A narrative commentary about interoperability in medical devices and data used in diabetes therapy from an academic EU/UK/US perspective.

People living with diabetes have many medical devices available to assist with disease management. A critical aspect that must be considered is how systems for continuous glucose monitoring and insulin pumps communicate with each other and how the data generated by these devices can be downloaded, integrated, presented and used. Not only is interoperability associated with practical challenges, but also devices must adhere to all aspects of regulatory and legal frameworks. Key issues around interoperability in terms of data ownership, privacy and the limitations of interoperability include where the responsibility/liability for device and data interoperability lies and the need for standard data-sharing protocols to allow the seamless integration of data from different sources. There is a need for standardised protocols for the open and transparent handling of data and secure integration of data into electronic health records. Here, we discuss the current status of interoperability in medical devices and data used in diabetes therapy, as well as regulatory and legal issues surrounding both device and data interoperability, focusing on Europe (including the UK) and the USA. We also discuss a potential future landscape in which a clear and transparent framework for interoperability and data handling also fulfils the needs of people living with diabetes and healthcare professionals.

Biomarkers of aging for the identification and evaluation of longevity interventions.

With the rapid expansion of aging biology research, the identification and evaluation of longevity interventions in humans have become key goals of this field. Biomarkers of aging are critically important tools in achieving these objectives over realistic time frames. However, the current lack of standards and consensus on the properties of a reliable aging biomarker hinders their further development and validation for clinical applications. Here, we advance a framework for the terminology and characterization of biomarkers of aging, including classification and potential clinical use cases. We discuss validation steps and highlight ongoing challenges as potential areas in need of future research. This framework sets the stage for the development of valid biomarkers of aging and their ultimate utilization in clinical trials and practice.

Exercise-Induced Vision Dysfunction Early After Sport-Related Concussion Is Associated With Persistent Postconcussive Symptoms.

OBJECTIVE: The purpose of this study was to determine if exercise-induced vision dysfunction [reduced performance and/or symptom exacerbation on a post-exercise King-Devick (KD) test] in adolescents early after sport-related concussion was associated with increased risk of persistent post-concussive symptoms (PPCS, recovery >28 days). We used exercise as a provocative maneuver before the KD test, hypothesizing that concussed adolescents with exercise-induced vision dysfunction would be more likely to develop PPCS. DESIGN: Secondary analysis of data from a multi-center, randomized clinical trial comparing KD test performance before and after the Buffalo Concussion Treadmill Test in adolescents within 10 days of sport-related concussion who were randomized to aerobic exercise or placebo stretching program. SETTING: Three university-associated sports medicine clinical programs. PARTICIPANTS: Ninety-nine adolescents with sport-related concussion (exercise group: n = 50, 15.3 ± 1 years, 60% M, 22% with PPCS; stretching group: n = 49, 15.9 ± 1 years, 65% M, 35% with PPCS) tested a mean of 6 ± 2 days from injury. INDEPENDENT VARIABLE: King-Devick test performed immediately before and 2 minutes after Buffalo Concussion Treadmill Test. MAIN OUTCOME MEASURE: Persistent post-concussive symptoms. RESULTS: Adolescents who demonstrated exercise-induced vision dysfunction upon initial evaluation developed PPCS at a significantly greater rate when compared with adolescents who did not (71% vs 34%, P < 0.001). Exercise-induced vision dysfunction corresponded to a relative risk of 3.13 for PPCS. CONCLUSIONS: Adolescents with exercise-induced vision dysfunction had a 3-fold greater relative risk of developing PPCS than those without exercise-induced vision dysfunction.

Diabetes Technology Meeting 2022.

Diabetes Technology Society hosted its annual Diabetes Technology Meeting from November 3 to November 5, 2022. Meeting topics included (1) the measurement of glucose, insulin, and ketones; (2) virtual diabetes care; (3) metrics for managing diabetes and predicting outcomes; (4) integration of continuous glucose monitor data into the electronic health record; (5) regulation of diabetes technology; (6) digital health to nudge behavior; (7) estimating carbohydrates; (8) fully automated insulin delivery systems; (9) hypoglycemia; (10) novel insulins; (11) insulin delivery; (12) on-body sensors; (13) continuous glucose monitoring; (14) diabetic foot ulcers; (15) the environmental impact of diabetes technology; and (16) spinal cord stimulation for painful diabetic neuropathy. A live demonstration of a device that can allow for the recycling of used insulin pens was also presented.

Oral insulin (ORMD-0801) in type 2 diabetes mellitus: A dose-finding 12-week randomized placebo-controlled study.

AIMS: To assess the safety and efficacy of multiple daily doses of oral insulin (ORMD-0801) in subjects with type 2 diabetes (T2DM) over 12 weeks. MATERIALS AND METHODS: Participants with T2DM on metformin or combination oral therapy with glycated haemoglobin (HbA1c) levels ≥ 7.5% (58 mmol/mol) were randomized to receive ORMD-0801 8 mg or 16 mg once (QD) or twice (BID) daily, or 32 mg QD, BID or three times daily (TID) over a 12-week period. RESULTS: A total of 373 subjects were randomized to active treatment or placebo (~60% male, age ~ 56 years, HbA1c 9%-9.8%; 75-84 mmol/mol). Placebo-adjusted HbA1c changes from baseline to Week 12 were observed with ORMD-0801 8 mg BID (-7.15 ± 3.57 mmol/mol [-0.65% ± 0.33%]; P = 0.046). However, a significant site interaction was observed in two sites. After excluding these, HbA1c reduction was observed with 8 mg QD (-0.81 ± 0.37%; -8.89 ± 4.01 mmol/mol; P = 0.028, n = 15), 8 mg BID (-0.82 ± 0.37%; -8.95 ± 4.08 mmol/mol; P = 0.029, n = 17), 32 mg QD (-0.54 ± 0.26%; -5.89 ± 2.78 mmol/mol;P = 0.036, n = 69) and 32 mg BID (-0.53 ± 0.26%; -5.80 ± 2.83 mmol/mol; P = 0.042, n = 68). No effect was observed with 16 mg QD (0.25 ± 0.37%; 2.76 ± 3.99 mmol/mol; P = 0.48, n = 18), 16 mg BID (-0.36 ± 0.40%; -3.97 ± P = 0.36, n = 15) or 32 mg TID (-0.45 ± 0.27%, -4.89 ± 2.90 mmol/mol; P = 0.093, n = 69). Continuous glucose monitor and serum glucose measurements showed similar trends but were not significant. ORMD-0801 was safe, well tolerated and not associated with weight gain or hypoglycaemia. CONCLUSIONS: Oral insulin (ORMD-0801) induced greater reductions in HbA1c when compared to placebo, and was safe and well tolerated in individuals with uncontrolled T2DM. The efficacy and safety findings support continued development of the 8-mg dose at bedtime, which is currently being evaluated in two Phase 3 trials.

Efficacy and safety of Tregopil, a novel, ultra-rapid acting oral prandial insulin analog, as part of a basal-bolus regimen in type 2 diabetes: a randomized, active-controlled phase 2/3 study.

BACKGROUND: Efficacy and safety of ultra-rapid acting oral prandial insulin Tregopil was compared with insulin aspart (IAsp) in patients with type 2 diabetes (T2D) on insulin glargine and metformin. RESEARCH DESIGN AND METHODS: In this open-label, active-controlled trial, patients with T2D, HbA1c ≥7%-≤9% and 2-h postprandial glucose (PPG) ≥180 mg/dL were randomized 1:1:1 to Tregopil (30 mg, n = 30; 45 mg, n = 31) and IAsp, n = 30. Primary outcome was change from baseline (CFB) in HbA1c at week 24. Secondary outcomes included PPG excursion (PPGE) and PPG assessed from standardized test meal (STM) and 9-point self-monitored blood glucose. RESULTS: The observed mean HbA1c did not improve at week 24 in Tregopil groups (30 mg [0.15%], 45 mg [0.22%] vs. a reduction in IAsp group [-0.77%]). Combined Tregopil group showed better 1-h PPGE control versus IAsp following STM (CFB, estimated treatment difference, 95% CI, -45.33 mg/dL [-71.91, -18.75], p = 0.001) and 1-h PPG trended toward better control. Tregopil showed lower PPGE at 15 min versus IAsp. Clinically significant hypoglycemia was lower with Tregopil versus. IAsp (rate ratio: 0.69). CONCLUSIONS: Tregopil demonstrated an ultrafast, short-duration prandial profile with good safety. While Tregopil's early postprandial effects were comparable to IAsp, its late postprandial effects were inferior. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT03430856).

PATAS, a First-in-Class Therapeutic Peptide Biologic, Improves Whole-Body Insulin Resistance and Associated Comorbidities In Vivo.

Adipose tissue is a key regulator of whole-body metabolic fitness because of its role in controlling insulin sensitivity. Obesity is associated with hypertrophic adipocytes with impaired glucose absorption, a phenomenon existing in the ultrarare monogenic disorder Alström syndrome consisting of severe insulin resistance. Inactivation of ALMS1 directly inhibits insulin-mediated glucose absorption in the white adipose tissue and induces severe insulin resistance, which leads to type 2 diabetes, accelerated nonalcoholic liver disease, and fibrosis. These phenotypes were reversed by specific adipocyte-ALMS1 reactivation in vivo. Subsequently, ALMS1 was found to bind to protein kinase C-α (PKCα) in the adipocyte, and upon insulin signaling, PKCα is released from ALMS1. α-Helices in the kinase domain of PKCα were therefore screened to identify a peptide sequence that interfered with the ALMS1-PKCα protein interaction. When incubated with cultured human adipocytes, the stapled peptide termed PATAS, for Peptide derived of PKC Alpha Targeting AlmS, triggered insulin-independent glucose absorption, de novo lipogenesis, and cellular glucose utilization. In vivo, PATAS reduced whole-body insulin resistance, and improved glucose intolerance, fasting glucose, liver steatosis, and fibrosis in rodents. Thus, PATAS represents a novel first-in-class peptide that targets the adipocyte to ameliorate insulin resistance and its associated comorbidities.

Experiences of augmented arm rehabilitation including supported self-management after stroke: a qualitative investigation.

OBJECTIVE: To explore the experiences of stroke survivors and their carers of augmented arm rehabilitation including supported self-management in terms of its acceptability, appropriateness and relevance. DESIGN: A qualitative design, nested within a larger, multi-centre randomized controlled feasibility trial that compared augmented arm rehabilitation starting at three or nine weeks after stroke, with usual care. Semi-structured interviews were conducted with participants in both augmented arm rehabilitation groups. Normalization Process Theory was used to inform the topic guide and map the findings. Framework analysis was applied. SETTING: Interviews were conducted in stroke survivors' homes, at Glasgow Caledonian University and in hospital. PARTICIPANTS: 17 stroke survivors and five carers were interviewed after completion of augmented arm rehabilitation. INTERVENTION: Evidence-based augmented arm rehabilitation (27 additional hours over six weeks), including therapist-led sessions and supported self-management. RESULTS: Three main themes were identified: (1) acceptability of the intervention (2) supported self-management and (3) coping with the intervention. All stroke survivors coped well with the intensity of the augmented arm rehabilitation programme. The majority of stroke survivors engaged in supported self-management and implemented activities into their daily routine. However, the findings suggest that some stroke survivors (male >70 years) had difficulties with self-management, needing a higher level of support. CONCLUSION: Augmented arm rehabilitation commencing within nine weeks post stroke was reported to be well tolerated. The findings suggested that supported self-management seemed acceptable and appropriate to those who saw the relevance of the rehabilitation activities for their daily lives, and embedded them into their daily routines.

The Need for Precision Medicine to be Applied to Diabetes.

Precision medicine refers to the tailoring of medical treatment for an individual based on large amounts of biologic and extrinsic data. The fast advancing fields of molecular biology, gene sequencing, machine learning, and other technologies enable precision medicine to utilize this detailed information to enhance clinical management decision-making for an individual in the real time of the disease course. Traditional clinical decision making is based on reacting to a relatively limited number of phenotypes that are determined by history, physical examination, and conventional lab tests. Precision medicine depends on highly detailed profiling of the patient's genetic, morphologic, and metabolic makeup. The precision medicine approach can be applied to individuals with diabetes to select treatments most likely to offer benefit and least likely to cause side effects, offering prospects of improved clinical outcomes and economic costs savings over current empiric practices. As genetic, metabolomic, immunologic, and other sophisticated testing becomes less expensive and more widespread in the medical record, it is expected that precision medicine will become increasingly applied to diabetes care.

Pharmacokinetics and Pharmacodynamics of Insulin Tregopil in Relation to Premeal Dosing Time, Between Meal Interval, and Meal Composition in Patients With Type 2 Diabetes Mellitus.

We evaluated the pharmacokinetics and pharmacodynamics of oral insulin tregopil in relation to premeal dosing time, between-meal interval, and meal composition type in type 2 diabetes mellitus patients in a randomized, placebo-controlled, crossover study consisting of 3 sequential cohorts. In Cohort 1, insulin tregopil administered 10 to 20 minutes before a meal resulted in optimal postmeal exposure and demonstrated better postprandial glucose-lowering effect (glucose area under concentration-time curve [AUC]) compared to the 30-minute group. In Cohort 2, insulin tregopil pharmacokinetic exposure (plasma AUC) showed a progressive increase through 4, 5, and 6 hours of between-meal interval. The 6-hour between-meal interval resulted in better absorption of insulin tregopil in comparison to 4- and 5-hour intervals. However, no significant differences were observed in pharmacodynamic parameters except for higher glucose AUC0-180min in the insulin tregopil 4-hour group during the afternoon meal as compared to the morning meal. In Cohort 3, a high-fiber meal had the least impact on insulin tregopil absorption and resulted in the highest reduction in plasma glucose levels in the afternoon. A high-fat meal reduced insulin tregopil absorption in the afternoon meal; however, pharmacodynamic response was not diminished significantly. Insulin tregopil has a rapid onset of action of approximately 10 minutes and, when administered 10 to 20 minutes before a meal, demonstrated up to 13% to 18% reduction in blood glucose levels compared to baseline. A 5-hour between-meal interval minimizes the impact of a meal on absorption of subsequent (afternoon) insulin tregopil dose, and the pharmacodynamic response of insulin tregopil is not altered by meal composition. Insulin tregopil was well tolerated in patients with type 2 diabetes mellitus.

Culinary Medicine: Advancing a Framework for Healthier Eating to Improve Chronic Disease Management and Prevention.

Unsustainable increases in the prevalence and costs of chronic disease in the United States call for low-cost, high-impact interventions that can be readily incorporated into people's daily lives. Culinary medicine is one such intervention. As a practical discipline, culinary medicine integrates the art of preparing, cooking, and presenting food with the science of medicine to achieve desired health outcomes. This article describes how the underpinnings and components of culinary medicine enhance existing nutrition interventions. Evidence of improved well-being and reduced resource utilization as the result of culinary medicine interventions is compiled for easy reference by health care organizations, medical professionals, people living with or at risk for chronic disease, food industry specialists, and payers in both the public and private sectors. Suggestions for individual and organizational implementation of culinary medicine strategies are offered with a proposed lexicon for continued development of the field.

Real-World Evidence Should Be Used in Regulatory Decisions About New Pharmaceutical and Medical Device Products for Diabetes.

Randomized clinical trials (RCTs) are no longer the sole source of data to inform guidelines, regulatory, and policy decisions. Real-world data (RWD), collected from registries, electronic health records, insurance claims, pharmacy records, social media, and sensor outputs from devices form real-world evidence (RWE), which can supplement evidence from RCTs. Benefits of using RWE include less time and cost to produce meaningful data; the ability to capture additional information, including social determinants of health that can impact health outcomes; detection of uncommon adverse events; and the potential to apply machine learning and artificial intelligence to the delivery of health care. Overall, combining data from RCTs and RWE would allow regulators to make ongoing and more evidence-based decisions in approving and monitoring products for diabetes.

Impact of Insulin Tregopil and Its Permeation Enhancer on Pharmacokinetics of Metformin in Healthy Volunteers: Randomized, Open-Label, Placebo-Controlled, Crossover Study.

Oral insulin tregopil (IN-105; a new drug under development) may be coadministered with oral antidiabetic drugs, such as metformin in patients with type 2 diabetes mellitus for optimal glycemic control. IN-105 has sodium caprate excipient, a permeation enhancer, for enhancing absorption in the stomach and increasing bioavailability via an oral route. Sodium caprate may increase bioavailability of metformin by a similar mechanism. Therefore, it was necessary to study the effect of IN-105 on pharmacokinetics (PKs) of metformin. In this randomized, open-label, cross-over study, metformin was administered to healthy volunteers receiving IN-105/placebo under fed/fasting conditions. The 90% confidence interval (CI) of the geometric mean ratio of the area under the curve from time zero to infinity (AUC0-inf ; fasting and fed) and peak plasma concentration (Cmax ; fed) of metformin were within 0.80-1.25 acceptance range. Under fasting conditions, the upper bound margin of Cmax was just beyond this range (i.e., 1.27) and was concluded as functionally not relevant. There was no clinically significant effect of sodium caprate/IN-105 on PKs of metformin under fasting/fed conditions, and it was safe.

Incorporating Site-less Clinical Trials Into Drug Development: A Framework for Action.

PURPOSE: Options for leveraging available telemedicine technologies, ranging from simple webcams and telephones to smartphone apps and medical-grade wearable sensors, are evolving faster than the culture of clinical research. Until recently, most clinical trials relied on paper-based processes and technology. This cost- and labor-intensive system, while slowly changing, remains an obstacle to new drug development. Alternatives that use existing tools and processes for collecting real-world data in home settings warrant closer examination. METHODS: The site-less clinical research organization (CRO) model, whereby pharmacists or other health care professionals provide useful and timely counseling for protocol compliance by regular phone and videoconferencing sessions, is a flexible approach to managing clinical trial participants directly from their homes. An expert panel, including clinical specialists in metabolic or neurodegenerative diseases, health information technology and CRO innovators, and the pharmaceutical industry, met in Dallas, Texas, December 2016, to discuss advancing avenues for site-less CRO and other remote clinical trial practices, taking into account investigator, sponsor, and regulatory perspectives. FINDINGS: Real-time "site-less" management of clinical trials can augment traditional research and development methods by providing data from a broader, more diverse group of patients in real-world practice settings. This methodology also helps to proactively identify safety profile and operational issues. Current use of site-less CRO practices constitutes an important bridge to alternative trial models, including "large simple trials" that strive to answer one or two questions using data derived from representative patient populations treated in typical clinical settings. IMPLICATIONS: Site-less CROs offer a working example of how remote technologies and in-home monitoring methods can address shortcomings of conventional drug development. This model maximizes time and cost, as well as potentially earlier identification of adverse events. Coordinated communication among investigators, sponsors, regulators, and patients will be needed to develop standardized strategies for incorporating site-less CROs into current and future study design.

Prompting healthier eating: testing the use of health and social norm based messages.

OBJECTIVE: Health based messages are commonly used to promote fruit and vegetable intake, but are limited in their effectiveness. Social norm messages, which suggest other people are eating healthily, may be more effective. Our aim was to compare the effect on food selection of a message containing health related information about fruit and vegetable consumption with a message containing social normative information about consumption of fruit and vegetables. METHOD: In two laboratory studies, predominantly young female adult students were exposed to a health or social norm message about fruit and vegetables. In Study 1, lunch meal food selections and intake were assessed and in Study 2, snack food selections and intake were assessed. Study 1 examined the effect of a descriptive social norm (information about what others are eating) versus a health message and Study 2 examined the effect of both a descriptive norm and an injunctive norm message (information about what others approve of) versus a health message. RESULTS: In Study 1, exposure to a descriptive social norm message resulted in significantly more vegetables being selected and eaten than exposure to a health message. In Study 2, exposure to a descriptive social norm message resulted in significantly more fruit and vegetables and less high energy dense snack food being selected and eaten than exposure to a health message. There was no effect of exposure to the injunctive norm message. In both studies, significant differences between the social norm and health message conditions were observed in low but not high usual consumers of fruit and vegetables. CONCLUSIONS: For the promotion of healthy eating, social norm messages may be more effective than health messages for consumers failing to adhere to dietary guidelines.

Obesity-induced tissue free radical generation: an in vivo immuno-spin trapping study.

Assessment of tissue free radical production is routinely accomplished by measuring secondary by-products of redox reactions and/or diminution of key antioxidants such as reduced thiols. However, immuno-spin trapping, a newly developed immunohistochemical technique for detection of free radical formation, is garnering considerable interest as it allows for the visualization of 5,5-dimethyl-1-pyrroline N-oxide (DMPO)-adducted molecules. Yet, to date, immuno-spin trapping reports have utilized in vivo models in which successful detection of free radical adducts required exposure to lethal levels of oxidative stress not reflective of chronic inflammatory disease. To study the extents and anatomic locations of more clinically relevant levels of radical formation, we examined tissues from high-fat (HF) diet-fed mice, a model of low-grade chronic inflammation known to demonstrate enhanced rates of reactive species production. Mice subjected to 20 weeks of HF diet displayed increased free radical formation (anti-DMPO mean fluorescence staining) in skeletal muscle (0.863±0.06 units vs 0.512±0.07 units), kidney (0.076±0.0036 vs 0.043±0.0025), and liver (0.275±0.012 vs 0.135±0.014) compared to control mice fed normal laboratory chow (NC). Western blot analysis of tissue homogenates confirmed these results showing enhanced DMPO immunoreactivity in HF mice compared to NC samples. The obesity-related results were confirmed in a rat model of pulmonary hypertension and right heart failure in which intense immunodetectable radical formation was observed in the lung and right ventricle of monocrotaline-treated rats compared to saline-treated controls. Combined, these data affirm the utility of immuno-spin trapping as a tool for in vivo assessment of altered extents of macromolecule oxidation to radical intermediates under chronic inflammatory conditions.