Codon-usage frequency mediated SNPs selection in lasR gene of cystic fibrosis Pseudomonas aeruginosa isolates.

Microbiol Res. 2019 Jun - Aug;223-225:137-143

Authors: Qiu H, Li Y, Dai W

Abstract
Pseudomonas aeruginosa is an opportunistic pathogen with high clinical relevance for hospital infections of patients. Accumulating DNA sequencing results of clinical P. aeruginosa isolates have revealed frequent mutations in lasR gene, which encodes the highest arches component of quorum-sensing system (QS). We analyzed the sequencing data of lasR gene from a large collection of cystic fibrosis (CF) P. aeruginosa isolates. Our systematical analyses revealed that single nucleotide polymorphisms (SNPs) selection in lasR gene were largely constrained by codon-usage frequency. As a whole, SNP-substituted codons encoding unconserved amino acid resulted in unfavored codons with relatively low codon-usage frequency, while those associating with conserved amino acid were not strictly regulated in such way. These SNPs substitutions gives rise to diverse functional LasR isoforms and contributes to the relative growth fitness of recombinant lasR variant strains. Our survey reveals a novel pattern of SNPs selections in lasR gene of CF isolates. Our findings could be served as a powerful resource for understanding adaptive mechanism of clinical isolates under environmental constrains and developing anti-bacteria drugs for CF patients.

PMID: 31178047 [PubMed - in process]

Iontophoresis burns: a peculiar cutaneous injury from a diagnostic sweat test for cystic fibrosis.

BMJ Case Rep. 2019 Jun 08;12(6):

Authors: Antrum JHG, Allison K

Abstract
An 8-month-old child presented after an emergency referral from a paediatric clinic. She had sustained a small burn injury to the left volar wrist during the sweat test for cystic fibrosis. The injury was managed conservatively. There is limited literature on burn injuries sustained during the sweat test, despite it being a known risk and the incidence is reported as very small. We wonder if such events are not being reported because the injury caused is usually minor and so may be more prevalent than previously considered.

PMID: 31177194 [PubMed - in process]

Focus on TRP channels in cystic fibrosis.

Cell Calcium. 2019 May 30;81:29-37

Authors: Grebert C, Becq F, Vandebrouck C

Abstract
The Transient Receptor Potential (TRP) protein superfamily is a group of cation channels expressed in various cell types and involved in respiratory diseases such as cystic fibrosis (CF), the genetic disease caused by CF Transmembrane conductance Regulator (CFTR) mutations. In human airway epithelial cells, there is growing evidence for a functional link between CFTR and TRP channels. TRP channels contribute to transmitting extracellular signals into the cells and, in an indirect manner, to CFTR activity via a Ca2+ rise signaling. Indeed, mutated CFTR-epithelial cells are characterized by an increased Ca2+ influx and, on the opposite, by a decreased of magnesium influx, both being mediated by TRP channels. This increasing cellular Ca2+ triggers the activation of calcium-activated chloride channels (CaCC) or CFTR itself, via adenylyl cyclase, PKA and tyrosine kinases activation, but also leads to an exaltation of the inflammatory response. Another shortcoming in mutated CFTR-epithelial cells is a [Mg2+]i decrease, associated with impaired TRPM7 functioning. This deregulation has to be taken into consideration in CF physiopathology, as Mg2+ is required for ATP hydrolysis and CFTR activity. The modulation of druggable TRP channels could supplement CF therapy either an anti-inflammatory drug or for CFTR potentiation, according to the balance between exacerbation and respite phases. The present paper focus on TRPA1, TRPC6, TRPM7, TRPV2, TRPV4, TRPV6 and ORAI 1, the proteins identified, for now, as dysfunctional channels, in CF cells.

PMID: 31176886 [PubMed - as supplied by publisher]

Abnormal pro-gly-pro pathway and airway neutrophilia in pediatric cystic fibrosis.

J Cyst Fibros. 2019 Jun 05;:

Authors: Turnbull AR, Pyle CJ, Patel DF, Jackson PL, Hilliard TN, Regamey N, Tan HL, Brown S, Thursfield R, Short C, Mc Fie M, Alton EWFW, Gaggar A, Blalock JE, Lloyd CM, Bush A, Davies JC, Snelgrove RJ

Abstract
BACKGROUND: Proline-glycine-proline (PGP) is a bioactive fragment of collagen generated by the action of matrix metalloproteinase-9 (MMP-9) and prolylendopeptidase (PE), and capable of eliciting neutrophil chemotaxis and epithelial remodelling. PGP is normally then degraded by leukotriene A4 hydrolase (LTA4H) to limit inflammation and remodelling. This study hypothesized that early and persistent airway neutrophilia in Cystic Fibrosis (CF) may relate to abnormalities in the PGP pathway and sought to understand underlying mechanisms.
METHODS: Broncho-alveolar lavage (BAL) fluid was obtained from 38 CF (9 newborns and 29 older children) and 24 non-CF children. BAL cell differentials and levels of PGP, MMP-9, PE and LTA4H were assessed.
RESULTS: Whilst PGP was present in all but one of the older CF children tested, it was absent in non-CF controls and the vast majority of CF newborns. BAL levels of MMP-9 and PE were elevated in older children with CF relative to CF newborns and non-CF controls, correlating with airway neutrophilia and supportive of PGP generation. Furthermore, despite extracellular LTA4H commonly being greatly elevated concomitantly with inflammation to promote PGP degradation, this was not the case in CF children, potentially owing to degradation by neutrophil elastase.
CONCLUSIONS: A striking imbalance between PGP-generating and -degrading enzymes enables PGP accumulation in CF children from early life and potentially supports airway neutrophilia.

PMID: 31176670 [PubMed - as supplied by publisher]

Non-fasting bioelectrical impedance analysis in cystic fibrosis: Implications for clinical practice and research.

J Cyst Fibros. 2019 Jun 05;:

Authors: Hollander-Kraaijeveld FM, Lindeman Y, de Roos NM, Burghard M, van de Graaf EA, Heijerman HGM

Abstract
BACKGROUND: Nutritional status affects pulmonary function in cystic fibrosis (CF) patients and can be monitored by using bioelectrical impedance analysis (BIA). BIA measurements are commonly performed in the fasting state, which is burdensome for patients. We investigated whether fasting is necessary for clinical practice and research.
METHODS: Fat free mass (FFM) and fat mass (FM) were determined in adult CF patients (n = 84) by whole body single frequency BIA (Bodystat 500) in a fasting and non-fasting state. Fasting and non-fasting BIA outcomes were compared with Bland-Altman plots. Pulmonary function was expressed as Forced Expiratory Volume at 1 s percentage predicted (FEV1%pred). Comparability of the associations between fasting and non-fasting body composition measurements with FEV1%pred was assessed by multiple linear regression.
RESULTS: Fasting FFM, its index (FFMI), and phase angle were significantly lower than non-fasting estimates (-0.23 kg, p = 0.006, -0.07 kg/m2, p = 0.002, -0.10°, p = 0.000, respectively). Fasting FM and its index (FMI) were significantly higher than non-fasting estimates (0.22 kg, p = 0.008) 0.32%, p = 0.005, and 0.07 kg/m2, (p = 0.005). Differences between fasting and non-fasting FFM and FM were <1 kg in 86% of the patients. FFMI percentile estimates remained similar in 83% of the patients when measured after nutritional intake. Fasting and non-fasting FFMI showed similar associations with FEV1%pred (β: 4.3%, 95% CL: 0.98, 7.70 and β: 4.6%, 95% CI: 1.22, 8.00, respectively).
CONCLUSION: Differences between fasting and non-fasting FFM and FM were not clinically relevant, and associations with pulmonary function remained similar. Therefore, BIA measurements can be performed in a non-fasting state.

PMID: 31176668 [PubMed - as supplied by publisher]

The gasotransmitter hydrogen sulfide inhibits transepithelial anion secretion of pregnant mouse endometrial epithelium.

Nitric Oxide. 2019 Jun 05;:

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

Abstract
Endometrial epithelium exhibits a robust ion transport activity required for dynamical regulation of uterine fluid environment and thus embryo implantation. However, there still lacks a thorough understanding of the ion transport processes and regulatory mechanism in peri-implantation endometrial epithelium. As a gaseous signaling molecule or gasotransmitter, hydrogen sulfide (H2S) regulates a myriad of cellular and physiological processes in various tissues, including the modulation of ion transport proteins in epithelium. This study aimed to investigate the effects of H2S on ion transport across mouse endometrial epithelium and its possible role in embryo implantation. The existence of endogenous H2S in pregnant mouse uterus was tested by the detection of two key H2S-generating enzymes and measurement of H2S production rate in tissue homogenates. Transepithelial ion transport processes were electrophysiologically assessed in Ussing chambers on early pregnant mouse endometrial epithelial layers, demonstrating that H2S suppressed the anion secretion by blocking cystic fibrosis transmembrane conductance regulator (CFTR). H2S increased intracellular Cl- concentration ([Cl-]i) in mouse endometrial epithelial cells, which was abolished by pretreatment with the CFTR selective inhibitor CFTRinh-172. The cAMP level in mouse endometrial epithelial cells was not affected by H2S, indicating that H2S blocked CFTR in a cAMP-independent way. In vivo study showed that interference with H2S synthesis impaired embryo implantation. In conclusion, our study demonstrated that H2S inhibits the transepithelial anion secretion of early pregnant mouse endometrial epithelium via blockade of CFTR, contributing to the preparation for embryo implantation.

PMID: 31175932 [PubMed - as supplied by publisher]

Fatigue in childhood chronic disease.

Arch Dis Child. 2019 Jun 07;:

Authors: Nap-van der Vlist MM, Dalmeijer GW, Grootenhuis MA, van der Ent CK, van den Heuvel-Eibrink MM, Wulffraat NM, Swart JF, van Litsenburg RRL, van de Putte EM, Nijhof SL

Abstract
BACKGROUND AND OBJECTIVES: Recently, in adults, the incidence and severity of fatigue was found to exist rather independently from the somatic diagnosis. Since fatigue is distressing when growing up with a chronic disease, we aim to investigate: (1) the prevalence and extent of fatigue among various paediatric chronic diseases and (2) the effect of fatigue on health-related quality of life (HRQoL).
DESIGN AND SETTING: Cross-sectional study in two children's hospitals.
PATIENTS: Children and adolescents 2-18 years of age with cystic fibrosis, an autoimmune disease or postcancer treatment visiting the outpatient clinic.
OUTCOME MEASURES: Fatigue and HRQoL were assessed using the Pediatric Quality of Life Inventory (PedsQL) multidimensional fatigue scale (with lower scores indicating more fatigue) and PedsQL generic core scales, respectively. Linear regression analysis and analysis of covariance were used to compare fatigue scores across disease groups and against two control groups. The effect of fatigue on HRQoL was calculated. Data were adjusted for age, sex and reporting method.
RESULTS: 481 children and adolescents were assessed (60% participation rate, mean age 10.7±4.9, 42% men). Children and adolescents with chronic disease reported more fatigue than the general population (mean difference -6.6, 95% CI -8.9 to -4.3 (range 0-100)), with a prevalence of severe fatigue of 21.2%. Fatigue scores did not differ significantly between disease groups on any fatigue domain. Fatigue was associated with lower HRQoL on all domains.
CONCLUSIONS: Fatigue in childhood chronic disease is a common symptom that presents across disease, age and sex groups. Fatigue affects HRQoL. Our findings underscore the need to systematically assess fatigue. Future studies should determine possible biological and psychosocial treatment targets.

PMID: 31175124 [PubMed - as supplied by publisher]

Highlights from the nutrition guidelines for cystic fibrosis in Australia and New Zealand.

J Cyst Fibros. 2019 Jun 04;:

Authors: van der Haak N, King SJ, Crowder T, Kench A, Painter C, Saxby N, Nutrition Guidelines for Cystic Fibrosis in Australia and New Zealand Authorship Group and Interdisciplinary Steering Committee

Abstract
Optimal nutrition care is important in the management of cystic fibrosis (CF). This paper summarises the '2017 Nutrition Guidelines for Cystic Fibrosis in Australia and New Zealand (NZ)'. CF dietitians formulated 68 practice questions which were used to guide a systematic literature search and review of the evidence for nutrition in CF. Identified papers underwent quality and evidence assessment using the American Dietetic Association quality criteria checklist and the National Health and Medical Research Council of Australia (NHMRC) rankings. Evidence statements, graded recommendations and practice points were developed covering core nutrition topics (assessment and nutrition interventions including oral, enteral and micronutrient supplementation); nutrition-related co-morbidities (including pancreatic insufficiency, CF-related diabetes, bone health and distal intestinal obstruction syndrome); and key new topic areas (genetic modulator therapies, overweight/obesity and complementary therapies). This paper showcases highlights from the guidelines, focussing on new topic areas and geographic and climate considerations for vitamin D, salt and hydration.

PMID: 31175004 [PubMed - as supplied by publisher]

Pharmacological analysis of CFTR variants of cystic fibrosis using stem cell-derived organoids.

Drug Discov Today. 2019 Jun 04;:

Authors: Chen KG, Zhong P, Zheng W, Beekman JM

Abstract
Cystic fibrosis (CF) is a life-shortening genetic disease caused by mutations of CFTR, the gene encoding cystic fibrosis transmembrane conductance regulator. Despite considerable progress in CF therapies, targeting specific CFTR genotypes based on small molecules has been hindered because of the substantial genetic heterogeneity of CFTR mutations in patients with CF, which is difficult to assess by animal models in vivo. There are broadly four classes (e.g., II, III, and IV) of CF genotypes that differentially respond to current CF drugs (e.g., VX-770 and VX-809). In this review, we shed light on the pharmacogenomics of diverse CFTR mutations and the emerging role of stem cell-based organoids in predicting the CF drug response. We discuss mechanisms that underlie differential CF drug responses both in organoid-based assays and in CF clinical trials, thereby facilitating the precision design of safer and more effective therapies for individual patients with CF.

PMID: 31173911 [PubMed - as supplied by publisher]

Ten years of chest MRI for patients with cystic fibrosis : Translation from the bench to clinical routine.

Radiologe. 2019 Jun 06;:

Authors: Leutz-Schmidt P, Eichinger M, Stahl M, Sommerburg O, Biederer J, Kauczor HU, Puderbach MU, Mall MA, Wielpütz MO

Abstract
BACKGROUND: Despite recent advances in our knowledge about the pathophysiology and treatment of cystic fibrosis (CF), pulmonary involvement remains the most important determinant of morbidity and mortality in patients with CF. Since lung function testing may not be sensitive enough for subclinical disease progression, and because young children may have normal spirometry results over a longer period of time, imaging today plays an increasingly important role in clinical routine and research for the monitoring of CF lung disease. In this regard, chest magnetic resonance imaging (MRI) could serve as a radiation-free modality for structural and functional lung imaging.
METHODS: Our research agenda encompassed the entire process of development, implementation, and validation of appropriate chest MRI protocols for use with infant and adult CF patients alike.
RESULTS: After establishing a general MRI protocol for state-of-the-art clinical 1.5-T scanners based on the available sequence technology, a semiquantitative scoring system was developed followed by cross-validation of the method against the established modalities of computed tomography, radiography, and lung function testing. Cross-sectional studies were then set up to determine the sensitivity of the method for the interindividual variation of the disease and for changes in disease severity after treatment. Finally, the MRI protocol was implemented at multiple sites to be validated in a multicenter setting.
CONCLUSION: After more than a decade, lung MRI has become a valuable tool for monitoring CF in clinical routine application and as an endpoint for clinical studies.

PMID: 31172247 [PubMed - as supplied by publisher]

Contribution of pancreatic enzyme replacement therapy to survival and quality of life in patients with pancreatic exocrine insufficiency.

World J Gastroenterol. 2019 May 28;25(20):2430-2441

Authors: Layer P, Kashirskaya N, Gubergrits N

Abstract
The objective of this study was to analyze the current evidence for the use of pancreatic enzyme replacement therapy (PERT) in affecting survival and quality of life in patients with pancreatic exocrine insufficiency (PEI). Systematic searches of the literature were performed using the PubMed database. Articles were selected for inclusion if they reported findings from trials assessing the effects of PERT on quality of life, survival, malabsorption, growth parameters (such as height, body weight and body mass index), or gastrointestinal symptoms (such as abdominal pain, stool consistency and flatulence). PERT improved PEI-related malabsorption and weight maintenance in patients with cystic fibrosis, chronic pancreatitis, pancreatic cancer, and post-surgical states. In patients with chronic pancreatitis, PERT improved PEI-related symptoms and quality of life measures. Several small retrospective studies have also suggested that PERT may have a positive impact on survival, but long-term studies assessing this effect were not identified. PERT is effective for treating malnutrition and supporting weight maintenance, and it is associated with improved quality of life and possibly with enhanced survival in patients with PEI. However, there is evidence that not all patients with PEI receive adequate PERT. Future work should aim to assess the long-term effects of PERT on the survival of patients with PEI.

PMID: 31171887 [PubMed - in process]

Cellular advective-diffusion drives the emergence of bacterial surface colonization patterns and heterogeneity.

Nat Commun. 2019 Jun 06;10(1):2471

Authors: Rossy T, Nadell CD, Persat A

Abstract
Microorganisms navigate and divide on surfaces to form multicellular structures called biofilms, the most widespread survival strategy found in the bacterial world. One common assumption is that cellular components guide the spatial architecture and arrangement of multiple species in a biofilm. However, bacteria must contend with mechanical forces generated through contact with surfaces and under fluid flow, whose contributions to colonization patterns are poorly understood. Here, we show how the balance between motility and flow promotes the emergence of morphological patterns in Caulobacter crescentus biofilms. By modeling transport of single cells by flow and Brownian-like swimming, we show that the emergence of these patterns is guided by an effective Péclet number. By analogy with transport phenomena we show that, counter-intuitively, fluid flow represses mixing of distinct clonal lineages, thereby affecting the interaction landscapes between biofilm-dwelling bacteria. This demonstrates that hydrodynamics influence species interaction and evolution within surface-associated communities.

PMID: 31171786 [PubMed - in process]

Draft Genome Sequence of Haemophilus haemolyticus Strain 16/010 O, Isolated from a Sputum Sample from a Cystic Fibrosis Patient.

Microbiol Resour Announc. 2019 Jun 06;8(23):

Authors: Fluit AC, Bayjanov JR, Tunney M, Elborn JS, Rogers MRC, Schürch AC, Ekkelenkamp MB

Abstract
Haemophilus haemolyticus is considered a commensal of the respiratory tract that can cause opportunistic infections. It is closely related to Haemophilus influenzae Here, we report the genome sequence of H. haemolyticus 16/010 O, which was isolated from sputum from a cystic fibrosis patient.

PMID: 31171614 [PubMed]

Rapid detection of the bacterial biomarker pyocyanin in artificial sputum using a SERS-active silicon nanowire matrix covered by bimetallic noble metal nanoparticles.

Talanta. 2019 Sep 01;202:171-177

Authors: Žukovskaja O, Agafilushkina S, Sivakov V, Weber K, Cialla-May D, Osminkina L, Popp J

Abstract
Early stage detection of Pseudomonas infections is life-saving, especially in the case of patients with cystic fibrosis. Pyocyanin (PYO) is a specific metabolite of the Pseudomonas aeruginosa bacteria, and detection of it directly in the sputum can significantly reduce the diagnosis time of the infection. In the present study, aiming to achieve this goal, a simple and cost-effective surface-enhanced Raman spectroscopy (SERS) detection platform was proposed. For this, a silicon nanowire (SiNW) matrix, produced by metal-assisted chemical etching of silicon substrates was variously modified by noble metal (silver and gold) nanoparticles (NPs) and tested for the detection of the metabolite PYO in the complex matrix of artificial sputum. We found the SERS substrate with Ag NPs on the bottom of SiNWs and deposited bimetallic Ag/Au NPs on the top of them the best suited for the sensitive detection of PYO. The investigated plasmonic substrate showed good point-to-point and batch-to-batch signal reproducibility and allowed for the detection of PYO in artificial sputum down to 6.25 μM, which is the required sensitivity for clinical applications.

PMID: 31171166 [PubMed - in process]

Cystic fibrosis revisited.

J Postgrad Med. 2019 Jun 06;:

Authors: Kulkarni H, Kansra S, Karande S

PMID: 31169132 [PubMed - as supplied by publisher]

Cystic Fibrosis: Proteostatic correctors of CFTR trafficking and alternative therapeutic targets.

Expert Opin Ther Targets. 2019 Jun 06;:

Authors: Hanrahan JW, Sato Y, Carlile GW, Jansen G, Young JC, Thomas DY

Abstract
Introduction: Cystic fibrosis (CF) is the most frequent lethal orphan disease and is caused by mutations in the CFTR gene. The most frequent mutation F508del-CFTR affects multiple organs; infections and subsequent infections and complications in the lung lead to death. Areas covered: This review focuses on new targets and mechanisms that are attracting interest for the development of CF therapies. The F508del-CFTR protein is retained in the endoplasmic reticulum (ER) but has some function if it can traffic to the plasma membrane. Cell-based assays have been used to screen chemical libraries for small molecule correctors that restore its trafficking. Pharmacological chaperones are correctors that bind directly to the F508del-CFTR mutant and promote its folding and trafficking. Other correctors fall into a heterogeneous class of proteostasis modulators that act indirectly by altering cellular homeostasis. Expert opinion: Pharmacological chaperones have so far been the most successful correctors of F508del-CFTR trafficking, but their level of correction means that more than one corrector is required. Proteostasis modulators have low levels of correction but hold promise because some can correct several different CFTR mutations. Identification of their cellular targets and the potential for development may lead to new therapies for CF.

PMID: 31169041 [PubMed - as supplied by publisher]

Lymphocyte-driven regional immunopathology in pneumonitis caused by impaired central immune tolerance.

Sci Transl Med. 2019 Jun 05;11(495):

Authors: Ferré EMN, Break TJ, Burbelo PD, Allgäuer M, Kleiner DE, Jin D, Xu Z, Folio LR, Mollura DJ, Swamydas M, Gu W, Hunsberger S, Lee CR, Bondici A, Hoffman KW, Lim JK, Dobbs K, Niemela JE, Fleisher TA, Hsu AP, Snow LN, Darnell DN, Ojaimi S, Cooper MA, Bozzola M, Kleiner GI, Martinez JC, Deterding RR, Kuhns DB, Heller T, Winer KK, Rajan A, Holland SM, Notarangelo LD, Fennelly KP, Olivier KN, Lionakis MS

Abstract
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic disorder caused by AIRE mutations, presents with several autoimmune diseases. Among these, endocrine organ failure is widely recognized, but the prevalence, immunopathogenesis, and treatment of non-endocrine manifestations such as pneumonitis remain poorly characterized. We enrolled 50 patients with APECED in a prospective observational study and comprehensively examined their clinical and radiographic findings, performed pulmonary function tests, and analyzed immunological characteristics in blood, bronchoalveolar lavage fluid, and endobronchial and lung biopsies. Pneumonitis was found in >40% of our patients, presented early in life, was misdiagnosed despite chronic respiratory symptoms and accompanying radiographic and pulmonary function abnormalities, and caused hypoxemic respiratory failure and death. Autoantibodies against BPIFB1 and KCNRG and the homozygous c.967_979del13 AIRE mutation are associated with pneumonitis development. APECED pneumonitis features compartmentalized immunopathology, with accumulation of activated neutrophils in the airways and lymphocytic infiltration in intraepithelial, submucosal, peribronchiolar, and interstitial areas. Beyond APECED, we extend these observations to lung disease seen in other conditions with secondary AIRE deficiency (thymoma and RAG deficiency). Aire-deficient mice had similar compartmentalized cellular immune responses in the airways and lung tissue, which was ameliorated by deficiency of T and B lymphocytes. Accordingly, T and B lymphocyte-directed immunomodulation controlled symptoms and radiographic abnormalities and improved pulmonary function in patients with APECED pneumonitis. Collectively, our findings unveil lung autoimmunity as a common, early, and unrecognized manifestation of APECED and provide insights into the immunopathogenesis and treatment of pulmonary autoimmunity associated with impaired central immune tolerance.

PMID: 31167928 [PubMed - in process]

Ambient air pollution and pulmonary vascular volume on computed tomography: the MESA Air Pollution and Lung cohort studies.

Eur Respir J. 2019 Jun;53(6):

Authors: Aaron CP, Hoffman EA, Kawut SM, Austin JHM, Budoff M, Michos ED, Hinckley Stukovsky K, Sack C, Szpiro AA, Watson KD, Kaufman JD, Barr RG

Abstract
BACKGROUND: Air pollution alters small pulmonary vessels in animal models. We hypothesised that long-term ambient air pollution exposure would be associated with differences in pulmonary vascular volumes in a population-based study.
METHODS: The Multi-Ethnic Study of Atherosclerosis recruited adults in six US cities. Personalised long-term exposures to ambient black carbon, nitrogen dioxide (NO2), oxides of nitrogen (NO x ), particulate matter with a 50% cut-off aerodynamic diameter of <2.5 μm (PM2.5) and ozone were estimated using spatiotemporal models. In 2010-2012, total pulmonary vascular volume was measured as the volume of detectable pulmonary arteries and veins, including vessel walls and luminal blood volume, on noncontrast chest computed tomography (TPVVCT). Peripheral TPVVCT was limited to the peripheral 2 cm to isolate smaller vessels. Linear regression adjusted for demographics, anthropometrics, smoking, second-hand smoke, renal function and scanner manufacturer.
RESULTS: The mean±sd age of the 3023 participants was 69.3±9.3 years; 46% were never-smokers. Mean exposures were 0.80 μg·m-3 black carbon, 14.6 ppb NO2 and 11.0 μg·m-3 ambient PM2.5. Mean±sd peripheral TPVVCT was 79.2±18.2 cm3 and TPVVCT was 129.3±35.1 cm3. Greater black carbon exposure was associated with a larger peripheral TPVVCT, including after adjustment for city (mean difference 0.41 (95% CI 0.03-0.79) cm3 per interquartile range; p=0.036). Associations for peripheral TPVVCT with NO2 were similar but nonsignificant after city adjustment, while those for PM2.5 were of similar magnitude but nonsignificant after full adjustment. There were no associations for NO x or ozone, or between any pollutant and TPVVCT.
CONCLUSIONS: Long-term black carbon exposure was associated with a larger peripheral TPVVCT, suggesting diesel exhaust may contribute to remodelling of small pulmonary vessels in the general population.

PMID: 31167881 [PubMed - in process]

"Switching partners": Piperacillin-avibactam is a highly potent combination against multidrug-resistant Burkholderia cepacia Complex and Burkholderia gladioli Cystic Fibrosis isolates.

J Clin Microbiol. 2019 Jun 05;:

Authors: Zeiser ET, Becka SA, Wilson BM, Barnes MD, LiPuma JJ, Papp-Wallace KM

Abstract
Background: In persons with cystic fibrosis (CF), airway infection with Burkholderia cepacia complex (Bcc) species or Burkholderia gladioli presents a significant challenge due to inherent resistance to multiple antibiotics. Two chromosomally-encoded inducible β-lactamases, a Pen-like class A and AmpC are produced in Bcc and B gladioli Previously, ceftazidime-avibactam demonstrated significant potency against Bcc and B gladioli isolated from the sputum of individuals with CF; however, 10% of the isolates tested resistant to ceftazidime-avibactam. Herein, we describe an alternative antibiotic combination to overcome ceftazidime-avibactam resistance.Methods: Antimicrobial susceptibility testing was performed on Bcc and B gladioli clinical and control isolates. Biochemical analysis was conducted on purified PenA1 and AmpC1 β-lactamases from Burkholderia multivorans ATCC 17616. Analytic isoelectric focusing and immunoblotting were conducted on cellular extracts of B. multivorans induced by various β-lactams or β-lactam-β-lactamase inhibitor combinations.Results: The combinations of piperacillin-avibactam as well as piperacillin-tazobactam plus ceftazidime-avibactam (the clinically available counterpart) were tested against a panel of ceftazidime-avibactam non-susceptible Bcc and B gladioli The piperacillin-avibactam and piperacillin-tazobactam-ceftazidime-avibactam combinations restored susceptibly to 99% of the isolates tested. Avibactam is a potent inhibitor of PenA1 (K i app = 0.5 μM), while piperacillin was found to inhibit AmpC1 (K i app = 2.6 μM). Moreover, piperacillin, tazobactam, ceftazidime, and avibactam as well as combinations thereof did not induce expression of bla penA1 and bla ampC1 in the B multivorans ATCC 17616 background.Conclusions: When ceftazidime-avibactam is combined with piperacillin-tazobactam, the susceptibility of Bcc and B gladioli to ceftazidime and piperacillin is restored in vitro Lack of bla penA1 induction as well as potent inactivation of PenA1 by avibactam likely provide the major contributions towards susceptibility. With in vivo validation, piperacillin-tazobactam-ceftazidime-avibactam may represent salvage therapy for individuals with CF and highly drug-resistant Bcc and B gladioli infections.

PMID: 31167848 [PubMed - as supplied by publisher]

Microbiological contamination of nebulizers used by cystic fibrosis patients: an underestimated problem.

J Bras Pneumol. 2019 May 30;45(3):e20170351

Authors: Riquena B, Monte LFV, Lopes AJ, Silva-Filho LVRFD, Damaceno N, Aquino EDS, Marostica PJC, Ribeiro JD

Abstract
OBJECTIVE: Home nebulizers are routinely used in the treatment of patients with cystic fibrosis (CF). This study aims to evaluate the contamination of nebulizers used for CF patients, that are chronically colonized by Pseudomonas aeruginosa, and the association of nebulizer contamination with cleaning, decontamination and drying practices.
METHODS: A cross-sectional, observational, multicenter study was conducted in seven CF reference centers in Brazil to obtain data from medical records, structured interviews with patients/caregivers were performed, and nebulizer's parts (interface and cup) were collected for microbiological culture.
RESULTS: overall, 77 CF patients were included. The frequency of nebulizer contamination was 71.6%. Candida spp. (52.9%), Stenotrophomonas maltophilia (11.9%), non-mucoid P. aeruginosa (4.8%), Staphylococcus aureus (4.8%) and Burkholderia cepacia complex (2.4%) were the most common isolated pathogens. The frequency of nebulizers' hygiene was 97.4%, and 70.3% of patients reported cleaning, disinfection and drying the nebulizers. The use of tap water in cleaning method and outdoor drying of the parts significantly increased (9.10 times) the chance of nebulizers' contamination.
CONCLUSION: Despite the high frequency hygiene of the nebulizers reported, the cleaning and disinfection methods used were often inadequate. A significant proportion of nebulizers was contaminated with potentially pathogenic microorganisms for CF patients. These findings support the need to include patients/caregivers in educational programs and / or new strategies for delivering inhaled antibiotics.

PMID: 31166553 [PubMed - in process]