Design and rationale for the SIB trial: a randomized parallel comparison of semaglutide versus placebo on intestinal barrier function in type 2 diabetes mellitus.

Objective: To describe the rationale and design of the SIB trial, an interventional clinical trial testing the hypothesis that subcutaneous (s.c.) once-weekly semaglutide can improve intestinal permeability and reduce systemic inflammation in participants with type 2 diabetes (T2D) and obesity. Methods: SIB (NCT04979130) is an investigator-initiated, single-center randomized, double-blinded, placebo-controlled clinical study being conducted at the University of Colorado Anschutz Medical Campus. The primary objective of this novel trial is to test the hypothesis that subcutaneous (s.c.) once-weekly semaglutide could improve intestinal permeability and reduce systemic inflammation in participants with T2D and obesity. Eligible participants had a diagnosis of type 2 diabetes, elevated body mass index, and evidence of systemic inflammation. Participants were randomized 1:1 to s.c. semaglutide or placebo. Participants were assessed for intestinal permeability and markers of inflammation at baseline, mid-study, and at the end of the study. Efficacy assessments were based on the analysis of the following: lactulose:mannitol ratio test, serum lipopolysaccharide-binding protein (LBP), fecal calprotectin, inflammatory biomarkers (IL-6, TNF, IL-1, IL-8, hs-CRP), and HbA1c. All participants who enrolled in the trial provided written informed consent after having received written and oral information on the trial. The risks of semaglutide use were minimized by administration according to FDA-labeled use and close monitoring for adverse events. Discussion: SIB is the first study to examine the effects of GLP-1 receptor agonists on intestinal permeability in humans and will provide important data on their impact on systemic inflammation and intestinal permeability in the setting of T2D and obesity.

Use of High-Resolution Geospatial and Genomic Data to Characterize Recent Tuberculosis Transmission, Botswana.

Combining genomic and geospatial data can be useful for understanding Mycobacterium tuberculosis transmission in high-burden tuberculosis (TB) settings. We performed whole-genome sequencing on M. tuberculosis DNA extracted from sputum cultures from a population-based TB study conducted in Gaborone, Botswana, during 2012-2016. We determined spatial distribution of cases on the basis of shared genotypes among isolates. We considered clusters of isolates with ≤5 single-nucleotide polymorphisms identified by whole-genome sequencing to indicate recent transmission and clusters of ≥10 persons to be outbreaks. We obtained both molecular and geospatial data for 946/1,449 (65%) participants with culture-confirmed TB; 62 persons belonged to 5 outbreaks of 10-19 persons each. We detected geospatial clustering in just 2 of those 5 outbreaks, suggesting heterogeneous spatial patterns. Our findings indicate that targeted interventions applied in smaller geographic areas of high-burden TB identified using integrated genomic and geospatial data might help interrupt TB transmission during outbreaks.

The Impact of COVID-19 on Pharmacy Student Stress During High-Stakes, Performance-Based Assessments in Skills-Based Courses.

Objective. To compare stress levels of pharmacy students in high-stakes, performance-based assessments administered during skills-based laboratory courses in normal classroom environments versus pandemic classroom environments impacted by COVID-19.Methods. In 2019, prior to the start of the COVID-19 pandemic, Doctor of Pharmacy (PharmD) students' stress levels were assessed via a voluntary, paper-based survey before and after performance-based assessments. Students were given a modified version of this survey in 2020 during the pandemic. The 2019 and 2020 survey responses were compared using Wilcoxon rank sum tests.Results. Pharmacy students reported higher perceived stress levels before performance-based assessments (3.8 vs 3.5) and after performance-based assessments (2.8 vs 2.5) prior to the pandemic compared to during the pandemic. Students identified stress as negatively impacting their performance-based assessment performance in both years (3.4 vs 3.1). Students had similar interest in wellness activities in both phases.Conclusion. Colleges of pharmacy should consider implementing stress relief programs around high-stakes assessments as well as prioritizing wellness initiatives within curricula.

Effect of death and dying elective on student empathy and attitudes toward mortality.

INTRODUCTION: Pharmacy graduates should be equipped for one inevitable aspect of health care, mortality, yet only 10% of United States pharmacy curricula courses cover end-of-life (EoL) with limited evidence of effectiveness. This study's objective was to evaluate the impact of an EoL elective on student pharmacists' empathy and attitudes toward mortality and caring for terminally ill persons. METHODS: First- through third-year student pharmacists enrolled in an EoL elective. Students completed pre- and post-course surveys on self-perceptions of empathy and mortality. Surveys included the following: Kiersma-Chen Empathy Scale (KCES), which assesses empathy of pharmacy and nursing students; revised Collett-Lester Fear of Death and Dying Scale (CL-FODS), which measures fear related to death; and Frommelt Attitudes Toward Care of the Dying Scale Form B (FATCOD-B), which measures health care professionals' attitudes toward EoL care. Anonymous identifiers were used to link pre- and post-course surveys and were collected with an online survey software. Data were analyzed using two-sided paired t-tests. RESULTS: Twenty-seven student pharmacists completed the elective. The change in overall mean scores for KCES, CL-FODS, and FATCOD-B correlated with increased empathy, reduced fear of death, and increased positive attitudes toward caring for terminal patients (KCES pre-course = 86.15 vs. post-course = 90.37; CL-FODS pre-course = 93.70 vs. post-course = 75.15; FATCOD-B pre-course = 115.89 vs. post-course = 124.04). CONCLUSIONS: After the EoL elective, student empathy and attitudes toward mortality and caring for terminally ill persons improved. Implementing EoL concepts in pharmacy curricula should be explored to better prepare graduates in patient care.

Should metformin remain the first-line therapy for treatment of type 2 diabetes?

Metformin is a biguanide that is used as first-line treatment of type 2 diabetes mellitus and is effective as monotherapy and in combination with other glucose-lowering medications. It is generally well-tolerated with minimal side effects and is affordable. Although the safety and efficacy of metformin have been well-established, there is discussion regarding whether metformin should continue to be the first choice for therapy as other anti-hyperglycemic medications exhibit additional advantages in certain populations. Despite a long-standing history of metformin use, there are limited cardiovascular outcomes data for metformin. Furthermore, the available studies fail to provide strong evidence due to either small sample size or short duration. Recent data from glucagon-like peptide-1 receptor agonist and sodium-glucose cotransporter-2 inhibitor cardiovascular and renal outcomes trials demonstrated additional protection from diabetes complications for some high-risk patients, which has impacted the guidelines for diabetes management. Post-hoc analyses comparing hazard ratios for participants taking metformin at baseline versus not taking metformin are inconclusive for these two groups. There are no data to suggest that metformin should not be initiated soon after the diagnosis of diabetes. Furthermore, the initiation of newer glycemic-lowering medications with cardiovascular benefits should be considered in high-risk patients regardless of glycemic control or target HbA1c. However, cost remains a major factor in determining appropriate treatment.

Diabetic gastroparesis: An overview of pathogenesis, clinical presentation and novel therapies, with a focus on ghrelin receptor agonists.

Diabetic gastroparesis is defined as delayed gastric emptying without mechanical obstruction in the setting of diabetes. Symptoms range from mild bloating to severe vomiting episodes and can result in frequent hospitalizations and poor quality of life. It is suspected that diabetic gastroparesis is underdiagnosed due to its similar presentation to other conditions such as gastroesophageal reflux disease. The pathogenesis of diabetic gastroparesis remains unclear, but proposed mechanisms include vagal dysfunction, hyperglycemia, interstitial cells of Cajal network disturbances, loss of neural nitric oxide synthase expression in the myenteric plexus, and oxidative stress. Current management for diabetic gastroparesis focuses on dietary and lifestyle changes as well as improved glycemic control. Limited options for medical therapies are available that include prokinetic and antiemetic medications. Metoclopramide is the only FDA-approved medication for the treatment of gastroparesis. Metoclopramide improves symptoms of gastroparesis although extended treatment presents challenges such as decreased efficacy over time and increased risks for adverse events. We summarize the current knowledge of the pathophysiology of diabetic gastroparesis and review current and investigational treatments for diabetes gastroparesis.

Student pharmacist perceptions of learning after strengths-based leadership skills lab and escape room in pharmacy practice skills laboratory.

BACKGROUND AND PURPOSE: Leadership is a required component of doctor of pharmacy programs. There is opportunity for students to receive instructional education on leadership concepts through serious games. EDUCATIONAL ACTIVITY AND SETTING: First-year pharmacy students (n = 146) participated in a required skills-based leadership lab including a team-based escape room activity. FINDINGS: Students reported a statistically significant increase in understanding of leadership concepts and application at the end of the global lab activities (p < 0.01) and a majority of the students found the escape room activity "very useful" (56%). SUMMARY: Escape rooms present a unique opportunity to engage students in active learning and problem solving. A majority of the students found the escape room activity useful and enjoyed the interactive application of leadership concepts. Potential challenges to implementing escape rooms such as time to develop, physical space requirements, supplies, and volunteers to facilitate the experience should be considered prior to implementation. Serious gaming is an emerging pedagogy, and this data supplements existing literature to support use in pharmacy education.

Pharmacist and pharmacy intern perceptions of adolescent vaccination administration.

OBJECTIVES: To characterize pharmacists' and pharmacy interns' perceptions of administering adolescent vaccinations. Secondary objectives were to model the association between 1) perceptions and respondent demographic information and 2) pre- and post-training survey responses. DESIGN: A 12-item survey, on the basis of the Theory of Self-Perception, was used to collect respondents' perceptions of adolescent vaccination administration retrospectively before and after pharmacist and pharmacy intern completion of Online training. The training reviewed Center for Disease Control and Advisory Committee on Immunization Practice recommendations for vaccination schedules, vaccine administration, managing adverse reactions, finding vaccine-related information, the importance of vaccinating, and dispelling common misconceptions. SETTING AND PARTICIPANTS: Pharmacists and pharmacy interns representing 114 Indiana community pharmacy locations within a national supermarket chain were eligible to complete an Online survey between March and April 2019. OUTCOME MEASURES: Descriptive statistics were used to characterize pharmacists' and pharmacy interns' perceptions of adolescent vaccination administration. A multivariable regression analysis was used to determine the association between perceptions and respondent demographic information. Differences in perceptions before and after the training module were evaluated using paired t tests. RESULTS: Of the 293 eligible pharmacists and pharmacy interns, 138 (47.1%) completed the survey and 124 (42.3%) responses were included for analysis. Pharmacists and pharmacy interns had positive perceptions of adolescent vaccination administration. There was a negative relationship between the number of years that a pharmacist had been in practice and their baseline perceptions of adolescent vaccination administration (P = 0.02). There was a statistically significant increase in perceptions following completion of the training module (P < 0.001). CONCLUSION: Pharmacists and pharmacy interns, specifically those who have been in practice for few years, had positive perceptions about adolescent vaccination administration but their perceptions were strengthened with additional training. Further research is needed to determine the relationship between additional training and vaccination rates.

Prevalence of microvascular and macrovascular disease in the Glycemia Reduction Approaches in Diabetes - A Comparative Effectiveness (GRADE) Study cohort.

AIMS: The Glycemia Reduction Approaches in Diabetes - A Comparative Effectiveness (GRADE) trial is a randomized clinical trial comparing glycemic effects of four diabetes medications added to metformin in type 2 diabetes (T2D). Microvascular and macrovascular diseases are secondary outcomes. We evaluated the prevalence and risk factor relationships for microvascular and macrovascular complications in the GRADE cohort at study entry. METHODS: Complication prevalence and risk factors were analyzed based on data from screening in all consenting participants meeting GRADE eligibility. Logistic regression and Z-statistics were used to assess risk factor relationships with complications. RESULTS: We enrolled 5047 T2D participants [mean age 57 years; 36% female; mean known T2D duration 4 years (all < 10 years); mean HbA1c 8.0% (∼64 mmol/mol) at screening]. Urinary albumin/creatinine ratio (ACR) ≥ 30 mg/gram was present in 15.9% participants; peripheral neuropathy (by Michigan Neuropathy Screening Instrument) in 21.5%; cardiovascular autonomic neuropathy by electrocardiography-derived indices in 9.7%; self-reported retinopathy in 1.0%. Myocardial infarction ascertained by self-report or electrocardiogram was present in 7.3%, and self-reported history of stroke in 2.0%. CONCLUSIONS: In the GRADE cohort with < 10 years of T2D and a mean HbA1c of 8.0%, diabetes complications were present in a substantial fraction of participants, more so than might otherwise have been expected.

Euglycemic Diabetic Ketoacidosis With Prolonged Glucosuria Associated With the Sodium-Glucose Cotransporter-2 Canagliflozin.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve glycemic control by a reversible inhibition of the sodium-glucose cotransporters in the renal proximal tubules resulting in increased urinary glucose. This unique mechanism, independent of insulin secretion and beta cell function, has made this class of medication desirable in patients with type 2 diabetes. However in May 2015, the US Food and Drug Administration issued a safety warning pertaining to the development of diabetic ketoacidosis (DKA) with the use of SGLT2 inhibitors. DKA associated with SGLT2 inhibitors frequently develops in the absence of hyperglycemia, which makes the diagnosis more challenging. Due to the reversible inhibition of SGLT2 by this class of medication, a quick recovery of glucosuria after cessation of medication is expected. In this article, we present a case of a 50-year-old woman with type 2 diabetes who developed euglycemic DKA after initiating therapy with canagliflozin. This case of DKA associated with SGLT2 inhibitor use was unique due to her hypoglycemic presentation and persistent glucosuria. SGLT2 inhibitors such as canagliflozin may predispose patients not only to diabetic ketoacidosis but also to prolonged glucosuria.

The social buffering effect of playful handling on responses to repeated intraperitoneal injections in laboratory rats.

Handling small animals for veterinary and experimental procedures can negatively affect animal wellbeing. We hypothesized that playful handling (tickling) would decrease stress associated with repeated injections in adult laboratory rats, especially those with prior tickling experience. We compared responses of 4 groups of male Sprague-Dawley rats to intraperitoneal injection of saline daily for 10 d. Rats either tickled or not tickled as juveniles (2 min/d for 21 d) were exposed as adults to either a passive hand or tickling for 2 min immediately before and after injections. Rates of vocalization (22- and 50-kHz ultrasonic vocalizations (USV), indicative of negative and positive affective states, respectively, and audible calls indicative of pain and discomfort) were quantified before, during, and after injection. Tickling before and after injection, especially when combined with juvenile tickling experience (ending 40 to 50 d earlier), increased 50-kHz USV rates before and after injection, reduced audible call rate during injection, and decreased the duration of the injection procedure. The treatments did not affect indicators of physiologic stress (body weight change; fecal corticosteroid levels). We conclude that playful handling performed in association with a mildly aversive procedure serves as a useful refinement by inducing a positive affective state that mitigates the aversiveness of the procedure and makes rats easier to handle, especially when they have been accustomed to tickling as juveniles.

General and persistent effects of high-intensity sweeteners on body weight gain and caloric compensation in rats.

In an earlier work (S. E. Swithers & T. L. Davidson, 2008), rats provided with a fixed amount of a yogurt diet mixed with saccharin gained more weight and showed impaired caloric compensation relative to rats given the same amount of yogurt mixed with glucose. The present 4 experiments examined the generality of these findings and demonstrated that increased body weight gain was also demonstrated when animals consumed a yogurt diet sweetened with an alternative high-intensity sweetener (acesulfame potassium; AceK) as well as in animals given a saccharin-sweetened base diet (refried beans) that was calorically similar but nutritionally distinct from low-fat yogurt. These studies also extended earlier findings by showing that body weight differences persist after saccharin-sweetened diets are discontinued and following a shift to a diet sweetened with glucose. In addition, rats first exposed to a diet sweetened with glucose still gain additional weight when subsequently exposed to a saccharin-sweetened diet. The results of these experiments add support to the hypothesis that exposure to weak or nonpredictive relationships between sweet tastes and caloric consequences may lead to positive energy balance.