Clinical Effectiveness of Continuous Glucose Monitoring in Pregnancies Affected by Type 1 Diabetes.

Background: Continuous glucose monitoring (CGM) improves neonatal outcomes in type 1 diabetes pregnancies; however, its effectiveness has not been assessed in a real-world setting in the United States. Objective: The Triple C Study aimed to examine the clinical effectiveness, assessed through maternal glucose control and gestational health outcomes, of CGM use compared with self-monitoring of blood glucose (SMBG) in pregnancies associated with type 1 diabetes in a real-world setting. Research Design and Methods: We retrospectively identified 160 type 1 diabetes pregnancies at the Barbara Davis Center for Diabetes managed with CGM therapy (n = 109) or SMBG (n = 51) over a 6.5-year period (2014-2020). Obstetric care was provided at multiple practices. CGM use was defined as ≥60% wear in the second and third trimesters of pregnancy. Data were obtained from the electronic medical record system, hospital records, and vital statistics departments (Colorado and Wyoming). We used Student's t-test for continuous variables and chi-square test for categorical variables to compare outcomes between groups. Results: The CGM group had more participants meeting trimester-specific hemoglobin A1C (HbA1c) goals throughout pregnancy and postpartum (P < 0.01 in each time period). The CGM group had fewer participants never meeting HbA1c goals in any trimester than the SMBG group (P < 0.001). There were no significant differences in neonatal outcomes between groups, other than for macrosomia (12.8% CGM vs. 29.4% SMBG, P = 0.01). Infants of CGM users required a neonatal intensive care unit admission less often (52.9% CGM vs. 68.3% SMBG, P = 0.0989). Conclusions: CGM use was associated with improved maternal glucose levels in a diverse real-world cohort.

TLR4 Ligation by eNAMPT, a Novel DAMP, is Essential to Sulfur Mustard- Induced Inflammatory Lung Injury and Fibrosis.

Objective: Human and preclinical studies of sulfur mustard (SM)-induced acute and chronic lung injuries highlight the role of unremitting inflammation. We assessed the utility of targeting the novel DAMP and TLR4 ligand, eNAMPT (extracellular nicotinamide phosphoribosyltransferase), utilizing a humanized mAb (ALT-100) in rat models of SM exposure. Methods: Acute (SM 4.2 mg/kg, 24 hrs), subacute (SM 0.8 mg/kg, day 7), subacute (SM 2.1 mg/kg, day 14), and chronic (SM 1.2 mg/kg, day 29) SM models were utilized. Results: Each SM model exhibited significant increases in eNAMPT expression (lung homogenates) and increased levels of phosphorylated NFkB and NOX4. Lung fibrosis (Trichrome staining) was observed in both sub-acute and chronic SM models in conjunction with elevated smooth muscle actin (SMA), TGFß, and IL-1ß expression. SM-exposed rats receiving ALT-100 (1 or 4 mg/kg, weekly) exhibited increased survival, highly significant reductions in histologic/biochemical evidence of lung inflammation and fibrosis (Trichrome staining, decreased pNFkB, SMA, TGFß, NOX4), decreased airways strictures, and decreased plasma cytokine levels (eNAMPT, IL-6, IL-1ß. TNFα). Conclusion: The highly druggable, eNAMPT/TLR4 signaling pathway is a key contributor to SM-induced ROS production, inflammatory lung injury and fibrosis. The ALT-100 mAb is a potential medical countermeasure to address the unmet need to reduce SM-associated lung pathobiology/mortality.

Mesna Improves Outcomes of Sulfur Mustard Inhalation Toxicity in an Acute Rat Model.

Inhalation of high levels of sulfur mustard (SM), a potent vesicating and alkylating agent used in chemical warfare, results in acutely lethal pulmonary damage. Sodium 2-mercaptoethane sulfonate (mesna) is an organosulfur compound that is currently Food and Drug Administration (FDA)-approved for decreasing the toxicity of mustard-derived chemotherapeutic alkylating agents like ifosfamide and cyclophosphamide. The nucleophilic thiol of mesna is a suitable reactant for the neutralization of the electrophilic group of toxic mustard intermediates. In a rat model of SM inhalation, treatment with mesna (three doses: 300 mg/kg intraperitoneally 20 minutes, 4 hours, and 8 hours postexposure) afforded 74% survival at 48 hours, compared with 0% survival at less than 17 hours in the untreated and vehicle-treated control groups. Protection from cardiopulmonary failure by mesna was demonstrated by improved peripheral oxygen saturation and increased heart rate through 48 hours. Additionally, mesna normalized arterial pH and pACO2 Airway fibrin cast formation was decreased by more than 66% in the mesna-treated group at 9 hour after exposure compared with the vehicle group. Finally, analysis of mixtures of a mustard agent and mesna by a 5,5'-dithiobis(2-nitrobenzoic acid) assay and high performance liquid chromatography tandem mass spectrometry demonstrate a direct reaction between the compounds. This study provides evidence that mesna is an efficacious, inexpensive, FDA-approved candidate antidote for SM exposure. SIGNIFICANCE STATEMENT: Despite the use of sulfur mustard (SM) as a chemical weapon for over 100 years, an ideal drug candidate for treatment after real-world exposure situations has not yet been identified. Utilizing a uniformly lethal animal model, the results of the present study demonstrate that sodium 2-mercaptoethane sulfonate is a promising candidate for repurposing as an antidote, decreasing airway obstruction and improving pulmonary gas exchange, tissue oxygen delivery, and survival following high level SM inhalation exposure, and warrants further consideration.