Cytological appearance of pancreatic cystosis on fine-needle aspiration.

Diagn Cytopathol. 2019 Sep 10;:

Authors: Aly FZ, Mostofizadeh S, Jawaid S

Abstract
A 22-year-old Caucasian male with cystic fibrosis and recently diagnosed insulin-dependent diabetes mellitus underwent magnetic resonance imaging (MRI) and was found to have multiple cystic lesions in the pancreas. Endoscopic ultrasound evaluation revealed multiple macro- and microcystic components without mural nodules. One of the cysts in the body of the pancreas was in clear direct communication with the nondilated main pancreatic duct. Fine-needle aspiration (FNA) of two cysts was performed and showed foamy macrophages and rare ductal as well as acinar cells. Cell blocks showed nonpolarizable pink crystalloid material and small nonlaminated concretions consistent with inspissated secretions. Special stains for chymotrypsin and trypsin highlighted the acinar cells. Periodic acid Schiff, with and without diastase, was negative. Biopsy of the cyst wall showed ductal epithelial cells with underlying fibrotic stroma. This is the first description of the FNA appearance of pancreatic cystosis. We discuss the cytological differential diagnosis of cystic lesions of the pancreas and the biochemical as well as imaging findings used to arrive at the diagnosis.

PMID: 31503419 [PubMed - as supplied by publisher]

Metabolite profiling of the cold adaptation of Pseudomonas putida KT2440 and cold-sensitive mutants.

Environ Microbiol Rep. 2019 Sep 10;:

Authors: Dethlefsen S, Jäger C, Klockgether J, Schomburg D, Tümmler B

Abstract
Free-living bacteria such as Pseudomonas putida are frequently exposed to temperature shifts and non-optimal growth conditions. We compared the transcriptome and metabolome of the cold adaptation of Pseudomonas putida KT2440 and isogenic cold-sensitive transposon mutants carrying transposons in their cbrA, cbrB, pcnB, vacB and bipA genes. P. putida changes the mRNA expression of about 43% of all annotated ORFs during this initial phase of cold adaptation, but only a small number of six to 93 genes were differentially expressed at 10°C between wild type strain and the individual mutants. The spectrum of metabolites underwent major changes during cold adaptation particularly in the mutants. Both KT2440 strain and the mutants increased the levels of the most abundant sugars and amino acids which were more pronounced in the cold-sensitive mutants. All mutants depleted their pools for core metabolites of aromatic and sugar metabolism, but increased their pool of polar amino acids which should be advantageous to cope with the cold stress. This article is protected by copyright. All rights reserved.

PMID: 31503400 [PubMed - as supplied by publisher]

Prevention of drug-related complications in cystic fibrosis.

Curr Opin Pulm Med. 2019 Sep 09;:

Authors: van der Meer R, Touw DJ, Heijerman HGM

Abstract
PURPOSE OF REVIEW: Due to continuous development of new drugs and better treatment strategies, survival of patients with cystic fibrosis has changed dramatically. Recently, targeted therapy of cystic fibrosis transmembrane conductance regulator (CFTR) modulators have become available. Despite these promising developments, treatment of this complex multiorgan disease constitutes a high and variable amount of other drugs. Complications of pharmacotherapeutic treatment are, therefore, expected to become more prevalent. This gives cause to review drug-related side effects in this new era in cystic fibrosis treatment.
RECENT FINDINGS: We will discuss cystic fibrosis-related pharmacotherapies with a focus on indication of treatment, side effects and their complications, drug--drug interactions, and options to monitor and prevent drug-induced toxicity. Many recent publications about pharmacotherapy in cystic fibrosis, focus on antifungal therapy and CFTR modulators. We will give an overview of the most important studies.
SUMMARY: With increased life expectancy which is, in part, because of better treatment options, the burden of pharmacotherapy in cystic fibrosis patients will increase. This has a high impact on quality of life as pharmacotherapy is time consuming and may cause side effects. Therefore, it is very important to be aware of possible pharmacotherapy-related side effects and their complications, drug--drug interactions, and options to monitor and prevent drug-induced toxicity.

PMID: 31503211 [PubMed - as supplied by publisher]

Survey of current treatment practices for venous thromboembolism in patients with cystic fibrosis.

Pediatr Pulmonol. 2019 Sep 10;:

Authors: Ratté MT, Jones AE, Witt DM, Young DC

Abstract
BACKGROUND: Patients with cystic fibrosis (CF) and venous thromboembolism (VTE) pose therapeutic challenges including potential drug interactions between CF-related therapies and anticoagulants. Despite these challenges, there are no recommendations for VTE management specific to patients with CF. Our objective was to describe VTE treatment practices among Cystic Fibrosis Foundation (CFF)-accredited care centers and affiliate programs in the United States.
METHODS: An online survey was distributed to CF center directors. The survey included questions regarding centers' demographics and posed a series of hypothetical clinical scenarios to gather centers' VTE treatment practices including choice of anticoagulant, dosing practices, duration decisions, and monitoring efforts. Descriptive statistics were utilized to summarize the survey results.
RESULTS: The survey response rate was 56.3%. Most centers reported treating zero to five VTE episodes per year. The following anticoagulants were used most often for VTE treatment: low-molecular-weight heparin (LMWH) (73.2%), apixaban (36.6%), warfarin (35.2%), rivaroxaban (33.8%), and unfractionated heparin (18.3%). On a scale of 0 to 100, the median confidence level in managing anticoagulant therapy was 50. Many centers expressed a desire for a CF-specific VTE treatment guideline. The most commonly cited challenging clinical situations were managing anticoagulant therapy complications (26.5%) and drug-drug interactions (21.3%). For common VTE scenarios, pediatric patients were most often treated with LMWH and warfarin, whereas adult patients were more often treated with apixaban or rivaroxaban.
CONCLUSIONS: Survey results indicated CF care centers find managing VTE in patients with CF challenging and indicated that a CF-specific VTE treatment guideline would be helpful.

PMID: 31502767 [PubMed - as supplied by publisher]

Corrigendum: Normal Calcium-Activated Anion Secretion in a Mouse Selectively Lacking TMEM16A in Intestinal Epithelium.

Front Physiol. 2019;10:1040

Authors: Vega G, Guequén A, Johansson MEV, Arike L, Martínez-Abad B, Nyström EEL, Scudieri P, Pedemonte N, Millar-Büchner P, Philp AR, Galietta LJ, Hansson GC, Flores CA

Abstract
[This corrects the article DOI: 10.3389/fphys.2019.00694.].

PMID: 31501653 [PubMed - in process]

G3BP1 inhibits ubiquitinated protein aggregations induced by p62 and USP10.

Sci Rep. 2019 Sep 09;9(1):12896

Authors: Anisimov S, Takahashi M, Kakihana T, Katsuragi Y, Kitaura H, Zhang L, Kakita A, Fujii M

Abstract
The aberrant accumulation of ubiquitinated protein aggregates in cells plays a critical role in the pathogenesis of several degenerative diseases, including Parkinson disease (PD) and cystic fibrosis (CF). In this study, we found that Ras GTPase-activating protein-binding protein 1 (G3BP1) inhibits ubiquitinated protein aggregations induced by p62 and USP10 in cultured cells. p62 is a ubiquitin receptor, and p62 and its binding partner USP10 have been shown to augment ubiquitinated protein aggregation. G3BP1 interacted with p62 and USP10 and inhibited p62/USP10-induced protein aggregation. The G3BP1 inhibition of protein aggregations targeted two aggregation-prone proteins, α-synuclein and CFTR-ΔF508, which are causative factors of PD and CF, respectively. G3BP1 depletion increased the amounts of ubiquitinated α-synuclein and CFTR-ΔF508 protein. A proteasome reporter indicated that G3BP1 depletion inhibits the proteasome activity. We herein present evidence that G3BP1, p62 and USP10 together control ubiquitinated protein toxicity by controlling both ubiquitination and aggregation. Taken together, these results suggest that G3BP1, p62 and USP10 could be therapeutic targets for ubiquitinated protein aggregation disorders, including PD and CF.

PMID: 31501480 [PubMed - in process]

Conceptual Model of Biofilm Antibiotic Tolerance that Integrates Phenomena of Diffusion, Metabolism, Gene Expression, and Physiology.

J Bacteriol. 2019 Sep 09;:

Authors: Stewart PS, White B, Boegli L, Hamerly T, Williamson KS, Franklin MJ, Bothner B, James GA, Fisher S, Vital-Lopez FG, Wallqvist A

Abstract
Transcriptomic, metabolomic, physiological, and computational modeling approaches were integrated to gain insight into the mechanisms of antibiotic tolerance in an in vitro biofilm system. Pseudomonas aeruginosa biofilms were grown in drip-flow reactors on a medium composed to mimic the exudate from a chronic wound. After four days, the biofilm was 114 μm thick with 9.45 log10 cfu cm-2 These biofilms exhibited tolerance, relative to exponential-phase planktonic cells, to subsequent treatment with ciprofloxacin. The biofilm specific growth rate was estimated via elemental balances to be approximately 0.37 h-1 and with a reaction-diffusion model to be 0.32 h-1 or one-third of the planktonic maximum specific growth rate. Global analysis of gene expression indicated decreased transcription of ribosomal genes and other anabolic functions in biofilms compared to exponential-phase planktonic cells and revealed the induction of multiple stress responses in biofilm cells including those associated with growth arrest, zinc limitation, hypoxia, and acyl-homoserine lactone quorum sensing. Metabolic pathways for phenazine biosynthesis and denitrification were transcriptionally activated in biofilms. A customized reaction-diffusion model predicted that steep oxygen concentration gradients form when these biofilms are thicker than about 40 μm. Mutant strains that were deficient in Psl polysaccharide synthesis, stringent response, stationary phase response, and membrane stress response exhibited increased ciprofloxacin susceptibility when cultured in biofilms. These results support a sequence of phenomena leading to biofilm antibiotic tolerance involving oxygen limitation, electron acceptor starvation and growth arrest, induction of associated stress responses, and differentiation into protected cell states.IMPORTANCE Bacteria in biofilms are protected from killing by antibiotics and this reduced susceptibility contributes to the persistence of infections such as those in the cystic fibrosis lung and chronic wounds. A generalized conceptual model of biofilm antimicrobial tolerance with these mechanistic steps is proposed: 1) establishment of concentration gradients in metabolic substrates and products; 2) active biological responses to these changes in the local chemical microenvironment; 3) entry of biofilm cells into a spectrum of states involving alternative metabolisms, stress responses, slow growth, cessation of growth, or dormancy (all prior to antibiotic treatment); 4) adaptive responses to antibiotic exposure; and 5) reduced susceptibility of microbial cells to antimicrobial challenges in some of the physiological states accessed through these changes.

PMID: 31501280 [PubMed - as supplied by publisher]

Single dose escalation studies with inhaled POL6014, a potent novel selective reversible inhibitor of human neutrophil elastase, in healthy volunteers and subjects with cystic fibrosis.

J Cyst Fibros. 2019 Sep 06;:

Authors: Barth P, Bruijnzeel P, Wach A, Sellier Kessler O, Hooftman L, Zimmermann J, Naue N, Huber B, Heimbeck I, Kappeler D, Timmer W, Chevalier E

Abstract
BACKGROUND: POL6014 is a novel, orally inhaled neutrophil elastase (NE) inhibitor in development for cystic fibrosis (CF).
METHODS: Two studies, one in healthy volunteers (HVs, doses 20 to 960 mg) and one in subjects with CF (doses 80 to 320 mg) were conducted to evaluate the safety, tolerability and pharmacokinetics (PK) of single ascending doses of inhaled POL6014 with a Pari eFlow® nebuliser. PK was evaluated over a period of 24 h. In addition, NE activity in CF sputum was measured.
RESULTS: After single doses, POL6014 was safe and well tolerated up to 480 mg in HVs and at all doses in subjects with CF. POL6014 showed a dose-linear PK profile in both populations with Cmax between 0.2 and 2.5 μM in HVs and between 0.2 and 0.5 μM in subjects with CF. Tmax was reached at approximately 2-3 h. Mean POL6014 levels in CF sputum rapidly reached 1000 μM and were still above 10 μM at 24 h. >1-log reduction of active NE was observed at 3 h after dosing.
CONCLUSION: Inhalation of POL6014 can safely lead to high concentrations within the lung and simultaneously low plasma concentrations, allowing for a clear inhibition of NE in the sputum of subjects with CF after single dosing.
TRIAL REGISTRATION: European Medicines Agency EudraCT-Nr. 2015-001618-83 and 2016-000493-38.

PMID: 31501052 [PubMed - as supplied by publisher]

Human cystic fibrosis monocyte derived macrophages display no defect in acidification of phagolysosomes when measured by optical nanosensors.

J Cyst Fibros. 2019 Sep 06;:

Authors: Law SM, Stanfield SJ, Hardisty GR, Dransfield I, Campbell CJ, Gray RD

Abstract
BACKGROUND: Defective macrophage phagolysosomal acidification is implicated in numerous lung diseases including Cystic Fibrosis (CF) and may contribute to defective pathogen killing. Conflicting reports relating to phagolysosomal pH in CF macrophages have been published, in part related to the use of pH-sensitive fluorescent probes where potential inadequacies in experimental design can be a contributing factor (e.g. employing probes with incorrect pKa for the cellular compartment of interest). We developed a reliable method to quantify macrophage phagolysosomal pH using surface-enhanced Raman spectroscopy-based nanosensors.
METHODS: Monocyte-derived macrophages from CF and healthy control participants were incubated with nanosensors. Live cell imaging identified phagocytosed nanosensors, and surface-enhanced Raman spectroscopy was performed using para-mercaptobenzoic acid functionalised gold nanoparticles which produce Raman spectra that change predictably with their environmental pH. Conventional fluorescence spectroscopy was carried out in comparison. Nanosensor localisation to phagolysosomes was confirmed by transmission electron microscopy.
RESULTS: Nanosensors were actively phagocytosed by macrophages into phagolysosomes and acidification occurred rapidly and remained stable for at least 60 min. There was no difference in phagolysosomal pH between healthy control and CF macrophages (5.41 ± 0.11 vs. 5.41 ± 0.20, p > .9999), further confirmed by inhibiting Cystic Fibrosis Transmembrane Conductance Regulator in healthy control monocyte-derived macrophages.
CONCLUSIONS: Optical nanosensors accurately measure macrophage phagolysosomal pH and demonstrate no phagolysosomal acidification defect in human CF monocyte-derived macrophages. Further studies using alveolar macrophages could extend the impact of our findings. Nanosensors represent a novel and precise means to measure organelle functions with widespread potential for the study and monitoring of several lung diseases.

PMID: 31501051 [PubMed - as supplied by publisher]

Pharmacokinetics of colistin after nebulization or intravenous administration of colistin methanesulphonate (Colimycin®) to cystic fibrosis patients.

J Cyst Fibros. 2019 Sep 06;:

Authors: Magréault S, Mankikian J, Marchand S, Diot P, Couet W, Flament T, Grégoire N

Abstract
OBJECTIVES: Colistin, administered as the prodrug colistin methanesulphonate (CMS), is an antibiotic frequently administered as aerosol in cystic fibrosis (CF) patient. Our aim was to assess the plasma PK of colistin in CF patients treated with CMS administered intravenously or as aerosol and to compare these results with those previously reported in healthy volunteers.
METHODS: Six CF patients were included, CMS and colistin concentrations were measured in plasma, urine and sputum. Either after single intravenous administration of 2 Million International Unit (MIU) or after repeated nebulizations of 2 MIU of CMS. PK of CMS and colistin were assessed by a mixed effect modeling approach.
RESULTS: Renal clearance of CMS was lower in CF patients compared to that previously reported in healthy volunteers (64.3 mL/min (RSE = 15%) vs. 103 mL/min (RSE = 8%)). However, apparent clearance of colistin was higher in CF patients compared to healthy volunteers (124 mL/min (RSE = 13%) vs. 48.7 mL/min (RSE = 15%)), resulting in reduced systemic exposure to colistin (dose normalized AUC (2 MIU) of 7.4 h.mg/L/MIU vs. 11.2 h.mg/L/MIU). After repeated nebulizations, colistin concentrations were very low in plasma (<0.21 mg/L).
CONCLUSIONS: Although our study suggests a lower median dose normalized colistin plasma concentrations in CF patients compared with healthy controls, this difference was not significant and a larger study is needed to substantiate this.

PMID: 31501050 [PubMed - as supplied by publisher]

Circadian rhythm of COPD symptoms in clinically based phenotypes. Results from the STORICO Italian observational study.

BMC Pulm Med. 2019 Sep 09;19(1):171

Authors: Nicola S, Raffaele AI, Francesco B, Pietro S, Giuseppina C, Alessandro Z, Alessandra O, Giorgio Walter C, STORICO study group

Abstract
BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) encompasses various phenotypes that severely limit the applicability of precision respiratory medicine. The present investigation is aimed to assess the circadian rhythm of symptoms in pre-defined clinical COPD phenotypes and its association with health-related quality of life (HR-QoL), the quality of sleep and the level of depression/anxiety in each clinical phenotype.
METHODS: The STORICO (NCT03105999) Italian observational prospective cohort study enrolled COPD subjects. A clinical diagnosis of either chronic bronchitis (CB), emphysema (EM) or mixed COPD-asthma (MCA) phenotype was made by clinicians at enrollment. Baseline early-morning, day-time and nocturnal symptoms (gathered via the Night-time, Morning and Day-time Symptoms of COPD questionnaire), HR-QoL (via the St. George's Respiratory Questionnaire), anxiety and depression levels (via the Hospital Anxiety and Depression Scale), quality of sleep (via COPD and Asthma Sleep Impact Scale), physical activity (via the International Physical Activity Questionnaire) as well as lung function were recorded.
RESULTS: 606 COPD subjects (age 71.4 ± 8.2 years, male 75.1%) were studied. 57.9, 35.5 5.3 and 1.3% of the sample belonged to the CB, EM, MCA and EM + CB phenotypes respectively. The vast majority of subjects reported early-morning and day-time symptoms (79.5 and 79.2% in the CB and 75.8 and 77.7% in the EM groups); the proportion suffering from night-time symptoms was higher in the CB than in the EM group (53.6% vs. 39.5%, p = 0.0016). In both CB and EM, indiscriminately, the presence of symptoms during the 24-h day was associated with poorer HR-QoL, worse quality of sleep and higher levels of anxiety/depression.
CONCLUSIONS: The findings highlight the primary classificatory role of nocturnal symptoms in COPD.
TRIAL REGISTRATION: Trial registration number: NCT03105999 , date of registration: 10th April 2017.

PMID: 31500607 [PubMed - in process]

Achromobacter spp. healthcare associated infections in the French West Indies: a longitudinal study from 2006 to 2016.

BMC Infect Dis. 2019 Sep 10;19(1):795

Authors: Marion-Sanchez K, Pailla K, Olive C, Le Coutour X, Derancourt C

Abstract
BACKGROUND: Bacteria of the Achromobacter genus, more particularly xylosoxidans species, are responsible for various healthcare associated infections (HAI) which are increasingly described since the last decade. Cystic fibrosis (CF) patients are considered as potential reservoirs in hospitals. We performed a retrospective study to estimate the frequencies of Achromobacter spp. HAI among patients from French West Indies, to determine characteristics of infected patients and establish a possible link between CF and infections.
METHODS: All adults with at least one Achromobacter spp. positive sample and infection criteria in accordance with European official definitions of HAI, hospitalized in University Hospital of Martinique from 2006 to 2016 for more than 48 h, were included. Patient clinical features, immune status and underlying diseases were obtained from medical files. A list of CF patients was given by clinicians. Antibiotic-susceptibility profiles of the strains were determined using an automated method.
RESULTS: Mean incidence density was 0.038/1000 days of hospitalization. Achromobacter spp. HAI evolved as an endemic situation with a low but pretty much stable incidence rate over the 11-year observation period. An epidemic peak was noticed in 2013. Among the 66 included patients, 56.1% were immunocompetent and no one had CF. Pneumonia and bacteraemia were the two main HAI. Among the 79 isolated strains, 92.4% were resistant to at least 1 major antibiotic and 16.4% met the definition of multidrug-resistant bacteria.
CONCLUSIONS: This microorganism, little known in our country because of the scarcity of CF patients, represents a threat for both immunosuppressed and immunocompetent patients and a therapeutic challenge because of its high resistance.

PMID: 31500579 [PubMed - in process]

Anthracyclines Suppress Both NADPH Oxidase- Dependent and -Independent NETosis in Human Neutrophils.

Cancers (Basel). 2019 Sep 07;11(9):

Authors: Khan MA, D'Ovidio A, Tran H, Palaniyar N

Abstract
Neutrophil extracellular traps (NETs) are cytotoxic DNA-protein complexes that play positive and negative roles in combating infection, inflammation, organ damage, autoimmunity, sepsis and cancer. However, NETosis regulatory effects of most of the clinically used drugs are not clearly established. Several recent studies highlight the relevance of NETs in promoting both cancer cell death and metastasis. Here, we screened the NETosis regulatory ability of 126 compounds belonging to 39 classes of drugs commonly used for treating cancer, blood cell disorders and other diseases. Our studies show that anthracyclines (e.g., epirubicin, daunorubicin, doxorubicin, and idarubicin) consistently suppress both NADPH oxidase-dependent and -independent types of NETosis in human neutrophils, ex vivo. The intercalating property of anthracycline may be enough to alter the transcription initiation and lead NETosis inhibition. Notably, the inhibitory doses of anthracyclines neither suppress the production of reactive oxygen species that are necessary for antimicrobial functions nor induce apoptotic cell death in neutrophils. Therefore, anthracyclines are a major class of drug that suppresses NETosis. The dexrazoxane, a cardioprotective agent, used for limiting the side effects of anthracyclines, neither affect NETosis nor alter the ability of anthracyclines to suppress NETosis. Hence, at correct doses, anthracyclines together with dexrazoxane could be considered as a therapeutic candidate drug for suppressing unwanted NETosis in NET-related diseases.

PMID: 31500300 [PubMed]

Oral non-steroidal anti-inflammatory drug therapy for lung disease in cystic fibrosis.

Cochrane Database Syst Rev. 2019 Sep 09;9:CD001505

Authors: Lands LC, Stanojevic S

Abstract
BACKGROUND: Progressive lung damage causes most deaths in cystic fibrosis. Non-steroidal anti-inflammatory drugs (such as ibuprofen) may prevent progressive pulmonary deterioration and morbidity in cystic fibrosis. This is an update of a previously published review.
OBJECTIVES: To assess the effectiveness of treatment with oral non-steroidal anti-inflammatory drugs in cystic fibrosis.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, hand searches of relevant journals and abstract books of conference proceedings. We contacted manufacturers of non-steroidal anti-inflammatory drugs and searched online trials registries.Latest search of the Group's Trials Register: 21 November 2018.
SELECTION CRITERIA: Randomized controlled trials comparing oral non-steroidal anti-inflammatory drugs, at any dose for at least two months, to placebo in people with cystic fibrosis.
DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for inclusion the review and their potential risk of bias. Two authors independently rated the quality of the evidence for each outcome using the GRADE guidelines.
MAIN RESULTS: The searches identified 17 trials; four are included (287 participants aged five to 39 years; maximum follow-up of four years) and one is currently awaiting classification pending publication of the full trial report and two are ongoing. Three trials compared ibuprofen to placebo (two from the same center with some of the same participants); one trial assessed piroxicam versus placebo.The three ibuprofen trials were deemed to have good or adequate methodological quality, but used various outcomes and summary measures. Reviewers considered measures of lung function, nutritional status, radiological assessment of pulmonary involvement, intravenous antibiotic usage, hospital admissions, survival and adverse effects. Combined data from the two largest ibuprofen trials showed a lower annual rate of decline for lung function, % predicted forced expiratory volume in one second (FEV1), mean difference (MD) 1.32 (95% confidence interval (CI) 0.21 to 2.42) (moderate-quality evidence); forced vital capacity (FVC), MD 1.27 (95% CI 0.26 to 2.28) (moderate-quality evidence); forced expiratory flow (FEF25%-75%), MD 1.80 (95% CI 0.15 to 3.45). The post hoc analysis of data from two trials split by age showed a slower rate of annual decline of FEV1 % predicted and FVC in the ibuprofen group in younger children, MD 1.41% (95% CI 0.03 to 2.80) (moderate-quality evidence) and MD 1.32% (95% CI 0.04 to 2.60) (moderate-quality evidence) respectively. Data from four trials demonstrated the proportion of participants with at least one hospitalization may be slightly lower in the ibuprofen group compared to placebo, Peto odds ratio 0.61 (95% CI 0.37 to 1.01) (moderate-quality evidence). In one trial, long-term use of high-dose ibuprofen was associated with reduced intravenous antibiotic usage, improved nutritional and radiological pulmonary status. No major adverse effects were reported, but the power of the trials to identify clinically important differences in the incidence of adverse effects was low.We did not have any concerns with regards to risk of bias for the trial comparing piroxicam to placebo. However, the trial did not report many data in a form that we could analyze in this review. No data were available for the review's primary outcome of lung function; available data for hospital admissions showed no difference between the groups. No analyzable data were available for any other review outcome.
AUTHORS' CONCLUSIONS: High-dose ibuprofen can slow the progression of lung disease in people with cystic fibrosis, especially in children, which suggests that strategies to modulate lung inflammation can be beneficial for people with cystic fibrosis.

PMID: 31499593 [PubMed - as supplied by publisher]

Lung clearance index to detect the efficacy of Aztreonam lysine inhalation in patients with cystic fibrosis and near normal spirometry - A single-centre feasibility study.

PLoS One. 2019;14(9):e0221673

Authors: Ellemunter H, Steinkamp G

Abstract
Comparing the efficacy of inhaled antibiotics can be difficult in small groups of patients with cystic fibrosis and mild lung disease. In a feasibility study we compared Aztreonam lysine for inhalation solution (AZLI; Cayston®) to standard inhaled antibiotic therapy in patients with cystic fibrosis and near normal spirometry. To detect treatment responses we used both lung clearance index (LCI) and forced expiratory volume in one second (FEV1). At baseline, median FEV1 was 87% pred. and median LCI was 8.6 (upper limit of normal: 7.0). After 4 weeks, LCI improved by -0.36 after AZLI and deteriorated by +0.12 after tobramycin treatment (p = 0.039). No significant differences between treatments (p = 0.195) were observed using FEV1. These results suggest that lung clearance index can be used to detect treatment induced changes in subjects with mild lung disease.

PMID: 31498805 [PubMed - in process]

A European ECMM-ESCMID survey on goals and practices for mycobiota characterization using Next Generation Sequencing.

Mycoses. 2019 Sep 09;:

Authors: Gangneux JP, Guegan H, Vandenborght LE, Buffet-Bataillon S, Enaud R, Delhaes L, ECMM-ESCMID NGS study group

Abstract
BACKGROUND: Although substantial efforts have been made to investigate about the composition of the microbiota, fungi that constitute the mycobiota play a pivotal role in maintaining microbial communities and physiological processes in the body.
OBJECTIVES: Here, we conducted an international-survey focusing on laboratory's current procedures regarding their goals and practices of mycobiota characterization using NGS.
METHODS: A questionnaire was proposed to laboratories affiliated to working groups from ECMM (NGS study group) and ESCMID (ESGHAMI and EFISG study groups). Twenty-six questionnaires from 18 countries were received.
RESULTS: The use of NGS to characterize the mycobiota was not in routine for most of the labs (N=23, 82%) and the main reason of using NGS were primary to understand the pathophysiology of a dysbiosis (N=20), to contribute to a diagnosis (N=16), or to implement a therapeutic strategy (N=12). Other reported reasons were to evaluate the exposome (environmental studies) (N=10), or to investigate epidemics (N=8). Sputum is the main sample studied, and cystic fibrosis represent a major disease studied via the analysis of pulmonary microbiota. No consensus has emerged for the choice of the targets with 18S, ITS1 and ITS2 used alternatively among the labs. Other answers are detailed in the manuscript.
CONCLUSIONS: We report a photography of mycobiota analysis that may become a major tool in the near future. We can draw some conclusions on the diversity of approaches within the answers of the 27 labs and underline the need for standardization.

PMID: 31498487 [PubMed - as supplied by publisher]

Magnesium for treating sickle cell disease.

Cochrane Database Syst Rev. 2019 Sep 09;9:CD011358

Authors: Than NN, Soe HHK, Palaniappan SK, Abas AB, De Franceschi L

Abstract
BACKGROUND: Sickle cell disease is an autosomal recessive inherited haemoglobinopathy which causes painful vaso-occlusive crises due to sickle red blood cell dehydration. Vaso-occlusive crises are common painful events responsible for a variety of clinical complications; overall mortality is increased and life expectancy decreased compared to the general population. Experimental studies suggest that intravenous magnesium has proven to be well-tolerated in individuals hospitalised for the immediate relief of acute (sudden onset) painful crisis and has the potential to decrease the length of hospital stay. Some in vitro studies and open studies of long-term oral magnesium showed promising effect on pain relief but failed to show its efficacy. The studies show that oral magnesium therapy may prevent sickle red blood cell dehydration and prevent recurrent painful episodes. There is a need to access evidence for the impact of oral and intravenous magnesium effect on frequency of pain, length of hospital stay and quality of life. This is an updated version of the review.
OBJECTIVES: To evaluate the effects of short-term intravenous magnesium on the length of hospital stay and quality of life in children and adults with sickle cell disease. To determine the effects of long-term oral magnesium therapy on the frequency of painful crises and the quality of life in children and adults with sickle cell disease.
SEARCH METHODS: We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books.Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 03 February 2019.Date of last search of other resources (clinical trials registries): 04 April 2019.
SELECTION CRITERIA: We searched for published and unpublished randomized controlled studies of oral or intravenous magnesium compared to placebo or no magnesium.
DATA COLLECTION AND ANALYSIS: Authors independently assessed the study quality and extracted the data using standard Cochrane methodologies.
MAIN RESULTS: We included five randomized placebo-controlled studies with a total of 386 participants (aged three to 53 years). Of these, two shorter parallel studies (n = 306) compared intravenous magnesium sulphate to placebo (normal saline) for admission to hospital due to a vaso-occlusive crisis, for which we were able to analyse data. The quality of evidence was moderate for studies in this comparison, mainly due to limitations due to risk of bias and imprecision. Two of the three longer-term studies comparing oral magnesium pidolate to placebo had a cross-over design. The third was a parallel factorial study which compared hydroxyurea and oral magnesium to each other and to placebo over a longer period of time; we only present the comparison of oral magnesium to placebo from this study. The quality of evidence was very low with uncertainty of the estimation.The eight-hourly dose levels in the two studies of intravenous magnesium were different; one used 100 mg/kg while the second used 40 mg/kg. Only one of these studies (n = 104) reported the mean daily pain score while hospitalised (a non-significant difference between groups, moderate quality evidence). The second study (n = 202) reported a number of child- and parent-reported quality of life scores. None of the scores showed any difference between treatment groups (low quality evidence). Data from one study (n = 106) showed no difference in length of stay in hospital between groups (low quality evidence). Both studies reported on adverse events, but not defined by severity as we had planned. One study showed significantly more participants receiving intravenous magnesium experienced warmth at infusion site compared to placebo; there were no differences between groups for other adverse events (low quality evidence).Three studies (n = 80) compared oral magnesium pidolate to placebo. None of them reported data which we were able to analyse. One study (n = 24) reported on the number of painful days and stated there was no difference between two groups (low quality evidence). None of the studies reported on quality of life or length of hospital stay. Two studies (n = 68) reported there were no differences in levels of magnesium in either plasma or red blood cells (moderate quality evidence). Two studies (n = 56) reported adverse events. One reported episodes of mild diarrhoea and headache, all of which resolved without stopping treatment. The second study reported adverse events as gastrointestinal disorders, headache or migraine, upper respiratory infections and rash; which were all evenly distributed across treatment groups (moderate quality evidence).
AUTHORS' CONCLUSIONS: Moderate to low quality evidence showed neither intravenous magnesium and oral magnesium therapy has an effect on reducing painful crisis, length of hospital stay and changing quality of life in treating sickle cell disease. Therefore, no definitive conclusions can be made regarding its clinical benefit. Further randomized controlled studies, perhaps multicentre, are necessary to establish whether intravenous and oral magnesium therapies have any effect on improving the health of people with sickle cell disease.

PMID: 31498421 [PubMed - as supplied by publisher]

Airway disease on chest computed tomography of preschool children with cystic fibrosis is associated with school-age bronchiectasis.

Pediatr Pulmonol. 2019 Sep 09;:

Authors: Bouma NR, Janssens HM, Andrinopoulou ER, Tiddens HAWM

Abstract
Airway wall thickening and mucus plugging are important characteristics of cystic fibrosis (CF) lung disease in the first 5 years of life.The aim of this study is to investigate the association of lung disease in preschool children (age, 2-6) with bronchiectasis and other clinical outcome measures in the school age (age >7). Deidentified computed tomography-scans were annotated using Perth-Rotterdam annotated grid morphometric analysis for CF. Preschool %disease (a composite score of %airway wall thickening, %mucus plugging, and %bronchiectasis) and %MUPAT (a composite score of %airway wall thickening and %mucus plugging) were used as predictors for %bronchiectasis and several other school-age clinical outcomes. For statistical analysis, we used regression analysis, linear mixed-effects models and two-way mixed models. Sixty-one patients were included. %Disease increased significantly with age (P  <  .01). Preschool %disease and %MUPAT were significantly associated with school-age %bronchiectasis (P  <  .01 and P  <  .01, respectively). No significant association was found between preschool %disease and %MUPAT and school-age forced expiratory volume 1 (FEV1%) predicted and quality of life (P  >  .05). Cross-sectional, %disease in school-age was associated with a low FEV1% predicted and low quality of life (P  =  .01 and P  =  .007, respectively). %Disease can be considered an early marker of diffuse airways disease and is a risk factor for school-age bronchiectasis.

PMID: 31496137 [PubMed - as supplied by publisher]

Rapidly Progressive Cystic Lung Disease.

Am J Respir Crit Care Med. 2018 07 15;198(2):264

Authors: Rogers C, Kent-Bramer J, Devaraj A, Nicholson AG, Molyneaux PL, Wells AU, Saikia S, Maher TM, George PM

PMID: 29625015 [PubMed - indexed for MEDLINE]

Essential Two-Component Systems Regulating Cell Envelope Functions: Opportunities for Novel Antibiotic Therapies.

J Membr Biol. 2018 02;251(1):75-89

Authors: Cardona ST, Choy M, Hogan AM

Abstract
Novel therapies are urgently needed to alleviate the current crisis of multiple drug-resistant infections. The bacterial signal transduction mechanisms, known as two-component systems (TCSs), are ideal targets of novel inhibitory molecules. Highly restricted to the bacterial world, TCSs control a diverse set of cellular functions, namely virulence, response to cell envelope stress, and drug efflux. Impaired regulation of any of these aspects could affect the susceptibility of bacterial pathogens to antibiotics, which highlights the potential of TCS as targets of antibiotic adjuvant therapies. Moreover, new high-density transposon mutagenesis methods have revealed the existence of TCSs required for growth and viability. Experimental validation of gene essentiality and phenotypic characterization of knockdown mutants indicate that essential TCSs regulate aspects of the cell envelope homeostasis in coordination with cell division. In this review, we describe essential TCSs, and their potentials as targets for antibacterial molecules. We also discuss methods for the identification of small molecules that inhibit TCSs and possible reasons why antibacterial molecules targeting essential TCSs have not yet reached clinical trials.

PMID: 29098331 [PubMed - indexed for MEDLINE]