Search

No medications are approved for cannabis use disorder (CUD), though a small clinical trial demonstrated that the voltage-dependent calcium channel (VDCC) ligand gabapentin reduced cannabis use in treatment seekers. VDCCs are modulated by cannabinoid (CB) ligands, and there are shared effects between CB agonists and VDCC ligands. This overlapping neuropharmacology and the initial clinical results supported the evaluation of pregabalin, a "next-generation" VDCC ligand, as a CUD medication. Two separate placebo-controlled, double-blind, counterbalanced, within-subjects human laboratory studies tested placebo and 300 (N = 2 females, 11 males; Experiment [EXP] 1) or 450 (N = 3 females, 11 males; EXP 2) mg/day pregabalin in cannabis users who were not seeking treatment or trying to reduce/quit their cannabis use. The protocol consisted of two outpatient maintenance phases (11 days in EXP 1 and 15 days in EXP 2) that concluded with four experimental sessions within each phase. During experimental sessions, maintenance continued, and participants completed two 2-day blocks of sampling and self-administration sessions to determine the reinforcing effects of smoked cannabis (0% and 5.9% delta⁹-tetrahydrocannabinol [THC]), as well as subjective, attentional bias, performance, and physiological responses. In addition, naturalistic cannabis use, side effects, sleep quality, craving, and other self-reported substance use were measured during pregabalin maintenance. Cannabis was self-administered and produced prototypical effects, but pregabalin generally did not impact the effects of cannabis or alter naturalistic use. These human laboratory results in cannabis users not trying to reduce/quit their use do not support the efficacy of pregabalin as a stand-alone pharmacotherapy for CUD. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

In the United States, diabetes is the seventh leading cause of death and continues to rise in prevalence, with type 2 diabetes accounting for 90–95% of all cases. Rates of diabetes in Kentucky, and, in particular, the Appalachian region, are among the highest in the nation and are increasing faster than the national average. Despite this disproportionate burden, barriers to clinical appointment attendance have not been fully explored in this population. This article examines the association among perceived barriers to clinical attendance, glycemic control, and diabetes self-care as part of an ongoing study. We used a 25-item checklist developed using the Chronic Care Model to assess participants’ barriers to clinic attendance. Glycemic control was assessed via A1C measurement. Diabetes self-care was assessed using the Summary of Diabetes Self-Care Activities measure. At the time of analysis, 123 of the 356 participants (34.6%) did not report any barriers to clinic attendance. For the remainder, the major reported barriers included forgetting appointments, inability to afford medicines or other treatment, and placing faith above medical care. The average A1C was 7.7%, and the average diabetes self-care summary score was 17.1 out of 35 points (with higher values indicating better self-care). Missing clinic appointments is associated with lower health outcomes, especially in vulnerable populations. This study can help educate clinic staff on perceived barriers to type 2 diabetes management among people with diabetes in Appalachia.

Background/aims This work is motivated by the HEALing Communities Study, which is a post-test only cluster randomized trial in which communities are randomized to two different trial arms. The primary interest is in reducing opioid overdose fatalities, which will be collected as a count outcome at the community level. Communities range in size from thousands to over one million residents, and fatalities are expected to be rare. Traditional marginal modeling approaches in the cluster randomized trial literature include the use of generalized estimating equations with an exchangeable correlation structure when utilizing subject-level data, or analogously quasi-likelihood based on an over-dispersed binomial variance when utilizing community-level data. These approaches account for and estimate the intra-cluster correlation coefficient, which should be provided in the results from a cluster randomized trial. Alternatively, the coefficient of variation or R coefficient could be reported. In this article, we show that negative binomial regression can also be utilized when communities are large and events are rare. The objectives of this article are (1) to show that the negative binomial regression approach targets the same marginal regression parameter(s) as an over-dispersed binomial model and to explain why the estimates may differ; (2) to derive formulas relating the negative binomial overdispersion parameter k with the intra-cluster correlation coefficient, coefficient of variation, and R coefficient; and (3) analyze pre-intervention data from the HEALing Communities Study to demonstrate and contrast models and to show how to report the intra-cluster correlation coefficient, coefficient of variation, and R coefficient when utilizing negative binomial regression. Methods Negative binomial and over-dispersed binomial regression modeling are contrasted in terms of model setup, regression parameter estimation, and formulation of the overdispersion parameter. Three specific models are used to illustrate concepts and address the third objective. Results The negative binomial regression approach targets the same marginal regression parameter(s) as an over-dispersed binomial model, although estimates may differ. Practical differences arise in regard to how overdispersion, and hence the intra-cluster correlation coefficient is modeled. The negative binomial overdispersion parameter is approximately equal to the ratio of the intra-cluster correlation coefficient and marginal probability, the square of the coefficient of variation, and the R coefficient minus 1. As a result, estimates corresponding to all four of these different types of overdispersion parameterizations can be reported when utilizing negative binomial regression. Conclusion Negative binomial regression provides a valid, practical, alternative approach to the analysis of count data, and corresponding reporting of overdispersion parameters, from community randomized trials in which communities are large and events are rare.

Background Intensive care unit acquired weakness is a serious problem, contributing to respiratory failure and reductions in ambulation. Currently, there is no pharmacological therapy for this condition. Studies indicate, however, that both beta-hydroxy-beta-methylbutyrate (HMB) and eicosapentaenoic acid (EPA) increase muscle function in patients with cancer and in older adults. The purpose of this study was to determine whether HMB and/or EPA administration would increase diaphragm and quadriceps strength in mechanically ventilated patients. Methods Studies were performed on 83 mechanically ventilated patients who were recruited from the Medical Intensive Care Units at the University of Kentucky. Diaphragm strength was assessed as the trans-diaphragmatic pressure generated by supramaximal magnetic phrenic nerve stimulation (PdiTw). Quadriceps strength was assessed as leg force generated by supramaximal magnetic femoral nerve stimulation (QuadTw). Diaphragm and quadriceps thickness were assessed by ultrasound. Baseline measurements of muscle strength and size were performed, and patients were then randomized to one of four treatment groups (placebo, HMB 3 gm/day, EPA 2 gm/day and HMB plus EPA). Strength and size measurements were repeated 11 days after study entry. ANCOVA statistical testing was used to compare variables across the four experimental groups. Results Treatments failed to increase the strength and thickness of either the diaphragm or quadriceps when compared to placebo. In addition, treatments also failed to decrease the duration of mechanical ventilation after study entry. Conclusions These results indicate that a 10-day course of HMB and/or EPA does not improve skeletal muscle strength in critically ill mechanically ventilated patients. These findings also confirm previous reports that diaphragm and leg strength in these patients are profoundly low. Additional studies will be needed to examine the effects of other anabolic agents and innovative forms of physical therapy. Trial registration: ClinicalTrials.gov, NCT01270516. Registered 5 January 2011, https://clinicaltrials.gov/ct2/show/NCT01270516?term=Supinski&draw=2&rank=4.

Context: Awareness of important injury risk factors associated with excessive pitching volume has been highlighted in the literature, but injury rates remain high. Shoulder pain in baseball players is associated with various changes in musculoskeletal movements, which presents as measurable impairments throughout the kinetic chain. Baseball coaches and rehabilitation professionals have utilized exercise programs targeting strength and flexibility of the throwing arm to prevent injuries. The purpose of this review is to summarize the current evidence regarding the effectiveness of arm care exercise programs in reducing upper extremity injury rates in adolescent baseball players. Evidence Acquisition: A search of electronic databases, including CINAHL with full text, MEDLINE, and SPORTDiscus was conducted to retrieve available articles in English from the years 2010 through 2020. The search terms injury prevention, exercise, and adolescent baseball were used. Study Design: Clinical review. Level of Evidence: Level 4. Results: Improving shoulder internal rotation range of motion by stretching the posterior shoulder muscles daily was associated with a 36% risk reduction of shoulder and elbow injuries. Group-based arm care exercise programs that target multiple musculoskeletal impairments demonstrated an approximately 50% reduced risk of elbow injury. Conclusion: For adolescent baseball players, arm care injury prevention programs focusing on important musculoskeletal impairments are effective at reducing injury incidence rates. Multimodal injury prevention programs that improve multiple musculoskeletal impairments are more comprehensive and may result in better injury reduction than programs focusing on a singular impairment.

BACKGROUNDBeige adipose tissue is associated with improved glucose homeostasis in mice. Adipose tissue contains β3-adrenergic receptors (β3-ARs), and this study was intended to determine whether the treatment of obese, insulin-resistant humans with the β3-AR agonist mirabegron, which stimulates beige adipose formation in subcutaneous white adipose tissue (SC WAT), would induce other beneficial changes in fat and muscle and improve metabolic homeostasis.METHODSBefore and after β3-AR agonist treatment, oral glucose tolerance tests and euglycemic clamps were performed, and histochemical analysis and gene expression profiling were performed on fat and muscle biopsies. PET-CT scans quantified brown adipose tissue volume and activity, and we conducted in vitro studies with primary cultures of differentiated human adipocytes and muscle.RESULTSThe clinical effects of mirabegron treatment included improved oral glucose tolerance (P < 0.01), reduced hemoglobin A1c levels (P = 0.01), and improved insulin sensitivity (P = 0.03) and β cell function (P = 0.01). In SC WAT, mirabegron treatment stimulated lipolysis, reduced fibrotic gene expression, and increased alternatively activated macrophages. Subjects with the most SC WAT beiging showed the greatest improvement in β cell function. In skeletal muscle, mirabegron reduced triglycerides, increased the expression of PPARγ coactivator 1 α (PGC1A) (P < 0.05), and increased type I fibers (P < 0.01). Conditioned media from adipocytes treated with mirabegron stimulated muscle fiber PGC1A expression in vitro (P < 0.001).CONCLUSIONMirabegron treatment substantially improved multiple measures of glucose homeostasis in obese, insulin-resistant humans. Since β cells and skeletal muscle do not express β3-ARs, these data suggest that the beiging of SC WAT by mirabegron reduces adipose tissue dysfunction, which enhances muscle oxidative capacity and improves β cell function.TRIAL REGISTRATIONClinicaltrials.gov NCT02919176.FUNDINGNIH: DK112282, P30GM127211, DK 71349, and Clinical and Translational science Awards (CTSA) grant UL1TR001998.

Rehabilitation strategies after traumatic spinal cord injury aim to maximize functional recovery by applying principles of neuroplasticity via task-specific, repetitive training. Rehabilitation of patients with traumatic spinal cord injury poses unique challenges, including bilateral limb involvement, autonomic dysfunction, loss of proprioception, and potentially spinal precautions/bracing. The purpose of this retrospective case series was to determine whether use of dynamic body weight support would yield greater improvement in functional recovery compared with standard of care in adults with traumatic spinal cord injury. Data were collected from patients with traumatic spinal cord injury who completed inpatient rehabilitation incorporating dynamic body weight support (n = 5) and who completed inpatient rehabilitation without dynamic body weight support (n = 5). The primary outcome measure was the change in Functional Independence Measures. The dynamic body weight support group had a significantly greater improvement in Total Functional Independence Measures and in Functional Independence Measures motor subscale compared with the standard of care group (P = 0.023 and P = 0.033, respectively). This study presents initial evidence that dynamic body weight support therapy during inpatient rehabilitation has the potential to improve functional independence compared with standard of care in patients with traumatic spinal cord injury. Larger prospective randomized studies need to be conducted to expand on these findings.

BackgroundThe stepped wedge cluster randomized trial (SW-CRT) design is now preferred for many health- related trials because of its flexibility on resource allocation and clinical ethics concerns. However, as a necessary extension of studying multiple interventions, multiphase stepped wedge designs (MSW-CRT) have not been studied adequately. Since estimated intervention effect from Generalized estimating equations (GEE) has a population-average interpretation, valid inference methods for binary outcomes based on GEE are preferred by public health policy makers.MethodsWe form hypothesis testing of add-on effect of a second treatment based on GEE analysis in an MSW-CRT design with limited number of clusters. Four variance-correction estimators are used to adjust the bias of the sandwich estimator. Simulation studies have been used to compare the statistical power and type I error rate of these methods under different correlation matrices.Results We demonstrate that an average estimator with t(I-3) can stably maintain type I error close to the nominal level with limited sample sizes in our settings. We show that power of testing the add-on effect depends on the baseline event rate, effect sizes of two interventions and the number of clusters. Moreover, by changing the design with including more sequences, power benefit can be achieved. ConclusionsFor designing the MSW-CRT, we suggest using more sequences and checking event rate after initiating the first intervention via interim analysis. When the number of clusters is not very large in MSW-CRTs, inference can be conduct using GEE analysis with an average estimator with t(I-3) sampling distribution.

Background: Preseason movement screening can identify modifiable risk factors, deterioration of function, and potential for injury in baseball players. Limited resources and time prevent high school baseball coaches from performing movement screens on their players. Hypothesis: The arm care screen (ACS) will be highly sensitive to detecting musculoskeletal risk factors. Study Design: Cross-sectional Level of evidence: Level 3 Methods: A total of 150 baseball players were independently scored on the ACS electronically by reviewing a video recording of each player’s screening performance. Discriminability of the ACS was determined with a 2 × 2 contingency table dichotomizing musculoskeletal risk factors as present or absent based on a predetermined cutoff value and those who passed or failed the corresponding ACS subtest. Results: High sensitivity was observed on the reciprocal shoulder mobility (0.89; 95% CI 0.81-0.94), 90/90 total body rotation (0.86; 95% CI 0.79-0.92), and lower body diagonal reach (0.85; 95% CI 0.78-0.91) tests of the ACS suggesting sufficient ability to identify musculoskeletal impairments and risk factors. Conclusion: The ACS is a simplistic screening tool that the coach can administer to discriminate between youth, high school, and college-level baseball players who possess musculoskeletal risk factors. The ACS subtests demonstrated high sensitivity for correctly identifying musculoskeletal risk factors common in baseball players and can be useful as a screening tool for baseball coaches developing arm care exercise programs. Clinical Relevance: A field-expedient screen could provide coaches the ability to identify musculoskeletal risk factors that need to be addressed to minimize injury risk factors in a time-efficient manner.

Critically ill mechanically ventilated (MV) patients develop significant muscle weakness, which has major clinical consequences. There remains uncertainty, however, regarding the severity of leg weakness, the precise relationship between muscle strength and thickness, and the risk factors for weakness in MV patients. We therefore measured both diaphragm (PdiTw) and quadriceps (QuadTw) strength in MV patients using magnetic stimulation and compared strength to muscle thickness. Both PdiTw and QuadTw were profoundly reduced for MV patients, with PdiTw 19 % of normal and QuadTw 6% of normal values. There was a poor correlation between strength and thickness for both muscles, with thickness often remaining in the normal range when strength was severely reduced. Regression analysis revealed reductions in PdiTw correlated with presence of infection (p = 0.006) and age (p = 0.007). QuadTw best correlated with duration of MV (p = 0.036). Limb muscles are profoundly weak in critically ill patients, with a severity that mirrors the level of weakness observed in the diaphragm.

Background Contemporary goals of rehabilitation after traumatic brain injury (TBI) aim to improve cognitive and motor function by applying concepts of neuroplasticity. This can be challenging to carry out in TBI patients with motor, balance, and cognitive impairments. Objective To determine whether use of dynamic body-weight support (DBWS) would allow safe administration of intensive motor therapy during inpatient rehabilitation and whether its use would yield greater improvement in functional recovery than standard-of-care (SOC) therapy in adults with TBI. Methods Data in this retrospective cohort study was collected from patients with TBI who receive inpatient rehabilitation incorporating DBWS (n = 6) and who received inpatient rehabilitation without DBWS (SOC, n = 6). The primary outcome measure was the change in Functional Independence Measures (FIM) scores from admission to discharge. Results There was significant improvement in total FIM scores at discharge compared to admission for both the DBWS (p = 0.001) and SOC (p = 0.005) groups. Overall, the DBWS group had greater improvement in total FIM score and FIM subscales compared to the SOC group. Conclusions Our results suggest DBWS has the potential to allow a greater intensity of therapy during inpatient rehabilitation and yield better outcomes compared to SOC in patients with TBI.

Context The gut microbiome is a source of inflammatory factors such as lipopolysaccharide (LPS; endotoxin) that influence metabolic homeostasis. Rifaximin is a well-tolerated antibiotic that may reduce LPS. Objective We sought to develop a method to accurately assess postprandial endotoxemia and to determine whether rifaximin treatment improves metabolic homeostasis in obese humans with metabolic syndrome. Design and Setting Plasma LPS, adipose inflammation, glucose and lipid metabolism, and insulin sensitivity were evaluated in a clinical research setting. Participants Twelve obese human research participants with prediabetes or three features of metabolic syndrome participated. Intervention The research participants were randomized to placebo control or rifaximin soluble solid dispersion (80 mg/d) treatment groups and treated for 12 weeks. Outcome Measures We evaluated changes in insulin sensitivity with a euglycemic clamp; changes in lipid and glucose metabolism with oral lipid and glucose tolerance tests; changes in plasma LPS during the lipid tolerance test; and changes in adipose tissue and systemic inflammation by measuring inflammatory cytokines. Results Rifaximin treatment slightly worsened insulin sensitivity (P = 0.03), did not improve glucose or lipid homeostasis, and did not significantly improve adipose tissue inflammation. Our efforts to accurately assess plasma LPS using limulus amebocyte lysate assays revealed that the majority of LPS is masked from detection by limulus amebocyte lysate assays, but can be unmasked using a pretreatment step with protease. Unmasked LPS increases during the lipid tolerance test, but rifaximin treatment did not reduce this. Conclusions Rifaximin treatment did not lower plasma LPS or improve metabolic homeostasis in obese humans.

OBJECTIVE: Socioemotional selectivity theory predicts that as the end of life approaches, goals and resources that provide immediate, hedonic reward become more important than those that provide delayed rewards. The present study tested whether these goal domains differentially affected psychological health in the context of marital dyads in which one partner had been diagnosed with amyotrophic lateral sclerosis (ALS), a life-limiting disease. DESIGN: ALS patients (N = 102) being treated in 3 multidisciplinary clinics and their spouses (N = 100) reported their loneliness, financial worry, and psychological health every 3 months for up to 18 months. MAIN OUTCOME MEASURE: Psychological health composite. RESULTS: In multilevel dyadic models, patients and spouses had similar levels of financial worry and loneliness. Both patients and spouses had worse psychological health with higher loneliness, but only spouses had worse psychological health with higher financial worry. Significant interactions with age and disease severity indicated that older spouses were more affected by loneliness than were younger spouses, and patients with less severe disease were more affected by financial worry than patients with more severe disease. CONCLUSION: The results provide good support for socioemotional selectivity theory’s implications for psychological health in a strong test of the theory.

Background Arm care programs consisting of upper extremity strengthening and stretching have been recommended for injury prevention for pitchers of all ages. There has been no investigation into high school baseball coaches’ usage and perceptions of arm care programs to mitigate physical impairments associated with injuries in baseball players. # Hypothesis/Purpose The purpose of this study was to investigate the current usage of arm care programs by high school baseball coaches. The primary objective was to determine if coaches use group-based or individualized arm care programs. The secondary objective sought to determine if the use of arm care programs is influenced by coaches’ age, education, and experience level. Finally, this study explored the potential barriers to arm care implementation and high school baseball coaches’ current awareness and beliefs of injury prevention. # Study Design Descriptive cross-sectional survey # Methods A 29-item online survey was emailed to 18,500 high school baseball coaches throughout the United States. Data were collected for three months, and the response rate was 3.7%. # Results A total of 87.3% (n=571/654) of responding coaches use arm care programs with their players. Of coaches performing arm care, only 18.5% of 571 individualize their arm care exercises based on specific player needs. However, older and more experienced coaches are more likely to individualize their programs. Among the 12.7% (n=83/654) of coaches who do not use arm care programs, the two most commonly cited reasons for not implementing arm care were lack of observed benefit (41%) and insufficient staff (31%). Although 42% of 654 coaches recognized reduced shoulder mobility as a major contributor to injury, risk factors such as throwing with a fatigued arm, previous injury history, and throwing \> 8 months per year were not consistently identified as primary risk factors. # Conclusion The results of this study suggest that the majority high school baseball coaches implement group-based arm care exercise programs to prevent injury. Lack of confidence in the effectiveness and staffing limitations were major barriers to implementation of arm care programming. However, the responding coaches exhibited inconsistent risk factor awareness and dated injury prevention beliefs. Therefore, better educational collaboration between rehabilitation professionals and high school coaches regarding injury risk factors and preventative strategies is warranted. # Level of Evidence Level 3

Background: Despite disproportionate rates of diabetes among Appalachian residents, barriers to attending clinical appointments have not been fully explored. We examined the association between barriers to clinic attendance, A1c, and self-care. Methods: We report baseline cross-sectional data from an ongoing study of participants in six counties in rural Appalachia Kentucky. Barriers to clinic attendance were measured using a 25-item checklist adapted from the Chronic Care Model and self-care was measured using a summary score from Toobert’s Diabetes Self-Care Activities. Linear regression models were fit with varying levels of adjustment. Results: Most study participants (N=356) where White (n=349), women (n=230), and had health insurance (n=349). Average A1c was 7.7% (SD=1.7%). No barriers were reported by 37.4% of participants. In fully adjusted models, not being worried about diabetes was significantly associated with diabetes self-care. Inaccessible transportation and co-payment, and the belief that God (but not them) will help their diabetes were significantly associated with A1c (Table 1). Conclusions: Both logistical and cognitive barriers obstruct clinic attendance in this sample. Additional aspects or barriers to clinical attendance could be cognitive or emotional, such as social support and cultural norms. Future research should develop interventions for these logistical and cognitive barriers. Disclosure B. L. Smalls: None. M. Lacy: None. L. Hieronymus: None. P. Westgate: None. M. Azam: None. S. C. Westneat: None. N. Schoenberg: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK112136)

BACKGROUND: Patient-reported measures guide physicians in clinical decision making and therefore it is critical to determine what clinical factors are associated with these scores. Psychological and physical factors are commonly studied separately in patients with rotator cuff tears to determine their influence on outcomes. It is well established that psychological distress and scapular motion change in the presence of a symptomatic rotator cuff tear. However, these factors have not been studied simultaneously in a clinical setting to determine their association with shoulder outcome scores. QUESTION/PURPOSE: After controlling for relevant confounding variables, what physical and psychological factors are associated with better (1) American Shoulder and Elbow Surgeons (ASES) scores for function, (2) ASES pain scores, and (3) total ASES scores? METHODS: Fifty-nine patients with a potential symptomatic rotator cuff tear were recruited and agreed to participate in this cross-sectional study. Of those, 85% (50 of 59) met eligibility criteria for a primary diagnosis of an MRI-confirmed symptomatic partial-thickness or full-thickness rotator cuff tear without a history of shoulder surgery. Demographics, rotator cuff tear size, arm flexion, and clinical scapular motion during active arm flexion were evaluated by experienced examiners using standardized procedures. Patients completed the ASES questionnaire and the Optimal Screening for Prediction of Referral and Outcomes-Yellow Flag assessment form, which measures 11 different pain-related psychological distress symptoms. Three separate stepwise multiple linear regression analyses were performed for ASES pain, function, and total scores, with significance set at p < 0.05. RESULTS: This model found that ASES function scores were associated with four factors: older age, increased arm flexion, increased percentage of scapular external rotation during arm flexion, and increased scores for acceptance of chronic pain (adjusted r(2) = 0.67; p = 0.01). Those four factors appear to explain 67% of the observed variance in ASES function scores in patients with rotator cuff tears. Furthermore, increased percentage of scapular external rotation during arm flexion and decreased fear-avoidance beliefs related to physical activity scores (adjusted r(2) = 0.36; p < 0.01) were associated with better ASES pain scores. And finally, better ASES total scores were associated with four factors: increased arm flexion, increased percentage of scapular upward rotation, increased scapular external rotation during arm flexion, and decreased fear-avoidance beliefs related to physical activity scores (adjusted r(2) = 0.65; p < 0.001). CONCLUSION: Our results favor adopting a comprehensive biopsychological clinical assessment for patients with rotator cuff tears that specifically includes humeral and scapular motion, fear-avoidance behaviors, and pain coping behaviors along with demographics. These particular physical and psychological variables were found to be associated with the ASES and, therefore, should be clinically examined simultaneously and targeted as part of a tailored treatment plan. LEVEL OF EVIDENCE: Level II, prognostic study.

BACKGROUND Bronchodilator responses among preterm infants are heterogeneous. Bedside measurements may identify responders. STUDY DESIGN Respiratory measurements (Resistance, Compliance, FiO2) and pulse oximetry (SpO2) patterns were downloaded from infants

BACKGROUND Beige and brown adipose tissue (BAT) are associated with improved metabolic homeostasis. We recently reported that the β3-adrenergic receptor agonist mirabegron induced beige adipose tissue in obese insulin-resistant subjects, and this was accompanied by improved glucose metabolism. Here we evaluated pioglitazone treatment with a combination pioglitazone and mirabegron treatment and compared these with previously published data evaluating mirabegron treatment alone. Both drugs were used at FDA-approved dosages. METHODS We measured BAT by PET CT scans, measured beige adipose tissue by immunohistochemistry, and comprehensively characterized glucose and lipid homeostasis and insulin sensitivity by euglycemic clamp and oral glucose tolerance tests. Subcutaneous white adipose tissue, muscle fiber type composition and capillary density, lipotoxicity, and systemic inflammation were evaluated by immunohistochemistry, gene expression profiling, mass spectroscopy, and ELISAs. RESULTS Treatment with pioglitazone or the combination of pioglitazone and mirabegron increased beige adipose tissue protein marker expression and improved insulin sensitivity and glucose homeostasis, but neither treatment induced BAT in these obese subjects. When the magnitude of the responses to the treatments was evaluated, mirabegron was found to be the most effective at inducing beige adipose tissue. Although monotherapy with either mirabegron or pioglitazone induced adipose beiging, combination treatment resulted in less beiging than either alone. The 3 treatments also had different effects on muscle fiber type switching and capillary density. CONCLUSION The addition of pioglitazone to mirabegron treatment does not enhance beiging or increase BAT in obese insulin-resistant research participants. TRIAL REGISTRATION ClinicalTrials.gov NCT02919176. FUNDING NIH DK112282 and P20GM103527 and Clinical and Translational Science Awards grant UL1TR001998.

Highlights • HEALing Communities Study is a parallel-group cluster randomized controlled trial. • Communities That HEAL intervention’s goal is to reduce opioid overdose deaths. • Structured consensus decision-making strategy guided study measure development. • More than 80 study measure specifications and a common data model were developed. • The study will provide methodology and longitudinal community data for research., Background Opioid overdose deaths remain high in the U.S. Despite having effective interventions to prevent overdose deaths, there are numerous barriers that impede their adoption. The primary aim of the HEALing Communities Study (HCS) is to determine the impact of an intervention consisting of community-engaged, data-driven selection, and implementation of an integrated set of evidence-based practices (EBPs) on reducing opioid overdose deaths. Methods The HCS is a four year multi-site, parallel-group, cluster randomized wait-list controlled trial. Communities (n = 67) in Kentucky, Massachusetts, New York and Ohio are randomized to active intervention (Wave 1), which starts the intervention in Year 1 or the wait-list control (Wave 2), which starts the intervention in Year 3. The HCS will test a conceptually driven framework to assist communities in selecting and adopting EBPs with three components: 1) A community engagement strategy with local coalitions to guide and implement the intervention; 2) A compendium of EBPs coupled with technical assistance; and 3) A series of communication campaigns to increase awareness and demand for EBPs and reduce stigma. An implementation science framework guides the intervention and allows for examination of the multilevel contexts that promote or impede adoption and expansion of EBPs. The primary outcome, number of opioid overdose deaths, will be compared between Wave 1 and Wave 2 communities during Year 2 of the intervention for Wave 1. Numerous secondary outcomes will be examined. Discussion The HCS is the largest community-based implementation study in the field of addiction with an ambitious goal of significantly reducing fatal opioid overdoses.

Treatment of subjects who are obese/insulin resistant with the β3AR agonist mirabegron resulted in increased beige adipose tissue, without a change in brown adipose tissue (BAT), along with an improvement in glucose tolerance, HbA1c, and an increase in type 1 fibers in skeletal muscle. Pioglitazone has been demonstrated to increase beiging, and it has been demonstrated that combination of a thiazolidinedione with a β3AR agonist further increased beige adipocyte markers in vitro. The goal of this study was to determine whether combination therapy with pioglitazone and mirabegron would further increase beiging, BAT volume or activity, or skeletal muscle fiber type switching, and improve glucose homeostasis more than each drug separately. We randomized obese and insulin-resistant (IR) research participants to mirabegron (50 mg/day), pioglitazone (30 mg/day), or combination treatment groups. Adipose and muscle tissue biopsies and PET-CT scans were performed at baseline and after 10 weeks of treatment. Mitochondrial bioenergetics were determined in purified mitochondria from adipose tissue. Although mirabegron and pioglitazone treatment significantly induced SC WAT beiging separately, the combination of the two drugs resulted in less beiging than mirabegron treatment alone, and did not increase mitochondrial uncoupling. Furthermore, neither pioglitazone nor combination therapy increased BAT or fiber-type switching to type 1 fibers. Although each drug improved glucose homeostasis, the effect of the combination was not significantly additive. Analysis of mRNA expression revealed that pioglitazone or combination treatment induced the expression of p107, which promotes white versus brown adipose gene expression, suggesting a mechanism for inhibition of mirabegron-induced beiging by pioglitazone. These results suggest that pioglitazone inhibits mirabegron-induced beiging and does not augment other beneficial effects of mirabegron treatment. Disclosure P.A. Kern: None. H. Memetimin: None. B. Zhu: None. A.L. Confides: None. Z. Johnson: None. H.J. Vekaria: None. P. Westgate: None. P.G. Sullivan: None. E.E. Dupont-Versteegden: None. B. Finlin: None. Funding National Institutes of Health (DK112282)

Introduction The Diabetes Prevention Program, an intensive lifestyle change program, effectively reduces the risk of progression from prediabetes to type 2 diabetes but is underutilized. An implementation study using formative research was undertaken to increase Diabetes Prevention Program referrals at a primary care clinic. Study design A pragmatic, cluster randomized, mixed-methods study. Setting/particpants Clusters were teams of primary care clinicians from 2 primary care clinics. The 3 intervention clusters had 8–11 clinicians, and the 3 control clusters had 7–20 clinicians. Intervention Implementation activities occurred from December 2017 to February 2019. The activities included targeted clinician education, a prediabetes clinician champion, and a custom electronic health record report identifying patients with prediabetes. Main outcome measures The primary outcome was referral of patients with prediabetes to the institutional Diabetes Prevention Program. Study data, including patient demographic and clinical variables, came from electronic health record. Interviews with clinicians evaluated the implementation strategies. Generalized estimating equation analyses that accounted for multiple levels of correlation and interview content analysis occurred in 2019. Results Study clinicians cared for 2,992 patients with a prediabetes diagnosis or HbA1c indicative of prediabetes (5.7%–6.4%). Clinicians in the intervention clusters referred 6.9% (87 of 1,262) of patients with prediabetes to the Diabetes Prevention Program and those in the control clusters referred 1.5% (26 of 1,730). When adjusted for patient age, sex, race, HbA1c value, HbA1c test location, and insurance type, intervention clinicians had 3.85 (95% CI=0.40, 36.78) greater odds of referring a patient with prediabetes to the Diabetes Prevention Program. The 11 interviewed intervention clinicians had mixed opinions about the utility of the interventions, reporting the prediabetes clinic champion (n=7, 64%) and educational presentations (n=6, 55%) as most helpful. Conclusions Intervention clinicians were more likely to make Diabetes Prevention Program referrals; however, the study lacked power to achieve statistical significance. Clinician interviews suggested that intervention components that triggered Diabetes Prevention Program referrals varied among clinicians.

Weighted generalized estimating equations (GEEs) are popular for the marginal analysis of longitudinal survey data. This popularity is due to the ability of these estimating equations to provide consistent regression parameter estimates and corresponding standard error estimates as long as the population mean and survey weights are correctly specified. Although the data analyst must incorporate a working correlation structure within the weighted GEEs, this structure need not be correctly specified. However, accurate modeling of this structure has the potential to improve regression parameter estimation (i.e., reduce standard errors) and therefore, the selection of a working correlation structure for use within GEEs has received considerable attention in standard longitudinal data analysis settings. In this article, we describe how correlation selection criteria can be extended for use with weighted GEE in the context of analyzing longitudinal survey data. Importantly, we provide and demonstrate an R function that we have created for such analyses. Furthermore, we discuss correlation selection in the context of using existing software that does not have this explicit capability. The methods are demonstrated via the use of data from a real survey in which we are interested in the mean number of falls that elderly individuals in a specific subpopulation experience over time.

Background Red blood cell (RBC) transfusion decreases intermittent hypoxemia (IH) events beyond the first week of life. This benefit may be related to improved perfusion to the respiratory control network. Perfusion index (PI) is a perfusion measure provided by the pulse oximeter. We hypothesized that the benefit in IH after RBC transfusion is associated with an increase in PI. In addition, we assessed the value of PI and clinical measures in predicting the effect of RBC transfusion on IH. Study design and methods We prospectively enrolled infants less than 30 weeks' gestation age. PI and oxygen saturation (SpO2 ) were monitored with high-resolution pulse oximeters 24 hours before and after RBC transfusion. Data were analyzed at three postnatal periods: Epoch 1, first week of life (1 to 7 days of life); Epoch 2, 2 to 4 weeks of life (8 to 28 days of life); and Epoch 3, 4 to 8 weeks of life. Results A total of 118 transfusions were analyzed. IH measures significantly decreased after transfusion in Epochs 2 and 3. PI significantly increased after transfusion, but it did not correlate with the decrease in IH measures. Mechanical ventilation, fraction of inspired oxygen (FiO2 ), and IH measures influenced the effects on oxygenation. Conclusions RBC transfusion improved IH after the first week of life. The benefit in IH did not correlate with PI increase after transfusion. Pretransfusion respiratory support and IH measures predicted the effect of transfusion on oxygenation.

OBJECTIVES: Determine the incidence of apnea in preterm and term infants after deep sedation (DS) compared with general anesthesia (GA). METHODS: A retrospective chart review was performed on infants who underwent elective DS or GA from January 2008 to December 2013, were RESULTS: There were 61 DS encounters (24 preterm and 37 term) and 175 GA encounters (120 preterm and 55 term) that met inclusion criteria. No recorded apneic events in either preterm or term infants were recorded after DS. After GA, 1.7% of infants had apneic events (2.5% preterm and 0 term; P = .57 versus DS). All events occurred within 2 hours of monitoring in recovery. CONCLUSIONS: None of the infants had apnea after DS. Rates from the literature would suggest that 2 to 6 of the preterm DS subjects should have experienced postsedation apnea. Sampled GA subjects had a rate of 2.5% in preterm infants exhibiting apnea after GA. Although the post-DS apnea rate is lower than what has been previously published, the small sample size and limitations of a retrospective design prevent us from directing a change in postsedation monitoring recommendations. However, we do support the need for prospective studies with strict monitoring criteria to reveal the true risk of post-DS apnea.