical trials. IMPLICATIONS FOR PRACTICE/CONCLUSIONS:Novel, life-prolonging treatment strategies in relapsed and refractory (R/R) Hodgkin lymphoma (HL) are greatly desired. The results of this multicenter analysis concur with a smaller, earlier report that checkpoint blockade therapy (CBT) use in R/R HL may sensitize patients to their subsequent treatment. This approach may potentially enhance therapeutic options or to bridge patients to transplant. Prospective data are warranted prior to practice implementation. As more work is done in this area, we may also be able to optimize sequencing of CBT and novel agents in the treatment paradigm to minimize treatment-related toxicity and thus improve patient quality of life.

Background/UNASSIGNED:Effective therapies to combat coronavirus 2019 (COVID-19) are urgently needed. Hydroxychloroquine (HCQ) has in vitro antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the clinical benefit of HCQ in treating COVID-19 is unclear. Randomized controlled trials are needed to determine the safety and efficacy of HCQ for the treatment of hospitalized patients with COVID-19. Methods/UNASSIGNED:We conducted a multicenter, double-blind randomized clinical trial of HCQ among patients hospitalized with laboratory-confirmed COVID-19. Subjects were randomized in a 1:1 ratio to HCQ or placebo for 5 days and followed for 30 days. The primary efficacy outcome was a severe disease progression composite end point (death, intensive care unit admission, mechanical ventilation, extracorporeal membrane oxygenation, and/or vasopressor use) at day 14. Results/UNASSIGNED: = .350). There were no significant differences in COVID-19 clinical scores, number of oxygen-free days, SARS-CoV-2 clearance, or adverse events between HCQ and placebo. HCQ was associated with a slight increase in mean corrected QT interval, an increased D-dimer, and a trend toward an increased length of stay. Conclusions/UNASSIGNED:In hospitalized patients with COVID-19, our data suggest that HCQ does not prevent severe outcomes or improve clinical scores. However, our conclusions are limited by a relatively small sample size, and larger randomized controlled trials or pooled analyses are needed.

INTRODUCTION/BACKGROUND:Perceived stress is linked to poor sexual and reproductive health, but its relationship with sexually transmitted infections (STIs) is less clear. The elevated burden of stress and STI among Black women suggests a need to examine racial differences in the associations on additive and multiplicative scales. METHODS:Using data from Black and White female participants from wave IV of the National Longitudinal Study of Adolescent to Adult Health (n = 4744), we examined the association of high stress (scores ≥6 on the Perceived Stress Scale-4) with self-reported past-year chlamydia diagnosis, combined curable STI, and lifetime pelvic inflammatory disease using modified Poisson regression with robust variance to estimate prevalence ratios and prevalence differences. Models included a race-stress product-interaction term and adjusted for sociodemographic variables, prior trauma and stressors, and mental health factors. RESULTS:In unadjusted analyses, stress was associated with STI among Black and White women. Adjusted associations were attenuated among White women; among Black women, stress remained associated with chlamydia (adjusted prevalence ratio, 2.22; 95% confidence interval, 1.30-3.79) and curable STI (adjusted prevalence ratio, 1.59; 95% confidence interval, 1.05-2.40), corresponding to approximately 5 excess cases of each. Among White women, poverty and personality traits were the strongest confounders; among Black women, poverty, trauma, and neurotic personality traits were the strongest confounders for chlamydia, although no factors seemed to confound the association with curable STI. CONCLUSIONS:Stress is independently linked to STI, particularly among Black women. Additional research with longitudinal data is needed to understand the role of stress on STI and address a significant health disparity.

The dynamics of viral load (VL) of the 2019 novel coronavirus (severe acute respiratory syndrome coronavirus 2) and its association with different clinical parameters remain poorly characterized in the US patient population. Herein, we investigate associations between VL and parameters, such as severity of symptoms, disposition (admission versus direct discharge), length of hospitalization, admission to the intensive care unit, length of need for oxygen support, and overall survival in a cohort of 205 patients from a tertiary care center in New York City. VL was determined using quantitative PCR and log10 transformed for normalization. Univariate and multivariate regression models were used to test these associations. We found that diagnostic viral load is significantly lower in hospitalized patients than in patients not hospitalized (log10 VL = 3.3 versus 4.0; P = 0.018) after adjusting for age, sex, race, body mass index, and comorbidities. Higher VL was associated with shorter duration of the symptoms in all patients and hospitalized patients only and shorter hospital stay (coefficient = -2.02, -2.61, and -2.18; P < 0.001, P = 0.002, and P = 0.013, respectively). No significant association was noted between VL, admission to intensive care unit, length of oxygen support, and overall survival. Our findings suggest a higher shedding risk in less symptomatic patients, an important consideration for containment strategies in severe acute respiratory syndrome coronavirus 2. Furthermore, we identify a novel association between viral load and history of cancer. Larger studies are warranted to validate our findings.