External Control Arms in Idiopathic Pulmonary Fibrosis Using Clinical Trial and Real-World Data Sources.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease for which novel therapies are needed. External controls (ECs) could enhance IPF trial efficiency, but the direct comparability of ECs versus concurrent controls is unknown. Objectives: To develop IPF ECs by fit-for-purpose data standards to historical randomized clinical trial (RCT), multicenter registry (Pulmonary Fibrosis Foundation Patient Registry), and electronic health record (EHR) data and to evaluate endpoint comparability among ECs and the phase II RCT of BMS-986020. Methods: After data curation, the rate of change in FVC from baseline to 26 weeks among participants receiving BMS-986020 600 mg twice daily was compared with the BMS-placebo arm and ECs using mixed-effects models with inverse probability weights. Measurements and Main Results: At 26 weeks, the rates of change in FVC were -32.71 ml for BMS-986020 and -130.09 ml for BMS-placebo (difference, 97.4 ml; 95% confidence interval [CI], 24.6-170.2), replicating the original BMS-986020 RCT. RCT ECs showed treatment effect point estimates within the 95% CI of the original BMS-986020 RCT. Pulmonary Fibrosis Foundation Patient Registry ECs and EHR ECs experienced a slower rate of FVC decline compared with the BMS-placebo arm, resulting in treatment-effect point estimates outside of the 95% CI of the original BMS-986020 RCT. Conclusions: IPF ECs generated from historical RCT placebo arms result in comparable primary treatment effects to that of the original clinical trial, whereas ECs from real-world data sources, including registry or EHR data, do not. RCT ECs may serve as a potentially useful supplement to future IPF RCTs.

A nonparametric test of group distributional differences for hierarchically clustered functional data.

Biological sex and gender are critical variables in biomedical research, but are complicated by the presence of sex-specific natural hormone cycles, such as the estrous cycle in female rodents, typically divided into phases. A common feature of these cycles are fluctuating hormone levels that induce sex differences in many behaviors controlled by the electrophysiology of neurons, such as neuronal membrane potential in response to electrical stimulus, typically summarized using a priori defined metrics. In this paper, we propose a method to test for differences in the electrophysiological properties across estrous cycle phase without first defining a metric of interest. We do this by modeling membrane potential data in the frequency domain as realizations of a bivariate process, also depending on the electrical stimulus, by adopting existing methods for longitudinal functional data. We are then able to extract the main features of the bivariate signals through a set of basis function coefficients. We use these coefficients for testing, adapting methods for multivariate data to account for an induced hierarchical structure that is a product of the experimental design. We illustrate the performance of the proposed approach in simulations and then apply the method to experimental data.

Socioeconomic variables explain rural disparities in US mortality rates: Implications for rural health research and policy.

OBJECTIVES: Rural disparities in age-adjusted mortality are growing in the United States. While socioeconomic variables have been found to explain significant variation in life expectancy across US counties, previous research has not examined the role of socioeconomic variables in explaining rural mortality disparities. The purpose of this study was to quantify the rural mortality disparity after controlling for socioeconomic variables. METHODS: Recursive partitioning, or tree regression, was used to fit models predicting premature mortality across counties in the United States, adjusted for age, median income, and percent in poverty in 4 time periods (from 2004 to 2012) with and without inclusion of an urban-rural variable. RESULTS: We found median income and percent in poverty explained about 50% of the variation in age-adjusted premature mortality rates across US counties in each of the four time periods. After controlling for these socioeconomic variables, rural mortality disparities largely disappeared, explaining less than 2% of the variance in premature mortality. CONCLUSIONS: Addressing poverty and other socioeconomic issues should be a priority to improve health in rural communities. Interventions designed to target social determinants of health in rural areas are needed to address the growing rural mortality disparity that is largely explained by measures of poverty and income. Researchers examining rural health disparities should routinely include socioeconomic variables in their analyses.

A limited evaluation of the association of race and anesthetic medication administration: A single-center experience with appendectomies.

BACKGROUND: Although it is known that a patient's race may influence their medical care, racial patterns of medication administration in pediatric anesthesia have not been well-studied. The aim of this study was to determine if differences exist between Black and White children with regard to administration of anesthetic and analgesic medications for a single procedure at our institution. METHODS: We conducted a retrospective review of medications administered to patients for emergency appendectomies at a large academic children's hospital from 2010 to 2015. We examined the association between patient race and administration of preoperative midazolam and intraoperative ondansetron, lidocaine, ketorolac, and weight-based doses of fentanyl and morphine. RESULTS: During the study period, 1680 patients (1329 White, 351 Black) underwent emergency appendectomy. There were no significant racial differences in administration of intraoperative anesthetic medications between Black and White children. In unadjusted analysis, Black children were less likely to receive preoperative midazolam than White children (OR=0.74 [95% CI, 0.58-0.94], P=.012). After adjusting for confounders, there was no evidence of racial differences in administration of preoperative or intraoperative medications. CONCLUSION: We did not find a significant difference in preoperative or intraoperative medication administration based on race when we adjusted for age, gender, and attending anesthesiologist practice patterns. We encourage all institutions to monitor their own practice patterns with regard to race.

Intramuscular Fentanyl and Ketorolac Associated with Superior Pain Control After Pediatric Bilateral Myringotomy and Tube Placement Surgery: A Retrospective Cohort Study.

BACKGROUND: Bilateral myringotomy and pressure equalization tube insertion (BMT) is the most common surgery in children. Multiple anesthetic techniques for BMT have been proposed, but that which reliably promotes ideal recovery remains unclear. We sought to assess associations between anesthetic regimens that included single-agent (fentanyl or ketorolac) or dual-agent (fentanyl and ketorolac) analgesic therapy and the primary outcome of maximal postanesthesia care unit (PACU) pain score. Secondary outcomes included in-hospital rescue analgesic administration, recovery time, and emesis incidence. METHODS: Principal analysis was conducted on a retrospective cohort of 3669 children aged 6 months to <7 years who underwent BMT over a 16-month period and received intraoperative fentanyl and/or ketorolac. Routine anesthetic care included preoperative oral midazolam, general anesthesia via a mask maintained with sevoflurane and N2O or air in O2, and intramuscular analgesic administration. Multivariable analyses were performed examining relationships between analgesic regimen with the following outcomes: maximum PACU Face, Legs, Activity, Cry, and Consolability (FLACC) score = 0 or 7 to 10, oxycodone administration, and time to discharge readiness. Demographic variables, midazolam exposure, and location (main hospital vs ambulatory surgery center) were included in the multivariable analyses as potential confounders. Associations with postoperative vomiting were studied separately in 2725 children from a subsequent, nonoverlapping 12-month period using similar inclusion criteria. Fentanyl and ketorolac dose-response relationships were evaluated for selected outcome variables. RESULTS: Maximum FLACC = 0, maximum FLACC score of 7 to 10, and oxycodone rescue were most strongly associated with dual-agent therapy versus single-agent ketorolac: odds ratios 4.89 (95% confidence interval [CI], 4.04-5.93), 0.13 (95% CI, 0.10-0.16), and 0.11 (98.3% CI, 0.09-0.14), respectively, P < .001 for each). Minor associations were found for age, Hispanic ethnicity, midazolam, and location, and none for sex or race. For subjects managed with higher dose fentanyl (≥1.5 µg/kg) and ketorolac (≥0.75 mg/kg), 90% had no demonstrable pain, agitation, or distress. Mean discharge readiness times were 21 ± 11 minutes (ketorolac), 26 ± 16 minutes (fentanyl), and 24 ± 14 minutes (dual) (P < .0001). Postoperative emesis incidences associated with ketorolac (2.7%) versus dual therapy (4.5%) were not different (P = .08). CONCLUSIONS: In this large retrospective pediatric BMT study, combination intramuscular fentanyl/ketorolac was strongly associated with superior PACU analgesia and reduced need for oxycodone rescue without clinically significant increases in recovery time or emesis incidence. Combination fentanyl at 1.5 to 2 µg/kg and 1 mg/kg ketorolac was associated with optimal outcomes. Dual therapy appears similarly effective in children of either European Caucasian or African ancestry or of Hispanic ethnicity.