Children's interstitial lung diseases (chILD) cover many rare entities, frequently not diagnosed or studied in detail. There is a great need for specialised advice and for internationally agreed ...subclassification of entities collected in a register.Our objective was to implement an international management platform with independent multidisciplinary review of cases at presentation for long-term follow-up and to test if this would allow for more accurate diagnosis. Also, quality and reproducibility of a diagnostic subclassification system were assessed using a collection of 25 complex chILD cases.
A web-based chILD management platform with a registry and biobank was successfully designed and implemented.
Over a 3-year period, 575 patients were included for observation spanning a wide spectrum of chILD. In 346 patients, multidisciplinary reviews were completed by teams at five international sites (Munich 51%, London 12%, Hannover 31%, Ankara 1% and Paris 5%). In 13%, the diagnosis reached by the referring team was not confirmed by peer review. Among these, the diagnosis initially given was wrong (27%), imprecise (50%) or significant information was added (23%).The ability of nine expert clinicians to subcategorise the final diagnosis into the chILD-EU register classification had an overall exact inter-rater agreement of 59% on first assessment and after training, 64%. Only 10% of the 'wrong' answers resulted in allocation to an incorrect category. Subcategorisation proved useful but training is needed for optimal implementation.
We have shown that chILD-EU has generated a platform to help the clinical assessment of chILD.
Results, NCT02852928.
•We developed the first chILD-specific patient education-program.•Preliminary results of our pilot study show improved self-efficacy among patients with chILD.•Participants reported high satisfaction ...with the program.•Physicians also reported high satisfaction with conducting patient education.•Participants did not experience changes in HrQoL after the intervention.
Patient education in children with rare chronic diseases like children’s interstitial lung disease (chILD) remains a challenge.
To develop and evaluate a component-based educational program for individual counselling and to improve patients’ and caregivers’ self-efficacy and treatment satisfaction. Furthermore, to create chILD-specific educational material and assess physicians’ satisfaction with the intervention as well as patients’ health-related quality of life (HrQoL).
The study was conducted in two German centers for pediatric pulmonology, as a single-group intervention with pre-post-follow-up design.
Participants (N = 107, age: M = 7.67, SD = 5.90) showed significant improvement of self-efficacy (self-report: t = 2.89, p < 0.01; proxy-report: t = 3.03, p < 0.01), and satisfaction (patients: t = 3.56, p = 0.001; parents t = 6.38, p < 0.001) with the medical consultations. There were no pre-post differences in HrQoL. Participants were highly satisfied with the material and the physicians with the program.
The chILD education-program is a promising strategy to improve patients’ and their parents’ self-efficacy and treatment-satisfaction. Specific effects of the intervention need to be determined in a randomized controlled trial.
Healthcare providers managing pediatric patients with chILD, may choose to use a patient education-program specifically tailored to the needs of chILD patients and their families, such as the program described here, which is the first of its kind.
Glutathione is the major antioxidant in the extracellular lining fluid of the lungs and depleted in patients with cystic fibrosis (CF).
We aimed to assess glutathione delivered by inhalation as a ...potential treatment for CF lung disease.
This randomized, double-blind, placebo-controlled trial evaluated inhaled glutathione in subjects with CF 8 years of age and older and FEV1 of 40-90% of predicted. Subjects were randomized to receive 646 mg glutathione in 4 ml (n = 73) or placebo (n = 80) via an investigational eFlow nebulizer every 12 hours for 6 months.
FEV1 (absolute values), both as pre-post differences (P = 0.180) and as area under the curves (P = 0.205), were the primary efficacy endpoints, and were not different between the glutathione group and the placebo group over the 6-month treatment period. Exploratory analysis showed an increase of FEV1 from baseline over placebo of 100 ml or 2.2% predicted; this was significant at 3 months, but not later. Subjects receiving glutathione had neither fewer pulmonary exacerbations, nor better scores for quality of life. Whereas increased glutathione and metabolites in sputum demonstrated significant delivery to the lungs, there was no indication of diminished oxidative stress to proteins or lipids, and no evidence for anti-inflammatory or antiproteolytic actions of glutathione supplemented to the airways. The adverse event incidence was similar between glutathione and placebo.
Inhaled glutathione in the dose administered did not demonstrate clinically relevant improvements in lung function, pulmonary exacerbation frequency, or patient-reported outcomes. Glutathione delivery to the airways was not associated with changes in markers of oxidation, proteolysis, or inflammation. Clinical trial registered with www.clinicaltrials.gov (NCT00506688) and https://eudract.ema.europa.eu/index.html (EudraCT 2005-003870-88).
No results of controlled trials are available for any of the few treatments offered to children with interstitial lung diseases (chILD). We evaluated hydroxychloroquine (HCQ) in a phase 2, ...prospective, multicentre, 1:1-randomized, double-blind, placebo-controlled, parallel-group/crossover trial. HCQ (START arm) or placebo were given for 4 weeks. Then all subjects received HCQ for another 4 weeks. In the STOP arm subjects already taking HCQ were randomized to 12 weeks of HCQ or placebo (= withdrawal of HCQ). Then all subjects stopped treatment and were observed for another 12 weeks.
26 subjects were included in the START arm, 9 in the STOP arm, of these four subjects participated in both arms. The primary endpoint, presence or absence of a response to treatment, assessed as oxygenation (calculated from a change in transcutaneous O
-saturation of ≥ 5%, respiratory rate ≥ 20% or level of respiratory support), did not differ between placebo and HCQ groups. Secondary endpoints including change of O
-saturation ≥ 3%, health related quality of life, pulmonary function and 6-min-walk-test distance, were not different between groups. Finally combining all placebo and all HCQ treatment periods did not identify significant treatment effects. Overall effect sizes were small. HCQ was well tolerated, adverse events were not different between placebo and HCQ.
Acknowledging important shortcomings of the study, including a small study population, the treatment duration, lack of outcomes like lung function testing below age of 6 years, the small effect size of HCQ treatment observed requires careful reassessments of prescriptions in everyday practice (EudraCT-Nr.: 2013-003714-40, www.clinicaltrialsregister.eu , registered 02.07.2013). Registration The study was registered on 2 July 2013 (Eudra-CT Number: 2013-003714-40), whereas the approval by BfArM was received 24.11.2014, followed by the approval by the lead EC of the University Hospital Munich on 20.01.2015. At clinicaltrials.gov the trial was additionally registered on November 8, 2015 (NCT02615938).
Improved inhalation device/drug combinations are necessary to advance inhaled antibiotic therapy in cystic fibrosis (CF). Previously, for a novel drug/inhaler combination, equivalent lung deposition ...was demonstrated; here, we investigated its safety and pharmacokinetics.
In a randomized, open-labeled, multicenter, active controlled, parallel 28-day study, we compared a new tobramycin formulation (T100 PARI, 150 mg/1.5 mL) nebulized with a drug-specific PARI eFlow(®) nebulizer and TOBI(®) (300 mg/5 mL) nebulized with a PARI LC PLUS(®) nebulizer in 78 CF patients.
Noninferiority of the primary endpoint peak plasma tobramycin concentrations and the secondary endpoint area under the concentration time curves in plasma were observed. Sputum concentrations exceeded expected minimum inhibitory concentrations of Pseudomonas aeruginosa and were the same across both treatment groups, as were tolerability and safety. The nebulization time (4.6 vs. 16.1 min) was much shorter for the new drug/device combination.
Inhaled therapy with T100 PARI delivered by an investigational eFlow offers a patient treatment time benefit and comparable safety and pharmacokinetics.
Patient-derived 3D cell culture systems are currently advancing cancer research since they potentiate the molecular analysis of tissue-like properties and drug response under well-defined conditions. ...However, our understanding of the relationship between the heterogeneity of morphological phenotypes and the underlying transcriptome is still limited. To address this issue, we here introduce "pheno-seq" to directly link visual features of 3D cell culture systems with profiling their transcriptome. As prototypic applications breast and colorectal cancer (CRC) spheroids were analyzed by pheno-seq. We identified characteristic gene expression signatures of epithelial-to-mesenchymal transition that are associated with invasive growth behavior of clonal breast cancer spheroids. Furthermore, we linked long-term proliferative capacity in a patient-derived model of CRC to a lowly abundant PROX1-positive cancer stem cell subtype. We anticipate that the ability to integrate transcriptome analysis and morphological patho-phenotypes of cancer cells will provide novel insight on the molecular origins of intratumor heterogeneity.
The sugar and alcohol industries provide promising alternative energy sources to replace the use of petroleum derivatives. Vinasse is a byproduct of the alcoholic fermentation of various raw ...materials, and is used in the fertirrigation of sugarcane plantations. However, its excessive use leads to many soil and groundwater related problems, including toxicity to living organisms, acidification of soil and water, accumulation of heavy metals, and contamination of groundwater. The use of integrated systems, such as stabilization, filtration, and phytoremediation, have attracted interest in the treatment of wastewater from various sources, as these highly effective biogeochemical systems can reduce the pollutant concentrations in wastewater, thereby reducing its adverse effects. The aim of this work was to develop a hybrid treatment system to optimize the physical and chemical characteristics of vinasse so that it can be used as fertilizer for crops with a lower pollution impact. The results of this study validated the effectiveness of the proposed system and demonstrated positive modifications of vinasse.
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•The stabilization is the essential step in the hybrid treatment system.•The phytoremediation was responsible to reduction of the biodegradable part.•Low COD/BOD index indicated the biological treatment was suitable to vinasse.•The hybrid treatment system is an effective biogeochemical system.
HIV-1 protease is subjected to dual selection pressure exerted by protease inhibitors (PIs) and cytotoxic T lymphocytes (CTL). Recently, we identified KMIGGIGGF (KF9) as a HLA-B*1501-restricted CTL ...epitope, including several major PI resistance mutations (M46I/L, I47A/V, G48V, I50V). To assess potential interactions between KF9-specific CTL and emergence of these important resistance mutations, we studied CTL recognition of the mutations and analyzed protease sequences in an HLA-I–typed patient cohort.
CTL recognition of KF9 and resistance mutations in KF9 were studied in 38 HLA-B*1501-positive HIV-1–infected patients using variant KF9 peptides in interferon-g enzyme-linked immunospot assays. Protease sequences were analyzed in 302 HLA-I–typed HIV-1–infected patients.
G48V abolished KF9 recognition by CTL in all patients. Furthermore, M46I, I47A, and I50V could impair or abolish CTL recognition in many patients. In contrast, M46L and I47V showed good CTL recognition in nearly all patients. HIV-1 protease sequence analysis showed no statistical correlation between the occurrence of resistance mutations in KF9 and HLA-B*1501. Viral load in patients failing therapy with KF9 mutations was significantly lower in HLA-B*1501-positive patients in comparison with HLA-B*1501-negative patients.
PI mutations, G48V, M46I, and I47A, can abrogate CTL recognition, indicating potential interactions between development of drug resistance and CTL response. However, we could not find evidence that development of these PI mutations is influenced by KF9-specific CTL.
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