Thickness of the airway surface liquid layer in the lung is affected in cystic fibrosis by compromised synergistic regulation of the ENaC ion channel.

J R Soc Interface. 2019 Aug 30;16(157):20190187

Authors: Olivença DV, Fonseca LL, Voit EO, Pinto FR

Abstract
The lung epithelium is lined with a layer of airway surface liquid (ASL) that is crucial for healthy lung function. ASL thickness is controlled by two ion channels: epithelium sodium channel (ENaC) and cystic fibrosis (CF) transmembrane conductance regulator (CFTR). Here, we present a minimal mathematical model of ENaC, CFTR and ASL regulation that sheds light on the control of ENaC by the short palate lung and nasal epithelial clone 1 (SPLUNC1) protein and by phosphatidylinositol 4,5-biphosphate (PI(4,5)P2). The model, despite its simplicity, yields a good fit to experimental observations and is an effective tool for exploring the interplay between ENaC, CFTR and ASL. Steady-state data and dynamic information constrain the model's parameters without ambiguities. Testing the hypothesis that PI(4,5)P2 protects ENaC from ubiquitination suggests that this protection does not improve the model results and that the control of the ENaC opening probability by PI(4,5)P2 is sufficient to explain all available data. The model analysis further demonstrates that ASL at the steady state is sensitive to small changes in PI(4,5)P2 abundance, particularly in CF conditions, which suggests that manipulation of phosphoinositide metabolism may promote therapeutic benefits for CF patients.

PMID: 31455163 [PubMed - in process]

Combined Thoracic and Abdominal Organ Transplantation: Special Considerations.

Semin Cardiothorac Vasc Anesth. 2019 Aug 27;:1089253219870631

Authors: Yager A, Khorsand S, Chokshi R, Cheruku S

Abstract
Combined thoracic-abdominal organ transplants are infrequently performed procedures indicated for patients with failure of two or more transplantable organs. In this review, we discuss recipient selection, surgical considerations, anesthetic management, and outcomes associated with common combinations of thoracic-abdominal transplant operations. General principles regarding the postoperative care of these patients are also discussed. These procedures present a unique challenge requiring specialized knowledge, technical expertise, and leadership from the anesthesiology team throughout the perioperative period.

PMID: 31455153 [PubMed - as supplied by publisher]

Specific Inhibition of the NLRP3 Inflammasome as an Anti-Inflammatory Strategy in Cystic Fibrosis.

Am J Respir Crit Care Med. 2019 Aug 27;:

Authors: McElvaney OJ, Zaslona Z, Becker-Flegler K, Palsson-McDermott EM, Boland F, Gunaratnam C, Gulbins E, O'Neill LA, Reeves EP, McElvaney NG

Abstract
RATIONALE: Cystic fibrosis (CF) pulmonary disease is characterized by chronic infection with Pseudomonas aeruginosa and sustained neutrophil-dominant inflammation. The lack of effective anti-inflammatory therapies for people with CF (PWCF) represents a significant challenge.
OBJECTIVES: To identify altered immunometabolism in the CF neutrophil, and investigate the feasibility of specific inhibition of the NLR family, pyrin domain-containing protein 3 (NLRP3) inflammasome as a CF anti-inflammatory strategy in vivo.
METHODS: Key markers of increased aerobic glycolysis, known as a Warburg effect, including cytosolic pyruvate kinase M2 (PKM2), phosphorylated PKM2, succinate, HIF-1α, lactate and the interleukin (IL)-1β precursor pro-IL-1β, as well as caspase-1 activity and processing of pro-IL-1β to IL-1β by the NLRP3 inflammasome, were measured in neutrophils from blood and airway secretions from healthy controls (n=12), PWCF (n=16) and PWCF post-double-lung transplant (n=6). The effects of specific inhibition of NLRP3 on airway inflammation and bacterial clearance in a murine CF model were subsequently assessed in vivo.
MAIN RESULTS: CF neutrophils display increased aerobic glycolysis in the systemic circulation. This effect is driven by low-level endotoxemia, unaffected by CFTR modulation, and resolves post-transplant. The increased pro-IL-1β produced is processed to its mature active form in the lipopolysaccharide-rich CF lung by the NLRP3 inflammasome via caspase-1. Specific NLRP3 inhibition in vivo with MCC950 inhibited IL-1β in the lungs of CF mice (P<0.0001), resulting in significantly reduced airway inflammation and improved Pseudomonas clearance (P<0.0001).
CONCLUSIONS: CF neutrophil immunometabolism is altered in response to inflammation. NLRP3 inflammasome inhibition may have an anti-inflammatory and anti-infective role in CF.

PMID: 31454256 [PubMed - as supplied by publisher]

Prevalence and Antibiotic Resistance of Stenotrophomonas maltophilia in Respiratory Tract Samples: A 10-Year Epidemiological Snapshot.

Health Serv Res Manag Epidemiol. 2019 Jan-Dec;6:2333392819870774

Authors: Gajdács M, Urbán E

Abstract
Background: Since the 1980s, Stenotrophomonas maltophilia has emerged as an important pathogen associated with significant mortality in pneumonia and bacteremia of severely immunocompromised, hospitalized patients. The drug of choice in S maltophilia infections is sulfamethoxazole-trimethoprim (SMX/TMP); SMX/TMP resistance is a serious concern in clinical practice. The aim of this study was to assess the prevalence of S maltophilia in lower respiratory tract (LRTI) samples at a tertiary-care university hospital.
Methods: This retrospective cohort study was carried out using microbiological data collected between January 2008 and December 2017. Routine antimicrobial susceptibility testing was performed for SMX/TMP and levofloxacin; in case of resistance, susceptibility testing for additional antibiotics (tigecycline, amikacin, and colistin) was also performed.
Results: A total of 579 individual S maltophilia isolates were identified (2008-2012: n = 160, 2013-2017: n = 419; P = .0008). In all, 78.46% of patients were younger than 5 or older than 50 years of age and had recent trauma, surgery, or underlying conditions (malignancies, respiratory distress syndrome, congenital disorders, and cystic fibrosis). In 28.16% of samples, more than 1 pathogen was identified, and 5.35% of coisolated pathogens were multidrug resistant (MDR). In all, 12.1% of isolates were SMX/TMP-resistant (2008-2012: 6.12%, 2013-2017: 18.06%; P = .034), while 8.99% were resistant to levofloxacin (2008-2012: 7.86%, 2013-2017: 10.12%; P > .05). SMX/TMP resistance was detected more frequently in samples originating from inpatients (n = 2.50 ± 2.39 vs n = 11.50 ± 3.76; P = .0002).
Conclusions: In all, 5.87% of isolates were extensively drug resistant (XDR), that is, in addition to SMX/TMP, they were resistant to levofloxacin, amikacin, colistin, and tigecycline. The results of our study correspond to the findings in the literature.

PMID: 31453265 [PubMed]

Adapting the James Lind Alliance priority setting process to better support patient participation: an example from cystic fibrosis.

Res Involv Engagem. 2019;5:24

Authors: Rowbotham NJ, Smith SJ, Elliott ZC, Leighton PA, Rayner OC, Morley R, Smyth AR

Abstract
Plain English summary: Cystic fibrosis (CF) is the commonest life-limiting inherited disorder in the UK. It affects many parts of the body including the lungs and gut leading to increased infection and problems digesting food. People with CF need to undergo many treatments each day throughout their whole lives. These include tablets, inhalers and breathing exercises, which are a huge burden, taking up several hours every dayIt is therefore, really important that the treatments we give are supported by good evidence, usually gathered from clinical trials. Unfortunately, we do not have good evidence for many of the CF treatments. We recently ran an exercise known as a James Lind Alliance Priority Setting Partnership (JLA PSP) to find out which the CF community feel are the top priority research questions. People with CF and those who look after them suggested questions to be answered by clinical trials. Through a series of online surveys and workshops these were then shortlisted to give a final top ten.Due to infection risk people with CF are advised not to mix, this meant we had to do things differently to the usual way JLA PSPs are carried out. We used videoconferencing to enable multiple people with CF to participate. Surveys were accessible online and promoted through social media.
Abstract: Background The James Lind Alliance (JLA) method is well recognised for setting research priorities. The JLA approach involves a combination of surveys and workshop interactions between patients, carers and health care professionals to identify and agree on a "top ten" list of research questions. Respiratory infection is one of the hallmarks of cystic fibrosis (CF). To avoid cross infection, patients are advised not to meet face to face, preventing us following standard JLA methodology. Here we describe adaptations made during our recent JLA Priority Setting Partnership (PSP) in CF. Methods We elicited and prioritised research questions, using sequential online surveys, promoted through social media. People with CF participated in steering committee meetings and the final workshop, using videoconferencing. Alterations to workshop methodology enabled participants attending in person and those joining remotely, to contribute equally. We also altered the JLA methodology to include "lone" questions, asked by only one survey respondent. We are now working with the CF community to co-produce research projects that answer these top ten. Results There were 482 respondents, from 23 countries, who submitted 1080 questions. Increases in the number of responses occurred just after promotion on social media. Use of videoconferencing enabled participation of multiple people with CF and ensured participation from anywhere in the world, including hospital inpatients. Inclusion of lone questions resulted in one being included in our top ten. Conclusions There is no "one-size-fits-all" for patient involvement methodologies. Through altering the JLA methods to fit our patient group we achieved wide participation. We believe that methods used in our project may also be applied to future partnerships to increase participation, especially where people may be hospitalised or be unable to travel. The methodology we are developing through the JLA PSP CF2 project may be useful for other PSPs to follow.

PMID: 31452934 [PubMed]

Belatacept-based immunosuppression: a calcineurin inhibitor-sparing regimen in heart transplant recipients.

Am J Transplant. 2019 Aug 26;:

Authors: Launay M, Guitard J, Dorent R, Prevot Y, Prion F, Beaumont L, Kably B, Lecuyer L, Billaud EM, Guillemain R

Abstract
Belatacept (BTC) is indicated for prophylaxis of graft rejection in adults receiving a renal transplant (Tx). This retrospective observational study (3 centers) included all heart-transplant recipients receiving BTC between 01/2014 and 10/2018. Forty EBV+ patients mean GFR 35±20mL/min/m² were identified, among whom belatacept was initiated during the first 3 months after transplantation in 12 patients, and later in 28 patients. Several patients were multi-organ-transplant recipients. Study outcomes were GFR, safety and changes in immunosuppressive therapy. The main reason for switching to BTC was to preserve renal function, resulting in discontinuation of CNI and changes in immunosuppressive therapy in 76% of cases. At study close-out, 24/40 patients were still on BTC therapy. GFR was improved (+59%, p=0.0002*) within 1 month, particularly in early group. More episodes of rejection were observed among "late" patients (1 death). Sixteen treatment discontinuations were recorded: GFR recovery (n=4), DSA no longer detectable (n=1), compliance issues (n=3), poor venous access (n=2), multiple infections (n=1), 1 death (fungal lung infection), and treatment failure (n=4). Median follow-up was 24 months. Four patients developed de novo DSA (MFI<1,500). BTC is an effective alternative immunosuppressive for postoperative transient kidney failure, stabilizing delayed renal function, with acceptable safety profile under careful monitoring. This article is protected by copyright. All rights reserved.

PMID: 31452337 [PubMed - as supplied by publisher]

Amikacin liposome inhalation suspension for chronic Pseudomonas aeruginosa infection in cystic fibrosis.

J Cyst Fibros. 2019 Aug 23;:

Authors: Bilton D, Pressler T, Fajac I, Clancy JP, Sands D, Minic P, Cipolli M, Galeva I, Solé A, Quittner AL, Liu K, McGinnis JP, Eagle G, Gupta R, Konstan MW, CLEAR-108 Study Group

Abstract
BACKGROUND: Shortcomings of inhaled antibiotic treatments for Pseudomonas aeruginosa infection in patients with cystic fibrosis (CF) include poor drug penetration, inactivation by sputum, poor efficiency due to protective biofilm, and short residence in the lung.
METHODS: Eligible patients with forced expiratory volume in 1 s (FEV1) ≥25% of predicted value at screening and CF with chronic P. aeruginosa infection were randomly assigned to receive 3 treatment cycles (28 days on, 28 days off) of amikacin liposome inhalation suspension (ALIS, 590 mg QD) or tobramycin inhalation solution (TIS, 300 mg BID). The primary endpoint was noninferiority of ALIS vs TIS in change from baseline to day 168 in FEV1 (per-protocol population). Secondary endpoints included change in respiratory symptoms by Cystic Fibrosis Questionnaire-Revised (CFQ-R).
RESULTS: The study was conducted February 2012 to September 2013. ALIS was noninferior to TIS (95% CI, -4.95 to 2.34) for relative change in FEV1 (L) from baseline. The mean increases in CFQ-R score from baseline on the Respiratory Symptoms scale suggested clinically meaningful improvement in both arms at the end of treatment in cycle 1 and in the ALIS arm at the end of treatment in cycles 2 and 3; however, the changes were not statistically significant between the 2 treatment arms. Treatment-emergent adverse events (TEAEs) were reported in most patients (ALIS, 84.5%; TIS, 78.8%). Serious TEAEs occurred in 17.6% and 19.9% of patients, respectively; most were hospitalisations for infective pulmonary exacerbation of CF.
CONCLUSIONS: Cyclical dosing of once-daily ALIS was noninferior to cyclical twice-daily TIS in improving lung function. ClinicalTrials.gov Identifier: NCT01315678.

PMID: 31451351 [PubMed - as supplied by publisher]

Psychological predictors of nutritional adherence in adolescents with cystic fibrosis.

Clin Nutr ESPEN. 2019 Oct;33:143-147

Authors: Borschuk AP, Filigno SS, Opipari-Arrigan L, Peugh J, Stark LJ

Abstract
BACKGROUND & AIMS: The CF medical regimen is notoriously burdensome, comprised of respiratory treatments, oral medications, and nutritional demands. Adequate caloric intake has been identified as a challenge over the lifespan; however, we lack detailed information about nutritional adherence in teens, and the contextual drivers of these behaviors. Adolescence is a time of increased responsibility, reduced parental monitoring, and growing peer connections. There is no literature examining the impact of familial attitudes (e.g., privacy, disease disclosure) and the social milieu (e.g., friendships) on teen nutritional adherence behavior. We hypothesized that better teen nutritional adherence behaviors would be predicted by more favorable familial privacy attitudes, better relationship quality, and greater comfort in disease disclosure.
METHODS: Assessment included questionnaires of caregiver privacy attitudes, relationship quality, and disease disclosure. Teens tracked PERT adherence for 1 month and logged daily caloric intake for 2 weeks. This produced detailed information on daily enzyme adherence, caloric intake, and eating frequency.
RESULTS: Average PERT adherence, caloric intake, and eating frequency were suboptimal in this sample. More comfort in disease disclosure and less teen/mother discord predicted better PERT adherence. Higher caregiver privacy and lower teen closeness with friends predicted greater caloric intake and eating frequency.
CONCLUSIONS: Results suggest that comfort in disease disclosure supports consistent PERT adherence across environments. Adolescents with close friendships may have less time for self-management (e.g., eating). Future research should collect more detailed information about friendships of teens with CF. Results suggest that daily structure and positive, appropriately supportive relationships should be encouraged by care teams.

PMID: 31451251 [PubMed - in process]

CK19 stabilizes CFTR at the cell surface by limiting its endocytic pathway degradation.

FASEB J. 2019 Aug 26;:fj201901050R

Authors: Hou X, Wu Q, Rajagopalan C, Zhang C, Bouhamdan M, Wei H, Chen X, Zaman K, Li C, Sun X, Chen S, Frizzell RA, Sun F

Abstract
Protein interactions that stabilize the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) at the apical membranes of epithelial cells have not yet been fully elucidated. We identified keratin 19 (CK19 or K19) as a novel CFTR-interacting protein. CK19 overexpression stabilized both wild-type (WT)-CFTR and Lumacaftor (VX-809)-rescued F508del-CFTR (where F508del is the deletion of the phenylalanine residue at position 508) at the plasma membrane (PM), promoting Cl- secretion across human bronchial epithelial (HBE) cells. CK19 prevention of Rab7A-mediated lysosomal degradation was a key mechanism in apical CFTR stabilization. Unexpectedly, CK19 expression was decreased by ∼40% in primary HBE cells from homogenous F508del patients with CF relative to non-CF controls. CK19 also positively regulated multidrug resistance-associated protein 4 expression at the PM, suggesting that this keratin may regulate the apical expression of other ATP-binding cassette proteins as well as CFTR.-Hou, X., Wu, Q., Rajagopalan, C., Zhang, C., Bouhamdan, M., Wei, H., Chen, X., Zaman, K., Li, C., Sun, X., Chen, S., Frizzell, R. A., Sun, F. CK19 stabilizes CFTR at the cell surface by limiting its endocytic pathway degradation.

PMID: 31450978 [PubMed - as supplied by publisher]

Off the street phasing (OTSP): no hassle haplotype phasing for molecular PGD applications.

J Assist Reprod Genet. 2019 Apr;36(4):727-739

Authors: Zeevi DA, Zahdeh F, Kling Y, Carmi S, Altarescu G

Abstract
PURPOSE: Pre-implantation genetic diagnosis (PGD) for molecular disorders requires the construction of parental haplotypes. Classically, haplotype resolution ("phasing") is obtained by genotyping multiple polymorphic markers in both parents and at least one additional relative. However, this process is time-consuming, and immediate family members are not always available. The recent availability of massive genomic data for many populations promises to eliminate the needs for developing family-specific assays and for recruiting additional family members. In this study, we aimed to validate population-assisted haplotype phasing for PGD.
METHODS: Targeted sequencing of CFTR gene variants and ~ 1700 flanking polymorphic SNPs (± 2 Mb) was performed on 54 individuals from 12 PGD families of (a) Full Ashkenazi (FA; n = 16), (b) mixed Ashkenazi (MA; n = 23 individuals with at least one Ashkenazi and one non-Ashkenazi grandparents), or (c) non-Ashkenazi (NA; n = 15) descent. Heterozygous genotype calls in each individual were phased using various whole genome reference panels and appropriate computational models. All computationally derived haplotype predictions were benchmarked against trio-based phasing.
RESULTS: Using the Ashkenazi reference panel, phasing of FA was highly accurate (99.4% ± 0.2% accuracy); phasing of MA was less accurate (95.4% ± 4.5% accuracy); and phasing of NA was predictably low (83.4% ± 6.6% accuracy). Strikingly, for founder mutation carriers, our haplotyping approach facilitated near perfect phasing accuracy (99.9% ± 0.1% and 98.2% ± 2.8% accuracy for W1282X and delF508 carriers, respectively).
CONCLUSIONS: Our results demonstrate the feasibility of replacing classical haplotype phasing with population-based phasing with uncompromised accuracy.

PMID: 30617673 [PubMed - indexed for MEDLINE]

In silico Analysis Reveals Distribution of Quorum Sensing Genes and Consistent Presence of LuxR Solos in the Pandoraea Species.

Front Microbiol. 2019;10:1758

Authors: Chua KO, See-Too WS, Ee R, Lim YL, Yin WF, Chan KG

Abstract
The most common quorum sensing (QS) system in Gram-negative bacteria consists of signaling molecules called N-acyl-homoserine lactones (AHLs), which are synthesized by an enzyme AHL synthase (LuxI) and detected by a transcriptional regulator (LuxR) that are usually located in close proximity. However, many recent studies have also evidenced the presence of LuxR solos that are LuxR-related proteins in Proteobacteria that are devoid of a cognate LuxI AHL synthase. Pandoraea species are opportunistic pathogens frequently isolated from sputum specimens of cystic fibrosis (CF) patients. We have previously shown that P. pnomenusa strains possess QS activity. In this study, we examined the presence of QS activity in all type strains of Pandoraea species and acquired their complete genome sequences for holistic bioinformatics analyses of QS-related genes. Only four out of nine type strains (P. pnomenusa, P. sputorum, P. oxalativorans, and P. vervacti) showed QS activity, and C8-HSL was the only AHL detected. A total of 10 canonical luxIs with adjacent luxRs were predicted by bioinformatics from the complete genomes of aforementioned species and publicly available Pandoraea genomes. No orphan luxI was identified in any of the genomes. However, genes for two LuxR solos (LuxR2 and LuxR3 solos) were identified in all Pandoraea genomes (except two draft genomes with one LuxR solo gene), and P. thiooxydans was the only species that harbored no QS-related activity and genes. Except the canonical LuxR genes, LuxIs and LuxR solos of Pandoraea species were distantly related to the other well-characterized QS genes based on phylogenetic clustering. LuxR2 and LuxR3 solos might represent two novel evolutionary branches of LuxR system as they were found exclusively only in the genus. As a few luxR solos were located in close proximity with prophage sequence regions in the genomes, we thus postulated that these luxR solos could be transmitted into genus Pandoraea by transduction process mediated by bacteriophage. The bioinformatics approach developed in this study forms the basis for further characterization of closely related species. Overall, our findings improve the current understanding of QS in Pandoraea species, which is a potential pharmacological target in battling Pandoraea infections in CF patients.

PMID: 31447806 [PubMed]

The Emergence of Rare Clinical Aspergillus Species in Qatar: Molecular Characterization and Antifungal Susceptibility Profiles.

Front Microbiol. 2019;10:1677

Authors: Salah H, Lackner M, Houbraken J, Theelen B, Lass-Flörl C, Boekhout T, Almaslamani M, Taj-Aldeen SJ

Abstract
Aspergillus are ubiquitous mold species that infect immunocompetent and immunocompromised patients. The symptoms are diverse and range from allergic reactions, bronchopulmonary infection, and bronchitis, to invasive aspergillosis. The aim of this study was to characterize 70 Aspergillus isolates recovered from clinical specimens of patients with various clinical conditions presented at Hamad general hospital in Doha, Qatar, by using molecular methods and to determine their in vitro antifungal susceptibility patterns using the Clinical and Laboratory Standards Institute (CLSI) M38-A2 reference method. Fourteen Aspergillus species were identified by sequencing β-tubulin and calmodulin genes, including 10 rare and cryptic species not commonly recovered from human clinical specimens. Aspergillus welwitschiae is reported in this study for the first time in patients with fungal rhinosinusitis (n = 6) and one patient with a lower respiratory infection. Moreover, Aspergillus pseudonomius is reported in a patient with fungal rhinosinusitis which is considered as the first report ever from clinical specimens. In addition, Aspergillus sublatus is reported for the first time in a patient with cystic fibrosis. In general, our Aspergillus strains exhibited low MIC values for most of the antifungal drugs tested. One strain of Aspergillus fumigatus showed high MECs for echinocandins and low MICs for the rest of the drugs tested. Another strain of A. fumigatus exhibited high MIC for itraconazole and categorized as non-wild type. These findings require further analysis of their molecular basis of resistance. In conclusion, reliable identification of Aspergillus species is achieved by using molecular sequencing, especially for the emerging rare and cryptic species. They are mostly indistinguishable by conventional methods and might exhibit variable antifungal susceptibility profiles. Moreover, investigation of the antifungal susceptibility patterns is necessary for improved antifungal therapy against aspergillosis.

PMID: 31447794 [PubMed]

Antimicrobial Treatment of Staphylococcus aureus in Patients With Cystic Fibrosis.

Front Pharmacol. 2019;10:849

Authors: Esposito S, Pennoni G, Mencarini V, Palladino N, Peccini L, Principi N

Abstract
Staphylococcus aureus is a ubiquitous human commensal pathogen. It is commonly isolated in cystic fibrosis (CF) patients and is considered one of the main causes of the recurrent acute pulmonary infections and progressive decline in lung function that characterize this inherited life-threatening multisystem disorder. However, the true role of S. aureus in CF patients is not completely understood. The main aim of this narrative review is to discuss the present knowledge of the role of S. aureus in CF patients. Literature review showed that despite the fact that the availability and use of drugs effective against S. aureus have coincided with a significant improvement in the prognosis of lung disease in CF patients, clearly evidencing the importance of S. aureus therapy, how to use old and new drugs to obtain the maximal effectiveness has not been precisely defined. The most important problem remains that the high frequency with which S. aureus is carried in healthy subjects prevents the differentiation of simple colonization from infection. Moreover, although experts recommend antibiotic administration in CF patients with symptoms and in those with persistent detection of S. aureus, the best antibiotic approach has not been defined. All these problems are complicated by the evidence that the most effective antibiotic against methicillin-resistant S. aureus (MRSA) cannot be used in patients with CF with the same schedules used in patients without CF. Further studies are needed to solve these problems and to assure CF patients the highest level of care.

PMID: 31447669 [PubMed]

The presence of Aspergillus fumigatus is associated with worse respiratory quality of life in cystic fibrosis.

J Cyst Fibros. 2019 Aug 21;:

Authors: Hong G, Alby K, Ng SCW, Fleck V, Kubrak C, Rubenstein RC, Dorgan DJ, Kawut SM, Hadjiliadis D

Abstract
BACKGROUND: The clinical effects of Aspergillus fumigatus in the cystic fibrosis (CF) airway, with the exception of allergic bronchopulmonary aspergillosis, is unclear.
METHODS: CF adolescents and adults (age 14 years and older) underwent bacterial and semi-selective fungal culture testing to determine the prevalence of fungi in the CF respiratory tract and the independent association between the presence of Aspergillus fumigatus and clinical characteristics.
RESULTS: Aspergillus fumigatus (10.3%) and Candida species (57.8%) were the most common filamentous fungi and yeast seen respectively in the sputa of 206 individuals with CF. Inhaled corticosteroid (ICS) use was more common in Aspergillus fumigatus-positive than Aspergillus fumigatusnegative (100% versus 75.8%, p = .01). Aspergillus fumigatus was significantly associated with lower respiratory domain score (β -8.74, 95% CI -16.6, -0.88, p = .03), representing worse respiratory-related quality of life, accounting for demographics, disease characteristics, and the presence of a pulmonary exacerbation.
CONCLUSION: The presence of Aspergillus fumigatus in CF sputum was associated with worse respiratory quality of life in CF in a crosssectional, single center study. Longitudinal analysis examining the clinical implications of Aspergillus fumigatus on respiratory health over time is needed.

PMID: 31446018 [PubMed - as supplied by publisher]

Surgical management of lumbar disc herniation in children and adolescents.

Clin Neurol Neurosurg. 2019 Aug 09;185:105486

Authors: Raghu ALB, Wiggins A, Kandasamy J

Abstract
Lumbar disc herniation (LDH) is a rare cause of morbidity in the paediatric population that can result in disruption to education and participation in social and athletic activities. Modern minimally invasive techniques have increasingly been adopted in paediatric spine surgery. The purpose of this review was to assess characteristics of paediatric LDH, evaluate current surgical techniques and their outcomes in recent literature, and compare paediatric outcomes with adults. A literature search was carried out identifying articles published from 2008 to 2018 relating to surgical treatment of LDH in children and adolescents. Original articles were scrutinised for outcome data and complications then compared by surgical approach. Over the last decade 1094 surgical cases have been published, mostly L4/L5 (52%) and L5/S1 (41%) intervertebral discs. These were predominantly operated with microdiscectomy and minimally invasive techniques: percutaneous endoscopic and tubular approaches to discectomy. Cystic fibrosis, trauma, extensive athletic activity, facet joint asymmetries and lumbosacral transition vertebrae may be risk factors for LDH. 55% had total resolution of pain after surgery, complications are rare and unsatisfactory resolution of pain and re-operation uncommon. In the short and medium-term, overall, paediatric patients do not have worse surgical outcomes than adult patients; they may recover faster and improve more. Minimally invasive approaches for LDH in adolescents are safe and efficacious. No technique has yet demonstrated clear superiority. Delaying surgery for conservative treatment is warranted, but for how long remains unclear.

PMID: 31445324 [PubMed - as supplied by publisher]

Characterization of spray dried powders with nucleic acid-containing PEI nanoparticles.

Eur J Pharm Biopharm. 2019 Aug 21;:

Authors: Keil TWM, Feldmann DP, Costabile G, Zhong Q, da Rocha S, Merkel OM

Abstract
Localized aerosol delivery of gene therapies is a promising treatment of severe pulmonary diseases including lung cancer, cystic fibrosis, COPD and asthma. The administration of drugs by inhalation features multiple benefits including an enhanced patient acceptability and compliance. The application of a spray dried powder formulation has advantages over solutions due to their increased stability and shelf life. Furthermore, optimal sizes of the powder can be obtained by spray drying to allow a deep lung deposition. The present study optimized the parameters involved with spray drying polyplexes formed by polyethylenimine (PEI) and nucleic acids in inert excipients to generate a nano-embedded microparticle (NEM) powder with appropriate aerodynamic diameter. Furthermore, the effects of the excipient matrix used to generate the NEM powder on the biological activity of the nucleic acid and the ability to recover the embedded nanoparticles was investigated. The study showed that bioactivity and nucleic acid integrity was preserved after spray drying, and that polyplexes could be reconstituted from the dry powders made with trehalose but not mannitol as a stabilizer. Scanning electron microscopy (SEM) showed trehalose formulations that formed fused, lightly corrugated spherical particles in the range between 1-5 µm, while mannitol formulations had smooth surfaces and consisted of more defined particles. After redispersion of the microparticles in water, polyplex dispersions are obtained that are comparable to the initial formulations before spray drying. Cellular uptake and transfection studies conducted in lung adenocarcinoma cells show that redispersed trehalose particles performed similar to or better than polyplexes that were not spray dried. A method for quantifying polymer and nucleic acid loss following spray drying was developed in order to ensure that equal nucleic acid amounts were used in all in vitro experiments. The results confirm that spray dried NEM formulations containing nucleic acids can be prepared with characteristics known to be optimal for inhalation therapy.

PMID: 31445157 [PubMed - as supplied by publisher]

Biochemistry of very-long-chain and long-chain ceramides in cystic fibrosis and other diseases: The importance of side chain.

Prog Lipid Res. 2019 Aug 21;:100998

Authors: Garić D, De Sanctis JB, Shah J, Dumut DC, Radzioch D

Abstract
Ceramides, the principal building blocks of all sphingolipids, have attracted the attention of many scientists around the world interested in developing treatments for cystic fibrosis, the most common genetic disease of Caucasians. Many years of fruitful research in this field have produced some fundamentally important, yet controversial results. Here, we aimed to summarize the current knowledge on the role of long- and very-long- chain ceramides, the most abundant species of ceramides in animal cells, in cystic fibrosis and other diseases. We also aim to explain the importance of the length of their side chain in the context of stability of transmembrane proteins through a concise synthesis of their biophysical chemistry, cell biology, and physiology. This review also addresses several remaining riddles in this field. Finally, we discuss the technical challenges associated with the analysis and quantification of ceramides. We provide the evaluation of the antibodies used for ceramide quantification and we demonstrate their lack of specificity. Results and discussion presented here will be of interest to anyone studying these enigmatic lipids.

PMID: 31445070 [PubMed - as supplied by publisher]

Antibiotic prophylaxis in anterior skull-base surgery: a survey of the North American Skull Base Society.

Int Forum Allergy Rhinol. 2019 Aug 23;:

Authors: Fang CH, Hawn VS, Agarwal V, Moskowitz HS, Kshettry VR, McKean EL, Bellile E, Akbar NA, Abuzeid WM

Abstract
BACKGROUND: There is a paucity of data evaluating antibiotic use in anterior skull-base surgery (ASBS). The goal of this study was to determine antibiotic prescribing patterns and factors that influence antibiotic use in ASBS.
METHODS: An online-based survey was distributed to the membership of the North American Skull Base Society in 2018. Outcomes included practitioner preference regarding intraoperative and postoperative antibiotic use, practice location and environment, surgeon experience, and patient factors influencing antibiotic use.
RESULTS: There were 208 respondents (25.6% response rate) of which 182 (87.5%) performed ASBS; 60.4% were in academic institutions. Respondents were neurosurgeons (59.3%) or otolaryngologists (40.7%), and 75.3% were fellowship-trained in ASBS. Most surgeons (95.0%) gave intraoperative antibiotics. Academic surgeons were 4 times more likely to prescribe intraoperative antibiotics than private practitioners (odds ratio [OR] 3.98; 95% confidence interval [CI], 1.53 to 10.36; p = 0.005). Among surgeons who did not routinely prescribe intraoperative antibiotics, regression analysis indicated that the presence of actively infected sinuses, transplantation, diabetes, human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), and pulmonary disease influenced decision-making (p < 0.03). Postoperative antibiotics were prescribed by 73.6% of respondents. European surgeons were 3 times less likely to prescribe postoperative antibiotics (OR 0.34; 95% CI, 0.15 to 0.80; p = 0.01). Regression modeling indicated that HIV/AIDS, cystic fibrosis, diabetes, transplantation, and pulmonary disease, as well as the use of absorbable packing influenced the decision to use postoperative antibiotics (p < 0.003).
CONCLUSION: This study demonstrates the significant variation in intra- and postoperative antibiotic use among surgeons performing ASBS. Prospective randomized studies are necessary to establish evidence-based practice guidelines for perioperative antibiotic use in ASBS.

PMID: 31442001 [PubMed - as supplied by publisher]

Predictors of Malnutrition in Children with Cystic Fibrosis.

Indian Pediatr. 2019 Aug 10;:

Authors: Dhochak N, Jat KR, Sankar J, Lodha R, Kabra SK

Abstract
OBJECTIVE: To determine occurrence of malnutrition in children with cystic fibrosis and identify predictors of malnutrition at time of enrolment and after 2 years of follow up.
DESIGN: Retrospective chart review.
SETTING: Pediatric chest clinic at tertiary-care centre in North India.
PATIENTS: Cystic fibrosis patients enrolled between 2009-2015 with at least 3 years follow-up.
PROCEDURE: Weight and height were noted at enrolment, and after 1 and 2 years of follow-up. Clinical details, medications, and pulmonary exacerbations during second year were recorded.
MAIN OUTCOME MEASURE: Occurrence of malnutrition i.e. weight for age Z-score ≤2.
RESULTS: 61 medical records were reviewed. Occurrence of malnutrition at baseline, and 1- and 2-year follow-up was 65.5%, 54.1% and 57.3%, respectively. Weight for age Z-score at enrolment significantly correlated with time to diagnosis from onset (r2=0.015, P=0.029). Weight for age Z-score at 2-year follow-up was significantly associated with steatorrhea (P=0.03), increased frequency of stools (P<0.01) and pulmonary exacerbation (P=0.03) during second year. Linear regression showed significant association between weight for age Z-score at 2 years with steatorrhea and pulmonary exacerbations, [r=-0.795 (-1.527, -0.062)] and [r=-0.261(-0.493, -0.028)]. Pulmonary exacerbations during second and third year had significant correlation with weight for age Z-score at the beginning of respective years (r = -0.219, P=0.015).
CONCLUSION: Occurrence of malnutrition is high in northern Indian children with cystic fibrosis, with uncontrolled fat malabsorption and recurrent respiratory infections being significant risk factors.

PMID: 31441435 [PubMed - as supplied by publisher]

Deciphering the Ecology of Cystic Fibrosis Bacterial Communities: Towards Systems-Level Integration.

Trends Mol Med. 2019 Aug 19;:

Authors: Bevivino A, Bacci G, Drevinek P, Nelson MT, Hoffman L, Mengoni A

Abstract
Despite over a decade of cystic fibrosis (CF) microbiome research, much remains to be learned about the overall composition, metabolic activities, and pathogenicity of the microbes in CF airways, limiting our understanding of the respiratory microbiome's relation to disease. Systems-level integration and modeling of host-microbiome interactions may allow us to better define the relationships between microbiological characteristics, disease status, and treatment response. In this way, modeling could pave the way for microbiome-based development of predictive models, individualized treatment plans, and novel therapeutic approaches, potentially serving as a paradigm for approaching other chronic infections. In this review, we describe the challenges facing this effort and propose research priorities for a systems biology approach to CF lung disease.

PMID: 31439509 [PubMed - as supplied by publisher]