Further Commentary.

Pediatr Pulmonol. 2020 01;55(1):23

Authors: Hengzhuang W, Høiby N

PMID: 31496043 [PubMed - indexed for MEDLINE]

Airway mycosis in allergic airway disease.

Adv Immunol. 2019;142:85-140

Authors: Li E, Knight JM, Wu Y, Luong A, Rodriguez A, Kheradmand F, Corry DB

Abstract
The allergic airway diseases, including chronic rhinosinusitis (CRS), asthma, allergic bronchopulmonary mycosis (ABPM) and many others, comprise a heterogeneous collection of inflammatory disorders affecting the upper and lower airways and lung parenchyma that represent the most common chronic diseases of humanity. In addition to their shared tissue tropism, the allergic airway diseases are characterized by a distinct pattern of inflammation involving the accumulation of eosinophils, type 2 macrophages, innate lymphoid cells type 2 (ILC2), IgE-secreting B cells, and T helper type 2 (Th2) cells in airway tissues, and the prominent production of type 2 cytokines including interleukin (IL-) 33, IL-4, IL-5, IL-13, and many others. These factors and related inflammatory molecules induce characteristic remodeling and other changes of the airways that include goblet cell metaplasia, enhanced mucus secretion, smooth muscle hypertrophy, tissue swelling and polyp formation that account for the major clinical manifestations of nasal obstruction, headache, hyposmia, cough, shortness of breath, chest pain, wheezing, and, in the most severe cases of lower airway disease, death due to respiratory failure or disseminated, systemic disease. The syndromic nature of the allergic airway diseases that now include many physiological variants or endotypes suggests that distinct endogenous or environmental factors underlie their expression. However, findings from different perspectives now collectively link these disorders to a single infectious source, the fungi, and a molecular pathogenesis that involves the local production of airway proteinases by these organisms. In this review, we discuss the evidence linking fungi and their proteinases to the surprisingly wide variety of chronic airway and systemic disorders and the immune pathogenesis of these conditions as they relate to environmental fungi. We further discuss the important implications these new findings have for the diagnosis and future therapy of these common conditions.

PMID: 31296304 [PubMed - indexed for MEDLINE]

Alignment of Inhaled Chronic Obstructive Pulmonary Disease Therapies with Published Strategies. Analysis of the Global Initiative for Chronic Obstructive Lung Disease Recommendations in SPIROMICS.

Ann Am Thorac Soc. 2019 02;16(2):200-208

Authors: Ghosh S, Anderson WH, Putcha N, Han MK, Curtis JL, Criner GJ, Dransfield MT, Barr RG, Krishnan JA, Lazarus SC, Cooper CB, Paine R, Peters SP, Hansel NN, Martinez FJ, Drummond MB, Current and former investigators of the SPIROMICS sites and reading centers

Abstract
RATIONALE: Despite awareness of chronic obstructive pulmonary disease (COPD) treatment recommendations, uptake is poor. The Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) spans 2010-2016, providing an opportunity to assess integration of 2011 Global Initiative for Obstructive Lung Disease (GOLD) treatment strategies over time in a large observational cohort study.
OBJECTIVES: To evaluate how COPD treatment aligns with 2011 GOLD strategies and determine factors associated with failure to align with recommendations.
METHODS: Information on inhaled medication use collected via questionnaire annually for 4 years was compiled into therapeutic classes (long-acting antimuscarinic agent, long-acting β-agonist, inhaled corticosteroids [ICS], and combinations thereof). Medications were not modified by SPIROMICS investigators. 2011 GOLD COPD categories A, B, C, and D were assigned. Alignment of inhaler regimen with first-/second-line GOLD recommendations was determined, stratifying into recommendation aligned or nonaligned. Recommendation-nonaligned participants were further stratified into overuse and underuse categories.
RESULTS: Of 1,721 participants with COPD, at baseline, 52% of regimens aligned with GOLD recommendations. Among participants with nonaligned regimens, 46% reported underuse, predominately owing to lack of long-acting inhalers in GOLD category D. Of the 54% reporting overuse, 95% were treated with nonindicated ICS-containing regimens. Among 431 participants with 4 years of follow-up data, recommendation alignment did not change over time. When we compared 2011 and 2017 recommendations, we found that 47% did not align with either set of recommendations, whereas 35% were in alignment with both recommendations.
CONCLUSIONS: Among SPIROMICS participants with COPD, nearly 50% reported inhaler regimens that did not align with GOLD recommendations. Nonalignment was driven largely by overuse of ICS regimens in milder disease and lack of long-acting inhalers in severe disease.

PMID: 30216731 [PubMed - indexed for MEDLINE]

Improved Prognosis in Cystic Fibrosis: Consideration for Intensive Care During the COVID-19 Pandemic.

Am J Respir Crit Care Med. 2020 Apr 14;:

Authors: Ramos KJ, Pilewski JM, Faro A, Marshall BC

PMID: 32289235 [PubMed - as supplied by publisher]

The history of respiratory disease management.

Medicine (Abingdon). 2020 Apr;48(4):239-243

Authors: Geddes D

Abstract
Over the past 200 years lung diseases have shifted from infections - tuberculosis, pneumonia - to diseases of dirty air - chronic obstructive pulmonary disease, asthma and lung cancer. New diseases have emerged from industrial pollution and HIV infection, while better imaging has revealed others previously unrecognized. Scientific advances in microbiology, imaging and clinical measurement have improved diagnosis and allowed better targeted treatment. Advances in treatment have been dramatic, the most important being drugs (antibiotics, cortisone, β2-adrenoceptor agonists), ventilatory support (from iron lung to nasal positive-pressure ventilation), inhaled therapy (metered dose inhalers, nebulizers) and lung surgery (resections, video-assisted thoracoscopic surgery, transplantation). Delivery of care has shifted from sanatoria for the rich but nothing at all for the poor, to universal coverage in both primary and hospital care. Generalists have turned into super-specialists and doctors have been joined by growing numbers of professions allied to medicine. Management of lung disease has vastly improved but the impact of disease remains.

PMID: 32288588 [PubMed - as supplied by publisher]

Molecular Diagnostics of Cystic Fibrosis in Serbia: Our Approach to Meet the Diagnostic Challenges.

Genet Test Mol Biomarkers. 2020 Apr;24(4):212-216

Authors: Divac Rankov A, Kusic-Tisma J, Ljujic M, Nikolic A, Milosevic K, Vilotijevic Dautovic G, Radojkovic D

Abstract
Background: High heterogeneity levels of cystic fibrosis transmembrane regulator (CFTR) are manifested in different populations. The aim of this study was to analyze comprehensively all mutations in the CFTR gene in Serbian patients with cystic fibrosis (CF) and to use the findings to propose a testing algorithm for the Serbian population. Materials and Methods: Cascade screening was employed to detect mutations in the CFTR gene of 90 patients suspected of having CF, using polymerase chain reaction (PCR), PCR-restriction fragment length polymorphism or PCR-mediated site directed mutagenesis, Sanger sequencing, and/or next-generation sequencing. Results: This is the first report for the Serbian CF population where single nucleotide polymorphisms, small insertions and deletions, large genome rearrangements, and copy number variants were analyzed in detail. A high degree of heterogeneity within the CFTR was documented among our cohort of 90 patients. We identified 19 CF-causing mutations and 3 with varying consequences, including a previously unreported deletion of the entire exon 11. Conclusion: Considering the spectrum and frequency of mutations found, we recommend a multistep sequencing algorithm in combination with evaluation of large rearrangements for future analyses of the CFTR gene in the Serbian population.

PMID: 32286879 [PubMed - as supplied by publisher]

Chloride channels regulate differentiation and barrier functions of the mammalian airway.

Elife. 2020 Apr 14;9:

Authors: He M, Wu B, Ye W, Le DD, Sinclair AW, Padovano V, Chen Y, Li KX, Sit R, Tan M, Caplan MJ, Neff N, Jan YN, Darmanis S, Jan LY

Abstract
The conducting airway forms a protective mucosal barrier and is the primary target of airway disorders. The molecular events required for the formation and function of the airway mucosal barrier, as well as the mechanisms by which barrier dysfunction leads to early onset airway diseases, remain unclear. In this study, we systematically characterized the developmental landscape of the mouse airway using single-cell RNA sequencing and identified remarkably conserved cellular programs operating during human fetal development. We demonstrated that in mouse, genetic inactivation of chloride channel Ano1/Tmem16a compromises airway barrier function, results in early signs of inflammation, and alters the airway cellular landscape by depleting epithelial progenitors. Mouse Ano1-/- mutants exhibited mucus obstruction and abnormal mucociliary clearance that resemble the airway defects associated with cystic fibrosis. The data reveal critical and non-redundant roles for Ano1 in organogenesis, and show that chloride channels are essential for mammalian airway formation and function.

PMID: 32286221 [PubMed - as supplied by publisher]

Treatment of allergic bronchopulmonary aspergillosis: from evidence to practice.

Future Microbiol. 2020 Mar;15:365-376

Authors: Dhooria S, Sehgal IS, Muthu V, Agarwal R

Abstract
Allergic bronchopulmonary aspergillosis (ABPA) is a complex pulmonary disorder caused by dysregulated immune responses against Aspergillus fumigatus. The disorder usually complicates the course of patients with asthma and cystic fibrosis. Patients with ABPA most often present with asthma that is poorly controlled despite inhaled corticosteroids and long-acting β2 agonists. The treatment of ABPA is complicated due to the occurrence of recurrent exacerbations and spontaneous remissions. The drugs used for treating ABPA include systemic glucocorticoids, antifungal agents and biologics, each with its own benefits and drawbacks. In this review, we illustrate the treatment pathway for ABPA in different situations, using a case-based approach. In each case, we present the options for treatment based on the available evidence from recent clinical trials.

PMID: 32286102 [PubMed - as supplied by publisher]

Target-Based Design of Promysalin Analogues Identifies a New Putative Binding Cleft in Succinate Dehydrogenase.

ACS Infect Dis. 2020 Apr 14;:

Authors: Post SJ, Keohane CE, Rossiter LM, Kaplan AR, Khowsathit J, Matuska K, Karanicolas J, Wuest WM

Abstract
Promysalin is a small-molecule natural product that specifically inhibits growth of the Gram-negative pathogen Pseudomonas aeruginosa (PA). This activity holds promise in the treatment of multidrug resistant infections found in immunocompromised patients with chronic illnesses, such as cystic fibrosis. In 2015, our lab completed the first total synthesis; subsequent analogue design and SAR investigation enabled identification of succinate dehydrogenase (Sdh) as the biological target in PA. Herein, we report the target-guided design of new promysalin analogues with varying alkyl chains, one of which is on par with our most potent analogue to date. Computational docking revealed that some analogues have a different orientation in the Sdh binding pocket, placing the terminal carbon proximal to a tryptophan residue. This inspired the design of an extended side chain analogue bearing a terminal phenyl moiety, providing a basis for the design of future analogues.

PMID: 32286041 [PubMed - as supplied by publisher]

The "Tango" of Problem Formulation: A patient/researcher reflection on an Action Design Research journey.

J Med Internet Res. 2020 Apr 09;:

Authors: Twomey M, Sammon D, Nagle T

Abstract
UNSTRUCTURED: This paper reports on the reflection of the lead researcher, a 48-year-old with Cystic Fibrosis (CF), and aims to portray his real-life experience of a 10-month Action Design Research (ADR) project. Playing a dual role, as both a patient and researcher, the lead research reflects deeply on his ADR experience with particular emphasis on the "problem formulation" stage of creating a simple yet impactful check list to aid memory recall of CF patients/carers within the medical appointment. Using Driscoll's (2001) Model of Reflection, a real-life un-sanitised ADR experience is carefully imparted via a series of four vignettes, including four key learnings, which highlight the connection between a meticulous considered approach to "problem formulation" and truly effective outcomes. By providing this rich account of "problem formulation" within ADR it is hoped that this reflection will help researchers to better understand the complexity of "problem formulation" in design orientated research, to avoid making assumptions and becoming "fixated on solutions", and move instead to an endpoint where several possible ways of examining a problem have been considered, explored, and understood. An endpoint, where through grit and determination successful end results are reached. This paper advocates for the inclusion and portrayal of the actual realities or "ups and downs" of this dynamic and evolving stage of ADR, capturing the often-tacit knowledge of "problem formulation". Begetting a sense of realism and humanity to ADR, serving as knowledge contributions in their own right. The lead researcher is the patient/researcher in this Action Design Research project. This is my story!

PMID: 32285802 [PubMed - as supplied by publisher]

An Infant with Severe Anemia and Hypoalbuminemia.

Indian Pediatr. 2020 Apr 15;57(4):349-355

Authors: Kumar J, Chatterjee D, Lal SB, Kumar P

Abstract
We discuss the case of a two-month-old girl admitted with complaints of progressive pallor, generalized body swelling and pale colored stool since the neonatal period. On examination, severe pallor, chubby cheeks and moderate hepatomegaly were noted. Investigations revealed isolated anemia, transaminitis, conjugated hyperbilirubinemia, prolonged prothrombin time and hyperlipidemia. She died due to severe sepsis, shock, and pulmonary hemorrhage. An autopsy revealed characteristic histopathology findings of cystic fibrosis in the liver, lungs, and pancreas. Genetic analysis performed on autopsy tissue was positive for F508del compound heterozygous (WT/F508del) mutation, confirming the diagnosis of cystic fibrosis.

PMID: 32284476 [PubMed - in process]

The Role of Pseudomonas aeruginosa Glutathione Biosynthesis in Lung and Soft Tissue Infection.

Infect Immun. 2020 Apr 13;:

Authors: Michie KL, Dees JL, Fleming D, Moustafa DA, Goldberg JB, Rumbaugh KP, Whiteley M

Abstract
The opportunistic pathogen Pseudomonas aeruginosa is a leading cause of morbidity and mortality worldwide. To survive in both the environment and in the host, P. aeruginosa must cope with redox stress. In P. aeruginosa, a primary mechanism for protection from redox stress is the antioxidant glutathione (GSH). GSH is a low molecular weight thiol-containing tripeptide (L-γ-glutamyl-L-cysteinyl-glycine) that can function as a reversible reducing agent. GSH plays an important role in P. aeruginosa physiology and is known to modulate several cellular and social processes that are likely important during infection. However, the role of GSH biosynthesis during mammalian infection is not well understood. In this study, we created a P. aeruginosa mutant defective in GSH biosynthesis to examine how loss of GSH biosynthesis affects P. aeruginosa virulence. We found that GSH is critical for normal growth in vitro and provides protection against hydrogen peroxide, bleach, antimicrobial peptides (AMPs) and ciprofloxacin. We also studied the role of P. aeruginosa GSH biosynthesis in four mouse infection models, including the surgical wound, abscess, burn wound, and acute pneumonia models. We discovered that the GSH biosynthesis mutant was slightly less virulent in the acute pneumonia infection model but was equally virulent in the three other models. This work provides new and complementary data regarding the role of GSH in P. aeruginosa during mammalian infection.

PMID: 32284368 [PubMed - as supplied by publisher]

Regulation of Virulence by Two-component Systems in Pathogenic Burkholderia.

Infect Immun. 2020 Apr 13;:

Authors: Schaefers MM

Abstract
The regulation and timely expression of bacterial genes during infection is critical for a pathogen to cause an infection. Bacteria have multiple mechanisms to regulate gene expression in response to their environment, one of which being two-component systems (TCS). TCS have two components. One component is a sensory histidine kinase that autophosphorylates when activated by a signal. The activated sensory histidine kinase then transfers the phosphoryl group to the second component, the response regulator, which activates transcription of target genes. The genus Burkholderia contains members that cause human disease and are often extensively resistant to many antibiotics. The Burkholderia cepacia complex (BCC) can cause severe lung infections in patients with cystic fibrosis (CF) or chronic granulomatous disease (CGD). BCC members have also recently been associated with several outbreaks of bacteremia from contaminated pharmaceutical products. Separate from the BCC is Burkholderia pseudomallei, the causative agent of melioidosis, a serious disease that occurs in the tropics and a potential bioterrorism weapon. Bioinformatic analysis of sequenced Burkholderia isolates predicts that most strains have at least 40 TCS. The vast majority of these TCS are uncharacterized both in terms of the signals that activate them and the genes that are regulated by them. This review will highlight TCS that have been described to play a role in virulence in either BCC or B. pseudomallei Since many of these TCS are involved in virulence, TCS are potential novel therapeutic targets, and elucidating their function is critical for understanding Burkholderia pathogenesis.

PMID: 32284365 [PubMed - as supplied by publisher]

The assessment of pancreatic exocrine function in patients with inoperable pancreatic cancer: In need of a new gold-standard.

Pancreatology. 2020 Apr 02;:

Authors: Carnie LE, Lamarca A, McNamara MG, Bibby N, O'Reilly DA, Valle JW

Abstract
BACKGROUND: Pancreatic exocrine insufficiency is commonplace in patients with pancreatic cancer, adversely impacting on quality of life and survival. Whilst the management of exocrine insufficiency is well established, diagnosis remains challenging in clinical practice. A plethora of diagnostic tests exist. Nevertheless, a lack of consensus remains about the optimal diagnostic method, specifically in patients with pancreatic cancer. Research, to date, has primarily been undertaken in patients with chronic pancreatitis and cystic fibrosis. This manuscript will review the current literature and will examine the evidence around the diagnostic tests available for pancreatic exocrine insufficiency and whether any exists specifically for pancreatic cancer cohorts.
FINDINGS: Evidence to recommend an individual test for the diagnosis of pancreatic exocrine insufficiency in clinical practice is lacking. Direct testing (by direct sampling of pancreatic secretions) has the highest specificity and sensitivity but is no longer routinely deployed or feasible in practice. Indirect testing, such as faecal elastase, is less accurate with high false-positive rates, but is routinely available in clinical practice. The 13C-mixed triglyceride breath test and the gold-standard 72-h faecal fat test have high specificity for indirect tests, but are not routinely available and cumbersome to undertake. A combination approach including nutritional markers and faecal elastase has more recently been proposed.
CONCLUSION: Further research is required to identify the most optimal and accurate diagnostic tool to diagnose pancreatic exocrine insufficiency in patients with pancreatic cancer in clinical practice.

PMID: 32284260 [PubMed - as supplied by publisher]

Gene therapy for cystic fibrosis paved the way for the use of AAV in gene therapy.

Hum Gene Ther. 2020 Apr 13;:

Authors: Cebotaru L, Guggino W

Abstract
Shortly after the cystic fibrosis (CF) gene was identified in 1989, the race began to develop a gene therapy for this condition1. Major efforts utilized full-length CFTR packaged into either adenovirus, adeno-associated virus (AAV), or liposomes and delivered to the airways. The drive to find a treatment for CF based on gene therapy drove the early stages of gene therapy in general, particularly those involving AAV gene therapy. Since general overviews of CF gene therapy have already been published2 3, this review considers specifically the efforts using adeno-associated virus and is focused on honoring the contributions of Dr. Barrie Carter.

PMID: 32283956 [PubMed - as supplied by publisher]

Optimization of western blotting for the detection of proteins of different molecular weights.

Biotechniques. 2020 Apr 14;:

Authors: Heda GD, Shrestha L, Thapa S, Ghimire S, Raut D

Abstract
Protein samples electroblotted onto nitrocellulose membranes and quenched with a mixture of blocking agents produced a strong signal for cystic fibrosis transmembrane-conductance regulator (CFTR), a high-molecular-weight protein, in western blotting. Optimized conditions for CFTR were then extended to medium- and low-molecular-weight proteins (LAMP1 and Rab11a, respectively) to determine the effects of methanol concentration (0-20%) in Towbin's transfer buffer (TTB). Methanol in TTB appears to have little to no effect on CFTR signal. However, for medium-sized (LAMP1) and small (Rab11a) proteins, a lower concentration of methanol (10%) was sufficient to produce a maximal signal. Therefore, methanol, a toxic solvent, can be removed from or reduced in TTB without compromising signal strength. Here, we show modifications may be useful in detecting and/or improving the signal of low-abundance proteins.

PMID: 32283940 [PubMed - as supplied by publisher]

Development of a database for the rapid and accurate routine identification of Schromobacter species by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS).

Clin Microbiol Infect. 2020 Apr 10;:

Authors: Garrigos T, Neuwirth C, Chapuis A, Bador J, Amoureux L, collaborators

Abstract
OBJECTIVES: Achromobacter spp. are emerging pathogens in respiratory samples from cystic fibrosis patients. The current reference methods (nrdA-sequencing or multilocus sequence typing) can identify 18 species which are often misidentified by conventional techniques as A. xylosoxidans. A few studies have suggested that matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF/MS) provides accurate identification of the genus but not of species. The aims of this study were (a) to generate a database for MALDI-TOF/MS Bruker including the 18 species, (b) to evaluate the suitability of the database for routine laboratory identification, and (c) to compare its performance with that of the currently available Bruker default database.
METHODS: A total of 205 isolates belonging to the 18 species identified by nrdA sequencing were used to build a local database. Main spectra profiles (MSPs) were created according to Bruker's recommendations for each isolate with the Biotyper software. Performance of the default Bruker database and ours for routine use were compared by testing 167 strains (including 38 isolates used from MSP creation) belonging to the 18 species identified by nrdA sequencing directly from colonies cultivated on various media.
RESULTS: Our new database accurately identified 99.4% (166/167) of the isolates from the 18 species (score ≥2.0) versus only 50.9% (85/167) with the Bruker database. In the Bruker database 17.4% of the isolates (29/167) were incorrectly identified as another species despite a score of ≥2.0.
CONCLUSIONS: The use of MALDI-TOF/MS in combination with a database developed with samples from 18 Achromobacter species provides rapid and accurate identification. This tool could be used to help future clinical studies.

PMID: 32283265 [PubMed - as supplied by publisher]

Cellular mechanisms underlying carbon monoxide stimulated anion secretion in rat epididymal epithelium.

Nitric Oxide. 2020 Apr 10;:

Authors: Peng L, Gao DD, Xu JW, Xu JB, Ke LJ, Qiu ZE, Zhu YX, Zhang YL, Zhou WL

Abstract
Epididymal epithelium possesses active ion transport properties conducive to the maintenance of appropriate epididymal intraluminal microenvironment. The endogenous gasotransmitter carbon monoxide (CO) regulates numerous cellular processes including water and electrolyte transport in various epithelia. However, the functional role of CO in epididymal epithelium is still elusive. This study aims to explore the potential regulatory effect of CO on transepithelial ion transport in rat epididymis. Using qPCR technique, we verified that endogenous CO synthase heme oxygenase 1 was expressed in rat caput, corpus, and cauda epididymis. In addition, endogenous CO was detected in rat cauda epididymis. Subsequently, Ussing chamber experiments showed that CORM-2, a CO donor, induced an increase of the short-circuit current (ISC) in a concentration-dependent manner in rat cauda epididymal epithelium. The ISC response could be abrogated by removing the ambient Cl- or HCO3-. Interfering with the cAMP signaling pathway or blocking cystic fibrosis transmembrane regulator (CFTR) partially suppressed the CO-stimulated ISC response. Moreover, the CO-evoked ISC response was significantly attenuated by blocking Ca2+-activated Cl- channel (CaCC) or chelating intracellular Ca2+. Elevation of intracellular Ca2+ level was also observed after CO stimulation in rat cauda epididymal epithelial cells. Collectively, this study demonstrated that CO stimulated anion secretion via activation of CFTR and CaCC in rat cauda epididymal epithelium, which might contribute to the formation of the appropriate microenvironment essential for sperm storage.

PMID: 32283263 [PubMed - as supplied by publisher]

Cystic fibrosis transmembrane conductance regulator function, not TAS2R38 gene haplotypes, predict sinus surgery in children and young adults with cystic fibrosis.

Int Forum Allergy Rhinol. 2020 Apr 13;:

Authors: Dalesio NM, Aksit MA, Ahn K, Raraigh KS, Collaco JM, McGrath-Morrow S, Zeitlin PL, An SS, Cutting GR

Abstract
BACKGROUND: Chronic rhinosinusitis symptomatology begins in early childhood individuals with cystic fibrosis (CF). Cystic fibrosis transmembrane conductance regulator (CFTR) function contributes to sinus development and disease. Genetic variants of the bitter taste receptor TAS2R38 have been suggested to contribute to sinus disease severity in individuals without CF. Our objective was to explore whether functional TAS2R38 haplotypes and CFTR function are associated with sinus disease or the need for sinus surgery in individuals with CF.
METHODS: We conducted a retrospective study using prospectively collected data from the CF Twin-Sibling Study. The function of CFTR was assessed via chloride conductance. Genotyping of the TAS2R38 gene identified patients who were homozygous for the functional haplotype, heterozygous, or homozygous for nonfunctional haplotypes. Clustered multivariate logistic regression was performed, controlling for sex and family relationship.
RESULTS: A total of 1291 patients were evaluated. Patients with ≤1% CFTR function were 1.56 times more likely to require sinus surgery than those with >1% CFTR function (p = 0.049). CFTR function did not correlate significantly with the presence of sinus disease (p = 0.30). In addition, there were no statistically significant differences in diagnosis of sinus disease or need for sinus surgery between patients with functional and nonfunctional TAS2R38 haplotypes.
CONCLUSION: CFTR function correlates with need for sinus surgery, whereas TAS2R38 function does not appear to contribute to sinus disease or the need for sinus surgery in patients with CF.

PMID: 32282124 [PubMed - as supplied by publisher]

Ataluren/ivacaftor combination therapy: Two N-of-1 trials in cystic fibrosis patients with nonsense mutations.

Pediatr Pulmonol. 2020 Apr 13;:

Authors: Peabody Lever JE, Mutyam V, Hathorne HY, Peng N, Sharma J, Edwards LJ, Rowe SM

Abstract
Premature termination codons (PTCs) in cystic fibrosis transmembrane conductance regulator (CFTR) produce nonfunctional protein. No approved therapies exist for PTC mutations, including W1282X. We hypothesized that ivacaftor, combined with readthrough therapy, may benefit W1282X patients. Two N-of-1 clinical trials were conducted with ataluren and ivacaftor in various combinations. No meaningful clinical benefit was observed in either patient with ivacaftor alone or ataluren/ivacaftor combination. However, isolated improvements of uncertain significance were noted by a nasal potential difference (NPD) and FEV1 % with ivacaftor in Patient-1 and with ataluren/ivacaftor combination by NPD and body mass index in Patient-2. Drug regimen composed of readthrough agents and potentiators warrant further development for W1282X and other CFTR nonsense mutations.

PMID: 32281737 [PubMed - as supplied by publisher]