Breastfeeding and IL-10 levels in children affected by cow's milk protein allergy: A restrospective study.

Immunobiology. 2017 Feb;222(2):358-362

Authors: Manti S, Lougaris V, Cuppari C, Tardino L, Dipasquale V, Arrigo T, Salpietro C, Leonardi S

Abstract
AIM: To assess the protective role of breast-feeding in infants with CMPA-related AEDS as well as IL-10 utility as marker of disease evolution.
METHODS: 64 breast-feeding children with CMPA-related AEDS (31 males and 33 females; mean age 5.56±2.41months; 21 mild AEDS; 25 moderate AEDS; 18 severe AEDS) and 60 artificial feeding babies (33 males and 27 females; mean age 6.01±2.08months; 26 mild AEDS; 19 moderate AEDS; 15 severe AEDS) were evaluated. In all patients serum IL-10 levels were detected.
RESULTS: Significant Score Atopic Dermatitis (SCORAD) index point differences between breastfed and not breastfed children (p<0.001) have been detected. The serum IL-10 levels were lower in children with CMPA-related AEDS as compared to the healthy control group (p<0.001). Moreover, a significant inverse correlation between serum IL-10 levels and SCORAD in both enrolled groups has been also noted. In particular, IL-10 levels, in both groups, were significantly lower in children with severe symptoms. Conversely, serum IL-10 levels were significantly increased in children with mild-severe symptoms in both groups. Furthermore, breastfed children, with lower severe symptoms, had higher serum IL-10 levels. Finally, serum total IgE levels were negatively correlated with serum IL-10 levels in both breastfed and non-breastfed children with CMPA-related AEDS (p<0.001).
CONCLUSIONS: We reported that exclusive breast-feeding induces hyposensitization in children with CMPA-related AEDS and it is associated with minor disease severity and higher serum IL-10 levels, resulting as useful disease-monitor marker.

PMID: 27622938 [PubMed - indexed for MEDLINE]

Are we missing the mark? Fever, respiratory symptoms, chest radiographs, and acute chest syndrome in sickle cell disease.

Am J Hematol. 2016 Aug;91(8):E332-3

Authors: Lazarus SG, Kelleman M, Adisa O, Zmitrovich AR, Hagbom R, Cohen S, McCracken CE, Morris CR

PMID: 27153121 [PubMed - indexed for MEDLINE]

Oral cavity health among cystic fibrosis patients: Literature overview.

Adv Clin Exp Med. 2017 Oct;26(7):1147-1153

Authors: Herman K, Kowalczyk-Zając M, Pytrus T

Abstract
Cystic fibrosis is a genetic disorder in which the mutation of the Cystis Fibrosis Transmembrane Conductance Regulator (CFTR) gene that codes the protein forming a chloride channel of epithelial cells results in its distorted functioning. The manifestations of the disorder are mainly observed in the respiratory and digestive system. Accumulation of sticky and thick mucus is the dominant clinical symptom; it leads to chronic infections and gradual tissue destruction. Although cystic fibrosis remains incurable, it is currently feasible to extend patients' life expectancy thanks to modern therapy possibilities. As cystic fibrosis is no longer the domain of pediatricians, health care to CF patients needs to be provided by doctors of various specializations. The multidisciplinary team of doctors should include a dentist aware of specific prevention and treatment needs of this group of patients. It results from the fact that in the course of cystic fibrosis it is possible to observe a variety of changes in the oral cavity environment. The study presents dental issues observed in CF patients and reported in literature. Particular attention was paid to dental caries, mineralization disorders of hard dental tissues, gingivitis and the change in the content and properties of saliva; moreover, prevention and treatment options regarding oral cavity health is this group of patients were taken into consideration.

PMID: 29211365 [PubMed - in process]

Pulmonary aspiration of sinus secretions in patients with cystic fibrosis.

Int Forum Allergy Rhinol. 2017 Dec 06;:

Authors: Nelson J, Karempalis P, Dunitz J, Hunter R, Boyer H

Abstract
BACKGROUND: Indirect evidence suggests that sinonasal secretions are aspirated into the lungs of patients with cystic fibrosis (CF), contributing to infection, subsequent tissue damage, and decreased lung function. Our objective is to determine whether sinonasal secretions are transferred to the lungs in patients with CF-related sinus disease and healthy subjects, particularly in the recumbent position and during sleep.
METHODS: We performed a prospective, controlled trial to detect pulmonary aspiration of radiolabeled albumin applied to the nasal mucosa of study subjects with chronic sinusitis related to CF and control subjects without sinus disease. Radioactive counts were measured in the lungs and compared to background counts in both groups after 8 hours of rest/sleep.
RESULTS: Complete data was collected on 12 CF patients and 6 controls. Eleven patients with CF demonstrated higher lung counts than background counts. The average counts of radiolabeled albumin in the lungs of CF patients were significantly greater than background counts (p = 0.03). Controls did not demonstrate this finding (p > 0.90), with only one-half demonstrating lung counts greater than background counts.
CONCLUSION: This study provides direct evidence of aspiration of sinonasal secretions into the lungs of patients with CF and healthy adults in the recumbent position. The fact that both patients and controls aspirated secretions suggests that aspiration alone does not account for the pathogenesis of lung disease in CF patients.

PMID: 29210505 [PubMed - as supplied by publisher]

Treating Specific Variants Causing Cystic Fibrosis.

JAMA. 2017 Dec 05;318(21):2130-2131

Authors: Cutting GR

PMID: 29209709 [PubMed - in process]

The Role of Multidetector Computed Tomography and the Forced Oscillation Technique in Assessing Lung Damage in Adults With Cystic Fibrosis.

Respir Care. 2017 Dec 05;:

Authors: Lacerda LS, Lopes AJ, Carvalho ARS, Guimarães ARM, Firmida MC, Castro MCS, Mogami R, Melo PL

Abstract
BACKGROUND: With increased survival rates and the consequent emergence of an adult population with cystic fibrosis (CF), developing novel tools for periodic evaluations of these patients has become a new challenge. Thus, we sought to determine the contribution of lung-volume quantification using multidetector computed tomography (CT) in adults with CF and to investigate the association between structural changes and functional abnormalities.
METHODS: This was a cross-sectional study in which 21 adults with CF and 22 control subjects underwent lung-volume quantification using multidetector CT. Voxel densities were divided into 4 bands: -1,000 to -900 Hounsfield units (HU) (hyperaerated region), -900 to -500 HU (normally aerated region), -500 to -100 HU (poorly aerated region), and -100 to 100 HU (non-aerated region). In addition, all participants performed pulmonary function tests including spirometry, body plethysmography, diffusion capacity for carbon monoxide, and the forced oscillation technique.
RESULTS: Adults with CF had more non-aerated regions and poorly aerated regions with lung-volume quantification using multidetector CT than controls. Despite these abnormalities, total lung volume measured by lung-volume quantification using multidetector CT did not differ between subjects and controls. Total lung capacity (TLC) measured by body plethysmography correlated with both total lung volume (rs = 0.71, P < .001) and total air volume (rs = 0.71, P < .001) as measured with lung-volume quantification using multidetector CT. While the hyperaerated regions correlated with the functional markers of gas retention in the lungs (increased residual volume (RV) and RV/TLC ratio), the poorly aerated regions correlated with the resistive parameters measured by the forced oscillation technique (increased intercept resistance and mean resistance). We also observed a correlation between normally aerated regions and highest pulmonary diffusion values (rs = 0.68, P < .001).
CONCLUSIONS: In adults with CF, lung-volume quantification using multidetector CT can estimate the lung volumes of compartments with different densities and determine the aerated and non-aerated contents of the lungs; furthermore, lung-volume quantification using multidetector CT is clearly related to pulmonary function parameters.

PMID: 29208759 [PubMed - as supplied by publisher]

Advancing the GI frontier for patients with CF.

J Cyst Fibros. 2017 Dec 02;:

Authors: Freedman SD, Wilschanski M, Schwarzenberg SJ

PMID: 29208346 [PubMed - as supplied by publisher]

Complexity of phenotypes induced by p.Asn1303Lys-CFTR correlates with difficulty to rescue and activate this protein.

Cell Mol Biol (Noisy-le-grand). 2017 Nov 30;63(11):106-110

Authors: Farhat R, El-Seedy A, Norez C, Talbot H, Pasquet MC, Adolphe C, Kitzis A, Ladevèze V

Abstract
Cystic Fibrosis is the most common recessive autosomal rare disease found in Caucasian. It is caused by mutations on the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) that encodes for a protein located on the apical membrane of epithelial cells. c.3909C&gt;G (p.Asn1303Lys) is one of the most common worldwide mutations located in nucleotide binding domain 2. The effect of the p.Asn1303Lys mutation on misprocessing was studied by immunofluorescence and western blotting analysis in presence and absence of treatment. To evaluate the functionality of potentially rescued p.Asn1303Lys-CFTR, we assessed the channel activity by radioactive iodide efflux. No recovery of the activity was observed in transfected cultured cells treated with VX-809. Thus, our results suggest that multiple drugs may be needed for the treatment of c.3909C&gt;G patients in order to correct and activate p.Asn1303Lys-CFTR as it shows folding and functional defects.

PMID: 29208182 [PubMed - in process]

Vitamin D Levels and Associations in Indian Patients with Primary Sjögren's Syndrome.

J Clin Diagn Res. 2017 Sep;11(9):OC33-OC36

Authors: Sandhya P, Mahasampath G, Mashru P, Bondu JD, Job V, Danda D

Abstract
Introduction: Vitamin D is a steroid hormone belonging to the class of secosteroids with myriad immune functions and has been implicated in aetiopathogenesis of various autoimmune diseases. Although, there have been various studies showing the association of vitamin D in rheumatoid arthritis and lupus in different populations, there have been limited studies on vitamin D and primary Sjögren's Syndrome (pSS). There are no studies on association of vitamin D and pSS from any tropical country including Indian subcontinent.
Aim: The purpose of the study was to look for any association between 25-hydroxyvitamin D (25(OH)D) levels and disease manifestations in Indian patients with pSS.
Materials and Methods: This is a retrospective cross-sectional study done at a tertiary teaching hospital in southern India in 235 patients with pSS. Patients satisfying the American European Consensus Group (AECG) or American College of Rheumatology (ACR) 2012 for pSS between 2008 and 2015 were included if baseline 25(OH)D levels using electrochemiluminescence were available in hospital's laboratory record, 25(OH)D <20 ng/ml,20-30 ng/ml and >30 ng/ml was defined as deficiency, insufficiency and normal, respectively. Clinical laboratory data and disease activity scoring by EULAR Sjögren's syndrome disease activity index (ESSDAI) were retrieved retrospectively. Latitude corresponding to residence of each patient and the season of performing the assay were recorded. Chi-square statistics was done to find associations between categorized 25(OH)D and outcomes and was reported as odds ratio(95% confidence interval).
Results: Mean 25(OH)D for 235 patients with pSS was 19.98(12.55)ng/ml. A vitamin D deficiency, insufficiency and sufficiency was seen in 141(60%), 60(25.5%) and 34.0(14.5%), respectively. No association was noted between latitude or season of performing assay and the levels. pSS with 25(OH)D ≤30ng/ml had more than two fold risk of higher grading on lip biopsy as well as Rheumatoid Factor (RF) positivity. However, low 25(OH)D seemed to be associated with lower ESSDAI and less pulmonary involvement.
Conclusion: Prevalence of 25(OH)D deficiency in Indian patients with pSS was comparable to that of general Indian population. Low 25(OH)D level ≤30ng/ml was associated with higher odds for RF positivity and positive grading on lip biopsy. Surprisingly, low 25(OH)D was associated with lower ESSDAI score.

PMID: 29207757 [PubMed]

Detectable Concentrations of Inhaled Tobramycin in Critically Ill Children Without Cystic Fibrosis: Should Routine Monitoring Be Recommended?

Pediatr Crit Care Med. 2017 Dec;18(12):e615-e620

Authors: Miller JL, Lepa TM, Ranallo C, Chaaban H, Skrepnek GH, Johnson PN

Abstract
OBJECTIVES: To determine the percentage of detectable tobramycin troughs and acute kidney injury in critically ill children without cystic fibrosis on inhaled therapy.
DESIGN: Historic cohort.
SETTING: Academic hospital.
PATIENTS: Forty children less than 18 years receiving inhaled tobramycin across 6.5 years.
INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: The primary objective was to determine the percentage of detectable tobramycin troughs greater than or equal to 0.5 µg/mL. Secondary objectives included a comparison of acute kidney injury in children with and without detectable troughs. Twenty-two (55%) had trough concentrations obtained. Ten of these (45.5%) had detectable concentrations, with a median of 0.85 µg/mL (interquartile range, 0.5-2.0). There was no statistical significance between the detectable and nondetectable groups in age, gender, and method of administration. However, patients in the detectable group tended to be younger than nondetectable group and more likely to have a tracheotomy. There was a clinically significant decrease in estimated glomerular filtration rate in the detectable trough group.
CONCLUSIONS: Detectable troughs were noted in almost half of patients with concentrations obtained. A clinically significant decrease in estimated glomerular filtration rate was noted in patients with detectable concentrations. Continued work should be directed to better understand outcomes and monitoring in children requiring inhaled tobramycin.

PMID: 29206744 [PubMed - in process]

Total Pancreatectomy With Intraportal Islet Autotransplantation as a Treatment of Chronic Pancreatitis in Patients With CFTR Mutations.

Pancreas. 2017 Dec 05;:

Authors: Colling KP, Bellin MD, Schwarzenberg SJ, Berry L, Wilhelm JJ, Dunn T, Pruett TL, Sutherland DER, Chinnakotla S, Dunitz JM, Beilman GJ

Abstract
OBJECTIVES: Chronic pancreatitis (CP) is an infrequent but debilitating complication associated with CFTR mutations. Total pancreatectomy with islet autotransplantation (TPIAT) is a treatment option for CP that provides pain relief and preserves β-cell mass, thereby minimizing the complication of diabetes mellitus. We compared outcomes after TPIAT for CP associated with CFTR mutations to CP without CTFR mutations.
METHODS: All TPIATs performed between 2002 and 2014 were retrospectively reviewed: identifying 20 CFTR homozygotes (cystic fibrosis [CF] patients), 19 CFTR heterozygotes, and 20 age-/sex-matched controls without CFTR mutations. Analysis of variance and χ tests were used to compare groups.
RESULTS: Baseline demographics were not different between groups. Postoperative glycosylated hemoglobin and C-peptide levels were similar between groups, as were islet yield and rate of postoperative complications. At 1 year, 40% of CF patients, 22% of CFTR heterozygotes, and 35% of control patients were insulin independent.
CONCLUSION: Total pancreatectomy with islet autotransplantation is a safe, effective treatment option for CF patients with CP, giving similar outcomes for those with other CP etiologies.

PMID: 29206667 [PubMed - as supplied by publisher]

The Na+/Cl--Coupled, Broad-Specific, Amino Acid Transporter SLC6A14 (ATB0,+): Emerging Roles in Multiple Diseases and Therapeutic Potential for Treatment and Diagnosis.

AAPS J. 2017 Dec 04;20(1):12

Authors: Sikder MOF, Yang S, Ganapathy V, Bhutia YD

Abstract
Amino acids are essential building blocks of all mammalian cells, and amino acid transporters play a vital role in transporting them into cells and their further distribution among the various cellular compartments. There are ~ 430 known transporters in the solute-linked carrier (SLC) gene family, divided into 52 distinct families. Eleven of these gene families contain one or more amino acid transporters. These transporters differ significantly from each other in terms of substrate specificity, ion dependence, and energetics. Given the variety of roles they fulfill in human physiology, it is not surprising that a number of diseases are associated with the malfunction of these transporters. In particular, as amino acids are critical for cell growth, survival, and proliferation, the role of amino acid transporters in cancer is gaining increasing attention in recent years. The present review primarily focuses on one particular amino acid transporter, SLC6A14 (also known as ATB0,+), with regard to its relevance to specific diseases, including cancer, and the molecular mechanisms underlying the disease-related alterations in the expression of the transporter. Furthermore, the review highlights the possible utility of this transporter in drug delivery and also its therapeutic potential for the treatment and diagnosis of cancer.

PMID: 29204754 [PubMed - in process]

Protective and antifungal properties of Nanodisk-Amphotericin B over commercially available Amphotericin B.

World J Otorhinolaryngol Head Neck Surg. 2017 Mar;3(1):2-8

Authors: Cho DY, Hoffman KJ, Gill GS, Lim DJ, Skinner D, Mackey C, Rowe SM, Woodworth BA

Abstract
Objective: Amphotericin B (AMB), a potent antifungal agent, has been employed as topical and systemic therapy for sinonasal fungal infections. A novel formulation of nanodisc (ND) containing super aggregated AMB (ND-AMB) for the treatment of fungal infections has been recently developed to provide greater protection from AMB toxicity than current, clinically approved lipid-based formulations. The objective of the current study was to evaluate the safety and potency of ND-AMB for sinonasal delivery using an in vitro model.
Methods: Human sinonasal tissue was harvested during endoscopic sinus surgery and grown at air-liquid interface until well-differentiated. Cultures were exposed to ND-AMB vs AMB and changes in K+ permeability and resistance were measured and recorded via Ussing chamber assay. Ciliary beat frequency (CBF) was analyzed in parallel as well as cytotoxic assay. Potency was assessed using real-time PCR measurement of the Aspergillus fumigatus 18S rRNA.
Results: Ussing chamber studies revealed K+ currents that increased rapidly within 30 s of adding AMB (10 μg/mL) to the apical side, indicating apical membranes had become permeable to K+ ions. In contrast, negligible induction of K+ current was obtained following addition of ND-AMB [AMB = (107.7 ± 15.9) μA/cm2 AMB vs ND-AMB = (2.3 ± 0.7) μA/cm2 ND-AMB; P = 0.005]. ND-AMB also protected nasal epithelial cells from cytotoxicity of AMB (P < 0.05). There was no difference in ciliary beat frequency between the two groups (P = 0.96). The expression of A. fumigatus 18S rRNA with exposure of lower dose of ND-AMB was significantly lower compared to that with AMB (P < 0.05).
Conclusions: Data from the present study suggests ND-AMB protects human nasal epithelia membranes from AMB toxicity by protecting against apical cell K+ permeability while maintaining uncompromised antifungal property compared to AMB. ND-AMB could provide a novel topical therapy for sinonasal fungal diseases.

PMID: 29204573 [PubMed]

Novel antibiotic combinations proposed for treatment of Burkholderia cepacia complex infections.

Antimicrob Resist Infect Control. 2017;6:120

Authors: El-Halfawy OM, Naguib MM, Valvano MA

Abstract
Effective strategies to manage Burkholderia cepacia complex (Bcc) infections in cystic fibrosis (CF) patients are lacking. We tested combinations of clinically available antibiotics and show that moxifloxacin-ceftazidime could inhibit 16 Bcc clinical isolates at physiologically achievable concentrations. Adding low dose of colistin improved the efficacy of the combo, especially at conditions mimicking CF respiratory secretions.

PMID: 29204272 [PubMed - in process]

Abnormal CFTR Affects Glucagon Production by Islet α Cells in Cystic Fibrosis and Polycystic Ovarian Syndrome.

Front Physiol. 2017;8:835

Authors: Huang WQ, Guo JH, Yuan C, Cui YG, Diao FY, Yu MK, Liu JY, Ruan YC, Chan HC

Abstract
Glucagon, produced by islet α cells, functions to increase blood glucose. Abnormal glucose levels are often seen in cystic fibrosis (CF), a systematic disease caused by mutations of the CF transmembrane conductance regulator (CFTR), and in polycystic ovarian syndrome (PCOS), an endocrine disorder featured with hyperandrogenism affecting 5-10% women of reproductive age. Here, we explored the role of CFTR in glucagon production in α cells and its possible contribution to glucagon disturbance in CF and PCOS. We found elevated fasting glucagon levels in CFTR mutant (DF508) mice compared to the wildtypes. Glucagon and prohormone convertase 2 (PC2) were also upregulated in CFTR inhibitor-treated or DF508 islets, as compared to the controls or wildtypes, respectively. Dihydrotestosterone (DHT)-induced PCOS rats exhibited significantly lower fasting glucagon levels with higher CFTR expression in α cells compared to that of controls. Treatment of mouse islets or αTC1-9 cells with DHT enhanced CFTR expression and reduced the levels of glucagon and PC2. The inhibitory effect of DHT on glucagon production was blocked by CFTR inhibitors in mouse islets, and mimicked by overexpressing CFTR in αTC1-9 cells with reduced phosphorylation of the cAMP/Ca2+ response element binding protein (p-CREB), a key transcription factor for glucagon and PC2. These results revealed a previously undefined role of CFTR in suppressing glucagon production in α-cells, defects in which may contribute to glucose metabolic disorder seen in CF and PCOS.

PMID: 29204121 [PubMed]

The efficacy of topical hyaluronan in rhinosinusitis: a systematic review.

J Biol Regul Homeost Agents. 2017 12 04;31(4 Suppl 2)

Authors: Casale M, Vella P, Moffa A, Grimaldi V, Sabatino L, Rinaldi V, Lopez MA, Baptista P, Salvinelli F

Abstract
Rhinosinusitis is one of the most common inflammatory conditions of the nasal cavity and paranasal sinuses and is one of the most common causes of absence from work and for visits to the family doctor. The treatment strategy in both acute rhinosinusitis (ARS) and chronic rhinosinusitis (CRS) is to reduce the severity of the symptoms, minimize the duration of the disease and prevent complications. Topical therapy has become an important tool in otolaryngologists’ armamentarium for rhinosinusitis treatment. Recently, topical hyaluronic acid (HA), the major component of many extracellular matrices that promotes tissue healing, including activation and moderation of the inflammatory responses, cell proliferation, migration and angiogenesis, has been proposed for ARS and CRS adjuvant tool. The aim of the study is to systematically review the published literature regarding all the therapeutic effects of HA on the ARS and CRS. Relevant published studies were found in PubMed, Google Scholar and Ovid, using a combined keyword search or medical subject headings. At the end of our study selection process, 5 relevant publications were included: 2 of them investigated the potential role of HA in reducing symptoms and preventing exacerbations of CRS in adult population, two of them in paediatric patients affected by upper respiratory tract infections and one of them in cystic fibrosis patients with bacterial rhinopharyngitis. Data deriving from the present review of 5 clinical studies showed that the use of topical HA represents a relevant therapeutic advance in rhinosinusitis to minimize symptoms and prevent reacutization with a significant improvement of their quality of life, as it avoids systemic side effects and increases local drug activity. Further studies on larger populations and with new specific nebulization devices for upper airway are needed to confirm these encouraging results.

PMID: 29202565 [PubMed - as supplied by publisher]

Nasospheroids permit measurements of CFTR-dependent fluid transport.

JCI Insight. 2017 Nov 16;2(22):

Authors: Guimbellot JS, Leach JM, Chaudhry IG, Quinney NL, Boyles SE, Chua M, Aban I, Jaspers I, Gentzsch M

Abstract
Expansion of novel therapeutics to all patients with cystic fibrosis (CF) requires personalized CFTR modulator therapy. We have developed nasospheroids, a primary cell culture-based model derived from individual CF patients and healthy subjects by a minimally invasive nasal biopsy. Confocal microscopy was utilized to measure CFTR activity by analyzing changes in cross-sectional area over time that resulted from CFTR-mediated ion and fluid movement. Both the rate of change over time and AUC were calculated. Non-CF nasospheroids with active CFTR-mediated ion and fluid movement showed a reduction in cross-sectional area, whereas no changes were observed in CF spheroids. Non-CF spheroids treated with CFTR inhibitor lost responsiveness for CFTR activation. However, nasospheroids from F508del CF homozygotes that were treated with lumacaftor and ivacaftor showed a significant reduction in cross-sectional area, indicating pharmacologic rescue of CFTR function. This model employs a simple measurement of size corresponding to changes in CFTR activity and is applicable for detection of small changes in CFTR activity from individual patients in vitro. Advancements of this technique will provide a robust model for individualized prediction of CFTR modulator efficacy.

PMID: 29202459 [PubMed - as supplied by publisher]

Making It Last: Storage Time and Temperature Have Differential Impacts on Metabolite Profiles of Airway Samples from Cystic Fibrosis Patients.

mSystems. 2017 Nov-Dec;2(6):

Authors: Wandro S, Carmody L, Gallagher T, LiPuma JJ, Whiteson K

Abstract
Metabolites of human or microbial origin have the potential to be important biomarkers of the disease state in cystic fibrosis (CF). Clinical sample collection and storage conditions may impact metabolite abundances with clinical relevance. We measured the change in metabolite composition based on untargeted gas chromatography-mass spectrometry (GC-MS) when CF sputum samples were stored at 4°C, -20°C, or -80°C with one or two freeze-thaw cycles. Daily measurements were taken for 1 week and then weekly for 4 weeks (4°C) and 8 weeks (-20°C). The metabolites in samples stored at -20°C maintained abundances similar to those found at-80°C over the course of 8 weeks (average change in Bray-Curtis distance, 0.06 ± 0.04) and were also stable after one or two freeze-thaw cycles. However, the metabolite profiles of samples stored at 4°C shifted after 1 day and continued to change over the course of 4 weeks (average change in Bray-Curtis distance, 0.31 ± 0.12). The abundances of several amino acids and other metabolites increased with time of storage at 4°C but remained constant at -20°C. Storage temperature was a significant factor driving the metabolite composition (permutational multivariate analysis of variance: r2 = 0.32 to 0.49, P < 0.001). CF sputum samples stored at -20°C at the time of sampling maintain a relatively stable untargeted GC-MS profile. Samples should be frozen on the day of collection, as more than 1 day at 4°C impacts the global composition of the metabolites in the sample. IMPORTANCE Metabolomics has great potential for uncovering biomarkers of the disease state in CF and many other contexts. However, sample storage timing and temperature may alter the abundance of clinically relevant metabolites. To assess whether existing samples are stable and to direct future study design, we conducted untargeted GC-MS metabolomic analysis of CF sputum samples after one or two freeze-thaw cycles and storage at 4°C and -20°C for 4 to 8 weeks. Overall, storage at -20°C and freeze-thaw cycles had little impact on metabolite profiles; however, storage at 4°C shifted metabolite abundances significantly. GC-MS profiling will aid in our understanding of the CF lung, but care should be taken in studies using sputum samples to ensure that samples are properly stored.

PMID: 29202048 [PubMed]

Flexible semiparametric joint modeling: an application to estimate individual lung function decline and risk of pulmonary exacerbations in cystic fibrosis.

Emerg Themes Epidemiol. 2017;14:13

Authors: Li D, Keogh R, Clancy JP, Szczesniak RD

Abstract
Background: Epidemiologic surveillance of lung function is key to clinical care of individuals with cystic fibrosis, but lung function decline is nonlinear and often impacted by acute respiratory events known as pulmonary exacerbations. Statistical models are needed to simultaneously estimate lung function decline while providing risk estimates for the onset of pulmonary exacerbations, in order to identify relevant predictors of declining lung function and understand how these associations could be used to predict the onset of pulmonary exacerbations.
Methods: Using longitudinal lung function (FEV1) measurements and time-to-event data on pulmonary exacerbations from individuals in the United States Cystic Fibrosis Registry, we implemented a flexible semiparametric joint model consisting of a mixed-effects submodel with regression splines to fit repeated FEV1 measurements and a time-to-event submodel for possibly censored data on pulmonary exacerbations. We contrasted this approach with methods currently used in epidemiological studies and highlight clinical implications.
Results: The semiparametric joint model had the best fit of all models examined based on deviance information criterion. Higher starting FEV1 implied more rapid lung function decline in both separate and joint models; however, individualized risk estimates for pulmonary exacerbation differed depending upon model type. Based on shared parameter estimates from the joint model, which accounts for the nonlinear FEV1 trajectory, patients with more positive rates of change were less likely to experience a pulmonary exacerbation (HR per one standard deviation increase in FEV1 rate of change = 0.566, 95% CI 0.516-0.619), and having higher absolute FEV1 also corresponded to lower risk of having a pulmonary exacerbation (HR per one standard deviation increase in FEV1 = 0.856, 95% CI 0.781-0.937). At the population level, both submodels indicated significant effects of birth cohort, socioeconomic status and respiratory infections on FEV1 decline, as well as significant effects of gender, socioeconomic status and birth cohort on pulmonary exacerbation risk.
Conclusions: Through a flexible joint-modeling approach, we provide a means to simultaneously estimate lung function trajectories and the risk of pulmonary exacerbations for individual patients; we demonstrate how this approach offers additional insights into the clinical course of cystic fibrosis that were not possible using conventional approaches.

PMID: 29201130 [PubMed]

Repaglinide versus insulin for newly diagnosed diabetes in patients with cystic fibrosis: a multicentre, open-label, randomised trial.

Lancet Diabetes Endocrinol. 2017 Nov 30;:

Authors: Ballmann M, Hubert D, Assael BM, Staab D, Hebestreit A, Naehrlich L, Nickolay T, Prinz N, Holl RW, CFRD Study Group

Abstract
BACKGROUND: As survival among patients with cystic fibrosis has improved in recent decades, complications have become increasingly relevant. The most frequent complication is cystic-fibrosis-related diabetes. The recommended treatment is injected insulin, but some patients are treated with oral antidiabetic drugs to ease the treatment burden. We assessed the efficacy and safety of oral antidiabetic drugs.
METHODS: We did a multicentre, open-label, comparative, randomised trial in 49 centres in Austria, France, Germany, and Italy. Eligible patients had cystic fibrosis, were older than 10 years, and had newly diagnosed diabetes. We used a central randomisation schedule derived from a Geigy random number table to assign patients 1:1 to receive insulin or repaglinide, stratified by sex and age (10-15 years or >15 years). The primary outcome was glycaemic control assessed by mean change in HbA1c concentration from baseline after 24 months of treatment. Differences between groups were assessed by linear models. The primary and safety analyses were done in the modified intention-to-treat population (including patients who stopped treatment early because of lack of efficacy). This trial is registered with ClinicalTrials.gov, number NCT00662714.
FINDINGS: We enrolled 34 patients in the repaglinide group and 41 in the insulin group, of whom 30 and 37, respectively, were included in the analyses. At 24 months, glycaemic control was similar in the repaglinide and insulin groups (mean change in HbA1c concentration from baseline 0·2% [SD 0·7%], 1·7 mmol/mol [8·1 mmol/mol] with repaglinide vs -0·2% [1·3%], -2·7 mmol/mol, [14·5 mmol/mol] with insulin; mean difference between groups -0·4%, (95% CI -1·1 to 0·2 [-4·4 mmol/mol, -11·5 to 2·7], p=0·15). The most frequent adverse events were pulmonary events (43 [40%] of 107 in the repaglinide group and 60 [45%] of 133 in the insulin group), and the most frequent serious adverse events were pulmonary events leading to hospital admission (five [50%] of ten and seven [54%] of 13, respectively).
INTERPRETATION: Repaglinide for glycaemic control in patients with cystic-fibrosis-related diabetes is as efficacious and safe as insulin.
FUNDING: Mukoviszidose eV, Vaincre la Mucoviscidose, ABCF Association, and Novo Nordisk.

PMID: 29199116 [PubMed - as supplied by publisher]