Exenatide extended release in patients with type 1 diabetes with and without residual insulin production

AimsTo test whether a long- acting GLP- 1 receptor agonist would improve glucose control in patients with type 1 diabetes (T1D) and to determine whether the presence of residual beta cell function would affect the response. In addition, we sought to determine whether the drug would affect beta cell function.MethodsWe performed a randomized placebo- controlled trial of exenatide extended release (ER) in participants with T1D with and without detectable levels of C- peptide. Seventy- nine participants were randomized to exenatide ER 2 mcg weekly, or placebo, stratified by the presence or absence of detectable C- peptide levels. The primary outcome was the difference in glycated haemoglobin (HbA1c) levels at 24- weeks. Participants were followed for another 6 months off study drug.ResultsAt week 24, the time of the primary outcome, the least squares (LS) mean HbA1c level was 7.76% (95% confidence interval [CI] 7.42, 8.10) in the exenatide ER group versus 8.0% (95% CI 7.64, 8.35) in the placebo group (P = 0.08). At week 12 the LS mean HbA1c levels were 7.71% (95% CI 7.37, 8.05) in the exenatide ER group versus 8.05% (95% CI 7.7, 8.4) in the placebo group (P = 0.01). The improvement at week 12 was driven mainly by those with detectable levels of C- peptide. Those treated with exenatide ER lost weight at 12 and 24- weeks compared to those treated with placebo (P- <0.001 and P = 0.007). The total insulin dose was lower, but not when corrected for body weight, and was not affected by residual insulin production. Adverse events were more frequent with exenatide ER, but hypoglycaemia was not increased.ConclusionTreatment with exenatide ER may have short- term benefits in some individuals with T1D who are overweight or who have detectable levels of C- peptide, but short- term improvements were not sustained.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163873/1/dom14121_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163873/2/dom14121.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163873/3/dom14121-sup-0001-Supinfo.pd

Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: A double-blind, phase 1/2a, randomized controlled trial

Acute respiratory distress syndrome (ARDS) in COVID-19 is associated with high mortality. Mesenchymal stem cells are known to exert immunomodulatory and anti-inflammatory effects and could yield beneficial effects in COVID-19 ARDS. The objective of this study was to determine safety and explore efficacy of umbilical cord mesenchymal stem cell (UC-MSC) infusions in subjects with COVID-19 ARDS. A double-blind, phase 1/2a, randomized, controlled trial was performed. Randomization and stratification by ARDS severity was used to foster balance among groups. All subjects were analyzed under intention to treat design. Twenty-four subjects were randomized 1:1 to either UC-MSC treatment (n = 12) or the control group (n = 12). Subjects in the UC-MSC treatment group received two intravenous infusions (at day 0 and 3) of 100 ± 20 × 106 UC-MSCs; controls received two infusions of vehicle solution. Both groups received best standard of care. Primary endpoint was safety (adverse events [AEs]) within 6 hours; cardiac arrest or death within 24 hours postinfusion). Secondary endpoints included patient survival at 31 days after the first infusion and time to recovery. No difference was observed between groups in infusion-associated AEs. No serious adverse events (SAEs) were observed related to UC-MSC infusions. UC-MSC infusions in COVID-19 ARDS were found to be safe. Inflammatory cytokines were significantly decreased in UC-MSC-treated subjects at day 6. Treatment was associated with significantly improved patient survival (91% vs 42%, P =.015), SAE-free survival (P =.008), and time to recovery (P =.03). UC-MSC infusions are safe and could be beneficial in treating subjects with COVID-19 ARDS

The Demise of Islet Allotransplantation in the US: A Call for an Urgent Regulatory Update The ISLETS FOR US Collaborative

Islet allotransplantation in the United States (US) is facing an imminent demise. Despite nearly three decades of progress in the field, an archaic regulatory framework has stymied US clinical practice. Current regulations do not reflect the state-of-the-art in clinical or technical practices. In the US, islets are considered biologic drugs and more than minimally manipulated human cell and tissue products (HCT/Ps). Across the world, human islets are appropriately defined as minimally manipulated tissue which has led to islet transplantation becoming a standard-of-care procedure for patients with type 1 diabetes mellitus and problematic hypoglycemia. As a result of the outdated US regulations, only eleven patients underwent allo-ITx in the US between 2011-2016 and all in the setting of a clinical trial. Herein, we describe the current regulations pertaining to islet transplantation in the United States. We explore the progress which has been made in the field and demonstrate why the regulatory framework must be updated to both, better reflect our current clinical practice and to deal with upcoming challenges. We propose specific updates to current regulations which are required for the renaissance of ethical, safe, effective, and affordable allo-ITx in the United States

The demise of islet allotransplantation in the United States: A call for an urgent regulatory update

Islet allotransplantation in the United States (US) is facing an imminent demise. Despite nearly three decades of progress in the field, an archaic regulatory framework has stymied US clinical practice. Current regulations do not reflect the state-of-the-art in clinical or technical practices. In the US, islets are considered biologic drugs and “more than minimally manipulated” human cell and tissue products (HCT/Ps). In contrast, across the world, human islets are appropriately defined as “minimally manipulated tissue” and not regulated as a drug, which has led to islet allotransplantation (allo-ITx) becoming a standard-of-care procedure for selected patients with type 1 diabetes mellitus. This regulatory distinction impedes patient access to islets for transplantation in the US. As a result only 11 patients underwent allo-ITx in the US between 2016 and 2019, and all as investigational procedures in the settings of a clinical trials. Herein, we describe the current regulations pertaining to islet transplantation in the United States. We explore the progress which has been made in the field and demonstrate why the regulatory framework must be updated to both better reflect our current clinical practice and to deal with upcoming challenges. We propose specific updates to current regulations which are required for the renaissance of ethical, safe, effective, and affordable allo-ITx in the United States

Gestión turística y tecnologías de la información y la comunicación (TIC) : el nuevo enfoque de los destinos inteligentes

Este artículo analiza el nuevo enfoque de los destinos inteligentes para la gestión turística a escala local. Se estudia su génesis y se realiza una propuesta de conceptualización desde una perspectiva sistémica, que se contrasta con la gestión turística actual mediante una encuesta a municipios turísticos de la Comunidad Valenciana. Los resultados ponen de relieve que no se ha asumido como objetivo de gestión el enfoque de los destinos inteligentes, el cual requiere un proyecto global que incorpore cinco ámbitos fundamentales: gobernanza, sostenibilidad, conectividad, sistema de información e innovación. No obstante, la complejidad asociada a este enfoque hace aconsejable un desarrollo de tipo flexible, escalable y adaptado a cada entorno territorial.Aquest article analitza la nova perspectiva de les destinacions intel·ligents per a la gestió turística a escala local. Se n'hi estudia la gènesi i s'hi realitza una proposta de conceptualització des d'un punt de vista sistèmic que es contrasta amb la gestió turística actual mitjançant una enquesta als municipis turístics de la Comunitat Valenciana. Els resultats demostren que no s'ha assumit com a objectiu de gestió la perspectiva de les destinacions intel·ligents, la qual requereix un projecte global que integre cinc àmbits fonamentals: governança, sostenibilitat, connectivitat, sistema d'informació i innovació. Tanmateix, la complexitat associada a aquesta perspectiva fa aconsellable un desenvolupament de tipus flexible, escalable i adaptat a cada entorn territorial.This article analyzes the new smart destinations approach to tourism management at the local level. We examine the origins of this approach and propose a conceptualization from a systemic perspective, which is contrasted with current tourism management strategies through a survey of tourist destinations in the Valencia Region. The results show that the smart destinations approach has not been considered as a management objective. This approach requires a global project incorporating five key areas: governance, sustainability, connectivity, information system and innovation. However, due to the complexity of the smart tourist destination approach, a particular kind of development that is flexible, scalable and adapted to each geographical environment is recommendable.Cet article analyse la nouvelle approche des destinations intelligentes pour la gestion du tourisme au niveau local. On étudie sa genèse et on propose une conceptualisation à partir d'un point de vue systémique, en contraste avec la gestion du tourisme actuel à travers une enquête auprès des destinations touristiques de la Région de Valence. Les résultats montrent que cette approche n'a pas été pries comme objectif de la gestion. Cette approche a besoin d'un projet global qui intègre cinq domaines clés: la gouvernance, la durabilité, la connectivité, le système d'information et l'innovation. Cependant, la complexité associée à cette approche réclame un développement flexible, échelonné et adapté à chaque type d'environnement géographique

Current challenges in islet transplantation

Allogeneic islet transplantation is becoming a treatment option for patients with unstable type 1 diabetes mellitus (T1DM). Around 80% of the islet recipients achieve insulin independence after one or two islet infusions under "Edmonton-like" immunosuppressive protocol, but only 10% will remain insulin independent over the long term. Islet transplantation leads to glucose stabilization, and severe hypoglycemia is prevented even in patients back on insulin injections. Thus, islet transplantation has achieved the proposed targets in patients with unstable T1DM: normalizing blood glucose and hemoglobin A(1c), preventing severe hypoglycemic episodes, and improving quality of life. The current aims of islet transplantation programs are to maintain the success achieved and to overcome remaining obstacles and limitations

Ethnic differences in progression of islet autoimmunity and type 1 diabetes in relatives at risk

We hypothesised that progression of islet autoimmunity and type 1 diabetes mellitus differs among races/ethnicities in at-risk individuals. In this study, we analysed the data from the Type 1 Diabetes TrialNet Pathway to Prevention Study. We studied 4873 non-diabetic, autoantibody-positive relatives of individuals with type 1 diabetes followed prospectively (11% Hispanic, 80.9% non-Hispanic white [NHW], 2.9% non-Hispanic black [NHB] and 5.2% non-Hispanic other [NHO]). Primary outcomes were time from single autoantibody positivity confirmation to multiple autoantibody positivity, and time from multiple autoantibody positivity to type 1 diabetes mellitus diagnosis. Conversion from single to multiple autoantibody positivity was less common in Hispanic individuals than in NHW individuals (HR 0.66 [95% CI 0.46, 0.96], p = 0.028) adjusting for autoantibody type, age, sex, Diabetes Prevention Trial Type 1 Risk Score and HLA-DR3-DQ2/DR4-DQ8 genotype. In participants who screened positive for multiple autoantibodies (n = 2834), time to type 1 diabetes did not differ by race/ethnicity overall (p = 0.91). In children who were <12 years old when multiple autoantibody positivity was determined, being overweight/obese had differential effects by ethnicity: type 1 diabetes risk was increased by 36% in NHW children (HR 1.36 [95% CI 1.04, 1.77], p = 0.024) and was nearly quadrupled in Hispanic children (HR 3.8 [95% CI 1.6, 9.1], p = 0.0026). We did not observe this interaction in participants who were ≥12 years old at determination of autoantibody positivity, although this group size was limited. No significant differential risks were observed between individuals of NHB and NHW ethnicity. The risk and rate of progression of islet autoimmunity were lower in Hispanic compared with NHW at-risk individuals, while significant differences in the development of type 1 diabetes were limited to children <12 years old and were modified by BMI