Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function Reduces Airway Bacteria and Inflammation in People with Cystic Fibrosis and Chronic Lung Infections

Rationale: Previous work indicates that ivacaftor improves cystic fibrosis transmembrane conductance regulator (CFTR) activity and lung function in people with cystic fibrosis and G551D-CFTR mutations but does not reduce density of bacteria or markers of inflammation in the airway. These findings raise the possibility that infection and inflammation may progress independently of CFTR activity once cystic fibrosis lung disease is established. Objectives: To better understand the relationship between CFTR activity, airway microbiology and inflammation, and lung function in subjects with cystic fibrosis and chronic airway infections. Methods: We studied 12 subjects with G551D-CFTR mutations and chronic airway infections before and after ivacaftor. We measured lung function, sputum bacterial content, and inflammation, and obtained chest computed tomography scans. Measurements and Main Results: Ivacaftor produced rapid decreases in sputum Pseudomonas aeruginosa density that began within 48 hours and continued in the first year of treatment. However, no subject eradicated their infecting P. aeruginosa strain, and after the first year P. aeruginosa densities rebounded. Sputum total bacterial concentrations also decreased, but less than P. aeruginosa. Sputum inflammatory measures decreased significantly in the first week of treatment and continued to decline over 2 years. Computed tomography scans obtained before and 1 year after ivacaftor treatment revealed that ivacaftor decreased airway mucous plugging. Conclusions: Ivacaftor caused marked reductions in sputum P. aeruginosa density and airway inflammation and produced modest improvements in radiographic lung disease in subjects with G551D-CFTR mutations. However, P. aeruginosa airway infection persisted. Thus, measures that control infection may be required to realize the full benefits of CFTR-targeting treatments

Vagus nerve stimulation in refractory idiopathic generalised epilepsy: an Irish retrospective observational study

Objective: Refractory idiopathic generalised epilepsy (IGE; also known as genetic generalised epilepsy) is a clinical challenge due to limited available therapeutic options. While vagus nerve stimulation (VNS) is approved as an adjunctive treatment for drug-resistant focal epilepsy, there is limited evidence supporting its efficacy for refractory IGE. Methods: We conducted a single-centre retrospective analysis of adult IGE patients treated with VNS between January 2003 and January 2022. We analysed the efficacy, safety, tolerability, stimulation parameters and potential clinical features of VNS response in this IGE cohort. Results: Twenty-three IGE patients were implanted with VNS between January 2003 and January 2022. Twenty-two patients (95.65%) were female. The median baseline seizure frequency was 30 per month (interquartile range [IQR]= 140), including generalised tonic-clonic seizures (GTCS), absences, myoclonus, and eyelid myoclonia with/without absences. The median number of baseline anti-seizure medications (ASM) was three (IQR= 2). Patients had previously failed a median of six ASM (IQR= 5). At the end of the study period, VNS therapy remained active in 17 patients (73.9%). amongst patients who continued VNS, thirteen (56.5% of the overall cohort) were considered responders (≥50% seizure frequency reduction). Amongst the clinical variables analysed, only psychiatric comorbidity correlated with poorer seizure outcomes, but was non-significant after applying the Bonferroni correction. Although 16 patients reported side-effects, none resulted in the discontinuation of VNS therapy. Significance: Over half of the patients with refractory IGE experienced a positive response to VNS therapy. VNS represents a viable treatment option for patients with refractory IGE, particularly for females, when other therapeutic options have been exhausted.</p

Time to Peak Glucose and Peak C-Peptide During the Progression to Type 1 Diabetes in the Diabetes Prevention Trial and TrialNet Cohorts

OBJECTIVE To assess the progression of type 1 diabetes using time to peak glucose or C-peptide during oral glucose tolerance tests (OGTTs) in autoantibody-positive relatives of people with type 1 diabetes. RESEARCH DESIGN AND METHODS We examined 2-h OGTTs of participants in the Diabetes Prevention Trial Type 1 (DPT-1) and TrialNet Pathway to Prevention (PTP) studies. We included 706 DPT-1 participants (mean ± SD age, 13.84 ± 9.53 years; BMI Z-score, 0.33 ± 1.07; 56.1% male) and 3,720 PTP participants (age, 16.01 ± 12.33 years; BMI Z-score, 0.66 ± 1.3; 49.7% male). Log-rank testing and Cox regression analyses with adjustments (age, sex, race, BMI Z-score, HOMA-insulin resistance, and peak glucose/C-peptide levels, respectively) were performed. RESULTS In each of DPT-1 and PTP, higher 5-year diabetes progression risk was seen in those with time to peak glucose >30 min and time to peak C-peptide >60 min (P < 0.001 for all groups), before and after adjustments. In models examining strength of association with diabetes development, associations were greater for time to peak C-peptide versus peak C-peptide value (DPT-1: χ2 = 25.76 vs. χ2 = 8.62; PTP: χ2 = 149.19 vs. χ2 = 79.98; all P < 0.001). Changes in the percentage of individuals with delayed glucose and/or C-peptide peaks were noted over time. CONCLUSIONS In two independent at-risk populations, we show that those with delayed OGTT peak times for glucose or C-peptide are at higher risk of diabetes development within 5 years, independent of peak levels. Moreover, time to peak C-peptide appears more predictive than the peak level, suggesting its potential use as a specific biomarker for diabetes progression