Addressing resistance to antibiotics in systematic reviews of antibiotic interventions.

J Antimicrob Chemother. 2016 Sep;71(9):2367-9

Authors: Leibovici L, Paul M, Garner P, Sinclair DJ, Afshari A, Pace NL, Cullum N, Williams HC, Smyth A, Skoetz N, Del Mar C, Schilder AG, Yahav D, Tovey D

Abstract
Antibiotics are among the most important interventions in healthcare. Resistance of bacteria to antibiotics threatens the effectiveness of treatment. Systematic reviews of antibiotic treatments often do not address resistance to antibiotics even when data are available in the original studies. This omission creates a skewed view, which emphasizes short-term efficacy and ignores the long-term consequences to the patient and other people. We offer a framework for addressing antibiotic resistance in systematic reviews. We suggest that the data on background resistance in the original trials should be reported and taken into account when interpreting results. Data on emergence of resistance (whether in the body reservoirs or in the bacteria causing infection) are important outcomes. Emergence of resistance should be taken into account when interpreting the evidence on antibiotic treatment in randomized controlled trials or systematic reviews.

PMID: 27169438 [PubMed - indexed for MEDLINE]

Pain is an underestimated symptom in cystic fibrosis.

Curr Opin Pulm Med. 2017 Aug 12;:

Authors: Masson A, Kirszembaum M, Sermet-Gaudelus I

Abstract
PURPOSE OF REVIEW: Life expectancy is increasing in cystic fibrosis and new aspects of the disease have to be taken into account in cystic fibrosis care.
RECENT FINDINGS: Pain is encountered among 70% of adult and pediatric patients with cystic fibrosis. This symptom is underestimated by the multidisciplinary team. It has been reported as impacting quality of life and adherence to treatments. The location of pain is inconstant among the different studies but the major symptoms are headaches, gastrointestinal, and chest pain. Pain is different for each patient and requires careful evaluation using questionnaires some of which specifically developed for patients with cystic fibrosis. Medical and nonmedical treatment such as ostheopathy or sophrology may relieve pain symptoms but have to be adjusted in the frame of a global personalized care.
SUMMARY: Pain maybe an underestimated symptom among patients with cystic fibrosis and impacts negatively on quality of life. VIDEO ABSTRACT.

PMID: 28806187 [PubMed - as supplied by publisher]

Pathogenic role of ADGRG2 in CBAVD patients replicated in Chinese population.

Andrology. 2017 Aug 14;:

Authors: Yang B, Wang J, Zhang W, Pan H, Li T, Liu B, Li H, Wang B

Abstract
Congenital bilateral absence of the vas deferens (CBAVD) is an important cause of obstructive azoospermia and male infertility worldwide. Cystic fibrosis transmembrane conductance regulator (CFTR) mutations are the main pathogenic cause, although a proportion of cases are still unexplained. Recently, adhesion G protein-coupled receptor G2 (ADGRG2) gene, a novel pathogenic gene for CBAVD was identified. We did a single population replication study in Chinese CBAVD patients to replicate its role in CBAVD developing. In this study, we performed whole-exome sequencing in 18 unrelated CBAVD patients and identified two missense variants in two patients (c.G1709A, p.C570Y; and c.A2968G, p.K990E). Both variants were predicted to be deleterious and highly conserved in silico. The p.C570Y variant is located in the G protein-coupled receptor (GPCR) proteolysis site domain, which is functionally necessary for autoproteolysis, while the p.K990E variant is in the N-terminal fragment that may regulate activity of the adhesion GPCR. We did not find any potential pathogenic CFTR variants, implying the ADGRG2 variants are the genetic cause in these patients. To the best of our knowledge, these are the first two ADGRG2 variants to be identified in Chinese CBAVD patients, which further validate the disease-causing role of ADGRG2 in this congenital defect.

PMID: 28805948 [PubMed - as supplied by publisher]

The Mechanistic Links between Insulin and Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Cl(-) Channel.

Int J Mol Sci. 2017 Aug 14;18(8):

Authors: Marunaka Y

Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel belongs to the ATP-binding cassette (ABC) transporter superfamily and regulates Cl(-) secretion in epithelial cells for water secretion. Loss-of-function mutations to the CFTR gene cause dehydrated mucus on the apical side of epithelial cells and increase the susceptibility of bacterial infection, especially in the airway and pulmonary tissues. Therefore, research on the molecular properties of CFTR, such as its gating mechanism and subcellular trafficking, have been intensively pursued. Dysregulated CFTR trafficking is one of the major pathological hallmarks in cystic fibrosis (CF) patients bearing missense mutations in the CFTR gene. Hormones that activate cAMP signaling, such as catecholamine, have been found to regulate the intracellular trafficking of CFTR. Insulin is one of the hormones that regulate cAMP production and promote trafficking of transmembrane proteins to the plasma membrane. The functional interactions between insulin and CFTR have not yet been clearly defined. In this review article, I review the roles of CFTR in epithelial cells, its regulatory role in insulin secretion, and a mechanism of CFTR regulation by insulin.

PMID: 28805732 [PubMed - in process]

Sensing Mg(2+) contributes to the resistance of Pseudomonas aeruginosa to complement-mediated opsonophagocytosis.

Environ Microbiol. 2017 Aug 14;:

Authors: Qadi M, Izquierdo-Rabassa S, Mateu Borrás M, Doménech-Sánchez A, Juan C, Goldberg JB, Hancock REW, Albertí S

Abstract
Pseudomonas aeruginosa adaptation to survive in the host hinges on its ability to probe the environment and respond appropriately. Rapid adaptation is often mediated by two-component regulatory systems, such as the PhoP/PhoQ system that responds to Mg(2+) ion concentration. However, there is limited information about the role of PhoQ in P. aeruginosa bloodstream infections. We used a murine model of systemic infection to test the virulence of a PhoQ-deficient mutant. Mutation of PhoQ impaired the virulence and the ability to cause bacteremia of P. aeruginosa. In the presence of blood concentrations of Mg(2+) , a PhoQ mutant bound more C3 and was more susceptible to complement-mediated opsonophagocytosis than the parent strain, suggesting a direct effect of the Mg(2+) on the modulation of expression of a bacterial component controlled by the PhoP/PhoQ system. Ligand blot analysis, C3 binding experiments and opsonophagocytosis assays identified this component as the outer membrane protein OprH, expression of which impaired the virulence of P. aeruginosa in a murine model of systemic infection. We demonstrate that expression of PhoQ is essential to detect Mg(2+) and reduce the expression of OprH, a previously unrecognized C3 binding molecule that promotes the opsonophagocytosis of P. aeruginosa. This article is protected by copyright. All rights reserved.

PMID: 28805355 [PubMed - as supplied by publisher]

Early seasonal influenza vaccination and delayed influenza peaks - a possible cause of end-of-season outbreaks.

J Infect. 2017 Aug 10;:

Authors: Tang JW, Mutuyimana J, Teo KW, Lea S, Galiano M, Lackenby A, Donaghy B, Blount J, Ellis J, Range S

Abstract
Intra-seasonal waning of influenza vaccine-induced immunity is now well-recognised. This phenomenon may lead to end-of-season influenza outbreaks despite a good antigenic match with the seasonal influenza vaccine. Influenza immunisation later in the season may reduce such outbreaks if late seasonal influenza incidence is regular and predictable for a given population.

PMID: 28804025 [PubMed - as supplied by publisher]

The AREST CF experience in biobanking - More than just tissues, tubes and time.

J Cyst Fibros. 2017 Aug 09;:

Authors: Garratt LW, Kicic A, Robertson C, Ranganathan S, Sly PD, Stick SM, AREST CF

Abstract
Research to further improve outcomes for people with CF is dependent upon well characterised, archived and accessible clinical specimens. The recent article by Beekman et al. published in Journal of Cystic Fibrosis summarised a scientific meeting at the 13th ECFS Basic Science Conference. This meeting discussed how well-annotated, clinical biobanks for CF could be established in Europe to meet the needs of therapeutic development. The Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) has conducted biobanking of CF research and clinical specimens since the late 1990s and is custodian of the most comprehensive paediatric CF biobank in the world that focuses on the first years of life. This short communication will describe the approach undertaken by AREST CF in establishing a clinical specimen biobank.

PMID: 28803050 [PubMed - as supplied by publisher]

Functional endoscopic sinus surgery improves the quality of life in children suffering from chronic rhinosinusitis with nasal polyps.

Int J Pediatr Otorhinolaryngol. 2017 Sep;100:145-148

Authors: Fetta M, Tsilis NS, Segas JV, Nikolopoulos TP, Vlastarakos PV

Abstract
OBJECTIVE: To evaluate the impact of FESS in children with chronic rhinosinusitis with nasal polyps, regarding their overall postoperative quality-of-life (QoL) and constituent QoL domains. Potential differences between cystic fibrosis (CF) sufferers and non-sufferers, or cases with recurrent sinonasal polyposis versus single-operations were also explored.
METHODS: 39 children were studied. The mean patient age was 10.9 years; four children suffered from cystic fibrosis. The children (or parents) completed the Glasgow Benefit Inventory for Children (GCBI) at least six months after their operation. The Mann-Whitney test compared the GCBI scores between non- and CF sufferers, as well as children with and without recurrent polyposis.
RESULTS: The median overall QoL score was 98. There were no statistically significant differences between CF sufferers and non-sufferers regarding their overall QoL, or the respective individual QoL domains, apart from their physical postoperative activity (p = 0.04). Twelve children demonstrated recurrent polyposis (30.7%); among them three were cystic fibrosis sufferers. No statistically significant differences were identified in the overall QoL score, or individual GCBI subscale scores between children with recurrent polyposis versus single-operations. Children with recurrent polyposis but not CF performed better regarding their overall QoL (p = 0.021) and medical status (p = 0.015), compared to their CF counterparts.
CONCLUSION: FESS performed for chronic rhinosinusitis with nasal polyps in children is associated with improved postoperative QoL, irrespective of the presence of CF (although the latter needs to be confirmed in larger patient cohorts). The absence of appreciable differences in the overall QoL, or its constituent domains, between single and re-operated children, indicate that the positive effect of FESS outweighed the burden of re-operation. Appropriate preoperative informed consent in cases of recurrent sinonasal polyposis necessitates acknowledging worse respective outcomes in CF sufferers.

PMID: 28802361 [PubMed - in process]

Reply: Epithelial alkalinity and hyperproliferation in the Cftr KO intestine.

Am J Physiol Gastrointest Liver Physiol. 2016 06 01;310(11):G1184

Authors: Walker NM, Liu J, Stein SR, Strubberg AM, Clarke LL

PMID: 27281735 [PubMed - indexed for MEDLINE]

CFTR and pHi regulation.

Am J Physiol Gastrointest Liver Physiol. 2016 06 01;310(11):G1183

Authors: Akiba Y, Kaunitz JD, Montrose MH

PMID: 27281734 [PubMed - indexed for MEDLINE]

Microbiome in lung explants of idiopathic pulmonary fibrosis: a case-control study in patients with end-stage fibrosis.

Thorax. 2017 Aug 11;:

Authors: Kitsios GD, Rojas M, Kass DJ, Fitch A, Sembrat JC, Qin S, Veraldi KL, Gibson KF, Lindell K, Pilewski JM, Methe B, Li K, McDyer J, McVerry BJ, Morris A

Abstract
The microbiome has been proposed to play a role in the progression of idiopathic pulmonary fibrosis (IPF) based on bronchoalveolar lavage analyses, but the microbiome of lung tissue in IPF has not been explored. In a case-control study of lung explants analysed by 16S rRNA gene sequencing, we could not reliably detect bacterial DNA in basilar tissue samples from patients with either chronic or acute exacerbations of IPF, in contrast to control candidate-donor lungs or cystic fibrosis explants. Thus, our data do not indicate microbiome alterations in regions of IPF lung with advanced fibrosis.

PMID: 28802277 [PubMed - as supplied by publisher]

Prerequisites for a dry powder inhaler for children with cystic fibrosis.

PLoS One. 2017;12(8):e0183130

Authors: Lexmond AJ, Hagedoorn P, Frijlink HW, Rottier BL, de Boer AH

Abstract
Correct inhalation technique is essential for effective use of dry powder inhalers (DPIs), as their effectiveness largely depends on the patient's inhalation manoeuvre. Children are an especially challenging target population for DPI development due to the large variability in understanding and inspiratory capacities. We previously performed a study in which we determined the prerequisites for a paediatric DPI in a mostly healthy paediatric population, for which we used an empty test inhaler with variable internal airflow resistance and mouthpiece. In the current study we investigated what specifications are required for a DPI for children with cystic fibrosis (CF), for which we expanded on our previous findings. We recorded flow profiles of 35 children with CF (aged 4.7-14.7 years) at three airflow resistances (0.031-0.045 kPa0.5.min.L-1) from which various inspiratory parameters were computed. Obstructions in the mouth during inhalation were recorded with a sinuscope. All children were able to perform a correct inhalation manoeuvre, although video analysis showed that children did not place the inhaler correctly in the mouth in 17% of the cases. No effect was found of medium to high airflow resistance on total inhaled volume, which implies that the whole resistance range tested is suitable for children with CF aged 4-14 years. No effect could be established of either mouthpiece design or airflow resistance on the occurrence of obstructions in the mouth cavity. This study confirms our previous conclusion that the development of DPIs specifically for children is highly desired. Such a paediatric DPI should function well at 0.5 L inhaled volume and a peak inspiratory flow rate of 20 to 30 L/min, depending on the internal airflow resistance. This resistance can be increased up to 0.045 kPa0.5.min.L-1 (medium-high) to reduce oropharyngeal deposition. A higher resistance may be less favourable due to its compromising effect on PIF and thereby on the energy available for powder dispersion.

PMID: 28800360 [PubMed - in process]

Reply from Authors of Correlation of LCI with Hyperpolarized (129)Xe Magnetic Resonance Imaging in Pediatric CF Subjects.

Am J Respir Crit Care Med. 2017 Aug 11;:

Authors: Kanhere N, Couch MJ, Rayment JH, Ratjen F, Santyr G

PMID: 28800249 [PubMed - as supplied by publisher]

Reply from the Authors of Comparison of Lung Clearance Index and Magnetic Resonance Imaging for Assessment of Lung Disease in Children with Cystic Fibrosis.

Am J Respir Crit Care Med. 2017 Aug 11;:

Authors: Stahl M, Wielpütz MO, Kauczor HU, Mall MA

PMID: 28800247 [PubMed - as supplied by publisher]

The Respective Roles of LCI and MRI in the Clinical Management of Cystic Fibrosis Patients.

Am J Respir Crit Care Med. 2017 Aug 11;:

Authors: Verbanck S, Vanderhelst E

PMID: 28800245 [PubMed - as supplied by publisher]

Increased Expression of Plasma-Induced ABCC1 mRNA in Cystic Fibrosis.

Int J Mol Sci. 2017 Aug 11;18(8):

Authors: Ideozu JE, Zhang X, Pan A, Ashrafi Z, Woods KJ, Hessner MJ, Simpson P, Levy H

Abstract
The ABCC1 gene is structurally and functionally related to the cystic fibrosis transmembrane conductance regulator gene (CFTR). Upregulation of ABCC1 is thought to improve lung function in patients with cystic fibrosis (CF); the mechanism underlying this effect is unknown. We analyzed the ABCC1 promoter single nucleotide polymorphism (SNP rs504348), plasma-induced ABCC1 mRNA expression levels, and ABCC1 methylation status and their correlation with clinical variables among CF subjects with differing CFTR mutations. We assigned 93 CF subjects into disease severity groups and genotyped SNP rs504348. For 23 CF subjects and 7 healthy controls, donor peripheral blood mononuclear cells (PBMCs) stimulated with plasma underwent gene expression analysis via qRT-PCR. ABCC1 promoter methylation was analyzed in the same 23 CF subjects. No significant correlation was observed between rs504348 genotypes and CF disease severity, but pancreatic insufficient CF subjects showed increased colonization with any form of Pseudomonas aeruginosa (OR = 3.125, 95% CI: 1.192-8.190) and mucoid P. aeruginosa (OR = 5.075, 95% CI: 1.307-28.620) compared to the pancreatic sufficient group. A significantly higher expression of ABCC1 mRNA was induced by CF plasma compared to healthy control plasma (p < 0.001). CF subjects with rs504348 (CC/CG) also had higher mRNA expression compared to those with the ancestral GG genotype (p < 0.005). ABCC1 promoter was completely unmethylated; therefore, we did not detect any association between methylation and CF disease severity. In silico predictions suggested that histone modifications are crucial for regulating ABCC1 expression in PBMCs. Our results suggest that ABCC1 expression has a role in CFTR activity thereby increasing our understanding of the molecular underpinnings of the clinical heterogeneity in CF.

PMID: 28800122 [PubMed - in process]

High usability of a smartphone application for reporting symptoms in adults with cystic fibrosis.

J Telemed Telecare. 2017 Jan 01;:1357633X17723366

Authors: Wood J, Jenkins S, Putrino D, Mulrennan S, Morey S, Cecins N, Hill K

Abstract
Introduction In cystic fibrosis, exacerbations impair lung function and health-related quality of life, increase healthcare costs and reduce survival. Delayed reporting of worsening symptoms can result in more severe exacerbations and worse clinical outcomes; therefore there is a need for a novel approach to facilitate the early identification and treatment of exacerbations in this population. This study investigated the usability of a smartphone application to report symptoms in adults with cystic fibrosis, and the observer agreement in clinical decision-making between senior clinicians interpreting smartphone application responses. Methods Adults with cystic fibrosis used the smartphone application weekly for four weeks. The application comprised 10 yes/no questions regarding respiratory symptoms and two regarding emotional well-being. Usability was measured with the System Usability Scale; Observer agreement was tested by providing a cystic fibrosis physician and a nurse practitioner with 45 clinical scenarios. For each scenario the clinicians, who were blinded to each other's responses, were asked to indicate whether or not they would: (i) initiate telephone contact, and/or (ii) request a clinic visit for the individual. Results Ten participants (five female), aged mean (SD) 33 (11) years, FEV1 49 (27)% predicted completed the study. The mean (SD) System Usability Scale score was 94 (6). There was perfect agreement between clinicians for initiating contact with the participant ( κ = 1.0, p < 0.001), and near-perfect for requesting a clinic visit ( κ = 0.86, p < 0.001). Discussion The use of a smartphone application for reporting symptoms in adults with cystic fibrosis has excellent usability and near-perfect agreement between senior clinicians when interpreting the application responses.

PMID: 28799841 [PubMed - as supplied by publisher]

Allergic and Noninvasive Infectious Pulmonary Aspergillosis Syndromes.

Clin Chest Med. 2017 Sep;38(3):521-534

Authors: Muldoon EG, Strek ME, Patterson KC

Abstract
Aspergillus spp are ubiquitous in the environment, and inhalation of Aspergillus spores is unavoidable. An intact immune system, with normal airway function, protects most people from disease. Globally, however, the toll from aspergillosis is high. The literature has largely focused on invasive aspergillosis, yet the burden in terms of chronicity and prevalence is higher for noninvasive Aspergillus conditions. This article discusses allergic aspergilloses and provides an update on the diagnosis and management of allergic bronchopulmonary aspergillosis, including in patients with cystic fibrosis, and an update on severe asthma with fungal sensitization. In addition, the presentation, investigation, and management of noninvasive infectious aspergilloses are reviewed.

PMID: 28797493 [PubMed - in process]

Fungal Infections After Lung Transplantation.

Clin Chest Med. 2017 Sep;38(3):511-520

Authors: Kennedy CC, Razonable RR

Abstract
Infection remains a significant source of morbidity and mortality after lung transplant, including fungal infection. Various antifungal prophylactic agents are administered for a variable duration after transplant with the goal of preventing invasive fungal infections. Alternatively, some programs target the use of antifungal agents only in those colonized with Aspergillus spp. Despite prophylaxis or preemptive therapy, a significant number of invasive fungal infections occur after lung transplant. Risk factors for fungal infections include single lung transplant, pretransplant Aspergillus colonization, environmental risks, structural lung disease such as cystic fibrosis, augmented immunosuppression, sinus disease, and use of indwelling airway stents.

PMID: 28797492 [PubMed - in process]

Recent advances in understanding Pseudomonas aeruginosa as a pathogen.

F1000Res. 2017;6:1261

Authors: Klockgether J, Tümmler B

Abstract
The versatile and ubiquitous Pseudomonas aeruginosa is an opportunistic pathogen causing acute and chronic infections in predisposed human subjects. Here we review recent progress in understanding P. aeruginosa population biology and virulence, its cyclic di-GMP-mediated switches of lifestyle, and its interaction with the mammalian host as well as the role of the type III and type VI secretion systems in P. aeruginosa infection.

PMID: 28794863 [PubMed]