Use of Hyaluronic Acid (HA) in Chronic Airway Diseases.

Cells. 2020 Sep 29;9(10):

Authors: Máiz Carro L, Martínez-García MA

Abstract
Hyaluronic acid (HA) is a key component of the extracellular matrix of the lungs. A unique attribute of HA is its water-retaining properties, so HA has a major role in the regulation of fluid balance in the lung interstitium. Hyaluronic acid has been widely used in the treatment of eyes, ears, joints and skin disorders, but in the last years, it has been also proposed in the treatment of certain lung diseases, including airway diseases, due to its anti-inflammatory and water-binding capacities. Hyaluronic acid aerosol decreases the severity of elastase-induced emphysema in murine models, prevents bronchoconstriction in asthmatics and improves some functional parameters in chronic obstructive pulmonary disease (COPD) patients. Due to the protection of HA against bronchoconstriction and its hydration properties, inhaled HA would increase the volume of airway surface liquid, resulting in mucus hydration, increased mucous transport and less mucous plugging of the airways. In addition, it has been seen in human studies that the treatment with nebulised HA improves the tolerability of nebulised hypertonic saline (even at 6% or 7% of concentration), which has been demonstrated to be an effective treatment in bronchial secretion management in patients with cystic fibrosis and bronchiectasis. Our objective is to review the role of HA treatment in the management of chronic airway diseases.

PMID: 33003557 [PubMed - in process]

Membrane phospholipid composition of Pseudomonas aeruginosa grown in a cystic fibrosis mucus-mimicking medium.

Biochim Biophys Acta Biomembr. 2020 Sep 28;:183482

Authors: Deschamps E, Schaumann A, Schmitz-Afonso I, Afonso C, Dé E, Loutelier-Bourhis C, Alexandre S

Abstract
BACKGROUND: Pseudomonas aeruginosa is a bacterium able to induce serious pulmonary infections in cystic fibrosis (CF) patients. This bacterium is very often antibiotic resistant, partly because of its membrane impermeability, which is linked to the membrane lipid composition. This work aims to study the membrane phospholipids of P. aeruginosa grown in CF sputum-like media.
METHODS: Three media were used: Mueller Hilton broth (MHB), synthetic cystic fibrosis medium (SCFM) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) complemented SCFM (SCFM-PC). Lipids were extracted and LC-MS/MS analyses were performed. Growth curves, atomic force microscopy images and minimal inhibitory concentration determination were performed in order to compare the growth and potentially link lipid modifications to antibiotic resistance.
RESULTS: Semi-quantification showed phospholipid quantity variation depending on the growth medium. Phosphatidylcholines were detected in traces in SCFM. MS/MS experiments showed an increase of phospholipids derived from DOPC in SCFM-PC. We observed no influence of the medium on the bacterial growth and a minor influence on the bacterial shape. MIC values were generally higher in SCFM and SCFM-PC than in MHB.
CONCLUSIONS: We defined a CF sputum-like media which can be used for the membrane lipid extraction of P. aeruginosa. We also showed that the growth medium does have an influence on its membrane lipid composition and antibiotic resistance, especially for SCFM-PC in which P. aeruginosa uses DOPC, in order to make its own membrane.
GENERAL SIGNIFICANCE: Our results show that considerable caution must be taken when choosing a medium for lipid identification and antibiotic testing -especially for phospholipids-enriched media.

PMID: 33002450 [PubMed - as supplied by publisher]

Mutations of the cystic fibrosis transmembrane conductance regulator gene in males with congenital bilateral absence of the vas deferens: Reproductive implications and genetic counseling (Review).

Mol Med Rep. 2020 Nov;22(5):3587-3596

Authors: Cui X, Wu X, Li Q, Jing X

Abstract
Congenital bilateral absence of the vas deferens (CBAVD) is predominantly caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CBAVD accounts for 2‑6% of male infertility cases and up to 25% of cases of obstructive azoospermia. With the use of pre‑implantation genetic diagnosis, testicular or epididymal sperm aspiration, intracytoplasmic sperm injection and in vitro fertilization, patients affected by CBAVD are able to have children who do not carry CFTR gene mutations, thereby preventing disease. Therefore, genetic counseling should be provided to couples receiving assisted reproductive techniques to discuss the impact of CFTR gene mutations on reproductive health. In the present article, the current literature concerning the CFTR gene and its association with CBAVD is reviewed.

PMID: 33000223 [PubMed - in process]

Oral CorticoSteroid sparing with biologics in severe asthma: A remark of the Severe Asthma Network in Italy (SANI).

World Allergy Organ J. 2020 Oct;13(10):100464

Authors: Canonica GW, Blasi F, Paggiaro P, Senna G, Passalacqua G, Spanevello A, Aliberti S, Bagnasco D, Bonavia M, Bonini M, Brussino L, Bucca C, Caiaffa MF, Calabrese C, Camiciottoli G, Caminati M, Carpagnano GE, Caruso C, Centanni S, Conte ME, Corsico AG, Cosmi L, Costantino MT, Crimi N, D'Alò S, D'Amato M, Del Giacco S, Farsi A, Favero E, Foschino Barbaro MP, Guarnieri G, Guida G, Latorre M, Lo Cicero S, Lombardi C, Macchia L, Mazza F, Menzella F, Milanese M, Montagni M, Montuschi P, Nucera E, Parente R, Patella V, Pelaia G, Pini L, Puggioni F, Ricciardi L, Ricciardolo FLM, Richeldi L, Ridolo E, Rolla G, Santus P, Scichilone N, Spadaro G, Vianello A, Viviano V, Yacoub MR, Zappa MC, Heffler E, SANI (Severe Asthma Network Italy)

Abstract
According to the data derived from several national and international registries, including SANI (Severe Asthma Network Italy), and considering the strong impact that frequent or regular use of oral corticosteroid has on quality of life (QoL) of severe asthmatics, as well as on the costs for managing corticosteroid-related diseases, oral corticosteroid sparing up to withdrawal should be considered a primary outcome in the management of severe asthma. New biologics have clearly demonstrated that this effect is possible, with concomitant reduction in the rate of exacerbations and in symptom control. Then, there is no reason for using so frequently oral corticosteroid before having explored all alternatives currently available for a large part of severe asthmatics.

PMID: 32999699 [PubMed]

Antimicrobial Peptide Exposure Selects for Resistant and Fit Stenotrophomonas maltophilia Mutants That Show Cross-Resistance to Antibiotics.

mSphere. 2020 Sep 30;5(5):

Authors: Blanco P, Hjort K, Martínez JL, Andersson DI

Abstract
Antimicrobial peptides (AMPs) are essential components of the innate immune system and have been proposed as promising therapeutic agents against drug-resistant microbes. AMPs possess a rapid bactericidal mode of action and can interact with different targets, but bacteria can also avoid their effect through a variety of resistance mechanisms. Apart from hampering treatment by the AMP itself, or that by other antibiotics in the case of cross-resistance, AMP resistance might also confer cross-resistance to innate human peptides and impair the anti-infective capability of the human host. A better understanding of how resistance to AMPs is acquired and the genetic mechanisms involved is needed before using these compounds as therapeutic agents. Using experimental evolution and whole-genome sequencing, we determined the genetic causes and the effect of acquired de novo resistance to three different AMPs in the opportunistic pathogen Stenotrophomonas maltophilia, a bacterium that is intrinsically resistant to a wide range of antibiotics. Our results show that AMP exposure selects for high-level resistance, generally without any reduction in bacterial fitness, conferred by mutations in different genes encoding enzymes, transporters, transcriptional regulators, and other functions. Cross-resistance to AMPs and to other antibiotic classes not used for selection, as well as collateral sensitivity, was observed for many of the evolved populations. The relative ease by which high-level AMP resistance is acquired, combined with the occurrence of cross-resistance to conventional antibiotics and the maintained bacterial fitness of the analyzed mutants, highlights the need for careful studies of S. maltophilia resistance evolution to clinically valuable AMPs.IMPORTANCE Stenotrophomonas maltophilia is an increasingly relevant multidrug-resistant (MDR) bacterium found, for example, in people with cystic fibrosis and associated with other respiratory infections and underlying pathologies. The infections caused by this nosocomial pathogen are difficult to treat due to the intrinsic resistance of this bacterium against a broad number of antibiotics. Therefore, new treatment options are needed, and considering the growing interest in using AMPs as alternative therapeutic compounds and the restricted number of antibiotics active against S. maltophilia, we addressed the potential for development of AMP resistance, the genetic mechanisms involved, and the physiological effects that acquisition of AMP resistance has on this opportunistic pathogen.

PMID: 32999081 [PubMed - in process]

Definition of Haptens Derived from Sulfamethoxazole: In Vitro and in Vivo.

Chem Res Toxicol. 2019 10 21;32(10):2095-2106

Authors: Tailor A, Waddington JC, Hamlett J, Maggs J, Kafu L, Farrell J, Dear GJ, Whitaker P, Naisbitt DJ, Park K, Meng X

Abstract
Hypersensitivity reactions occur frequently in patients upon treatment with sulfamethoxazole (SMX). These adverse effects have been attributed to nitroso sulfamethoxazole (SMX-NO), the reactive product formed from auto-oxidation of the metabolite SMX hydroxylamine. The ability of SMX-NO to prime naïve T-cells in vitro and also activate T-cells derived from hypersensitive patients has illustrated that T-cell activation may occur through the binding of SMX-NO to proteins or through the direct modification of MHC-bound peptides. SMX-NO has been shown to modify cysteine residues in glutathione, designer peptides, and proteins in vitro; however, the presence of these adducts have not yet been characterized in vivo. In this study a parallel in vitro and in vivo analysis of SMX-NO adducts was conducted using mass spectrometry. In addition to the known cysteine adducts, multiple SMX-NO-derived haptenic structures were found on lysine and tyrosine residues of human serum albumin (HSA) in vitro. On lysine residues two haptenic structures were identified including an arylazoalkane adduct and a Schiff base adduct. Interestingly, these adducts are labile to heat and susceptible to hydrolysis as shown by the presence of allysine. Furthermore, SMX-modified HSA adducts were detected in patients on long-term SMX therapy illustrated by the presence of an arylazoalkane adduct derived from a proposed carboxylic acid metabolite of SMX-NO. The presence of these adducts could provide an explanation for the immunogenicity of SMX and the strong responses to SMX-NO observed in T-cell culture assays. Also, the degradation of these adducts to allysine could lead to a stress-related innate immune response required for T-cell activation.

PMID: 31468968 [PubMed - indexed for MEDLINE]

Prophylactic anti-staphylococcal antibiotics for cystic fibrosis.

Cochrane Database Syst Rev. 2020 Sep 30;9:CD001912

Authors: Rosenfeld M, Rayner O, Smyth AR

Abstract
BACKGROUND: Staphylococcus aureus causes pulmonary infection in young children with cystic fibrosis. Prophylactic antibiotics are prescribed hoping to prevent such infection and lung damage. Antibiotics have adverse effects and long-term use might lead to infection with Pseudomonas aeruginosa. This is an update of a previously published review.
OBJECTIVES: To assess continuous oral antibiotic prophylaxis to prevent the acquisition of Staphylococcus aureus versus no prophylaxis in people with cystic fibrosis, we tested the following hypotheses to investigate whether prophylaxis: 1. improves clinical status, lung function and survival; 2. leads to fewer isolates of Staphylococcus aureus; 3. causes adverse effects (e.g. diarrhoea, skin rash, candidiasis); 4. leads to fewer isolates of other common pathogens from respiratory secretions; 5. leads to the emergence of antibiotic resistance and colonisation of the respiratory tract with Pseudomonas aeruginosa.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Companies manufacturing anti-staphylococcal antibiotics were contacted. Most recent search of the Group's Register: 27 February 2020. Online trials registries were also searched. Most recent search of online trials registries: 15 September 2020.
SELECTION CRITERIA: Randomised trials of continuous oral prophylactic antibiotics (given for at least one year) compared to intermittent antibiotics given 'as required', in people with cystic fibrosis of any disease severity.
DATA COLLECTION AND ANALYSIS: The authors assessed studies for eligibility and methodological quality and extracted data. The quality of the evidence was assessed using the GRADE criteria. The review's primary outcomes of interest were lung function by spirometry (forced expiratory volume in one second (FEV1)) and the number of people with one or more isolates of Staphylococcus aureus (sensitive strains).
MAIN RESULTS: We included four studies, with a total of 401 randomised participants aged zero to seven years on enrolment; one study is ongoing. The two older included studies generally had a higher risk of bias across all domains, but in particular due to a lack of blinding and incomplete outcome data, than the two more recent studies. We only regarded the most recent study as being generally free of bias, although even here we were not certain of the effect of the per protocol analysis on the study results. Evidence quality was judged to be low for all outcomes assessed after being downgraded based on GRADE assessments. Downgrading decisions were due to limitations in study design (all outcomes), for imprecision and for inconsistency . Prophylactic anti-staphylococcal antibiotics probably make little or no difference to lung function measured as FEV1 % predicted after six years (mean difference (MD) -2.30, 95% confidence interval (CI) -13.59 to 8.99, one study, n = 119, low-quality evidence); but may reduce the number of children having one or more isolates of Staphylococcus aureus at two years (odds ratio (OR) 0.21, 95% CI 0.13 to 0.35, three studies, n = 315, low-quality evidence). At the same time point, there may be little or no effect on nutrition as reported using weight z score (MD 0.06, 95% CI -0.33 to 0.45, two studies, n = 140, low-quality evidence), additional courses of antibiotics (OR 0.18, 95% CI 0.01 to 3.60, one study, n = 119, low-quality evidence) or adverse effects (low-quality evidence). There was no difference in the number of isolates of Pseudomonas aeruginosa between groups at two years (OR 0.74, 95% CI 0.45 to 1.23, three studies, n = 312, low-quality evidence), though there was a trend towards a lower cumulative isolation rate of Pseudomonas aeruginosa in the prophylaxis group at two and three years and towards a higher rate from four to six years. As the studies reviewed lasted six years or less, conclusions cannot be drawn about the long-term effects of prophylaxis.
AUTHORS' CONCLUSIONS: Anti-staphylococcal antibiotic prophylaxis may lead to fewer children having isolates of Staphylococcus aureus, when commenced early in infancy and continued up to six years of age. The clinical importance of this finding is uncertain. Further research may establish whether the trend towards more children with CF with Pseudomonas aeruginosa, after four to six years of prophylaxis, is a chance finding and whether choice of antibiotic or duration of treatment might influence this.

PMID: 32997797 [PubMed - as supplied by publisher]

Mortality risk of antipsychotic augmentation for adult depression.

PLoS One. 2020;15(9):e0239206

Authors: Gerhard T, Stroup TS, Correll CU, Setoguchi S, Strom BL, Huang C, Tan Z, Crystal S, Olfson M

Abstract
IMPORTANCE: Randomized controlled trials have demonstrated increased all-cause mortality in elderly patients with dementia treated with newer antipsychotics. It is unknown whether this risk generalizes to non-elderly adults using newer antipsychotics as augmentation treatment for depression.
OBJECTIVE: This study examined all-cause mortality risk of newer antipsychotic augmentation for adult depression.
DESIGN: Population-based new-user/active comparator cohort study.
SETTING: National healthcare claims data from the US Medicaid program from 2001-2010 linked to the National Death Index.
PARTICIPANTS: Non-elderly adults (25-64 years) diagnosed with depression who after ≥3 months of antidepressant monotherapy initiated either augmentation with a newer antipsychotic or with a second antidepressant. Patients with alternative indications for antipsychotic medications, such as schizophrenia, psychotic depression, or bipolar disorder, were excluded.
EXPOSURE: Augmentation treatment for depression with a newer antipsychotic or with a second antidepressant.
MAIN OUTCOME: All-cause mortality during study follow-up ascertained from the National Death Index.
RESULTS: The analytic cohort included 39,582 patients (female = 78.5%, mean age = 44.5 years) who initiated augmentation with a newer antipsychotic (n = 22,410; 40% = quetiapine, 21% = risperidone, 17% = aripiprazole, 16% = olanzapine) or with a second antidepressant (n = 17,172). The median chlorpromazine equivalent starting dose for all newer antipsychotics was 68mg/d, increasing to 100 mg/d during follow-up. Altogether, 153 patients died during 13,328 person-years of follow-up (newer antipsychotic augmentation: n = 105, follow-up = 7,601 person-years, mortality rate = 138.1/10,000 person-years; antidepressant augmentation: n = 48, follow-up = 5,727 person-years, mortality rate = 83.8/10,000 person-years). An adjusted hazard ratio of 1.45 (95% confidence interval, 1.02 to 2.06) indicated increased all-cause mortality risk for newer antipsychotic augmentation compared to antidepressant augmentation (risk difference = 37.7 (95%CI, 1.7 to 88.8) per 10,000 person-years). Results were robust across several sensitivity analyses.
CONCLUSION: Augmentation with newer antipsychotics in non-elderly patients with depression was associated with increased mortality risk compared with adding a second antidepressant. Though these findings require replication and cannot prove causality, physicians managing adults with depression should be aware of this potential for increased mortality associated with newer antipsychotic augmentation.

PMID: 32997687 [PubMed - as supplied by publisher]

E-cigarette constituents propylene glycol and vegetable glycerine decrease glucose uptake and its metabolism in airway epithelial cells in vitro.

Am J Physiol Lung Cell Mol Physiol. 2020 Sep 30;:

Authors: Woodall M, Jacob J, Kalsi K, Davis E, Kenyon B, Khan IH, Garnett JP, Tarran R, Baines DL

Abstract
Electronic nicotine delivery systems, or e.cigarettes utilise a liquid solution that normally contains propylene glycol (PG) and vegetable glycerine (VG) to generate vapour and act as a carrier for nicotine and flavourings. Evidence indicated these 'carriers' reduced growth and survival of epithelial cells including those of the airway. We hypothesised that 3% PG or PG mixed with VG (3% PG:VG, 55:45) inhibited glucose uptake in human airway epithelial cells as a first step to reducing airway cell survival. Exposure of H441 or human bronchiolar epithelial cells (HBEC) to PG and PG/VG (30-60 minutes) inhibited glucose uptake and mitochondrial ATP synthesis. PG/VG inhibited glycolysis. PG/VG and mannitol reduced cell volume and height of air-liquid interface cultures. Mannitol but not PG/VG increased phosphorylation of p38 MAPK. PG/VG reduced TEER which was associated with increased transepithelial solute permeability. PG/VG decreased FRAP of GFP linked glucose transporters GLUT1 and GLUT10 indicating that glucose transport function was compromised. Puffing PG/VG vapour onto the apical surface of primary HBEC for 10 mins to mimic the effect of e.cigarette smoking also reduced glucose transport. In conclusion, short term exposure to PG/VG, key components of e.cigarettes, decreased glucose transport and metabolism in airway cells. We propose that this was a result of PG/VG reduced cell volume and membrane fluidity, with further consequences on epithelial barrier function. Taken together, we suggest these factors contribute to reduced defensive properties of the epithelium. We propose that repeated/chronic exposure to these agents are likely to contribute to airway damage in e-cigarette users.

PMID: 32996783 [PubMed - as supplied by publisher]

Stakeholder feedback informs investigations for chronic rhinosinusitis in cystic fibrosis.

Int Forum Allergy Rhinol. 2020 Sep 29;:

Authors: Beswick DM, Saavedra MT

PMID: 32996261 [PubMed - as supplied by publisher]

Development and Application of a Patient Group Engagement Prioritization Tool for Use in Medical Product Development.

Ther Innov Regul Sci. 2020 Sep 29;:

Authors: Perry B, Dombeck C, Smalley JB, Levitan B, Leventhal D, Patrick-Lake B, Brennan L, McKenna K, Hallinan Z, Corneli A

Abstract
INTRODUCTION: Patient group engagement is increasingly used to inform the design, conduct, and dissemination of clinical trials and other medical research activities. However, the priorities of industry sponsors and patient groups differ, and there is currently no framework to help these groups identify mutually beneficial engagement activities.
METHODS: We conducted 28 qualitative, semi-structured interviews with representatives from research sponsor organizations (n = 14) and patient groups (n = 14) to determine: (1) how representatives define benefits and investments of patient group engagement in medical product development, and (2) to refine a list of 31 predefined patient group engagement activities.
RESULTS: Patient group and sponsor representatives described similar benefits: engagement activities can enhance the quality and efficiency of clinical trials by improving patient recruitment and retention, reduce costs, and help trials meet expectations of regulators and payers. All representatives indicated that investments include both dedicated staff time and expertise, and financial resources. Factors to consider when evaluating benefits and investments were also identified as were suggestions for clarifying the list of engagement activities.
DISCUSSION: Using these findings, we refined the 31 engagement activities to 24 unique activities across the medical product development lifecycle. We also developed a web-based prioritization tool ( https://prioritizationtool.ctti-clinicaltrials.org/ ) to help clinical research sponsors and patient groups identify high-priority engagement activities. Use of this tool can help sponsors and patient groups identify the engagement activities that they believe will provide the most benefit for the least investment and may lead to more meaningful and mutually beneficial partnerships in medical product development.

PMID: 32996107 [PubMed - as supplied by publisher]

Immune transcriptomes of highly exposed SARS-CoV-2 asymptomatic seropositive versus seronegative individuals from the Ischgl community.

Res Sq. 2020 Sep 23;:

Authors: Lee HK, Knabl L, Pipperger L, Volland A, Furth P, Kang K, Smith H, Knabl L, Bellmann R, Bernhard C, Kaiser N, Gänzer H, Ströhle M, Walser A, Laer DV, Hennighausen L

Abstract
To investigate prevalence of ongoing activation of inflammation following asymptomatic SARS-CoV-2 infection we characterized immune cell transcriptomes from 43 asymptomatic seropositive and 52 highly exposed seronegative individuals with few underlying health issues following a community superspreading event. Four mildly symptomatic seropositive individuals examined three weeks after infection as positive controls demonstrated immunological activation. Approximately four to six weeks following the event, the two asymptomatic groups showed no significant differences. Two seropositive patients with underlying genetic disease impacting immunological activation were included (Cystic Fibrosis (CF), Nuclear factor-kappa B Essential Modulator (NEMO) deficiency). CF, but not NEMO, associated with significant immune transcriptome differences including some associated with severe SARS-CoV-2 infection (IL1B, IL17A, respective receptors). All subjects remained in their usual state of health from event through five-month follow-up. Here, asymptomatic infection resolved without evidence of prolonged immunological activation. Inclusion of subjects with underlying genetic disease illustrated the pathophysiological importance of context on impact of immunological response.

PMID: 32995765 [PubMed]

The first report on immunoglobulins A, E, G and M levels in cystic fibrosis patients in Saudi Arabia.

Saudi J Biol Sci. 2020 Oct;27(10):2617-2621

Authors: Alothaid H, Banjar H, Kebir FM, Alharbi A, Bin-Zuman G

Abstract
Background: Previous reports have shown that pulmonary and systemic hypergamma-globulinemia in CF patients is a reflection of chronic pulmonary infection. Infection with Pseudomonas aeruginosa is known to have major prognostic significance in patients CF. This study aims to identify the incidence of immunoglobulins (especially: IgG, and IgE) in a cohort of CF patients.
Methods: A total of 297 patients recruited all over the country's region for this study were a as part of the CF registry data from 1st January 1984 to 1st June 2016. All patients had their immunoglobulin levels measured by enzyme link immunosorbent assay (ELISA) in 3 stages, at presentation and two follow-ups.
Results: Of the 297 patients recruited, 139 (46.8%) were males while 158 (53.2%) were females. IgA and IgM levels were found not to have risen above the previously reported levels in healthy individuals in all stages. On the contrary, IgE level increased from 209.51 ± 32.30 KU/L to 303.58 ± 37.11 KU/L from baseline to stage 3 while IgG level rose from 12.26 ± 0.43 mg/mL to 17.17 ± 1.68 mg/mL for baseline and stage 3 respectively all above previously reported levels in healthy individuals.
Conclusion: This study establishes a potential for the use of IgE and IgG in disease diagnosis as well as the prognostic implications. However, further study is needed to identify the role of infection or medications in relation to the rise of both IgE and IgG with advancement of age and progression of disease severity which may inherently confound the observed results.

PMID: 32994719 [PubMed]

Sex Steroids Induce Membrane Stress Responses and Virulence Properties in Pseudomonas aeruginosa.

mBio. 2020 Sep 29;11(5):

Authors: Vidaillac C, Yong VFL, Aschtgen MS, Qu J, Yang S, Xu G, Seng ZJ, Brown AC, Ali MK, Jaggi TK, Sankaran J, Foo YH, Righetti F, Nedumaran AM, Mac Aogáin M, Roizman D, Richard JA, Rogers TR, Toyofuku M, Luo D, Loh E, Wohland T, Czarny B, Horvat JC, Hansbro PM, Yang L, Li L, Normark S, Henriques Normark B, Chotirmall SH

Abstract
Estrogen, a major female sex steroid hormone, has been shown to promote the selection of mucoid Pseudomonas aeruginosa in the airways of patients with chronic respiratory diseases, including cystic fibrosis. This results in long-term persistence, poorer clinical outcomes, and limited therapeutic options. In this study, we demonstrate that at physiological concentrations, sex steroids, including testosterone and estriol, induce membrane stress responses in P. aeruginosa This is characterized by increased virulence and consequent inflammation and release of proinflammatory outer membrane vesicles promoting in vivo persistence of the bacteria. The steroid-induced P. aeruginosa response correlates with the molecular polarity of the hormones and membrane fluidic properties of the bacteria. This novel mechanism of interaction between sex steroids and P. aeruginosa explicates the reported increased disease severity observed in females with cystic fibrosis and provides evidence for the therapeutic potential of the modulation of sex steroids to achieve better clinical outcomes in patients with hormone-responsive strains.IMPORTANCE Molecular mechanisms by which sex steroids interact with P. aeruginosa to modulate its virulence have yet to be reported. Our work provides the first characterization of a steroid-induced membrane stress mechanism promoting P. aeruginosa virulence, which includes the release of proinflammatory outer membrane vesicles, resulting in inflammation, host tissue damage, and reduced bacterial clearance. We further demonstrate that at nanomolar (physiological) concentrations, male and female sex steroids promote virulence in clinical strains of P. aeruginosa based on their dynamic membrane fluidic properties. This work provides, for the first-time, mechanistic insight to better understand and predict the P. aeruginosa related response to sex steroids and explain the interindividual patient variability observed in respiratory diseases such as cystic fibrosis that are complicated by gender differences and chronic P. aeruginosa infection.

PMID: 32994320 [PubMed - in process]

High-Intensity Interval Training Is Effective at Increasing Exercise Endurance Capacity and Is Well Tolerated by Adults with Cystic Fibrosis.

J Clin Med. 2020 Sep 25;9(10):

Authors: Sawyer A, Cavalheri V, Jenkins S, Wood J, Cecins N, Bear N, Singh B, Gucciardi D, Hill K

Abstract
BACKGROUND: To optimize outcomes in people with cystic fibrosis (CF), guidelines recommend 30 to 60 min of moderate-intensity aerobic exercise on most days. Accumulating this volume of exercise contributes importantly to the substantial treatment burden associated with CF. Therefore, the main aim of this study was to investigate the effects of low-volume high-intensity interval training (HIIT) on exercise capacity in people with CF.
METHODS: This randomized controlled trial included people with CF aged ≥15 years, who were allocated to either eight weeks of thrice-weekly 10-min sessions of HIIT (experimental group) or eight weeks of weekly contact (control group). Before and after the intervention period, participants completed measurements of time to symptom limitation (Tlim) during a constant work rate cycle ergometry test (primary outcome), and maximal work rate (Wmax) during a ramp-based cycle ergometry test and health-related quality of life (HRQoL).
RESULTS: Fourteen participants (median (IQR) age 31 (28, 35) years, forced expiratory volume in 1 second (FEV1) 61 (45, 80) % predicted) were included (seven in each group). Compared to the control group, participants in the experimental group demonstrated a greater magnitude of change in Tlim, Wmax (p = 0.017 for both) and in the physical function domain of HRQoL (p = 0.03). No other between-group differences were demonstrated. Mild post-exercise muscle soreness was reported on a single occasion by four participants. Overall, participants attended 93% of all HIIT sessions.
DISCUSSION: Eight weeks of low-volume (i.e., 30-min/week) HIIT produced gains in exercise capacity and self-reported physical function and was well tolerated by people with CF.

PMID: 32992871 [PubMed]

Clinical Presentation of the c.3844T>C (p.Trp1282Arg, W1282R) Variant in Russian Cystic Fibrosis Patients.

Genes (Basel). 2020 Sep 27;11(10):

Authors: Petrova NV, Kashirskaya NY, Krasovskiy SA, Amelina EL, Kondratyeva EI, Marakhonov AV, Vasilyeva TA, Voronkova AY, Sherman VD, Ginter EK, Kutsev SI, Zinchenko RA

Abstract
The goal was to study the phenotypic manifestations of c.3844T>C (p.Trp1282Arg, W1282R) variant, a CF-causing mutation, in patients from the Russian Federation. Clinical manifestations and complications (the age at CF diagnosis, sweat test, pancreatic status, lung function, microbial infection, body mass index (BMI), the presence of meconium ileus (MI), diabetes, and severe liver disease) were compared in four groups: group 1-patients carrying c.3844T>C and severe class I or II variant in trans; group 2-3849+10kbC>T/F508del patients; group 3-F508del/F508del patients; and group 4-patients with W1282R and "mild" variant in trans. Based on the analyses, W1282R with class I or II variant in trans appears to cause at least as severe CF symptoms as F508del homozygotes as reflected in the early age of diagnosis, high sweat chloride concentration, insufficient pancreatic function, and low lung function, in contrast to 3849+10kbC-T/F508del compound heterozygotes having milder clinical phenotypes. The W1282R pathogenic variant is seemed to lead to severe disease phenotype with pancreatic insufficiency similarly to the F508del homozygous genotype.

PMID: 32992607 [PubMed - in process]

The Potential Role and Regulatory Mechanisms of MUC5AC in Chronic Obstructive Pulmonary Disease.

Molecules. 2020 Sep 27;25(19):

Authors: Li J, Ye Z

Abstract
Chronic obstructive pulmonary disease (COPD) is associated with high morbidity and mortality globally. Studies show that airway mucus hypersecretion strongly compromises lung function, leading to frequent hospitalization and mortality, highlighting an urgent need for effective COPD treatments. MUC5AC is known to contribute to severe muco-obstructive lung diseases, worsening COPD pathogenesis. Various pathways are implicated in the aberrant MUC5AC production and secretion MUC5AC. These include signaling pathways associated with mucus-secreting cell differentiation [nuclear factor-κB (NF-κB)and IL-13-STAT6- SAM pointed domain containing E26 transformation-specific transcription factor (SPDEF), as well as epithelial sodium channel (ENaC) and cystic fibrosis transmembrane conductance regulator (CFTR)], and signaling pathways related to mucus transport and excretion-ciliary beat frequency (CBF). Various inhibitors of mucus hypersecretion are in clinical use but have had limited benefits against COPD. Thus, novel therapies targeting airway mucus hypersecretion should be developed for effective management of muco-obstructive lung disease. Here, we systematically review the mechanisms and pathogenesis of airway mucus hypersecretion, with emphasis on multi-target and multi-link intervention strategies for the elucidation of novel inhibitors of airway mucus hypersecretion.

PMID: 32992527 [PubMed - in process]

Nebulizer Care and Inhalation Technique in Children with Cystic Fibrosis.

Children (Basel). 2020 Sep 27;7(10):

Authors: Petrocheilou A, Kaditis AG, Troupi E, Loukou I

Abstract
Nebulizers are used by the great majority of cystic fibrosis patients for delivery of cornerstone treatments. Inhalation technique and adequate disinfection and maintenance are important for optimizing medication delivery. In this study, inhalation technique and nebulizer disinfection/maintenance were assessed in cystic fibrosis patients by direct observation in clinic and completion of a scoring sheet. A total of 108 patients were recruited. The maximum inhalation technique score was attained by 30.5% and adequate inhalation technique score by 74.08% of patients. The inhalation technique score was best with the vibrating mesh nebulizer (p = 0.038), while patient age and number of nebulized medications did not affect ITS significantly (p > 0.05). Nebulizer disinfection/maintenance score was excellent in only 31.48%. Most families kept the nebulizer clean and used appropriate disinfection method, but only half of them replaced the nebulizer and nebulizer cup at the recommended time intervals. Nebulizer disinfection/maintenance score was positively affected by a number of nebulized medications and negatively by years of equipment use (p = 0.009 and p = 0.001, respectively). Even though inhalation technique and disinfection/maintenance practices were found to be adequate in a large proportion of cases, there is still a need for regular review and education. The type of nebulizer was associated with improved inhalation technique, but more data are required before making specific recommendations.

PMID: 32992472 [PubMed]

Inflammation and endothelial activation in early adulthood are associated with future emphysema: the CARDIA Lung Study.

Eur Respir J. 2019 01;53(1):

Authors: Wells JM, Colangelo LA, Sivarajan L, Thyagarajan B, Dransfield MT, Iribarren C, Reyfman PA, Jacobs DR, Washko GR, Kalhan R

PMID: 30464011 [PubMed - indexed for MEDLINE]

Mortality Risk Assessment Using CHA(2)DS(2)-VASc Scores In Patients Hospitalized With COVID -19 Infection.

Am J Cardiol. 2020 Sep 26;:

Authors: Ruocco G, McCullough PA, Tecson KM, Mancone M, De Ferrari GM, D'Ascenzo F, De Rosa FG, Paggi A, Forleo G, Secco GG, Pistis G, Monticone S, Vicenzi M, Rota I, Blasi F, Pugliese F, Fedele F, Palazzuoli A

Abstract
Early risk stratification for complications and death related to COVID-19 infection is needed. Because many patients with COVID-19 who developed acute respiratory distress syndrome have diffuse alveolar inflammatory damage associated with microvessel thrombosis, we aimed to investigate a common clinical tool, the CHA(2)DS(2)-VASc, to aid in the prognostication of outcomes for COVID-19 patients. We analyzed consecutive patients from the multicenter observational CORACLE registry, which contains data of patients hospitalized for COVID-19 infection in 4 regions of Italy, according to data-driven tertiles of CHA(2)DS(2)-VASc score. The primary outcomes were inpatient death and a composite of inpatient death or invasive ventilation. Of 1045 patients in the registry, 864(82.7%) had data available to calculate CHA(2)DS(2)-VASc score and were included in the analysis. Of these, 167(19.3%) died, 123(14.2%) received invasive ventilation, and 249(28.8%) had the composite outcome. Stratification by CHA(2)DS(2)-VASc tertiles (T1: ≤1; T2: 2-3; T3: ≥4) revealed increases in both death (8.1%, 24.3%, 33.3%, respectively;p<0.001) and the composite endpoint (18.6%, 31.9%, 43.5%, respectively;p<0.001). The odds ratios(ORs) for mortality and the composite endpoint for T2 patients versus T1 CHA(2)DS(2)-VASc score were 3.62(95% CI:2.29-5.73,p<0.001) and 2.04(95% CI:1.42-2.93, p<0.001), respectively. Similarly, the ORs for mortality and the composite endpoint for T3 patients versus T1 were 5.65(95% CI:3.54-9.01,p<0.001) and 3.36(95% CI:2.30-4.90,p<0.001), respectively. In conclusion, among Italian patients hospitalized for COVID-19 infection, the CHA(2)DS(2)-VASc risk score for thromboembolic events enhanced the ability to achieve risk stratification for complications and death .

PMID: 32991860 [PubMed - as supplied by publisher]