The association of pediatric cystic fibrosis-related diabetes screening on clinical outcomes by center: A CF patient registry study.

J Cyst Fibros. 2019 Aug 19;:

Authors: Franck Thompson E, Watson D, Benoit CM, Landvik S, McNamara J

Abstract
BACKGROUND: Cystic fibrosis related diabetes (CFRD) has been associated with pulmonary function decline, nutritional status decline and increased mortality. In 2010, the CFRD Clinical Care Guideline were updated, recommending all patients with CF begin CFRD screening at 10 years old. This study uses CF Foundation Patient Registry to examine the impact of screening practices at centers across the United States from 2008 to 2015. We examined the association of screening practices and CFRD diagnosis at individual centers and trends in ppFEV1 and BMI percentile prior to and after diagnosis.
METHODS: The cohort was defined as patients with CF and without CFRD who turned 10 years old from 2009 to 2015. Centers were classified based on their CFRD screening rates. Kaplan-Meier curves summarized the distribution of age at CFRD diagnosis. Among patients diagnosed with CFRD, we examined differences in ppFEV1 and BMI percentile two years prior to diagnosis and two years post-diagnosis by clinic screening rate.
RESULTS: Of 3553 patients, 445 (13%) were diagnosed with CFRD. The average age of diagnosis was 13 years old. The screening rate of the patients' clinic was significantly associated with time to diagnosis (pvalue=0.0001). Among patients diagnosed with CFRD, clinics with lower screening rates of CFRD had steeper rates of pulmonary decline two years prior to diagnosis.
CONCLUSION: Centers that screen for CFRD more tend to diagnose a larger percent of patients with CFRD and at a younger age. Additionally, patients at centers with lower screening rates have faster rates of pulmonary decline prior to CFRD diagnosis.

PMID: 31439463 [PubMed - as supplied by publisher]

Comparative study of immune responses elicited by outer membrane vesicles of different Pseudomonas aeruginosa strains.

Comp Immunol Microbiol Infect Dis. 2019 Jul 04;66:101328

Authors: Satarian F, Nejadsattari T, Vaziri F, Siadat SD

Abstract
BACKGROUND: Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic mucosal human pathogen that naturally releases outer membrane vesicles (OMVs) in different environments, as do other Gram-negative bacteria. The intestinal tract infections caused by P. aeruginosa increase the risk of respiratory infections and mortality of other diseases related to gut infections. Therefore, in this study, we attempted to investigate toll-like receptor (TLR) signaling pathways and immune response profiles of human colon adenocarcinoma (Caco2) cell line exposed to the OMVs of three different P. aeruginosa strains (i.e., antibiotic-susceptible, multi-drug resistant (MDR), and standard lab ATCC 17933).
MATERIALS AND METHODS: Real-time quantitative reverse transcription PCR array was carried out to determine mRNA expression in 84 TLRs signaling pathway genes, and the production of specific cytokines was measured by ELISA.
RESULTS: OMVs of different strains could induce unique changes in regulating TLRs signaling pathways, such that there were remarkable differences in pro-inflammatory effects and anti-inflammatory responses among the three strains.
CONCLUSION: The more complete immune responses observed through the MAMPs caused by MDR strain OMVs interactions with Caco2 lead us to the conclusion that the use of MDR or cystic fibrosis strain OMVs for better known the host immune responses seems preferable.

PMID: 31437676 [PubMed - as supplied by publisher]

Opportunities to Improve Utilization of Palliative Care among Adults with Cystic Fibrosis: A Systematic Review.

J Pain Symptom Manage. 2019 Aug 19;:

Authors: Marmor M, Jonas A, Mirza A, Rad E, Wong H, Aslakson RA

Abstract
CONTEXT: Individuals with Cystic Fibrosis (CF) frequently survive into adulthood and many have multi-faceted symptoms that impair quality of life.
OBJECTIVE: We conducted a systematic review to investigate opportunities to improve utilization of palliative care among adults with CF.
METHODS: We searched PubMed, Embase, Scopus, Web of Science and CINAHL databases from inception until September 27, 2018, and reviewed references manually. Eligible articles were published in English, involved adults age 18 years and older with CF and contained original data regarding patient outcomes related to presence of advanced care planning (ACP), symptom experience, and preferred and/or received end-of-life care.
RESULTS: We screened 652 article abstracts and 32 full text articles; 12 studies met inclusion criteria. All studies were published between 2000 and 2018. Pertinent findings include that while 43% to 65% of adults with CF had contemplated completing ACP, the majority only completed ACP during their terminal hospital admission. Patients also reported high prevalence of untreated symptoms, with adequate symptom control reported in 45% among those with dyspnea, 22% among those with pain and 51% among those with anxiety and/or depression. Prevalence of in-hospital death ranged from 62% to 100%, with a third dying in the intensive care unit (ICU). The majority received antibiotics and preventative treatments during their terminal hospitalization. Finally, treatment from a palliative care specialist was associated with a higher prevalence of patient completion of advanced directives, decreased likelihood of in-ICU death and decreased use of mechanical ventilation at end-of-life.
CONCLUSION: Adults with CF often have untreated symptoms and many opportunities exist for palliative care specialists to improve ACP completion and quality of end-of-life care.

PMID: 31437475 [PubMed - as supplied by publisher]

Integrating Clinical Ultrasound into Screening for Cystic Fibrosis Liver Disease: Approach with Caution and Optimism.

J Pediatr Gastroenterol Nutr. 2019 Jul 10;:

Authors: Narkewicz MR

PMID: 31436709 [PubMed - as supplied by publisher]

Liver Ultrasound Patterns in Children With Cystic Fibrosis Correlate With Noninvasive Tests of Liver Disease.

J Pediatr Gastroenterol Nutr. 2019 Sep;69(3):351-357

Authors: Ling SC, Ye W, Leung DH, Navarro OM, Weymann A, Karnsakul W, Freeman AJ, Magee JC, Narkewicz MR

Abstract
OBJECTIVES: Early identification of children with cystic fibrosis (CF) at risk for severe liver disease (CFLD) would enable targeted study of preventative therapies. There is no gold standard test for CFLD. Ultrasonography (US) is used to identify CFLD, but with concerns for its diagnostic accuracy. We aim to determine if differences in standard blood tests, imaging variables and noninvasive liver fibrosis indices correlate with liver US patterns, and thus provide supportive evidence that a heterogeneous US liver pattern reflects clinically relevant liver disease.
METHODS: We studied baseline research abdominal US and bloodwork from 244 children with pancreatic insufficient CF, ages 3 to 12 years, enrolled in a prospective study of the ability of US to predict CF cirrhosis (PUSH study). Children with a heterogeneous (HTG) liver pattern on US (n = 62) were matched 1 : 2 in design with children with normal US (NL, n = 122). Analyses included children with nodular (NOD, n = 22) and homogeneous hyperechoic (HMG, n = 38) livers.
RESULTS: Univariate analysis showed significant differences between US groups for standard blood tests, spleen size, and noninvasive liver fibrosis indices. Multivariable models discriminated NOD versus NL with excellent accuracy (AUROC 0.96). Models also distinguish HTG versus NL (AUROC 0.76), NOD versus HTG (0.78), and HMG versus NL (0.79).
CONCLUSIONS: Liver US patterns in children with CF correlate with platelet count, spleen size and indices of liver fibrosis. Multivariable models of these biomarkers have excellent discriminating ability for NL versus NOD, and good ability to distinguish other US patterns, suggesting that US patterns correlate with clinically relevant liver disease.

PMID: 31436672 [PubMed - in process]

Prevention of transmission of Mycobacterium abscessus among patients with cystic fibrosis.

Curr Opin Pulm Med. 2019 Aug 20;:

Authors: Gross JE, Nick JA, Martiniano SL

Abstract
PURPOSE OF REVIEW: Pulmonary nontuberculous mycobacterial (NTM) infection is recognized as one of the most challenging infections to treat among cystic fibrosis patients. The source of NTM infection, modes of transmission, and exposure risks are poorly understood. Healthcare-associated transmission of Mycobacterium abscessus among cystic fibrosis patients has been suspected and is a growing concern for cystic fibrosis centers worldwide. This review describes our current understanding of prevention of healthcare-associated transmission of M. abscessus among patients with cystic fibrosis.
RECENT FINDINGS: Multiple healthcare-associated outbreaks of M. abscessus among cystic fibrosis patients within cystic fibrosis care centers have been reported. The percentage of patients involved in the reported outbreaks, as well as the perceived impact of patient-to-patient transmission varies dramatically between the reporting centers and population surveys. Several groups have now proposed M. abscessus-specific measures to limit future outbreaks.
SUMMARY: Improved NTM surveillance combined with a standardized, systematic approach to epidemiologic investigation of potential episodes of healthcare-associated transmission will help to reveal risk factors for NTM acquisition and inform future evidence-based infection prevention and control measures for patients with cystic fibrosis.

PMID: 31436542 [PubMed - as supplied by publisher]

Efficacy and safety of tobramycin inhalation powder in bronchiectasis patients with P. aeruginosa infection: Design of a dose-finding study (iBEST-1).

Pulm Pharmacol Ther. 2019 Aug 18;:101834

Authors: Loebinger MR, Polverino E, Blasi F, Elborn SJ, Chalmers JD, Tiddens HA, Goossens H, Tunney M, Zhou W, Angyalosi G, Hill AT, Haworth CS, iBEST-1 Trial Team

Abstract
In patients with bronchiectasis (BE), infection with Pseudomonas aeruginosa (Pa) results in disease progression, frequent pulmonary exacerbations and lung function decline. However, at present, no inhaled antibiotics have been approved for the treatment of these patients. Tobramycin inhalation powder (TIP), approved for treatment of Pa infection in cystic fibrosis, could be a promising candidate. We aimed to assess effective and well-tolerated doses and regimens of TIP in BE patients with Pa infection. In this phase II, double-blind, placebo-controlled, randomised study, three different daily doses of TIP are administered either as continuous or cyclical regimens. The study protocol comprises 7-28 days of screening, 112 days of double-blind treatment and 56 days of follow-up. The plan was to enrol 180 patients (aged ≥18 years) with BE, documented Pa infection and a history of exacerbations. The primary outcome is change in sputum Pa density from baseline. Key secondary outcomes include number of pulmonary exacerbations, use of antipseudomonal antibiotics, serum and sputum tobramycin concentrations, quality of life and safety. Exploratory endpoints include lung clearance index, sputum inflammatory markers and microbiome analysis. As of October 2018, 107/180 patients were enrolled at 34 sites (six countries) following which recruitment was closed for administrative reasons unrelated to safety findings. Despite a reduced sample size from initially planned enrolment, the unique design may inform the benefit-risk profile of TIP in BE patients with chronic Pa infection. Moreover, several novel and exploratory endpoints (lung clearance index, inflammatory biomarkers, lung microbiome), will contribute to the advancement of research in this area.

PMID: 31433997 [PubMed - as supplied by publisher]

Phosphatidylcholine Passes by Paracellular Transport to the Apical Side of the Polarized Biliary Tumor Cell Line Mz-ChA-1.

Int J Mol Sci. 2019 Aug 19;20(16):

Authors: Stremmel W, Staffer S, Weiskirchen R

Abstract
Phosphatidylcholine (PC) translocation into mucus of the intestine was shown to occur via a paracellular transport across the apical/lateral tight junction (TJ) barrier. In case this could also be operative in biliary epithelial cells, this may have implication for the pathogenesis of primary sclerosing cholangitis (PSC). We here evaluated the transport of PC across polarized cholangiocytes. Therefore, the biliary tumor cell line Mz-ChA-1 was grown to confluency. In transwell culture systems the translocation of PC to the apical compartment was analyzed. After 21 days in culture, polarized Mz-ChA-1 cells revealed a predominant apical translocation of choline containing phospholipids including PC with minimal intracellular accumulation. Transport was suppressed by TJ destruction employing chemical inhibitors and pretreatment with siRNA to TJ forming proteins as well as the apical transmembrane mucin 3 as PC acceptor. Apical translocation was dependent on a negative apical electrical potential created by the cystic fibrosis transmembrane conductance regulator (CFTR) and the anion exchange protein 2 (AE2). It was stimulated by apical application of secretory mucins. The results indicated the existence of a paracellular PC passage across apical/lateral TJ of the polarized biliary epithelial tumor cell line Mz-ChA-1. This has implication for the generation of a protective mucus barrier in the biliary tree.

PMID: 31430850 [PubMed - in process]

Dehiscence of Bronchial Anastomosis After Lung Transplantation: A Successful Unconventional Treatment.

Ann Thorac Surg. 2018 08;106(2):e81-e83

Authors: Bottero S, Meucci D, Trozzi M, Carotti A

Abstract
Anastomotic airway complications, including the dehiscence of the bronchial anastomosis, are a severe cause of morbidity after lung transplantation. We present a case of dehiscence treated by placing an uncovered metal stent into the main bronchus. We usually use this procedure for bronchial stenosis, but in this case, the stent favored the growth of granulation tissue and so the closure of the dehiscence. This procedure was minimally invasive and may be an alternative to an open repair, without precluding open repair in case of failure.

PMID: 29596819 [PubMed - indexed for MEDLINE]

Fluoroquinolones for the Treatment of Other Respiratory Tract Infections: A Review of Clinical Effectiveness, Cost-Effectiveness, and Guidelines

Book. 2019 05 31

Authors: Cowling T, Farrah K

Abstract
Fluoroquinolones (FQs) are a common class of antibiotic used for the treatment of infections, including those of the respiratory tract. However, the use of FQs has been controversial as certain types are associated with antibiotic resistance and adverse events. Antibiotic resistance is of significant concern due to the broad-spectrum nature and common use of FQs, and FQ resistance occurs through a number of potential individual or combined mechanisms.1 Recent global surveillance studies have found increasing rates of FQ resistance among almost all species of bacteria, and this has been demonstrated in urinary tract infection, respiratory tract infections, intraabdominal infections, skin and skin structure infections, and sexually transmitted infections.2,3 FQ resistance has likely been driven by the widespread use of the antibiotic, and adjustments clinical practice guidelines may be warranted to limit misuse of FQs. Common adverse events include gastrointestinal and central nervous system toxicities, while other adverse events include rashes and other allergic reactions, tendinitis and tendon rupture, QT prolongation, hypoglycemia and hyperglycemia, and hematologic toxicity. Several FQs have been withdrawn from the market due to adverse events.4 In the United States, examples include the withdrawal of grepafloxacin in 1999 due to fatal cardiovascular events, temafloxacin in 1992 due to severe adverse reactions (e.g. hemolytic anemia, acute renal failure, hepatotoxicity, and death), and alatrofloxacin in 2006 due to liver toxicity and death.5 The association of FQ use with serious adverse events has led to reevaluations of the use of FQs for uncomplicated infections in several jurisdictions. In 2016, the United Sates Food and Drug Administration (FDA) released a statement advising the restriction of FQ use in patients with acute sinusitis, acute bronchitis, and uncomplicated urinary tract infections who have other treatment options, because the risk of serious side effects generally outweighed the benefits.6 As a result, Health Canada undertook a review of FQs and associated adverse events, and posted the results in their Summary Safety Review in January 2017. The review concluded that adverse events associated with FQ use may be persistent and disabling in rare cases, and that Health Canada would collaborate with drug manufacturers to update product safety information to reflect this potential risk.7 There remains uncertainty in the use of FQs for the treatment of infections. This report is an extension of a previous Rapid Response report,8 which identified evidence for the clinical effectiveness, cost-effectiveness, and guidelines for FQs in pneumonia and chronic obstructive pulmonary disease (COPD). The report found inconsistent results in the systematic reviews of the clinical effectiveness of FQ use in pneumonia, while there was a limited volume of evidence in the clinical effectiveness in COPD, and cost-effectiveness of FQ use in pneumonia. The current report aims to identify and synthesize the evidence describing the clinical effectiveness, cost-effectiveness and guidelines for the use of FQs in other respiratory tract infections (excluding COPD, pneumonia, cystic fibrosis and tuberculosis).

PMID: 31433606

Prevalence of chronic rhinosinusitis in bronchiectasis patients suspected of ciliary dyskinesia.

Int Forum Allergy Rhinol. 2019 Aug 20;:

Authors: McCormick JP, Weeks CG, Rivers NJ, Owen JD, Kelly DR, Rowe SM, Solomon GM, Woodworth BA, Cho DY

Abstract
BACKGROUND: Mucociliary clearance is a main defense mechanism of the airway and is impaired in ciliary dyskinesia. The objective of this study was to evaluate the prevalence of chronic rhinosinusitis (CRS) and its characteristics in bronchiectasis patients suspected of harboring ciliary dyskinesia.
METHODS: Bronchiectasis patients referred to a rhinology clinic for nasal brush biopsy (NBB) were included in this study. NBB was performed using a curettage technique whereby ciliated epithelial cells were obtained from the surface of the inferior nasal turbinate. Results of transmission electron microscopy findings, primary ciliary dyskinesia (PCD) gene (35 genes) analyses (Invitae), and sinus computed tomography (CT) scans were reviewed.
RESULTS: Twenty-three patients (age, 54 ± 2.9 years) were referred for NBB between 2015 and 2018. Thirteen patients (56.5%) met the criteria for diagnosis of CRS. Nineteen patients had ciliary ultrastructural defects. The most common finding was compound cilia (n = 11, 47.8%). Five patients (21.7%) had central microtubule defects (CMD) with higher forced expiratory volume in 1 second (FEV1 ) at the time of referral than those without CMD (CMD+ , 91 ± 3.7%; CMD- , 73.5 ± 5.7%; p = 0.023). Of 15 subjects with a PCD gene panel, 67% (9 of 15) carried at least 1 gene associated with PCD. Only 1 patient reached diagnosis of PCD. Approximately 50% of non-PCD carriers had a smoking history (p < 0.05). Lund-Mackay scores did not significantly differ between PCD and non-PCD carriers (p = 0.72).
CONCLUSION: Nearly half of bronchiectasis patients referred for NBB had concurrent CRS. The presence of ciliary abnormalities was not amplified in bronchiectasis patients with CRS compared to those without CRS. Extrinsic factors may be related to ciliary structural abnormalities in non-PCD gene carriers.

PMID: 31430425 [PubMed - as supplied by publisher]

Cystic Fibrosis: The Sense of Smell.

Am J Rhinol Allergy. 2019 Aug 20;:1945892419870450

Authors: Di Lullo AM, Iacotucci P, Comegna M, Amato F, Dolce P, Castaldo G, Cantone E, Carnovale V, Iengo M

PMID: 31430187 [PubMed - as supplied by publisher]

To treat or not to treat: dysglycaemia in cystic fibrosis.

Diabet Med. 2019 Aug 20;:

Authors: Adler AI

Abstract
Good evidence for treating hyperglycaemia in cystic fibrosis is lacking. The accompanying commentary [1] questions whether treating cystic fibrosis-related diabetes (CFRD) and, specifically, lesser degrees of dysglycaemia in people with cystic fibrosis leads to better outcomes [1]. Although epidemiological studies have documented that people with cystic fibrosis and diabetes die earlier than people with cystic fibrosis without diabetes [2], and among people with CFRD, those with higher compared to lower measures of glycaemia also die earlier [3], this evidence falls short of proving that treating people for hyperglycaemia will make them live longer. Warren, then, is correct to offer a 'reality check', and chooses to focus not on CFRD, but rather on dysglycaemia, that is, values of blood glucose approaching, but not attaining, the diagnostic criteria for diabetes. This article is protected by copyright. All rights reserved.

PMID: 31429490 [PubMed - as supplied by publisher]

Using Large Datasets to Understand Nanotechnology.

Adv Mater. 2019 Aug 20;:e1902798

Authors: Paunovska K, Loughrey D, Sago CD, Langer R, Dahlman JE

Abstract
Advances in sequencing technologies have made studying biological processes with genomics, transcriptomics, and proteomics commonplace. As a result, this suite of increasingly integrated techniques is well positioned to study drug delivery, a process that is influenced by many biomolecules working in concert. Omics-based approaches can be used to study the vast nanomaterial chemical space as well as the biological factors that affect the safety, toxicity, and efficacy of nanotechnologies. The generation and analysis of large datasets, methods to interpret them, and dataset applications to nanomaterials to date, are demonstrated here. Finally, new approaches for how sequencing-generated datasets can answer fundamental questions in nanotechnology based drug delivery are proposed.

PMID: 31429126 [PubMed - as supplied by publisher]

A high prevalence of chronic gastrointestinal symptoms in adults with cystic fibrosis is detected using tools already validated in other GI disorders.

United European Gastroenterol J. 2019 Aug;7(7):881-888

Authors: Hayee B, Watson KL, Campbell S, Simpson A, Farrell E, Hutchings P, Macedo P, Perrin F, Whelan K, Elston C

Abstract
Background: People with cystic fibrosis (CF) report a variety of gastrointestinal (GI) symptoms, independent of pancreatic enzyme insufficiency (PEI), reminiscent of other chronic GI disorders. There are currently no accepted or validated assessment tools and neither the range, frequency nor severity of GI symptoms has been systematically described in CF. We present results of a cross-sectional study using established tools and compare them to current measures of quality of life (QOL).
Methods: Consecutive patients attending specialist CF appointments were asked to complete questionnaires including the GI Symptom Rating Scale (GSRS); Irritable Bowel Syndrome Symptom Severity Score (IBS-SSS) and Cystic Fibrosis Questionnaire (CFQ-R). Questionnaire terminology was altered to replace references to 'IBS' with 'GI symptoms'.
Results: In total, 107 patients were recruited (mean age, 27.8 ± 9.6 years; 60 female), and 94 (88%) had PEI. Body mass index was 22.1 ± 3.6 kg/m2, forced expiratory volume in one second was 59 + 27.7% predicted. Fifty-three (49.5%) were p.Phe508del homozygous. Overall 69/107 (65%) reported significant GI symptoms independent of PEI or adherence to pancreatic enzyme replacement therapy (PERT), with the four most frequent being attributable to the lower GI tract: bloating/distension, flatulence, abdominal pain and borborygmi (gurgling). There was no numerical correlation between any CFQ-R domain (particularly Digestion domain) and GSRS or SSS.
Conclusion: This is the first systematic study measuring GI symptoms in CF using validated GI tools. Symptoms are not related to PERT or genotype and appear to be captured well by the GSRS. Further research will study longitudinal changes with treatment, and therapeutic trials in CF may use these tools to demonstrate a positive impact on 'non-respiratory' symptoms and QOL.

PMID: 31428412 [PubMed]

To establish a treatment for GI symptoms of cystic fibrosis, it is necessary to develop a symptom evaluation tool.

United European Gastroenterol J. 2019 Aug;7(7):873-874

Authors: Suzuki H

PMID: 31428410 [PubMed]

Metabolic Reprograming of Cystic Fibrosis Macrophages via the IRE1α Arm of the Unfolded Protein Response Results in Exacerbated Inflammation.

Front Immunol. 2019;10:1789

Authors: Lara-Reyna S, Scambler T, Holbrook J, Wong C, Jarosz-Griffiths HH, Martinon F, Savic S, Peckham D, McDermott MF

Abstract
Cystic Fibrosis (CF) is a recessive genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR mutations cause dysregulation of channel function with intracellular accumulation of misfolded proteins and endoplasmic reticulum (ER) stress, with activation of the IRE1α-XBP1 pathway that regulates a subset of unfolded protein response (UPR) genes. This pathway regulates a group of genes that control proinflammatory and metabolic responses in different immune cells; however, the metabolic state of immune cells and the role of this pathway in CF remain elusive. Our results indicate that only innate immune cells from CF patients present increased levels of ER stress, mainly affecting neutrophils, monocytes, and macrophages. An overactive IRE1α-XBP1 pathway reprograms CF M1 macrophages toward an increased metabolic state, with increased glycolytic rates and mitochondrial function, associated with exaggerated production of TNF and IL-6. This hyper-metabolic state, seen in CF macrophages, is reversed by inhibiting the RNase domain of IRE1α, thereby decreasing the increased glycolic rates, mitochondrial function and inflammation. Altogether, our results indicate that innate immune cells from CF patients are primarily affected by ER stress. Moreover, the IRE1α-XBP1 pathway of the UPR is responsible for the hyper-metabolic state seen in CF macrophages, which is associated with the exaggerated inflammatory response. Modulating ER stress, metabolism and inflammation, by targeting IRE1α, may improve the metabolic fitness of macrophages, and other immune cells in CF and other immune-related disorders.

PMID: 31428093 [PubMed - in process]

Large-scale identification of pathogen essential genes during coinfection with sympatric and allopatric microbes.

Proc Natl Acad Sci U S A. 2019 Aug 19;:

Authors: Lewin GR, Stacy A, Michie KL, Lamont RJ, Whiteley M

Abstract
Recent evidence suggests that the genes an organism needs to survive in an environment drastically differ when alone or in a community. However, it is not known if there are universal functions that enable microbes to persist in a community and if there are functions specific to interactions between microbes native to the same (sympatric) or different (allopatric) environments. Here, we ask how the essential functions of the oral pathogen Aggregatibacter actinomycetemcomitans change during pairwise coinfection in a murine abscess with each of 15 microbes commonly found in the oral cavity and 10 microbes that are not. A. actinomycetemcomitans was more abundant when coinfected with allopatric than with sympatric microbes, and this increased fitness correlated with expanded metabolic capacity of the coinfecting microbes. Using transposon sequencing, we discovered that 33% of the A. actinomycetemcomitans genome is required for coinfection fitness. Fifty-nine "core" genes were required across all coinfections and included genes necessary for aerobic respiration. The core genes were also all required in monoinfection, indicating the essentiality of these genes cannot be alleviated by a coinfecting microbe. Furthermore, coinfection with some microbes, predominately sympatric species, induced the requirement for over 100 new community-dependent essential genes. In contrast, in other coinfections, predominately with nonoral species, A. actinomycetemcomitans required 50 fewer genes than in monoinfection, demonstrating that some allopatric microbes can drastically alleviate gene essentialities. These results expand our understanding of how diverse microbes alter growth and gene essentiality within polymicrobial infections.

PMID: 31427504 [PubMed - as supplied by publisher]

ORKAMBI®mediated rescue of mucociliary clearance in CF primary respiratory cultures is enhanced by arginine uptake, arginase inhibition and promotion of nitric oxide signaling to the CFTR channel.

Mol Pharmacol. 2019 Aug 19;:

Authors: Wu YS, Jiang J, Ahmadi S, Lew A, Laselva O, Xia S, Bartlett C, Ip W, Wellhauser L, Ouyang H, Gonska T, Moraes TJ, Bear C

Abstract
ORKAMBI®, a combination of the corrector, lumacaftor, and the potentiator, ivacaftor, partially rescues the defective processing and anion channel activity conferred by the major Cystic Fibrosis causing mutation, F508del, in in vitro studies. Clinically, the improvement in lung function after ORKAMBI® treatment is modest and variable, prompting the search for complementary interventions. As our previous work identified a positive effect of arginine-dependent nitric oxide signaling on residual F508del-Cftr function in murine intestinal epithelium, we were prompted to determine if strategies aimed at increasing arginine would enhance F508del-CFTR channel activity in patient-derived airway epithelia. Now, we show that the addition of arginine together with inhibition of intracellular arginase activity increased cytosolic nitric oxide and enhanced the rescue effect of ORKAMBI® on F508del-CFTR mediated chloride conductance at the cell surface of patient-derived bronchial and nasal epithelial cultures. Interestingly, arginine addition plus arginase inhibition also enhanced ORKAMBI® mediated increases in ciliary beat frequency and mucociliary movement, two in vitro Cystic Fibrosis phenotypes that are downstream of the channel defect. This work suggests that strategies to manipulate arginine metabolism in combination with approved CFTR modulators may lead to better clinical outcomes. SIGNIFICANCE STATEMENT: The limited efficacy of the Cystic Fibrosis therapy, ORKAMBI®, in improving patient health prompted the search for additional modulators of the CF causing mutant protein, called F508del-CFTR. We showed that the response to ORKAMBI® can be boosted using a small molecule, called CB1158, that is currently in clinical trials as a therapy for the treatment of solid tumours. CB1158 inhibits arginase activity in patients’ airway cells and boosts the ORKAMBI® response because it increases availability of a positive regulator, nitric oxide. These proof-of-concept studies show that compounds in clinical trials for diseases other than Cystic Fibrosis may be repurposed to augment the therapeutic efficacy of poorly effective CF-specific drugs.

PMID: 31427400 [PubMed - as supplied by publisher]

Discrete choice experiment to evaluate preferences of patients with cystic fibrosis among alternative treatment-related health outcomes: a protocol.

BMJ Open. 2019 Aug 18;9(8):e030348

Authors: McLeod C, Norman R, Schultz A, Mascaro S, Webb S, Snelling T

Abstract
INTRODUCTION: Clinical decision-making is a complex process. Patient preference information regarding desirable health states should inform treatment and is critical to agreeing on goals of therapy. Cystic fibrosis (CF) is a common, inheritable multisystem disorder for which the major manifestation is progressive, chronic lung disease. Intermittent pulmonary exacerbations are a hallmark of disease and these drive lung damage that results in premature death. We suspect that clinicians make assumptions, most likely implicit assumptions, about outcomes that are desired by patients who are treated for pulmonary exacerbations. The aim of this study is to identify and quantify the preferences of patients with cystic fibrosis regarding treatment outcomes.
METHODS AND ANALYSIS: We will develop a discrete choice experiment (DCE) in collaboration with people with CF and their carers, and evaluate how patients make trade-offs between different aspects of health-related status when considering treatment options.
ETHICS AND DISSEMINATION: Ethics approval for all aspects of this study was granted by the Western Australia Child and Adolescent Health Service Human Research Ethics Committee [RGS903]. Weighted preference information from the DCE will be used to develop a multiattribute utility instrument as a measure of treatment success in the upcoming Bayesian Evidence-Adaptive Trial to optimise management of CF. Dissemination of results will also occur through peer-reviewed publications and presentations to relevant stakeholders and research networks.

PMID: 31427340 [PubMed - in process]