Cdon is essential for organ left-right patterning by regulating dorsal forerunner cells clustering and Kupffer's vesicle morphogenesis.

Cdon and boc are members of the cell adhesion molecule subfamily III Ig/fibronectin. Although they have been reported to be involved in muscle and neural development at late developmental stage, their early roles in embryonic development remain unknown. Here, we discovered that in zebrafish, cdon, but not boc, is expressed in dorsal forerunner cells (DFCs) and the epithelium of Kupffer's vesicle (KV), suggesting a potential role for cdon in organ left-right (LR) patterning. Further data showed that liver and heart LR patterning were disrupted in cdon morphants and cdon mutants. Mechanistically, we found that loss of cdon function led to defect in DFCs clustering, reduced KV lumen, and defective cilia, resulting in randomized Nodal/spaw signaling and subsequent organ LR patterning defects. Additionally, predominant distribution of a cdon morpholino (MO) in DFCs caused defects in DFC clustering, KV morphogenesis, cilia number/length, Nodal/spaw signaling, and organ LR asymmetry, similar to those observed in cdon morphants and cdon -/- embryos, indicating a cell-autonomous role for cdon in regulating KV formation during LR patterning. In conclusion, our data demonstrate that during gastrulation and early somitogenesis, cdon is essential for proper DFC clustering, KV formation, and normal cilia, thereby playing a critical role in establishing organ LR asymmetry.

Computational biomechanics for a standing human body: Modal analysis and simulation.

We develop computational mechanical modeling and methods for the analysis and simulation of the motions of a human body. This type of work is crucial in many aspects of human life, ranging from comfort in riding, the motion of aged persons, sports performance and injuries, and many ergonomic issues. A prevailing approach for human motion studies is through lumped parameter models containing discrete masses for the parts of the human body with empirically determined spring, mass, damping coefficients. Such models have been effective to some extent; however, a much more faithful modeling method is to model the human body as it is, namely, as a continuum. We present this approach, and for comparison, we choose two digital CAD models of mannequins for a standing human body, one from the versatile software package LS-DYNA and another from open resources with some of our own adaptations. Our basic view in this paper is to regard human motion as a perturbation and vibration from an equilibrium position which is upright standing. A linear elastodynamic model is chosen for modal analysis, but a full nonlinear viscoelastoplastic extension is possible for full-body simulation. The motion and vibration of these two mannequin models is analyzed by modal analysis, where the normal vibration modes are determined. LS-DYNA is used as the supercomputing and simulation platform. Four sets of low-frequency modes are tabulated, discussed, visualized, and compared. Higher frequency modes are also selectively displayed. We have found that these modes of motion and vibration form intrinsic basic modes of biomechanical motion of the human body. This view is supported by our finding of the upright walking motion as a low-frequency mode in modal analysis. Such a "walking mode" shows the in-phase and out-of-phase movements between the legs and arms on the left and right sides of a human body, implying that this walking motion is spontaneous, likely not requiring any directives from the brain. Dynamic motions of CAD mannequins are also simulated by drop tests for comparisons and the validity of the models is discussed through Fourier frequency analysis. All computed modes of motion are collected in several sets of video animations for ease of visualization. Samples of LS-DYNA computer codes are also included for possible use by other researchers.

Administration of Gracilariopsis lemaneiformis polysaccharide attenuates cisplatin-induced inflammation and intestinal mucosal damage in colon-26 carcinoma tumor-bearing mice.

BACKGROUND: Our preliminary research revealed that the polysaccharide GP90 from Gracilariopsis lemaneiformis enhanced the antitumor effect of cisplatin, indicating that GP90 may increase the chemotherapeutic sensitivity. However, it is still necessary to fully understand whether GP90 can also improve the intestinal barrier dysfunction and systemic inflammation induced by cisplatin. RESULTS: GP90 has been demonstrated to inhibit the excessive release of nitirc oxide, interleukin (IL)-6, IL-1ß and tumor necrosis factor (TNF)-α induced by lipopolysaccharide in RAW264.7 cells. In vivo, GP90 effectively ameliorated the decrease in the serum CD4+ /CD8+ T-cell ratio induced by cisplatin and significantly reduced the increase in the inflammatory cytokines, CD4+ Foxp3+ , CD4+ granzyme B+ and CD4+ TNF-α induced by cisplatin. Furthermore, when combined with cisplatin, GP90 increases the protein expression levels of mucin-2 and zonula occludens-1 in the mouse small intestine. Additionally, GP90 combined with cisplatin has a modulatory effect on the intestinal microbiota by elevating the Firmicutes-to-Bacteroidetes ratio and the relative abundance of beneficial microorganisms (Lachnospiraceae bacterium), at the same time as reducing the abundance of cisplatin specific Bacteroides acidifaciens and elevating the content of butyric acid and isobutyric acid. CONCLUSION: Collectively, these findings indicate that GP90 potentially mitigates inflammation and protects the intestinal barrier in tumor-bearing organisms undergoing chemotherapy. © 2024 Society of Chemical Industry.

The Launch of the iCoDE-2 Standard Project: Integration of Connected Diabetes Device Data Into the Electronic Health Record.

INTRODUCTION: Diabetes Technology Society virtually hosted the first meeting of the Integration of Connected Diabetes Device Data Into the Electronic Health Record #2 (iCoDE-2) Standards Project on May 31, 2023, via Zoom. METHODS: Clinicians, patients, data aggregators, informaticists, manufacturers, attorneys, and cybersecurity experts discussed dosing data currently available from insulin delivery devices and data aggregators and the types of information that patients and clinicians want to see. This information along with technical and regulatory aspects of (1) data standards and (2) integration into the electronic health record (EHR) are the basis of iCoDE-2. RESULTS: Six sessions were hosted discussing themes including (1) What's Currently Available: The Continuous Glucose Monitor Experience; (2) What's Currently Available: The Aggregator Experience; (3) What's Currently Available: The Insulin Pump Experience; (4) What's Currently Available: The Insulin Pen Experience; (5) What Do Clinicians and Patients Want Out of iCoDE-2 Data?; and (6) Technical and Regulatory Aspects of Data Aggregation. CONCLUSION: Additional working group meetings to discuss data standard and clinical workflow will be held to create additional technical specifications and clinical workflows to aid in insulin dosing data integration into the EHR. A mid-project meeting will convene in the second half of 2023.

NIH Fifth Artificial Pancreas Workshop 2023: Meeting Report: The Fifth Artificial Pancreas Workshop: Enabling Fully Automation, Access, and Adoption.

The Fifth Artificial Pancreas Workshop: Enabling Fully Automation, Access, and Adoption was held at the National Institutes of Health (NIH) Campus in Bethesda, Maryland on May 1 to 2, 2023. The organizing Committee included representatives of NIH, the US Food and Drug Administration (FDA), Diabetes Technology Society, Juvenile Diabetes Research Foundation (JDRF), and the Leona M. and Harry B. Helmsley Charitable Trust. In previous years, the NIH Division of Diabetes, Endocrinology, and Metabolic Diseases along with other diabetes organizations had organized periodic workshops, and it had been seven years since the NIH hosted the Fourth Artificial Pancreas in July 2016. Since then, significant improvements in insulin delivery have occurred. Several automated insulin delivery (AID) systems are now commercially available. The workshop featured sessions on: (1) Lessons Learned from Recent Advanced Clinical Trials and Real-World Data Analysis, (2) Interoperability, Data Management, Integration of Systems, and Cybersecurity, Challenges and Regulatory Considerations, (3) Adaptation of Systems Through the Lifespan and Special Populations: Are Specific Algorithms Needed, (4) Development of Adaptive Algorithms for Insulin Only and for Multihormonal Systems or Combination with Adjuvant Therapies and Drugs: Clinical Expected Outcomes and Public Health Impact, (5) Novel Artificial Intelligence Strategies to Develop Smarter, More Automated, Personalized Diabetes Management Systems, (6) Novel Sensing Strategies, Hormone Formulations and Delivery to Optimize Close-loop Systems, (7) Special Topic: Clinical and Real-world Viability of IP-IP Systems. "Fully automated closed-loop insulin delivery using the IP route," (8) Round-table Panel: Closed-loop performance: What to Expect and What are the Best Metrics to Assess it, and (9) Round-table Discussion: What is Needed for More Adaptable, Accessible, and Usable Future Generation of Systems? How to Promote Equitable Innovation? This article summarizes the discussions of the Workshop.

Continuous Subcutaneous Infusion Versus Multiple Daily Injections of Insulin for Pregestational Diabetes in Pregnancy: A Systematic Review and Meta-Analysis.

BACKGROUND: The use of continuous subcutaneous insulin infusion (CSII) therapy in pregnancies affected by pregestational diabetes mellitus (DM) has generated mixed outcome data worthy of further investigation. This systematic review and meta-analysis aims to evaluate clinical outcomes associated with CSII versus multiple daily injections (MDIs) in pregnant persons with pregestational DM. METHODS: A predefined, systematic, librarian-assisted search of MEDLINE (PubMed), Embase, Cochrane Library, Scopus, ClinicalTrials.gov, and World Health Organization International Clinical Trial Registry Platform (published from 2010 to 2022) yielded 3003 studies describing pregnancy outcomes associated with CSII and/or MDI for pregestational DM. The primary exposure was mode of insulin administration, with cesarean delivery and neonatal hypoglycemia as the primary maternal and neonatal outcomes, respectively. Secondary outcomes included hypertensive disorders of pregnancy, first and third-trimester glycemic control, large-for-gestational age (LGA) neonate, preterm birth, neonatal intensive care unit admission, need for respiratory support, hyperbilirubinemia, 5-minute Apgar <7, shoulder dystocia, and perinatal mortality. We calculated pooled odds ratios (OR) with 95% confidence intervals (CI) using random-effects models. RESULTS: Among 39 eligible studies, 39% of the 5518 pregnancies included were exposed to CSII. Odds of cesarean delivery were higher with CSII (20 studies: 63% vs 56%, odds ratio [OR] 1.3 [95% confidence interval (CI) 1.2-1.5]), but we did not identify a difference in the odds of neonatal hypoglycemia (23 studies: 31% vs 34%, OR 1.1 [95% CI 0.9-1.5]). Among secondary outcomes, only the odds of LGA (20 studies: 47% vs 38%, OR 1.4 [95% CI 1.2-1.6]) were higher in individuals using CSII versus MDI. CONCLUSIONS: Use of CSII (vs MDI) for pregestational DM in pregnancy is associated with higher odds of cesarean delivery and delivery of an LGA neonate. Further evaluation of how CSII use may influence neonatal size and delivery route is warranted.

Use of Continuous Glucose Monitors in the Hospital: The Diabetes Technology Society Hospital Meeting Report 2023.

The annual Virtual Hospital Diabetes Meeting was hosted by the Diabetes Technology Society on April 14 and 15, 2023, with the goal of reviewing the progress made in the hospital use of continuous glucose monitors (CGMs). Meeting topics included (1) Nursing Issues, Protocols, Order Sets, and Staff Education for Using CGMs, (2) Implementing CGM Programs for Use in the Wards, (3) Quality Metrics and Financial Implications of CGMs in the Hospital, (4) CGMs in the Critical Care Setting, (5) Special Situations: Labor/Delivery and Hemodialysis, (6) Research Session on CGMs in the Hospital, (7) Starting a CGM on Hospitalized Patients, (8) Automated Insulin Delivery Systems in the Hospital, (9) CGMs in Children, (10) Data Integration of CGMs for Inpatient Use and Telemetry, (11) Accuracy of CGMs/Comparison with Point-of-care Blood Glucose Testing, and (12) Discharge Planning with CGMs. Outcome data as well as shared collective real-life experiences were reviewed, and expert recommendations for CGM implementation were formulated.

Lipohypertrophy and Insulin: An Update From the Diabetes Technology Society.

Lipohypertrophy is a common skin complication associated with insulin-treated diabetes. The impact of lipohypertrophy as a contributing factor to suboptimal glycemic control, glucose variability, and hypoglycemia is often under-recognized by health care professionals. In a recent Webinar on April 26, 2023, Diabetes Technology Society asked international experts to provide updates on the latest knowledge related to lipohypertrophy for practicing clinicians and educators, researchers, and industries involved in insulin delivery. A recording of the Webinar is freely available on the Diabetes Technology Society Web site (https://www.diabetestechnology.org/).

A Consensus Statement for Continuous Glucose Monitoring Metrics for Inpatient Clinical Trials.

Diabetes Technology Society organized an expert consensus panel to develop metrics for research in the use of continuous glucose monitors (CGMs) in a hospital setting. The experts met virtually in small groups both before and after an April 13, 2023 virtual meeting of the entire panel. The goal of the panel was to develop consensus definitions in anticipation of greater use of CGMs in hospital settings in the future. Establishment of consensus definitions of inpatient analytical metrics will be easier to compare outcomes between studies. Panelists defined terms related to 10 dimensions of measurements related to the use of CGMs including (1) hospital hypoglycemia, (2) hospital hyperglycemia, (3) hospital time in range, (4) hospital glycemic variability, (5) hospital glycemia risk index, (6) accuracy of CGM devices and reference methods for CGMs in the hospital, (7) meaningful time blocks for hospital glycemic goals, (8) hospital CGM data sufficiency, (9) using CGM data for insulin dosing, and (10) miscellaneous factors. The panelists voted on 51 proposed recommendations. Based on the panel vote, 51 recommendations were classified as either strong (43) or mild (8). Additional research is needed on CGM performance in the hospital. This consensus report is intended to support that type of research intended to improve outcomes for hospitalized people with diabetes.

Diabetes Research and Resource Sharing During the COVID-19 Pandemic: A Systematic Review and Experience from an Academic/Non-Profit Resource Website.

BACKGROUND: The magnitude of the response of the diabetes professional community to the COVID-19 pandemic is not known. We aimed to examine diabetes technology research trends and resources offered by professional organizations during this period. METHODS: We explored patterns of the response from the professional diabetes community to the pandemic by (1) systematically searching for articles related to diabetes, COVID-19, and diabetes technologies; (2) examining publication trends of research protocols (clinicaltrials.gov) and preprints (medRxiv); and (3) reviewing online resources from professional organizations including our website (COVIDinDiabetes.org; an Emory University-Diabetes Technology Society collaboration). RESULTS: We identified 492 articles published between December 2019 and December 2022 meeting our inclusion criteria. Telemedicine and continuous glucose monitoring were the most common reported technologies from most parts of the world. The largest number of preprint articles was published in 2020, with a decline in 2021 and 2022. The number of research protocols related to COVID-19 was the highest in 2020 and declined in 2021 and 2022. Resources from organizations included protocols adapted to treat patients with diabetes and COVID-19, training programs, emergency preparedness, and literature on diabetes and COVID-19. On our website (COVIDinDiabetes.org), there were 12 236 visits and 18 149 pageviews, with 1.6 actions per visits, with most visits coming from North America (N = 7233, 54.2%), South America (N = 2663, 21.8%), and Europe (N = 1219). CONCLUSIONS: We conclude that the COVID-19 pandemic promoted unprecedented global research productivity related to diabetes and COVID-19 and that the transition to the use of technology resources has been evident during this period.

Twenty-first century management of diabetes with shared telemedicine appointments.

This commentary article discusses the benefits of utilizing telemedicine to conduct shared medical appointments for people with type 1 diabetes and type 2 diabetes. We conducted a literature review of articles about shared medical appointments or group medical visits in people with diabetes with associated clinical data. We identified 43 articles. Models of this approach to care have demonstrated positive outcomes in adults and children with type 1 diabetes. Shared telemedicine appointments also have the potential to improve diabetes self-management, reduce the treatment burden, and improve psychosocial outcomes in adults with type 2 diabetes. Ten key recommendations for implementation are presented to guide the development of shared telemedicine appointments for diabetes. These recommendations can improve care for diabetes.

People With Diabetes Using Insulin Flying Across Multiple Time Zones: Limitations and Opportunities for Diabetes Technologies.

Increasingly, people with diabetes (PWD) are using wearable and other devices to support self-management. During air travel, there are 4 stakeholders involved in maximizing the safety of wireless devices for diabetes care used in flight: (1) manufacturers of the devices, (2) airlines, (3) the Transportation Security Administration, and (4) the U.S. Food and Drug Administration. These stakeholders have all developed technologies and policies that assist PWD who prepare for and take appropriate actions during long-haul flights. This article discusses the performance and use of 6 classes of specific wireless diabetes devices during an airplane flight, including the following: (1) blood glucose monitors, (2) continuous glucose monitors, (3) insulin pumps, (4) smart pens for dosing insulin injections, (5) advanced hybrid closed-loop systems, and (6) spinal cord stimulators for painful diabetic neuropathy. Through the policies and safeguards of the 4 stakeholders and the proper self-care measures that insulin-using PWD can take, it is possible to maintain safe glycemic levels on flights across multiple time zones.

The Need for Data Standards and Implementation Policies to Integrate Insulin Delivery Data Into the Electronic Health Record.

Integration of insulin dosing data into the electronic health record (EHR), combined with other patient-generated health care data, would facilitate the use of wirelessly connected insulin delivery systems, including smart insulin pens, insulin pumps, and advanced hybrid closed-loop systems. In 2022, Diabetes Technology Society developed the Integration of Continuous Glucose Monitoring Data into the EHR (iCoDE) Project, which is the first consensus standard for integrating data from a wearable device into the EHR. The iCoDE Standard is a comprehensive guide for any health care delivery organization or hospital for automatically integrating continuous glucose monitoring data into the EHR. Diabetes Technology Society is following iCoDE with the Integration of Connected Diabetes Device Data into the EHR (iCoDE-2) Project, to similarly provide guidance for integrating insulin delivery data into the EHR alongside continuous glucose monitoring data.

Biomarkers for the Diagnosis of Heart Failure in People with Diabetes: A Consensus Report from Diabetes Technology Society.

Diabetes Technology Society assembled a panel of clinician experts in diabetology, cardiology, clinical chemistry, nephrology, and primary care to review the current evidence on biomarker screening of people with diabetes (PWD) for heart failure (HF), who are, by definition, at risk for HF (Stage A HF). This consensus report reviews features of HF in PWD from the perspectives of 1) epidemiology, 2) classification of stages, 3) pathophysiology, 4) biomarkers for diagnosing, 5) biomarker assays, 6) diagnostic accuracy of biomarkers, 7) benefits of biomarker screening, 8) consensus recommendations for biomarker screening, 9) stratification of Stage B HF, 10) echocardiographic screening, 11) management of Stage A and Stage B HF, and 12) future directions. The Diabetes Technology Society panel recommends 1) biomarker screening with one of two circulating natriuretic peptides (B-type natriuretic peptide or N-terminal prohormone of B-type natriuretic peptide), 2) beginning screening five years following diagnosis of type 1 diabetes (T1D) and at the diagnosis of type 2 diabetes (T2D), 3) beginning routine screening no earlier than at age 30 years for T1D (irrespective of age of diagnosis) and at any age for T2D, 4) screening annually, and 5) testing any time of day. The panel also recommends that an abnormal biomarker test defines asymptomatic preclinical HF (Stage B HF). This diagnosis requires follow-up using transthoracic echocardiography for classification into one of four subcategories of Stage B HF, corresponding to risk of progression to symptomatic clinical HF (Stage C HF). These recommendations will allow identification and management of Stage A and Stage B HF in PWD to prevent progression to Stage C HF or advanced HF (Stage D HF).

Lipohypertrophy and Insulin: An Old Dog That Needs New Tricks.

OBJECTIVE: To review the current status of practical knowledge related to insulin-associated lipohypertrophy (LH) - an accumulation of fatty subcutaneous nodules commonly caused by repeated injections and/or infusions of insulin into the same site. METHODS: Review of published literature with additional contributions from leading multidisciplinary experts with the emphasis on clinical aspects including pathophysiology, clinical and economic consequences, diagnosis, prevention and treatment. RESULTS: LH is the most common dermatologic complication of insulin therapy. Risk factors for the development of lipohypertrophy include repeated delivery of large amounts of insulin into the same location over time, repeated injection trauma to the skin and subcutaneous tissue, and multiple injections using the same needle. Subcutaneous insulin injection in skin areas with lipohypertrophy is associated with reduced pain; however, this problem can interfere with insulin absorption, thereby increasing the likelihood of glucose variability, hypo- and hyperglycemia when a site is changed. Modern visualization technology of the subcutaneous space with ultrasound can demonstrate lipohypertrophy early in the course of its development. CONCLUSIONS: The physiological and psychological consequences of developing insulin lipohypertrophy can be prevented and treated with education focusing on insulin injection techniques.

Antidiabetic effects of protein hydrolysates from Trachinotus ovatus and identification and screening of peptides with α-amylase and DPP-IV inhibitory activities.

In the present study, the antidiabetic properties of Trachinotus ovatus protein hydrolysates (TOH) in streptozotocin-induced diabetic mice were investigated, and peptides with α-amylase (AAM) and dipeptidyl peptidase IV (DPP-IV) inhibitory activities were identified and screened. The results showed that TOH alleviated body weight loss, polyphagia, blood glucose elevation and insulin secretion decline in diabetic mice. After 4 weeks of TOH administration, random blood glucose (RBG) decreased significantly. The TOH groups showed a dose-dependent reduction in fasting blood glucose (FBG), especially in the high-dose TOH group, which reduced FBG by 58% versus the effect of metformin. Moreover, TOH exerted a remarkable protective effect on hepatorenal function, as evidenced by increased superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) and decreased serum urea levels. Histopathological studies confirmed that TOH can significantly protect the kidney and pancreas from histological changes, which was of great benefit for ensuring the normal secretion of insulin and preventing the occurrence of complications such as diabetic nephropathy. Two fractions with higher inhibitory activity against AAM and DPP-IV, F4 and F6, were obtained from the ultrafiltration of TOH-2 (≤3 kDa). A total of 19 potentially active peptides from F4 and 3 potentially active peptides from F6 were screened by LC‒MS/MS combined with bioinformatic analysis. These peptides are small molecular peptides composed of 2-6 amino acids, rich in characteristic amino acids such as proline, arginine, phenylalanine and asparagine, and contain high proportions of peptides (68% for F4, 67% for F6) with hydrophobicity ≥50%. They offer potent antidiabetic potential and could potentially bind to the active sites in the internal cavities of the target enzymes AAM and DPP-IV. In summary, this study revealed for the first time the antidiabetic effects of protein hydrolysates of Trachinotus ovatus and their derived peptides, which are promising natural ingredients with the potential to be used for the treatment or prevention of diabetes.

Update on Measuring Ketones.

Ketone bodies are an energy substrate produced by the liver and used during states of low carbohydrate availability, such as fasting or prolonged exercise. High ketone concentrations can be present with insulin insufficiency and are a key finding in diabetic ketoacidosis (DKA). During states of insulin deficiency, lipolysis increases and a flood of circulating free fatty acids is converted in the liver into ketone bodies-mainly beta-hydroxybutyrate and acetoacetate. During DKA, beta-hydroxybutyrate is the predominant ketone in blood. As DKA resolves, beta-hydroxybutyrate is oxidized to acetoacetate, which is the predominant ketone in the urine. Because of this lag, a urine ketone test might be increasing even as DKA is resolving. Point-of-care tests are available for self-testing of blood ketones and urine ketones through measurement of beta-hydroxybutyrate and acetoacetate and are cleared by the US Food and Drug Administration (FDA). Acetone forms through spontaneous decarboxylation of acetoacetate and can be measured in exhaled breath, but currently no device is FDA-cleared for this purpose. Recently, technology has been announced for measuring beta-hydroxybutyrate in interstitial fluid. Measurement of ketones can be helpful to assess compliance with low carbohydrate diets; assessment of acidosis associated with alcohol use, in conjunction with SGLT2 inhibitors and immune checkpoint inhibitor therapy, both of which can increase the risk of DKA; and to identify DKA due to insulin deficiency. This article reviews the challenges and shortcomings of ketone testing in diabetes treatment and summarizes emerging trends in the measurement of ketones in the blood, urine, breath, and interstitial fluid.

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.