SGLT2 Inhibitor Therapy Improves Blood Glucose but Does Not Prevent Diabetic Bone Disease in Diabetic DBA/2J Male Mice

Persons with type 1 and type 2 diabetes have increased fracture risk, attributed to deficits in the microarchitecture and strength of diabetic bone, thought to be mediated, in part, by the consequences of chronic hyperglycemia. Therefore, to examine the effects of a glucose-lowering SGLT2 inhibitor on blood glucose (BG) and bone homeostasis in a model of diabetic bone disease, male DBA/2J mice with or without streptozotocin (STZ)-induced hyperglycemia were fed chow containing the SGLT2 inhibitor, canagliflozin (CANA), or chow without drug, for 10 weeks of therapy. Thereafter, serum bone biomarkers were measured, fracture resistance of cortical bone was assessed by μCT analysis and a three-point bending test of the femur, and vertebral bone strength was determined by compression testing. In the femur metaphysis and L6 vertebra, long-term diabetes (DM) induced deficits in trabecular bone microarchitecture. In the femur diaphysis, a decrease in cortical bone area, cortical thickness and minimal moment of inertia occurred in DM (p \u3c 0.0001, for all) while cortical porosity was increased (p \u3c 0.0001). These DM changes were associated with reduced fracture resistance (decreased material strength and toughness; decreased structural strength and rigidity; p \u3c 0.001 for all). Significant increases in PTH (p \u3c 0.0001), RatLAPs (p = 0.0002), and urine calcium concentration (p \u3c 0.0001) were also seen in DM. Canagliflozin treatment improved BG in DM mice by ~35%, but did not improve microarchitectural parameters. Instead, in canagliflozin-treated diabetic mice, a further increase in RatLAPs was evident, possibly suggesting a drug-related intensification of bone resorption. Additionally, detrimental metaphyseal changes were noted in canagliflozin-treated control mice. Hence, diabetic bone disease was not favorably affected by canagliflozin treatment, perhaps due to insufficient glycemic improvement. Instead, in control mice, long-term exposure to SGLT2 inhibition was associated with adverse effects on the trabecular compartment of bone

Effects of Allergen Sensitization on Response to Therapy in Children with Eosinophilic Esophagitis

Background: In children with eosinophilic esophagitis (EoE) foods are the most common disease triggers, but environmental allergens are also suspected culprits. Objective: To determine the effects of environmental allergen sensitization on response to treatment in children with EoE in the southeastern United States. Methods: Patients 2 to 18 years old who were referred to the Arkansas Children’s Hospital Eosinophilic Gastrointestinal Disorders Clinic from January 2012 to January 2016 were enrolled in a prospective, longitudinal cohort study with collection of demographics, clinical symptoms, medical history, allergy sensitization profiles, and response to treatment over time. Comparisons were made between complete responders (peak esophageal eosinophil count \u3c 15 per high-power field [HPF]) and nonresponders (\u3e 25 eosinophils per HPF) after treatment with diet elimination alone, swallowed corticosteroids alone, or diet elimination and swallowed corticosteroids. Sensitization patterns to environmental allergens found in the southeastern United States were analyzed for the effect on treatment response. Results: A total of 223 individuals were enrolled. Of these, 182 had environmental allergy profiling and at least one endoscopy while receiving proton pump inhibitor (PPI) therapy. Twenty-nine individuals had PPI-responsive EoE and were excluded from further analysis, leaving 123 individuals with none-PPI-responsive EoE who were further analyzed; 72 (58.5%) were complete responders and 33 (26.8%) were nonresponders. Seventeen individuals (13.8%) were partial responders (≥ 1 but ≤ 25 eosinophils per HPF) and excluded from further analysis. Nonresponders were more likely to be sensitized to perennial allergens (P = .02). There was no significant difference in response based on seasonal allergen sensitization. Individuals with mold or cockroach sensitization were more likely to fail combination diet and swallowed corticosteroid treatment (P = .02 and P = .002). Conclusion: Perennial allergen and mold sensitization may lead to nonresponse to EoE treatment in some patients. Additional studies are needed to further understand the effect of environmental allergens on EoE

Impact of intensive care unit attending physician training background on outcomes in children undergoing heart operations

Background : The existing training pathways to become a pediatric cardiac intensivist are very variable with physicians coming from varied training backgrounds of pediatric critical care, pediatric cardiology, neonatology, or pediatric anesthesia. Aim : To evaluate the impact of cardiac Intensive Care Unit (ICU) attending physician training background on outcomes in children undergoing heart operations. Setting and Design : Patients in the age group from 1 day to 18 years undergoing heart operation at a Pediatric Health Information System database participating hospital were included (2010–2015). Patients and Methods : Based on the training background of majority of attending physicians in an ICU, the participating ICUs were divided into three groups: critical care medicine (CCM), cardiology, and indeterminate. Statistical Analysis : Multivariable logistic regression models were fitted to evaluate the association of ICU physician training background with study outcomes. Results : A total of 54,935 patients from 42 ICUs were included. Of these, 31,815 patients (58%) were treated in the CCM group (26 ICUs), 19,340 patients (35%) were treated in the cardiology group (12 ICUs), and 3780 patients (7%) were treated in the indeterminate group (4 ICUs). In adjusted models, no specific group based on ICU attending physician training background was associated with lower mortality (CCM vs. cardiology, odds ratio: 0.75, 95% confidence interval: 0.48–1.18), or lower incidence of cardiac arrest, or prolonged hospital length of stay, or prolonged mechanical ventilation. Conclusions : This large observational study did not demonstrate any impact of ICU attending training background on outcomes in children undergoing heart operations

Galcanezumab Provides Consistent Efficacy Throughout the Dosing Interval Among Patients with Episodic and Chronic Migraine : A Post Hoc Analysis

The consistency of the treatment effect of galcanezumab throughout the dosing interval is examined in patients with episodic and chronic migraine. This study was a post hoc analysis of clinical trial data from episodic (EVOLVE-1; EVOLVE-2; both 6-month duration) and chronic (REGAIN; 3-month duration) migraine double-blind trials evaluating the efficacy of a once-monthly injection of galcanezumab 120 mg relative to placebo. Adults with episodic (placebo, n = 894; galcanezumab, n = 444) or chronic migraine (placebo, n = 558; galcanezumab, n = 278) were included. Mean change from baseline in weekly migraine headache days, averaged across all months for each week of the dosing interval, was compared between groups and within the galcanezumab group during weeks 1 and 4. Additional analyses examined the mean difference from placebo in weekly migraine headache days and a day-by-day analysis. Weekly migraine headache day reduction was significantly greater with galcanezumab relative to placebo every week (P < 0.001) and did not differ during weeks 1 and 4 for those with episodic (P = 0.740) or chronic migraine (P = 0.231) taking galcanezumab. Estimated probabilities of migraine on day 2 and day 30 did not differ for those with episodic (P = 0.61) or chronic migraine (P = 0.616) taking galcanezumab. This analysis demonstrates once monthly galcanezumab exhibits consistent efficacy throughout the dosing interval among the population of patients with migraine in three clinical trials evaluating the efficacy of galcanezumab. There is no evidence from these trials that the effect of galcanezumab "wears off" at the end of the dosing interval. ClinicalTrials.gov identifier: EVOLVE-1 (NCT02614183); EVOLVE-2 (NCT02614196); REGAIN (NCT02614261)

Effects of long-term doxycycline on bone quality and strength in diabetic male DBA/2J mice

In type 1 diabetes, diabetic bone disease (DBD) is characterized by decreased bone mineral density, a state of low bone turnover and an increased risk of fracture. Animal models of DBD demonstrate that acquired alterations in trabecular and cortical bone microarchitecture contribute to decreased bone strength in diabetes. With anti-collagenolytic and anti-inflammatory properties, tetracycline derivatives may prevent diabetes-related decreases in bone strength. To determine if doxycycline, a tetracycline class antibiotic, can prevent the development of DBD in a model of long-term diabetes, male DBA/2J mice, with or without diabetes, were treated with doxycycline-containing chow for 10 weeks (dose range, 28–92 mg/kg/day). Long-term doxycycline exposure was not deleterious to the microarchitecture or biomechanical properties of healthy bones in male DBA/2J mice. Doxycycline treatment also did not prevent or alleviate the deleterious changes in trabecular microarchitecture, cortical structure, and biomechanical properties of bone induced by chronic diabetes