Effect of Pregnenolone vs Placebo on Self-reported Chronic Low Back Pain Among US Military Veterans: A Randomized Clinical Trial.

Importance: In response to the national opioid public health crisis, there is an urgent need to develop nonopioid solutions for effective pain management. Neurosteroids are endogenous molecules with pleotropic actions that show promise for safe and effective treatment of chronic low back pain. Objective: To determine whether adjunctive pregnenolone has therapeutic utility for the treatment of chronic low back pain in Iraq- and Afghanistan-era US military veterans. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled clinical trial that enrolled for 42 months, from September 2013 to April 2017. Participants were Iraq- and Afghanistan-era veterans aged 18 to 65 years with chronic low back pain who received treatment in the Durham VA Health Care System in Durham, North Carolina, over 6 weeks. Data analysis began in 2018 and was finalized in March, 2019. Interventions: Following a 1-week placebo lead-in, participants were randomized to pregnenolone or placebo for 4 weeks. Pregnenolone and placebo were administered at fixed, escalating doses of 100 mg for 1 week, 300 mg for 1 week, and 500 mg for 2 weeks. Main Outcomes and Measures: The primary outcome measure was the change in mean pain intensity ratings from a daily pain diary (numerical rating scale, 0-10) between visit 3 (baseline) and visit 6. Secondary outcomes included pain interference scores (Brief Pain Inventory, Short Form). Preintervention and postintervention neurosteroid levels were quantified by gas chromatography with tandem mass spectrometry. Hypotheses tested were formulated prior to data collection. Results: A total of 94 participants (84 [89.4%] male; mean [SD] age, 37.5 [9.8] years; 53 [56.4%] of self-reported Caucasian race and 31 [33.0%] of self-reported African American race) were included. Forty-eight participants were randomized to pregnenolone and 52 to placebo, of whom 45 and 49, respectively, were included in baseline demographic characteristics secondary to noncompliance with medications as per protocol. Veterans randomized to pregnenolone reported significant reductions in low back pain relative to those randomized to placebo. Baseline unadjusted mean (SE) pain diary ratings were 4.83 (0.23) and 5.24 (0.22) for the placebo- and pregnenolone-treated groups, respectively (baseline unadjusted mean [SE] ratings for pain recall were 4.78 [0.24] and 5.15 [0.23], respectively). Unadjusted mean (SE) ratings following treatment (visit 6) were 4.74 (0.26) in the placebo group and 4.19 (0.30) in the pregnenolone-treated group. Unadjusted mean (SE) ratings for pain recall following treatment were 4.86 (0.27) for placebo and 4.18 (0.29) for pregnenolone. Least-square mean (LSM) analysis showed that pain scores significantly improved in the pregnenolone-treated group compared with placebo (LSM [SE] change in pain diary rating, -0.56 [0.25]; P = .02; LSM [SE] change in pain recall, -0.70 [0.27]; P = .01). Pain interference scores for work (LSM [SE] change, 0.71 [0.12]; P = .04) and activity (LSM [SE] change, 0.71 [0.11]; P = .03) were also improved in veterans randomized to pregnenolone compared with placebo. Pregnenolone was well tolerated. Conclusions and Relevance: Participants receiving pregnenolone reported a clinically meaningful reduction in low back pain and 2 pain interference domains compared with those receiving placebo. Pregnenolone may represent a novel, safe, and potentially efficacious treatment for the alleviation of chronic low back pain in Iraq- and Afghanistan-era veterans. Trial Registration: ClinicalTrials.gov Identifier: NCT01898013.

Evaluation of a Training Program to Improve Organizational Capacity for Health Systems Analytics.

OBJECTIVE: The Leadership in Analytics and Data Science (LEADS) course was evaluated for effectiveness. LEADS was a 6-month program for working biomedical and health informatics (BMHI) professionals designed to improve analytics skills, knowledge of enterprise applications, data stewardship, and to foster an analytics community of practice through lectures, hands-on skill building workshops, networking events, and small group projects. METHODS: The effectiveness of the LEADS course was evaluated using the Kirkpatrick Model by assessing pre- and postcourse knowledge, analytics capabilities, goals, practice, class lecture reaction, and change in the size of participant professional networks. Differences in pre- and postcourse responses were analyzed with a Wilcoxon signed rank test to determine significance, and effect sizes were computed using a z-statistic. RESULTS: Twenty-nine students completed the course with 96% of respondents reporting that they were "very" or "extremely" likely to recommend the course. Participants reported improvement in several analytics capabilities including Epic data warehousing (p = 0.017), institutional review board policy (p = 0.005), and data stewardship (p = 0.007). Changes in practice patterns mirrored those in self-reported capability. On average, the participant professional network doubled. CONCLUSION: LEADS was the first course targeted to working BMHI professional at a large academic medical center to have a formal effectiveness evaluation be published in the literature. The course achieved the goals of expansion of BMHI knowledge, skills, and professional networks. The LEADS course provides a template for continuing education of working BMHI professionals.

Overcoming Site Heterogeneity In Search of Metal Nanocatalysts.

Site heterogeneity of metal nanocatalysts poses grand challenges for catalyst design from first principles. To accelerate catalyst discovery, it is of pivotal importance to develop an approach that efficiently maps catalytic activity of nanoparticles onto geometry-based descriptors while considering the geometric strain and metal ligand of an active site. We demonstrate that there exist linear correlations between orbitalwise coordination numbers CNα and free formation energies of oxygen species (e.g., *OH and *OOH) at Pt sites. Kinetic analysis along with herein developed structure-activity relationships accurately predicts the activity trend of pure Pt nanoparticles (∼1-7 nm) toward oxygen reduction. Application of the approach to a search of Pt nanoalloys leads to several Pt monolayer core-shell nanostructures with enhanced oxygen reduction activity and reduced cost. The approach presented here facilitates a transition from traditional single-crystal models to nanoparticles in theory-guided catalyst discovery.

Coordination numbers for unraveling intrinsic size effects in gold-catalyzed CO oxidation.

Geometry-based reactivity descriptors, e.g., regular, generalized, and orbitalwise coordination numbers, were used for unraveling intrinsic size effects of Au nanocatalysts towards CO oxidation. For an ensemble of Au nanoparticles with varying sizes and shapes, s-orbital coordination numbers (CNs) linearly correlate with *CO and *O adsorption energies at the on-top and hollow sites, respectively, outperforming their regular (CN) and generalized (C[combining macron]N[combining macron]) counterparts attributed to an explicit consideration of interatomic interactions. To take into account the geometric strain of surface atoms, the embedded-atom method (EAM) potential trained with ab initio energies of the bulk, nanoclusters, and extended surfaces at the GGA-PBE level was used for optimizing the Wulff-shaped, free-standing Au nanoparticles up to 7.2 nm. Microkinetic analysis of CO oxidation on extended {111}, {100}, {211}, and {532} surfaces, along with a facile and accurate prediction of *CO and *O adsorption energies at nanoparticles using the herein developed structure-reactivity relationships, captures experimentally measured activity trends of supported Au nanoparticles of varying sizes on a wide variety of metal oxides and illustrates the importance of under-coordinated atoms and insensitivity of surface strains in Au-catalyzed CO oxidation.

Clinical and immunologic manifestations of mixed connective tissue disease in a Miami population compared to a Midwestern US Caucasian population.

OBJECTIVE: A cross-sectional study of mixed connective tissue disease (MCTD) was performed to determine if there were identifiable differences in the clinical expression of MCTD associated with race or ethnicity. METHODS: Miami, Florida, and Midwestern US (Missouri) Caucasian MCTD cohorts were studied. Clinical and laboratory features of the 2 MCTD cohorts were compared. A concurrently collected cohort of Sm-positive patients with systemic lupus erythematosus (SLE) was studied as a control. Disease activity and severity and functional status were measured. CD4+CD25(high)-expressing T-regulatory cells were enumerated and serum soluble L selectin was measured as biomarkers of disease activity. RESULTS: The Miami and Missouri Caucasian MCTD groups, while differing from the SLE group, were largely similar; however, gastroesophageal reflux, sclerodactyly, and malar rash were significantly more frequent in the Missouri MCTD group and alopecia was more frequent in the Miami MCTD group. Significant clinical and laboratory differences were found between the Miami MCTD and Miami SLE groups despite similar disease duration, activity, severity and functional status. Raynaud's phenomenon (RP), hand swelling, synovitis, myositis, and sclerodactyly were all significantly more common in RNP-positive MCTD versus Sm-positive SLE subjects. CONCLUSION Ethnic differences were observed in the frequency of end-organ involvement in the Miami MCTD versus the Missouri Caucasian MCTD groups. Clinical and laboratory features of all MCTD groups were clearly different from the SLE group, despite similar disease activity, disease severity, and functional status. Disease activity measures appeared to behave similarly as valid measures of disease activity in SLE and MCTD.