Understanding Patient Utilization Patterns of Cochlear Implant Processors.

OBJECTIVE: To evaluate the extent of benefit the second processor provides and to better understand utilization patterns regarding cochlear implant (CI) sound processors. BACKGROUND: Institutional contracts determine the external CI sound processor hardware that a patient is eligible for. Despite the high prevalence of CI worldwide, there is a paucity in the literature regarding patient preferences and how patients utilize provided external hardware. METHODS: A close-ended, multiple-choice survey was mailed to all patients over the age of 18 years who underwent CI between 2016 to 2020 at a tertiary academic medical center. Patients who received their CI hardware prior to 2018 were provided 2 processors, whereas those who received their hardware in 2018 or later were provided 1 processor. RESULTS: A total of 100/263 surveys were returned for a response rate of 38.0%. Of the cohort with 1 processor, 31.3% experienced a period without a functioning processor and access to sound compared to 5.6% of the cohort with 2 processors (P = -.003). Of the cohort with 2 processors, 24.3% noted that they often or always utilize their second processor. When asked how important having a second processor was, 62.9% of the 2-processor group responded that it was very important (P = .001). The most common reason for utilizing the second processor was a damaged primary processor. Patients who received 2 processors had a significantly lower number of postoperative audiology clinic visits for device troubleshooting (P < .001). CONCLUSION: Patients who have 2 CI external processors identify this as being very important to them and experience significantly less time without access to sound due to lack of a functioning processor. As institutional contracts often dictate whether a patient will receive 1 or 2 sound processors with their CI hardware, it is important to understand patient preferences and utilization patterns in order to guide patient-centric policies.

Expanding Understanding of Electrocochleography in Cochlear Implantation: Auditory Neuropathy Spectrum Disorder With Normal Pure Tone Average.

Objective: Describe the preoperative decision-making, intraoperative electrocochleographic (ECoG) findings, and outcome of cochlear implantation (CI) in a patient with auditory neuropathy spectrum disorder (ANSD) and normal pure-tone thresholds. Patients: A 19-year-old with a history of hypoxic ischemic encephalopathy and seizures was referred for hearing rehabilitation in the setting of typical hearing by pure tone audiometry but poor speech understanding. A diagnosis of ANSD was made based on acoustic brainstem response (ABR), distortion product otoacoustic emission, and acoustic reflex testing. Imaging revealed no central cause of hearing impairment. Interventions: Right-sided CI. Main Outcome Measures: Preoperative and postoperative audiometric data. Intraoperative ECoG. Results: Preoperatively the patient underwent comprehensive audiologic testing with behavioral audiometry, ABR testing, and CI candidacy evaluation. In the right ear, the pure tone average (PTA) was 15 dB and word recognition score was 36%. ABR confirmed ANSD. Preoperative CNC and AzBio in quiet were 8% and 0%, respectively. Intraoperative ECoG amplitudes and audiometry showed responses in the 100 uV range and estimated PTA of 42 dB HL. Postoperative testing at 1-month post-initial activation revealed PTA of 45 dB HL and unchanged word and sentence scores. However, the patient cites an improved ability to communicate and increased confidence and averages over 14 hours of device use daily. Conclusions: To our knowledge, this is the first reported case of CI in an ear with normal PTA. Given that nearly all presently available ECoG data comes from patients with greater degrees of hearing loss, this unique case adds to our understanding of hearing preservation in CI.

Professional skills for physiology majors: defining and refining.

Changing labor markets require a workforce that is broadly trained for a variety of possible careers. Recognizing this, government and industry representatives, along with students and their families, are encouraging universities and colleges to focus more on developing transferable skills to maximize employability of their graduates. In response, academic institutions and professional organizations have begun to develop lists of transferable professional skills that they expect students to have acquired on graduation. At the 2018 Physiology Majors Interest Group (P-MIG) meeting, participants stated that there was a need to define a list of professional skills for undergraduates completing a physiology major. To this end, a professional skills committee was established. Initially members of the committee worked together to develop a draft list of skills. An iterative process of refining the list was then undertaken through presentations/small-group discussions at appropriate international meetings and via an online survey. Over 60 physiology educators, the majority of whom teach in undergraduate programs, provided input. The final list (presented here) consists of 13 skills grouped in four broad categories: think critically, communicate effectively, behave in a socially and scientifically responsible manner, and demonstrate laboratory proficiency. It is anticipated that the list will be used for curriculum mapping and to guide the development of new physiology courses and major programs. The professional skills committee now plans to develop rubrics and tools that will allow for the assessment of these skills.

Putting the guidelines to work: moving from undergraduate physiology curricular guidelines to program development and improvement.

The first curricular guidelines for undergraduate physiology programs, currently under development by the Physiology Majors Interest Group (P-MIG), outline learning outcomes applicable for a wide range of physiology and physiology-related programs with diverse student populations. These outcomes for knowledge of core physiological concepts, professional skills, and advising provide a standard for undergraduate physiology education and a benchmark for student learning. Evaluation of how programs meet the curricular guidelines and assessment of the impact of programmatic approaches on student learning are essential for programmatic improvement. The collection and dissemination of evaluation and assessment findings, facilitated by P-MIG, is a critical resource for established undergraduate physiology and physiology-related programs seeking to improve their learning outcomes and new programs developing their curriculum. Strategies for institutional evaluation and assessment are provided to outline possible approaches for programs to use the guidelines to improve or develop their curriculum. P-MIG member expertise and knowledge of curricular implementation provide the foundation for possible collaborations among organizations and institutions to develop a program consultation model, where external consultants provide evaluation and assessment guidance and feedback as an additional resource for physiology educators.

Undergraduate biological sciences and biotechnology students' reflective essays focus on descriptive details of experiential learning experiences.

Experiential learning experiences (ELEs), opportunities for students to apply knowledge and skills critically in a hands-on environment, are fundamental to the apprenticeship model of biological and biotechnological sciences. ELEs enhance student-learning gains, increase career readiness, and provide important networking opportunities. However, students do not often recognize the benefits of ELEs. Reflection is a highly effective tool to articulate learning gains and connect new content with established knowledge. Therefore, senior undergraduate students (n = 23), majoring in biological sciences or biotechnology, wrote required reflective essays about their ELE, in response to an intentionally vague prompt. Qualitative assessment of the reflective essays identified themes present in the reflective essays that typically included descriptions of what students did, with whom they worked, and what they learned during their ELE, but lacked critical analysis or deep reflection about their experience. Differences were also present between different types of ELEs. These results provide a foundation for guiding students to deeper reflection, ultimately resulting in greater benefits from their ELEs. To promote more robust reflection, and, therefore, theoretically enhance learning gains from ELEs, we suggest multiple iterations of reflection, instructor feedback and coaching, and ELE-specific prompts that focus on the placement of ELEs within students' personal and professional trajectory.

Inclusive practices for diverse student populations: Experimental Biology 2017.

As student populations become more diverse, it is essential for educators, administrators, and institutions to implement practices that ensure the success of all students. This is particularly true in the sciences, as students from traditionally underrepresented populations in STEM compose an increasingly greater proportion of the national student demographic. The Teaching Section of the American Physiological Society sponsored a symposium, "Inclusive Practices for Diverse Student Populations," at 2017 Experimental Biology in Chicago, IL, introducing practices that promote inclusion in diverse student populations in STEM. The symposium began with an introduction to quantitative and qualitative assessment strategies of equity and inclusion. The second half of the symposium discussed structural bias and effective inclusive practices.

Implementing inclusive practices in an active learning STEM classroom.

What do you bring to a conversation about diversity, equity, and inclusion? While acknowledging this conversation is important, many science, technology, engineering, and math (STEM) faculty shy away from engaging these topics. STEM educators often hesitate to participate in these discussions due to their self-perceived lack of knowledge or training. However, as institutions welcome ever-diversifying student populations, STEM faculty must consider how their teaching and mentoring approaches affect their students. During the 2018 American Physiological Society (APS) Institute for Teaching and Learning, STEM faculty and administrators engaged in conversations to better understand how their own approaches to diversity, equity, and inclusion affect the success of their students. During my plenary workshop, "Inclusive Practices for Diverse Student Populations," participants investigated their own perspectives and practices. They also discussed approaches to implementing inclusive practices that complement active pedagogical best practices. In an attempt to replicate this workshop environment, I ask you to engage with an interactive set of exercises to investigate your own perspective on the topics of diversity, inclusion, and equity. After you consider your own approaches to these topics, I provide practical examples of inclusive practices that align or enhance active leaning pedagogy. By building confidence, providing support, and promoting various pathways to success, inclusive practices enhance student learning and decrease social disparities in STEM education, ultimately supporting STEM innovation.

Rheumatoid-nodule-like cutaneous granuloma associated with recombinase activating gene 1-deficient severe combined immunodeficiency: A rare case.

Cutaneous granulomas without detectable infectious etiology rarely occur in children and adults with primary immunodeficiency disorders. These cutaneous granulomas are primarily seen in combined variable immunodeficiency, ataxia-telangiectasia, and severe combined immunodeficiency (SCID) and can emulate the reaction patterns seen in sarcoidosis and granuloma annulare. To date, the literature has described only six cases of non-infectious cutaneous granulomas in SCID. We report an unusual case of cutaneous granuloma, mimicking a sarcoma, in a 40-year old male with recombinase activating gene 1-deficient SCID, who presented with a slow-growing globus mass over the lateral aspect of the right elbow. There was heterogeneous enhancement on MRI, which was concerning for neoplasm but no malignancy was found on frozen or permanent sections. GMS, PAS with diastase, and AFB stains, as well as microbiology cultures, were negative. An AE1/AE3 stain was negative and a CD163 stain highlighted histiocytes. No infectious etiology was identified and histopathology revealed palisaded granulomatous dermatitis, most closely resembling a rheumatoid nodule. Although cutaneous manifestations have been reported in nearly half of primary immunodeficiency disorder cases, non-infectious cutaneous granulomas are exceedingly rare in SCID. To our knowledge, this is the first case report of cutaneous palisaded granulomatous dermatitis mimicking a rheumatoid nodule in a major joint.

Global changes in gene expression of Barrett's esophagus compared to normal squamous esophagus and gastric cardia tissues.

BACKGROUND: Barrett's esophagus (BE) is a metaplastic precursor lesion of esophageal adenocarcinoma (EA), the most rapidly increasing cancer in western societies. While the prevalence of BE is increasing, the vast majority of EA occurs in patients with undiagnosed BE. Thus, we sought to identify genes that are altered in BE compared to the normal mucosa of the esophagus, and which may be potential biomarkers for the development or diagnosis of BE. DESIGN: We performed gene expression analysis using HG-U133A Affymetrix chips on fresh frozen tissue samples of Barrett's metaplasia and matched normal mucosa from squamous esophagus (NE) and gastric cardia (NC) in 40 BE patients. RESULTS: Using a cut off of 2-fold and P<1.12E-06 (0.05 with Bonferroni correction), we identified 1324 differentially-expressed genes comparing BE vs NE and 649 differentially-expressed genes comparing BE vs NC. Except for individual genes such as the SOXs and PROM1 that were dysregulated only in BE vs NE, we found a subset of genes (n = 205) whose expression was significantly altered in both BE vs NE and BE vs NC. These genes were overrepresented in different pathways, including TGF-ß and Notch. CONCLUSION: Our findings provide additional data on the global transcriptome in BE tissues compared to matched NE and NC tissues which should promote further understanding of the functions and regulatory mechanisms of genes involved in BE development, as well as insight into novel genes that may be useful as potential biomarkers for the diagnosis of BE in the future.

Effects of intraportal exenatide on hepatic glucose metabolism in the conscious dog.

Incretins improve glucose metabolism through multiple mechanisms. It remains unclear whether direct hepatic effects are an important part of exenatide's (Ex-4) acute action. Therefore, the objective of this study was to determine the effect of intraportal delivery of Ex-4 on hepatic glucose production and uptake. Fasted conscious dogs were studied during a hyperglycemic clamp in which glucose was infused into the hepatic portal vein. At the same time, portal saline (control; n = 8) or exenatide was infused at low (0.3 pmol·kg⁻¹·min⁻¹, Ex-4-low; n = 5) or high (0.9 pmol·kg⁻¹·min⁻¹, Ex-4-high; n = 8) rates. Arterial plasma glucose levels were maintained at 160 mg/dl during the experimental period. This required a greater rate of glucose infusion in the Ex-4-high group (1.5 ± 0.4, 2.0 ± 0.7, and 3.7 ± 0.7 mg·kg⁻¹·min⁻¹ between 30 and 240 min in the control, Ex-4-low, and Ex-4-high groups, respectively). Plasma insulin levels were elevated by Ex-4 (arterial: 4,745 ± 428, 5,710 ± 355, and 7,262 ± 1,053 µU/ml; hepatic sinusoidal: 14,679 ± 1,700, 15,341 ± 2,208, and 20,445 ± 4,020 µU/ml, 240 min, area under the curve), whereas the suppression of glucagon was nearly maximal in all groups. Although glucose utilization was greater during Ex-4 infusion (5.92 ± 0.53, 6.41 ± 0.57, and 8.12 ± 0.54 mg·kg⁻¹·min⁻¹), when indices of hepatic, muscle, and whole body glucose uptake were expressed relative to circulating insulin concentrations, there was no indication of insulin-independent effects of Ex-4. Thus, this study does not support the notion that Ex-4 generates acute changes in hepatic glucose metabolism through direct effects on the liver.

General self-efficacy influences affective task reactions during a work simulation: the temporal effects of changes in workload at different levels of control.

This study investigated the effects of workload, control, and general self-efficacy on affective task reactions (i.e., demands-ability fit, active coping, and anxiety) during a work simulation. The main goals were (1) to determine the extent general self-efficacy moderates the effects of demand and control on affective task reactions and (2) to determine if this varies as a function of changes in workload. Participants (N=141) completed an inbox activity under conditions of low or high control and within low and high workload conditions. The order of trials varied so that workload increased or decreased. Results revealed individuals with high general self-efficacy reported better demands-abilities fit and active coping as well as less anxiety. Three interactive effects were found. First, it was found that high control increased demands-abilities fit from trial 1 to trial 2, but only when workload decreased. Second, it was found that low efficacious individuals active coping increased in trial 2, but only under high control. Third, it was found that high control helped high efficacious individuals manage anxiety when workload decreased. However, for individuals with low general self-efficacy, neither high nor low control alleviated anxiety (i.e., whether workload increased or decreased over time).

Endogenously released GLP-1 is not sufficient to alter postprandial glucose regulation in the dog.

Glucagon-like peptide-1 (GLP-1) is secreted from the L cell of the gut in response to oral nutrient delivery. To determine if endogenously released GLP-1 contributes to the incretin effect and postprandial glucose regulation, conscious dogs (n = 8) underwent an acclimation period (t = -60 to -20 min), followed by a basal sampling period (t = -20 to 0 min) and an experimental period (t = 0-320 min). At the beginning of the experimental period, t = 0 min, a peripheral infusion of either saline or GLP-1 receptor (GLP-1R) antagonist, exendin (9-39) (Ex-9, 500 pmol/kg/min), was started. At t = 30 min, animals consumed a liquid mixed meal, spiked with acetaminophen. All animals were studied twice (± Ex-9) in random fashion, and the experiments were separated by a 1-2-week washout period. Antagonism of the GLP-1R did not have an effect, as indicated by repeated-measures MANOVA analysis of the Δ AUC from t = 45-320 min of arterial plasma glucose, GLP-1, insulin, glucagon, and acetaminophen levels. Therefore, endogenous GLP-1 is not sufficient to alter postprandial glucose regulation in the dog.

Dutogliptin, a dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus.

Dutogliptin (PHX-1149T), being developed by Phenomix Corp, Forest Laboratories Inc and Chiesi Farmaceutici SpA, is a small-molecule dipeptidyl peptidase-4 (DPP-4) inhibitor for the potential oral treatment of type 2 diabetes mellitus (T2DM). DPP-4 quickly degrades the insulin secretory hormones, glucose-dependent insulinotropic peptide and glucagon-like peptide-1; thus inhibiting the degradation of these hormones is a viable treatment option for patients with T2DM. In preclinical studies, dutogliptin potently inhibited DPP-4 and, in a model of T2DM, treatment with dutogliptin improved glucose homeostasis. Pharmacokinetic analyses in animals, healthy individuals and patients with T2DM demonstrated that drug exposure increased in a dose-dependent manner. Results from phase II clinical trials indicated that once-daily dutogliptin, in combination with other oral diabetes therapies, reduces postprandial blood glucose and HbA1c levels, both indicators of successful diabetes management. In phase I and II trials, dutogliptin was safe, well tolerated and associated with extremely low rates of hypoglycemia. At the time of publication, phase III trials were underway and the results of these will be imperative to determine the efficacy of dutogliptin compared with other small molecule DPP-4 inhibitors, such as sitagliptin and vildagliptin.

Effects of insulin on the metabolic control of hepatic gluconeogenesis in vivo.

OBJECTIVE: Insulin represses the expression of gluconeogenic genes at the mRNA level, but the hormone appears to have only weak inhibitory effects in vivo. The aims of this study were 1) to determine the maximal physiologic effect of insulin, 2) to determine the relative importance of its effects on gluconeogenic regulatory sites, and 3) to correlate those changes with alterations at the cellular level. RESEARCH DESIGN AND METHODS: Conscious 60-h fasted canines were studied at three insulin levels (near basal, 4x, or 16x) during a 5-h euglycemic clamp. Pancreatic hormones were controlled using somatostatin with portal insulin and glucagon infusions. Glucose metabolism was assessed using the arteriovenous difference technique, and molecular signals were assessed. RESULTS: Insulin reduced gluconeogenic flux to glucose-6-phosphate (G6P) but only at the near-maximal physiological level (16x basal). The effect was modest compared with its inhibitory effect on net hepatic glycogenolysis, occurred within 30 min, and was associated with a marked decrease in hepatic fat oxidation, increased liver fructose 2,6-bisphosphate level, and reductions in lactate, glycerol, and amino acid extraction. No further diminution in gluconeogenic flux to G6P occurred over the remaining 4.5 h of the study, despite a marked decrease in PEPCK content, suggesting poor control strength for this enzyme in gluconeogenic regulation in canines. CONCLUSIONS: Gluconeogenic flux can be rapidly inhibited by high insulin levels in canines. Initially decreased hepatic lactate extraction is important, and later reduced gluconeogenic precursor availability plays a role. Changes in PEPCK appear to have little or no acute effect on gluconeogenic flux.

Mechanistic basis for differential inhibition of the F1Fo-ATPase by aurovertin.

The mitochondrial F(1)F(o)-ATPase performs the terminal step of oxidative phosphorylation. Small molecules that modulate this enzyme have been invaluable in helping decipher F(1)F(o)-ATPase structure, function, and mechanism. Aurovertin is an antibiotic that binds to the beta subunits in the F(1) domain and inhibits F(1)F(o)-ATPase-catalyzed ATP synthesis in preference to ATP hydrolysis. Despite extensive study and the existence of crystallographic data, the molecular basis of the differential inhibition and kinetic mechanism of inhibition of ATP synthesis by aurovertin has not been resolved. To address these questions, we conducted a series of experiments in both bovine heart mitochondria and E. coli membrane F(1)F(o)-ATPase. Aurovertin is a mixed, noncompetitive inhibitor of both ATP hydrolysis and synthesis with lower K(i) values for synthesis. At low substrate concentrations, inhibition is cooperative suggesting a stoichiometry of two aurovertin per F(1)F(o)-ATPase. Furthermore, aurovertin does not completely inhibit the ATP hydrolytic activity at saturating concentrations. Single-molecule experiments provide evidence that the residual rate of ATP hydrolysis seen in the presence of saturating concentrations of aurovertin results from a decrease in the binding change mechanism by hindering catalytic site interactions. The results from these studies should further the understanding of how the F(1)F(o)-ATPase catalyzes ATP synthesis and hydrolysis.

Current strategies for the inhibition of hepatic glucose production in type 2 diabetes.

Diabetes is a complex disease involving multiple organs with dysregulation in glucose and lipid metabolism. Hepatic insulin insensitivity can contribute to elevated fasting glucose levels and impaired glucose tolerance in individuals with diabetes. Several currently available therapeutics address defects at the liver. Metformin inhibits glucose production, potentially through effects on AMPK. Thiazolidinediones activate PPAR-gamma and improve hepatic insulin sensitivity, primarily through indirect effects on lipid metabolism. Insulin analogs and secretagogues suppress glucose production and increase liver glucose utilization by both direct and indirect hepatic actions. Incretins, incretin mimetics, and dipeptidyl peptidase-4 inhibitors reduce postprandial hepatic glucose production by increasing insulin secretion and limiting glucagon release, as well as through possible direct effects on the liver. Pramlintide reduces the increase in plasma glucagon that occurs following a meal in individuals with diabetes, and may thereby suppress inappropriate stimulation of liver glucose production. Many other hepatic targets are being considered which may lead to alternative strategies for the treatment of diabetes. This review focuses on currently available therapeutics which target insulin resistance in the liver.

Inhibition of dipeptidyl peptidase-4 by vildagliptin during glucagon-like Peptide 1 infusion increases liver glucose uptake in the conscious dog.

OBJECTIVE: This study investigated the acute effects of treatment with vildagliptin on dipeptidyl peptidase-4 (DPP-4) activity, glucagon-like peptide 1 (GLP-1) concentration, pancreatic hormone levels, and glucose metabolism. The primary aims were to determine the effects of DPP-4 inhibition on GLP-1 clearance and on hepatic glucose uptake. RESEARCH DESIGN AND METHODS: Fasted conscious dogs were studied in the presence (n = 6) or absence (control, n = 6) of oral vildagliptin (1 mg/kg). In both groups, GLP-1 was infused into the portal vein (1 pmol . kg(-1) . min(-1)) for 240 min. During the same time, glucose was delivered into the portal vein at 4 mg . kg(-1) . min(-1) and into a peripheral vein at a variable rate to maintain the arterial plasma glucose level at 160 mg/dl. RESULTS: Vildagliptin fully inhibited DPP-4 over the 4-h experimental period. GLP-1 concentrations were increased in the vildagliptin-treated group (50 +/- 3 vs. 85 +/- 7 pmol/l in the portal vein in control and vildagliptin-treated dogs, respectively; P < 0.05) as a result of a 40% decrease in GLP-1 clearance (38 +/- 5 and 22 +/- 2 ml . kg(-1) . min(-1), respectively; P < 0.05). Although hepatic insulin and glucagon levels were not significantly altered, there was a tendency for plasma insulin to be greater (hepatic levels were 73 +/- 10 vs. 88 +/- 15 microU/ml, respectively). During vildagliptin treatment, net hepatic glucose uptake was threefold greater than in the control group. This effect was greater than that predicted by the change in insulin. CONCLUSIONS: Vildagliptin fully inhibited DPP-4 activity, reduced GLP-1 clearance by 40%, and increased hepatic glucose disposal by means beyond the effects of GLP-1 on insulin and glucagon secretion.

Intraportally delivered GLP-1, in the presence of hyperglycemia induced via peripheral glucose infusion, does not change whole body glucose utilization.

After a meal, glucagon-like peptide-1 (GLP-1) and glucose levels are significantly greater in the hepatic portal vein than in the artery. We have previously reported that, in the presence of intraportal glucose delivery, a physiological increase of GLP-1 in the hepatic portal vein increases nonhepatic glucose uptake via a mechanism independent of changes in pancreatic hormone secretion. The aim of the present study was to determine whether intraportal glucose delivery is required to observe this effect. Experiments consisted of a 40-min basal period, followed by a 240-min experimental period, during which conscious 42-h fasted dogs received glucose peripherally to maintain arterial plasma glucose levels at approximately 160 mg/dl. In addition, either saline (n = 6) or GLP-1 (1 pmol.kg(-1).min(-1); GLP-1, n = 6) was administered intraportally during the experimental period. As in the previous study, the presence of GLP-1 did not alter pancreatic hormone levels; however, in the present study, intraportal GLP-1 infusion did not result in an increase in whole body glucose utilization. This is despite the fact that arterial and hepatic portal vein GLP-1 levels were maintained at the same level as the previous study. Therefore, a physiological elevation of GLP-1 in the hepatic portal vein does not increase whole body glucose uptake when hyperglycemia is induced by peripheral glucose infusion. This indicates that a physiological increase in GLP-1 augments glucose utilization only when GLP-1 and glucose gradients conditions mimic the postprandial state.