Key conceptional considerations on nebulization of antimicrobial agents to mechanically ventilated patients.

Clin Microbiol Infect. 2017 Mar 24;:

Authors: Rello J, Rouby JJ, Sole-Lleonart C, Chastre J, Blot S, Luyt CE, Riera J, Vos MC, Monsel A, Dhanani J, Roberts JA

Abstract
Nebulized antibiotics have an established role in patients with cystic fibrosis or bronchiectasis. Their potential benefit to treat respiratory infections in mechanically ventilated patients is receiving increasing interest. In this Consensus Paper of the European Society of Clinical Microbiology and Infectious Diseases, the body of evidence of the therapeutic utility of aerosolized antibiotics in mechanically ventilated patients was reviewed and resulted in the following recommendations: A. Vibrating mesh nebulizers should be preferred to jet or ultrasonic nebulizers; B. To decrease turbulence and limit circuit and tracheobronchial deposition, we recommend: (i) - the use of specifically designed respiratory circuits avoiding sharp angles and characterized by smooth inner surfaces, (ii) - the use of specific ventilator settings during nebulization including use of a volume controlled mode using constant inspiratory flow, tidal volume 8 ml/kg, respiratory frequency 12-15 bpm, inspiratory:expiratory ratio 50 %, inspiratory pause 20 % and positive end-expiratory pressure 5-10 cmH2O, (iii) - the administration of a short-acting sedative agent if coordination between the patient and the ventilator is not obtained, to avoid patient's flow triggering and episodes of peak decelerating inspiratory flow. C. A filter should be inserted on the expiratory limb to protect the ventilator flow device and changed between each nebulization to avoid expiratory flow obstruction. D. A heat and moisture exchanger and/or conventional heated humidifier should be stopped during the nebulization period to avoid a massive loss of aerosolized particles through trapping and condensation. If these technical requirements are not followed, there is a high risk of treatment failure and adverse events in mechanically ventilated patients receiving nebulized antibiotics for pneumonia.

PMID: 28347790 [PubMed - as supplied by publisher]

Liver disease in cystic fibrosis presents as non-cirrhotic portal hypertension.

J Cyst Fibros. 2017 Mar 24;:

Authors: Witters P, Libbrecht L, Roskams T, De Boeck K, Dupont L, Proesmans M, Vermeulen F, Maleux G, Monbaliu D, Pirenne J, Cassiman D

PMID: 28347603 [PubMed - as supplied by publisher]

Inflammatory biomarkers in asthma endotypes and consequent personalized therapy.

Expert Rev Clin Immunol. 2017 Mar 27;:

Authors: Ciprandi G, Tosca MA, Silvestri M, Ricciardolo FL

Abstract
Introduction We argue that asthma be considered a syndrome caused by multiple inflammatory pathogenic processes. Bronchial hyperresponsiveness, reversible airflow limitation, and chronic airway inflammation characterize asthma pathophysiology. Personalized Medicine, i.e. a tailored management approach, is appropriate for asthma management and is based on the identification of discrete phenotypes and endotypes. Biomarkers can help define phenotypes and endotypes. Several biomarkers have been described in asthma, but most of them are not commonly available or still need external validation. Areas covered This review presents useful pragmatic biomarkers available in daily clinical practice for assessing airway inflammation in asthmatic patients. Expert commentary Eosinophil counts and serum allergen-specific IgE assessments are the most reliable biomarkers. Lung function, mainly concerning FEF25-75, and nasal cytology may be envisaged as ancillary biomarkers in asthma management. In conclusion, biomarkers have a clinical relevance in asthma in identifying asthma endotypes to direct personalized therapy.

PMID: 28347164 [PubMed - as supplied by publisher]

The clinical course of hereditary pancreatitis in children - A comprehensive analysis of 41 cases.

Pancreatology. 2016 Jul-Aug;16(4):535-41

Authors: Oracz G, Kolodziejczyk E, Sobczynska-Tomaszewska A, Wejnarska K, Dadalski M, Grabarczyk AM, Kierkus J, Woynarowski M, Wertheim-Tysarowska K, Ryzko J, Bal J, Rygiel AM

Abstract
BACKGROUND: Available data from adult patients do not reflect natural course of hereditary pancreatitis (HP) in children. To date, no study has assessed the clinical course of HP in children.
OBJECTIVE: To investigate the clinical course of HP in children and compare it to non-HP group with chronic pancreatitis (CP).
METHODS: A group of 265 children with CP, hospitalized from 1988 to 2014, were enrolled in the study. Medical records of those patients were reviewed for data on presentation, diagnostic findings and treatment. All children were screened for mutations in major pancreatitis-associated genes, i.e. PRSS1, SPINK1, and CFTR.
RESULTS: HP was diagnosed in 41 children (15.5%). Family history was positive in 88% of children with HP. Mutations of PRSS1 gene were found in 80% (33/41) of HP patients. We detected p.R122H, p.R122C, p.N29I, and p.E79K mutation in 34% (14/41), 27% (11/41), 12% (5/41), and 7% (3/41) of HP patients, respectively. Patients with paternal inheritance had first symptoms earlier than those with maternal inheritance (5.9 vs. 9.1 years; P < 0.05). Children with HP showed more severe changes in ERCP then those from non-HP group (2.05 Cambridge grade, vs. 1.6°; P < 0.05). ESWL was performed more frequently in HP group (12.2% vs. 3.1%; P < 0.05). There was no difference in age of disease onset (7.98 vs. 8.9 years; NS), pancreatic duct stenting (46.3% vs. 33%; NS), or number of surgical interventions (12.2% vs. 14.3%; NS) between both groups.
CONCLUSIONS: Children with HP reveal significantly more severe clinical presentation of the disease than non-HP patients, despite the same age of onset.

PMID: 27179762 [PubMed - indexed for MEDLINE]

Genetic Mutations in Pediatric Pancreatitis.

Pancreas. 2016 08;45(7):992-6

Authors: Vue PM, McFann K, Narkewicz MR

Abstract
OBJECTIVES: The aim of our study was to describe the prevalence, characteristics, and outcomes of children with acute recurrent (ARP) or chronic (CP) pancreatitis with or without mutations in PRSS1, CFTR or SPINK1.
METHODS: Retrospective chart review of children with ARP or CP with and without testing for PRSS1, CFTR, and SPINK1. Demographics, clinical features, management, and outcome were collected. Analysis of variance was used to compare continuous variables and χ or Fisher exact test for categorical variables.
RESULTS: Ninety-one subjects with ARP (n = 77) or CP (n = 14) were identified and included in this study. Of these, 37 (41%) were male, 44 were white, and 30 were Hispanic. Thirty-three (36%) had at least 1 mutation identified (Pan-Mut): PRSS1 (7), CFTR (21), SPINK1 (3), SPINK/CFTR (2). Thirty-six were tested but had no mutation, and 22 were not tested. The Pan-Mut subjects were more likely to have a family history of pancreatitis but there were no differences in the clinical features, imaging or outcome.
CONCLUSIONS: Mutations in CFTR, SPINK1 or PRSS1 are present in one third of pediatric ARP and CP with no other cause. No clinical features or outcomes differentiated between the Pan-Mut group and the no-mutation group. The Pan-Mut subjects were more likely to have a family history of pancreatitis. Pediatric ARP and CP without identified cause should undergo genetic testing.

PMID: 26692446 [PubMed - indexed for MEDLINE]

Optimization of adeno-associated virus vector-mediated gene transfer to the respiratory tract.

Gene Ther. 2017 Mar 27;:

Authors: Kurosaki F, Uchibori R, Mato N, Sehara Y, Saga Y, Urabe M, Mizukami H, Sugiyama Y, Kume A

Abstract
An efficient adeno-associated virus (AAV) vector was constructed for the treatment of respiratory diseases. AAV serotypes, promoters, and routes of administration potentially influencing the efficiency of gene transfer to airway cells were examined in the present study. Among the nine AAV serotypes (AAV1-9) screened in vitro and four serotypes (AAV1, 2, 6, 9) evaluated in vivo, AAV6 showed the strongest transgene expression. As for promoters, the cytomegalovirus (CMV) early enhancer/chicken β-actin (CAG) promoter resulted in more robust transduction than the CMV promoter. Regarding delivery routes, intratracheal administration resulted in strong transgene expression in the lung, whereas the intravenous and intranasal administration routes yielded negligible expression. The combination of the AAV6 capsid and CAG promoter resulted in sustained expression, and the intratracheally administered AAV6-CAG vector transduced bronchial cells and pericytes in the lung. These results suggest that AAV6-CAG vectors are more promising than the previously preferred AAV2 vectors for airway transduction, particularly when administered into the trachea. The present study offers an optimized strategy for AAV-mediated gene therapy for lung diseases, such as cystic fibrosis and pulmonary fibrosis.Gene Therapy accepted article preview online, 27 March 2017. doi:10.1038/gt.2017.19.

PMID: 28346434 [PubMed - as supplied by publisher]

Identifying Inhibitors of the Hsp90-Aha1 Protein Complex, a Potential Target to Drug Cystic Fibrosis, by Alpha Technology.

SLAS Discov. 2017 Jan 01;:2472555216688312

Authors: Ihrig V, Obermann WM

Abstract
Deletion of a single phenylalanine residue at position 508 of the protein CFTR (cystic fibrosis transmembrane conductance regulator), a chloride channel in lung epithelium, is the most common cause for cystic fibrosis. As a consequence, folding of the CFTRΔF508 protein and delivery to the cell surface are compromised, resulting in degradation of the polypeptide. Accordingly, decreased surface presence of CFTRΔF508 causes impaired chloride ion conductivity and is associated with mucus accumulation, a hallmark of cystic fibrosis. Molecular chaperones such as Hsp90 and its co-chaperone partner Aha1 are thought to play a key role in targeting folding-deficient CFTRΔF508 for degradation. Thus, pharmacologic manipulation to inhibit Hsp90-Aha1 chaperone complex formation appears beneficial to inhibit proteolysis of CFTRΔF508 and rescue its residual chloride channel activity. Therefore, we have screened a collection of 14,400 druglike chemical compounds for inhibitors of the Hsp90-Aha1 complex by amplified luminescence proximity homogeneous assay (Alpha). We identified two druglike molecules that showed promising results when we tested their ability to restore chloride channel activity in culture cells expressing the mutant CFTRΔF508 protein. The two molecules were most effective in combination with the corrector VX-809 and may therefore serve as a lead compound that can be further developed into a drug to treat cystic fibrosis patients.

PMID: 28346090 [PubMed - as supplied by publisher]

Liposomes loaded with bioactive lipids enhance antibacterial innate immunity irrespective of drug resistance.

Sci Rep. 2017 Mar 27;7:45120

Authors: Poerio N, Bugli F, Taus F, Santucci MB, Rodolfo C, Cecconi F, Torelli R, Varone F, Inchingolo R, Majo F, Lucidi V, Mariotti S, Nisini R, Sanguinetti M, Fraziano M

Abstract
Phagocytosis is a key mechanism of innate immunity, and promotion of phagosome maturation may represent a therapeutic target to enhance antibacterial host response. Phagosome maturation is favored by the timely and coordinated intervention of lipids and may be altered in infections. Here we used apoptotic body-like liposomes (ABL) to selectively deliver bioactive lipids to innate cells, and then tested their function in models of pathogen-inhibited and host-impaired phagosome maturation. Stimulation of macrophages with ABLs carrying phosphatidic acid (PA), phosphatidylinositol 3-phosphate (PI3P) or PI5P increased intracellular killing of BCG, by inducing phagosome acidification and ROS generation. Moreover, ABLs carrying PA or PI5P enhanced ROS-mediated intracellular killing of Pseudomonas aeruginosa, in macrophages expressing a pharmacologically-inhibited or a naturally-mutated cystic fibrosis transmembrane conductance regulator. Finally, we show that bronchoalveolar lavage cells from patients with drug-resistant pulmonary infections increased significantly their capacity to kill in vivo acquired bacterial pathogens when ex vivo stimulated with PA- or PI5P-loaded ABLs. Altogether, these results provide the proof of concept of the efficacy of bioactive lipids delivered by ABL to enhance phagosome maturation dependent antimicrobial response, as an additional host-directed strategy aimed at the control of chronic, recurrent or drug-resistant infections.

PMID: 28345623 [PubMed - in process]

Amplification of FSH signaling by CFTR and nuclear soluble adenylyl cyclase in the ovary.

Clin Exp Pharmacol Physiol. 2017 Mar 27;:

Authors: Chen H, Chan HC

Abstract
cAMP/PKA pathway is one of the most important signaling pathways widely distributed in most eukaryotic cells. The activation of the canonical cAMP/PKA pathway depends on transmembrane adenylyl cyclase (tmAC). Recently, soluble adenylyl cyclase (sAC), which is activated by HCO3(-) or Ca(2+) , emerges to provide an alternative way to activate cAMP/PKA pathway with the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated Cl(-) / HCO3(-) -conducting anion channel, as a key player. This review summarizes new progress in the investigation of the CFTR/HCO3(-) -dependent sAC signaling and its essential role in various reproductive processes, particularly in ovarian functions. We present the evidence for a CFTR/HCO3(-) -dependent nuclear sAC signaling cascade that amplifies the FSH-stimulated cAMP/PKA pathway, traditionally thought to involve tmAC, in granulosa for the regulation of estrogen production and granulosa cell proliferation. The implication of the CFTR/HCO3(-) /sAC pathway in amplifying other receptor-activated cAMP/PKA signaling in a wide variety of cell types and pathophysiological processes, including aging, is also discussed. This article is protected by copyright. All rights reserved.

PMID: 28345252 [PubMed - as supplied by publisher]

The effects of exogenous lipid on THP-1 cells: an in vitro model of airway aspiration?

ERJ Open Res. 2017 Jan;3(1):

Authors: Hayman YA, Sadofsky LR, Williamson JD, Hart SP, Morice AH

Abstract
Chronic inflammatory diseases of the airways are associated with gastro-oesophageal reflux (GOR) and aspiration events. The observation of lipid-laden macrophages (LLMs) within the airway may indicate aspiration secondary to GOR. The proposed mechanism, that lipid droplets from undigested or partially digested food are aspirated leading to accumulation in scavenging macrophages, led us to hypothesise that an activated population of LLMs could interact with other immune cells to induce bronchial inflammation. To test this, we generated an in vitro model using differentiated THP-1 cells, which were treated with a high-fat liquid feed. Here, we show that THP-1 cells can take up lipid from the high-fat feed independent of actin polymerisation or CD36-dependent phagocytosis. These cells did not exhibit M1 or M2 polarisation. Gene array analysis confirmed over 8000 genes were upregulated by at least twofold following high fat exposure, and IL-8 was the most upregulated gene. Pathway analysis revealed upregulation of genes known to be involved in chronic obstructive pulmonary disease (COPD) pathophysiology. We suggest that aspiration and macrophage phagocytosis may be important mechanisms in the aetiology of diseases such as COPD and cystic fibrosis that are characterised by high levels of IL-8 within the airways.

PMID: 28344981 [PubMed - in process]

Non-Classic Cystic Fibrosis: The Value in Family History.

Am J Med. 2017 Mar 23;:

Authors: Lui JK, Kilch J, Fridlyand S, Dheyab A, Bielick Kotkowski C

PMID: 28344137 [PubMed - as supplied by publisher]

Measurement of ion fluxes across epithelia.

Prog Biophys Mol Biol. 2017 Mar 22;:

Authors: Zajac M, Dolowy K

Abstract
Epithelial tissues line all wet surfaces of vertebrate bodies. Their major function is directional transport of ions and water. Cells forming an epithelial layer are bound together by a tight junction that forms a barrier to ion flux. Ions and water are transported via specialized molecules. The presence of a defect in a single ion channel molecule leads to cystic fibrosis - the most common, fatal, human genetic disease. The paper describes ion transport data obtained by means of different experimental techniques. Special attention is given to radiochemical tracers, transepithelial resistance determination, open circuit potential and short circuit current measurements, the nasal potential difference in healthy and cystic fibrosis patients, the use of ion selective electrodes, and electrochemical mapping of the cell membrane surface. The effect of different activators and blockers of ion transport molecules on measured parameters are also discussed.

PMID: 28342743 [PubMed - as supplied by publisher]

Asthma management in a specialist setting: Results of an Italian Respiratory Society survey.

Pulm Pharmacol Ther. 2017 Mar 21;:

Authors: Braido F, Ilaria B, Alleri P, Bacci E, Barbetta C, Bellocchia M, Benfante A, Blasi F, Bucca C, Busceti MT, Centanni S, Colanardi MC, Contoli M, Corsico A, D 'Amato M, Di Marco F, Marco D, Ferrari M, Florio G, Fois AG, Foschino Barbaro MP, Silvia G, Girbino G, Grosso A, Latorre M, Maniscalco S, Mazza F, Mereu C, Molinengo G, Ora J, Paggiaro P, Patella V, Pelaia G, Pirina P, Proietto A, Rogliani P, Santus P, Scichilone N, Simioli F, Solidoro P, Terraneo S, Zuccon U, Canonica GW

Abstract
BACKGROUND: Asthma considerably impairs patients' quality of life and increases healthcare costs. Severity, morbidity, and degree of disease control are the major drivers of its clinical and economic impact. National scientific societies are required to monitor the application of international guidelines and to adopt strategies to improve disease control and better allocate resources.
AIM: to provide a detailed picture of the characteristics of asthma patients and modalities of asthma management by specialists in Italy and to develop recommendations for the daily management of asthma in a specialist setting.
METHOD: A quantitative research program was implemented. Data were collected using an ad hoc questionnaire developed by a group of specialists selected by the Italian Pneumology Society/Italian Respiratory Society.
RESULTS: The records of 557 patients were analyzed. In the next few years, specialists are expected to focus their activity patients with more severe disease and will be responsible for selection of patients for personalized biological therapy; however, only 20% of patients attending Italian specialist surgery can be considered severe. In 84.4% of cases, the visit was a follow-up visit requested in 82.2% of cases by the specialist him/herself. The Asthma Control Test is used only in 65% of patients. When available, a significant association has been observed between the test score and asthma control as judged by the physician, although concordance was only moderate (κ = 0.68). Asthma was considered uncontrolled by the specialist managing the case in 29.1% of patients; nevertheless, treatment was not stepped up in uncontrolled or partly controlled patients (modified in only 37.2% of patients).
CONCLUSIONS: The results of this survey support re-evaluation of asthma management by Italian specialists. More resources should be made available for the initial visit and for more severely ill patients. In addition, more extensive use should be made of validated tools, and available drugs should be used more appropriately.

PMID: 28341462 [PubMed - as supplied by publisher]

Molecular Structure of the Human CFTR Ion Channel.

Cell. 2017 Mar 23;169(1):85-95.e8

Authors: Liu F, Zhang Z, Csanády L, Gadsby DC, Chen J

Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-binding cassette (ABC) transporter that uniquely functions as an ion channel. Here, we present a 3.9 Å structure of dephosphorylated human CFTR without nucleotides, determined by electron cryomicroscopy (cryo-EM). Close resemblance of this human CFTR structure to zebrafish CFTR under identical conditions reinforces its relevance for understanding CFTR function. The human CFTR structure reveals a previously unresolved helix belonging to the R domain docked inside the intracellular vestibule, precluding channel opening. By analyzing the sigmoid time course of CFTR current activation, we propose that PKA phosphorylation of the R domain is enabled by its infrequent spontaneous disengagement, which also explains residual ATPase and gating activity of dephosphorylated CFTR. From comparison with MRP1, a feature distinguishing CFTR from all other ABC transporters is the helix-loop transition in transmembrane helix 8, which likely forms the structural basis for CFTR's channel function.

PMID: 28340353 [PubMed - in process]

Viruses in cystic fibrosis patients' airways.

Crit Rev Microbiol. 2017 Mar 24;:1-19

Authors: Billard L, Le Berre R, Pilorgé L, Payan C, Héry-Arnaud G, Vallet S

Abstract
Although bacteria have historically been considered to play a major role in cystic fibrosis (CF) airway damage, a strong impact of respiratory viral infections (RVI) is also now recognized. Emerging evidence confirms that respiratory viruses are associated with deterioration of pulmonary function and exacerbation and facilitation of bacterial colonization in CF patients. The aim of this review is to provide an overview of the current knowledge on respiratory viruses in CF airways, to discuss the resulting inflammation and RVI response, to determine how to detect the viruses, and to assess their clinical consequences, prevalence, and interactions with bacteria. The most predominant are Rhinoviruses (RVs), significantly associated with CF exacerbation. Molecular techniques, and especially multiplex PCR, help to diagnose viral infections, and the coming rise of metagenomics will extend knowledge of viral populations in the complex ecosystem of CF airways. Prophylaxis and vaccination are currently available only for Respiratory syncytial and Influenza virus (IV), but antiviral molecules are being tested to improve CF patients' care. All the points raised in this review highlight the importance of taking account of RVIs and their potential impact on the CF airway ecosystem.

PMID: 28340310 [PubMed - as supplied by publisher]

In silico search for modifier genes associated with pancreatic and liver disease in Cystic Fibrosis.

PLoS One. 2017;12(3):e0173822

Authors: Trouvé P, Génin E, Férec C

Abstract
Cystic Fibrosis is the most common lethal autosomal recessive disorder in the white population, affecting among other organs, the lung, the pancreas and the liver. Whereas Cystic Fibrosis is a monogenic disease, many studies reveal a very complex relationship between genotype and clinical phenotype. Indeed, the broad phenotypic spectrum observed in Cystic Fibrosis is far from being explained by obvious genotype-phenotype correlations and it is admitted that Cystic Fibrosis disease is the result of multiple factors, including effects of the environment as well as modifier genes. Our objective was to highlight new modifier genes with potential implications in the lung, pancreatic and liver outcomes of the disease. For this purpose we performed a system biology approach which combined, database mining, literature mining, gene expression study and network analysis as well as pathway enrichment analysis and protein-protein interactions. We found that IFI16, CCNE2 and IGFBP2 are potential modifiers in the altered lung function in Cystic Fibrosis. We also found that EPHX1, HLA-DQA1, HLA-DQB1, DSP and SLC33A1, GPNMB, NCF2, RASGRP1, LGALS3 and PTPN13, are potential modifiers in pancreas and liver, respectively. Associated pathways indicate that immune system is likely involved and that Ubiquitin C is probably a central node, linking Cystic Fibrosis to liver and pancreatic disease. We highlight here new modifier genes with potential implications in Cystic Fibrosis. Nevertheless, our in silico analysis requires functional analysis to give our results a physiological relevance.

PMID: 28339466 [PubMed - in process]

Respiratory syncytial virus - host interaction in the pathogenesis of bronchiolitis and its impact on respiratory morbidity in later life.

Pediatr Allergy Immunol. 2017 Mar 24;:

Authors: Rossi GA, Colin AA

Abstract
Rossi GA, Colin AA(.) Respiratory syncytial virus - host interaction in the pathogenesis of bronchiolitis and its impact on respiratory morbidity in later life. Pediatr Allergy Immunol. Respiratory syncytial virus (RSV) is the most common agent of severe airway disease in infants and young children. Large epidemiologic studies have demonstrated a clear relationship between RSV infection and subsequent recurrent wheezing and asthma into childhood, thought to be predominantly related to long-term changes in neuroimmune control of airway tone rather than to allergic sensitization. These changes appear to be governed by the severity of the first RSV infection in infancy which in term depends on viral characteristics and load, but perhaps as importantly, on the genetic susceptibility and on the constitutional characteristic of the host. A variety of viral and host factors and their interplay modify the efficiency of the response to infection, including viral replication and the magnitude of structural and functional damage to the respiratory structures, and ultimately the extent, severity and duration of subsequent wheezing. This article is protected by copyright. All rights reserved.

PMID: 28339145 [PubMed - as supplied by publisher]

Dirhamnolipids secreted from Pseudomonas aeruginosa modify anjpegungal susceptibility of Aspergillus fumigatus by inhibiting β1,3 glucan synthase activity.

ISME J. 2017 Mar 24;:

Authors: Briard B, Rasoldier V, Bomme P, ElAouad N, Guerreiro C, Chassagne P, Muszkieta L, Latgé JP, Mulard L, Beauvais A

Abstract
Pseudomonas aeruginosa and Aspergillus fumigatus are the two microorganisms responsible for most of the chronic infections in cystic fibrosis patients. P. aeruginosa is known to produce quorum-sensing controlled rhamnolipids during chronic infections. Here we show that the dirhamnolipids secreted from P. aeruginosa (i) induce A. fumigatus to produce an extracellular matrix, rich in galactosaminogalactan, 1,8-dihydroxynaphthalene (DHN)- and pyo-melanin, surrounding their hyphae, which facilitates P. aeruginosa binding and (ii) inhibit A. fumigatus growth by blocking β1,3 glucan synthase (GS) activity, thus altering the cell wall architecture. A. fumigatus in the presence of diRhls resulted in a growth phenotype similar to that upon its treatment with anjpegungal echinocandins, showing multibranched hyphae and thicker cell wall rich in chitin. The diRhl structure containing two rhamnose moieties attached to fatty acyl chain is essential for the interaction with β1,3 GS; however, the site of action of diRhls on GS is different from that of echinocandins, and showed synergistic anjpegungal effect with azoles.The ISME Journal advance online publication, 24 March 2017; doi:10.1038/ismej.2017.32.

PMID: 28338676 [PubMed - as supplied by publisher]

Preventing perioperative bleeding in patients with inherited bleeding disorders.

Evid Based Dent. 2017 Mar;18(1):28-29

Authors: Watterson C, Beacher N

Abstract
Data sourcesCochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, a regularly updated database informed by trials identified within electronic databases including MEDLINE. Further defined searches were undertaken in PubMed, Embase, The Cochrane Library, ClinicalTrials.gov and WHO International Clinical Trials Registry Platform. Additional hand searching of relevant journals and books of conference proceedings was undertaken.Study selectionRandomised and quasi-randomised controlled trials in people of all ages with haemophilia or VWD undergoing oral or dental procedures using antifibrinolytic agents (tranexamic acid (TXA) or epsilon aminocaproic acid (EACA)) to prevent perioperative bleeding compared to no intervention with or without placebo.Data extraction and synthesisTwo authors independently assessed identified publications for inclusion based on defined selection criteria. The two authors performed data extraction and risk of bias assessments using standardised forms and the Cochrane risk of bias tools. A third author, deemed to have particular subject expertise, verified eligibility of inclusion.ResultsOne randomised, double-blinded placebo controlled trial and one quasi-randomised trial were included. A total of 59 participants with haemophilia undergoing dental extraction were involved. Both trials evidenced a notable reduction in post-operative bleeding following dental extraction when either TXA or EACA were used, in addition to routine preoperative factor replacement, when compared to placebo. The number of post-operative bleeds, amount of blood loss and the need for additional clotting factors were reduced in the groups receiving antifibrinolytic therapy. No eligible trials in people with VWD were identified.ConclusionsLow quality evidence exists to support the use of adjuvant antifibrinolytic therapy to reduce perioperative bleeding in patients with haemophilia undergoing dental extraction. The limited number of trials identified (N=2), minimal sample size (N=28, N=31) and historic nature of the studies, originating from the 1970s, in addition to study heterogeneity and subsequent selection bias results in a low quality evidence grade for recommending adjuvant antifibrinolytic therapy. There is no clear indication to alter current practice utilising antifibrinolytic therapy to manage patients with haemophilia undergoing dental surgery in accordance with internationally accepted guidelines. However, further research with standardised study deigns would be welcomed in order to enhance the evidence base in the management of people with haemophilia and VWD.

PMID: 28338025 [PubMed - in process]

An Early Health Economic Analysis of the Potential Cost Effectiveness of an Adherence Intervention to Improve Outcomes for Patients with Cystic Fibrosis.

Pharmacoeconomics. 2017 Mar 23;:

Authors: Tappenden P, Sadler S, Wildman M

Abstract
BACKGROUND: Cystic fibrosis (CF) negatively impacts upon health-related quality of life and survival. Adherence to nebulised treatments is low; improving adherence is hypothesised to reduce rates of exacerbation requiring intravenous antibiotics and lung function decline.
OBJECTIVE: A state transition model was developed to assess the cost effectiveness of an intervention aimed at increasing patient adherence to nebulised and inhaled antibiotics compared with current CF care, in advance of the forthcoming CFHealthHub randomised controlled trial (RCT).
METHODS: The model estimated the costs and health outcomes for each option from the perspective of the UK National Health Service and Personal Social Services over a lifetime horizon. Health gains were valued in terms of quality-adjusted life-years (QALYs) gained. Forced expiratory volume in 1 second (FEV1) trajectories were predicted over three lung function strata: (1) FEV1 ≥70%, (2) FEV1 40-69% and (3) FEV1 <40%. Additional states were included to represent 'post-lung transplantation' and 'dead'. The model was populated using CF Registry data, literature and expert opinion. Costs were presented at 2016 values. Uncertainty was assessed using deterministic and probabilistic sensitivity analyses.
RESULTS: If effective, the adherence intervention is expected to produce an additional 0.19 QALYs and cost savings of £64,078 per patient. Across all analyses, the intervention dominated current care. Over a 5-year period, the intervention is expected to generate cost savings of £49.5 million for the estimated 2979 patients with CF with Pseudomonas aeruginosa currently aged ≥16 years in the UK. If applied to a broader population of adult patients with CF receiving any nebulised therapy, the expected savings could be considerably greater.
CONCLUSIONS: If effective, the adherence intervention is expected to produce additional health gains at a lower cost than current CF care. However, the economic analysis should be revisited upon completion of the full RCT. More generally, the analysis suggests that considerable gains could be accrued through the implementation of adherence interventions that shift care from expensive hospital-based rescue to community-based prevention.

PMID: 28337719 [PubMed - as supplied by publisher]