Particle coating alters mucociliary transit in excised rat trachea: A synchrotron X-ray imaging study.

Sci Rep. 2019 Jul 29;9(1):10983

Authors: Gardner M, McCarron A, Morgan K, Parsons D, Donnelley M

Abstract
We have previously developed non-invasive in vivo mucociliary transport (MCT) monitoring methods using synchrotron phase contrast X-ray imaging (PCXI) to evaluate potential therapies for cystic fibrosis (CF). However, previous in vivo measurements of MCT velocity using this method were lower than those from alternate methods. We hypothesise this was due to the surface chemistry of the uncoated particles. We investigated the effect of particle surface coating on MCT marker performance by measuring the velocity of uncoated, positively-charged (aminated; NH2), and negatively-charged (carboxylated; COOH) particles. The effect of aerosolised hypertonic saline (HS) was also investigated, as previous in vivo measurements showed HS significantly increased MCT rate. PCXI experiments were performed using an ex vivo rat tracheal imaging setup. Prior to aerosol delivery there was little movement of the uncoated particles, whilst the NH2 and COOH particles moved with MCT rates similar to those previously reported. After application of HS the uncoated and COOH particle velocity increased and NH2 decreased. This experiment validated the use of COOH particles as MCT marker particles over the uncoated and NH2 coated particles. Our results suggest that future experiments measuring MCT using synchrotron PCXI should use COOH coated marker particles for more accurate MCT quantification.

PMID: 31358851 [PubMed - in process]

Case report of synchronous post-lung transplant colon cancers in the era of colorectal cancer screening recommendations in cystic fibrosis: screening "too early" before it's too late.

BMC Gastroenterol. 2019 Jul 29;19(1):137

Authors: Abraham JM, Mahan K, Mettler T, Dunitz JM, Khoruts A

Abstract
BACKGROUND: The increasing life expectancy of individuals with Cystic Fibrosis (CF) is likely to be associated with new age-related challenges, colorectal cancer (CRC) most notably; recent consensus recommendations for CRC screening published in 2018 represent an important early step in addressing the emerging awareness of CF as a gastrointestinal cancer syndrome. These recommendations, however, need to be further refined based on more systematic data. We discuss an illustrative first-ever case of synchronous CRC arising in a post-lung transplant individual with CF within the recommended surveillance interval after a well-documented prior normal colonoscopy.
CASE PRESENTATION: A 51-year-old female individual with homozygous F508del CF, presents to clinic with abdominal discomfort and intermittent blood in stools. She had previously undergone bilateral lung transplantation 18 years earlier, as well as two kidney transplants related to immunosuppression-related nephrotoxicity. A diagnostic colonoscopy was performed which revealed the presence of two separate synchronous colon cancers in the cecum and transverse colon; she had undergone a colonoscopy three years prior to this exam which was structurally normal. Endoscopic quality indicators, including a good quality bowel preparation, colonoscopic withdrawal time > 12 min, and quarterly Adenoma Detection Rate (ADR) ranging from 50 to 70% for both male and female patients for the endoscopist from both colonoscopic exams, as well as secondary retrospective comparative review of the pertinent case images, diminish the risk for a "missed" cancer or advanced lesion on the index exam. These cancers did not demonstrate any immunohistochemical features suggestive of Lynch Syndrome, though the rapid progression to cancer within the surveillance interval (possibly non-polypoid in nature) is similar. This cancer presentation within the newly-established recommended colon cancer screening interval warrants concern.
CONCLUSIONS: This case prompts serious discussion regarding the length of surveillance intervals in the post-transplant CF population (a population at 20-30 times greater risk for CRC compared to the general non-CF population), as well as the importance of documenting endoscopic quality benchmarks, particularly if a narrative of interval CRC development continues to develop with further prospective monitoring and multi-center experience.

PMID: 31357954 [PubMed - in process]

Patient Receives First Genetically Engineered Phage Treatment.

JAMA. 2019 Jul 09;322(2):107

Authors: Abbasi J

PMID: 31287505 [PubMed - indexed for MEDLINE]

A novel mutation (-195C>A) in the promoter region of CFTR gene is associated with Chinese Congenital Bilateral Absence of Vas Deferens (CBAVD).

Gene. 2019 Jul 26;:144007

Authors: Feng J, Wu X, Zhang Y, Yang X, Ma G, Chen S, Luo S, Zhang Y

Abstract
Congenital bilateral absence of vas deferens (CBAVD), a frequent cause of obstructive azoospermia and male infertility in Chinese, is mainly due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This study aim to explore the promoter region of CFTR gene in CBAVD patients and study the mutations by functional analysis, and to discuss the significance of mutation testing in this area. We performed screening analysis on 65 CBAVD patients and 50 controls to detect mutations in the CFTR gene, and studied the functions of promoter mutations using reporter gene constructs, transient transfection techniques and subsequent assessment of transcriptional activity and expression levels. Mutations c.-195C>A and c.-34C>T in the promoter region of the CFTR gene were detected in 4 of our Chinese CBAVD patients, one of which was novel (c.-195C>A) and located in the conservative area, as well as the binding site of SP1 transcription factor through the prediction of bioinformatics analysis. By reverse transcription qPCR assay and luciferase assay, we validated it as a functional disease-causing variant that down-regulates the CFTR gene expression, and this effect was related to the amount of transcription factors. This study was the first to explore the promoter region of the CFTR gene in Chinese, and we believe that mutations in this region are associated with Chinese CBAVD patients. We also suggest a systematic strategy for genotyping Chinese CBAVD couples, which should help in developing reproductive counseling.

PMID: 31357024 [PubMed - as supplied by publisher]

Call for Changes in Lung Allocation to Reduce Transplant Waitlist Mortality for Cystic Fibrosis.

Am J Respir Crit Care Med. 2019 Jul 29;:

Authors: Nolley EP, Pilewski JM

PMID: 31356757 [PubMed - as supplied by publisher]

DNA Methylation Changes in Regional Lung Macrophages Are Associated with Metabolic Differences.

Immunohorizons. 2019 Jul 02;3(7):274-281

Authors: Armstrong DA, Chen Y, Dessaint JA, Aridgides DS, Channon JY, Mellinger DL, Christensen BC, Ashare A

Abstract
A number of pulmonary diseases occur with upper lobe predominance, including cystic fibrosis and smoking-related chronic obstructive pulmonary disease. In the healthy lung, several physiologic and metabolic factors exhibit disparity when comparing the upper lobe of the lung to lower lobe, including differences in oxygenation, ventilation, lymphatic flow, pH, and blood flow. In this study, we asked whether these regional differences in the lung are associated with DNA methylation changes in lung macrophages that could potentially lead to altered cell responsiveness upon subsequent environmental challenge. All analyses were performed using primary lung macrophages collected via bronchoalveolar lavage from healthy human subjects with normal pulmonary function. Epigenome-wide DNA methylation was examined via Infinium MethylationEPIC (850K) array and validated by targeted next-generation bisulfite sequencing. We observed 95 CpG loci with significant differential methylation in lung macrophages, comparing upper lobe to lower lobe (all false discovery rate < 0.05). Several of these genes, including CLIP4, HSH2D, NR4A1, SNX10, and TYK2, have been implicated as participants in inflammatory/immune-related biological processes. Functionally, we identified phenotypic differences in oxygen use, comparing upper versus lower lung macrophages. Our results support a hypothesis that epigenetic changes, specifically DNA methylation, at a multitude of gene loci in lung macrophages are associated with metabolic differences regionally in lung.

PMID: 31356157 [PubMed - in process]

Characterization of Tn6349, a novel mosaic transposon carrying poxtA, cfr and other resistance determinants, inserted in the chromosome of an ST5-MRSA-II strain of clinical origin.

J Antimicrob Chemother. 2019 Jul 17;:

Authors: D'Andrea MM, Antonelli A, Brenciani A, Di Pilato V, Morroni G, Pollini S, Fioriti S, Giovanetti E, Rossolini GM

Abstract
OBJECTIVES: To characterize the genetic element carrying the poxtA oxazolidinone resistance gene found in the poxtA index strain Staphylococcus aureus AOUC-0915 isolated from a cystic fibrosis patient.
METHODS: The genetic context of poxtA was investigated by bioinformatics analysis of WGS data of strain AOUC-0915, followed by PCR and confirmatory Sanger sequencing for repetitive regions. Conjugation and electrotransformation experiments were carried out to assess horizontal transferability using S. aureus and Enterococcus faecalis recipients. Production of phage particles was evaluated by PCR using DNA preparations obtained after phage induction. Excision of the transposon carrying poxtA was evaluated by inverse PCR experiments for detection of circular intermediates.
RESULTS: poxtA was found to be associated with a 48 kb composite transposon of original structure, named Tn6349, inserted into a φN315-like prophage. The transposon was bounded by two IS1216 insertion sequences, carried several resistance genes [erm(B), cfr, poxtA and fexB] and exhibited a mosaic structure made by a derivative of plasmid pE35048-oc (previously described in an Enterococcus faecium clinical isolate) and Tn6657, a novel composite transposon carrying the poxtA and fexB genes. Excision ability of Tn6349 as a circular intermediate was demonstrated. Transferability of Tn6349 or modules thereof to S. aureus or E. faecalis by either conjugation or electrotransformation was not detected. Induction of the φN315-like prophage carrying Tn6349 was not observed.
CONCLUSIONS: This study describes the structure of Tn6349, a novel composite transposon carrying several resistance determinants to anti-ribosomal drugs, including cfr and poxtA, from an oxazolidinone-resistant MRSA strain. Analysis of Tn6349 revealed a modular structure that could favour the mobilization of its resistance determinants.

PMID: 31355850 [PubMed - as supplied by publisher]

Pseudomonas aeruginosa populations in the cystic fibrosis lung lose susceptibility to newly applied β-lactams within 3 days.

J Antimicrob Chemother. 2019 Jul 17;:

Authors: Tueffers L, Barbosa C, Bobis I, Schubert S, Höppner M, Rühlemann M, Franke A, Rosenstiel P, Friedrichs A, Krenz-Weinreich A, Fickenscher H, Bewig B, Schreiber S, Schulenburg H

Abstract
BACKGROUND: Chronic pulmonary infections by Pseudomonas aeruginosa require frequent intravenous antibiotic treatment in cystic fibrosis (CF) patients. Emergence of antimicrobial resistance is common in these patients, which to date has been investigated at long-term intervals only.
OBJECTIVES: To investigate under close to real-time conditions the dynamics of the response by P. aeruginosa to a single course of antibiotic therapy and the potentially associated rapid spread of antimicrobial resistance, as well as the impact on the airway microbiome.
METHODS: We investigated a cohort of adult CF patients that were treated with a single course of antimicrobial combination therapy. Using daily sampling during treatment, we quantified the expression of resistance by P. aeruginosa (median of six isolates per daily sample, 347 isolates in total), measured bacterial load by P. aeruginosa-specific quantitative PCR and characterized the airway microbiome with a 16S rRNA-based approach. WGS was performed to reconstruct intrapatient strain phylogenies.
RESULTS: In two patients, we found rapid and large increases in resistance to meropenem and ceftazidime. Phylogenetic reconstruction of strain relationships revealed that resistance shifts are probably due to de novo evolution and/or the selection of resistant subpopulations. We observed high interindividual variation in the reduction of bacterial load, microbiome composition and antibiotic resistance.
CONCLUSIONS: We show that CF-associated P. aeruginosa populations can quickly respond to antibiotic therapy and that responses are patient specific. Thus, resistance evolution can be a direct consequence of treatment, and drug efficacy can be lost much faster than usually assumed. The consideration of these patient-specific rapid resistance shifts can help to improve treatment of CF-associated infections, for example by deeper sampling of bacteria for diagnostics, repeated monitoring of pathogen susceptibility and switching between drugs.

PMID: 31355848 [PubMed - as supplied by publisher]

An aging population of patients with cystic fibrosis undergoes lung transplantation: An analysis of the ISHLT Thoracic Transplant Registry.

J Heart Lung Transplant. 2019 Jul 04;:

Authors: Benden C, Goldfarb SB, Stehlik J

Abstract
BACKGROUND: Since lung transplantation became a viable option for cystic fibrosis (CF) lung disease, adult transplant recipients with CF have superior survival than all the other major diagnostic indications. However, among adults, recipients with CF have a younger age at transplant than other transplant recipients. Over time, the frequency and proportion of lung transplants for CF has increased for adults compared with children. Using a large international transplant registry, we investigated time trends in numbers of transplants, age at transplant, and post-transplant survival and cause of death for recipients with CF.
METHODS: We conducted a retrospective cohort study of primary lung-alone deceased-donor transplants with a primary diagnostic indication of CF reported to the International Society for Heart and Lung Transplantation Thoracic Transplant Registry from January 2005 through December 2014. We assessed outcomes through December 31, 2015. The study defined the pediatric group as age <18 years at transplant and the adult as ≥18 years at transplant. We assessed time trends (Era I 2005-2009, Era II 2010-2014) in age and compared post-transplant outcomes of age sub-groups with Kruskal-Wallis or chi-square tests. Kaplan-Meier survival analysis estimated the incidence of survival, censoring for loss to follow-up, end of study, and retransplant. In addition, we compared outcomes in age groups and transplant eras with the log-rank test.
RESULTS: Of the 5,613 transplanted recipients with CF, the pediatric group comprised 10.9% and the adult group comprised 89.1%. Of the adults, 73.3% were aged 18 to 39 years and 15.9% were ≥40 years old. During Era I, 2,508 of transplant recipients had CF, whereas 3,105 recipients had CF in Era II (p < 0.001). Comparing Era I with Era II, recipient mean age increased from 28.4 years to 29.5 years (p < 0.001) and the proportion of pediatric CF recipients dropped from 12.4% to 9.6% (p < 0.001), whereas the proportion with age ≥40 years increased from 14.2% to 17.2% (p < 0.001). Mean donor age was significantly lower in children than in recipients aged 18 to 39 years and ≥40 years (17.0 vs 37.0 vs 41.0 years, p < 0.001). Pediatric CF transplant recipients had lower survival in the first 3 years post-transplant than adults (p < 0.0001). Chronic graft failure caused most pediatric deaths, whereas infection was the leading cause of death in adult recipients.
CONCLUSION: As survival of patients with CF has improved in recent decades, the mean age of lung transplant recipients with CF has increased. Currently, an increasing number of adults undergoes lung transplant for this indication. Adult CF transplant recipients continue to have better survival than pediatric recipients, and among adults, older adults have had better survival than younger adults.

PMID: 31353276 [PubMed - as supplied by publisher]

Risk factors for adverse outcome in infancy in meconium ileus cystic fibrosis infants: A multicentre Italian study.

J Cyst Fibros. 2019 Jul 25;:

Authors: Padoan R, Cirilli N, Falchetti D, Cesana BM, Meconium Ileus Project Study Group

Abstract
BACKGROUND: Meconium ileus (MI) is a risk factor for poor outcomes in cystic fibrosis (CF) patients. The aim of this study was to identify the risk factors for poor 12-month clinical outcomes in MI-CF newborns.
METHODS: This retrospective, multicentre, observational study of MI-CF infants born 2009-2015 recorded their pre- and neonatal histories, intestinal occlusion treatments, post-surgical history, nutrition, CF diagnosis, and compared the patients with 12-month faltering growth or chronic Pseudomonas aeruginosa respiratory infection (cases) with the others (controls).
RESULTS: About 25% of the 85 patients enrolled by 13 Italian CF centres (24% premature, 18% of low birth weight) had prenatally diagnosed bowel obstruction, and 39% had complex MI. Seventy-one required surgery (the 33 with complex MI and 38 with simple MI), of whom 58 (82%) required post-surgical intensive care, including 25 (35%) needing ventilatory support. Forty-six (54%) were breastfed; exclusively parenteral nutrition was started in 52 (61%). Cholestasis was diagnosed in 21%. Thirty-one (37%) experienced negative outcomes: the only risk factors were prenatally diagnosed intestinal obstruction and a need for intensive care and oxygen therapy. The cases had significantly higher first blood immunoreactive trypsinogen (b-IRT) levels (P = .008). Logistic regression showed that the probability of having negative outcome is decreased in the absence of cholestasis (Odds Ratio = 0.125) and a need for intensive therapy (OR = 0.141), and increased by not having been breastfed (OR = 2.921).
CONCLUSIONS: High b-IRT levels, prenatally diagnosed intestinal obstruction, a severe post-surgical clinical picture and early liver disease are risk factors for negative outcomes. Breastfeeding may be protective.

PMID: 31353045 [PubMed - as supplied by publisher]

Steric Inhibition of 5' UTR Regulatory Elements Results in Upregulation of Human CFTR.

Mol Ther. 2019 Jul 12;:

Authors: Sasaki S, Sun R, Bui HH, Crosby JR, Monia BP, Guo S

Abstract
Cystic fibrosis (CF) is an autosomal recessive monogenic disease caused by mutations in the CFTR gene. Therapeutic approaches that are focused on correcting CFTR protein face the challenge of the heterogeneity in CFTR mutations and resulting defects. Thus, while several small molecules directed at CFTR show benefit in the clinic for subsets of CF patients, these drugs cannot treat all CF patients. Additionally, the clinical benefit from treatment with these modulators could be enhanced with novel therapies. To address this unmet need, we utilized an approach to increase CFTR protein levels through antisense oligonucleotide (ASO)-mediated steric inhibition of 5' UTR regulatory elements. We identified ASOs to upregulate CFTR protein expression and confirmed the regulatory role of the sites amenable to ASO-mediated upregulation. Two ASOs were investigated further, and both increased CFTR protein expression and function in cell lines and primary human bronchial epithelial cells with distinct CF genotypes. ASO treatment further increased CFTR function in almost all CF genotypes tested on top of treatment with the FDA approved drug Symdeko (ivacaftor and tezacaftor). Thus, we present a novel approach to CFTR therapeutic intervention, through ASO-mediated modulation of translation.

PMID: 31351782 [PubMed - as supplied by publisher]

Targeting Vitamin D Deficiency to Limit Exacerbations in Respiratory Diseases: Utopia or Strategy With Potential?

Calcif Tissue Int. 2019 Jul 26;:

Authors: Maes K, Serré J, Mathyssen C, Janssens W, Gayan-Ramirez G

Abstract
Patients with respiratory diseases such as cystic fibrosis, chronic obstructive pulmonary disease, or asthma often experience an acute worsening of respiratory symptoms, termed exacerbations. Although the course of exacerbations is disease specific, they are mostly triggered by a respiratory infection. Exacerbations often require hospitalization and are an important cause of mortality. Treatments of exacerbations aim to minimize the negative impact and to prevent subsequent events. Despite many existing therapy options, many patients do not benefit from therapy and suffer from recurrent events. Vitamin D deficiency is a worldwide problem and is extremely prevalent in these patients. Vitamin D, known for its calcemic effects, also has immunomodulatory and anti-infectious actions and can therefore be a possible agent to treat or prevent exacerbations. This review will focus on vitamin D as a potential candidate to treat or prevent exacerbations in CF, COPD, and asthma.

PMID: 31350569 [PubMed - as supplied by publisher]

A general protein O-glycosylation machinery conserved in Burkholderia species improves bacterial fitness and elicits glycan immunogenicity in humans.

J Biol Chem. 2019 Jul 26;:

Authors: Fathy Mohamed Y, Scott NE, Molinaro A, Creuzenet C, Ortega X, Lertmemongkolchai G, Tunney MM, Green H, Jones AM, DeShazer D, Currie BJ, Foster LJ, Ingram R, De Castro C, Valvano MA

Abstract
The Burkholderia genus encompasses many Gram-negative bacteria living in the rhizosphere. Some Burkholderia species can cause life-threatening human infections, highlighting the need for clinical interventions targeting specific Burkholderia proteins. Burkholderia cenocepacia O-linked protein glycosylation has been reported, but the chemical structure of the O-glycan and the machinery required for its biosynthesis are unknown and could reveal potential therapeutic targets. Here, using bioinformatics approaches, gene-knockout mutants, purified recombinant proteins, LC-MS-based analyses of O-glycans, and NMR-based structural analyses, we identified a B. cenocepacia O-glycosylation (ogc) gene cluster in necessary for synthesis, assembly, and membrane translocation of a lipid-linked O-glycan, as well as its structure, which consists of a β-Gal-(1,3)-α-GalNAc-(1,3)-β-GalNAc trisaccharide. We demonstrate that the ogc cluster is conserved in the Burkholderia genus and confirm the production of glycoproteins with similar glycans in the Burkholderia species B. thailandensis, B. gladioli, and B. pseudomallei Further, we show that absence of protein O-glycosylation severely affects bacterial fitness and accelerates bacterial clearance in a Galleria mellonella larva infection model. Finally, our experiments revealed that patients infected with B. cenocepacia, B. multivorans, B. pseudomallei, or B. mallei develop O-glycan-specific antibodies. Together, these results highlight the importance of general protein O-glycosylation in the biology of the Burkholderia genus and its potential as a target for inhibition or immunotherapy approaches to control Burkholderia infections.

PMID: 31350337 [PubMed - as supplied by publisher]

Bronchoalveolar Lavage Fluid from COPD Patients Reveals More Compounds Associated with Disease than Matched Plasma.

Metabolites. 2019 Jul 25;9(8):

Authors: Halper-Stromberg E, Gillenwater L, Cruickshank-Quinn C, O'Neal WK, Reisdorph N, Petrache I, Zhuang Y, Labaki WW, Curtis JL, Wells J, Rennard S, Pratte KA, Woodruff P, Stringer KA, Kechris K, Bowler RP

Abstract
Smoking causes chronic obstructive pulmonary disease (COPD). Though recent studies identified a COPD metabolomic signature in blood, no large studies examine the metabolome in bronchoalveolar lavage (BAL) fluid, a more direct representation of lung cell metabolism. We performed untargeted liquid chromatography-mass spectrometry (LC-MS) on BAL and matched plasma from 115 subjects from the SPIROMICS cohort. Regression was performed with COPD phenotypes as the outcome and metabolites as the predictor, adjusted for clinical covariates and false discovery rate. Weighted gene co-expression network analysis (WGCNA) grouped metabolites into modules which were then associated with phenotypes. K-means clustering grouped similar subjects. We detected 7939 and 10,561 compounds in BAL and paired plasma samples, respectively. FEV1/FVC (Forced Expiratory Volume in One Second/Forced Vital Capacity) ratio, emphysema, FEV1 % predicted, and COPD exacerbations associated with 1230, 792, eight, and one BAL compounds, respectively. Only two plasma compounds associated with a COPD phenotype (emphysema). Three BAL co-expression modules associated with FEV1/FVC and emphysema. K-means BAL metabolomic signature clustering identified two groups, one with more airway obstruction (34% of subjects, median FEV1/FVC 0.67), one with less (66% of subjects, median FEV1/FVC 0.77; p < 2 × 10-4). Associations between metabolites and COPD phenotypes are more robustly represented in BAL compared to plasma.

PMID: 31349744 [PubMed]

In Vitro Synergism of Colistin and N-acetylcysteine against Stenotrophomonas maltophilia.

Antibiotics (Basel). 2019 Jul 25;8(3):

Authors: Ciacci N, Boncompagni S, Valzano F, Cariani L, Aliberti S, Blasi F, Pollini S, Rossolini GM, Pallecchi L

Abstract
Stenotrophomonas maltophilia is an emerging global opportunistic pathogen, responsible for a wide range of human infections, including respiratory tract infections. Intrinsic multidrug resistance and propensity to form biofilms make S. maltophilia infections recalcitrant to treatment. Colistin is among the second-line options in case of difficult-to-treat S. maltophilia infections, with the advantage of being also administrable by nebulization. We investigated the potential synergism of colistin in combination with N-acetylcysteine (NAC) (a mucolytic agent with antioxidant and anti-inflammatory properties) against S. maltophilia grown in planktonic phase and biofilm. Eighteen S. maltophilia clinical isolates (comprising three isolates from cystic fibrosis (CF) and two trimethoprim-sulfamethoxazole (SXT)-resistant strains) were included. Checkerboard assays showed a synergism of colistin/NAC combinations against the strains with colistin Minimum Inhibitory Concentration (MIC) >2 µg/mL (n = 13), suggesting that NAC could antagonize the mechanisms involved in colistin resistance. Nonetheless, time-kill assays revealed that NAC might potentiate colistin activity also in case of lower colistin MICs. A dose-dependent potentiation of colistin activity by NAC was also clearly observed against S. maltophilia biofilms, also at sub-MIC concentrations. Colistin/NAC combinations, at concentrations likely achievable by topical administration, might represent a valid option for the treatment of S. maltophilia respiratory infections and should be examined further.

PMID: 31349560 [PubMed]

BJN Awards: respiratory nurse of the year 2019: runner up.

Br J Nurs. 2019 Jul 25;28(14):918-919

Authors: Hartfield J

PMID: 31348705 [PubMed - in process]

Airway Surface Liquid and Impaired Antiviral Defense in Cystic Fibrosis.

Am J Respir Cell Mol Biol. 2019 Jul 26;:

Authors: Voynow JA, Zheng S

PMID: 31348689 [PubMed - as supplied by publisher]

Prophylactic low-dose paracetamol administration associated with lowered rate of patent ductus arteriosus in preterm infants - Impact on outcome and pain perception.

Pediatr Neonatol. 2019 Jul 03;:

Authors: Höck M, Brunner B, Rier V, Thöni S, Trawöger R, Geiger R, Schermer E, Karall T, Kiechl-Kohlendorfer U

Abstract
BACKGROUND: To determine the rate of patent ductus arteriosus after prophylactic low-dose paracetamol administration, the impact on outcome parameters, possible treatment side-effects and the influence on pain perception.
METHODS: We report retrospective single-centre outcome data of premature infants ≤ 32 weeks of gestation (n = 476). The intervention group received intravenous paracetamol, the control group obtained no preventive therapy. Ductal closure rate and outcome parameters were compared between the two groups. Adverse effects were determined by laboratory parameters. For the assessment of pain the Bernese Pain Scale for Neonates was used.
RESULTS: The rate of patent ductus arteriosus was significantly lower in the paracetamol-treated group compared to the control group (13.6% vs. 38.2%, p < 0.001). With regard to secondary outcome parameters, severe and moderate bronchopulmonary dysplasia (2.7% vs. 7.4%, p = 0.023), severe retinopathy of prematurity (0% vs. 4.4%, p = 0.002) and late onset sepsis (2.7% vs. 8.3%, p = 0.009) were significantly less frequent in the paracetamol group. Except for a 1.5-fold increased risk for hyperbilirubinemia (86.0% vs. 77.6%, p = 0.035) in the paracetamol group following treatment, no significant differences in laboratory parameters were found. Relating to pain, the administration of Glucose 33% was significantly more often necessary in the control group compared to the paracetamol-treated group (mean 13.48 vs. 8.71, p < 0.001), just as the need for additional treatment with systemic analgesics, which was more frequent in the control group (mean 0.72 vs. 0.57, p = 0.361).
CONCLUSION: In our study we were able to show a significantly lower rate of patent ductus arteriosus after prophylactic paracetamol administration without serious adverse effect, but a beneficial influence of this regime on the patient's pain perception.

PMID: 31345732 [PubMed - as supplied by publisher]

A Retrospective Claims Analysis of Dual Bronchodilator Fixed-Dose Combination Versus Bronchodilator Monotherapy in Patients with Chronic Obstructive Pulmonary Disease.

Chronic Obstr Pulm Dis. 2019 Jul 24;6(3):221-232

Authors: Strange C, Walker V, Tong J, Kurlander J, Carlyle M, Millette LA, Wittbrodt E

Abstract
Introduction: Patients with chronic obstructive pulmonary disease (COPD) increasingly receive combination bronchodilator therapies. Real world evidence for the benefits of combination therapy compared to monotherapy is lacking.
Methods: COPD patients aged ≥ 40 years initiating monotherapy (MT) with either a long-acting muscarinic antagonist (LAMA) or long-acting beta2-agonist (LABA) or dual therapy (DT) with a LAMA/LABA fixed dose combination (FDC) between January 1, 2016 and December 31, 2016 were identified from a large U.S. administrative claims database. Patients diagnosed with cystic fibrosis, idiopathic pulmonary fibrosis, or asthma were excluded. Cohorts were propensity score matched 1:1 using baseline measures (e.g., exacerbations, hospitalizations) as proxies for COPD severity to create balanced cohorts.
Results: Following propensity score matching (PSM), 1286 patients remained in each cohort for analysis. Patients were followed for approximately 1 year. Patients in the DT versus MT cohort had lower rates of exacerbations leading to hospitalization (incidence rate ratio 0.7886; p=0.019), lower mean COPD-related pharmacy costs per patient per month (PPPM) ($300 versus $379, respectively; p<0.001) and total costs PPPM ($990 versus $1203, respectively; p=0.003). This occurred despite lower mean COPD-related pharmacy fills PPPM in the DT versus MT cohorts (1.41 versus 1.51, respectively; p=0.038). Patients in the DT cohort had lower rates of switching (p<0.001) and augmentation (p<0.001), and higher rates of non-persistence (p<0.001) versus the MT cohort. Rates of discontinuation were similar.
Conclusions: Patients in the DT cohort had lower rates of exacerbations leading to hospitalization, lower COPD-related pharmacy and total costs PPPM, and lower rates of switching and augmentation compared to patients in the MT cohort.

PMID: 31342728 [PubMed]

Molecular analysis and antimicrobial resistance pattern of distinct strains of Pseudomonas aeruginosa isolated from cystic fibrosis patients in Iran.

Iran J Microbiol. 2019 Apr;11(2):98-107

Authors: Emaneini M, Kalantar-Neyestanaki D, Jabalameli L, Hashemi M, Beigverdi R, Jabalameli F

Abstract
Background and Objectives: Colonization of Pseudomonas aeruginosa in Cystic Fibrosis (CF) patients may lead to severe pulmonary disease and death. Different characteristics of P. aeruginosa from these patients were determined in the present study.
Materials and Methods: Antimicrobial susceptibility and AmpC-overproduction were determined. The β-lactamase genes were detected by PCR and the oprD gene was sequenced in some of the carbapenem resistance isolates. Distribution of exo genes was determined by PCR. Cytotoxicity of Exo effector proteins was measured using A549 cells. Biofilm production was determined by microtiter plate assay. Random amplified polymorphic DNA (RAPD) -PCR was performed for molecular analysis.
Results: Polymyxin B, piperacillin/tazobactam and meropenem were the most active antibiotics and 9.6% of isolates were ampC overproducers. The prevalence of bla VEB, bla OXA, bla VIM, and bla PER genes were as follow: 22.7%, 3.75%, 6.25% and 3.75%, respectively. A high proportion (83.5%) of isolates was able to produce biofilm. The exoT gene was present in all isolates while exoU was present in about 35% of them. RAPD-PCR revealed 49 patterns among 78 tested isolates in which 34 patterns were detected once.
Conclusion: Biofilm formation ability and relatively high frequency of exoS may contribute to the persistence of bacteria within lungs of CF patients. Some characteristics of isolates recovered from a single patient after several sampling procedures were similar, while others lacked resemblance.

PMID: 31341563 [PubMed]