ACCRUAL OF BONE MASS IN CHILDREN AND ADOLESCENTS WITH CYSTIC FIBROSIS.

J Clin Endocrinol Metab. 2017 Feb 22;:

Authors: Sharma S, Jaksic M, Fenwick S, Byrnes C, Cundy T

Abstract
Context: Low bone density is a recognised complication of cystic fibrosis (CF).
Hypothesis: Accrual of bone mass is most impaired in the sickest children, as judged by nutritional status and pulmonary function.
Design: Retrospective analysis of correlation between lumbar spine BMD, BMI and FEV1 z-score in children and adolescents with CF.
Setting: Specialist CF service at a pediatric hospital.
Patients: 60 participants aged 5.9 - 18.8 years (24 female), with confirmed CF.
Interventions: Lumbar spine BMD, BMI and FEV1 z-score measured at time of first BMD scan. 40 participants had sequential scans. Change in L1-L4 z-score over time was used as a measure of bone accrual, and BMI as a measure of nutritional status.
Outcome measures: Correlations between lumbar spine BMD, BMI and FEV1 z-scores.
Results: Mean BMI and BMD z-score were strongly correlated at the initial scan (p <0.0001) suggesting that nutritional status is a major determinant of BMD. In the sequential scan at a mean age of 16.1 years, height centile was maintained, indicating normal linear growth. Changes in BMI and BMD z-score were positively correlated (p= 0.001), indicating that patients failing to gain weight appropriately with growth were also failing to acquire bone normally. Change in FEV1 z-score was correlated with both change in BMD z-score (p <0.0001), and change in BMI z-score (p= 0.02).
Conclusion: Although they may be maintaining normal growth in height, bone accrual is impaired in those young people with CF who have the poorest nutritional status and lung function.

PMID: 28323913 [PubMed - as supplied by publisher]

Boosting joint models for longitudinal and time-to-event data.

Biom J. 2017 Mar 21;:

Authors: Waldmann E, Taylor-Robinson D, Klein N, Kneib T, Pressler T, Schmid M, Mayr A

Abstract
Joint models for longitudinal and time-to-event data have gained a lot of attention in the last few years as they are a helpful technique clinical studies where longitudinal outcomes are recorded alongside event times. Those two processes are often linked and the two outcomes should thus be modeled jointly in order to prevent the potential bias introduced by independent modeling. Commonly, joint models are estimated in likelihood-based expectation maximization or Bayesian approaches using frameworks where variable selection is problematic and that do not immediately work for high-dimensional data. In this paper, we propose a boosting algorithm tackling these challenges by being able to simultaneously estimate predictors for joint models and automatically select the most influential variables even in high-dimensional data situations. We analyze the performance of the new algorithm in a simulation study and apply it to the Danish cystic fibrosis registry that collects longitudinal lung function data on patients with cystic fibrosis together with data regarding the onset of pulmonary infections. This is the first approach to combine state-of-the art algorithms from the field of machine-learning with the model class of joint models, providing a fully data-driven mechanism to select variables and predictor effects in a unified framework of boosting joint models.

PMID: 28321912 [PubMed - as supplied by publisher]

The Pseudomonas aeruginosa two-component regulator AlgR directly activates rsmA expression in a phosphorylation independent manner.

J Bacteriol. 2017 Mar 20;:

Authors: Stacey SD, Williams DA, Pritchett CL

Abstract
Pseudomonas aeruginosa is an important pathogen of the immunocompromised, causing both acute and chronic infections. In cystic fibrosis (CF) patients, P. aeruginosa causes chronic disease. The impressive sensory network of P. aeruginosa allows the bacteria to sense and respond to a variety of stimuli found in diverse environments. Transcriptional regulators, including alternative sigma factors and response regulators, integrate signals changing gene expression allowing P. aeruginosa to cause infection. The two-component transcriptional regulator AlgR is important in P. aeruginosa pathogenesis in both acute and chronic infections. In chronic infections, AlgR and the alternative sigma factor AlgU activate the genes responsible for alginate production. Previous work demonstrated that AlgU controlled rsmA expression. RsmA is a post-transcriptional regulator that is antagonized by two small RNAs, RsmY and RsmZ. In this work, we demonstrate that AlgR directly activates rsmA expression from the same promoter as AlgU. In addition, phosphorylation was not necessary for AlgR activation of rsmA using algR and algZ mutant strains. AlgU and AlgR appear to affect the antagonizing small RNAs, rsmY and rsmZ, indirectly. RsmA was active in a mucA22 strain using leader fusions of two RsmA targets, tssA1 and hcnA AlgU and AlgR were necessary for posttranscriptional regulation of tssA1 and hcnA Altogether, our work demonstrates that the alginate regulators, AlgU and AlgR, are important in the control of the RsmA posttranscriptional regulatory system. These findings suggest that RsmA plays an unknown role in mucoid strains due to AlgU and AlgR activity.IMPORTANCEP. aeruginosa infections are difficult to treat and frequently cause significant mortality in CF patients. Understanding the mechanisms of persistence is important. Our work has demonstrated that the alginate regulatory system also significantly impacts the posttranscriptional regulator system RsmA/Y/Z. We demonstrate AlgR directly activates rsmA expression and this impacts the RsmA regulon. This leads to the possibility that the RsmA/Y/Z system plays a role in helping P. aeruginosa persist during chronic infection. In addition, this furthers our understanding of the reach of the alginate regulators AlgU and AlgR.

PMID: 28320883 [PubMed - as supplied by publisher]

Nutritional status, nutrient intake and use of enzyme supplements in paediatric patients with Cystic Fibrosis; a European multicentre study with reference to current guidelines.

J Cyst Fibros. 2017 Mar 17;:

Authors: Calvo-Lerma J, Hulst JM, Asseiceira I, Claes I, Garriga M, Colombo C, Fornés V, Woodcock S, Martins T, Boon M, Ruperto M, Walet S, Speziali C, Witters P, Masip E, Barreto C, de Boeck K, Ribes-Koninckx C, MyCyFAPP Project

Abstract
BACKGROUND: The New European guidelines have established the most updated recommendations on nutrition and pancreatic enzyme replacement therapy (PERT) in CF. In the context of MyCyFAPP project - a European study in children with CF aimed at developing specific tools for improvement of self-management - the objective of the current study was to assess nutritional status, daily energy and macronutrient intake, and PERT dosing with reference to these new guidelines.
METHODS: Cross sectional study in paediatric patients with CF from 6 European centres. SD-scores for weight-for-age (WFA), height-for-age (HFA) and body mass index-for-age (BMI) were obtained. Through a specific 4-day food and enzyme-dose record, energy and macronutrients intake and PERT-use (LU/g lipids) were automatically calculated by the MyCyFAPP system. Comparisons were made using linear regression models.
RESULTS: The lowest quartiles for BMI and HFA were between 0 and -1SD in all the centres with no significant differences, and 33.5% of the patients had a SD-score <0 for all three parameters. The minimum energy intake recommendation was not reached by 40% of the children and mean nutrients intake values were 14%, 51% and 34% of the total energy for protein, carbohydrates and lipids respectively. When assessed per centre, reported PERT doses were in the recommended range in only 13.8% to 46.6% of the patients; from 5.6% up to 82.7% of children were above the recommended doses and 3.3% to 75% were below.
CONCLUSION: Among the 6 centres, a large variability and inconsistency with new guidelines on nutrition and PERT-use was found. Our findings document the lack of a general criterion to adjust PERT and suggest the potential benefit of educational and self-managerial tools to ensure adherence to therapies, both for clinical staff and families. They will be taken into account when developing these new tools during the next stages of MyCyFAPP Project.

PMID: 28320633 [PubMed - as supplied by publisher]

Is acute recurrent pancreatitis in children a precursor of chronic pancreatitis? A long-term follow-up study of 93 cases.

Dig Liver Dis. 2017 Mar 06;:

Authors: Poddar U, Yachha SK, Borkar V, Srivastava A

Abstract
BACKGROUND/AIMS: In view of paucity of literature we analyzed our experience of acute recurrent pancreatitis (ARP) to study clinical profile and long-term outcome.
METHODS: Over 13 years, 93 consecutive children (≤18 years) diagnosed to have ARP were included in this study. Magnetic resonance cholangiopancreatography was done at baseline and on follow-up. Common mutations for serine-protease-inhibitor (SPINK1 N34S), protease inhibitor (PRSS1 R122S) and cystic fibrosis transmembrane conductance regulator (CFTR deltaF508, 5T) were studied in 22 idiopathic cases.
RESULTS: The median age of the children with ARP was 13 (10-14.5) years, 53 were males. Etiology included biliary in 14 (15%), pancreas divisum in 6 (7%), others in 3 (3.5%) and idiopathic in the remaining 70 (75%). SPINK1 mutation was found in 10/22 (45%) cases. Over a median follow-up of 25.5 (8.25-48) months, 37 (42%) of 88 (5 lost to follow-up) developed chronic pancreatitis (CP). On multivariate analysis idiopathic etiology (p<0.03), presence of SPINK1 mutation (p=0.01), longer follow-up (p<0.001) were associated with progression to CP.
CONCLUSIONS: Biliopancreatic structural/obstructive causes should always be looked for. It seems ARP is a precursor of CP and progression is associated with idiopathic etiology and presence of genetic mutations. Hence, patients with ARP should be kept on regular follow-up to detect CP.

PMID: 28320629 [PubMed - as supplied by publisher]

Mutation of Growth Arrest Specific 8 Reveals a Role in Motile Cilia Function and Human Disease.

PLoS Genet. 2016 07;12(7):e1006220

Authors: Lewis WR, Malarkey EB, Tritschler D, Bower R, Pasek RC, Porath JD, Birket SE, Saunier S, Antignac C, Knowles MR, Leigh MW, Zariwala MA, Challa AK, Kesterson RA, Rowe SM, Drummond IA, Parant JM, Hildebrandt F, Porter ME, Yoder BK, Berbari NF

Abstract
Ciliopathies are genetic disorders arising from dysfunction of microtubule-based cellular appendages called cilia. Different cilia types possess distinct stereotypic microtubule doublet arrangements with non-motile or 'primary' cilia having a 9+0 and motile cilia have a 9+2 array of microtubule doublets. Primary cilia are critical sensory and signaling centers needed for normal mammalian development. Defects in their structure/function result in a spectrum of clinical and developmental pathologies including abnormal neural tube and limb patterning. Altered patterning phenotypes in the limb and neural tube are due to perturbations in the hedgehog (Hh) signaling pathway. Motile cilia are important in fluid movement and defects in motility result in chronic respiratory infections, altered left-right asymmetry, and infertility. These features are the hallmarks of Primary Ciliary Dyskinesia (PCD, OMIM 244400). While mutations in several genes are associated with PCD in patients and animal models, the genetic lesion in many cases is unknown. We assessed the in vivo functions of Growth Arrest Specific 8 (GAS8). GAS8 shares strong sequence similarity with the Chlamydomonas Nexin-Dynein Regulatory Complex (NDRC) protein 4 (DRC4) where it is needed for proper flagella motility. In mammalian cells, the GAS8 protein localizes not only to the microtubule axoneme of motile cilia, but also to the base of non-motile cilia. Gas8 was recently implicated in the Hh signaling pathway as a regulator of Smoothened trafficking into the cilium. Here, we generate the first mouse with a Gas8 mutation and show that it causes severe PCD phenotypes; however, there were no overt Hh pathway phenotypes. In addition, we identified two human patients with missense variants in Gas8. Rescue experiments in Chlamydomonas revealed a subtle defect in swim velocity compared to controls. Further experiments using CRISPR/Cas9 homology driven repair (HDR) to generate one of these human missense variants in mice demonstrated that this allele is likely pathogenic.

PMID: 27472056 [PubMed - indexed for MEDLINE]

Autogenic Drainage in Children With Cystic Fibrosis.

Pediatr Phys Ther. 2017 Mar 17;:

Authors: Corten L, Morrow BM

Abstract
PURPOSE: Airway clearance is an essential part of the management of cystic fibrosis (CF) as it facilitates clearance of viscous pulmonary secretions. This review aimed to determine the effect of autogenic drainage (AD) and assisted autogenic drainage (AAD) compared with no, sham, or other types of airway clearance in children with CF.
SUMMARY OF KEY POINTS: Two pediatric randomized cross-over trials were identified on the use of AD in children with CF; no studies were available on the use of AAD. In one study AD had a positive influence on the Huang score, and is preferred over postural drainage in this population.
CONCLUSIONS AND RECOMMENDATIONS: We could not determine the efficacy of AD and AAD in children with CF. We recommend the implementation of pediatric-specific randomized controlled trials with adequate sample sizes, appropriate clinical outcome measures, and analysis of adverse effects.

PMID: 28319489 [PubMed - as supplied by publisher]

Stenotrophomonas maltophilia healthcare-associated infections: identification of two main pathogenic genetic backgrounds.

J Hosp Infect. 2017 Feb 09;:

Authors: Corlouer C, Lamy B, Desroches M, Ramos-Vivas J, Mehiri-Zghal E, Lemenand O, Delarbre JM, Decousser JW, Collège de Bactériologie-Virologie-Hygiène des Hôpitaux de France

Abstract
BACKGROUND: Stenotrophomonas maltophilia is an opportunistic multi-drug-resistant bacterium responsible for healthcare-associated infections. Strategies for in-hospital infection control and management of carriers and environmental reservoirs remain controversial.
AIM: To determine the population structure of S. maltophilia strains in hospitalized infected patients and to identify putative highly pathogenic subpopulations that require upgraded infection control measures.
METHODS: Eighty-three diverse human strains of various clinical origins from 18 geographically distant hospitals were characterized phenotypically and genotypically using a multi-locus sequence typing (MLST) approach.
FINDINGS: Neither a predominant nor emerging sequence type (ST) was identified. Among the 80 typeable strains, only 29% corresponded to described STs, especially ST5 (N=6) and ST4/26/31 (N=2). The ST distribution and the phylogenic tree based on the concatenated MLST genes did not account for geographical, clinical origin or antimicrobial susceptibility clustering. A phylogenic tree that included 173 ST profiles from the MLST database and the 80 typeable strains confirmed the high genetic diversity of S. maltophilia, the previously reported genogroup organization and the predominance of genogroup 6, as it represented 41% (33/80) of the strains. Unexpectedly, genogroup 2 was the second most prevalent genogroup and included 16% (13/80) of the strains. These genogroups represented 57% (20/35) of the strains in respiratory patients and 75% (9/12) of the strains in patients with cystic fibrosis.
CONCLUSION: Beyond MLST, the over-representation of some genogroups among strains responsible for healthcare-associated infections was confirmed. Genogrouping affiliation is recommended to implement infection control measures selectively for the most pathogenic strains isolated from patient or environmental reservoirs.

PMID: 28318778 [PubMed - as supplied by publisher]

Vibrating-mesh nebulizer maintenance by CF patients: Results from a French survey.

Pulm Pharmacol Ther. 2017 Mar 14;:

Authors: Baravalle-Einaudi M, Dufeu N, Dupont C, Vecellio L, Delaisi B, Carsin A, Dubus JC, GRAM (Aerosols and Cystic Fibrosis Workgroup of the French Cystic Fibrosis Society)

Abstract
PURPOSE OF THE STUDY: Vibrating-mesh nebulizers are widely used at home for cystic fibrosis (CF) treatment, with a therapeutic efficiency closely linked to the mesh performance. This national study looks at the maintenance at home by CF patients and their families of the mesh of the eFlow(®)rapid nebulizer. Ninety-two patients from 34 French CF centers, treated at home with inhaled drugs delivered with a vibrating-mesh nebulizer, answered to a phone standardized questionnaire specifying the different techniques of maintenance of the nebulizer.
PRINCIPAL RESULTS: Patients were aged from 2 to 68 years (58.7% of children). They inhaled a mean of 1.8 nebulizations per day. Maintenance was assumed by patients in 36% of the cases. All steps of the theoretical maintenance of a nebulizer were respected in 66% of the cases. The mesh was not cleaned in 45.6%, not disinfected or not thermically disinfected in 32.5%, and not rinsed after chemical disinfection in 45.5% of the case. Only 49% of the patients knew the role of the MeshCare(®) system in the mesh maintenance, and only 39% had already used it when the nebulization duration reached 10 min.
CONCLUSIONS: Efforts about education, particularly for the maintenance of the mesh, are needed for CF patients using a vibrating-mesh nebulizer at home.

PMID: 28315491 [PubMed - as supplied by publisher]

Potential for Screening for Pancreatic Exocrine Insufficiency Using the Fecal Elastase-1 Test.

Dig Dis Sci. 2017 Mar 17;:

Authors: Domínguez-Muñoz JE, D Hardt P, Lerch MM, Löhr MJ

Abstract
The early diagnosis of pancreatic exocrine insufficiency (PEI) is hindered because many of the functional diagnostic techniques used are expensive and require specialized facilities, which prevent their widespread availability. We have reviewed current evidence in order to compare the utility of these functional diagnostic techniques with the fecal elastase-1 (FE-1) test in the following three scenarios: screening for PEI in patients presenting with symptoms suggestive of pancreatic disease, such as abdominal pain or diarrhea; determining the presence of PEI in patients with an established diagnosis of pancreatic disease, such as chronic pancreatitis or cystic fibrosis; determining exocrine status in disorders not commonly tested for PEI, but which have a known association with this disorder. Evidence suggests the FE-1 test is reliable for the evaluation of pancreatic function in many pancreatic and non-pancreatic disorders. It is non-invasive, is less time-consuming, and is unaffected by pancreatic enzyme replacement therapy. Although it cannot be considered the gold-standard method for the functional diagnosis of PEI, the advantages of the FE-1 test make it a very appropriate test for screening patients who may be at risk of this disorder.

PMID: 28315028 [PubMed - as supplied by publisher]

Technological advances shed light on left ventricular cardiac disturbances in cystic fibrosis.

J Cyst Fibros. 2017 Mar 14;:

Authors: Sayyid ZN, Sellers ZM

Abstract
Cystic fibrosis (CF), the most common autosomal recessive lethal disease in Caucasians, causes chronic pulmonary disease and can lead to cor pulmonale with right ventricular dysfunction. The presence of the cystic fibrosis transmembrane conductance regulator (CFTR) in cardiac myocardia has prompted debate regarding possible defective ion channel-induced cardiomyopathy. Clinical heart disease in CF is considered rare and is restricted to case reports. It has been unclear if this is due to the lack of physiological importance of CFTR in the heart, the relatively short lifespan of those with CF, or a technical inability to detect subclinical disease. Extensive echocardiographic investigations have yielded contradictory results, leading to the dogma that left ventricular defects in CF occur secondary to lung disease. In this review, we consider why studies examining heart function in CF have not provided clarity on this topic. We then focus on data from new echocardiographic and magnetic resonance imaging technology, which are providing greater insight into cardiac function in CF and demonstrating that, in addition to secondary effects from pulmonary disease, there may be an intrinsic primary defect in the CF heart. With advancing lifespans and activity levels, understanding the risk of cardiac disease is vital to minimizing morbidity in adults with CF.

PMID: 28314540 [PubMed - as supplied by publisher]

Immediate effects of lumacaftor/ivacaftor administration on lung function in patients with severe cystic fibrosis lung disease.

J Cyst Fibros. 2017 Mar 14;:

Authors: Popowicz N, Wood J, Tai A, Morey S, Mulrennan S

Abstract
Safety-data for lumacaftor/ivacaftor (LUM/IVA) combination therapy in patients with severe lung disease (percent predicted forced expiratory volume in 1s [ppFEV1] <40) remain limited. We report immediate post-dose respiratory-related adverse events in 12 patients with severe cystic fibrosis (CF) lung disease (median [IQR] ppFEV1: 34 [31-36]) prescribed LUM/IVA. All patients experienced a decline in ppFEV1 from baseline at 2-hours (median [IQR] relative change: -19 [-21 to -11]%, p<0.001) that persisted at 24-hours but recovered in most patients at 1-month. No pre- and post-differences in bronchodilator response were observed. Ten (83.3%) patients reported non-severe respiratory-related adverse events within 24-hours of LUM/IVA initiation. At 1-month, eight (67%) patients had persistent symptoms and six (50%) were treated for a pulmonary exacerbation. Our results highlight that LUM/IVA respiratory-related adverse events are common in patients with a ppFEV1<40. We recommend close assessment of adverse events. Further studies are required to evaluate the efficacy of LUM/IVA in patients with severe lung disease.

PMID: 28314539 [PubMed - as supplied by publisher]

Towards Increasing the Clinical Relevance of In Silico Methods to Predict Pathogenic Missense Variants.

PLoS Comput Biol. 2016 05;12(5):e1004725

Authors: Masica DL, Karchin R

PMID: 27171182 [PubMed - indexed for MEDLINE]

Innovative approach for self-management and social welfare of children with cystic fibrosis in Europe: development, validation and implementation of an mHealth tool (MyCyFAPP).

BMJ Open. 2017 Mar 16;7(3):e014931

Authors: Calvo-Lerma J, Martinez-Jimenez CP, Lázaro-Ramos JP, Andrés A, Crespo-Escobar P, Stav E, Schauber C, Pannese L, Hulst JM, Suárez L, Colombo C, Barreto C, de Boeck K, Ribes-Koninckx C, MyCyFAPP

Abstract
INTRODUCTION: For the optimal management of children with cystic fibrosis, there are currently no efficient tools for the precise adjustment of pancreatic enzyme replacement therapy, either for advice on appropriate dietary intake or for achieving an optimal nutrition status. Therefore, we aim to develop a mobile application that ensures a successful nutritional therapy in children with cystic fibrosis.
METHODS AND ANALYSIS: A multidisciplinary team of 12 partners coordinate their efforts in 9 work packages that cover the entire so-called 'from laboratory to market' approach by means of an original and innovative co-design process. A cohort of 200 patients with cystic fibrosis aged 1-17 years are enrolled. We will develop an innovative, clinically tested mobile health application for patients and health professionals involved in cystic fibrosis management. The mobile application integrates the research knowledge and innovative tools for maximising self-management with the aim of leading to a better nutritional status, quality of life and disease prognosis. Bringing together different and complementary areas of knowledge is fundamental for tackling complex challenges in disease treatment, such as optimal nutrition and pancreatic enzyme replacement therapy in cystic fibrosis. Patients are expected to benefit the most from the outcomes of this innovative project.
ETHICS AND DISSEMINATION: The project is approved by the Ethics Committee of the coordinating organisation, Hospital Universitari La Fe (Ref: 2014/0484). Scientific findings will be disseminated via journals and conferences addressed to clinicians, food scientists, information and communications technology experts and patients. The specific dissemination working group within the project will address the wide audience communication through the website (http://www.mycyfapp.eu), the social networks and the newsletter.

PMID: 28302638 [PubMed - in process]

Immunomodulatory effects of pidotimod in adults with community-acquired pneumonia undergoing standard antibiotic therapy.

Pulm Pharmacol Ther. 2017 Mar 13;:

Authors: Trabattoni D, Clerici M, Centanni S, Mantero M, Garziano M, Blasi F

Abstract
The morbidity and mortality of community-acquired pneumonia (CAP) are still elevated and two aspects seem to contribute to a worse outcome: an uncontrolled inflammatory reaction and an inadequate immune response. Adjuvants, including corticosteroids and intravenous immunoglobulins, have been proposed to counterbalance these effects but their efficacy is only partial. We examined the immunomodulatory activity of Pidotimod (PDT), a synthetic dipeptide molecule in adult patients hospitalized for CAP. Sixteen patients with a diagnosis of CAP and a PSI score III or IV and/or a CURB-65 0-2 were randomized to receive either levofloxacin 500 mg b.i.d. alone or levofloxacin plus PDT (800mg, 2 daily doses). Blood samples were drawn at baseline (T0), before initiation of therapy, as well as 3 (T3), and 5 (T5) days after initiation of therapy. Immunologic and clinical parameters were analyzed at each time point. Supplementation of antibiotic therapy with PDT resulted in an upregulation of antimicrobial and of immunomodulatory proteins as well as in an increased percentage of Toll like receptor (TLR)2- and TLR4, and of CD80- and CD86-expressing immune cells. Notably, Pidotimod supplementation was also associated with a robust reduction of TNFα-producing immune cells. No significant differences were observed in clinical parameters. These results confirm that supplementation of antibiotic therapy with Pidotimod in patients with CAP results in a potentially beneficial modulation of innate immunity.

PMID: 28302543 [PubMed - as supplied by publisher]

The CF-CARES primary palliative care model: A CF-specific structured assessment of symptoms, distress, and coping.

J Cyst Fibros. 2017 Mar 14;:

Authors: Friedman D, Linnemann RW, Altstein LL, Islam S, Bach KT, Lamb C, Volpe J, Doolittle C, St John A, O'Malley PJ, Sawicki GS, Georgiopoulos AM, Yonker LM, Moskowitz SM

Abstract
BACKGROUND: Current palliative care tools do not address distressing chronic symptoms that are most relevant to cystic fibrosis.
METHODS: A CF-specific structured assessment based on a primary palliative care framework was administered to 41 adolescents and adults with CF. Descriptive and correlational analyses were conducted.
RESULTS: Patients reported numerous physical and psychological symptoms (mean of 10 per patient), with psychological symptoms rated as more distressing. Anxiety (34%) and depression (44%) were prevalent and correlated with distress attributable to physical symptoms and difficulty with CF self-management, but did not correlate with disease severity.
CONCLUSIONS: Individuals with CF, regardless of disease severity, face challenges managing symptom burden. Frequently reported symptoms are not consistently associated with distress, suggesting the importance of individualized evaluation. The CF-CARES (Coping, goal Assessment, and Relief from Evolving CF Symptoms) primary palliative care assessment model provides a framework for patients experiencing chronic symptoms to explore interventional options with their clinicians.

PMID: 28302366 [PubMed - as supplied by publisher]

Pseudomonas aeruginosa biofilm, a programmed bacterial life for fitness.

J Microbiol Biotechnol. 2017 Mar 17;:

Authors: Lee K, Yoon SS

Abstract
Biofilm is a community of microbes that typically inhabits on surfaces and is encased in an extracellular matrix. Biofilms display very dissimilar characteristics to their planktonic counterparts. Biofilms are ubiquitous in the environments and influence our life tremendously in both positive and negative ways. Pseudomonas aeruginosa is a bacterium, known to produce robust biofilms. P. aeruginosa biofilms cause severe problems in immunocompromised patients including those with cystic fibrosis or wound infection. Moreover, the unique biofilm properties further complicates the eradication of the biofilm infection and leading to the development of chronic infections. In this review, we discuss a history of biofilm research and general characteristics of bacterial biofilms. Then, distinct features pertaining to each stage of P. aeruginosa biofilm development are highlighted. Furthermore, infections caused by biofilms of its own or in association with other bacterial species (i.e., multi-species biofilms) are discussed in detail.

PMID: 28301918 [PubMed - as supplied by publisher]

Negative News: Cl- and HCO3- in the Vascular Wall.

Physiology (Bethesda). 2016 09;31(5):370-83

Authors: Boedtkjer E, Matchkov VV, Boedtkjer DM, Aalkjaer C

Abstract
Cl(-) and HCO3 (-) are the most prevalent membrane-permeable anions in the intra- and extracellular spaces of the vascular wall. Outwardly directed electrochemical gradients for Cl(-) and HCO3 (-) permit anion channel opening to depolarize vascular smooth muscle and endothelial cells. Transporters and channels for Cl(-) and HCO3 (-) also modify vascular contractility and structure independently of membrane potential. Transport of HCO3 (-) regulates intracellular pH and thereby modifies the activity of enzymes, ion channels, and receptors. There is also evidence that Cl(-) and HCO3 (-) transport proteins affect gene expression and protein trafficking. Considering the extensive implications of Cl(-) and HCO3 (-) in the vascular wall, it is critical to understand how these ions are transported under physiological conditions and how disturbances in their transport can contribute to disease development. Recently, sensing mechanisms for Cl(-) and HCO3 (-) have been identified in the vascular wall where they modify ion transport and vasomotor function, for instance, during metabolic disturbances. This review discusses current evidence that transport (e.g., via NKCC1, NBCn1, Ca(2+)-activated Cl(-) channels, volume-regulated anion channels, and CFTR) and sensing (e.g., via WNK and RPTPγ) of Cl(-) and HCO3 (-) influence cardiovascular health and disease.

PMID: 27511463 [PubMed - indexed for MEDLINE]

Modulation of behaviour and virulence of a high alginate expressing Pseudomonas aeruginosa strain from cystic fibrosis by oral commensal bacterium Streptococcus anginosus.

PLoS One. 2017;12(3):e0173741

Authors: Waite RD, Qureshi MR, Whiley RA

Abstract
Cystic fibrosis (CF) airways harbour complex and dynamic polymicrobial communities that include many oral bacteria. Despite increased knowledge of CF airway microbiomes the interaction between established CF pathogens and other resident microbes and resulting impact on disease progression is poorly understood. Previous studies have demonstrated that oral commensal streptococci of the Anginosus group (AGS) can establish chronic pulmonary infections and become numerically dominant in CF sputa indicating that they play an important role in CF microbiome dynamics. In this study a strain of Pseudomonas aeruginosa (DWW2) of the mucoid alginate overproducing phenotype associated with chronic CF airway infection and a strain of the oral commensal AGS species Streptococcus anginosus (3a) from CF sputum were investigated for their ability to co-exist and their responses to biofilm co-culture. Bacteria in biofilms were quantified, pyocyanin expression by DWW2 was measured and the effect of AGS strain 3a on reversion of DWW2 to a non-mucoidal phenotype investigated. The virulence of DWW2, 3a and colony variant phenotypes of DWW2 in mono- and co-culture were compared in a Galleria mellonella infection model. Co-culture biofilms were formed in normoxic, hypercapnic (10% CO2) and anoxic atmospheres with the streptococcus increasing in number in co-culture, indicating that these bacteria would be able to co-exist and thrive within the heterogeneous microenvironments of the CF airway. The streptococcus caused increased pyocyanin expression by DWW2 and colony variants by stimulating reversion of the mucoid phenotype to the high pyocyanin expressing non-mucoid phenotype. The latter was highly virulent in the infection model with greater virulence when in co-culture with the streptococcus. The results of this study demonstrate that the oral commensal S. anginosus benefits from interaction with P. aeruginosa of the CF associated mucoid phenotype and modulates the behaviour of the pseudomonad in ways that may be clinically relevant.

PMID: 28301571 [PubMed - in process]

Impact of CFTR Modulation on Intestinal pH, Motility, and Clinical Outcomes in Patients With Cystic Fibrosis and the G551D Mutation.

Clin Transl Gastroenterol. 2017 Mar 16;8(3):e81

Authors: Gelfond D, Heltshe S, Ma C, Rowe SM, Frederick C, Uluer A, Sicilian L, Konstan M, Tullis E, Roach RN, Griffin K, Joseloff E, Borowitz D

Abstract
OBJECTIVES: A defect in bicarbonate secretion contributes to the pathophysiology of gastrointestinal complications in patients with cystic fibrosis (CF). We measured gastrointestinal pH, clinical outcomes, and intestinal transit profiles in patients with the G551D mutation before and after treatment with ivacaftor, a CF transmembrane regulator channel (CFTR) potentiator.
METHODS: Observational studies of ivacaftor effectiveness were conducted in the United States and Canada. A subset of subjects ingested a wireless motility capsule (n=10) that measures in vivo pH, both before therapy with ivacaftor and 1 month after treatment; values obtained were compared for mean pH and area under the pH curve, and regional intestinal motility. We also queried subjects about abdominal pain and recorded body weight before and after treatment.
RESULTS: One month after administering ivacaftor, a significant increase in mean pH was observed after gastric emptying (P<0.05). Area under the pH curve analyses indicate increased bicarbonate mass (P<0.05 for select 5 min intervals and all segments >30 min); mean weight gain was 1.1 kg (P=0.08). No difference in abdominal pain or regional transit times was seen.
CONCLUSIONS: CFTR modulation improves the proximal small intestinal pH profile in patients with the G551D CFTR mutation and we observed clinically relevant, contemporaneous weight gain, although it did not reach statistical significance. These data provide in vivo evidence that CFTR is an important regulator of bicarbonate secretion, which may be a translational link between CFTR function and clinical improvement.

PMID: 28300821 [PubMed - in process]