"Structure-Function Imaging of Lung Disease Using Ultrashort Echo Time MRI".

Acad Radiol. 2019 Jan 15;:

Authors: Torres L, Kammerman J, Hahn AD, Zha W, Nagle SK, Johnson K, Sandbo N, Meyer K, Schiebler M, Fain SB

Abstract
RATIONALE AND OBJECTIVES: The purpose of this review is to acquaint the reader with recent advances in ultrashort echo time (UTE) magnetic resonance imaging (MRI) of the lung and its implications for pulmonary MRI when used in conjunction with functional MRI technique.
MATERIALS AND METHODS: We provide an overview of recent technical advances of UTE and explore the advantages of combined structure-function pulmonary imaging in the context of restrictive and obstructive pulmonary diseases such as idiopathic pulmonary fibrosis (IPF) and cystic fibrosis (CF).
RESULTS: UTE MRI clearly shows the lung parenchymal changes due to IPF and CF. The use of UTE MRI, in conjunction with established functional lung MRI in chronic lung diseases, will serve to mitigate the need for computed tomography in children.
CONCLUSION: Current limitations of UTE MRI include long scan times, poor delineation of thin-walled structures (e.g. cysts and reticulation) due to limited spatial resolution, low signal to noise ratio, and imperfect motion compensation. Despite these limitations, UTE MRI can now be considered as an alternative to multidetector computed tomography for the longitudinal follow-up of the morphological changes from lung diseases in neonates, children, and young adults, particularly as a complement to the unique functional capabilities of MRI.

PMID: 30658930 [PubMed - as supplied by publisher]

Inhaled liposomal ciprofloxacin in patients with non-cystic fibrosis bronchiectasis and chronic lung infection with Pseudomonas aeruginosa (ORBIT-3 and ORBIT-4): two phase 3, randomised controlled trials.

Lancet Respir Med. 2019 Jan 15;:

Authors: Haworth CS, Bilton D, Chalmers JD, Davis AM, Froehlich J, Gonda I, Thompson B, Wanner A, O'Donnell AE

Abstract
BACKGROUND: In patients with non-cystic fibrosis bronchiectasis, lung infection with Pseudomonas aeruginosa is associated with frequent pulmonary exacerbations and admission to hospital for treatment, reduced quality of life, and increased mortality. Although inhaled antibiotics are conditionally recommended for long-term management of non-cystic fibrosis bronchiectasis with frequent exacerbations, there is no approved therapy. We investigated the safety and efficacy of inhaled liposomal ciprofloxacin (ARD-3150) in two phase 3 trials.
METHODS: ORBIT-3 and ORBIT-4 were international, randomised, double-blind, placebo-controlled, phase 3 trials run concurrently in similar geographical regions. Eligible patients had non-cystic fibrosis bronchiectasis, had had at least two pulmonary exacerbations treated with antibiotics in the previous 12 months, and had a history of chronic P aeruginosa lung infection. Patients were randomly assigned (2:1) to receive either ARD-3150 or placebo. ARD-3150 (3 mL liposome encapsulated ciprofloxacin 135 mg and 3 mL free ciprofloxacin 54 mg) or 6 mL placebo (3 mL dilute empty liposomes mixed with 3 mL of saline) was self-administered once daily for six 56-day treatment cycles, for 48 weeks. The primary endpoint was time to first pulmonary exacerbation from the date of randomisation to week 48. We did primary and secondary efficacy, safety, and microbiology analyses on the full analysis population, which comprised all randomised patients who received at least one dose of study drug. ORBIT-3 and ORBIT-4 are registered with ClinicalTrials.gov, numbers NCT01515007 and NCT02104245, respectively.
FINDINGS: Between March 31, 2014, and Aug 19, 2015, we screened 514 patients in ORBIT-3 and 533 patients in ORBIT-4. The full analysis populations consisted of 278 patients in ORBIT-3 (183 patients received at least one dose of ARD-3150 and 95 received placebo) and 304 patients in ORBIT-4 (206 patients received at least one dose of ARD-3150 and 98 received placebo). In ORBIT-4, the median time to first pulmonary exacerbation was 230 days in the ARD-3150 group compared with 158 days in the placebo group, a statistically significant difference of 72 days (hazard ratio [HR] 0·72 [95% CI 0·53-0·97], p=0·032). In ORBIT-3, the median time to first pulmonary exacerbation was 214 days in the ARD-3150 group and 136 days in the placebo group, a non-statistically significant difference of 78 days (HR 0·99 [95% CI 0·71-1·38], p=0·97). In a pooled analysis of data from both ORBIT-3 and ORBIT-4, the median time to first pulmonary exacerbation was 222 days in the ARD-3150 group and 157 days in the placebo group, a non-statistically significant difference of 65 days (0·82 [0·65-1·02], p=0·074). The numbers of adverse events and serious adverse events were similar in both groups in ORBIT-3 and ORBIT-4.
INTERPRETATION: In patients with non-cystic fibrosis bronchiectasis and chronic P aeruginosa lung infection requiring antibiotic therapy in the preceding year, ARD-3150 led to a significantly longer median time to first pulmonary exacerbation compared with placebo in ORBIT-4, but not in ORBIT-3 or the pooled analysis. Inconsistency between the trials suggests further research is needed into the heterogeneity of non-cystic fibrosis bronchiectasis and optimal outcome measures for inhaled antibiotics.
FUNDING: Aradigm Corporation.

PMID: 30658914 [PubMed - as supplied by publisher]

A specific combined long-chain polyunsaturated fatty acid supplementation reverses fatty acid profile alterations in a mouse model of chronic asthma.

Lipids Health Dis. 2019 Jan 18;18(1):16

Authors: Fussbroich D, Zimmermann K, Göpel A, Eickmeier O, Trischler J, Zielen S, Schubert R, Beermann C

Abstract
BACKGROUND: The immune-modulating potential of long-chain polyunsaturated fatty acids (LCPUFAs) based on their conversion into lipid mediators in inflammatory situations has been proven by several studies. Respecting the immune-modulative role of lipid mediators in bronchoconstriction, airway inflammation and resolution of inflammatory processes, LCPUFAs play an important role in asthma. To design a disease-specific and most beneficial LCPUFA supplementation strategy, it is essential to understand how asthma alters LCPUFA profiles. Therefore, this study characterizes the alterations of LCPUFA profiles induced by allergic asthma. In addition, this study explores whether a simple eicosapentaenoic acid (EPA) alone or a specific combined LCPUFA supplementation could restore imbalanced LCPUFA profiles.
METHODS: Mice were sensitized with a daily dose of 40 μg house dust mite (HDM)-extract in a recall model and fed with either normal diet, EPA or a specific combined (sc)-LCPUFA supplementation containing EPA, docosahexaenoic acid (DHA), γ -linolenic acid (GLA) and stearidonic acid (SDA) for 24 days. After recall with HDM, mice were sacrificed and blood and lung tissue were collected. Fatty acid profiles were determined in plasma, blood cells and lung cells of asthmatic mice by capillary gas-chromatography.
RESULTS: In lung cells of asthmatic mice, arachidonic acid (AA, p < 0.001) and DHA (p < 0.01) were increased while dihomo-γ-linolenic acid (DGLA, p < 0.05) was decreased. EPA supplementation increased only EPA (p < 0.001) and docosapentaenoic acid (DPA, p < 0.001), but neither DGLA nor DHA in lung cells of asthmatic mice. In contrast, a specific combined dietary supplementation containing n-3 and n-6 LCPUFAs could decrease AA (p < 0.001), increase EPA (p < 0.001), DPA (p < 0.001) and DHA (p < 0.01) and could reverse the lack of DGLA (p < 0.05).
CONCLUSIONS: In summary, allergic asthma alters LCPUFA profiles in blood and lung tissue. In contrast to the EPA supplementation, the distinct combination of n-3 and n-6 LCPUFAs restored the LCPUFA profiles in lung tissue of asthmatic mice completely. Subsequently, sc-LCPUFA supplementation is likely to be highly supportive in limiting and resolving the inflammatory process in asthma.

PMID: 30658644 [PubMed - in process]

Wearable Potentiometric Sensors for Medical Applications.

Sensors (Basel). 2019 Jan 17;19(2):

Authors: Cuartero M, Parrilla M, Crespo GA

Abstract
Wearable potentiometric sensors have received considerable attention owing to their great potential in a wide range of physiological and clinical applications, particularly involving ion detection in sweat. Despite the significant progress in the manner that potentiometric sensors are integrated in wearable devices, in terms of materials and fabrication approaches, there is yet plenty of room for improvement in the strategy adopted for the sample collection. Essentially, this involves a fluidic sampling cell for continuous sweat analysis during sport performance or sweat accumulation via iontophoresis induction for one-spot measurements in medical settings. Even though the majority of the reported papers from the last five years describe on-body tests of wearable potentiometric sensors while the individual is practicing a physical activity, the medical utilization of these devices has been demonstrated on very few occasions and only in the context of cystic fibrosis diagnosis. In this sense, it may be important to explore the implementation of wearable potentiometric sensors into the analysis of other biofluids, such as saliva, tears and urine, as herein discussed. While the fabrication and uses of wearable potentiometric sensors vary widely, there are many common issues related to the analytical characterization of such devices that must be consciously addressed, especially in terms of sensor calibration and the validation of on-body measurements. After the assessment of key wearable potentiometric sensors reported over the last five years, with particular attention paid to those for medical applications, the present review offers tentative guidance regarding the characterization of analytical performance as well as analytical and clinical validations, thereby aiming at generating debate in the scientific community to allow for the establishment of well-conceived protocols.

PMID: 30658434 [PubMed - in process]

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"Cystic Fibrosis"

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PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

β1 syntrophin supports autophagy initiation and protects against cerulein-induced acute pancreatitis.

Am J Pathol. 2019 Jan 14;:

Authors: Ye R, Onodera T, Blanchard PG, Kusminski CM, Esser V, Brekken RA, Scherer PE

Abstract
Syntrophins are a family of proteins forming membrane-anchored scaffolds and serving as adaptors for various transmembrane and intracellular signaling molecules. To understand the physiological roles of β1 syntrophin, one of the least characterized members, we generated mouse models to eliminate β1 syntrophin specifically in the endocrine or exocrine pancreas. β1 syntrophin is dispensable for the morphology and function of insulin-producing β-cells. However, mice with β1 syntrophin deletion in exocrine acinar cells exhibit increased severity of cerulein-induced acute pancreatitis. Reduced expression of cystic fibrosis transmembrane conductance regulator and dilation of acinar lumen are potential predisposition factors. During the disease progression, a relative lack of autophagy is associated with deficiencies in both actin assembly and endoplasmic reticulum nucleation. Our findings reveal for the first time that β1 syntrophin is a critical regulator of actin cytoskeleton and autophagy in pancreatic acinar cells, and is potently protective against cerulein-induced acute pancreatitis.

PMID: 30653956 [PubMed - as supplied by publisher]

Defective FXR-FGF15 signaling and bile acid homeostasis in cystic fibrosis mice can be restored by the laxative polyethylene glycol.

Am J Physiol Gastrointest Liver Physiol. 2019 Jan 17;:

Authors: Bertolini A, van de Peppel IP, Doktorova-Demmin M, Bodewes FAJA, de Jonge HR, Bijvelds MJC, Verkade HJ, Jonker JW

Abstract
The gastrointestinal phenotype of cystic fibrosis (CF) features intestinal bile acid (BA) malabsorption, impaired intestinal farnesoid X receptor (FXR) activation and consequently reduced fibroblast growth factor 19 (FGF19, FGF15 in mice) production. The osmotic laxative polyethylene glycol (PEG) has been shown to decrease intestinal mucus accumulation in CF mice and could, by doing so, improve BA reabsorption. Here we determined the effect of PEG on BA excretion and FXR-FGF15 signaling in CF mice. Male Cftr-/-tm1Unc (CF) and wild type (WT) littermates were administered PEG 4000 in drinking water and fed either chow or a semisynthetic diet. PEG was withdrawn for three days before termination. Fecal BA excretion was measured at PEG dosages of 37 g/L (100%) and 0 g/L (0%). Ileal FXR activation was assessed by gene expression of its downstream targets Fgf15 and Shp. In CF mice, PEG withdrawal increased fecal BA excretion on either diet as compared to full PEG dosage (chow, 2-fold, p=0.06; semisynthetic, 4.4-fold, p=0.007). PEG withdrawal did not affect fecal BA excretion in WT mice on either diet. After PEG withdrawal, gene expression levels of intestinal FXR target genes Fgf15 and Shp were decreased in CF mice, but unaffected in WT littermates. PEG did not affect the gene expression of the main intestinal BA transporter ASBT. PEG treatment ameliorates intestinal BA malabsorption in CF mice and restores intestinal FXR-FGF15 signaling, independently from Asbt gene expression. These findings highlight the potential of PEG in the prevention and treatment of the gastrointestinal phenotype of CF.

PMID: 30653340 [PubMed - as supplied by publisher]

A review of non-cystic fibrosis bronchiectasis in children with a focus on the role of long-term treatment with macrolides.

Pediatr Pulmonol. 2019 Jan 16;:

Authors: El Boustany P, Gachelin E, Colomban C, Cernoia J, Sudour P, Carsin A, Dubus JC

Abstract
Bronchiectasis is a rare chronic airway disease arising from several respiratory and systemic diseases. The grade of evidence for specific treatment of childhood bronchiectasis unrelated to cystic fibrosis (CF) is low with very few randomized controlled trials. Treatment has been based mainly on evidence from studies in adults with non-cystic fibrosis bronchiectasis and patients with cystic fibrosis. Recently, long-term treatment with macrolides has been proposed. These molecules offer the advantage of anti-inflammatory and immunomodulatory properties in addition to their antibacterial properties. A total of three randomized double-blind placebo-controlled trials conducted in adults showed that macrolides taken for 6-12 months led to a significant reduction in exacerbation rates. Only one long-term, randomized double-blind placebo-controlled trial was conducted in the pediatric population. It showed that azithromycin administered weekly for up to 24 months reduced pulmonary exacerbations. Further randomized controlled studies are needed to determine the optimal dose and duration of treatment with macrolides. The clinical profile of children who would benefit from this treatment also needs to be determined.

PMID: 30652424 [PubMed - as supplied by publisher]

Evaluation of 1,2,3-Triazoles as Amide Bioisosteres In Cystic Fibrosis Transmembrane Conductance Regulator Modulators VX-770 and VX-809.

Chemistry. 2019 Jan 16;:

Authors: Doiron JE, Le CA, Ody BK, Brace JB, Post SJ, Thacker NL, Hill HM, Breton GW, Mulder MJ, Chang S, Bridges TM, Tang L, Wang W, Rowe SM, Aller SG, Turlington M

Abstract
The 1,2,3-triazole has been successfully utilized as an amide bioisostere in multiple therapeutic contexts. Based on this precedent, triazole analogs derived from VX-809 and VX-770, prominent amide-containing modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), were synthesized and evaluated for CFTR modulation. Triazole 11, derived from VX-809, displayed markedly reduced efficacy in F508del-CFTR correction in cellular TECC assays in comparison to VX-809. Surprisingly, triazole analogs derived from potentiator VX-770 displayed no potentiation of F508del, G551D, or WT-CFTR in cellular Ussing chamber assays. However, patch clamp analysis revealed that triazole 60 potentiates WT-CFTR similarly to VX-770. The efficacy of 60 in the cell-free patch clamp experiment suggests that the loss of activity in the cellular assay could be due to the inability of VX-770 triazole derivatives to reach the CFTR binding site. Moreover, in addition to the negative impact on biological activity, triazoles in both structural classes displayed decreased metabolic stability in human microsomes relative to the analogous amides. In contrast to the many studies that demonstrate the advantages of using the 1,2,3-triazole, these findings highlight the negative impacts that can arise from replacement of the amide with the triazole and suggest that caution is warranted when considering use of the 1,2,3-triazole as an amide bioisostere.

PMID: 30650214 [PubMed - as supplied by publisher]

Benefit-Risk Assessment of Plecanatide in the Treatment of Chronic Idiopathic Constipation.

Drug Saf. 2019 Jan 16;:

Authors: Miner PB

Abstract
Plecanatide, a uroguanylin analog, activates the guanylate cyclase C receptors in the epithelial lining of the gastrointestinal tract in a pH-dependent fashion initiating (1) the conversion of intracellular guanosine triphosphate to cyclic guanosine monophosphate, which increases the activity of the cystic fibrosis transmembrane conductance regulator to increase chloride and bicarbonate secretion into the intestinal lumen and (2) a decrease in activity of the sodium-hydrogen ion exchanger. The resulting ionic shifts cause an increase in lumenal fluid to facilitate digestion. Plecanatide has been approved by the FDA for use in chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation. This manuscript is a critical assessment of the therapeutic efficacy and potential risks associated with the use of plecanatide in CIC. The discussion of CIC as a clinical and investigative disorder focuses on the importance of this problem as well and the difficulties involved in clinical management and scholarly investigation of a symptom arising from multiple pathophysiologic mechanisms. Clinical data from studies of recently approved drugs for CIC are utilized to construct a platform for thoughtful understanding of CIC and of how changes in investigation guidelines influence the interpretation of study data and guide symptom management. Plecanatide is a safe and effective medication for the management of adults with CIC.

PMID: 30649746 [PubMed - as supplied by publisher]

Use of ceftazidime/avibactam for the treatment of MDR Pseudomonas aeruginosa and Burkholderia cepacia complex infections in cystic fibrosis: a case series.

J Antimicrob Chemother. 2019 Jan 11;:

Authors: Spoletini G, Etherington C, Shaw N, Clifton IJ, Denton M, Whitaker P, Peckham DG

Abstract
Background: The efficacy of antibiotic treatment in pulmonary and systemic infections in cystic fibrosis (CF) is limited by the increased prevalence of MDR strains of Pseudomonas aeruginosa and Burkholderia cepacia complex. Ceftazidime/avibactam is a new combination which, in vitro, appears to have good activity against MDR strains of P. aeruginosa and B. cepacia complex.
Methods: A retrospective analysis was performed including adult patients with CF who received at least one course of ceftazidime/avibactam owing to pulmonary exacerbations not responding to conventional antibiotic treatment.
Results: Treatment with ceftazidime/avibactam was associated with reduction in inflammatory markers and improvement in lung function. No episodes of acute kidney injury or elevation in transaminase were observed.
Conclusions: Ceftazidime/avibactam appeared to be well tolerated and improved patients' outcomes. Further studies are needed to better assess the role of this new combination in CF.

PMID: 30649419 [PubMed - as supplied by publisher]

Management of Acute Respiratory Failure Due to Community-Acquired Pneumonia: A Systematic Review.

Med Sci (Basel). 2019 Jan 14;7(1):

Authors: Vanoni NM, Carugati M, Borsa N, Sotgiu G, Saderi L, Gori A, Mantero M, Aliberti S, Blasi F

Abstract
Community-acquired pneumonia (CAP) is a leading cause of mortality worldwide. CAP mortality is driven by the development of sepsis and acute respiratory failure (ARF). We performed a systematic review of the available English literature published in the period 1 January 1997 to 31 August 2017 and focused on ARF in CAP. The database searches identified 189 articles-of these, only 29 were retained for data extraction. Of these 29 articles, 12 addressed ARF in CAP without discussing its ventilatory management, while 17 evaluated the ventilatory management of ARF in CAP. In the studies assessing the ventilatory management, the specific treatments addressed were: high-flow nasal cannula (HFNC) (n = 1), continuous positive airway pressure (n = 2), non-invasive ventilation (n = 9), and invasive mechanical ventilation (n = 5). When analyzed, non-invasive ventilation (NIV) success rates ranged from 20% to 76% and they strongly predicted survival, while NIV failure led to an increased risk of adverse outcome. In conclusion, ARF in CAP patients may require both ventilatory and non-ventilatory management. Further research is needed to better evaluate the use of NIV and HFNC in those patients. Alongside the prompt administration of antimicrobials, the potential use of steroids and the implementation of severity scores should also be considered.

PMID: 30646626 [PubMed]

TALEN-Mediated Gene Targeting for Cystic Fibrosis-Gene Therapy.

Genes (Basel). 2019 Jan 11;10(1):

Authors: Xia E, Zhang Y, Cao H, Li J, Duan R, Hu J

Abstract
Cystic fibrosis (CF) is an inherited monogenic disorder, amenable to gene-based therapies. Because CF lung disease is currently the major cause of mortality and morbidity, and the lung airway is readily accessible to gene delivery, the major CF gene therapy effort at present is directed to the lung. Although airway epithelial cells are renewed slowly, permanent gene correction through gene editing or targeting in airway stem cells is needed to perpetuate the therapeutic effect. Transcription activator-like effector nuclease (TALEN) has been utilized widely for a variety of gene editing applications. The stringent requirement for nuclease binding target sites allows for gene editing with precision. In this study, we engineered helper-dependent adenoviral (HD-Ad) vectors to deliver a pair of TALENs together with donor DNA targeting the human AAVS1 locus. With homology arms of 4 kb in length, we demonstrated precise insertion of either a LacZ reporter gene or a human cystic fibrosis transmembrane conductance regulator (CFTR) minigene (cDNA) into the target site. Using the LacZ reporter, we determined the efficiency of gene integration to be about 5%. In the CFTR vector transduced cells, we were able to detect CFTR mRNA expression using qPCR and function correction using fluorometric image plate reader (FLIPR) and iodide efflux assays. Taken together, these findings suggest a new direction for future in vitro and in vivo studies in CF gene editing.

PMID: 30641980 [PubMed]

Long-term expanding human airway organoids for disease modeling.

EMBO J. 2019 Jan 14;:

Authors: Sachs N, Papaspyropoulos A, Zomer-van Ommen DD, Heo I, Böttinger L, Klay D, Weeber F, Huelsz-Prince G, Iakobachvili N, Amatngalim GD, de Ligt J, van Hoeck A, Proost N, Viveen MC, Lyubimova A, Teeven L, Derakhshan S, Korving J, Begthel H, Dekkers JF, Kumawat K, Ramos E, van Oosterhout MF, Offerhaus GJ, Wiener DJ, Olimpio EP, Dijkstra KK, Smit EF, van der Linden M, Jaksani S, van de Ven M, Jonkers J, Rios AC, Voest EE, van Moorsel CH, van der Ent CK, Cuppen E, van Oudenaarden A, Coenjaerts FE, Meyaard L, Bont LJ, Peters PJ, Tans SJ, van Zon JS, Boj SF, Vries RG, Beekman JM, Clevers H

Abstract
Organoids are self-organizing 3D structures grown from stem cells that recapitulate essential aspects of organ structure and function. Here, we describe a method to establish long-term-expanding human airway organoids from broncho-alveolar resections or lavage material. The pseudostratified airway organoids consist of basal cells, functional multi-ciliated cells, mucus-producing secretory cells, and CC10-secreting club cells. Airway organoids derived from cystic fibrosis (CF) patients allow assessment of CFTR function in an organoid swelling assay. Organoids established from lung cancer resections and metastasis biopsies retain tumor histopathology as well as cancer gene mutations and are amenable to drug screening. Respiratory syncytial virus (RSV) infection recapitulates central disease features, dramatically increases organoid cell motility via the non-structural viral NS2 protein, and preferentially recruits neutrophils upon co-culturing. We conclude that human airway organoids represent versatile models for the in vitro study of hereditary, malignant, and infectious pulmonary disease.

PMID: 30643021 [PubMed - as supplied by publisher]

Cystic fibrosis-associated Stenotrophomonas maltophilia strain-specific adaptations and responses to pH.

J Bacteriol. 2019 Jan 14;:

Authors: Gallagher T, Phan J, Oliver A, Chase AB, England WE, Wandro S, Hendrickson C, Riedel SF, Whiteson K

Abstract
The airway fluids of cystic fibrosis (CF) patients contain local pH gradients and are more acidic than that of healthy indviduals. pH is a critical factor that is often overlooked in studies seeking to recapitulate the infection microenvironment. We sought to determine the impact of pH on the physiology of a ubiqituous yet understudied microbe, Stenotrophomonas maltophilia. Phylogenomics was first used to reconstruct evolutionary relationships between 74 strains of S. maltophilia (59 from CF patients). Neither the core genome (2,158 genes) nor the accessory genome (11,978 genes) distinguish the CF and non-CF isolates, however, strains from similar isolation sources grouped into the same sub-clades. We grew two human and six CF S. maltophilia isolates from different subclades in a range of pH, and observed impaired growth and altered antibiotic tolerances in pH 5. Transcriptomes revealed increased expression of both antibiotic-resistance and DNA repair genes in acidic conditions. Although the gene expression profiles of S. maltophilia in lab cultures and CF sputum were distinct, we found that the same genes associated with low pH were also expressed during infection and the higher pH cultures were more similar to sputum metatranscriptomes. Our findings suggest S. maltophilia is not well-adapted to acidity and may cope with low pH by expressing stress response genes and colonizing less acidic microenvironments. As a whole, our study underlines the impact of microenvironments on bacterial colonization and adaptation in CF infections.IMPORTANCE Understanding bacterial responses to physiological conditions is an important priority for combating opportunistic infections. The majority of CF patients succumb to inflammation and necrosis in the airways, arising from chronic infection due to ineffective mucociliary clearance. Steep pH gradients characterize the CF airways, but are not often incorporated in standard microbiology culture conditions. Stenotrophomonas maltophilia is a prevalent CF opportunistic pathogen also found in many disparate environments, yet this bacterium's contribution to CF lung damage and its response to changing environmental factors remain largely understudied. Here, we show pH impacts the physiology and antibiotic susceptibility of S. maltophilia, with implications for the development of relevant in vitro models and assessment of antibiotic sensitivity.

PMID: 30642989 [PubMed - as supplied by publisher]

Application of multiple event analysis as an alternative approach to studying pulmonary exacerbations as an outcome measure.

J Cyst Fibros. 2019 Jan 11;:

Authors: Juarez-Colunga E, Rosenfeld M, Zemanick ET, Wagner B

Abstract
BACKGROUND: Pulmonary exacerbations (PEx) are important contributors to morbidity and mortality in cystic fibrosis (CF). Understanding risk factors for PEx is critical to improve treatment; pulmonary exacerbations also serve as an important outcome in CF clinical trials. Current risk estimates generally only evaluate time to the first PEx. Methods accounting for multiple exacerbations during the observation period could provide more power to detect significant risk factors.
METHODS: The Early Pseudomonas Infection Control (EPIC) Observational Study enrolled participants between 2004 and 2006 who were ≤ 12 years of age and negative for Pseudomonas aeruginosa. First and multiple event analyses were used to investigate risk factors for pulmonary exacerbations.
RESULTS: We evaluated a total of 5129 PEx from 1734 CF patients in the EPIC study. Multiple event analysis identified 2 more factors associated with occurrence of PEx compared to first event analysis. After adjusting for multiple factors, the following were associated with higher occurrence of PExs: female gender, older age at enrollment, household cigarette smoke exposure, increased cough at the most recent encounter, having used antibiotics since the previous encounter, a positive culture for any CF organism at the most recent encounter, and having had a PEx in the last 30 days.
CONCLUSIONS: Multiple event analyses use all PEx events and may identify more risk factors for PEx than analysis of time to first PEx. We have provided an example of how to apply this type of analysis and how to interpret estimates in the context of the EPIC study.

PMID: 30642785 [PubMed - as supplied by publisher]

Zinc Nutritional Status in Patients with Cystic Fibrosis.

Nutrients. 2019 Jan 11;11(1):

Authors: Escobedo Monge MF, Barrado E, Alonso Vicente C, Redondo Del Río MP, Marugán de Miguelsanz JM

Abstract
BACKGROUND: Zinc is an essential nutrient for all forms of life and its deficiency affects the normal growth and development of human beings.
OBJECTIVE: The main aim was to investigate zinc nutritional status by serum zinc concentration (SZC) and dietary zinc intake and their association in cystic fibrosis (CF) patients.
METHODS: A cross-sectional study was conducted in CF patients. Anthropometric measurements and respiratory and pancreatic tests were conducted. Hypozincemia was determined by SZC while using atomic absorption spectrophotometry and dietary zinc deficiency by prospective 72-h dietary surveys.
RESULTS: Mean SZC (87.2 ± 16.7 μg/dL) and dietary zinc intake (97 ± 26.9% Dietary Reference Intake) were normal. Three of 17 patients with CF (17.6%) had hypozincemia and four (23.5%) had a dietary zinc deficiency. No patient with dietary zinc deficiency had hypozincemia. A positive and significant association was observed between SZC and Z-score of BMI-for-age (p = 0.048) and weight-for-height (p = 0.012) and between dietary zinc intake and energy intake (EI, p = 0.036) and Z-score of weight-for-high (p = 0.029).
CONCLUSION: SZC was associated with the nutritional status, expressed as BMI (Body Mass Index) and weight-for-height Z score, and dietary zinc intake with EI and weight-for-height Z-score. No patient with hypozincemia had dietary zinc deficiency. This situation should alert us to a marginal zinc deficiency and it may explain why there were no overlapping cases between the two groups. We suggest that probably 41% of the cases in this study would be at elevated risk of zinc deficiency and a zinc supplementation may be considered.

PMID: 30642010 [PubMed - in process]

Lipid- and polymer-based plexes as therapeutic carriers for bioactive molecules.

Int J Pharm. 2019 Jan 11;:

Authors: Shende P, Ture N, Gaud RS, Trotta F

Abstract
Recently, promising strategies of plexes include the complexation of nucleic acids with lipids (lipoplexes) and different kinds of polymers (polyplexes) for delivery of actives and genetic material in abnormal conditions like cancer, cystic fibrosis and genetic disorders. The present review article focuses on the comparative aspects of lipoplexes and polyplexes associated with molecular structure, cellular transportation and formulation aspects. The major advantages of lipoplexes and polyplexes over conventional liposomes involve non-immunogenic viral gene transfer, facile manufacturing and preservation of genetic material encapsulated within the nanocarriers. Lipoplexes and polyplexes enhance the transfection of DNA into the cell by stepwise electrostatic cationic-anionic interaction with DNA backbones. The ease and cost-effective formation of complexes extend their applications in the treatment of cancer and genetic disorders. Lipoplexes and polyplexes necessitate intensive research in the fields of quality, toxicity and methods of preparation for commercialization.

PMID: 30641179 [PubMed - as supplied by publisher]

Correction: Within-host whole genome analysis of an antibiotic resistant Pseudomonas aeruginosa strain sub-type in cystic fibrosis.

PLoS One. 2019;14(1):e0210929

Authors: Sherrard LJ, Tai AS, Wee BA, Ramsay KA, Kidd TJ, Ben Zakour NL, Whiley DM, Beatson SA, Bell SC

Abstract
[This corrects the article DOI: 10.1371/journal.pone.0172179.].

PMID: 30640960 [PubMed - in process]

Decreased Fecal Calprotectin Levels in Cystic Fibrosis Patients After Antibiotic Treatment for Respiratory Exacerbation.

J Pediatr Gastroenterol Nutr. 2018 Oct 29;:

Authors: Schnapp Z, Hartman C, Livnat G, Shteinberg M, Elenberg Y

Abstract
OBJECTIVES: In all patients with cystic fibrosis (CF), gastrointestinal (GI) tract cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction occurs early in life. .The identical pathophysiological triad of obstruction, infection and inflammation causes disease of the airways and in the intestinal tract (CF enteropathy). Mucus accumulation within GI tract is a niche for abnormal microbial colonization, leading to dysbiosis. Fecal calprotectin (FC) is a neutrophil cytosolic protein released during apoptosis and necrosis and reflects inflammatory status. Systemic antibiotic treatment for pulmonary exacerbations has been shown to improve systemic inflammatory markers as well as serum and sputum calprotectin. Antibiotic treatment aimed at pulmonary complaints may improve GI tract inflammatory status. We hypothesized that high levels of fecal calprotectin present during pulmonary exacerbation are due, in part, to multi-organ dysbiosis and thus should diminish with systemic antibiotic treatment.
METHODS: This prospective pilot study enrolled 14 patients with CF, with no current GI symptoms. FC levels and lung function were measured at the beginning and end of systemic antibiotic treatment.
RESULTS: Compared to pre-antibiotic treatment baseline values, end of treatment FC levels declined significantly after antibiotic treatment, P = 0.004 and similarly, there was significant improvement in FEV1.0, P = 0.002.
CONCLUSIONS: High levels of FC during respiratory exacerbation may reflect a systemic exacerbation rather than solely pulmonary. Antibiotic treatment lowered the FC levels possibly by its impact on the intestinal microbiome.

PMID: 30640865 [PubMed - as supplied by publisher]