Fluorescent C-NanoDots for rapid detection of BRCA1, CFTR and MRP3 gene mutations.

Mikrochim Acta. 2019 Apr 23;186(5):293

Authors: García-Mendiola T, Elosegui CG, Bravo I, Pariente F, Jacobo-Martin A, Navio C, Rodriguez I, Wannemacher R, Lorenzo E

Abstract
The authors report on a fluorometric method for the rapid detection of BRCA1, CFRT and MRP3 gene mutations. These are associated with breast cancer, cystic fibrosis and autoimmune hepatitis diseases, respectively. Carbon nanodots with blue fluorescence (with excitation/emission maxima at 340/440 nm) were synthesized and characterized, and their interactions with DNA were investigated. Changes in the fluorescence intensity following interaction with ssDNA and dsDNA were used for specific DNA sequence of BRCA1, CFRT and MRP3 genes detection. The response to DNAs is linear up to 200 nM and the detection limit is 270 pM. The assay selectivity allows the detection of single gene mutations. Under optimum conditions, the assay can rapidly discriminate between wild type and mutated samples. Graphical abstract Schematic representation of fluorescence assay for rapid detection of gene mutation based on fluorescent carbon nanodots.

PMID: 31016506 [PubMed - in process]

The value of high-resolution computed tomography (HRCT) to determine exercise ventilatory inefficiency and dynamic hyperinflation in adult patients with cystic fibrosis.

Respir Res. 2019 Apr 24;20(1):78

Authors: Crisafulli E, Teopompi E, Luceri S, Longo F, Tzani P, Pagano P, Ielpo A, Longo C, Di Paolo M, Sverzellati N, Palange P, Chetta A, Pisi G

Abstract
INTRODUCTION: In Cystic Fibrosis (CF), exercise ventilatory inefficiency and dynamic hyperinflation (DH) cause exercise limitation and induce poor exercise tolerance. High-resolution computed tomography (HRCT) of the lung can detect pulmonary abnormalities in CF patients. We aimed to identify the determinants of exercise ventilatory inefficiency and DH using HRCT-derived metrics.
METHODS: Fifty-two adult CF patients were prospectively enrolled; all participants underwent cardio-pulmonary exercise test (CPET) and HRCT. Radiological impairment was evaluated by the Brody II scoring system. Slope and intercept of the minute ventilation/CO2 production (V'E/V'CO2) regression line and the ratio of inspiratory capacity/total lung capacity (IC/TLC) at rest and at peak of exercise were measured.
RESULTS: Four groups of patients were identified based on the combination of ventilatory efficiency (Vef) or inefficiency (Vin) and the presence/absence of DH. Compared to other groups, CF adults with Vin and DH had worse functional status and higher total (T), bronchiectasis (B) and air trapping (AT) scores at HRCT. Significant correlations were found between V'E/V'CO2 intercept and V'E/V'CO2 slope (ρ - 0.455, p = 0.001) and between V'E/V'CO2 intercept and Δ inspiratory capacity (IC) (ρ - 0.334, p = 0.015). Regression analysis identified AT score (cut-off 7.9, odds ratio-OR 3.50) as the only independent predictor of Vin and T (cut-off 53.6, OR 4.98), B (cut-off 16.1, OR 4.88), airways wall thickening (AWT) (cut-off 13, OR 3.41), and mucous plugging (MP) scores (cut-off 11.7, OR 4.18) as significant predictors of DH.
CONCLUSION: In adult CF cohort, values of HRCT metrics are determinants of Vin (AT) and DH (T, B, AWT, MP).

PMID: 31014329 [PubMed - in process]

Folding Status Is Determinant over Traffic-Competence in Defining CFTR Interactors in the Endoplasmic Reticulum.

Cells. 2019 Apr 14;8(4):

Authors: Santos JD, Canato S, Carvalho AS, Botelho HM, Aloria K, Amaral MD, Matthiesen R, Falcao AO, Farinha CM

Abstract
The most common cystic fibrosis-causing mutation (F508del, present in ~85% of CF patients) leads to CFTR misfolding, which is recognized by the endoplasmic reticulum (ER) quality control (ERQC), resulting in ER retention and early degradation. It is known that CFTR exit from the ER is mediated by specific retention/sorting signals that include four arginine-framed tripeptide (AFT) retention motifs and a diacidic (DAD) exit code that controls the interaction with the COPII machinery. Here, we aim at obtaining a global view of the protein interactors that regulate CFTR exit from the ER. We used mass spectrometry-based interaction proteomics and bioinformatics analyses to identify and characterize proteins interacting with selected CFTR peptide motifs or full-length CFTR variants retained or bypassing these ERQC checkpoints. We conclude that these ERQC trafficking checkpoints rely on fundamental players in the secretory pathway, detecting key components of the protein folding machinery associated with the AFT recognition and of the trafficking machinery recognizing the diacidic code. Furthermore, a greater similarity in terms of interacting proteins is observed for variants sharing the same folding defect over those reaching the same cellular location, evidencing that folding status is dominant over ER escape in shaping the CFTR interactome.

PMID: 31014000 [PubMed]

Quorum Sensing as Antivirulence Target in Cystic Fibrosis Pathogens.

Int J Mol Sci. 2019 Apr 13;20(8):

Authors: Scoffone VC, Trespidi G, Chiarelli LR, Barbieri G, Buroni S

Abstract
Cystic fibrosis (CF) is an autosomal recessive genetic disorder which leads to the secretion of a viscous mucus layer on the respiratory epithelium that facilitates colonization by various bacterial pathogens. The problem of drug resistance has been reported for all the species able to colonize the lung of CF patients, so alternative treatments are urgently needed. In this context, a valid approach is to investigate new natural and synthetic molecules for their ability to counteract alternative pathways, such as virulence regulating quorum sensing (QS). In this review we describe the pathogens most commonly associated with CF lung infections: Staphylococcus aureus, Pseudomonas aeruginosa, species of the Burkholderia cepacia complex and the emerging pathogens Stenotrophomonas maltophilia, Haemophilus influenzae and non-tuberculous Mycobacteria. For each bacterium, the QS system(s) and the molecules targeting the different components of this pathway are described. The amount of investigations published in the last five years clearly indicate the interest and the expectations on antivirulence therapy as an alternative to classical antibiotics.

PMID: 31013936 [PubMed - in process]

Nanoparticles Equipped with α2,8-Linked Sialic Acid Chains Inhibit the Release of Neutrophil Extracellular Traps.

Nanomaterials (Basel). 2019 Apr 12;9(4):

Authors: Bornhöfft KF, Viergutz T, Kühnle A, Galuska SP

Abstract
Neutrophils can combat the invasion of pathogens by the formation of neutrophil extracellular traps (NETs). The NET mechanism is not only an effective tool for combating pathogens, but is also associated with diseases. Therefore, NETs are a potential target for combating pathologies, such as cystic fibrosis and thrombosis. We investigated the potential of nanoparticles, which were modified with α2,8-linked sialic acid chains, to modulate NET release during phorbol myristate acetate stimulation. Interestingly, when these nanoparticles were applied, the formation of reactive oxygen species was partly inhibited and the release of NET was counteracted. However, although the release of NET fibers was prevented, the nuclei still lost their characteristic segmented structure and became swollen, indicating that only the release, and not complete activation was suppressed. Intriguingly, coincubation of α2,8-sialylated particles with free sialic acid chains prevented the outlined inhibitory effects. Thus, the sialic acid chains must be attached to a linker molecule to generate an active bioconjugate that is able to inhibit the release of NET.

PMID: 31013834 [PubMed]

SPLUNC1 Loses its Antimicrobial Activity in Acidic Cystic Fibrosis Airway Secretions.

Am J Respir Crit Care Med. 2019 Apr 23;:

Authors: Ahmad S, Gilmore RC, Alexis NE, Tarran R

PMID: 31013116 [PubMed - as supplied by publisher]

Poly(lactide- co-glycolide) Nanoparticles for Prolonged Therapeutic Efficacy of Esculentin-1a-Derived Antimicrobial Peptides against Pseudomonas aeruginosa Lung Infection: in Vitro and in Vivo Studies.

Biomacromolecules. 2019 Apr 23;:

Authors: Casciaro B, d'Angelo I, Zhang X, Loffredo MR, Conte G, Cappiello F, Quaglia F, Di YP, Ungaro F, Mangoni ML

Abstract
Due to their excellent in vitro activity against multidrug resistant bacteria, antimicrobial peptides (AMPs) hold promise for treatment of Pseudomonas aeruginosa lung infections in cystic fibrosis (CF) sufferers. In this work, poly(lactide- co-glycolide) (PLGA) nanoparticles for lung delivery of AMPs deriving from the frog-skin esculentin-1a, namely, Esc(1-21) and Esc(1-21)-1c (Esc peptides), were successfully developed. Improved peptide transport through artificial CF mucus and simulated bacterial extracellular matrix was achieved in vitro. The formulations were effectively delivered through a liquid jet nebulizer already available to patients. Notably, Esc peptide-loaded nanoparticles displayed an improved efficacy in inhibiting P. aeruginosa growth in vitro and in vivo in the long term. A single intratracheal administration of Esc peptide-loaded nanoparticles in a mouse model of P. aeruginosa lung infection resulted in a 3-log reduction of pulmonary bacterial burden up to 36 h. Overall, results unravel the potential of PLGA nanoparticles as a reliable delivery system of AMPs to lungs.

PMID: 31013061 [PubMed - as supplied by publisher]

Pathogen acquisition in patients with cystic fibrosis receiving ivacaftor or lumacaftor/ivacaftor.

Pediatr Pulmonol. 2019 Apr 22;:

Authors: Singh SB, McLearn-Montz AJ, Milavetz F, Gates LK, Fox C, Murry LT, Sabus A, Porterfield HS, Fischer AJ

Abstract
BACKGROUND: The cystic fibrosis transmembrane conductance regulator (CFTR) modulators ivacaftor and lumacaftor/ivacaftor improve the status of existing infections in patients with cystic fibrosis (CF). It is unknown how well these drugs protect patients against incident infections. We hypothesized that CFTR modulator treatment would decrease new infections with Pseudomonas aeruginosa or Staphylococcus aureus.
METHODS: We retrospectively studied a single-center cohort of patients with CF during two time periods (2008-2011, Era 1) and (2012-2015, Era 2) based on the January 2012 approval of ivacaftor. Using Kaplan-Meier analysis, we compared the time to any new infection with P. aeruginosa, methicillin-resistant S. aureus (MRSA), or methicillin-sensitive S. aureus (MSSA) that was absent during a 2-year baseline. We stratified the analysis based on whether patients received ivacaftor or lumacaftor/ivacaftor during Era 2. We used the log-rank test and considered P < 0.05 statistically significant.
RESULTS: For patients receiving ivacaftor or lumacaftor/ivacaftor in Era 2, there was a statistically significant delay in the time to new bacterial acquisition in Era 2 vs. Era 1 ( P = 0.008). For patients who did not receive CFTR modulators, there was a trend toward slower acquisition of new bacterial infections in Era 2 compared to Era 1, but this was not statistically significant ( P = 0.10).
CONCLUSIONS: Patients receiving ivacaftor or lumacaftor/ivacaftor for CF had significantly delayed acquisition of P. aeruginosa and S. aureus after these drugs were released. This method for analyzing incident infections may be useful for future studies of CFTR modulators and bacterial acquisition in CF registry cohorts.

PMID: 31012285 [PubMed - as supplied by publisher]

Rapid early increase in BMI is associated with impaired longitudinal growth in children with cystic fibrosis.

Pediatr Pulmonol. 2019 Apr 22;:

Authors: Hak SF, Arets HGM, van der Ent CK, van der Kamp HJ

Abstract
BACKGROUND: We aimed to assess whether final height in children with cystic fibrosis (CF) is affected by body mass index (BMI), BMI increase, pulmonary function, and cystic fibrosis-related diabetes (CFRD).
STUDY DESIGN: A longitudinal, retrospective study was performed in a cohort of 57 patients with CF (30 boys, 27 girls) born between 1997 and 2001. Height and weight were recorded annually from ages 0.5 to 10 years and biannually up to the age of 18. Measurements were converted to height-for-age-adjusted-for-target-height (HFA-TH) and BMI-for-age z-scores. Analyses were performed using the independent t tests and the Pearson's correlation.
RESULTS: For both boys and girls, HFA-TH and BMI-for-age z-scores were significantly lower in the first year of life, these scores increased rapidly until the age of 11 and 8 years, respectively. In boys, HFA-TH z-scores declined during puberty, with subsequently significantly impaired final height (z-score, -0.56, n = 30, standard deviation [SD] = 0.81, P = 0.001). In girls, HFA-TH z-scores briefly declined after the age of 8 years, but then increased to a z-score of -0.21 (n = 27, SD = 0.87) at age 18, which is not significantly lower than the national average (P = 0.22). Pulmonary function and the presence of CFRD were not associated with final height. However, rapid BMI increase between ages 1 and 6 was negatively associated with final height in boys (n = 29, r =-0.420; P = 0.023) and girls (n = 25, r =-0.466; P = 0.019).
CONCLUSIONS: In boys and girls, early BMI increase was associated with impaired final height. We suggest that early childhood serves as a "window" in which nutritional variations may program subsequent growth. Further refinement of nutritional strategies could be needed.

PMID: 31012271 [PubMed - as supplied by publisher]

The impact of mannose-binding lectin polymorphisms on lung function in primary ciliary dyskinesia.

Pediatr Pulmonol. 2019 Apr 22;:

Authors: Videbaek K, Buchvald F, Holgersen MG, Henriksen A, Eriksson F, Garred P, Nielsen KG

Abstract
OBJECTIVE: Primary ciliary dyskinesia (PCD) is a congenital lung disease that leads to recurrent and chronic lung infection. The resulting inflammation causes lung damage and declines in lung function. Mannose-binding lectin (MBL) is a first line host defense protein of importance for the innate immunity. Polymorphisms in the MBL gene named MBL2 result in unstable and low functional levels MBL proteins. MBL insufficiency is linked to an increased risk of lung infection and to declines in lung function in patients with cystic fibrosis. We investigated whether there is a similar link in patients with PCD.
METHODS: This retrospective longitudinal study included 85 patients with PCD. Diagnostics and age at diagnosis were recorded, complete spirometry data starting at diagnosis, and Pseudomonas aeruginosa infection status over the last 2 years were collected, and the patients were grouped according to MBL2 genotype status (MBL2-sufficient or MBL2-deficient).
RESULTS: MBL-deficient patients were diagnosed almost 3 years earlier than MBL-sufficient patients (median 6.1 vs 8.9 years, P  < 0.05). There were no differences in the first measured spirometry values, but MBL-deficient patients showed greater declines in forced expiratory volume in one sec (FEV1 ) than patients with MBL sufficiency (z-score: -0.049 per year [95% CI, -0.075; -0.021] vs -0.009 per year [95% CI, -0.033; 0.015]; P = 0.023). No differences were found in forced vital capacity (FVC), FEV1 /FVC, or infection status.
CONCLUSION: MBL-deficiency, which is associated with MBL2 mutations, was associated with a lower age at diagnosis and with steeper declines in FEV1 in patients with PCD. This suggests that the MBL genotype might be a disease modifier in PCD.

PMID: 31012247 [PubMed - as supplied by publisher]

Ready-to-Use Supplemental Food for Nutritional Supplementation in Cystic Fibrosis.

Curr Dev Nutr. 2019 May;3(5):nzz016

Authors: Pitman RT, Mui M, Michelson PH, Manary MJ

Abstract
Undernutrition is common in cystic fibrosis (CF) and is correlated with long-term outcomes, yet current nutritional interventions have not demonstrated consistent improvements in energy intake, and subsequently, growth. Development of novel nutritional interventions to increase energy intake is essential to improve clinical outcomes of individuals with CF. Ready-to-use supplemental food (RUSF) is a modifiable, inexpensive, palatable, safe, and nutrient-dense food for treatment or prevention of acute malnutrition in developing countries. Utilizing a linear-programming tool we identified 6 RUSF formulations with sufficient nutrient density (495 kcal/100 g), protein, and fat for children with CF. Palatability was established by a taste-trial and affirmed by a 2-wk tolerability assessment that demonstrated consistent consumption and tolerance of the RUSF. Although preliminary, this study demonstrates the potential for developing RUSF as a nutritional supplement for increasing energy intake in children with CF.

PMID: 31011716 [PubMed]

Oral health of cystic fibrosis patients at a north american center: A pilot study.

Med Oral Patol Oral Cir Bucal. 2019 Apr 23;:

Authors: Abu-Zahra R, Antos NJ, Kump T, Angelopoulou MV

Abstract
BACKGROUND: The objective of this study was to describe the oral health status of Cystic Fibrosis (CF) children in a US facility.
MATERIAL AND METHODS: Twenty CF children ages 6-18 were recruited from Children's Hospital of Wisconsin Pulmonary Clinic. Parents completed a health questionnaire. Clinical examinations checked dental caries using the dmft/DMFT index, dental hygiene using the Simplified Greene-Vermillion Index (DI-S), gingival inflammation using the Community Periodontal Index of Treatment Needs, and enamel defects using the modified Developmental Defects of Enamel Index.
RESULTS: The majority (90%) brush twice a day, 65% consume sugary snacks, and 70% visit the dentist every 6 months. Clinically, they presented DMFT 0.25 and dmft 0.90, fair oral hygiene with DI-S 1.02, 75% had mild gingivitis and 50% had enamel defects. The more antibiotics they took, significantly more frequent (p=0.007) and more severe (p=0.017) enamel defects were noted. Similar trend was found between the number of surgeries and the presence of enamel defects (p=0.076) and dental caries (p=0.028).
CONCLUSIONS: Within the limitations of this study, CF patients were found to be at oral health risk due to the high prevalence of dental enamel defects. Oral health for CF children should be part of the multidisciplinary care.

PMID: 31011138 [PubMed - as supplied by publisher]

Fitting pieces into the puzzle of Pseudomonas aeruginosa type III secretion system gene expression.

J Bacteriol. 2019 Apr 22;:

Authors: Williams McMackin EA, Djapgne L, Corley JM, Yahr TL

Abstract
Type III secretion systems (T3SS) are widely distributed in Gram-negative microorganisms and critical for host-pathogen and host-symbiont interactions with plants and animals. Central features of the T3SS are a highly conserved set of secretion and translocation genes and contact-dependence wherein host-pathogen interactions trigger effector protein delivery and serve as an inducing signal for T3SS gene expression. In addition to these conserved features there are also pathogen-specific properties that include a unique repertoire of effector genes and mechanisms to control T3SS gene expression. The Pseudomonas aeruginosa T3SS serves as a model system to understand transcriptional and post-transcriptional mechanisms involved in the control of T3SS gene expression. The central regulatory feature is a partner-switching system that controls the DNA-binding activity of ExsA, the primary regulator of T3SS gene expression. Superimposed upon the partner-switching mechanism are cyclic AMP and cyclic-di-GMP signaling systems, two-component systems, global regulators, and RNA-binding proteins that have positive and negative effects on ExsA transcription and/or synthesis. In the present review we discuss advances in our understanding of how these regulatory systems orchestrate activation of T3SS gene expression in the context of acute infections and repression of the T3SS as P. aeruginosa adapts to and colonizes the cystic fibrosis airways.

PMID: 31010903 [PubMed - as supplied by publisher]

Efficacy of aerosolized rifaximin versus tobramycin for the treatment of Pseudomonas aeruginosa pneumonia in mice.

Antimicrob Agents Chemother. 2019 Apr 22;:

Authors: Kirby BD, Al Ahmar R, Withers TR, Valentine ME, Valentovic M, Long TE, Gaskins JR, Yu HD

Abstract
Pseudomonas aeruginosa is a Gram-negative opportunistic bacterial pathogen that can cause chronic lung infections in patients with cystic fibrosis (CF). The current preferred treatment for CF lung infections includes inhaled tobramycin (TOB); however, studies suggest TOB cannot effectively inhibit biofilm formation. Using a NIH small compounds drug library approved for safe use in humans, we identified rifaximin (RFX), a semisynthetic, rifamycin family, non-systemic antibiotic that inhibits alginate production and growth in P. aeruginosa Inhibition of alginate production was further analyzed using the uronic acid carbazole assay and a promoter reporter assay that measures the transcription of the alginate biosynthetic operon. Compared to TOB, RFX significantly reduced alginate production in laboratory and CF sputum isolates of P. aeruginosa In addition, RFX showed a narrow range of minimum inhibitory concentrations when measured with multidrug-resistant bacterial species of clinical relevance, synergistic activities with TOB or amikacin against clinical isolates, as well as reduction towards in vitro pre-formed biofilms. In C57BL/6 mice, penetration of nebulized TOB into the lungs was shown at a higher level compared to RFX. Further in vivo assessment using a DBA/2 mouse lung-infection model found increased survival rates with a single-dose treatment of nebulized RFX and decreased P. aeruginosa PAO1 bio-burden with multiple-dose treatment of RFX plus TOB. In addition, mice treated with a single exposure to dimethyl sulfoxide (DMSO), a solvent that dissolves RFX, showed no apparent toxicity. In summary, RFX may be used to supplement the TOB inhalation therapy to increase the efficacy against P. aeruginosa biofilm infections.

PMID: 31010865 [PubMed - as supplied by publisher]

Biofilm-associated Mycobacterium abscessus cells have altered antibiotic tolerance and surface glycolipids in Artificial Cystic Fibrosis Sputum Media.

Antimicrob Agents Chemother. 2019 Apr 22;:

Authors: Hunt-Serracin AC, Parks BJ, Boll J, Boutte C

Abstract
Mycobacterium abscessus (Mab) is a biofilm-forming, multi-drug resistant, non-tuberculous mycobacterial (NTM) pathogen increasingly found in Cystic Fibrosis patients. Antibiotic treatment for these infections is often unsuccessful, partly due to Mab's high intrinsic antibiotic resistance. It is not clear whether antibiotic tolerance caused by biofilm formation also contributes to poor treatment outcomes. We studied the surface glycolipids and antibiotic tolerance of Mab biofilms grown in Artificial Cystic Fibrosis Sputum (ACFS) media in order to determine how they are affected by nutrient conditions that mimic infection. We found that Mab displays more of the virulence lipid trehalose dimycolate when grown in ACFS compared to standard lab media. In ACFS media, biofilm-associated cells are more antibiotic tolerant than planktonic cells in the same well. This contrasts with standard lab medias, where biofilm and planktonic cells are both highly antibiotic tolerant. These results indicate that Mab cell physiology in biofilms depends on environmental factors, and that nutrient conditions found within Cystic Fibrosis infections could contribute to both increased virulence and antibiotic tolerance.

PMID: 31010859 [PubMed - as supplied by publisher]

Sustained Glycemic Control With Ivacaftor in Cystic Fibrosis-Related Diabetes.

J Investig Med High Impact Case Rep. 2019 Jan-Dec;7:2324709619842898

Authors: Christian F, Thierman A, Shirley E, Allen K, Cross C, Jones K

Abstract
Cystic fibrosis-related diabetes (CFRD) is a common comorbidity in cystic fibrosis with pancreatic insufficiency occurring early in the disease process. Current treatment is exogenous insulin therapy as CFRD is due to impaired insulin secretion. Recent small studies have shown improvement in endogenous insulin secretion with a short period of ivacaftor therapy in primarily pediatric patients with cystic fibrosis transmembrane conductance regulator mutations amenable to potentiation. In this article, we present the case of an adult patient with long-standing CFRD who developed sustained improvement in glycemic control after initiation of ivacaftor.

PMID: 31010313 [PubMed - in process]

New ISE-Based Apparatus for Na+, K+, Cl-, pH and Transepithelial Potential Difference Real-Time Simultaneous Measurements of Ion Transport across Epithelial Cells Monolayer⁻Advantages and Pitfalls.

Sensors (Basel). 2019 Apr 20;19(8):

Authors: Zając M, Lewenstam A, Stobiecka M, Dołowy K

Abstract
Cystic Fibrosis (CF) is the most common fatal human genetic disease, which is caused by a defect in an anion channel protein (CFTR) that affects ion and water transport across the epithelium. We devised an apparatus to enable the measurement of concentration changes of sodium, potassium, chloride, pH, and transepithelial potential difference by means of ion-selective electrodes that were placed on both sides of a 16HBE14σ human bronchial epithelial cell line that was grown on a porous support. Using flat miniaturized ISE electrodes allows for reducing the medium volume adjacent to cells to approximately 20 μL and detecting changes in ion concentrations that are caused by transport through the cell layer. In contrast to classic electrochemical measurements, in our experiments neither the calibration of electrodes nor the interpretation of results is simple. The calibration solutions might affect cell physiology, the medium composition might change the direction of actions of the membrane channels and transporters, and water flow that might trigger or cut off the transport pathways accompanies the transport of ions. We found that there is an electroneutral transport of sodium chloride in both directions of the cell monolayer in the isosmotic transepithelial concentration gradient of sodium or chloride ions. The ions and water are transported as an isosmotic solution of 145 mM of NaCl.

PMID: 31009998 [PubMed - in process]

Clinical Review Report: Lumacaftor/Ivacaftor (Orkambi): (Vertex Pharmaceuticals (Canada) Incorporated): Indication: For the treatment of cystic fibrosis in patients aged six years and older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator gene

Book. 2018 10

Authors:

Abstract
Orkambi is a fixed-dose combination tablet containing lumacaftor and ivacaftor (LUM/IVA). It is indicated for the treatment of cystic fibrosis (CF) in patients aged six years and older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane regulator (CFTR) gene. This is the most common CF-causing mutation worldwide and approximately half of all Canadian patients with CF are homozygous for the F508del mutation. LUM/IVA is the first treatment specifically indicated for the treatment of patients who are homozygous for the F508del mutation in the CFTR gene. The manufacturer has requested that LUM/IVA receive a recommendation to reimburse in accordance with the Health Canada–approved indication. CADTH previously reviewed LUM/IVA for treatment of patients aged 12 years and older. The indication was subsequently expanded to include patients who are least six years of age. The current CADTH Common Drug Review submission is for the full Health Canada–approved indication.

PMID: 31013018

A Survey Identifying Nutritional Needs in a Contemporary Adult Cystic Fibrosis Cohort.

BMC Nutr. 2019;5:

Authors: Kapnadak SG, Ramos KJ, Lopriore AM, Goss CH, Aitken ML

Abstract
Background: Cystic fibrosis (CF) is a disease in which nutritional barriers are diverse and common, with malnutrition greatly influencing pulmonary trajectory and overall outcomes. Despite this, the most effective methods to optimize CF nutrition are unknown, and literature describing patients' perspectives on their specific nutritional needs is lacking, particularly in the modern era of CF care. This study aimed to identify the most important nutritional needs and desired health-improvement resources in a contemporary adult CF cohort.
Methods: A 14-question investigator-designed survey addressing nutrition concerns, preferred health-improvement resources, and dietary/exercise routines was administered to CF adults. Clinical characteristics and survey responses are presented with descriptive statistics, and responses compared by body mass index (BMI) category (<18.5 kg/m2; 18.5-24.99 kg/m2; 25-29.99 kg/m2; ≥30 kg/m2), gender, and socioeconomic status using Chi square or Fisher's Exact testing.
Results: Of 66 total patients, nine (13.6%) were underweight (BMI <18.5 kg/m2), while 19 (28.8%) were overweight or obese (BMI ≥ 25kg/m2). In the overall cohort, the most common primary concern was preventing weight loss [in 20/66 patients (30.3%)], but there were significant differences by BMI (p< 0.001), with the most common concern in the overweight subgroup being preventing weight gain. Fifteen (46.9%) men (BMI mean 20.7, range 16.4-29.2 kg/m2) listed preventing weight loss as the primary concern, compared to only 5 (14.7%) women (BMI mean 18.4, range 16.2-19.9 kg/m2), representing a trend toward a difference in primary concerns by gender (p=0.066).The most commonly desired health-improvement resource was online CF nutrition and fitness information, found in 26 patients (39.4%) in the overall cohort, without significant differences by BMI (p=0.814) or gender (p=0.199). Financial assistance was the preferred resource in 17 (26.2%), without differences by socioeconomic status (p=0.367).
Conclusions: We identified a wide variety of nutritional needs in CF adults, including a high prevalence of overweight status, many patients desiring weight loss, and many seeking financial resources. Our findings support the individualization of modern-day CF nutrition programs and development of online resources, in an effort to address the heterogeneous barriers that exist in the contemporary CF population and improve outcomes in patients with the disease.

PMID: 31007939 [PubMed]

A model-based economic evaluation of four newborn screening strategies for cystic fibrosis in Flanders, Belgium.

Acta Clin Belg. 2019 Apr 22;:1-9

Authors: Schmidt M, Werbrouck A, Verhaeghe N, De Wachter E, Simoens S, Annemans L, Putman K

Abstract
OBJECTIVES: The most cost-effective newborn screening strategy for cystic fibrosis (CF) for Flanders, Belgium, is unknown. The aim of this study was to assess the cost-effectiveness of four existing newborn screening strategies for CF: IRT-DNA (immunoreactive trypsinogen, cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation analysis), IRT-PAP (pancreatitis-associated protein), IRT-PAP-DNA, and IRT-PAP-DNA-EGA (extended CFTR gene analysis).
METHODS: Using data from published literature, the cost-effectiveness of the screening strategies was calculated for a hypothetical cohort of 65,606 newborns in Flanders, Belgium. A healthcare payer perspective was used, and the direct medical costs associated with screening were taken into account. The robustness of the model outcomes was assessed in sensitivity analyses.
RESULTS: The IRT-PAP strategy was the most cost-effective strategy in terms of costs per CF case detected (€9314 per CF case detected). The IRT-DNA strategy was more costly (€13,966 per CF case detected), but with an expected sensitivity of 93.4% also the most effective strategy, and was expected to detect 2.2 more cases of CF than the IRT-PAP strategy. The incremental cost-effectiveness ratio of IRT-DNA vs. IRT-PAP was €54,180/extra CF case detected. The IRT-PAP-DNA strategy and the IRT-PAP-DNA-EGA strategy were both strongly dominated by the IRT-PAP strategy.
CONCLUSION: The IRT-PAP strategy was the most cost-effective strategy in terms of costs per CF case detected. However, the strategy did not fulfil the European Cystic Fibrosis Society guidelines for sensitivity and positive predictive value. Therefore, the more costly and more effective IRT-DNA strategy may be the most appropriate newborn screening strategy for Flanders.

PMID: 31007159 [PubMed - as supplied by publisher]