Experience of Using a Semielemental Formula for Home Enteral Nutrition in Children: A Multicenter Cross-sectional Study.

J Pediatr Gastroenterol Nutr. 2019 Apr;68(4):585-590

Authors: Leonard M, Caldari D, Mas E, Lambe C, Comte A, Ley D, Peretti N, Borderon C, Marinier E, Coste ME, Lamireau T, Rubio A, Turquet A, Dubern B, Dabadie A, Gautry J, Kyheng M, Guimber D, Gottrand F

Abstract
OBJECTIVES: The use of semielemental diets concerns a small proportion of children on enteral nutrition whose characteristics have never been reported. Our aim was to describe a cohort of patients on home enteral nutrition with Peptamen Junior, including the tolerance and nutritional efficacy of this product.
METHODS: We performed a retrospective multicenter survey on a cohort of patients receiving this semielemental diet at home between 2010 and 2015 in 14 tertiary pediatric French centers. We recorded at baseline, 3, 6, and 12 months, and then every year the anthropometric characteristics of the patients, indications and modalities of administration of the diet, and the tolerance and adverse events.
RESULTS: We recruited 136 patients ages 9.8 ± 4.4 years at baseline. Mean body mass index z score was -1.0 ± 1.8; mean height z score was -1.1 ± 1.9. The main underlying diseases were digestive (35.3%), neurological (33.1%), and hematological (19.9%). The indications for a semielemental diet were failure of another diet in 70 patients (51.9%), severe malnutrition in 19 (14.1%), cystic fibrosis in 11 (8.1%), and switch from parenteral nutrition in 11 (8.1%). Side effects were observed in 39.2% of the patients, and required medical attention in 8.2%. Body mass index improved or remained normal in 88.3% of children.
CONCLUSIONS: This semielemental diet seems to be well tolerated and efficient in the setting of home enteral nutrition in children with complex diseases featuring malabsorption and/or after failure of polymeric diet.

PMID: 30896609 [PubMed - in process]

Cutaneous small-vessel vasculitis associated with paediatric ulcerative colitis: A case study and literature review.

J Paediatr Child Health. 2019 Mar 20;:

Authors: Romano C, Valenti S, Pidone C, Spina M, Caruso RA, Gallizzi R, Dipasquale V

PMID: 30895688 [PubMed - as supplied by publisher]

In vitro Interactions of Pseudomonas aeruginosa With Scedosporium Species Frequently Associated With Cystic Fibrosis.

Front Microbiol. 2019;10:441

Authors: Homa M, Sándor A, Tóth E, Szebenyi C, Nagy G, Vágvölgyi C, Papp T

Abstract
Members of the Scedosporium apiospermum species complex are the second most frequently isolated pathogens after Aspergillus fumigatus from cystic fibrosis (CF) patients with fungal pulmonary infections. Even so, the main risk factors for the infection are unrevealed. According to previous studies, bacterial infections might reduce the risk of a fungal infection, but an antibacterial therapy may contribute to the airway colonization by several fungal pathogens. Furthermore, corticosteroids, which are often used to reduce lung inflammation in children and adults with CF, are also proved to enhance the growth of A. fumigatus in vitro. Considering all the above discussed points, we aimed to test how Pseudomonas aeruginosa influences the growth of scedosporia and to investigate the potential effect of commonly applied antibacterial agents and corticosteroids on Scedosporium species. Direct interactions between fungal and bacterial strains were tested using the disk inhibition method. Indirect interactions via volatile compounds were investigated by the plate-in-plate method, while the effect of bacterial media-soluble molecules was tested using a modified cellophane assay and also in liquid culture media conditioned by P. aeruginosa. To test the effect of bacterial signal molecules, antibacterial agents and corticosteroids on the fungal growth, the broth microdilution method was used. We also investigated the germination ability of Scedosporium conidia in the presence of pyocyanin and diffusible signal factor by microscopy. According to our results, P. aeruginosa either inhibited or enhanced the growth of scedosporia depending on the culture conditions and the mode of interactions. When the two pathogens were cultured physically separately from each other in the plate-in-plate tests, the presence of the bacteria was able to stimulate the growth of several fungal isolates. While in direct physical contact, bacterial strains inhibited the fungal growth. This effect might be attributed to bacterial signal molecules, which also proved to inhibit the germination and growth of scedosporia. In addition, antibacterial agents showed growth-promoting, while corticosteroids exhibited growth inhibitory effect on several Scedosporium isolates. These data raise the possibility that a P. aeruginosa infection or a previously administered antibacterial therapy might be able to increase the chance of a Scedosporium colonization in a CF lung.

PMID: 30894846 [PubMed]

Glucose tolerance in Canadian and French cystic fibrosis adult patients.

Sci Rep. 2019 Mar 18;9(1):4763

Authors: Reynaud Q, Boudreau V, Touzet S, Desjardins K, Bourdy SP, Blond E, Berthiaume Y, Rabasa-Lhoret R, Durieu I

Abstract
Cystic fibrosis (CF)-related diabetes is associated with increased mortality. We analysed the clinical and glycemic profiles of two cohorts of patients treated according to the same guidelines in France and Canada. To investigate incidence differences in phenotypic and glucose abnormalities and to explore the evolution over a 4-year follow-up period, two cohorts of 224 Canadian and 147 French adult CF patients (≥18 years) without treated CF-related diabetes (CFRD) were followed over a 4 year period. In each of these groups, we investigated the longitudinal relationship between glucose tolerance and pulmonary function. An annual 2-hour oral glucose tolerance test was performed: fasting blood glucose (G0) and 2-h blood glucose (G2) were measured. Patients were classified at inclusion according to their glucose tolerance status: Normal glucose tolerant, abnormal glucose tolerant or de novo CFRD. Age, sex ratio and proportion of F508del homozygous patients were not statistically different between both cohorts. Canadian patients had better pulmonary function (median %FEV1 (IQR): 71.0 (55.0-82.0) vs. 64.0 (40.0-78.0), p < 0.001) and greater body mass index (BMI; median BMI in kg/m2) (IQR) 21.1 (19.5-22.8) vs. 19.9 (18.4-21.4), p < 0.001). Glucose values: G0 (5.4 (5.0-5.9) vs. 4.8 (4.5-5.1) mmol/L, p < 0.001) and G2 (7.6 (5.8-9.7) vs. 6.5 (5.2-8.5) mmol/L, p = 0.001) were higher in the Canadian cohort translating into a higher incidence of de novo CFRD diagnosis (19.2 vs. 9.8%, p = 0.003). Decline in FEV1 over time was not different between patients according to glucose tolerance groups. Despite higher glucose levels and incidence of de novo CFRD, Canadian CF patients have a better lung function and a higher BMI than French patients. In spite of these differences between the cohorts, the decline in FEV1 in patients with abnormal glucose tolerance is similar between these groups.

PMID: 30894563 [PubMed - in process]

Rapid cell division of Staphylococcus aureus during colonization of the human nose.

BMC Genomics. 2019 Mar 20;20(1):229

Authors: Szafrańska AK, Junker V, Steglich M, Nübel U

Abstract
BACKGROUND: Staphylococcus aureus is an important opportunistic pathogen and a commensal bacterium, thriving in the nasal cavities of 20% of the human population. Little is known about the dynamics of asymptomatic colonization and the occasional transition to infectious disease.
RESULTS: In this study, we inferred that S. aureus cells replicate every one to three hours on average while colonizing the human nose, based on two independent lines of genomic evidence. First, we collected nasal swab samples from human subjects, extracted and sequenced metagenomic DNA, and analyzed the distribution of sequencing coverage along the staphylococcal chromosome. Calibration of this data by comparison to a laboratory culture enabled measuring S. aureus cell division rates in nasal samples. Second, we applied mutation accumulation experiments paired with genome sequencing to measure spontaneous mutation rates at a genome scale. Relating these mutation rates to annual evolutionary rates confirmed that nasal S. aureus continuously pass several thousand cell divisions per year when averaged over large, globally distributed populations and over many years, corresponding to generation times of less than two hours.
CONCLUSIONS: The cell division rates we determined were higher than the fastest documented rates during fulminant disease progression (in a mouse model of systemic infection) and much higher than those previously measured in expectorated sputum from cystic fibrosis patients. This paper supplies absolute in-vivo generation times for an important bacterial commensal, indicating that colonization of the human upper respiratory tract is characterized by a highly dynamic equilibrium between bacterial growth and removal.

PMID: 30894139 [PubMed - in process]

Cell-Selective Regulation of CFTR Gene Expression: Relevance to Gene Editing Therapeutics.

Genes (Basel). 2019 Mar 19;10(3):

Authors: Swahn H, Harris A

Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) gene is an attractive target for gene editing approaches, which may yield novel therapeutic approaches for genetic diseases such as cystic fibrosis (CF). However, for gene editing to be effective, aspects of the three-dimensional (3D) structure and cis-regulatory elements governing the dynamic expression of CFTR need to be considered. In this review, we focus on the higher order chromatin organization required for normal CFTR locus function, together with the complex mechanisms controlling expression of the gene in different cell types impaired by CF pathology. Across all cells, the CFTR locus is organized into an invariant topologically associated domain (TAD) established by the architectural proteins CCCTC-binding factor (CTCF) and cohesin complex. Additional insulator elements within the TAD also recruit these factors. Although the CFTR promoter is required for basal levels of expression, cis-regulatory elements (CREs) in intergenic and intronic regions are crucial for cell-specific and temporal coordination of CFTR transcription. These CREs are recruited to the promoter through chromatin looping mechanisms and enhance cell-type-specific expression. These features of the CFTR locus should be considered when designing gene-editing approaches, since failure to recognize their importance may disrupt gene expression and reduce the efficacy of therapies.

PMID: 30893953 [PubMed]

Contribution of Anoctamins to Cell Survival and Cell Death.

Cancers (Basel). 2019 Mar 19;11(3):

Authors: Kunzelmann K, Ousingsawat J, Benedetto R, Cabrita I, Schreiber R

Abstract
Before anoctamins (TMEM16 proteins) were identified as a family of Ca2+-activated chloride channels and phospholipid scramblases, the founding member anoctamin 1 (ANO1, TMEM16A) was known as DOG1, a marker protein for gastrointestinal stromal tumors (GIST). Meanwhile, ANO1 has been examined in more detail, and the role of ANO1 in cell proliferation and the development of different types of malignomas is now well established. While ANO5, ANO7, and ANO9 may also be relevant for growth of cancers, evidence has been provided for a role of ANO6 (TMEM16F) in regulated cell death. The cellular mechanisms by which anoctamins control cell proliferation and cell death, respectively, are just emerging; however, the pronounced effects of anoctamins on intracellular Ca2+ levels are likely to play a significant role. Recent results suggest that some anoctamins control membrane exocytosis by setting Ca2+i levels near the plasma membrane, and/or by controlling the intracellular Cl- concentration. Exocytosis and increased membrane trafficking induced by ANO1 and ANO6 may enhance membrane expression of other chloride channels, such as CFTR and volume activated chloride channels (VRAC). Notably, ANO6-induced phospholipid scrambling with exposure of phosphatidylserine is pivotal for the sheddase function of disintegrin and metalloproteinase (ADAM). This may support cell death and tumorigenic activity of IL-6 by inducing IL-6 trans-signaling. The reported anticancer effects of the anthelminthic drug niclosamide are probably related to the potent inhibitory effect on ANO1, apart from inducing cell cycle arrest through the Let-7d/CDC34 axis. On the contrary, pronounced activation of ANO6 due to a large increase in intracellular calcium, activation of phospholipase A2 or lipid peroxidation, can lead to ferroptotic death of cancer cells. It therefore appears reasonable to search for both inhibitors and potent activators of TMEM16 in order to interfere with cancer growth and metastasis.

PMID: 30893776 [PubMed]

Successful ceftazidime-avibactam treatment of post-surgery Burkholderia multivorans genomovar II bacteremia and brain abscesses in a young lung transplanted woman with cystic fibrosis.

Transpl Infect Dis. 2019 Mar 20;:e13082

Authors: Daccò V, Claut L, Piconi S, Castellazzi L, Garbarino F, Teri A, Colombo C

Abstract
Burkholderia cepacia complex (Bcc) includes several phenotypically similar but genotypically distinct gram-negative bacteria (GNB) that can colonize the respiratory tract of Cystic Fibrosis (CF) patients. Pathogens are difficult to treat due to intrinsic resistance to multiple antibiotics and are associated to a more rapid decline in lung function and to increased mortality, particularly after lung transplantation. For all these reasons chronic infection by Burkholderia (B) cenocepacia is presently considered a relative or absolute contraindication in almost all lung transplant centres. We report the case of a young adult CF patient chronically colonized by B. multivorans genomovar II, with diabetes and end-stage renal disease treated with renal replacement therapy: a few months after lung transplantation, she developed post-surgery B. multivorans bacteraemia and multiple brain abscesses. This severe infection did not improve despite multiple standard antibiotic regimen. The introduction of ceftazidime-avibactam, a new β-lactam/ β-lactamase inhibitor combination resulted in clinical recovery and in radiological and biochemical improvement. This article is protected by copyright. All rights reserved.

PMID: 30892778 [PubMed - as supplied by publisher]

Infection prevention and control in cystic fibrosis: a systematic review of interventions.

Expert Rev Respir Med. 2019 Mar 20;:

Authors: Rowbotham NJ, Palser SC, Smith SJ, Smyth AR

Abstract
INTRODUCTION: Cystic fibrosis is a life-limiting genetic condition characterized by recurrent pulmonary infection. Acquisition of infection can occur from environmental reservoirs, person-to-person transmission and from the healthcare environment. Primary prevention of infections through infection prevention and control measures is an important strategy in cystic fibrosis care. Areas covered: Here we present a systematic review of the evidence base around infection prevention and control in cystic fibrosis. We found 36 studies and 7 guidelines that met our inclusion criteria. Strategies covered include cohort segregation, individual segregation, hand hygiene, facemasks, combination strategies, equipment strategies and adherence. Quality of evidence overall was deemed low or very low. Most guideline recommendations have little or no evidence to support them. Expert opinion: Although low quality, there is an abundance of evidence suggesting segregation is beneficial in reducing pathogen spread. Undertaking high quality studies may therefore be ethically challenging. Large-scale registry studies may provide a better strategy for answering questions on efficacy of infection control policy. With the rise of antibiotic resistance, effective eradication of cystic fibrosis pathogens is becoming more difficult so primary prevention through infection control will become increasingly important over the coming years.

PMID: 30892097 [PubMed - as supplied by publisher]

Acetyl-CoA carboxylase inhibition regulates microtubule dynamics and intracellular transport in cystic fibrosis epithelial cells.

Am J Physiol Lung Cell Mol Physiol. 2019 Mar 20;:

Authors: Rymut SM, Lu B, Perez A, Corey DA, Lamb K, Cotton CU, Kelley TJ

Abstract
The use of high-dose ibuprofen as an anti-inflammatory therapy in cystic fibrosis has been shown to be an effective intervention though use is limited due to potential adverse events. Identifying the mechanism of ibuprofen efficacy would aid in the development of new therapies that avoid these adverse events. Previous findings demonstrated that ibuprofen treatment restores the regulation of microtubule dynamics in cystic fibrosis (CF) epithelial cells through a 5' adenosine monophosphate-activated protein kinase (AMPK)-dependent mechanism. The goal of this study is to define the AMPK pathway that leads to microtubule regulation. Here, it is identified that inhibition of acetyl-CoA carboxylase (ACC) is the key step in mediating the AMPK effect. ACC inhibition with 5-(Tetradecyloxy)-2-furoic acid (TOFA) increases microtubule reformation rates in cultured and primary CF epithelial cells to WT rates. TOFA treatment also restores microtubule dependent distribution of cholesterol and Rab7-positive organelles, as well as reduces expression of the pro-inflammatory signaling molecule RhoA to WT levels. ACC activation with citrate replicates these CF phenotypes in WT cells further supporting the role of AMPK signaling through ACC as a key mediator in CF cell signaling. It is concluded that ACC inhibition is the key step in the efficacy of AMPK activation at the cellular level and could represent a novel site of therapeutic intervention to address inflammation in CF.

PMID: 30892081 [PubMed - as supplied by publisher]

Pseudomonas aeruginosa in cystic fibrosis: A chronic cheater.

Proc Natl Acad Sci U S A. 2019 Mar 19;:

Authors: Waters CM, Goldberg JB

PMID: 30890646 [PubMed - as supplied by publisher]

Persistent Adherence to Airway Clearance Therapy in Adults With Cystic Fibrosis.

Respir Care. 2019 Mar 19;:

Authors: Sherman AC, Simonton-Atchley S, Campbell D, Reddy RM, O'Brien CE, Guinee B, Wagner LD, Anderson PJ

Abstract
BACKGROUND: Airway clearance therapy (ACT) is a core component of daily treatment for cystic fibrosis (CF). However, surprisingly little is known about sustained or persistent use of ACT over time among adults with CF. This longitudinal study examined persistent adherence to ACT over 12 months and its modifiable predictors, drawing on aspects of Social Cognitive Theory and the Theory of Planned Behavior.
METHODS: Subjects were drawn from a regional CF center in the southern United States. Predictor variables evaluated at baseline included self-efficacy for ACT (ie, self-confidence in overcoming barriers), outcome expectations (ie, perceived necessity of ACT and concerns about its disruptive effects), and subjective norms (ie, perceptions of being influenced by others). The Cystic Fibrosis Treatment Questionnaire (CFTQ) was used to assess self-reported adherence to ACT at baseline, at 6 months, and at 12 months.
RESULTS: The mean age of subjects was 27.2 ± 9.1 y, and mean FEV1% predicted was 65.5 ± 24.8. Forty-six percent of subjects reported persistent use of ACT (classified as adherent at all assessment periods). In bivariate analyses, all social cognitive predictor variables assessed at baseline were significantly related to persistent adherence (all P < .03), except subjective norms. In logistic regression analyses that modeled the effects of these predictors simultaneously while controlling for FEV1%, fewer baseline concerns about ACT (odds ratio = 0.82, 95% CI 0.69-0.99) and greater self-efficacy (odds ratio = 1.09, 95% CI 1.01-1.18) remained significant independent predictors.
CONCLUSIONS: This longitudinal study addresses an important gap in the literature regarding adherence to ACT over time (12 mo) in a routine clinical setting. Persistent adherence was problematic. As anticipated, social cognitive variables (self-confidence and perceived concerns) predicted self-reported persistence, and these may represent practical targets for intervention.

PMID: 30890632 [PubMed - as supplied by publisher]

Higher Levels of Education Are Associated With Full-Time Work in Adults With Cystic Fibrosis.

Respir Care. 2019 Mar 19;:

Authors: Lian R, Cavalheri V, Wood J, Jenkins S, Straker LM, Hill K

Abstract
BACKGROUND: This study sought to explore factors in adults with cystic fibrosis (CF) that predicted whether (i) someone was engaged in full-time paid work, and (ii) those engaged in paid work reported problems with absenteeism and/or presenteeism.
METHODS: Adults with cystic fibrosis who live in Western Australia completed absenteeism and presenteeism questions from the World Health Organization's Health Performance Questionnaire. The participants were grouped by work status (full time vs part time or unemployed) and by self-reported absenteeism and presenteeism (evidence of vs no evidence of). We explored whether factors such as air-flow obstruction, level of education, health-related quality of life (measured by using the Cystic Fibrosis Questionnaire-Revised), and treatment adherence predicted group membership.
RESULTS: Of the 50 participants for whom data were available (median [interquartile range] age 30 [25-36] y; mean ± SD FEV1% predicted, 60 ± 18%); 34 (68%) worked full time. A higher education level increased the odds of working full time (odds ratio 1.74, 95% CI 1.36-1.89). Among the employed participants, problems with absenteeism and presenteeism were reported by 20 (47%) and 7 (16%), respectively. Both those who reported problems with absenteeism or presenteeism were characterized only by lower scores on the role domain of the Cystic Fibrosis Questionnaire-Revised (P = .02).
CONCLUSIONS: In this study, the majority of adults with cystic fibrosis worked full time and a low percentage of the sample reported problems with absenteeism and presenteeism.

PMID: 30890629 [PubMed - as supplied by publisher]

Choline Supplementation in Cystic Fibrosis-The Metabolic and Clinical Impact.

Nutrients. 2019 Mar 18;11(3):

Authors: Bernhard W, Lange R, Graepler-Mainka U, Engel C, Machann J, Hund V, Shunova A, Hector A, Riethmüller J

Abstract
BACKGROUND: Choline is essential for the synthesis of liver phosphatidylcholine (PC), parenchymal maintenance, bile formation, and lipoprotein assembly to secrete triglycerides. In choline deficiency, the liver accretes choline/PC at the expense of lung tissue, thereby impairing pulmonary PC homoeostasis. In cystic fibrosis (CF), exocrine pancreas insufficiency results in impaired cleavage of bile PC and subsequent fecal choline loss. In these patients, the plasma choline concentration is low and correlates with lung function. We therefore investigated the effect of choline supplementation on plasma choline/PC concentration and metabolism, lung function, and liver fat.
METHODS: 10 adult male CF patients were recruited (11/2014⁻1/2016), and orally supplemented with 3 × 1 g choline chloride for 84 (84⁻91) days. Pre-/post-supplementation, patients were spiked with 3.6 mg/kg [methyl-D₉]choline chloride to assess choline/PC metabolism. Mass spectrometry, spirometry, and hepatic nuclear resonance spectrometry served for analysis.
RESULTS: Supplementation increased plasma choline from 4.8 (4.1⁻6.2) µmol/L to 10.5 (8.5⁻15.5) µmol/L at d84 (p < 0.01). Whereas plasma PC concentration remained unchanged, D₉-labeled PC was decreased (12.2 [10.5⁻18.3] µmol/L vs. 17.7 [15.5⁻22.4] µmol/L, p < 0.01), indicating D₉-tracer dilution due to higher choline pools. Supplementation increased Forced Expiratory Volume in 1 second percent of predicted (ppFEV1) from 70.0 (50.9⁻74.8)% to 78.3 (60.1⁻83.9)% (p < 0.05), and decreased liver fat from 1.58 (0.37⁻8.82)% to 0.84 (0.56⁻1.17)% (p < 0.01). Plasma choline returned to baseline concentration within 60 h.
CONCLUSIONS: Choline supplementation normalized plasma choline concentration and increased choline-containing PC precursor pools in adult CF patients. Improved lung function and decreased liver fat suggest that in CF correcting choline deficiency is clinically important. Choline supplementation of CF patients should be further investigated in randomized, placebo-controlled trials.

PMID: 30889905 [PubMed - in process]

Higher Plasma Endothelial Markers in Adults with Cystic Fibrosis Compared to Healthy Age Matched Controls.

Ann Am Thorac Soc. 2019 Mar 19;:

Authors: Bhatraju PK, Hisert KB, Aitken ML, Goss CH, Liles WC, Altemeier WA

PMID: 30889361 [PubMed - as supplied by publisher]

Correlating CFTR Function with Clinical Features to Inform Precision Treatment of Cystic Fibrosis.

Am J Respir Crit Care Med. 2019 Mar 19;:

Authors: McCague AF, Raraigh KS, Pellicore MJ, Davis-Marcisak EF, Evans TA, Han ST, Lu Z, Joynt AT, Sharma N, Castellani C, Collaco JM, Corey M, Lewis MH, Penland CM, Rommens JM, Stephenson AL, Sosnay PR, Cutting GR

Abstract
RATIONALE: The advent of precision treatment for cystic fibrosis (CF) using small-molecule therapeutics has created a need to estimate potential clinical improvements attributable to increases in cystic fibrosis transmembrane conductance regulator (CFTR) function.
OBJECTIVE: Derive CFTR function of a variety of CFTR genotypes and correlate with key clinical features (sweat chloride concentration, pancreatic exocrine status, and lung function) to develop benchmarks for assessing response to CFTR modulators.
METHODS: CFTR function assigned to 226 unique CFTR genotypes was correlated with the clinical data of 54,671 individuals enrolled in the Clinical and Functional TRanslation of CFTR (CFTR2) project. Cross-sectional FEV1% predicted measurements were plotted by age at which measurement was obtained. Shifts in sweat chloride concentration and lung function reported in CFTR modulator trials were compared to function-phenotype correlations to assess potential efficacy of therapies.
MEASUREMENTS AND MAIN RESULTS: CFTR genotype function exhibited a logarithmic relationship with each clinical feature. Modest increases in CFTR function related to differing genotypes were associated with clinically-relevant improvements in cross-sectional FEV1% predicted over a range of ages (6 to 82 years). Therapeutic responses to modulators corresponded closely to predictions from the CFTR2-derived relationship between CFTR genotype function and phenotype.
CONCLUSIONS: Increasing CFTR function in individuals with severe disease will have a proportionally greater effect on outcomes compared to similar increases in CFTR function in individuals with mild disease and should reverse a substantial fraction of the disease process. This study provides reference standards for clinical outcomes that may be achieved by increasing in CFTR function.

PMID: 30888834 [PubMed - as supplied by publisher]

Exophiala dermatitidis: key issues of an opportunistic fungal pathogen.

Virulence. 2019 Mar 19;:

Authors: Kirchhoff L, Olsowski M, Rath PM, Steinmann J

Abstract
The black yeast Exophiala dermatitidis is an opportunistic pathogen, causing phaeohyphomycosis in immunosuppressed patients, chromoblastomycosis and fatal infections of the central nervous system in otherwise healthy Asian patients. In addition, it is also regularly isolated from respiratory samples from cystic fibrosis patients, with rates varying between 1 and 19 %. Melanin, as part of the cell wall of black yeasts, is one major factor known contributing to pathogenicity of E. dermatitidis and increased resistance against host defense and anti-infective therapeutics. Further virulence factors, e.g. the capability to adhere to surfaces and to form biofilm were reported. A better understanding of the pathogenicity of E. dermatitidis is essential for the development of novel preventive and therapeutic strategies. In this review, the current knowledge of E. dermatitidis prevalence, clinical importance, diagnosis, microbiological characteristics, virulence attributes, susceptibility and resistances as well as therapeutically strategies are discussed.

PMID: 30887863 [PubMed - as supplied by publisher]

Linkage of the CF foundation patient registry with the pediatric health information system database.

Pediatr Pulmonol. 2019 Mar 18;:

Authors: Cogen JD, Hall M, Loeffler DR, Gove N, Onchiri F, Sawicki GS, Fink AK

Abstract
INTRODUCTION: The Cystic Fibrosis Foundation Patient Registry (CFFPR) contains clinical and demographic data from ∼85% of US cystic fibrosis (CF) patients across 120 care centers, but lacks robust inpatient hospitalization data. In contrast, the Pediatric Health Information System (PHIS) database includes inpatient clinical and resource utilization data from 49 US children's hospitals. The creation of a linked CFFPR-PHIS dataset can uniquely address questions related to in-hospital pediatric CF treatment and management. We assessed the feasibility of linking the CFFPR and PHIS databases and determined if successfully linked CF patients were generalizable to unlinked patients.
METHODS: CF patients ≤21 years were eligible for linkage. The CFFPR and PHIS databases were linked at the patient level using indirect identifiers in a stepwise, deterministic, linkage approach. A validation cohort was created using a subset of patients to determine linkage accuracy. Clinical and demographic characteristics between linked and unlinked patients were compared to determine generalizability of the linked cohort.
RESULTS: Of the 11 735 CF patients eligible for linkage from January 1st, 2005 through December 31st, 2016, 10 660 (91%) were successfully linked. Results of our single center validation cohort illustrated 100% accuracy. When compared to unlinked CF patients, fewer linked patients were born before 1990, more were Hispanic, and more were from West-affiliated PHIS hospitals. Otherwise, no clinically meaningful differences were seen between linked and unlinked CF patients.
CONCLUSIONS: We demonstrated successful linkage of the CFFPR and PHIS databases, and created a large generalizable pediatric CF cohort for use in CF-related research.

PMID: 30887732 [PubMed - as supplied by publisher]

Identifying pediatric lung disease: A comparison of forced oscillation technique outcomes.

Pediatr Pulmonol. 2019 Mar 18;:

Authors: Evans DJ, Schultz A, Verheggen M, Hall GL, Simpson SJ

Abstract
RATIONALE: Increasing evidence suggests the forced oscillation technique (FOT) has the capacity to provide non-invasive monitoring and diagnosis of respiratory disease in young children. However, which FOT outcomes provide the most pertinent clinical information is currently unknown. The aim of this study was to determine which FOT outcomes were most sensitive for differentiating between health and specific childhood respiratory disease.
METHODS: Respiratory impedance was measured using a commercial device (i2M, Chess Medical, Belgium) in children aged between 3 and 7 years, who had been diagnosed with either cystic fibrosis (N = 84), asthma (N = 99) or were born very preterm (N = 114). Z-scores were calculated for respiratory system resistance (Rrs) and reactance (Xrs) at 6, 8, and 10 Hz, the resonance frequency (Fres), frequency dependence (Fdep4-24 ), and area under the reactance curve (AX). Pairwise comparisons of the area under the receiver operating characteristic (ROC) curve were used to determine the most relevant FOT variables.
RESULTS AND CONCLUSIONS: The FOT outcomes best able to discern between health and disease were Fres (P < 0.0001) in cystic fibrosis, Fres (P < 0.0001) in asthma and Xrs8 (P < 0.0001) in children born preterm. These findings suggest the utility of specific FOT outcomes is dependent on the respiratory disease being assessed. It is hoped that a disease-specific approach to interpreting FOT data can help further refine the FOT technique to aid in the diagnosis of children with pediatric respiratory disease.

PMID: 30887730 [PubMed - as supplied by publisher]

Validity and Reliability of a Novel Multimodal Questionnaire for the Assessment of Abdominal Symptoms in People with Cystic Fibrosis (CFAbd-Score).

Patient. 2019 Mar 18;:

Authors: Jaudszus A, Zeman E, Jans T, Pfeifer E, Tabori H, Arnold C, Michl RK, Lorenz M, Beiersdorf N, Mainz JG

Abstract
BACKGROUND AND OBJECTIVE: For people with cystic fibrosis, validated patient-reported outcome measures for the assessment of the complex abdominal involvement are lacking. The objective of this study was to examine whether the CFAbd-Score, a novel questionnaire consisting of 28 items, meets the essential requirements (validity and reliability) for a patient-reported outcome measure according to US Food and Drug Administration recommendations.
METHODS: Content validity was assessed by recording the frequencies and severity of symptoms that occurred during the prior 2 weeks in patients with cystic fibrosis (n = 116; aged ≥ 6 years). Comparing the CFAbd-Score results obtained from patients with cystic fibrosis and healthy controls (n = 88), we determined known-groups validity. To explore the structure of the patient-reported outcome measure, a factor analysis was conducted. Internal consistency of the five extracted score domains was assessed using Cronbach's alpha. For test-retest reliability, a subgroup of patients (n = 43) was reevaluated and intra-class correlation coefficients were determined.
RESULTS: The CFAbd-Score differentiated patients with cystic fibrosis from healthy controls with a large effect size (17.3 ± 1.1 vs. 8.0 ± 0.7 points; p < 0.001; Cohen's d = 0.85). Items, domains, and scores reflected the relevance to patients with cystic fibrosis and allowed a differentiation between subgroups of patients with cystic fibrosis (e.g., patients with and without abdominal pain, pancreatic sufficiency, and age groups). High item-domain loadings as well as good to excellent internal consistency and reproducibility (Cronbach's α = 0.70-0.92; intra-class correlation coefficient = 0.932, 95% confidence interval 0.874-0.963) indicated construct validity and reliability.
CONCLUSIONS: The CFAbd-Score has successfully passed through key steps of the iterative process of patient-reported outcome measure development. Prospectively, the CFAbd-Score is proposed as a patient-centered instrument for monitoring abdominal symptoms and, most interestingly, for evaluating changes in symptoms with novel treatments such as cystic fibrosis transmembrane regulator modulators.
TRAIL REGISTRATION: ClinicalTrials.gov: NCT03052283.

PMID: 30887269 [PubMed - as supplied by publisher]