The Teamwork, Targets, and Technology for Tight Glycemia (4T) Program has demonstrated effectiveness in early continuous glucose monitor use with remote patient monitoring among three diverse cohorts of youth with new onset type 1 diabetes (T1D, n = 451). Based on promising single center experience, we examine the potential for program scaling to the T1D Exchange Quality Improvement (T1DX-QI) Collaborative using an implementation science approach. We used the Simplified Implementation Logic Model to identify contextual determinants of implementation success. Then, we described the connections between the implementation support strategies used in 4T to address the contextual determinants and barriers to program reach to youth with T1D and provider adoption. We hypothesized mechanisms linking barriers and strategies to effectiveness and implementation outcomes. Limited clinician time was identified as a major barrier to program success. Several targeted strategies were used to address this, including the creation of the Timely Interventions for Diabetes Excellence (TIDE) clinical decision support tool early in the program and ongoing refinement of the tool. After clinical effectiveness of the 4T Program was established, the next phase focused on further allocating clinician monitoring to participants who would benefit the most. Additionally, cost to the family participants, cost to the clinic, and interest-holder engagement were other determinants addressed by the program strategies. This implementation evaluation informed connections between determinants, support strategies, mechanisms, and outcomes of the 4T Program. This enabled a more precise design in preparation to scale the program across a national network of pediatric diabetes clinics in the T1DX-QI.
Background and aims:Rodent studies suggest that endurance training may promote the browning of white adipose tissue and enhances adipose tissue thermogenesis during cold exposure. However, it remains unclear whether endurance training leads to similar adaptations in humans. The aim of this study was therefore to find out whether six weeks of intensive, fartlek-style cycle endurance training alters responses to cold exposure, specifically cold-induced changes of oxygen uptake, plasma noradrenaline concentrations and the effect of conditioned serum on markers of adipocyte browning in culture. Methods and results:Twenty-four healthy, untrained participants completed a six-week fartlek-style cycling intervention (3 sessions/week) or control period. We estimated cold-induced adaptive thermogenesis before and after the intervention by indirect calorimetry during 60 min of mild cold exposure at 18 °C. Endurance training increased on average the V˙O₂max by 5 ml/kg/min (95% CI 1 to 8; p = 0.010), maximal power output by 19 W (95% CI 5 to 33; p = 0.011), and power at the 4 mmol/l lactate threshold by 30 W (95% CI 18 to 43; p < 0.001). However, training did not alter cold-induced oxygen uptake, carbon dioxide production, energy expenditure, supraclavicular skin temperature, or mean skin temperature compared with controls. In an exploratory analysis, the cold-induced increase in plasma noradrenaline was attenuated after endurance training (-176 pg/ml, 95% CI -337 to -14; p = 0.035), whereas the exercise-induced noradrenaline response not altered significantly. Cold- or exercise-conditioned serum did not alter UCP1 mRNA expression in human beige adipocytes. Conclusion:Six weeks of fartlek-style endurance training increased cardiorespiratory and metabolic fitness but had little effect on the response to cold exposure with no evidence for adipose tissue browning based on the conducted serum incubation experiment.
Purpose To determine whether gender-affirming hormone therapy (GAHT) influences tear system health in transgender individuals. Methods This retrospective cohort observational study analyzed data from transgender men and women ages ≥18-years between 2004 and 2024 via electronic medical record (EMR) data. Following propensity score matching, subjects on hormone therapy included 23,623 transgender men, 15,933 transgender women, and an equal number in each matched control group. Results Among transgender men and women, respectively, tear system disorders occurred in 0.90% and 0.94% of those using GAHT and 0.90% and 1.17% of those not using GAHT (p = 0.211, p = 0.072). There was no significant difference in those with documented utilization of GAHT versus no GAHT, for both transgender men and women, respectively, in lacrimal system disorder (p = 0.427, p = 0.292), meibomian gland dysfunction (p = 0.687, p = 0.255), keratoconjunctivitis sicca (p = 0.685, p = 0.576), and combined tear disorders (p = 0.527, p = 0.168). Conclusions In this cohort, EMR-documented masculinizing or feminizing GAHT was not associated with an increased incidence of recorded tear-system disorders.
The molecular drivers of thyroid cancer are predominantly involved in the MAP kinase pathway, especially the BRAF and RAS pathogenic variants. The DNA repair pathways are rarely implicated in thyroid tumorigenesis. The MRE11-RAD50-NBS1 (MRN) complex is a key mediator of homologous recombination mode of double-strand break repair, and its role in thyroid cancer is poorly understood. We describe a patient with radioactive iodine-refractory, metastatic oncocytic thyroid carcinoma with an NBN gene (c.2166_2167delGCinsAT) pathogenic variant, who developed progressive disease despite receiving systemic therapy with lenvatinib and pembrolizumab. A gene query analysis for the three MRN complex genes (MRE11, RAD50, and NBN) across three thyroid cancer repositories on the cBioPortal database showed a prevalence of pathogenic variants in one or more MRN complex genes in 35/762 (4.6%) patients, and all the 35 patients had anaplastic thyroid cancer (ATC). Upon filtering the dataset to include only ATCs, the pathogenic variant prevalence increased to 22.2% (35/158 patients). The overall survival in ATC patients with MRN complex gene alterations was similar to ATC patients without the altered MRN complex genes [HR: 1.42 (95% CI: 0.93-2.17)]. A mutual exclusivity analysis demonstrated a tendency for pathogenic variants in one MRN complex genes to co-occur with pathogenic variants in the other two MRN complex genes. In conclusion, the MRN complex pathogenic variants could be potentially oncogenic in TCs and may be linked to aggressive forms of TC.
Currently, no clinical early predictive biomarkers of GDM exist. A key challenge is that many candidate biomarkers fluctuate during pregnancy. Previous studies with a single time point identified several miRNAs in early pregnancy associated with insulin sensitivity between 24 and 29 weeks of gestation, suggesting they serve as potential predictive biomarkers for GDM. However, the lack of longitudinal data limits our understanding of how these miRNAs behave over time. We conducted a longitudinal pilot study to evaluate the patterns of ten miRNAs, previously identified as potential early predictors of GDM. Blood samples were collected from 18 GDM women and 18 healthy pregnancies at 4 time points (GDM diagnosis, 28 weeks, 32 weeks, and one day before delivery). The levels of four placenta-specific C19MC miRNAs (miRNA-519d-5p, miRNA-512-3p, miRNA-516a-5p, and miRNA-517-5p) and six non-C19MC miRNAs (miRNA-141-3p, miRNA-143-3p, miRNA-218-5p, miRNA-221-3p, miRNA-483-5p, and miRNA-489-3p) were measured. The relative expressions of four C19MC miRNAs were significantly increased in GDM women at diagnosis, at 28 weeks of gestation, and one day before delivery. The relative expression of non-C19MC miRNA-221-3p was significantly decreased across all time points. The expression of non-C19MC miRNA-143-3p increased significantly at diagnosis and 28 weeks, and then declined before delivery. In contrast, the levels of non-C19MC miRNA-483-5p, miRNA-218-5p, and miRNA-489-3p were significantly decreased across all time points. No changes in miRNA-141-3p level were observed. Our pilot longitudinal study supports the predictive potential of C19MC miRNAs (miRNA-512-3p, miRNA-516a-5p, miRNA-517-5p) and non-C19MC miRNA-221-3p, which were previously identified as having elevated levels in early gestation.
