A comparison of the performance of voltammetric aptasensors for glycated haemoglobin on different carbon nanomaterials-modified screen printed electrodes.

Mater Sci Eng C Mater Biol Appl. 2019 Aug;101:423-430

Authors: Eissa S, Almusharraf AY, Zourob M

Abstract
The integration of carbon nanomaterials into electrochemical aptasensors has gained significant interest in the recent years because of their high electrical conductivity, mechanical strength, and large surface area. However, no comparative study has been reported so far between different carbon nanomaterials for aptasensing applications. Here, we report, a comparative investigation of six carbon electrode materials (carbon, graphene (G), graphene oxide (GO), multi-wall carbon nanotube (MWCNT), single walled carbon nanotube (SWCNT) and carbon nanofiber (CNF)) on the performance of glycated haemoglobin (HbA1c) aptasensor prepared by physical adsorption. The aptamers were non-covalently immobilized on the six nanomaterial electrodes via π-π stacking interactions between the DNA nucleobases and the surface of the carbon material which creates a barrier to the electron transfer. However, upon binding of the target protein to the aptamer, the aptamer dissociates from the surface leading to enhancement of the electron transfer which represent the basis of the detection. The aptamer adsorption, sensors responses and selectivity of the different nanomaterials were compared showing better performance of the SWCNT-based sensor. The voltammetric SWCNT aptasensors showed high sensitivity and selectivity with detection limits of 0.13 pg/mL and 0.03 pg/mL for total haemoglobin (tHb) and HbA1c, respectively. The aptasensor showed selectivity against other proteins in the blood including cystic fibrosis transmembrane conductance regulator (CFTR), survival motor neuron (SMN), dedicator of cytokinesis 8 (DOCK8), signal transducer and activator of transcription 3 (STAT3). This SWCNT aptasensor was superior to the reported detection assays for HbA1c in terms of sensitivity, selectivity and cost. Moreover, our results demonstrate that the choice of the carbon nanomaterial can have a profound impact on the biosensing performance.

PMID: 31029337 [PubMed - in process]

A Review on the Use of Cystic Fibrosis Transmembrane Conductance Regulator Gene Modulators in Pediatric Patients.

J Pediatr Health Care. 2019 May - Jun;33(3):356-364

Authors: Bitonti M, Fritts L, So TY

Abstract
The literature surrounding the use of cystic fibrosis transmembrane conductance regulator-targeted pharmacotherapies in pediatric patients continues to evolve. These therapies represent a departure from symptom management and infection prevention, which have been the mainstay of cystic fibrosis management in pediatrics, to targeting the genetic defect present within these patients. This article reviews the clinical studies evaluating the safety and efficacy of ivacaftor, ivacaftor/lumacaftor, and ivacaftor/tezacaftor. These medications were initially studied in adults and adolescents but have begun to be studied in younger populations. Further investigation into the use of these drugs with different CFTR mutations and in younger age groups will continue to expand the number of patients who can benefit from these therapies.

PMID: 31029283 [PubMed - in process]

Inconclusive diagnosis after a positive newborn bloodspot screening result for cystic fibrosis; clarification of the harmonised international definition.

J Cyst Fibros. 2019 Apr 24;:

Authors: Southern KW, Barben J, Gartner S, Munck A, Castellani C, Mayell SJ, Davies JC, Winters V, Murphy J, Salinas D, McColley SA, Ren CL, Farrell PM

PMID: 31027826 [PubMed - as supplied by publisher]

Prospective multicenter randomized patient recruitment and sample collection to enable future measurements of sputum biomarkers of inflammation in an observational study of cystic fibrosis.

BMC Med Res Methodol. 2019 Apr 26;19(1):88

Authors: Liou TG, Adler FR, Argel N, Asfour F, Brown PS, Chatfield BA, Daines CL, Durham D, Francis JA, Glover B, Heynekamp T, Hoidal JR, Jensen JL, Keogh R, Kopecky CM, Lechtzin N, Li Y, Lysinger J, Molina O, Nakamura C, Packer KA, Poch KR, Quittner AL, Radford P, Redway AJ, Sagel SD, Sprandel S, Taylor-Cousar JL, Vroom JB, Yoshikawa R, Clancy JP, Elborn JS, Olivier KN, Cox DR

Abstract
BACKGROUND: Biomarkers of inflammation predictive of cystic fibrosis (CF) disease outcomes would increase the power of clinical trials and contribute to better personalization of clinical assessments. A representative patient cohort would improve searching for believable, generalizable, reproducible and accurate biomarkers.
METHODS: We recruited patients from Mountain West CF Consortium (MWCFC) care centers for prospective observational study of sputum biomarkers of inflammation. After informed consent, centers enrolled randomly selected patients with CF who were clinically stable sputum producers, 12 years of age and older, without previous organ transplantation.
RESULTS: From December 8, 2014 through January 16, 2016, we enrolled 114 patients (53 male) with CF with continuing data collection. Baseline characteristics included mean age 27 years (SD = 12), 80% predicted forced expiratory volume in 1 s (SD = 23%), 1.0 prior year pulmonary exacerbations (SD = 1.2), home elevation 328 m (SD = 112) above sea level. Compared with other patients in the US CF Foundation Patient Registry (CFFPR) in 2014, MWCFC patients had similar distribution of sex, age, lung function, weight and rates of exacerbations, diabetes, pancreatic insufficiency, CF-related arthropathy and airway infections including methicillin-sensitive or -resistant Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia complex, fungal and non-tuberculous Mycobacteria infections. They received CF-specific treatments at similar frequencies.
CONCLUSIONS: Randomly-selected, sputum-producing patients within the MWCFC represent sputum-producing patients in the CFFPR. They have similar characteristics, lung function and frequencies of pulmonary exacerbations, microbial infections and use of CF-specific treatments. These findings will plausibly make future interpretations of quantitative measurements of inflammatory biomarkers generalizable to sputum-producing patients in the CFFPR.

PMID: 31027503 [PubMed - in process]

The combination of tezacaftor and ivacaftor in the treatment of patients with cystic fibrosis: clinical evidence and future prospects in cystic fibrosis therapy.

Ther Adv Respir Dis. 2019 Jan-Dec;13:1753466619844424

Authors: Lommatzsch ST, Taylor-Cousar JL

Abstract
Years of tremendous study have dawned a new era for the treatment of cystic fibrosis (CF). For years CF care was rooted in the management of organ dysfunction resulting from the mal-effects of absent anion transport through the CF transmembrane regulator (CFTR) protein. CFTR, an adenosine triphosphate binding anion channel, has multiple functions, but primarily regulates the movement of chloride anions, thiocyanate and bicarbonate across luminal cell membranes. Additional roles include effects on other electrolyte channels such as the epithelial sodium channel (ENaC) and on pulmonary innate immunity. Inappropriate luminal anion movement leads to elevated sweat chloride concentrations, dehydrated airway surface liquid, overall viscous mucous production, and inspissated bile and pancreatic secretions. As a result, patients develop the well-known CF symptoms and disease-defining complications such as chronic cough, oily stools, recurrent pulmonary infections, bronchiectasis, chronic sinusitis and malnutrition. Traditionally, CF has been symptomatically managed, but over the past 6 years those with CF have been offered a new mode of therapy; CFTR protein modulation. These medications affect the basic defect in CF: abnormal CFTR function. Ivacaftor, approved for use in the United States in 2012, is the first medication in CF history to improve CFTR function at the molecular level. Its study and approval were followed by two additional CFTR modulators, lumacaftor/ivacaftor and tezacaftor/ivacaftor. To effectively use currently available CF therapies, clinicians should be familiar with the side effects of the drugs and their impacts on patient outcomes. As many new modulators are on the horizon, this information will equip providers to discuss the benefits and shortcomings of modulator therapy especially in the context of limited healthcare resources.

PMID: 31027466 [PubMed - in process]

Impact of Intermediate Cystic Fibrosis Classification on Parents' Perceptions of Child Vulnerability and Protectiveness.

J Fam Nurs. 2019 Apr 26;:1074840719842834

Authors: Tluczek A, Levy H, Rock MJ, Ondoma C, Brown RL

Abstract
This cross-sectional, mixed-method study examined factors associated with parent perceptions of child vulnerability and protectiveness in three groups: cystic fibrosis (CF-group, n = 40), intermediate CF classification (I-group, n = 20), and healthy (H-group, n = 50). A composite indicator structural equation (CISE) using Bayesian estimation tested two mediational models: psychological and biological. Significant results ( p < .05) from the psychological model showed I-group and CF-group parents perceived their children to be more vulnerable than H-group parents but reported lower levels of protectiveness than H-group parents. Perceptions of vulnerability mediated protectiveness for CF- and I-groups. The biological model showed I-group children had significantly less severe genotype and phenotype, and lower sweat chloride levels than the CF-group; I-group parents had lower expectations about children developing CF symptoms. Both models showed negative associations between children's ages and protectiveness. Psychological factors explained perceptions of child vulnerability and protectiveness; biological factors explained protectiveness. Parent perceptions of vulnerability and protectiveness are separate, independent constructs.

PMID: 31027440 [PubMed - as supplied by publisher]

Genetic defects in human azoospermia.

Basic Clin Androl. 2019;29:4

Authors: Ghieh F, Mitchell V, Mandon-Pepin B, Vialard F

Abstract
As with many other diseases, genetic testing in human azoospermia was initially restricted to karyotype analyses (leading to diagnostic chromosome rearrangement tests for Klinefelter and other syndromes). With the advent of molecular biology in the 1980s, genetic screening was broadened to analyses of Y chromosome microdeletions and the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR). Decades later, the emergence of whole-genome techniques has led to the identification of other genetic defects associated with human azoospermia. Although TEX11 and ADGRG2 defects are frequently described in men with azoospermia, most of the causal gene defects found to date are private (i.e. identified in a small number of consanguineous families). Here, we provide an up-to-date overview of all the types of genetic defects known to be linked to human azoospermia and try to give clinical practice guidelines according to azoospermia phenotype. Along with homozygous mutations, polymorphisms and epigenetic defects are also briefly discussed. However, as these variations predispose to azoospermia, a specific review will be needed to compile data on all the particular genetic variations reported in the literature.

PMID: 31024732 [PubMed]

Draft Genome Sequence of a bla NDM-1- and bla PME-1-Harboring Pseudomonas aeruginosa Clinical Isolate from Pakistan.

Microbiol Resour Announc. 2019 Apr 25;8(17):

Authors: Irum S, Potter RF, Kamran R, Mustafa Z, Wallace MA, Burnham CA, Dantas G, Andleeb S

Abstract
We performed Illumina whole-genome sequencing on a carbapenem-resistant Pseudomonas aeruginosa strain isolated from a cystic fibrosis patient with chronic airway colonization. The draft genome comprises 6,770,411 bp, including the carbapenemase bla NDM-1 and the extended-spectrum beta-lactamase bla PME-1 This isolate harbors 3 prophages, 14 antibiotic resistance genes, and 257 virulence genes.

PMID: 31023810 [PubMed]

Mortality in Adults with Cystic Fibrosis Requiring Mechanical Ventilation: Cross-Sectional Analysis of Nationwide Events.

Ann Am Thorac Soc. 2019 Apr 26;:

Authors: Siuba M, Attaway A, Zein J, Wang X, Han X, Strausbaugh S, Jacono F, Dasenbrook EC

Abstract
RATIONALE: Survival in patients with cystic fibrosis (CF) is improving over time. Traditionally, there has been concern about high mortality in individuals with cystic fibrosis requiring invasive mechanical ventilation (IMV) for respiratory failure.
OBJECTIVES: We hypothesized that mortality has decreased over time in this population due to improvements in disease-specific therapies.
METHODS: The U.S. Nationwide Healthcare Cost and Utilization Project database was used to identify adult patients with CF undergoing IMV between 2002-2014. Patients with non-urgent/non-emergent admissions, pregnancy, and encounters related to lung transplantation were excluded. Demographic, geographic, and comorbidities were analyzed. The Cochran-Armitage trend test was used to examine trends in mortality over time. Multivariate mixed effects logistic regression was used to account for possible differences in hospital mortality patterns.
RESULTS: We identified 58,799 CF admissions from 2002-2014, with 3,727 (6.3%) undergoing IMV. After exclusions, 1711 admissions remained. In 762 (44.5%) of adult hospitalizations, the patient died. Annual mortality per hospitalization ranged from 29.9% to 55.3%. The Cochran-Armitage trend test suggested an increased probability of survival over time. Factors significantly associated with mortality in multivariate analysis included female sex (Odds Ratio (OR) 1.54, 95% confidence interval (CI) 1.14-2.09), acute renal failure (OR 1.99, 95% CI 1.32-3.01)) and malnutrition (OR 1.44, 95% CI 1.01-2.06). IMV greater than 96 hours was associated with increased mortality in univariate analysis (OR 1.51, 95% CI 1.14-1.98), however, after adjustment for potential confounders, the association was no longer statistically significant (OR 1.05, 95% CI 0.77-1.43).
CONCLUSION: Mortality per hospitalization in adults with CF who are not bridging to lung transplant and require emergent IMV is 44.5%, suggesting IMV is not futile. Furthermore, mortality decreased over the study period. These finding may help providers, families, and patients with CF weigh the risks and benefits of IMV for respiratory failure.

PMID: 31026405 [PubMed - as supplied by publisher]

Restoration of F508-del Function by Transcomplementation: The Partners Meet in the Endoplasmic Reticulum.

Cell Physiol Biochem. 2019;52(6):1267-1279

Authors: Bergbower EAS, Sabirzhanova I, Boinot C, Guggino WB, Cebotaru L

Abstract
BACKGROUND/AIMS: Because of the small size of adeno-associated virus, AAV, the cystic fibrosis conductance regulator, CFTR, cDNA is too large to fit within AAV and must be truncated. We report here on two truncated versions of CFTR, which, when inserted into AAV1 and used to infect airway cells, rescue F508-del CFTR via transcomplementation. The purpose of this study is to shed light on where in the cell transcomplementation occurs and how it results in close association between the endogenous F508-del and truncated CFTR.
METHODS: We treated CF airway cells (CFBE41o-) with AAV2/1 (AAV2 inverted terminal repeats/AAV1 capsid) containing truncated forms of CFTR, ∆264 and ∆27-264 CFTR, who can restore the function of F508-del by transcomplementation. We addressed the aims of the study using a combination of confocal microscopy and short circuit currents measurements. For the latter, CF bronchial epithelial cells (CFBE) were grown on permeable supports.
RESULTS: We show that both F508del and the truncation mutants colocalize in the ER and that both the rescued F508-del and the transcomplementing mutants reach the plasma membrane together. There was significant fluorescence resonance energy transfer (FRET) between F508-del and the transcomplementing mutants within the endoplasmic reticulum (ER), suggesting that transcomplementation occurs through a bimolecular interaction. We found that transcomplementation could increase the Isc in CFBE41o- cells stably expressing additional wt-CFTR or F508-del and in parental CFBE41o- cells expressing endogenous levels of F508-del.
CONCLUSION: We conclude that the functional rescue of F508-del by transcomplementation occurs via a bimolecular interaction that most likely begins in the ER and continues at the plasma membrane. These results come at an opportune time for developing a gene therapy for CF and offer new treatment options for a wide range of CF patients.

PMID: 31026390 [PubMed - in process]

The cumulative effect of inflammation and infection on structural lung disease in early CF.

Eur Respir J. 2019 Apr 25;:

Authors: Rosenow T, Mok LC, Turkovic L, Berry LJ, Sly PD, Ranganathan S, Tiddens HAWM, Stick SM

Abstract
INTRODUCTION: Pulmonary inflammation and infection are important clinical and prognostic markers of lung disease in cystic fibrosis (CF). However, whether in young children they are transient findings or have cumulative, long-term impacts on respiratory health is largely unknown. We aimed to determine whether their repeated detection has a deleterious effect on structural lung disease.
METHODS: All patients aged below six with annual CT and bronchoalveolar lavage (BAL) were included. Structural lung disease on computed tomography (%Disease) was determined using the PRAGMA-CF method. The number of times free neutrophil elastase (NE) and infection were detected in BAL were counted, to determine cumulative BAL history. Linear mixed model analysis, accounting for repeat visits and adjusted for age, was used to determine associations.
RESULTS: Two hundred and sixty-five children (683 scans) were included for analysis, with BAL history comprising 1161 visits. %Disease was significantly associated with the number of prior NE (0.31 [0.09, 0.54]; p=0.007) but not infection (0.23 [-0.01, 0.47]; p=0.060) detections. Reference equations are presented.
CONCLUSIONS: Pulmonary inflammation in surveillance BAL has a cumulative effect on structural lung disease extent: more so than infection. This provides a strong rationale for therapies aimed at reducing inflammation in young children.

PMID: 31023850 [PubMed - as supplied by publisher]

Intestinal organoids to model Cystic Fibrosis.

Eur Respir J. 2019 Apr 25;:

Authors: van Mourik P, Beekman JM, van der Ent CK

Abstract
Recent advances in adult stem cell biology have resulted in the development of organoid culture technologies using a variety of tissue sources such as intestine, lung, and kidney [1]. Organoids are three-dimensional, multi-cellular structures that recapitulate tissue features of the parental organ and are usually grown from donor tissue fragments [1]. As organoids are functional expressions of individual genomes, these cultures are particularly useful to understand how genetic factors contribute to individual disease. As such, they are used to study hereditary diseases like cystic fibrosis (CF), and more common diseases such as cancer where genetics can influence disease severity and drug efficacy [2, 3].

PMID: 31023844 [PubMed - as supplied by publisher]

Employment of an algorithm of care including chest physiotherapy results in reduced hospitalizations and stability of lung function in bronchiectasis.

BMC Pulm Med. 2019 Apr 25;19(1):82

Authors: Powner J, Nesmith A, Kirkpatrick DP, Nichols JK, Bermingham B, Solomon GM

Abstract
BACKGROUND: There is a paucity of data on long term clinical effects of high frequency chest wall oscillation (HFCWO) in the Bronchiectasis population. Other therapies such as nebulized mucolytics and long term antibiotics have proven benefit on quality of life and exacerbation rate. In this study a treatment algorithm that included HFCWO as a component was initiated to see what the long term effects of the proposed algorithm were on lung function, antibiotic use, and exacerbation rates.
METHODS: This was an observational comparative retrospective cohort study from database of patients with Bronchiectasis. Patients with > 2 exacerbations and significant symptom burden were enrolled to receive a treatment algorithm. The algorithm included: nebulized bronchodilators, mucolytics (hypertonic saline (3-7%) or n-acetylcysteine) inhaled daily or twice daily, thrice weekly macrolide therapy when appropriate, and high frequency chest wall oscillation (HFCWO) therapy (daily to twice daily per issued protocol) Outcomes from the cohort were analyzed for the subsequent twelve months after initiation to observe longitudinal lung function and clinical outcomes. Chart review was then done to obtain data the year prior to the start of the algorithm in this same cohort of patients.
RESULTS: Sixty-five patients received the Smart Vest® HFCWO system and were enrolled into the algorithm for treatment during the study period. Of the sixty-five patients, forty-three were eligible due to adequate 1-year baseline and follow up data at the time of the study initiation. The mean FEV1 remained stable at 1-year post enrollment (1.85 ± 0.60 L pre vs 1.89 ± 0.60 L post, p = NS) and the number of exacerbations requiring hospitalization was reduced (1.3 ± 1.0 pre vs. 0.46 ± 0.81 hospitalizations, post initiation, p < 0.0001). Antibiotic use overall was also reduced (2.5 ± 0.86 courses/year pre vs 2.1 ± 0.92 courses per year post initiation, p < 0.0001).
CONCLUSION: Standardized care for Bronchiectasis involving an algorithm for Mucociliary clearance that centers on initiation of HFCWO may help to reduce lung function decline, need for oral antibiotics, and reduced hospitalization rate.

PMID: 31023284 [PubMed - in process]

Clinical characteristics and outcomes of patients receiving outpatient parenteral antibiotic therapy in a Belgian setting: a single-center pilot study.

Acta Clin Belg. 2019 Apr 25;:1-9

Authors: Briquet C, Cornu O, Servais V, Blasson C, Vandeleene B, Yildiz H, Stainier A, Yombi JC

Abstract
BACKGROUND: Outpatient parenteral antibiotic therapy (OPAT) was not used in Belgium before 2013, except for patients with cystic fibrosis. Thus, we have performed a pilot study to evaluate clinical characteristics and outcomes of patient receiving OPAT in a Belgian setting.
METHODS: The study was a prospective observational single-center study of patients receiving OPAT between 1 September 2013 and 31 December, 2017.
RESULTS: We included 218 OPATs. The median age was 58 years and 71% were men. At the end of the treatment, 92% of the patients on OPAT were cured. Risk factors for treatment failure were obesity, diabetes and diabetic foot infections, longer duration of hospitalization before OPAT, and duration of OPAT >16 days. An average of 24 days of hospitalization per patient discharge was saved, which amounted to 5205 days saved during the project. During the OPAT and 30 days thereafter, 71 (32.6%) of patients were readmitted, but only 26 (12%) readmissions were directly related to OPAT. Risk factors for readmissions were diabetes and diabetic foot infections, endovascular infections, longer duration of hospitalization before OPAT, duration of OPAT >30 days, and history of hospitalizations in the year before OPAT. There were 2.3 intravenous catheter-related events per 1000 days of catheter use. Patients' level of satisfaction was high (99.5%) Conclusions: In this pilot study, OPAT is found to be efficacious in saving hospitalization's days, with a low rate of readmissions and complications and a high patients' level of satisfaction. We therefore conclude that OPAT is feasible and safe Background: Outpatient parenteral antibiotic therapy (OPAT) was not used in Belgium before 2013, except for patients with cystic fibrosis. Thus, we have performed a pilot study to evaluate clinical characteristics and outcomes of patient receiving OPAT in a Belgian setting.
METHODS: The study was a prospective observational single-center study of patients receiving OPAT between 1 September 2013 and 31 December, 2017.
RESULTS: We included 218 OPATs. The median age was 58 years and 71% were men. At the end of the treatment, 92% of the patients on OPAT were cured. Risk factors for treatment failure were obesity, diabetes and diabetic foot infections, longer duration of hospitalization before OPAT, and duration of OPAT >16 days. An average of 24 days of hospitalization per patient discharge was saved, which amounted to 5205 days saved during the project. During the OPAT and 30 days thereafter, 71 (32.6%) of patients were readmitted, but only 26 (12%) readmissions were directly related to OPAT. Risk factors for readmissions were diabetes and diabetic foot infections, endovascular infections, longer duration of hospitalization before OPAT, duration of OPAT >30 days, and history of hospitalizations in the year before OPAT. There were 2.3 intravenous catheter-related events per 1000 days of catheter use. Patients' level of satisfaction was high (99.5%) Conclusions: In our study, OPAT is found to be efficacious in saving hospitalization's days, with a low rate of readmissions and complications and a high patients' level of satisfaction. We therefore conclude that OPAT is feasible and safe.

PMID: 31023169 [PubMed - as supplied by publisher]

Effects of Curcumin on Ion Channels and Pumps: A Review.

IUBMB Life. 2019 Apr 25;:

Authors: Tabeshpour J, Banaeeyeh S, Eisvand F, Sathyapalan T, Hashemzaei M, Sahebkar A

Abstract
Curcumin, an orange-yellow lipophilic polyphenolic molecule, is the active component of Curcuma longa, which is extensively used as a spice in most of the Asian countries. This natural compound is able to interact with a large number of molecular structures like proteins, enzymes, lipids, DNA, RNA, transporter molecules, and ion channels. It has been reported to possess several biological effects such as antioxidant, anti-inflammatory, wound healing, antimicrobial, anticancer, antiangiogenic, antimutagenic, and antiplatelet aggregation properties. These beneficial effects of curcumin are because of its extraordinary chemical interactions such as extensive hydrogen and covalent bonding, metal chelation, and so on. Therefore, the aim of this review was to outline the evidence in which curcumin could affect different types of ion channels and ion channel-related diseases, and also to elucidate basic molecular mechanisms behind it. © 2019 IUBMB Life, 2019.

PMID: 31020791 [PubMed - as supplied by publisher]

Metabolic Modeling of Cystic Fibrosis Airway Communities Predicts Mechanisms of Pathogen Dominance.

mSystems. 2019 Mar-Apr;4(2):

Authors: Henson MA, Orazi G, Phalak P, O'Toole GA

Abstract
Cystic fibrosis (CF) is a fatal genetic disease characterized by chronic lung infections due to aberrant mucus production and the inability to clear invading pathogens. The traditional view that CF infections are caused by a single pathogen has been replaced by the realization that the CF lung usually is colonized by a complex community of bacteria, fungi, and viruses. To help unravel the complex interplay between the CF lung environment and the infecting microbial community, we developed a community metabolic model comprised of the 17 most abundant bacterial taxa, which account for >95% of reads across samples, from three published studies in which 75 sputum samples from 46 adult CF patients were analyzed by 16S rRNA gene sequencing. The community model was able to correctly predict high abundances of the "rare" pathogens Enterobacteriaceae, Burkholderia, and Achromobacter in three patients whose polymicrobial infections were dominated by these pathogens. With these three pathogens removed, the model correctly predicted that the remaining 43 patients would be dominated by Pseudomonas and/or Streptococcus. This dominance was predicted to be driven by relatively high monoculture growth rates of Pseudomonas and Streptococcus as well as their ability to efficiently consume amino acids, organic acids, and alcohols secreted by other community members. Sample-by-sample heterogeneity of community composition could be qualitatively captured through random variation of the simulated metabolic environment, suggesting that experimental studies directly linking CF lung metabolomics and 16S sequencing could provide important insights into disease progression and treatment efficacy. IMPORTANCE Cystic fibrosis (CF) is a genetic disease in which chronic airway infections and lung inflammation result in respiratory failure. CF airway infections are usually caused by bacterial communities that are difficult to eradicate with available antibiotics. Using species abundance data for clinically stable adult CF patients assimilated from three published studies, we developed a metabolic model of CF airway communities to better understand the interactions between bacterial species and between the bacterial community and the lung environment. Our model predicted that clinically observed CF pathogens could establish dominance over other community members across a range of lung nutrient conditions. Heterogeneity of species abundances across 75 patient samples could be predicted by assuming that sample-to-sample heterogeneity was attributable to random variations in the CF nutrient environment. Our model predictions provide new insights into the metabolic determinants of pathogen dominance in the CF lung and could facilitate the development of improved treatment strategies.

PMID: 31020043 [PubMed]

Aztreonam Lysine Inhalation Solution in Cystic Fibrosis.

Clin Med Insights Circ Respir Pulm Med. 2019;13:1179548419842822

Authors: Elson EC, Mermis J, Polineni D, Oermann CM

Abstract
Patients with cystic fibrosis (CF) develop pulmonary disease secondary to airway infection and dysregulated inflammation. Therapeutic innovations such as nebulized antimicrobial therapy targeting specific pathogens have resulted in improvements in quality of life and life expectancy. Aztreonam lysine for inhalation (AZLI) solution was initially approved to improve respiratory symptoms in CF patients with Pseudomonas aeruginosa (PA) in 2010 by the Food and Drug Administration. Since then, research broadening labeling and clinical application has been developed. In this review, we analyze published and ongoing research regarding AZLI therapy in CF. A search of the Cochrane Database of Systematic Reviews and the PubMed and ClinicalTrials.gov databases was conducted to identify publications about AZLI. Three pre-approval studies were identified and assessed. Two are Phase 3, placebo-controlled trials, assessing a variety of safety and efficacy endpoints, leading to FDA approval. The third is an open-label extension of the two previous trials. An additional seven post-approval, completed trials were identified and are included in this review. They represent a variety of study designs including safety and efficacy in patients with mild lung disease and young patients, an active comparator trial vs inhaled tobramycin, an eradication study, a study among patients with Burkholderia cepacia, and a study assessing continuous alternating antibiotic therapy. Finally, five ongoing clinical trials are discussed. Overall, studies demonstrated that inhaled aztreonam is a safe and effective antimicrobial treatment for the eradication of newly acquired P. aeruginosa and long-term suppressive therapy of chronic endobronchial infection among people with cystic fibrosis.

PMID: 31019373 [PubMed]

Airway surface liquid acidification initiates host defense abnormalities in Cystic Fibrosis.

Sci Rep. 2019 Apr 24;9(1):6516

Authors: Simonin J, Bille E, Crambert G, Noel S, Dreano E, Edwards A, Hatton A, Pranke I, Villeret B, Cottart CH, Vrel JP, Urbach V, Baatallah N, Hinzpeter A, Golec A, Touqui L, Nassif X, Galietta LJV, Planelles G, Sallenave JM, Edelman A, Sermet-Gaudelus I

Abstract
Cystic fibrosis (CF) is caused by defective Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. Morbidity is mainly due to early airway infection. We hypothesized that S. aureus clearance during the first hours of infection was impaired in CF human Airway Surface Liquid (ASL) because of a lowered pH. The ASL pH of human bronchial epithelial cell lines and primary respiratory cells from healthy controls (WT) and patients with CF was measured with a pH microelectrode. The antimicrobial capacity of airway cells was studied after S. aureus apical infection by counting surviving bacteria. ASL was significantly more acidic in CF than in WT respiratory cells. This was consistent with a defect in bicarbonate secretion involving CFTR and SLC26A4 (pendrin) and a persistent proton secretion by ATP12A. ASL demonstrated a defect in S. aureus clearance which was improved by pH normalization. Pendrin inhibition in WT airways recapitulated the CF airway defect and increased S. aureus proliferation. ATP12A inhibition by ouabain decreased bacterial proliferation. Antimicrobial peptides LL-37 and hBD1 demonstrated a pH-dependent activity. Normalizing ASL pH might improve innate airway defense in newborns with CF during onset of S. aureus infection. Pendrin activation and ATP12A inhibition could represent novel therapeutic strategies to normalize pH in CF airways.

PMID: 31019198 [PubMed - in process]

Direct Lung Sampling Indicates That Established Pathogens Dominate Early Infections in Children with Cystic Fibrosis.

Cell Rep. 2019 Apr 23;27(4):1190-1204.e3

Authors: Jorth P, Ehsan Z, Rezayat A, Caldwell E, Pope C, Brewington JJ, Goss CH, Benscoter D, Clancy JP, Singh PK

Abstract
Culture and sequencing have produced divergent hypotheses about cystic fibrosis (CF) lung infections. Culturing suggests that CF lungs are uninfected before colonization by a limited group of CF pathogens. Sequencing suggests diverse communities of mostly oral bacteria inhabit lungs early on and diversity decreases as disease progresses. We studied the lung microbiota of CF children using bronchoscopy and sequencing, with measures to reduce contamination. We found no evidence for oral bacterial communities in lung lavages that lacked CF pathogens. Lavage microbial diversity varied widely, but decreases in diversity appeared to be driven by increased CF pathogen abundance, which reduced the signal from contaminants. Streptococcus, Prevotella, and Veillonella DNA was detected in some lavages containing CF pathogens, but DNA from these organisms was vastly exceeded by CF pathogen DNA and was not associated with inflammation. These findings support the hypothesis that established CF pathogens are primarily responsible for CF lung infections.

PMID: 31018133 [PubMed - in process]

Comparing modalities of conducting the six-minute walk test in healthy children and adolescents.

Minerva Pediatr. 2019 Jun;71(3):229-234

Authors: Rauchenzauner M, Schneider J, Colleselli V, Ruepp M, Cortina G, Högler W, Neururer S, Geiger R

Abstract
BACKGROUND: The 6-minute walk test (6MWT) in children can be performed in the conventional way, or by using a measuring wheel. This study aimed to compare these test modalities and to determine influencing factors.
METHODS: The study included 317 healthy children (172 boys) between 6 and 15 years from elementary schools and high schools, who were randomly assigned to perform a 6MWT either with or without a measuring wheel according to the guidelines of the American Thoracic Society. The 6-minute walk distance (6MWD) was compared between the two measuring modalities as well as different school types.
RESULTS: The use of a measuring wheel during the 6MWT led to a significantly greater 6MWD compared to conventional walking. Students of sports schools walked substantially farther than those attending general high schools, irrespective of test modality. In multivariate regression analysis height, post-test heart rate, male sex and the measuring wheel itself were all independently associated with greater 6MWD.
CONCLUSIONS: The use of a measuring wheel during a 6MWT reflects physical performance in children and adolescents more accurately as it includes the stretch of way around the cones during lap turns. Test modalities and sports background should be taken into account, especially when performing longitudinal monitoring and multicenter studies.

PMID: 31017381 [PubMed - in process]