Faculty Bibliography

PURPOSE:This study characterizes the association of risk factors including race, ethnicity, and insurance status with presenting visual acuity (VA) and diabetic retinopathy (DR) severity in patients initiating treatment with anti-vascular endothelial growth factor (VEGF) therapy for diabetic macular edema (DME). DESIGN:Retrospective, cross-sectional study. PARTICIPANTS:The Academy Intelligent Research in Sight (IRIS) Registry database was queried for patients who initiated anti-VEGF injection treatment for DME between 2012 and 2020 (n = 203 707). METHODS:Multivariate regression analyses were conducted to understand how race, ethnicity, insurance status, and geographic location were associated with baseline features. MAIN OUTCOME MEASURES:Visual acuity and DR severity. RESULTS:Patients on Medicare and private insurance presented with higher baseline VA compared with patients on Medicaid (median of 2.31 and 4.17 greater Early Treatment Diabetic Retinopathy Scale [ETDRS] letters, respectively P < 0.01). White and non-Hispanic patients presented with better VA compared with their counterparts (median of 0.68 and 2.53 greater ETDRS letters, respectively; P < 0.01). Black and Hispanic patients presented with a worse baseline DR severity compared with White and non-Hispanic patients (odds ratio, 1.23 and 1.71, respectively; P < 0.01). CONCLUSIONS:There are ethnic and insurance-based disparities in VA and disease severity upon initiation of anti-VEGF therapy for DME treatment. Public health initiatives could improve timely initiation of treatment.

BACKGROUND:Clinical research indicates that successful posttraumatic stress disorder (PTSD) treatment does not lead to improvements in alcohol use outcomes in comorbid PTSD and alcohol use disorder (AUD). Emerging theory suggests that treating PTSD may not disrupt an association between negative affect and alcohol craving, which underlies negative reinforcement drinking. The goal of the current study was to determine the respective influences of PTSD symptoms, coping motives, and negative affect on trauma and alcohol cue reactivity to inform theoretical models of co-occurring PTSD and AUD. METHODS:The sample consisted of 189 young adults (50.3% women; 49.2% current PTSD; 84.0% current AUD) who endorsed interpersonal trauma (e.g., sexual/physical assault) and current weekly alcohol use. Participants completed a trauma and alcohol cue reactivity assessment, in which subjective (e.g., craving, affect) and physiological (i.e., salivation) measures were recorded in response to 4 narrative (i.e., personalized trauma or standard neutral) and in vivo beverage (i.e., personalized alcohol or water) cue combinations. RESULTS:Forward-fitted linear mixed-effects (LME) models confirmed that trauma cue-elicited craving was elevated among those high but not low in PTSD symptoms, consistent with prior research and theory. Trauma cue-elicited craving was fully explained by increases in negative affect, with no evidence of a direct effect of trauma cue on craving. PTSD symptoms moderated an association between trauma cue and negative affect (but not negative affect and craving), and coping motives for alcohol moderated an association between negative affect and craving (but not trauma cue and negative affect). CONCLUSIONS:This study provides novel laboratory evidence for the respective contributions of negative affect, PTSD symptoms, and coping motives on alcohol craving in trauma-exposed drinkers. It offers a methodological framework in which to evaluate novel strategies that aim to disrupt negative reinforcement drinking in individuals with co-occurring PTSD and AUD.

OBJECTIVES/OBJECTIVE:Findings are inconsistent regarding the relationship between worry and anxious arousal (AA). Effortful control (EC) capacity may explain these inconsistent findings, such that only high worriers with higher EC are able to suppress autonomic arousal through worrying. The current study investigated these main and interactive effects of worry and EC on AA as well as depression. METHODS:Participants (N = 1210, 779 females) were recruited from Amazon's Mechanical Turk website and completed self-report measures assessing worry, EC, AA, depression, and negative affect intensity. RESULTS:Regression models revealed that EC moderated the relationship between worry and AA, with individuals lower in EC demonstrating a stronger positive relationship between worry and AA. EC also moderated the relationship between worry and depression, with individuals lower in EC demonstrating a stronger positive relationship between worry and depression. Results remained the same when controlling for age, gender, and negative affect intensity. CONCLUSIONS:Results support the idea that low EC may help to explain a range of comorbid psychiatric symptoms. PRACTITIONER POINTS/CONCLUSIONS:Individuals low in effortful control demonstrate a stronger association between worry and anxious arousal, as well as between worry and depression Those low in effortful control may be especially vulnerable to comorbid worry and depression High worriers who are high in effortful control may be motivated to continue worrying due to their ability to reduce anxious arousal during worry.

Despite support for the role of self-medication alcohol use in the etiology and maintenance of comorbid posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD), theoretical and empirical models of PTSD-AUD rarely account for the role of common comorbidities in risk processes, such as major depressive disorder (MDD). The current study examined the main and interactive effects of PTSD and depressive symptoms on patterns of trauma and alcohol cue reactivity to elucidate potential influences of depression on conditioned craving responses to trauma memories. It was hypothesized that depressive symptoms would be associated with greater cue reactivity (i.e., craving and salivation) to personalized trauma cues, above and beyond the influence of PTSD symptoms. Participants were 184 trauma-exposed young adults (50% female) endorsing current weekly alcohol use. Patterns of craving and salivation were assessed in response to four combinations of narrative (trauma vs. neutral) and beverage (alcohol vs. water) cues. Forward-fitted linear mixed effects models with deviance testing were conducted to ascertain the impact of the within-subjects factors (narrative and beverage cues) and covariates (PTSD and depressive symptoms) on self-reported and physiological (salivation) alcohol craving. Depressive symptoms were associated with elevated drinking coping motives, AUD symptom severity, and alcohol use problems at baseline; however, depressive symptoms did not show main or interactive effects with narrative or beverage cues to predict craving or salivation, p's > 0.05. Results suggest that, in the context of PTSD symptoms, depressive symptoms may not exacerbate alcohol craving responses to trauma reminders or alcohol cues.

To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results: Patients (N = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p = 0.09; muscle strength mega-score, p = 0.31). Post hoc analyses pooling all active reldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898).

This phase 2, double-blind, placebo-controlled, hypothesis-generating study evaluated the effects of oral reldesemtiv, a fast skeletal muscle troponin activator, in patients with spinal muscular atrophy (SMA). Patients ≥ 12 years of age with type II, III, or IV SMA were randomized into 2 sequential, ascending reldesemtiv dosing cohorts (cohort 1: 150 mg bid or placebo [2:1]; cohort 2: 450 mg bid or placebo [2:1]). The primary objective was to determine potential pharmacodynamic effects of reldesemtiv on 8 outcome measures in SMA, including 6-minute walk distance (6MWD) and maximum expiratory pressure (MEP). Changes from baseline to weeks 4 and 8 were determined. Pharmacokinetics and safety were also evaluated. Patients were randomized to reldesemtiv 150 mg, 450 mg, or placebo (24, 20, and 26, respectively). The change from baseline in 6MWD was greater for reldesemtiv 450 mg than for placebo at weeks 4 and 8 (least squares [LS] mean difference, 35.6 m [p = 0.0037] and 24.9 m [p = 0.058], respectively). Changes from baseline in MEP at week 8 on reldesemtiv 150 and 450 mg were significantly greater than those on placebo (LS mean differences, 11.7 [p = 0.038] and 13.2 cm H₂O [p = 0.03], respectively). For 6MWD and MEP, significant changes from placebo were seen in the highest reldesemtiv peak plasma concentration quartile (C_max > 3.29 μg/mL; LS mean differences, 43.3 m [p = 0.010] and 28.8 cm H₂O [p = 0.0002], respectively). Both dose levels of reldesemtiv were well tolerated. Results suggest reldesemtiv may offer clinical benefit and support evaluation in larger SMA patient populations.