Antidelaminating, Thermally Stable, and Cost-Effective Flexible Kapton Platforms for Nitrate Sensors, Mercury Aptasensors, Protein Sensors, and p-Type Organic Thin-Film Transistors.

The inkjet printing of metal electrodes on polymer films is a desirable manufacturing process due to its simplicity but is limited by the lack of thermal stability and serious delaminating flaws in various aqueous and organic solutions. Kapton, adopted worldwide due to its superior thermal durability, allows the high-temperature sintering of nanoparticle-based metal inks. By carefully selecting inks (Ag and Au) and Kapton substrates (Kapton HN films with a thickness of 135 µm and a thermal resistance of up to 400 °C) with optimal printing parameters and simplified post-treatments (sintering), outstanding film integrity, thermal stability, and antidelaminating features were obtained in both aqueous and organic solutions without any pretreatment strategy (surface modification). These films were applied in four novel devices: a solid-state ion-selective (IS) nitrate (NO3-) sensor, a single-stranded DNA (ssDNA)-based mercury (Hg2+) aptasensor, a low-cost protein printed circuit board (PCB) sensor, and a long-lasting organic thin-film transistor (OTFT). The IS NO3- sensor displayed a linear sensitivity range between 10-4.5 and 10-1 M (r2 = 0.9912), with a limit of detection of 2 ppm for NO3-. The Hg2+ sensor exhibited a linear correlation (r2 = 0.8806) between the change in the transfer resistance (RCT) and the increasing concentration of Hg2+. The protein PCB sensor provided a label-free method for protein detection. Finally, the OTFT demonstrated stable performance, with mobility values in the linear (µlin) and saturation (µsat) regimes of 0.0083 ± 0.0026 and 0.0237 ± 0.0079 cm2 V-1 S-1, respectively, and a threshold voltage (Vth) of -6.75 ± 3.89 V.

Distinct mechanisms mediate pacemaker dysfunction associated with catecholaminergic polymorphic ventricular tachycardia mutations: Insights from computational modeling.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-induced ventricular arrhythmia associated with rhythm disturbance and impaired sinoatrial node cell (SANC) automaticity (pauses). Mutations associated with dysfunction of Ca2+-related mechanisms have been shown to be present in CPVT. These dysfunctions include impaired Ca2+ release from the ryanodine receptor (i.e., RyR2R4496C mutation) or binding to calsequestrin 2 (CASQ2). In SANC, Ca2+ signaling directly and indirectly mediates pacemaker function. We address here the following research questions: (i) what coupled-clock mechanisms and pathways mediate pacemaker mutations associated with CPVT in basal and in response to ß-adrenergic stimulation? (ii) Can different mechanisms lead to the same CPVT-related pacemaker pauses? (iii) Can the mutation-induced deteriorations in SANC function be reversed by drug intervention or gene manipulation? We used a numerical model of mice SANC that includes membrane and intracellular mechanisms and their interconnected signaling pathways. In the basal state of RyR2R4496C SANC, the model predicted that the Na+-Ca2+ exchanger current (INCX) and T-type Ca2+ current (ICaT) mediate between changes in Ca2+ signaling and SANC dysfunction. Under ß-adrenergic stimulation, changes in cAMP-PKA signaling and the sodium currents (INa), in addition to INCX and ICaT, mediate between changes in Ca2+ signaling and SANC automaticity pauses. Under basal conditions in Casq2-/-, the same mechanisms drove changes in Ca2+ signaling and subsequent pacemaker dysfunction. However, SANC automaticity pauses in response to ß-AR stimulation were mediated by ICaT and INa. Taken together, distinct mechanisms can lead to CPVT-associated SANC automaticity pauses. In addition, we predict that specifically increasing SANC cAMP-PKA activity by either a pharmacological agent (IBMX, a phosphodiesterase (PDE) inhibitor), gene manipulation (overexpression of adenylyl cyclase 1/8) or direct manipulation of the SERCA phosphorylation target through changes in gene expression, compensate for the impairment in SANC automaticity. These findings suggest new insights for understanding CPVT and its therapeutic approach.

Survey on hypoglycemia among insulin-treated patients with diabetes: The Colombian International Operations Hypoglycemia Assessment Tool population / Encuesta sobre hipoglucemia en pacientes con diabetes tratados con insulina: la población colombiana del International Operations Hypoglycemia Assessment Tool

INTRODUCTION: The non-interventional International Operations Hypoglycemia Assessment Tool (IO-HAT) study assessed the incidence of hypoglycemia in patients with insulin-treated diabetes across nine countries, including a cohort of patients in Colombia. MATERIALS AND METHODS: Hypoglycemia incidence among patients with insulin-treated diabetes was assessed across 26 sites in Colombia. Hypoglycaemic events (any, nocturnal or severe) were reported in self-assessment questionnaires (SAQ) and patient diaries based on capillary blood glucose measurement or symptoms. Retrospective events (severe events 6 months before baseline and any event 4 weeks before baseline) were recorded in SAQ, Part 1, and prospective events (4 weeks from baseline) were recorded in SAQ, Part 2, and patient diaries. Differences in hypoglycemia incidence reported in the retrospective and prospective periods were assessed using two-sided tests. RESULTS: Of the 664 patients assessed, 213 had type 1 diabetes (T1D) and 451 had type 2 diabetes (T2D). Nearly all patients experienced at least one hypoglycaemic event in the prospective period (97.1% T1D; 93.3% T2D). Rates of hypoglycemia (events per personyear, PPY) were higher prospectively than retrospectively for any hypoglycemia (T1D: 121.6 vs. 83.2, p<0.001; T2D: 28.1 vs. 24.6, p=0.127) and severe hypoglycemia (T1D: 15.3 vs. 9.2, p=0.605; T2D: 9.5 vs. 3.5 p=0.040). CONCLUSION: These results, the first from a patient-reported dataset on hypoglycemia in insulin-treated patients with diabetes in Colombia, show that patients reported higher rates of any hypoglycemia during the prospective period. CLINICAL TRIAL REGISTRATION NUMBER: NCT02306681.

Introducción. En el estudio no intervencionista International Operations Hypoglycemia Assessment Tool (IO-HAT), se evalúo la incidencia de hipoglucemia en pacientes diabéticos tratados con insulina en nueve países, incluido Colombia. Materiales y métodos. La incidencia de hipoglucemia entre pacientes diabéticos tratados con insulina se evaluó en 26 centros médicos en Colombia. Los episodios de hipoglucemia determinados con base en la medición de la glucemia capilar o en los síntomas se reportaron en el cuestionario de autoevaluación (Self-Assessment Questionnaire, SAQ) y en el diario del paciente. Los episodios retrospectivos (episodios graves y cualquiera ocurrido 6 meses y 4 semanas antes del inicio del estudio, respectivamente) se registraron en el SAQ, parte 1, y los eventos prospectivos (4 semanas desde el inicio), en el SAQ, parte 2, y en el diario del paciente. Las diferencias en la incidencia de la hipoglucemia entre los períodos retrospectivo y prospectivo se evaluaron mediante una prueba de dos colas. Resultados. De los 664 pacientes evaluados, 213 tenían diabetes de tipo 1 y 451 tenían diabetes de tipo 2. Casi todos los pacientes experimentaron al menos un episodio de hipoglucemia en el período prospectivo (97,1 %, diabetes de tipo 1, y 93,3 %, diabetes de tipo 2). Los índices de hipoglucemia (episodios año-persona) fueron mayores prospectivamente que retrospectivamente para cualquier tipo de hipoglucemia (diabetes de tipo 1: 121,6 Vs. 83,2; p<0,001; la diabetes de tipo 2: 28,1 Vs. 24,6; p=0,127) y para la hipoglucemia grave (diabetes de tipo 1: 15,3 Vs. 9,2; p=0,605; diabetes de tipo 2: 9,5 Vs. 3,5; p=0,040). Conclusión. Estos resultados, que constituyen el primer conjunto de datos sobre hipoglucemia informados por pacientes diabéticos colombianos tratados con insulina, evidenciaron tasas más altas para ambos tipos de hipoglucemia durante el período prospectivo. Número de registro del ensayo clínico: NCT02306681

Defining High Glycemic Variability in Type 1 Diabetes: Comparison of Multiple Indexes to Identify Patients at Risk of Hypoglycemia.

Background: International consensus on the use of continuous glucose monitoring (CGM) recommends coefficient of variation (CV) as the metric of choice to express glycemic variability (GV) with a cutoff of 36% to define unstable diabetes. Even though, CV is associated with hypoglycemia in type 2 diabetes patients, the evidence on the use of one particular measure of GV in type 1 diabetes (T1DM) patients as a predictor of hypoglycemia is limited. Methods: A cohort of T1DM ambulatory patients was evaluated using CGM. Number and incidence rate of events <54 and <70 mg/dL were calculated. Bivariate and multivariate analysis of different glycemic indexes and clinical variables were performed to identify those associated with hypoglycemia. Receiver operating characteristic (ROC) curve analysis for each of the glycemic indexes was performed to define the best index and its optimal cutoff threshold to discriminate patients with events of hypoglycemia. Results: Seventy-three patients were included. A total of 128 events <54 mg/dL were recorded in 34 patients, and 350 events <70 mg/dL were registered in 51 patients. CV was the only variable significantly associated with hypoglycemia <54 mg/dL in the multivariate analysis (adjusted relative risk [aRR] 1.44, 95% confidence interval [CI]: 1.10-1.88, P = 0.008). CV, HbA1c (glycated hemoglobin), and mean glucose were associated with events <70 mg/dL. ROC curve analysis showed that, among GV metrics, CV had the best performance to discriminate patients with events <54 mg/dL (area under the curve [AUC] 0.87, 95% CI: 0.79-0.95) and events <70 mg/dL (AUC 0.79, 95% CI: 0.68-0.90) with optimal cutoff thresholds values of 34% and 31%, respectively. Among glycemic risk (GR) indexes, low blood glucose index (LBGI) showed the best performance. Conclusions: This analysis shows that CV is the best GV index, and LBGI the best GR index, to identify patients at risk of clinically significant hypoglycemia and hypoglycemia alert events in T1DM patients.

Clinical and economic benefits of integrated pump/CGM technology therapy in patients with type 1 diabetes in Colombia. / Beneficios clínicos y económicos de la terapia con bomba de insulina integrada a sistema de monitoreo continuo de glucosa en los pacientes diabéticos tipo 1 en Colombia.

OBJECTIVE: To assess the long-term clinical and economic impact of integrated pump/CGM technology therapy as compared to multiple daily injections (MDI), for the treatment of type 1 diabetes (T1D) in Colombia. METHODS: The CORE Diabetes Model was used to simulate a hypothetical cohort of patients with T1D. Mean baseline characteristics were taken from a clinical study conducted in Colombia and a healthcare payer perspective was adopted, with a 5% annual discount rate applied to both costs and outcomes. RESULTS: The integrated pump/CGM improved mean life expectancy by 3.51 years compared with MDI. A similar increase occurred in mean quality-adjusted life expectancy with an additional 3.81 quality-adjusted life years (QALYs). Onset of diabetes-related complications was also delayed as compared to MDI, and mean survival time free of complication increased by 1.74 years with integrated pump/CGM. Although this increased treatment costs of diabetes as compared to MDI, savings were achieved thanks to reduced expenditure on diabetes-related complications. The estimated incremental cost-effectiveness ratio (ICER) for SAP was Colombian Pesos (COP) 44,893,950 (approximately USD$23,200) per QALY gained. CONCLUSIONS: Improved blood glucose control associated to integrated pump/CGM results in a decreased incidence of diabetes-related complications and improves life expectancy as compared to MDI. Using recommended thresholds from the World Health Organization and previous coverage decisions about health technologies in Colombia, it is a cost-effective alternative to MDI for the treatment of type 1 diabetes in Colombia.