20 research outputs found
Correction factors for oxygen and flow-rate effects on neonatal Fleisch and Lilly pneumotachometers
Objective: To assess the effects of different oxygen concentrations and flow rates on the measurement errors of neonatal pneumotachometers in heated and unheated situations and to develop correction factors to correct for these effects. Design: Prospective laboratory study. Setting: Outpatient clinic with equipment in a standardized setting. Subjects: Neonatal pneumotachometers. Interventions: In standardized conditions, the tested pneumotachometer was calibrated at a flow rate of 3 L/min with 60% oxygen and was set in series with a closed spirometer system being used as a reference. Different air-flow levels (1-9 L/min) and oxygen concentrations (21-100%) were infused into the closed system with the pneumotachometer and spirometer. Measurements and Main Results: The pneumotachometers were significantly affected by changing oxygen concentrations (p < .01) and increasing flow rates (p < .01), increasing the actually measured flow rate. Correction factors, developed by multiple regression analysis, significantly reduced the overall maximum errors of the pneumotachometers from -1.1 to 0.6 L/min to -0.5 to 0.4 L/min. Conclusions: The effects of changes in oxygen concentrations and flow rates on neonatal pneumotachometers could be considerably decreased by the use of correction factors such as were calculated in this study. This will preclude frequent calibration procedures with actual flow and oxygen levels during changes in experimental settings. Copyrigh
Organoid-guided synergistic treatment of minimal function CFTR mutations with CFTR modulators, roflumilast and simvastatin:a personalised approach
CFTR activity is enhanced by the novel corrector GLPG2222, given with and without ivacaftor in two randomized trials
Background Several treatment approaches in cystic fibrosis (CF) aim to correct CF transmembrane conductance regulator (CFTR) function; the efficacy of each approach is dependent on the mutation(s) present. A need remains for more effective treatments to correct functional deficits caused by the F508del mutation. Methods Two placebo-controlled, phase 2a studies evaluated GLPG2222, given orally once daily for 29 days, in subjects homozygous for F508del (FLAMINGO) or heterozygous for F508del and a gating mutation, receiving ivacaftor (ALBATROSS). The primary objective of both studies was to assess safety and tolerability. Secondary objectives included assessment of pharmacokinetics, and of the effect of GLPG2222 on sweat chloride concentrations, pulmonary function and respiratory symptoms. Results Fifty-nine and 37 subjects were enrolled into FLAMINGO and ALBATROSS, respectively. Treatment-related treatment-emergent adverse events (TEAEs) were reported by 29.2% (14/48) of subjects in FLAMINGO and 40.0% (12/30) in ALBATROSS; most were mild to moderate in severity and comprised primarily respiratory, gastrointestinal, and infection events. There were no deaths or discontinuations due to TEAEs. Dose-dependent decreases in sweat chloride concentrations were seen in GLPG2222-treated subjects (maximum decrease in FLAMINGO: –17.6 mmol/L [GLPG2222 200 mg], p < 0.0001; ALBATROSS: –7.4 mmol/L [GLPG2222 300 mg], p < 0.05). No significant effects on pulmonary function or respiratory symptoms were reported. Plasma GLPG2222 concentrations in CF subjects were consistent with previous studies in healthy volunteers and CF subjects. Conclusions GLPG2222 was well tolerated. Sweat chloride reductions support on-target enhancement of CFTR activity in subjects with F508del mutation(s). Significant improvements in clinical endpoints were not demonstrated. Observed safety results support further evaluation of GLPG2222, including in combination with other CFTR modulators. Funding Galapagos NV. Clinical trial registration numbers FLAMINGO, NCT03119649; ALBATROSS, NCT0304552
Maternal use of probiotics during pregnancy and effects on their offspring’s health in an unselected population
Intestinal organoids and personalized medicine in cystic fibrosis : A successful patient-oriented research collaboration
Purpose of review New therapeutics have been introduced for cystic fibrosis that modulate cystic fibrosis transmembrane conductance regulator (CFTR) function in a mutation-specific fashion. Despite CFTR genotype-based stratification of treatments, treatment efficacy is variable between study participants suggesting that individual factors further contribute to drug efficacy. Moreover, these treatments are licensed for a limited amount of CFTR mutations, and study participants with rare mutations that can potentially benefit from available treatments may be missed. New approaches that better support the identification of responders to CFTR modulators are, therefore, needed. Recent findings We, here, review how a patient-oriented research collaboration between basic and clinical scientists and a national cystic fibrosis patient organization led to the development of a CFTR-dependent assay using primary stem cell cultures termed intestinal organoids that can measure the individual efficacy of CFTR modulators in a preclinical laboratory setting. Early observations suggest that drug responses in organoids reflect drug responses in vivo. Summary We particularly focus on the importance of patient-oriented research collaborations, and how such a collaboration helped to develop a personalized medicine approach for CFTR modulators. Intestinal organoids and biobanks thereof may be used to select optimal, individually tailored treatments for current and future (combinations of) CFTR modulators with only limited patient discomfort
Maternal use of probiotics during pregnancy and effects on their offspring's health in an unselected population
Probiotics are used by women in the perinatal period and may improve balance of microbiota, with possible health benefits for both mother and baby. Characteristics and (health) behaviour patterns of mothers using probiotics during pregnancy, and health effects on their offspring, were investigated. Differences between mothers using probiotics during pregnancy and those who did not, were assessed. In total, 341 out of 2491 (13.7 %) mothers reported use of probiotics during pregnancy. There were no significant differences in maternal features (gestation, age, ethnicity, education) between users and non-users. Logistic regression analyses showed that consumption of probiotics was significantly associated with use of homeopathic products [odds ratio (OR) 1.65, 95 % confidence interval (CI) 1.17-2.33, p = 0.005], maternal history of smoking (OR 1.72, 95 % CI 1.25-2.37, p = 0.001) and paternal history of smoking (OR 1.39, 95 % CI 1.01-1.89, p = 0.05). Common disease symptoms during the first year of life in the offspring did not differ between both groups. CONCLUSION: The use of probiotics or other health-related products without doctor's prescription during pregnancy might point to compensation for types of less favourable behaviour. Probiotic use during pregnancy does not seem to induce positive health effects in the offspring in an unselected population. What is Known: • Aberrant microbiota compositions have been detected during critical periods when early programming occurs including pregnancy and early neonatal life. • Probiotics modulate intestinal microbiota composition and are associated with positive health effects. What is New: • The use of probiotics or other health-related products without doctor's prescription during pregnancy is associated with and might point to compensation for types of less favourable behaviour. • Probiotic use during pregnancy does not induce positive health effects in the offspring in this unselected population
Organoid-guided synergistic treatment of minimal function CFTR mutations with CFTR modulators, roflumilast and simvastatin:a personalised approach
Physiological predictors of cardiorespiratory fitness in children and adolescents with cystic fibrosis without ventilatory limitation
Objectives: [1] To investigate the cardiorespiratory fitness (CRF) levels in children and adolescents with cystic fibrosis (CF) with no ventilatory limitation (ventilatory reserve ⩾ 15%) during exercise, and [2] to assess which physiological factors are related to CRF. Methods: A cross-sectional study design was used in 8- to 18-year-old children and adolescents with CF. Cardiopulmonary exercise testing was used to determine peak oxygen uptake normalized to body weight as a measure of CRF. Patients were defined as having ‘low CRF’ when CRF was less than 82%predicted. Physiological predictors used in this study were body mass index z-score, P. Aeruginosa lung infection, impaired glucose tolerance (IGT) including CF-related diabetes, CF-related liver disease, sweat chloride concentration, and self-reported physical activity. Backward likelihood ratio (LR) logistic regression analysis was used. Results: Sixty children and adolescents (51.7% boys) with a median age of 15.3 years (25th–75th percentile: 12.9–17.0 years) and a mean percentage predicted forced expiratory volume in 1 second of 88.5% (±16.9) participated. Mean percentage predicted CRF (ppVO 2peak/kg ) was 81.4% (±12.4, range: 51%–105%). Thirty-three patients (55.0%) were classified as having ‘low CRF’. The final model that best predicted low CRF included IGT ( p  = 0.085; Exp(B) = 6.770) and P. Aeruginosa lung infection (p = 0.095; Exp(B) = 3.945). This model was able to explain between 26.7% and 35.6% of variance. Conclusions: CRF is reduced in over half of children and adolescents with CF with normal ventilatory reserve. Glucose intolerance and P. Aeruginosa lung infection seem to be associated to low CRF in children and adolescents with CF
Prediction of Real-World Long-Term Outcomes of People with CF Homozygous for the F508del Mutation Treated with CFTR Modulators
The clinical response to cystic fibrosis transmembrane conductance regulator (CFTR) modulators is variable within people with cystic fibrosis (pwCF) homozygous for the F508del mutation. The prediction of clinical effect in individual patients would be useful to target therapy to those who would benefit from it. A multicenter observational cohort study was conducted including 97 pwCF (F508del/F508del), who started lumacaftor/ivacaftor (LUM/IVA) treatment before June 2018. In order to assess the associations of individual in vivo and in vitro biomarkers with clinical outcomes, we collected clinical data regarding sex, age, and sweat chloride concentration (SwCl) at baseline and after six months of LUM/IVA; the percent predicted forced expiratory volume in 1 s (ppFEV1) and the number of pulmonary exacerbations (PEx) during the three years before up to three years after modulator initiation; and the forskolin-induced swelling (FIS) responses to LUM/IVA, quantified in intestinal organoids. On a group level, the results showed an acute change in ppFEV1 after LUM/IVA initiation (2.34%, 95% CI 0.85–3.82, p = 0.003), but no significant change in annual ppFEV1 decline in the three years after LUM/IVA compared to the three years before (change: 0.11% per year, 95%CI: −1.94–2.19, p = 0.913). Neither of these two outcomes was associated with any of the candidate predictors on an individual level. The median number of pulmonary exacerbations (PEx) per patient year did not significantly change in the three years after LUM/IVA compared to the years before (median: 0.33/patient year, IQR: 0–0.67 before vs. median: 0/patient year, IQR: 0–0.67 after p = 0. 268). The PEx rate after modulator initiation was associated with the PEx rate before (IRR: 2.26, 95%CI: 1.67–3.08, p p = 0.001) and with sweat chloride concentration (SwCl) at baseline (IRR: 0.96, 95%CI: 0.94–0.98, p = 0.001). The change in SwCl was also significant (−22.9 mmol/L (95%CI: −27.1–−18.8, p p p = 0.013). In conclusion, ppFEV1 decline after CFTR modulator initiation remains difficult to predict in individual patients in a real-world setting, with limited effectiveness for double CFTR modulator therapies. The PEx rate prior to CFTR modulator treatment initiation, sex and SwCl at baseline could be potential predictors of long-term PEx rate and of changes in SwCl after modulator initiation