Background: We evaluated the effect of meloxicam on insulin lispro pharmacokinetics and glucose pharmacodynamics over 10 days of continuous subcutaneous insulin infusion (CSII) at one infusion site in people with type 1 diabetes (T1D). Method: This phase 1, randomized, double-blind, single-center, two-way crossover study enrolled adults with T1D for ≥1 year on stable CSII for ≥3 months. Participants randomly received U100 insulin lispro and LY900027 (U100 insulin lispro + 0.25 mg/mL meloxicam). Primary end points were area under the insulin lispro curve from 0 to 5 hours (AUCIns.0-5h) after bolus administration prior to a mixed-meal tolerance test (MMTT) and maximum observed concentration of insulin lispro (CIns.max) on days 5, 7, and 10, versus day 3 (baseline). Results: A total of 20 participants were randomized. Insulin absorption was accelerated for insulin lispro and LY900027 from days 1 to 7. The AUCIns.0-5h was significantly lower on day 10 versus day 3 for LY900027 (−19%) and insulin lispro (−14%); the AUCIns.0-5h did not differ significantly between treatments. The CIns.max increased with LY900027 and insulin lispro (by ~14%-23% and ~16%-51%) on days 5, 7, and 10 versus day 3. The CIns.max of LY900027 was ~14%-23% lower than insulin lispro CIns.max on days 7 and 10 ( P ≤ .0805). Accelerated insulin absorption and a modest loss of total insulin exposure led to a loss of MMTT glycemic control at later time points. Conclusions: The pharmacokinetics of insulin changed over catheter wear time even when an anti-inflammatory agent was present. Postprandial glycemic control was adversely affected by the accelerated insulin absorption and decreased insulin exposure.

Physical activity trajectories from the Trial of Activity in Adolescent Girls (TAAG) capture the various exercise habits over female adolescence. Previous analyses of this longitudinal data from the University of Maryland field site, examined the effect of various individual-, social-, and environmental-level factors impacting the change in physical activity levels over 14 to 23 years of age. We aimed to understand the differences in physical activity levels after controlling for these factors. Using a Bayesian linear mixed model incorporating a model-based clustering procedure for random deviations that does not specify the number of groups a priori, we find that physical activity levels are starkly different for about 5

Current guidelines recommend 15-20 g of carbohydrate (CHO) for treatment of mild to moderate hypoglycemia. However, these guidelines do not account for reduced insulin during suspensions with predictive low-glucose suspend (PLGS). We assessed insulin suspensions, hypoglycemic events, and CHO treatment during a 20-h inpatient evaluation of an investigational system with a PLGS feature, including an overnight basal up-titration period to activate the PLGS. Among 10 adults with type 1 diabetes, there were 59 suspensions; 7 suspensions were associated with rescue CHO and 5 with hypoglycemia. Rescue treatment consisted of median 9 g CHO (range: 5-16 g), with no events requiring repeat CHO. No rescue CHO were given during or after insulin suspension for the overnight basal up-titration. To minimize rebound hyperglycemia and needless calorie intake from hypoglycemia overtreatment, updated guidance for PLGS systems should reflect possible need to reduce CHO amounts for hypoglycemia rescue associated with an insulin suspension. The clinical trial was registered with ClinicalTrials.gov (NCT03890003).

Background:Automated insulin delivery (AID) systems have demonstrated improvements in time-in-range (TIR, blood glucose 70-180 mg/dL) without increasing hypoglycemia. Testing a closed-loop system in an inpatient environment with supervised challenges allows for initial evaluation of performance and safety of the system. Methods:Adults with type 1 diabetes (T1D) were enrolled into two similar studies (n = 10 per study), with 3-day inpatient analysis periods. Participants tested a Lilly hybrid closed-loop (HCL) system comprising an investigational insulin pump, insulin lispro, a pump-embedded model predictive control algorithm, a continuous glucose monitor (CGM), and an external dedicated controller. Each protocol included meal-related and exercise challenges to simulate real-world diabetes self-management errors. Only study staff interacted with the HCL system. Performance was assessed using standard CGM metrics overall and within prespecified periods. Results:Participants (25% male) had mean +/- standard deviation (SD) age 44.7 +/- 14.2 years, T1D duration 30.2 +/- 11.1 years, A1C 7.2% +/- 0.8%, and insulin usage 0.53 +/- 0.21 U/(kg center dot day). Percentage TIR 70-180 mg/dL (mean +/- SD) was 81.2 +/- 8.4 overall, 85.2 +/- 8.1 outside of challenge periods, 97.3 +/- 5.3 during the nocturnal periods, and 74.5 +/- 16.2 for the postprandial periods. During challenge periods, percentage TIR for the overbolus challenge was 65.4 +/- 29.2 and that for the delayed bolus challenge was 57.1 +/- 25.1. No adverse events (AEs), serious AEs, or unanticipated adverse device events occurred while participants were using the HCL system. Conclusions:In participants with T1D, Lilly AID system demonstrated expected algorithm performance and safety with satisfactory glycemic outcomes overall and in response to simulated diabetes management challenges. Additional studies in less supervised conditions and with broader patient populations are warranted.ClinicalTrials.govRegistration number NCT03743285, NCT03849612.

Generalized linear mixed models (GLMM) are commonly used to model the treatment effect over time while controlling for important clinical covariates. Standard software procedures often provide estimates of the outcome based on the mean of the covariates; however, these estimates will be biased for the true group means in the GLMM. Implementing GLMM in the frequentist framework can lead to issues of convergence. A simulation study demonstrating the use of fully Bayesian GLMM for providing unbiased estimates of group means is shown. These models are very straightforward to implement and can be used for a broad variety of outcomes (eg, binary, categorical, and count data) that arise in clinical trials. We demonstrate the proposed method on a data set from a clinical trial in diabetes.

Introduction: In the era of mandatory work hour restrictions for residency programs, the opportunity for mastery of complex surgical skills in the operating room (OR) has been compromised. All the while, gynecologic surgical techniques have continued to expand. Surgical simulation offers an adjuvant modality for helping young surgeons hone their surgical techniques. We sought to design, construct, and pilot a model for simulating a minimally invasive myomectomy procedure for the purpose of resident training. We undertook a preliminary evaluation of the model’s validity. Methods: Gynecologic surgical simulation models were constructed from polyvinyl alcohol poured into 3D-printed injection molds. A total of 12 laparoscopic and 12 robot-assisted simulated myomectomies were performed using the models. Face and content validity were evaluated with post-simulation questionnaires. Construct validity was assessed by comparing procedural metrics (time to completion and estimated blood loss) between residents and attending surgeons. Results: In the post-simulation survey, the majority of attending surgeons agreed the model was realistic (83.3%) and included the critical steps of a myomectomy (87.5%). Most residents agreed they would feel more prepared for a myomectomy if they practiced on the model beforehand (87.5%) and the majority of attending surgeons agreed they would feel comfortable giving a resident more operative autonomy if the resident had previously completed the simulation (71.4%). Procedural metrics were not significantly associated with expertise level. Conclusion: We were able to successfully create a model for simulating a minimally invasive myomectomy. Initial simulations using the model were well received by participants. Further development and investigation of the model will be pursued to determine if this is a valid and useful tool for teaching and practicing a minimally invasive myomectomy.

Bayesian model–based clustering provides a powerful and flexible tool that can be incorporated into regression models to better understand the grouping of observations. Using data from the Seychelles Child Development Study, we explore the effect of prenatal methylmercury exposure on 20 neurodevelopmental outcomes measured in 9‐year‐old children. Rather than cluster individual subjects, we cluster the outcomes within a multiple outcomes model. By using information in the data to nest the outcomes into groups called domains, the model more accurately reflects the shared characteristics of neurodevelopmental domains and improves estimation of the overall and outcome‐specific exposure effects by shrinking effects within and between domains selected by the data. The Bayesian paradigm allows for sampling from the posterior distribution of the grouping parameters; thus, inference can be made about group membership and their defining characteristics. We avoid the often difficult and highly subjective requirement of a priori identification of the total number of groups by incorporating a Dirichlet process prior to form a fully Bayesian multiple outcomes model.

Environmental exposure effects on human development can be small and difficult to detect due to the nature of observational data. In the Seychelles Child Development Study, researchers examined the effect of prenatal methylmercury exposure using a battery of tests measuring aspects of child development [23, 25]. We build a multiple outcomes model similar to that of the previous analyses (see [23, 25]); however, our multiple outcomes model makes no assumptions of relationships between the testing outcomes. Instead, the nesting of outcomes into domains is a clustering problem we address with a Dirichlet process mixture model implemented through a Bayesian MCMC approach [16]. This model provides inference for the methylmercury exposure effect as well as greater insight into the similarities and differences across the outcomes.

Objective: To examine the associations of two obesity-associated genes, FTO (rs9939609) and GNB3 (rs5443) single nucleotide polymorphisms (SNPs), with early pregnancy body mass index, gestational weight gain, and postpartum weight retention. Methods: Secondary data analysis of self-identified white (n = 580) and black (n = 194) women who participated in a randomized controlled trial (2009-2014) and provided a saliva sample of DNA. Bivariate relationships were assessed using analysis of variance. Multiple regression models assessed the relationship between outcomes and gene SNPs, controlling for income, parity, and smoking status. Results: FTO and GNB3 gene associations with pregnancy weight were different by racial group and early pregnancy body mass index. Obese black women homozygote for the FTO risk allele (AA) had a higher gestational weight gain compared with non-risk homozygotes (TT) (P = 0.006). GNB3 non-risk CC homozygotes tended to have a lower gestational weight gain compared with heterozygotes (P=0.05). White GNB3 C carriers tended to be heavier in early pregnancy (P < 0.1) and. GNB3 homozygote (TT) overweight women tended to have lower postpartum weight retention than C carriers. Conclusions: The FTO gene and possibly the GNB3 gene are associated with high gestational weight gain in obese black women. Obese carriers of the FTO risk allele gained 4.1 kg (AT) and 7.6 kg (TT) more than those without risk alleles. Overweight GNB3 heterozygotes (CT) gained 6.6 kg less than homozygotes (CC). Overweight or obese black women who have either risk variant are at risk for high gestational weight gain. (C) 2017 Elsevier Inc. All rights reserved.

Background: Comprehensive examinations of placental metal concentrations and correlations with infant parameters are under-investigated. Chattanooga, Tennessee's consistently high incidence of low birth weight and potential for metal exposure provides an ideal opportunity to investigate potential correlations. Objectives: To investigate the associations between a wide variety of metals in placental tissue and multiple infant parameters. Methods: A total of 31 elements were screened via ICP-MS in 374 individual placental samples. Of those, 14 were quantifiable in > 86% of the samples. We examined correlations between metal concentrations and infant parameters (birth weight, gestational age, birth weight centile, placental weight, birth length and head circumference). We fit multivariable regression models to estimate the covariate-adjusted associations of birth weight with In-transformed concentrations of each of the 14 metals and used generalized additive models to examine nonlinear relationships. Results: Some of the strongest relationships with infant parameters came from several lesser-studied metals. Placental rhodium concentrations were negatively correlated with almost all infant parameters. In the fully adjusted regression model, birth weight was significantly associated with several metals. On an IQR (25th to the 75th percentile) basis, estimated changes in birthweight were: for cobalt (82.5 g, IQR = 6.05 mu g/kg, p = 0.006), iron (-51.5 g, IQR = 171800 mu g/kg, p = 0.030), manganese (-27.2 g, IQR = 152.1 mu g/kg, p = 0.017), lead (-72.7 g, IQR = 16.55 mu g/kg, p = 0.004) and rhodium (-1365.5 g, IQR = 0.33 mu g/kg, p < 0.001). Finally, a generalized additive model showed significant nonlinear relationships between birth weight and concentrations of Co and Rh. Conclusions: Our comprehensive examination of placental metals illustrate many strong associations between lesser-studied metals and infant parameters. These data, in combination with our correlations of well-studied metals, illustrate a need to consider in utero exposure to a broad array of metals when considering fetal development.

Objectives: Arthroscopic hip surgery has gained considerable popularity over the past several years. Attempts to optimize peri and postoperative pain control continues to represent a challenge and opportunity for clinical improvement. Multiple regional anesthesia strategies have been utilized by arthroscopic hip surgeons, including lumbar plexus and femoral nerve blockade, however these options can be associated with setbacks including technical difficulty, intravascular injection, increased post-operative fall risk and the development of peripheral neuritis. Therefore, exploration of alternative regional anesthesia strategies holds promise for improved clinical outcomes. This study aims to explore the efficacy and complication rate of intra-articular anesthetic administration in patients undergoing arthroscopic hip surgery. Methods: A retrospective analysis of prospectively collected data was conducted to identify all patients undergoing elective arthroscopic hip surgery between November 2013 and April 2015. Subjects were stratified into either a group that had received a preoperative femoral nerve block for perioperative pain control or a group that had an intra-articular injection of local anesthetic administered by the surgical team intraoperatively. Objective data, including pre and post-op pain scores in the PACU, total dose of narcotics required perioperatively, occurrence of falls and development of peripheral neuropathy were collected for analysis. Data was compared between the two groups using linear and logistic regression modeling. Statistical significance was determined as p<0.05. Results: After excluding patients who did not meet the criteria for study participation, a total of 193 patients were included in this study. At the time of surgery, one hundred eighty three patients (95%) demonstrated evidence of labralchondral pathology and bony morphology characteristic of femoroacetabular impingement (FAI). One hundred five patients (54%) received a pre-operative femoral nerve block and 88 patients (46%) received an intra-operative intra-articular injection of anesthetic agents. Linear models for post-operative pain, controlled for patient age and pre-operative pain levels, revealed that patients receiving pre-operative femoral nerve blocks had significantly less pain at discharge (p<0.05). There was no statistically significant difference in pain scores between patients receiving pre-operative femoral nerve blocks and those receiving intra-articular injections at post-operative weeks 1, 3 and 6. Patients receiving pre-operative femoral nerve blocks were found to be 3.6 times more likely to experience a post-operative fall (OR 3.58, p < 0.05) and were 14 times more likely to experience post-operative neuropathy (OR 13.99, p < 0.01) than patients receiving an intra-articular injection. Conclusion: Intra-articular anesthetic administration was found to be similar in efficacy to pre-operative femoral nerve blocks at reducing post-operative pain in patients undergoing hip arthroscopy. Additionally, patients receiving intra-articular injections had a significantly decreased risk of falling post-operatively or developing peripheral neuritis, known complications of femoral nerve blocks. With this information, intra-articular anesthetic administration appears to be a safe alternative to femoral nerve blocks in patients undergoing hip arthroscopy. [Table: see text][Table: see text]

Claudins are a family of integral membrane proteins and are components of tight junctions (TJs). Many TJ proteins are known to tighten the cell structure and maintain a barrier. Claudin-2 forms gated paracellular channels and allows sodium ions and other small positively charged ions to cross between adjacent cells. Recently, we found that vitamin D receptor (VDR) enhanced Claudin-2 expression in colon and that bile salt receptors VDR and Takeda G-protein coupled receptor5 (TGR5) were highly expressed in esophageal adenocarcinoma (EAC) and precancerous lesions. Here, we examined the expression of Claudin-2 in EAC and precancerous lesions and its association with VDR and TGR5 expression.

Bile acid reflux in the esophagus plays an important role in the carcinogenesis of esophageal adenocarcinoma (EAC). The G-protein coupled bile acid receptor (TGR5) has been associated with the development of gastrointestinal cancer. However, little is known regarding the role of TGR5 in esophageal carcinoma and precancerous lesions. We analyzed genomic DNA from 116 EACs for copy number aberrations via Affymetrix SNP6.0 microarrays. The TGR5 gene locus was amplified in 12.7% (14/116) of the EACs. The TGR5 protein expression was also assessed using immunohistochemistry from tissue microarrays, including Barrett’s esophagus (BE), low-(LGD) and high-grade dysplasia (HGD), columnar cell metaplasia (CM), squamous epithelium (SE), EAC and squamous cell carcinoma. The TGR5 protein was highly expressed in 71% of EAC (75/106), 100% of HGD (11/11), 72% of LGD (13/18), 66% of BE (23/35), 84% of CM (52/62), and 36% of SE (30/83). The patients with high expression of TGR5 exhibited significantly worse overall survival compared to the patients with nonhigh expression. TGR5 high expression was significantly increased in the males compared to the females in all cases with an odds ratio of 1.9 times. The vitamin D receptor (VDR) was significantly correlated with TGR5 expression. Our findings indicated that TGR5 may play an important role in the development and prognosis of EAC through a bile acid ligand. Gender differences in TGR5 and VDR expression may explain why males have a higher incidence of EAC compared to females.

INTRODUCTION Cost of care can be influenced by factors unrelated to quality. We previously demonstrated that, for patients undergoing pituitary tumor surgery, hospital costs, charges, and length of stay (LOS) across New York State were significantly affected by surgeon volume and geographic location. To identify factors that may have gone unnoticed, we conducted further analysis to identify patient-related factors present in low- vs high-charging hospitals. METHODS We performed cost analysis on pituitary tumor surgery cases previously identified in the New York State inpatient database (SPARCS 2006-2012). Controlling for surgeon volume, hospital location, and LOS, a Bayesian model-based clustering method segregated hospitals into low, medium, and high charging; subsequent analysis of variance (ANOVA) and linear regression identified patient factors that were statistically different between these groups. RESULTS Two thousand seven hundred eighty-four surgeries were performed in New York (2006-2012), 63% of patients were white, and 66% were privately insured, with Medicare/Medicaid covering 32%. Among low (6), medium (31), and high charge hospitals (32), median charges were $10 740, $24 221, and $43 520, respectively. Mean percentages of white patients were 14%, 48%, and 54%; mean percentages of privately insured patients were 28%, 40% and 60%. The association between race, insurance status and hospital charges was significant using both one-way ANOVA (race, P = .047; insurance status P = .011) and linear regression (race, P = .035; insurance status, P = .003). Costs and LOS were not different between low-, medium-, and high-charging hospitals. CONCLUSION When studying patients having pituitary tumor surgery, high-charging hospitals had a statistically significant increased proportion of white and privately insured patients, even though the cost of providing the service and the LOS (an indirect proxy for quality) was no different from low-charging hospitals. Understanding the forces that influence hospital charges will be important to improve health care quality and cost effectiveness.

Minichromosomal maintenance (MCM) proteins are participants of DNA replication and may represent more accurate markers in determining the proliferative fraction within a tumor than proliferative marker Ki-67. Our study investigated the correlation between MCM4 and MCM7 expression and Ki-67, Bmi1, and cyclin E expression in esophageal adenocarcinoma, squamous cell carcinoma, and precancerous lesions. MCM4 and MCM7 expression had similar distribution as Ki-67 and Bmi1 expression in esophageal carcinoma and precancerous lesions. The mean percentage of MCM4, MCM7, and Ki-67 expression increased from squamous epithelium (5.5%, 7.3%, and 5.9%, respectively), to columnar cell metaplasia (11.2, 13.5%, and 3.4%), Barrett's esophagus (27.7%, 35.3%, and 8.3%), low-grade dysplasia (42.6%, 52.2%, and 12.9%), high-grade dysplasia (63.2%, 77.7%, and 29.6%), adenocarcinoma (61.3%, 75.5%, and 24.5%), and squamous cell carcinoma (74.1, 85.4%, and 36.3%). The percentages of MCM4 and MCM7 expression were significantly higher than Ki-67 expression. Using univariate analysis we found a high percentage of MCM4 expression (>70%) to be significantly associated with lymph node metastasis and shorter survival in the adenocarcinoma group. We also demonstrated the percentage of MCM4 and MCM7 expression to be significantly correlated with Ki-67, Bmi1, and cyclin E expression in esophageal carcinoma and precancerous lesions. MCM4 and MCM7 may serve as more sensitive proliferative markers for the evaluation of esophageal lesions.

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