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Abstract Background Congenital heart defect (CHD) account for 25% of all human congenital abnormalities. However, very few CHD-causing genes have been identified so far. A promising approach for the identification of essential cardiac regulators whose mutations may be linked to human CHD, is the molecular and genetic analysis of heart development. With the use of a triple retinoic acid competitive antagonist (BMS189453) we previously developed a mouse model of congenital heart defects (81%), thymic abnormalities (98%) and neural tube defects (20%). D-TGA (D-transposition of great arteries) was the most prevalent cardiac defect observed (61%). Recently we were able to partially rescue this abnormal phenotype (CHD were reduced to 64.8%, p = 0.05), by oral administration of folic acid (FA). Now we have performed a microarray analysis in our mouse models to discover genes/transcripts potentially implicated in the pathogenesis of this CHD. Results We analysed mouse embryos (8.5 dpc) treated with BMS189453 alone and with BMS189453 plus folic acid (FA) by microarray and qRT-PCR. By selecting a fold change (FC) ≥ ± 1.5, we detected 447 genes that were differentially expressed in BMS-treated embryos vs. untreated control embryos, while 239 genes were differentially expressed in BMS-treated embryos whose mothers had also received FA supplementation vs. BMS-treated embryos. On the basis of microarray and qRT-PCR results, we further analysed the Hif1α gene. In fact Hif1α is down-regulated in BMS-treated embryos vs. untreated controls (FCmicro = -1.79; FCqRT-PCR = -1.76; p = 0.005) and its expression level is increased in BMS+FA-treated embryos compared to BMS-treated embryos (FCmicro = +1.17; FCqRT-PCR = +1.28: p = 0.005). Immunofluorescence experiments confirmed the under-expression of Hif1α protein in BMS-treated embryos compared to untreated and BMS+FA-treated embryos and, moreover, we demonstrated that at 8.5 dpc, Hif1α is mainly expressed in the embryo heart region. Conclusions We propose that Hif1α down-regulation in response to blocking retinoic acid binding may contribute to the development of cardiac defects in mouse newborns. In line with our hypothesis, when Hif1α expression level is restored (by supplementation of folic acid), a decrement of CHD is found. To the best of our knowledge, this is the first report that links retinoic acid metabolism to Hif1α regulation and the development of D-TGA.

Background: The level of spinal cord injury affects the severity of respiratory impairment and the alteration of respiratory pattern and gas exchanges. Lesions at the C3-C5 level (phrenic nerve nucleus) cause disruption of descending input with paralysis of the main inspiratory muscle, often requiring tracheostomy and prolonged mechanical ventilation. Oxygen therapy is essential to switch from ventilatory support to removal of the endotracheal tube to correct residual difficulties in oxygenation management., Case Presentation: A 58-year-old man had tracheostomy and tetraparesis as complication of tonsillectomy and adenoidectomy treatment for a history of obstructive sleep apnea. A respiratory rehabilitation program with protocol of oxygen therapy with high flow cannula alternated with a low-flow system by Venturi mask during daytime hours only was started. The patient was constantly monitored with capillary partial oxygen saturation to obtain adequate oxygenation (≥ 94%) and registered every 15 minutes in the clinical chart. There was gradual improvement of respiratory function. Oxygen by Venturi mask was gradually reduced due to improvement of partial pressure oxygen values. Over the course of days, the optimal results of respiratory parameters led to a gradual weaning from the Venturi mask until the complete discontinuation of the low-flow system during daytime and decreased of the high-flow fraction of inspired oxygen to the maximal tolerated level during nighttime., Conclusions: Implementing a combined protocol of nighttime oxygen with high flow cannula and daytime Venturi mask improves intensive motor training of patients by promoting the acquisition of ability to perform chair/bed transitions and to be able to achieve standing and begin gait training. More research is needed whether or noted to determine the role of this promising approach in patients with severe SCI and in other critically ill patients., Learning Points: This is a presentation of a new respiratory training protocol of combined oxygen therapy by high flow cannula and Venturi mask in a patient with cervical spinal cord injury and respiratory failure.Due to this new respiratory training, from the weaning of ventilation devices the patient had greater independence and improved quality of life, with more intensive motor training in the gym, improvement of the motor program and the patient tolerance to training.Oxygen therapy with high flow cannula and Venturi mask could be valid and reliable combined respiratory training to improve the respiratory pattern in severely hypoxemic and hypercapnic patients, without adverse events., Competing Interests: Conflicts of Interests: The Authors declare that there are no competing interests., (© EFIM 2024.)

Introduction: Primary aim was to provide real-world evidence of the outcomes after the switch to glargine 300 U/ml (Gla-300) from other basal insulins (first or second generation) in Italy., Methods: Multicenter, observational, retrospective study based on electronic medical records., Results: Overall, 953 T2DM insulin ± OAD treated people switched to Gla-300 or Gla-100 from January 2015 to July 2018. Three clinically relevant cohorts were identified: patients switching to Gla-300 from first-generation basal insulin (cohort 1), patients switching to Gla-300 from degludec-100 (Deg-100) (cohort 2), and those switching to Gla-100 from any basal insulin (cohort 3). The three cohorts differed in terms of age, diabetes duration, and metabolic control. HbA1c changes after 6 months from the switch were - 0.27% (95% CI - 0.38; - 0.16), - 0.06% (95% CI - 0.31; 0.19), and - 0.30% (95% CI - 0.51; - 0.09) in the three cohorts, respectively. FPG significantly decreased in cohort 1 (- 14.07 mg/dl, 95% CI - 20.25; - 7.89), while body weight significantly decreased in cohort 2 (- 1.47 kg, 95% CI - 2.55; - 0.39). Doses of insulin marginally changed during the follow-up (+ 0.89 U in basal insulin daily dose in cohort 1 and + 2.07 U in short-acting insulin daily dose in cohort 2)., Conclusions: Switching to Gla-300 from first-generation basal insulin in the real world is associated with improvements in metabolic control despite a suboptimal titration of both basal and short-acting insulins. Inertia in insulin titration documented in the Gla-100 cohort is also observed with the second-generation basal insulin. The switch to Gla-300 from Deg-100 was associated with a decrease in body weight of - 1.47 kg despite a slight increase in short-acting insulin daily doses of about + 2 U.

Introduction: Based on existing data regarding the durability of liraglutide in type 2 diabetes, this study aimed to assess its long-term effectiveness at 5 years and its overall impact on cardiovascular (CV) risk., Methods: This was a multicenter retrospective observational study. Liraglutide was used under routine clinical practice conditions. Changes from baseline to 60 months in HbA1c, fasting plasma glucose (FPG), body weight, blood pressure, and lipid profile were assessed. United Kingdom Prospective Diabetes Study (UKPDS) scores were calculated at baseline and after 60 months to assess changes in the estimated 5- and 10-year risk for fatal and nonfatal coronary heart disease (CHD) and fatal and nonfatal stroke., Results: Overall, 103 patients (age 59.0 ± 7.9 years, diabetes duration 10.4 ± 6.8 years) were involved in the study. After 60 months, HbA1c levels were reduced by - 1.0 ± 1.2%, FPG levels by - 24.5 ± 43.4 mg/dl, body weight by - 5.3 ± 6.4 kg, systolic blood pressure by - 6.5 ± 18.5 mmHg, diastolic blood pressure by - 3.6 ± 11.8 mmHg, and total cholesterol by - 16.9 ± 37.4 mg/dl. The proportion of patients achieving HbA1c levels  of < 7% increased from 12.7% to 39.8% (p = 0.02). Based on the UKPDS scores, statistically significant reductions in the 5- and 10-year risk of nonfatal CHD and fatal CHD were found, with no change in the 5- and 10-year risk of fatal and nonfatal stroke., Conclusion: In patients prolonging treatment with liraglutide for 5 years, the benefits in relation to metabolic control and CV risk factors are maintained. The UKPDS risk scores suggest that liraglutide is associated with a reduced CHD risk, but not with a reduced stroke risk.

Introduction: Hypoglycemia is the major limiting factor in the glycemic management of diabetes. Aim of this study was to produce a risk stratification tool to support the medical decision making, by facilitating the identification of patients at higher risk of hypoglycemia., Evidence Acquisition: A multistep approach was adopted, including a systematic review of observational studies investigating risk factors for severe hypoglycemia in type 2 diabetes (T2DM), followed by an expert input forum to identify factors perceived as relevant and at the same time reliably detectable, to be used for the development of a risk score., Evidence Synthesis: The systematic review led to the identification of 41 studies. Many factors have been seldom investigated, and their association with the risk of hypoglycemia is still unclear. Factors more frequently associated with a high risk of hypoglycemia were: low level of education, ethnicity, irregular meals/malnutrition, insulin and sulfonylurea therapy, polypharmacy, previous hypoglycemia, impaired renal function, cognitive impairment, depression and frailty. The expert input forum involved 35 diabetologists. Following the ranking of the relevance of the factors identified, a parsimonious yet comprehensive set of risk factors was identified., Conclusions: The process led to the identification of relevant factors, to be used for the development of a hypoglycemia risk score. An ad-hoc study will be performed to assess the contribution of these risk factors and their relative weight. If the risk score will confirm its ability to correctly stratify patients according to their risk of hypoglycemia, it will represent a useful support to optimize the care of people with T2DM.

Introduction: Hyperglycemia in inpatients is a major problem, especially when nutritional support is required. This study aims to assess the impact of treatment with insulin degludec (IDeg) on mean blood glucose (BG) and glycemic variability in noncritical hospitalized patients with and without type 2 diabetes (T2DM) receiving enteral and/or parenteral nutrition (EN, PN)., Methods: Mean BG and glycemic variability from admission up to 7 days of hospitalization were evaluated in consecutive cases with and without T2DM. Percentage of coefficient of variation (CV) for glucose was used to express glycemic variability., Results: Overall, 26 patients (13 with and 13 without T2DM) were admitted to the hospital for any cause. Subjects were 65.4% men and they were mainly elderly (mean age 66.3 ± 13.4 years). PN was administered in 88.5% of patients and EN in 19.2%. At admission, mean HbA1c level was 5.9 ± 0.7% in patients without diabetes and 9.1 ± 2.5% in patients with T2DM. During hospitalization, mean daily BG levels changed from 151 ± 47.3 mg/dl (day 1) to 157 ± 66.7 mg/dl (day 7) in patients without diabetes and from 210 ± 66.5 mg/dl to 192 ± 48.6 mg/dl in patients with T2DM. CV decreased from 14% (day 1) to 11% (day 7) in patients without diabetes and from 20% (day 1) to 9% (day 7) in patients with T2DM. No symptomatic or severe hypoglycemia occurred., Conclusions: Despite the small sample size and the lack of control group, this study represents the first proof-of-concept that IDeg in hospitalized patients with or without T2DM who require nutritional support has the potential to maintain stable levels of BG and reduce glycemic variability., Funding: Novo Nordisk S.p.A. grant.