Progress in understanding the molecular pathology and microbiology of cystic fibrosis.

Lancet Respir Med. 2019 Sep 27;:

Authors: Tümmler B

PMID: 31570319 [PubMed - as supplied by publisher]

The future of cystic fibrosis care: a global perspective.

Lancet Respir Med. 2019 Sep 27;:

Authors: Bell SC, Mall MA, Gutierrez H, Macek M, Madge S, Davies JC, Burgel PR, Tullis E, Castaños C, Castellani C, Byrnes CA, Cathcart F, Chotirmall SH, Cosgriff R, Eichler I, Fajac I, Goss CH, Drevinek P, Farrell PM, Gravelle AM, Havermans T, Mayer-Hamblett N, Kashirskaya N, Kerem E, Mathew JL, McKone EF, Naehrlich L, Nasr SZ, Oates GR, O'Neill C, Pypops U, Raraigh KS, Rowe SM, Southern KW, Sivam S, Stephenson AL, Zampoli M, Ratjen F

Abstract
The past six decades have seen remarkable improvements in health outcomes for people with cystic fibrosis, which was once a fatal disease of infants and young children. However, although life expectancy for people with cystic fibrosis has increased substantially, the disease continues to limit survival and quality of life, and results in a large burden of care for people with cystic fibrosis and their families. Furthermore, epidemiological studies in the past two decades have shown that cystic fibrosis occurs and is more frequent than was previously thought in populations of non-European descent, and the disease is now recognised in many regions of the world. The Lancet Respiratory Medicine Commission on the future of cystic fibrosis care was established at a time of great change in the clinical care of people with the disease, with a growing population of adult patients, widespread genetic testing supporting the diagnosis of cystic fibrosis, and the development of therapies targeting defects in the cystic fibrosis transmembrane conductance regulator (CFTR), which are likely to affect the natural trajectory of the disease. The aim of the Commission was to bring to the attention of patients, health-care professionals, researchers, funders, service providers, and policy makers the various challenges associated with the changing landscape of cystic fibrosis care and the opportunities available for progress, providing a blueprint for the future of cystic fibrosis care. The discovery of the CFTR gene in the late 1980s triggered a surge of basic research that enhanced understanding of the pathophysiology and the genotype-phenotype relationships of this clinically variable disease. Until recently, available treatments could only control symptoms and restrict the complications of cystic fibrosis, but advances in CFTR modulator therapies to address the basic defect of cystic fibrosis have been remarkable and the field is evolving rapidly. However, CFTR modulators approved for use to date are highly expensive, which has prompted questions about the affordability of new treatments and served to emphasise the considerable gap in health outcomes for patients with cystic fibrosis between high-income countries, and low-income and middle-income countries (LMICs). Advances in clinical care have been multifaceted and include earlier diagnosis through the implementation of newborn screening programmes, formalised airway clearance therapy, and reduced malnutrition through the use of effective pancreatic enzyme replacement and a high-energy, high-protein diet. Centre-based care has become the norm in high-income countries, allowing patients to benefit from the skills of expert members of multidisciplinary teams. Pharmacological interventions to address respiratory manifestations now include drugs that target airway mucus and airway surface liquid hydration, and antimicrobial therapies such as antibiotic eradication treatment in early-stage infections and protocols for maintenance therapy of chronic infections. Despite the recent breakthrough with CFTR modulators for cystic fibrosis, the development of novel mucolytic, anti-inflammatory, and anti-infective therapies is likely to remain important, especially for patients with more advanced stages of lung disease. As the median age of patients with cystic fibrosis increases, with a rapid increase in the population of adults living with the disease, complications of cystic fibrosis are becoming increasingly common. Steps need to be taken to ensure that enough highly qualified professionals are present in cystic fibrosis centres to meet the needs of ageing patients, and new technologies need to be adopted to support communication between patients and health-care providers. In considering the future of cystic fibrosis care, the Commission focused on five key areas, which are discussed in this report: the changing epidemiology of cystic fibrosis (section 1); future challenges of clinical care and its delivery (section 2); the building of cystic fibrosis care globally (section 3); novel therapeutics (section 4); and patient engagement (section 5). In panel 1, we summarise key messages of the Commission. The challenges faced by all stakeholders in building and developing cystic fibrosis care globally are substantial, but many opportunities exist for improved care and health outcomes for patients in countries with established cystic fibrosis care programmes, and in LMICs where integrated multidisciplinary care is not available and resources are lacking at present. A concerted effort is needed to ensure that all patients with cystic fibrosis have access to high-quality health care in the future.

PMID: 31570318 [PubMed - as supplied by publisher]

A patient's experience of cystic fibrosis care.

Lancet Respir Med. 2019 Sep 27;:

Authors: Brennan S

PMID: 31570317 [PubMed - as supplied by publisher]

Cystic fibrosis lung disease and bronchiectasis.

Lancet Respir Med. 2019 Sep 27;:

Authors: Chalmers JD

PMID: 31570316 [PubMed - as supplied by publisher]

Characterization of poxtA, a novel phenicol-oxazolidinone-tetracycline resistance gene from an MRSA of clinical origin.

J Antimicrob Chemother. 2018 07 01;73(7):1763-1769

Authors: Antonelli A, D'Andrea MM, Brenciani A, Galeotti CL, Morroni G, Pollini S, Varaldo PE, Rossolini GM

Abstract
Objectives: To characterize a novel phenicol-oxazolidinone-tetracycline resistance gene, named poxtA, identified in a previously described MRSA strain that was highly resistant to linezolid and also carried the cfr gene.
Methods: The poxtA gene was identified by bioinformatic analysis of the whole genome sequence of Staphylococcus aureus AOUC-0915. The poxtA gene was cloned in a shuttle plasmid vector and expressed in Escherichia coli, S. aureus and Enterococcus faecalis to investigate the protein function. Comparative sequence analyses at the protein and genetic levels were carried out using standard procedures.
Results: The poxtA gene encodes a protein that is 32% identical to OptrA and exhibits structural features typical of the F lineage of the ATP-binding cassette (ABC) protein superfamily that cause antibiotic resistance by ribosomal protection. Expression of poxtA in E. coli, S. aureus and E. faecalis was able to decrease susceptibility to phenicols, oxazolidinones and tetracyclines. A database search identified the presence of poxtA in E. faecalis, Enterococcus faecium and Pediococcus acidilactici strains, mostly of animal origin, and revealed the presence of poxtA homologues in the genomes of some Clostridiales. Analysis of the genetic context revealed that poxtA was located in a composite transposon-like structure containing two IS1216 elements.
Conclusions: A novel resistance gene, named poxtA, encoding a protein of the antibiotic resistance (ARE) ABC-F lineage, was identified in the genome of an MRSA of clinical origin. PoxtA can confer decreased susceptibility to phenicols, oxazolidinones and tetracyclines and is associated with a putative mobile element that could contribute to its horizontal dissemination.

PMID: 29635422 [PubMed - indexed for MEDLINE]

Association between fat-soluble nutrient status and auditory and visual related potentials in newly diagnosed non-screened infants with cystic fibrosis: A case-control study.

Prostaglandins Leukot Essent Fatty Acids. 2019 Sep 05;150:21-30

Authors: Léveillé P, Knoth IS, Denis MH, Morin G, Barlaam F, Nyalendo C, Daneault C, Marcotte JE, Rosiers CD, Ferland G, Lippé S, Mailhot G

Abstract
Nutritional deficiencies often precede the diagnosis of cystic fibrosis (CF) in infants, and occur at a stage where the rapidly developing brain is more vulnerable to insult. We aim to compare fat-soluble nutrient status of newly diagnosed non-screened infants with CF to that of healthy infants, and explore the association with neurodevelopment evaluated by electroencephalography (EEG). Our results show that CF infants had lower levels of all fat-soluble vitamins and docosahexaenoic acid (DHA) compared to controls. The auditory evoked potential responses were higher in CF compared to controls whereas the visual components did not differ between groups. DHA levels were correlated with auditory evoked potential responses. Although resting state frequency power was similar between groups, we observed a negative correlation between DHA levels and low frequencies. This study emphasizes the need for long-term neurodevelopmental follow-up of CF infants and pursuing intervention strategies in the future.

PMID: 31568924 [PubMed - as supplied by publisher]

Area Deprivation as a Risk Factor for Methicillin-resistant Staphylococcus aureus Infection in Pediatric Cystic Fibrosis.

Pediatr Infect Dis J. 2019 Sep 17;:

Authors: Oates GR, Harris WT, Rowe SM, Solomon GM, Dey S, Zhu A, Hoover WC, Gutierrez HH

Abstract
BACKGROUND: In US cystic fibrosis (CF) patients, methicillin-resistant Staphylococcus aureus (MRSA) rates have tripled in the past 2 decades. Known clinical risk factors include exposure to a healthcare setting, Pseudomonas aeruginosa and CF-related diabetes. Area-level socio-environmental exposures have not been evaluated. We explored the association of area-level deprivation with MRSA prevalence in a pediatric CF Center in the Southeastern United States.
METHODS: Patients' residential addresses were geocoded and linked to a composite Area Deprivation Index and Rural-Urban Commuting Area scores. The association of MRSA with Area Deprivation Index and Rural-Urban Commuting Area scores was evaluated using logistic regression with robust standard errors adjusted for sociodemographic covariates (age, sex, race, mother's and father's education and household income), clinical risk factors (P. aeruginosa, CF-related diabetes, hospitalizations and number of clinic visits) and clustering.
RESULTS: The study included all pediatric patients (N = 231; mean age 12) at a single CF Center. MRSA was present in 44% of subjects. Higher area-level deprivation was correlated with rural residence, lack of parental college education and lower household income (P < 0.001 for each). In a multiple regression model fully adjusted for patient-level sociodemographic covariates, clinical risk factors and clustering, neighborhood deprivation was associated with more than 2-fold increase in the odds of having MRSA [OR 2.26 (1.14-4.45), P < 0.05].
CONCLUSIONS: Neighborhood deprivation is a risk factor for MRSA in pediatric CF, doubling the odds of infection. Community-level socioeconomic risk factors should be considered when developing prevention strategies and treatment plans for MRSA infection in pediatric patients with CF.

PMID: 31568067 [PubMed - as supplied by publisher]

A Retrospective Cohort Study of Growth in the First Two Years of Life in Preterm Infants with Cystic Fibrosis.

J Pediatr Gastroenterol Nutr. 2019 Sep 23;:

Authors: Holland KJ, Slaven JE, Ren CL, Sanders DB, Bennett WE

Abstract
BACKGROUND: Late preterm infants (born 34 to 36 weeks gestation) without cystic fibrosis (CF) are at risk for growth failure during the first two years of life. Infants with CF are at risk of being born premature and thus at risk for growth failure. The aim for this study was to assess weight-for-length (WFL) at two years of age for late preterm infants compared to term infants with CF.
METHODS: Data were collected from the U.S. CF Foundation Patient Registry. We compared growth parameters between late preterm and term infants with CF born from 2010 to 2013. Our primary outcome was WFL <10 and <50 percentile at two years of age. A multivariate logistical regression analysis evaluated late preterm gestation and WFL<10 or <50 percentile.
RESULTS: A total of 2955 infants were born from 2010 to 2013 with CF. Eight percent late preterm. Forty five percent late preterm versus 43% term were below the 50 percentile for WFL at age two (p = 0.75). Twelve percent late preterm versus 6% term for WFL <10 percentile at age two (p = 0.010). The multivariate regression model identified two-fold increased odds of being < 10 percentile for WFL at age two (p = 0.025) for preterm over term. Late preterm infants used higher calorie dense feeds and more feeding tubes (p = 0.035 and p = 0.006).
CONCLUSIONS: Late preterm infants with CF are at higher risk of being below the 10 percentile for WFL at two years of age compared to their term peers. This indicates a population that is at risk for growth failure.

PMID: 31567647 [PubMed - as supplied by publisher]

Prevention of osteoporosis in cystic fibrosis.

Curr Opin Pulm Med. 2019 Sep 20;:

Authors: Chedevergne F, Sermet-Gaudelus I

Abstract
PURPOSE OF REVIEW: The increased life span of patients with cystic fibrosis has lead to the detection of new complications. Osteopenia is present in up to 50% of adult patients with cystic fibrosis, and osteoporosis in 10-34% and can cause a difficult management problem..
RECENT FINDINGS: In children, defects in bone health become apparent generally at adolescence because of suboptimall bone peak mass achievement. Malnutrition, inflammation, vitamin D and vitamin K deficiency, altered sex hormone production, glucocorticoid therapy, and physical inactivity potentiate poor bone health.
SUMMARY: Monitoring bone mineral density and preventive care of osteoporosis are necessary from childhood to minimize cystic fibrosis-related bone disease in adult cystic fibrosis patients.

PMID: 31567515 [PubMed - as supplied by publisher]

Prevention of malnutrition in cystic fibrosis.

Curr Opin Pulm Med. 2019 Sep 24;:

Authors: Slae M, Wilschanski M

Abstract
PURPOSE OF REVIEW: Malnutrition is one of the major burdens of disease in cystic fibrosis. The prevention of malnutrition remains a priority throughout the life of a patient with cystic fibrosis. Literature and guidelines on the management of nutrition in cystic fibrosis have been published; however, here we review updated findings in cystic fibrosis nutrition as well as the role of novel treatments.
RECENT FINDINGS: We review the latest studies on the importance and consequences of nutrition in cystic fibrosis. Novel findings on specific nutrients such as vitamin D and sodium can improve our care and thereby health and growth outcomes. The role of exercise has been further studied. In the field of new treatments, we review the role of cystic fibrosis transmembrane-conductance regulator potentiators and modulators in cystic fibrosis nutrition. A new feeding tube fat-digesting device has been developed and shows promise in cystic fibrosis enteral nutrition.
SUMMARY: Advances in the nutritional care of cystic fibrosis are forming and believed to further develop in the near future, adding to the recent progress in cystic fibrosis patients' health, survival, and quality of life.

PMID: 31567328 [PubMed - as supplied by publisher]

Long-Term Inhaled Antipseudomonal Antibiotics in Cystic Fibrosis.

Am J Nurs. 2019 Oct;119(10):49

Authors: Greenslade R

Abstract
Editor's note: This is a summary of a nursing care-related systematic review from the Cochrane Library. For more information, see http://nursingcare.cochrane.org.

PMID: 31567255 [PubMed - in process]

New Drug Indications for Pediatric Type 2 Diabetes, Cystic Fibrosis, and Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia.

Am J Nurs. 2019 Oct;119(10):23

Authors: Aschenbrenner DS

PMID: 31567247 [PubMed - in process]

Adherence to long-term therapies in cystic fibrosis: a French cross-sectional study linking prescribing, dispensing, and hospitalization data.

Patient Prefer Adherence. 2019;13:1497-1510

Authors: Rouzé H, Viprey M, Allemann S, Dima AL, Caillet P, Denis A, Poupon-Bourdy S, Camara B, Llerena C, Reix P, Durieu I, Reynaud Q, Touzet S

Abstract
Background: Cystic fibrosis (CF) is a life-shortening genetic condition that usually affects several organs and involves significant treatment burden. Adherence to medication is important for successful CF management.
Objective: To describe medication adherence according to age, therapeutic class, and pharmaceutical form in adults and children followed in four regional CF centers in France.
Methods: We conducted a cross-sectional study with non-transplanted patients followed in two adult and two pediatric centers during 2015 who were covered by the French National Health Insurance (NHI). Sociodemographic, clinical, hospitalization, and prescription data were collected from patient medical records. Medication dispensations were extracted from the regional French NHI database. Adherence was calculated over 12 months using continuous medication availability (CMA) accounting for dose adjustments and hospitalizations. Drug-specific CMA was computed in R with the AdhereR package for each medication prescribed more than 3 months, which was averaged to obtain a composite CMA score (cCMA) for all treatments and per therapeutic class as well as pharmaceutical form for each patient.
Results: A total of 228 patients were included. The number of chronic medications increased with age (r=0.50, p<0.001): a median of 7 medications per patient were prescribed. The mean±SD cCMA was significantly different between age groups (p=0.0098): it was 0.71±0.20 for the 0-5 years age group, 0.73±0.16 for 6-11 years, 0.64±0.17 for 12-17 years, 0.57±0.23 for 18-25 years, and 0.65±0.20 for the over 25 years age group. cCMA varied significantly according to pharmaceutical forms: the mean±SD cCMA was 0.70±0.21 for oral medications and 0.54±0.28 for inhaled medications (p<0.001).
Conclusion: This study suggests that adherence to medication regimens in CF patients remains suboptimal and varies substantially between age groups and pharmaceutical forms. These variations in adherence should be considered when developing effective strategies to improve adherence.

PMID: 31564837 [PubMed]

Commentaries on Viewpoint: Use aerobic energy expenditure instead of oxygen uptake to quantify exercise intensity and predict endurance performance.

J Appl Physiol (1985). 2018 08 01;125(2):676-682

Authors: Barnes KR, Kilding AE, Blagrove RC, Howatson G, Hayes PR, Boone J, Bourgois J, Fletcher JR, MacIntosh BR, González-Mohíno F, Yustres I, Santos-García DJ, González-Ravé JM, Hopker JG, Coleman DA, Kerhervé HA, Solomon C, Malatesta D, Lanzi S, Fernandez-Menendez A, Borrani F, Sandford GN, Maunder E, McNulty CR, Robergs RA, Pavei G, de Oliveira Barreto T, de Lima Conceição MR, Souza DS, Tenan MS, Macfarlane D, Hackney AC, Adamic EM, Shei RJ, Freemas JA, Barenie M, Barton J, Yeager Z, Nowak M, Paris HL, Mickleborough TD

PMID: 30138048 [PubMed - indexed for MEDLINE]

Effect of T1 relaxation on ventilation mapping using hyperpolarized 129 Xe multiple breath wash-out imaging.

Magn Reson Med. 2018 12;80(6):2670-2680

Authors: Morgado F, Couch MJ, Stirrat E, Santyr G

Abstract
PURPOSE: To investigate the effect of incorporating T1 as a function of wash-out breath number (T1 (n)) on estimation of fractional ventilation (r) using hyperpolarized 129 Xe multiple breath wash-out (MBWO) imaging in rats.
METHODS: MBWO imaging was performed in 8 healthy mechanically ventilated rats at several inter-image delay times (τ) and tidal volumes (TV). r maps were calculated from the imaging data using a model of T1 (n) (assuming that the longitudinal relaxation rate of 129 Xe in the lung is directly proportional to pA O2 ) and compared to r maps obtained by assuming a fixed T1 measured before wash-out breaths (r').
RESULTS: Fractional ventilation was overestimated by up to 19.3% when T1 was fixed. An inverse relationship between bias (Δr) and ventilation was observed at all τ and TV. Additionally, Δr significantly increased when TV was decreased (F statistic F(2,7) = 48.97, P < 10-4 ). Histograms from r' maps were significantly more skewed toward lower values as compared to r histograms at all τ and TV (P < 0.05) except TV = Vdose - 1 mL.
CONCLUSION: Analysis of hyperpolarized 129 Xe MBWO imaging using a model incorporating T1 (n) corrects for an overestimating bias in the mapping of fractional ventilation in mechanically ventilated rats introduced by assuming a fixed T1 .

PMID: 30009427 [PubMed - indexed for MEDLINE]

Enzyme-encapsulating polymeric nanoparticles: A potential adjunctive therapy in Pseudomonas aeruginosa biofilm-associated infection treatment.

Colloids Surf B Biointerfaces. 2019 Sep 20;184:110512

Authors: Han C, Goodwine J, Romero N, Steck KS, Sauer K, Doiron A

Abstract
Pseudomonas aeruginosa is a pathogen known to be associated with a variety of diseases and conditions such as cystic fibrosis, chronic wound infections, and burn wound infections. A novel approach was developed to combat the problem of biofilm antibiotic tolerance by reverting biofilm bacteria back to the planktonic mode of growth. This reversion was achieved through the enzymatic depletion of available pyruvate using pyruvate dehydrogenase, which induced biofilm bacteria to disperse from the surface-associated mode of growth into the surrounding environment. However, direct use of the enzyme in clinical settings is not practical as the enzyme is susceptible to denaturation under various storage conditions. We hypothesize that by encapsulating pyruvate dehydrogenase into degradable, biocompatible poly(lactic-co-glycolic) acid nanoparticles, the activity of the enzyme can be extended to deplete available pyruvate and induce dispersion of mature Pseudomonas aeruginosa biofilms. Several particle formulations were attempted in order to permit the use of the smallest dose of nanoparticles while maintaining pyruvate dehydrogenase activity for an extended time length. The nanoparticles synthesized using the optimal formulation showed an average size of 266.7 ± 1.8 nm. The encapsulation efficiency of pyruvate dehydrogenase was measured at 17.9 ± 1.4%. Most importantly, the optimal formulation dispersed biofilms and exhibited enzymatic activity after being stored at 37 °C for 6 days.

PMID: 31563809 [PubMed - as supplied by publisher]

Inflammatory role of extracellular sphingolipids in Cystic Fibrosis.

Int J Biochem Cell Biol. 2019 Sep 26;:105622

Authors: Zulueta A, Peli V, Dei Cas M, Colombo M, Paroni R, Falleni M, Baisi A, Bollati V, Chiaramonte R, Del Favero E, Ghidoni R, Caretti A

Abstract
Ceramide is emerging as one of the players of inflammation in lung diseases. However, data on its inflammatory role in Cystic Fibrosis (CF) as part of the extracellular machinery driven by lung mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) are missing. We obtained an in vitro model of CF-MSC by treating control human lung MSCs with a specific CFTR inhibitor. We characterized EVs populations derived from MSCs (ctr EVs) and CF-MSCs (CF-EVs) and analyzed their sphingolipid profile by LC-MS/MS. To evaluate their immunomodulatory function, we treated an in vitro human model of CF, with both EVs populations. Our data show that the two EVs populations differ for the average size, amount, and rate of uptake. CF-EVs display higher ceramide and dihydroceramide accumulation as compared to control EVs, suggesting the involvement of the de novo biosynthesis pathway in the parental CF-MSCs. Higher sphingomyelinase activity in CF-MSCs, driven by inflammation-induced ceramide accumulation, sustains the exocytosis of vesicles that export new formed pro-inflammatory ceramide. Our results suggest that CFTR dysfunction associates with an enhanced sphingolipid metabolism leading to the release of EVs that export the excess of pro-inflammatory Cer to the recipient cells, thus contributing to maintain the unresolved inflammatory status of CF.

PMID: 31563560 [PubMed - as supplied by publisher]

Retrospective Study on the Association of Biomarkers With Real-world Outcomes of Omalizumab-treated Patients With Allergic Asthma.

Clin Ther. 2019 Sep 25;:

Authors: Kavati A, Zhdanava M, Ortiz B, Lecocq J, Schiffman B, Pilon D, Ho H, Lefebvre P, Stone B

Abstract
PURPOSE: Biomarkers, including blood eosinophils (EoS) and fractional exhaled nitric oxide (FeNO), may affect omalizumab outcomes in allergic asthma, but evidence in the literature remains mixed. This study assessed omalizumab outcomes in real-world patients with allergic asthma stratified by pretreatment biomarker levels.
METHODS: Patients with allergic asthma aged ≥12 years initiated on omalizumab with ≥12 months of data after index were identified in the Allergy Partners electronic medical records (2007-2018). Patients with ≥1 diagnosis of chronic obstructive pulmonary disease in combination with ≥10 pack-years of smoking, cystic fibrosis, Alpha-1 antitrypsin deficiency, bronchiectasis, interstitial lung disease, and sarcoidosis in the 12 months before or after index were excluded. Patients were stratified by pretreatment EoS (≥/<300 cells/μL) and FeNO (≥/<25 parts per billion). Outcomes, including Asthma Control Test (ACT) scores, forced expiratory volume in 1 second (FEV1), and FEV1 as a percentage of predicted value (FEV1% predicted), were compared using generalized estimating equations at 6 and 12 months after versus before index date in stratified patients with outcome measures available at both time periods.
FINDINGS: A total of 77 and 86 patients were stratified into the high and low EoS strata, respectively, and 56 patients into each of the intermediate-high and low FeNO strata. Compared with 6 months before index, mean difference (MD) in ACT scores at 6 months after index reached the minimally important difference of ≥3 points in high (MD = 3.75; 95% CI, 2.05-5.45) and low (MD = 4.56; 95% CI, 2.86-6.26) EoS, as well in the intermediate-high (MD = 3.75; 95% CI, 1.95-5.55) and low (MD = 3.55; 95% CI, 1.53-5.57) FeNO strata. Statistically significant improvements in mean FEV1 were observed in the high EoS (MD = 0.22 L/s; 95% CI, 0.08-0.35 L/s) and intermediate-high FeNO (MD = 0.13 L/s; 95% CI, 0.03-0.24 L/s) strata but not in the lower strata. In terms of mean FEV1% predicted, a statistically significant improvement was observed in high EoS stratum (MD = 4.95%; 95% CI, 0.60%-9.30%). Results that compared 12 months after versus before index date were similar.
IMPLICATIONS: Omalizumab was associated with statistically significant improvements in ACT scores largely reaching or exceeding minimally important difference across biomarker levels and with a statistically significant improvement in lung function more evident in high biomarker strata. Although response varied by biomarkers for some outcomes, all strata indicated improvements on ≥1 measure. Real-world patients with allergic asthma could benefit from omalizumab regardless of pretreatment biomarker levels, suggesting that pretreatment biomarker levels might not inform response.

PMID: 31563391 [PubMed - as supplied by publisher]

Adjusting for time-varying confounders in survival analysis using structural nested cumulative survival time models.

Biometrics. 2019 Sep 28;:

Authors: Seaman S, Dukes O, Keogh R, Vansteelandt S

Abstract
Accounting for time-varying confounding when assessing causal effects of time-varying exposures on survival time is challenging. Standard survival methods that incorporate time-varying confounders as covariates generally yield biased effect estimates. Estimators using weighting by inverse probability of exposure can be unstable when confounders are highly predictive of exposure or the exposure is continuous. Structural nested accelerated failure time models require artificial recensoring, which can cause estimation difficulties. Here, we introduce the structural nested cumulative survival time model (SNCSTM). This model assumes that intervening to set exposure at time t to zero has an additive effect on the subsequent conditional hazard given exposure and confounder histories when all subsequent exposures have already been set to zero. We show how to fit it using standard software for generalised linear models and describe two more efficient, double robust, closed-form estimators. All three estimators avoid the artificial recensoring of accelerated failure time models and the instability of estimators that use weighting by the inverse probability of exposure. We examine the performance of our estimators using a simulation study and illustrate their use on data from the UK Cystic Fibrosis Registry. The SNCSTM is compared with a recently proposed structural nested cumulative failure time model, and several advantages of the former are identified. This article is protected by copyright. All rights reserved.

PMID: 31562652 [PubMed - as supplied by publisher]

Regulation of CFTR Bicarbonate Channel Activity by WNK1: Implications for Pancreatitis and CFTR-related disorders.

Cell Mol Gastroenterol Hepatol. 2019 Sep 24;:

Authors: Kim Y, Jun I, Shin DH, Yoon JG, Piao H, Jung J, Park HW, Cheng MH, Bahar I, Whitcomb DC, Lee MG

Abstract
BACKGRAOUD & AIMS: Aberrant epithelial bicarbonate (HCO3-) secretion caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is associated with several diseases including cystic fibrosis and pancreatitis. Dynamically regulated ion channel activity and anion selectivity of CFTR by kinases sensitive to intracellular chloride concentration ([Cl-]i) play an important role in epithelial HCO3- secretion. However, the molecular mechanisms of how [Cl-]i-dependent mechanisms regulate CFTR are unknown.
METHODS: We examined the mechanisms of the CFTR HCO3- channel regulation by [Cl-]i-sensitive kinases using an integrated electrophysiological, molecular, and computational approach including whole-cell, outside-out, and inside-out patch clamp recordings and molecular dissection of WNK1 and CFTR proteins. In addition, we analyzed the effects of pancreatitis-causing CFTR mutations on the WNK1-mediated regulation of CFTR.
RESULTS: Among the WNK1, SPAK, and OSR1 kinases that constitute a [Cl-]i-sensitive kinase cascade, the expression of WNK1 alone was sufficient to increase the CFTR bicarbonate permeability (PHCO3/PCl) and conductance (GHCO3) in patch clamp recordings. Molecular dissection of the WNK1 domains revealed that the WNK1 kinase domain is responsible for CFTR PHCO3/PCl regulation by direct association with CFTR, while the surrounding N-terminal regions mediate the [Cl-]i-sensitivity of WNK1. Furthermore, the pancreatitis-causing R74Q and R75Q mutations in the elbow helix 1 of CFTR hampered WNK1-CFTR physical associations and reduced WNK1-mediated CFTR PHCO3/PCl regulation.
CONCLUSION: The CFTR HCO3- channel activity is regulated by [Cl-]i and a WNK1-dependent mechanism. Our results provide new insights into the regulation of the ion selectivity of CFTR and the pathogenesis of CFTR-related disorders.

PMID: 31561038 [PubMed - as supplied by publisher]