Non-invasive ventilation versus oxygen therapy in cystic fibrosis: Long-term effects - Reply.

Respirology. 2019 Oct 11;:

Authors: Milross MA, Piper AJ, Dwyer TJ, Bye PTP

PMID: 31605432 [PubMed - as supplied by publisher]

Bile Acids, Microbiota, and Cystic Fibrosis: Channeling Intestinal FXR Signals.

Cell Mol Gastroenterol Hepatol. 2019 Oct 08;:

Authors: Mchenry S, Davidson NO

PMID: 31604089 [PubMed - as supplied by publisher]

Changes in Airway Microbiome and Inflammation with Ivacaftor Treatment in Patients with Cystic Fibrosis and the G551D Mutation.

Ann Am Thorac Soc. 2019 Oct 11;:

Authors: Harris JK, Wagner BD, Zemanick ET, Robertson CE, Stevens MJ, Heltshe SL, Rowe SM, Sagel SD, GOAL Investigators of the Cystic Fibrosis Foundation Therapeutics Development Network

Abstract
RATIONALE: Modulation of the cystic fibrosis transmembrane conductance regulator (CFTR) protein improves clinical outcomes in patients with cystic fibrosis (CF) and specific CFTR genetic mutations. It remains unclear how improving CFTR function modifies existing airway infection and inflammation.
OBJECTIVE: To compare sputum microbiome and markers of inflammation before and after 6 months of ivacaftor treatment Methods: The study included 31 people with CF, ages 10 and older, with at least one G551D CFTR allele and an FEV1 ≥ 40% predicted who were enrolled in the G551D Observational (GOAL) study. Sputum samples were collected either by induction (n = 14) or by spontaneous expectoration (n = 17) before and 6 months after initiation of ivacaftor. Changes in bacterial community indices by sequencing of 16S rRNA amplicons, total and specific bacterial load, and a panel of proteases, antiproteases, and inflammatory cytokines were determined.
RESULTS: The cohort that spontaneously expectorated sputum had a lower FEV1, higher proportion with Pseudomonas aeruginosa infection, and higher concentrations of sputum inflammatory markers compared with the cohort that provided sputum by induction. While the overall cohort experienced significant improvements in FEV1 and reductions in sweat chloride, no significant changes in bacterial diversity, specific bacterial pathogens, or markers of inflammation were observed in these subjects. Neither total bacterial load nor presence of Pseudomonas changed significantly between paired samples with ivacaftor treatment. Younger patients experienced more shifts in their microbial communities than older patients.
CONCLUSIONS: In this multicenter cohort, six months of ivacaftor treatment were not associated with significant changes in airway microbial communities or measures of inflammation. These data suggest that concomitant antimicrobial and anti-inflammatory treatments will still be needed to manage airway disease in CF patients treated with highly effective CFTR modulator therapy, especially in older patients with more advanced disease.

PMID: 31604026 [PubMed - as supplied by publisher]

Quantifying Long-term Changes in Lung Function and Exacerbations after Initiation of Azithromycin in Cystic Fibrosis.

Ann Am Thorac Soc. 2019 Oct 11;:

Authors: Denis A, Touzet S, Diabaté L, Durieu I, Lemonnier L, Poupon-Bourdy S, Iwaz J, Reynaud Q, Rabilloud M

Abstract
RATIONALE: In cystic fibrosis, information on the efficacy of azithromycin past 12 months of treatment is still scarce.
OBJECTIVE: The study sought to quantify the changes in lung function and the number of intravenous antibiotic courses after initiation of azithromycin in patients included in the French Cystic Fibrosis Registry.
METHODS: The study followed-up 1,065 children and 990 adults from 2 years before to 5 years after long-term azithromycin treatment initiated between 2001 and 2011. Mixed change-point models were used to quantify the changes in the forced expiratory volume in one second and the yearly number of intravenous antibiotic courses.
RESULTS: In the year of treatment initiation, the mean forced expiratory volume was significantly higher than expected (+1.6%, p=0.007 in children and +1.3%, p=0.02 in adults). The decline of the forced expiratory volume over time was less marked after than before treatment initiation (slope difference: +0.7% per year, p=0.03 in children and +0.6% per year, p=0.06 in adults). The mean increase in the yearly number of intravenous antibiotic courses was lower after than before treatment initiation. The rate ratio quantifying the effect on the mean increase was 0.93 (95% CI: [0.88; 0.99]; p=0.02) in children and 0.95 (95% CI: [0.90; 1.01]; p=0.08) in adults.
CONCLUSION: In children, long-term azithromycin treatment was associated with immediate and sustained beneficial changes in lung function and sustained beneficial changes in the frequency of pulmonary exacerbations. In adults, it was associated with immediate beneficial changes in lung function.

PMID: 31604024 [PubMed - as supplied by publisher]

Inhaled nitric oxide for treating pain crises in people with sickle cell disease.

Cochrane Database Syst Rev. 2019 Oct 11;10:CD011808

Authors: Aboursheid T, Albaroudi O, Alahdab F

Abstract
BACKGROUND: In people with sickle cell disease, sickled red blood cells cause the occlusion of small blood vessels which presents as episodes of severe pain known as pain crises or vaso-occlusive crises. The pain can occur in the bones, chest, or other parts of the body, and may last several hours to days. Pain relief during crises includes both pharmacologic and non-pharmacologic treatments. The efficacy of inhaled nitric oxide in pain crises has been a controversial issue and hypotheses have been made suggesting a beneficial response due to its vasodilator properties. Yet no conclusive evidence has been presented.This review aims to evaluate the available randomised controlled studies which address this topic.
OBJECTIVES: To capture the available body of evidence evaluating the efficacy and safety of the use of inhaled nitric oxide in treating pain crises in people with sickle cell disease; and to assess the treatment's relevance, robustness, and validity, in order to better guide medical practice in the fields of haematology and palliative care (since recent literature seems to favour the involvement of palliative care for those people).
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register. Unpublished work is identified by searching the abstract books of the European Haematology Association conference; the American Society of Hematology conference; the British Society for Haematology Annual Scientific Meeting; the Caribbean Health Research Council Meetings; and the National Sickle Cell Disease Program Annual Meeting.Date of most recent search: 19 September 2019.We also searched ongoing study registries, date of most recent search: 26 September 2019.
SELECTION CRITERIA: Randomised and quasi-randomised trials comparing inhaled nitric oxide with placebo, or standardized way of treatment of pain crises in people with sickle cell disease.
DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data (including adverse event data). A third author helped clarify any disagreement. When the data were not reported in the text, we attempted to extract the data from any table or figure available. We contacted trial authors for additional information. We assessed the quality of the evidence using the GRADE criteria MAIN RESULTS: We identified six trials, three of which (188 participants) were eligible for inclusion in the review. There were equal numbers of males and females; and most participants were adults, although one small trial was conducted in a children's hospital and recruited children over the age of 10 years. All three parallel trials compared inhaled nitric oxygen (80 ppm) to placebo (room air) for four hours; one trial continued administering nitric oxide (40 ppm) for a further four hours. This extended trial had an overall low risk of bias; however, in the remaining two trials we had concerns about the risk of bias from the small sample size and additionally a high risk of bias due to financial conflicts of interest in one of these smaller trials. We were only able to analyse some limited data from the eight-hour trial and report the remaining results narratively.The time to pain resolution was only reported in one trial (150 participants), showing there may be little or no difference between the two groups: with inhaled nitric oxide median 73.0 hours (95% confidence interval (CI) 46.0 to 91.0) and with placebo median 65.5 hours (95% CI 48.1 to 84.0) (low-quality evidence). No trial reported on the duration of the initial pain crisis. Only one large trial reported on the frequency of pain crises in the follow-up period and found there may be little or no difference between the inhaled nitric oxide and placebo groups for a return to the ED, risk ratio 0.73 (95% CI 0.31 to 1.71) or for re-hospitalisation, risk ratio 0.53 (95% CI 0.25 to 1.11) (150 participants; low-quality evidence).There may be little or no difference between treatment and placebo in terms of reduction in pain score at any time point up to eight hours (150 participants). The two smaller trials reported a beneficial effect of inhaled nitric oxide in reducing the visual analogue pain score after four hours of the intervention, but these trials were small and limited compared to the first trial.Analgesic use was reported not to differ greatly between the inhaled nitric oxide group and placebo group in any of the three trials, but no analysable data were provided. The median duration of hospitalisation was reported by two trials, in the largest trial the placebo group had the shorter duration and in the second smaller (paediatric) trial hospitalisation was shorter in the treatment group.Only the largest trial (150 participants) reported serious adverse events, with no increase in the inhaled nitric oxide group during or after the intervention compared to the control group (acute chest syndrome occurred in 5 out of 75 participants from each group, pyrexia in 1 out of 75 participants from each group, dysphagia and a drop in haemoglobin were each reported in 1 out of 75 participants in the inhaled nitric oxide group, but not in the placebo group) (low-quality evidence).
AUTHORS' CONCLUSIONS: The currently available trials do not provide sufficient evidence to determine the effects (benefits or harms) of using inhaled nitric oxide to treat pain (vaso-occlusive) crises in people with sickle cell disease. Large-scale, long-term trials are needed to provide more robust data in this area. Patient-important outcomes (e.g. measures of pain and time to pain resolution and amounts of analgesics used), as well as use of healthcare services should be measured and reported in a standardized form.

PMID: 31603241 [PubMed - as supplied by publisher]

Osteopenia and Osteoporosis in Patients with Bronchiectasis: Association with Respiratory Parameters, Body Composition, Muscle Strength and Bone Remodeling Biomarkers.

Sci Rep. 2019 Oct 10;9(1):14496

Authors: Contreras-Bolívar V, Olveira G, Porras N, Acosta E, Rubio-Martín E, Tapia-Guerrero MJ, Abuin-Fernández J, Olveira C

Abstract
The prevalence of osteopenia/osteoporosis has not been sufficiently studied in people with bronchiectasis not due to cystic fibrosis (BC), nor has its relationship with other variables (clinical, body composition and bone turnover and inflammation markers) been sufficiently studied. Our aim was to determine the prevalence of osteopenia and osteoporosis and related factors in patients with BC. We did a cross-sectional study in people with BC in a clinically stable state. Spirometric parameters, annual exacerbations and analysis with bone turnover markers (BTM) and inflammation markers were evaluated. Densitometry (DXA) was performed for body composition, bone mineral density (BMD) and handgrip strength. 123 patients were studied (65% women, mean age 49.6 ± 18.8, Body Mass Index (BMI) 24.8 ± 4.7 kg/m2). 62.8% and 62.5% of men and women, respectively, had normal bone mineral density, 30.2% and 22.2% osteopenia and 7% and 15% osteoporosis. 52 patients (56.2%) had low fat-free mass: 68.9% women and 28.6% men. Patients with decreased bone mass had significantly lower muscle strength, maximum expiratory volume in the first second (FEV1%), vitamin D, higher levels of C-terminal telopeptide of type 1 collagen (CTX) and total osteocalcin and underarboxylated osteocalcin (ucOC). We observed significant and negative correlations between BMD and the number of serious exacerbations per year CTX and undercarboxylated osteocalcin. We observed significant positive correlations between BMD, fat free mass index (FFMI) and handgrip dynamometry. The study suggest that the prevalence of osteoporosis was high in relation to the demographic characteristics. Respiratory parameters, body composition, muscle strength and bone remodeling markers were associated with a lower bone mineral density.

PMID: 31601899 [PubMed - in process]

Cl- channels regulate lipid droplet formation via Rab8a expression during adipocyte differentiation.

Biosci Biotechnol Biochem. 2019 Oct 10;:1-9

Authors: Ouchi K, Yoshie S, Miyake M, Hazama A

Abstract
Several studies have shown that Cl- channels regulate the differentiation of some cell types. Thus, we investigated the role of Cl- channels on adipocyte differentiation using adipose tissue-derived stem cells (ASCs) and Cl- channel blocker. We induced rabbit ASCs into adipocytes using Cl- channel blocker. The expression levels of adipocyte markers were no significant difference between the cells treated with a Cl- channel blocker NPPB and untreated cells. However, when the cells were treated with NPPB, lipid droplets (LDs) sizes decreased compared with the untreated control. Interestingly, the expression levels of Rab8a, which is known as a regulator of LD fusion, were also decreased in the cells treated with NPPB. Other Cl- channel blockers, DIDS and IAA-94, also inhibited large LDs formation and Rab8a expression. These results demonstrate that Cl- channels do not regulate the adipocyte differentiation, but do regulate the LDs formation via Rab8a expression. Abbreviations: ASCs: adipose tissue-derived stem cells; LDs: lipid droplets; RUNX2: runt-related transcription factor 2; CFTR: cystic fibrosis transmembrane conductance regulator; TG: triacylglycerol; FA: fatty acid; GLUT4: glucose transporter type 4; ER: endoplasmic reticulum; ADRP: adipose differentiation-related protein; TIP47: tail-interacting protein of 47 kD; HSL: hormone sensitive lipase; PBS: phosphate-buffered saline; DMEM: Dulbecco's modified Eagle Medium; FBS: fetal bovine serum; SMA: smooth muscle actin; FAS: fatty acid synthase; ZONAB: ZO-1 associated nucleic acid binding protein; PPAR-γ: peroxisome proliferator-activated receptor-γ; C/EBPα: CCAAT/enhancer binding protein α; CE: cholesteryl ester; V-ATPase: vacuolar H+ ATPase.

PMID: 31601151 [PubMed - as supplied by publisher]

Real-Life Safety and Effectiveness of Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis.

Am J Respir Crit Care Med. 2019 Oct 11;:

Authors: Burgel PR, Munck A, Durieu I, Chiron R, Mely L, Prevotat A, Murris-Espin M, Porzio M, Abely M, Reix P, Marguet C, Macey J, Sermet-Gaudelus I, Corvol H, Bui S, Lemonnier L, Dehilotte C, Da Silva J, Paillasseur JL, Hubert D, French Cystic Fibrosis Reference Network study group

Abstract
RATIONALE: Lumacaftor-ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination recently approved for patients with cystic fibrosis (CF) homozygous for the Phe508del mutation.
OBJECTIVES: To evaluate the safety and effectiveness of lumacaftor-ivacaftor in adolescents (≥12 years) and adults (≥18 years) in a real-life post-approval setting.
METHODS: The study was conducted in the 47 CF reference centers in France. All patients who initiated lumacaftor-ivacaftor from January 1st to December 31st 2016 were eligible. Patients were evaluated for lumacaftor-ivacaftor safety and effectiveness over the first year of treatment following the French CF learning society's recommendations.
MAIN RESULTS: Among the 845 patients (292 adolescents, 553 adults) who initiated lumacaftor-ivacaftor, 18.2% (154 patients) discontinued treatment due to respiratory (48.1%, 74 patients) or non-respiratory (27.9%, 43 patients) adverse events. In multivariable logistic regression, factors associated with increased rates of discontinuation included adult age group, percent predicted forced expiratory volume in 1 sec (ppFEV1)<40% and numbers of intravenous antibiotic courses during the year prior to lumacaftor-ivacaftor initiation. Patients with continuous exposure to lumacaftor-ivacaftor showed an absolute increase in ppFEV1 (+3.67%), an increase in body mass index (+0.73 kg/m2), and a decrease in intravenous antibiotic courses by 35%. Patients who discontinued treatment had significant decrease in ppFEV1, without improvement in BMI or decrease in intravenous antibiotic courses.
CONCLUSIONS: Lumacaftor-ivacaftor was associated with improvement in lung disease and nutritional status in patients who tolerated treatment. Adults who discontinued lumacaftor-ivacaftor, often due to adverse events, were found at high risk of clinical deterioration.

PMID: 31601120 [PubMed - as supplied by publisher]

N-acetylcysteine for Management of Distal Intestinal Obstruction Syndrome.

J Pediatr Pharmacol Ther. 2019 Sep-Oct;24(5):390-397

Authors: Schauble AL, Bisaccia EK, Lee G, Nasr SZ

Abstract
With the improving life expectancy of cystic fibrosis patients, new manifestations of the disease are emerging. Distal intestinal obstruction syndrome is one of the increasingly noted complications. Traditionally this syndrome was treated surgically. N-acetylcysteine is sometimes used as a non-surgical treatment option despite lack of definitive evidence for its efficacy and safety and not being mentioned in current treatment guidelines. The existing case reports suggest that N-acetylcysteine may have a place in therapy for older patients with incomplete distal intestinal obstruction syndrome to relieve the initial obstruction or following disimpaction to ensure clearance of remaining ileus and to prevent obstruction recurrence. In younger patients (e.g., <3 years of age), efficacy of N-acetylcysteine has been controversial and its use has been associated with drug-induced liver injury and hypernatremia. In the cases included in this review, 4% N-acetylcysteine was the formulation most commonly used. Since higher concentrations have been associated with increased adverse effects and mucosal injury, lower concentrations and dosages should be used when using N-acetylcysteine until further evidence becomes available. Proper administration technique and monitoring parameters are not well defined in current literature. Prospective, well-designed clinical trials are lacking and would be helpful to better define the role of N-acetylcysteine in distal intestinal obstruction syndrome.

PMID: 31598102 [PubMed]

Reducing Health Care Disparities in Sickle Cell Disease: A Review.

Public Health Rep. 2019 Oct 10;:33354919881438

Authors: Lee L, Smith-Whitley K, Banks S, Puckrein G

Abstract
Sickle cell disease (SCD) is an inherited blood disorder most common among African American and Hispanic American persons. The disease can cause substantial, long-term, and costly health problems, including infections, stroke, and kidney failure, many of which can reduce life expectancy. Disparities in receiving health care among African Americans and other racial/ethnic minority groups in the United States are well known and directly related to poor outcomes associated with SCD. As an orphan disease-one that affects <200 000 persons nationwide-SCD does not receive the research funding and pharmaceutical investment directed to other orphan diseases. For example, cystic fibrosis affects fewer than half the number of persons but receives 3.5 times the funding from the National Institutes of Health and 440 times the funding from national foundations. In this review, we discuss the health inequities affecting persons with SCD, describe programs intended to improve their care, and identify actions that could be taken to further reduce these inequities, improve care, control treatment costs, and ease the burden of disease.

PMID: 31600481 [PubMed - as supplied by publisher]

Putting CHIP(S) on the Table - Introducing Nitrosothiols (SNOs) into the Arena of CFTR Modulation.

Am J Respir Cell Mol Biol. 2019 Oct 10;:

Authors: Addy C, Schock BC

PMID: 31600091 [PubMed - as supplied by publisher]

Health care provider's experiences, practices, and recommendations for interventions and screening of cystic fibrosis patients with disordered eating: A qualitative analysis.

Chronic Illn. 2019 Oct 10;:1742395319881182

Authors: Quick V, Chang G

PMID: 31600084 [PubMed - as supplied by publisher]

S-Nitrosylation of CHIP Enhances F508Del CFTR Maturation.

Am J Respir Cell Mol Biol. 2019 Oct 09;:

Authors: Zaman K, Knight J, Hussain F, Cao R, Estabrooks SK, Altawallbeh G, Holloway K, Jafri A, Sawczak V, Li Y, Getsy P, Sun F, Raffay T, Cotton C, Brodsky JL, Periasamy A, Lewis SJ, Gaston B

Abstract
S-Nitrosothiols (SNOs) are endogenous signaling compounds with a diverse spectrum of beneficial airway effects that are both cGMP-dependent and -independent. SNOs are present in healthy human airways, but levels are low in the airways of cystic fibrosis (CF) patients. Here, we evaluated the interactions of SNOs with molecular co-chaperone C-terminus Hsc70 interacting protein (CHIP)- an E3 ubiquitin ligase that targets improperly folded CFTR for degradation. CHIP was expressed in primary human bronchial epithelial and CFBE41o - cells expressing either wild type or F508del CFTR. Confocal microscopy and immunoprecipitation studies showed the cellular co-localization of CFTR and CHIP and showed that GSNO inhibits the CHIP-CFTR interaction. SNOs significantly reduced both the expression and activity of CHIP, leading to higher levels of both the immature and mature forms of F508del CFTR; in fact, inhibition of the expression and function of CHIP by SNOs not only improved CFTR maturation, but also increased CFTR stability at the cell membrane. GSNO treated cells also had more S-nitrosylated CHIP and less ubiquitinated CFTR than untreated cells, suggesting that S-nitrosylation of CHIP prevents CFTR ubiquitination by inhibiting CHIP's E3 ubiquitin ligase function. Further, the exogenous SNOs S-nitrosoglutathione diethyl ester (GNODE) and S-nitro-N-acetylcysteine (SNOAC) increased CFTR expression at the cell surface. Following CHIP knockdown with siRNA duplexes specific for CHIP, F508del CFTR expression increased at the cell surface. We conclude that SNOs effectively reduce CHIP-mediated degradation of CFTR, resulting in increased F508del CFTR expression on the surface of airway epithelial cells.

PMID: 31596601 [PubMed - as supplied by publisher]

The Use of Ultrasound as a Tool to Evaluate Pulmonary Disease in Cystic Fibrosis.

Respir Care. 2019 Oct 08;:

Authors: Peixoto AO, Marson FA, Dertkigil SS, Dertkigil RP, Souza TH, Fraga AM, Ribeiro AF, Toro AA, Ribeiro JD

Abstract
BACKGROUND: Lung ultrasound is an examination that allows the assessment of pulmonary involvement by analyzing artifacts. Our primary aim was to correlate our lung ultrasound findings with pulmonary function and the modified Bhalla score in patients with cystic fibrosis.
METHODS: Subjects with cystic fibrosis were evaluated based on the results of lung ultrasound, pulmonary function exams (ie, spirometry before and after the use of a bronchodilator and S pO2 ), and the modified Bhalla score. The partial correlation set by age between lung ultrasound, pulmonary function, and modified Bhalla score was carried out. Lung ultrasound was graded according to a new score, ranging from 0 to 36, with a higher score being associated with a greater degree of involvement. We performed Bland-Altman and linear regression analysis to identify bias between lung ultrasound and modified Bhalla score. Alpha = 0.05.
RESULTS: 18 subjects with cystic fibrosis were included. In partial correlation controlled by age, we observed significant ultrasound score values with weight (partial correlation = -0.579), body mass index (partial correlation = -0.609), S pO2 (partial correlation = -0.728), FVC% (pre-bronchodilator: partial correlation = -0.538; post-bronchodilator: partial correlation = -0.560), FEV1% (pre-bronchodilator: partial correlation = -0.536; post-bronchodilator: partial correlation = -0.546), and modified Bhalla score (partial correlation = 0.607). We did not identify bias between lung ultrasound and modified Bhalla score measured by z-score.
CONCLUSIONS: Lung ultrasound seems to be effective and corroborates with high-resolution computed tomography when evaluated by the modified Bhalla score. At the same time, lung ultrasound had significant correlation with pulmonary function and nutritional status.

PMID: 31594833 [PubMed - as supplied by publisher]

Using digital technology for home monitoring, adherence and self-management in cystic fibrosis: a state-of-the-art review.

Thorax. 2019 Oct 08;:

Authors: Calthorpe RJ, Smith S, Gathercole K, Smyth AR

Abstract
Digital healthcare is a rapidly growing healthcare sector. Its importance has been recognised at both national and international level, with the WHO recently publishing its first global strategy for digital health. The use of digital technology within cystic fibrosis (CF) has also increased. CF is a chronic, life-limiting condition, in which the treatment burden is high and treatment regimens are not static. Digital technologies present an opportunity to support the lives of people with CF. We included 59 articles and protocols in this state-of-the-art review, relating to 48 studies from 1999 until 2019. This provides a comprehensive overview of the expansion and evolution of the use of digital technology. Technology has been used with the aim of increasing accessibility to healthcare, earlier detection of pulmonary exacerbations and objective electronic adherence monitoring. It may also be used to promote adherence and self-management through education, treatment management Apps and social media.

PMID: 31594802 [PubMed - as supplied by publisher]

GLPG2737 in lumacaftor/ivacaftor-treated CF subjects homozygous for the F508del mutation: A randomized phase 2A trial (PELICAN).

J Cyst Fibros. 2019 Oct 05;:

Authors: van Koningsbruggen-Rietschel S, Conrath K, Fischer R, Sutharsan S, Kempa A, Gleiber W, Schwarz C, Hector A, Van Osselaer N, Pano A, Corveleyn S, Bwirire D, Santermans E, Muller K, Bellaire S, Van de Steen O

Abstract
BACKGROUND: Triple combinations of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators demonstrate enhanced clinical efficacy in CF patients with F508del mutation, compared with modest effects of dual combinations. GLPG2737 was developed as a novel corrector for triple combination therapy.
METHODS: This multicenter, randomized, double-blind, placebo-controlled, phase 2a study evaluated GLPG2737 in F508del homozygous subjects who had been receiving lumacaftor 400mg/ivacaftor 250mg for ≥12weeks. The primary outcome was change from baseline in sweat chloride concentration. Other outcomes included assessment of pulmonary function, respiratory symptoms, safety, tolerability, and pharmacokinetics.
RESULTS: Between November 2017 and April 2018, 22 subjects were enrolled and randomized to oral GLPG2737 (75mg; n=14) or placebo (n=8) capsules twice daily for 28days. A significant decrease from baseline in mean sweat chloride concentration occurred at day 28 for GLPG2737 versus placebo (least-squares-mean difference-19.6mmol/L [95% confidence interval (CI) -36.0, -3.2], p=.0210). The absolute improvement, as assessed by least-squares-mean difference in change from baseline, in forced expiratory volume in 1s (percent predicted) at day 28 for GLPG2737 versus placebo was 3.4% (95% CI -0.5, 7.3). Respiratory symptoms in both groups remained stable. Mild/moderate adverse events occurred in 10 (71.4%) and 8 (100%) subjects receiving GLPG2737 and placebo, respectively. Lower exposures of GLPG2737 (and active metabolite M4) were observed than would be expected if administered alone (as lumacaftor induces CYP3A4). Lumacaftor and ivacaftor exposures were as expected.
CONCLUSIONS: GLPG2737 was well tolerated and yielded significant decreases in sweat chloride concentration versus placebo in subjects homozygous for F508del receiving lumacaftor/ivacaftor, demonstrating evidence of increased CFTR activity when added to a potentiator-corrector combination.
FUNDING: Galapagos NV.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03474042.

PMID: 31594690 [PubMed - as supplied by publisher]

Two novel and correlated CF-causing insertions in the (TG)mTn tract of the CFTR gene.

PLoS One. 2019;14(10):e0222838

Authors: Pierandrei S, Blaconà G, Fabrizzi B, Cimino G, Cirilli N, Caporelli N, Angeloni A, Cipolli M, Lucarelli M

Abstract
Two novel and related pathogenic variants of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene were structurally and functionally characterized. These alterations have not been previously described in literature. Two patients with diagnosis of Cystic Fibrosis (CF) based on the presence of one mutated allele, p.Phe508del, pathological sweat test and clinical symptoms were studied. To complete the genotypes of both patients, an extensive genetic and functional analysis of the CFTR gene was performed. Extensive genetic characterization confirmed the presence of p.Phe508del pathogenic variant and revealed, in both patients, the presence of an insertion of part of intron 10 in intron 9 of the CFTR gene, within the (TG)m repeat, with a variable poly-T stretch. The molecular lesions resulted to be very similar in both patients, with only a difference in the number of T in the poly-T stretch. The functional characterization at RNA level revealed a complete anomalous splicing, without exon 10, from the allele with the insertion of both patients. Consequently, the alleles with the insertions are expected not to contribute to the formation of a functional CFTR protein. Molecular and functional features of these alterations are compatible with the definition of novel CF-causing variants of the CFTR gene. This also allowed the completion of the genetic characterization of both patients.

PMID: 31593572 [PubMed - in process]

Secondhand Smoke Exposure and Serum Trypsinogen in Cystic Fibrosis Carriers.

Pancreas. 2019 Oct 08;:

Authors: Ellery KM, Kopp B, Conwell DL, Gariepy C

Abstract
OBJECTIVE: The objective of this study was to determine if infants carrying 1 cystic fibrosis transmembrane receptor (CFTR) mutation demonstrate pancreatic inflammation in response to tobacco exposure.
METHODS: Cystic fibrosis carrier infants aged 4 to 16 weeks were prospectively enrolled. Tobacco exposure was assessed by survey and maternal hair nicotine analysis. Serum immunoreactive trypsinogen (IRT) levels at birth and at the time of recruitment were analyzed relative to the presence or absence of tobacco exposure. The effect of the severity of the CFTR mutation carried by the infant on the tobacco-IRT relationship was also analyzed.
RESULTS: Forty-eight infants completed the study. Newborn screen and follow-up IRT levels were not different between exposed infants (19 by hair analysis) and nonexposed infants (29 by hair analysis). Follow-up IRT levels were lower in infants with more severe CFTR mutations (P = 0.005). There was no difference in follow-up IRT based on CFTR mutation severity in exposed infants. Nonexposed infants with milder CFTR mutations had higher median IRT values on follow-up testing than those with more severe CFTR mutations (P < 0.05).
CONCLUSIONS: The pancreas of cystic fibrosis carrier infants is affected by tobacco exposure, and those carrying less severe CFTR mutations may be more susceptible to tobacco effects.

PMID: 31593019 [PubMed - as supplied by publisher]

Restless Legs Syndrome in Chronic Kidney Disease: Is Iron or Inflammatory Status To Blame?

J Clin Sleep Med. 2019 Oct 08;:

Authors: Riar SK, Greenbaum LA, Bliwise DL, Leu RM

Abstract
STUDY OBJECTIVES: Restless legs syndrome (RLS) is increased in pediatric chronic kidney disease (CKD). In adults without CKD, central nervous system iron deficiency is involved in RLS pathogenesis and a low serum ferritin levels is consequently an indication for initiation of iron therapy. However, children with CKD are at risk for iron deficiency and inflammation, which raises serum ferritin. We examined the role of iron deficiency and inflammation in RLS in pediatric CKD.
METHODS: This cross-sectional study examined RLS prevalence in three groups of pediatric patients with CKD: nontransplant, nondialysis CKD (estimated GFR < 60 mL/min/1.73 m²) (n = 27); renal transplant recipients (n = 65); and dialysis (n = 32). RLS was diagnosed using a validated questionnaire. Serum ferritin < 100 ng/mL or transferrin saturation < 20% defined iron deficiency. Serum high sensitivity C-reactive protein ≥ 1 mg/L defined inflammation.
RESULTS: Among 124 patients, RLS prevalence was 15.3%; this did not differ across groups. There was no significant difference in RLS prevalence between those with and without iron deficiency, defined by either reduced ferritin or transferrin. Median ferritin levels in patients with RLS tended to be higher than in those without RLS (51.2 versus 40.1 ng/mL; P = .08). Inflammation (elevated CRP) also did not differ significantly by RLS status (57.9% [with RLS] versus 41.2% [without RLS], P = .18).
CONCLUSIONS: Neither ferritin nor inflammation differentiated pediatric patients with CKD with and without RLS. This study suggests that the factors mediating the pathogenesis and, potentially, treatment, of RLS in pediatric CKD may be different from non-CKD populations.

PMID: 31591957 [PubMed - as supplied by publisher]

Anaphylaxis and anaphylactoid reactions associated with the insertion of peripherally inserted central catheters: A multiyear comparative retrospective cohort study.

Infect Control Hosp Epidemiol. 2019 Oct 08;:1-7

Authors: Thornton CS, Dumanski J, Margherit C, Vaz-Gonsalves S, McDiarmid S, Parkins MD, Conly JM

Abstract
OBJECTIVE: Peripherally inserted central catheters (PICCs) are a mainstay of nonpermanent vascular access devices. In this study, we assessed patients displaying anaphylaxis or anaphylactoid reactions to the PowerPICC SOLO and Groshong PICC (Bard Access Systems) using the Sherlock tip locating system (TLS).
METHODS: Patients from 2 tertiary-care hospitals were systematically monitored over 4 years for adverse events following the insertion of a PICC using the Sherlock TLS. Insertion data were also collected using the BioFlo PICC (Angiodynamics)from a third hospital site and from The Ottawa Hospital over 4 years as an additional comparator. Three definitions of anaphylaxis and anaphylactoid reactions were utilized, and the Cohen κ was used to assess interrater agreement. Analysis of reactions among the patient cohorts was performed using the χ2 test with Yates correction or the Fisher exact test as appropriate.
RESULTS: Among 8,257 insertions using the TLS PICCs, 37 potential reactions (0.45%) were recorded. Using specific definitions for anaphylaxis or anaphylactoid reactions, 54.1%-91.9% met criteria. Comparator populations using data from Calgary (n = 491) and Ottawa (n = 7,889) using the BioFlo PICC insertion found no reactions. Anaphylactic or anaphylactoid reactions were significantly associated with the PowerPICC SOLO and Groshong PICC with the TLS compared to the BioFlo PICC (P < .0001) across all definitions. The largest subset of patients experiencing adverse reactions had cystic fibrosis (CF) (n = 4, 10.8%).
CONCLUSION: Our study results demonstrate significant adverse events associated with the PowerPICC SOLO and Groshong PICC using the Sherlock TLS inserted across a range of patient populations. The incidence rate of anaphylaxis or anaphylactoid reactions in the CF population at our center is significantly higher than in non-CF patients (P < .001).

PMID: 31591954 [PubMed - as supplied by publisher]