Pulm Pharmacol Ther. 2021 Jul 19:102058. doi: 10.1016/j.pupt.2021.102058. Online ahead of print.

ABSTRACT

BACKGROUND: /Question: Nontuberculous mycobacteria (NTM) infections are increasingly detected but difficult to cure given complex drug-resistance patterns. Select U.S. centers have incorporated clofazimine in the treatment of NTM but experience is limited as procurement restrictions hamper widespread use.

METHODS: A prospective cohort study was performed in patients diagnosed with pulmonary or extrapulmonary NTM infection and treated with clofazimine between February 2015 and April 2019 at a tertiary referral hospital. Treatment success was defined by a combined outcome of clinical stabilization, microbiologic cure and radiologic improvement. Secondary outcomes included all-cause mortality and time to sputum culture conversion. Uni/multi-variate regression were used to define associations between pre-determined predictor variables and overall treatment outcome.

RESULTS: Of 44 patients enrolled, 39 (89%) received clofazimine along with a median of 3 concomitant antibiotics. Thirty-one (80%) of patients had pulmonary NTM infection, with Mycobacterium abscessus group and Mycobacterium avium complex being the most common species groups identified. Of 36 people with evaluable outcomes, 35 (97%) survived and 22 (58%) had treatment success, including 12 of 19 (63%) with Mycobacterium abscessus group. In multivariate analysis, patients with Mycobacterium abscessus group were more likely to experience treatment success (OR 18.22, 95%CI 0.972-341.43, p=0.052), while macrolide resistance predicted a lack of treatment success (OR 0.053, 95%CI 0.003-0.841, p= 0.037). Clofazimine was well-tolerated.

CONCLUSION: Adding clofazimine to multi-class antibiotic regimens for drug-resistant NTM infection led to treatment success in the majority treated. Randomized controlled studies are needed to determine the individual impact of clofazimine within an otherwise optimized drug regimen.

PMID:34293446 | DOI:10.1016/j.pupt.2021.102058

Prog Biophys Mol Biol. 2021 Jul 19:S0079-6107(21)00085-7. doi: 10.1016/j.pbiomolbio.2021.07.004. Online ahead of print.

ABSTRACT

The pulmonary epithelial sodium ion channel (ENaC) is gaining importance for its sodium gating and mechanosensitive roles. The mechano functional studies on ENaC suggest direct molecular interactions between the ENaC protein with cytoskeleton microtubules and other extracellular matrix components. Also, in few mechanotransduction studies, ENaC was shown to respond both to membrane stretch as well as cell volume changes. However, the conformational characteristic of ENaC during sodium and mechano gating are yet to be fully elucidated. Thus obtaining ENaC protein conformational spectrum based on Fourier Transform Infrared Radiation (FTIR) spectroscopy in solution will be useful in predicting the nature of conformational changes occurring during any cell volume changes in an epithelial cell. The conformational spectrum looks promising in studying the disease biology of cystic fibrosis (CF) and CF like conditions that arise due to abnormal ion conductance membrane proteins and subsequent frequent fluid retentions. This review article presents the basics of epithelial ENaC protein as a gated mechanosensor and FTIR for developing fluid dynamics of ENaC protein. This can be applied to develop an ENaC based quantum mechanosensor for the prognosis as well as diagnosis of cystic fibrosis (CF) and allied lung diseases.

PMID:34293339 | DOI:10.1016/j.pbiomolbio.2021.07.004

Pediatr Pulmonol. 2021 Jul 22. doi: 10.1002/ppul.25579. Online ahead of print.

ABSTRACT

We report the case of a patient with cystic fibrosis (CF) presenting with a full-blown cytokine storm syndrome probably triggered by infection. This condition is rare and the diagnosis can be particularly difficult in patients with a complex chronic disease such as CF. However, timely recognition and appropriate treatment in the early stages are key to avoiding a potentially fatal course.

PMID:34293253 | DOI:10.1002/ppul.25579

Microb Genom. 2021 Jul;7(7). doi: 10.1099/mgen.0.000606.

ABSTRACT

Achromobacter species are increasingly being detected in cystic fibrosis (CF) patients, where they can establish chronic infections by adapting to the lower airway environment. To better understand the mechanisms contributing to a successful colonization by Achromobacter species, we sequenced the whole genome of 54 isolates from 26 patients with occasional and early/late chronic lung infection. We performed a phylogenetic analysis and compared virulence and resistance genes, genetic variants and mutations, and hypermutability mechanisms between chronic and occasional isolates. We identified five Achromobacter species as well as two non-affiliated genogroups (NGs). Among them were the frequently isolated Achromobacter xylosoxidans and four other species whose clinical importance is not yet clear: Achromobacter insuavis, Achromobacter dolens, Achromobacter insolitus and Achromobacter aegrifaciens. While A. insuavis and A. dolens were isolated only from chronically infected patients and A. aegrifaciens only from occasionally infected patients, the other species were found in both groups. Most of the occasional isolates lacked functional genes involved in invasiveness, chemotaxis, type 3 secretion system and anaerobic growth, whereas the great majority (>60%) of chronic isolates had these genomic features. Interestingly, almost all (n=22/23) late chronic isolates lacked functional genes involved in lipopolysaccharide production. Regarding antibiotic resistance, we observed a species-specific distribution of blaOXA genes, confirming what has been reported in the literature and additionally identifying blaOXA-2 in some A. insolitus isolates and observing no blaOXA genes in A. aegrifaciens or NGs. No significant difference in resistance genes was found between chronic and occasional isolates. The results of the mutator genes analysis showed that no occasional isolate had hypermutator characteristics, while 60% of early chronic (<1 year from first colonization) and 78% of late chronic (>1 year from first colonization) isolates were classified as hypermutators. Although all A. dolens, A. insuavis and NG isolates presented two different mutS genes, these seem to have a complementary rather than compensatory function. In conclusion, our results show that Achromobacter species can exhibit different adaptive mechanisms and some of these mechanisms might be more useful than others in establishing a chronic infection in CF patients, highlighting their importance for the clinical setting and the need for further studies on the less clinically characterized Achromobacter species.

PMID:34292148 | DOI:10.1099/mgen.0.000606

Med J Aust. 2021 Jul 21. doi: 10.5694/mja2.51183. Online ahead of print.

NO ABSTRACT

PMID:34291464 | DOI:10.5694/mja2.51183

ERJ Open Res. 2021 Jul 19;7(3):00636-2020. doi: 10.1183/23120541.00636-2020. eCollection 2021 Jul.

ABSTRACT

RESEARCH QUESTION: Pulmonary disease progression in patients with cystic fibrosis (CF) is characterised by inflammation and fibrosis and aggravated by Pseudomonas aeruginosa (Pa). We investigated the impact of Pa specifically on: 1) protease/antiprotease balance; 2) inflammation; and 3) the link of both parameters to clinical parameters of CF patients.

METHODS: Transforming growth factor-β1 (TGF-β1), interleukin (IL)-1β, IL-8, neutrophil elastase (NE) and elastase inhibitor elafin were measured (ELISA assays), and gene expression of the NF-κB pathway was assessed (reverse transcriptase PCR) in the sputum of 60 CF patients with a minimum age of 5 years. Spirometry was assessed according to American Thoracic Society guidelines.

RESULTS: Our results demonstrated the following: 1) NE was markedly increased in Pa-positive sputum, whereas elafin was significantly decreased; 2) increased IL-1β/IL-8 levels were associated with both Pa infection and reduced forced expiratory volume in 1 s, and sputum TGF-β1 was elevated in Pa-infected CF patients and linked to an impaired lung function; and 3) gene expression of NF-κB signalling components was increased in sputum of Pa-infected patients, and these findings were positively correlated with IL-8.

CONCLUSION: Our study links Pa infection to an imbalance of NE and NE inhibitor elafin and increased inflammatory mediators. Moreover, our data demonstrate an association between high TGF-β1 sputum levels and a progress in chronic lung inflammation and pulmonary fibrosis in CF. Controlling the excessive airway inflammation by inhibition of NE and TGF-β1 might be promising therapeutic strategies in future CF therapy and a possible complement to cystic fibrosis transmembrane conductance regulator (CFTR) modulators.

PMID:34291109 | PMC:PMC8287132 | DOI:10.1183/23120541.00636-2020

Front Immunol. 2021 Jul 5;12:693149. doi: 10.3389/fimmu.2021.693149. eCollection 2021.

ABSTRACT

Chronic obstructive pulmonary disease (COPD) is a systemic disease strongly associated with cigarette smoking, airway inflammation, and acute disease exacerbations. Changes in terminal sialylation and fucosylation of asparagine (N)-linked glycans have been documented in COPD, but the role that glycosyltransferases may play in the regulation of N-linked glycans in COPD has not been fully elucidated. Recent studies suggest that modulation of ST6GAL1 (ST6 beta-galactoside alpha-2,6-sialyltransferase-1), which catalyzes terminal α2-6 sialylation of cellular proteins, may regulate inflammation and contribute to COPD phenotype(s). Interestingly, it has been previously demonstrated that ST6GAL1, a Golgi resident protein, can be proteolytically processed by BACE1 (beta-site amyloid precursor protein cleaving enzyme-1) to a circulating form that retains activity. In this study, we showed that loss of ST6GAL1 expression increased interleukin (IL)-6 expression and secretion in human bronchial epithelial cells (HBECs). Furthermore, exposure to cigarette smoke medium/extract (CSE) or BACE1 inhibition resulted in decreased ST6GAL1 secretion, reduced α2-6 sialylation, and increased IL-6 production in HBECs. Analysis of plasma ST6GAL1 levels in a small COPD patient cohort demonstrated an inverse association with prospective acute exacerbations of COPD (AECOPD), while IL-6 was positively associated. Altogether, these results suggest that reduced ST6GAL1 and α2-6 sialylation augments IL-6 expression/secretion in HBECs and is associated with poor clinical outcomes in COPD.

PMID:34290711 | PMC:PMC8287524 | DOI:10.3389/fimmu.2021.693149

Eur Respir J. 2021 Jul 21:2100432. doi: 10.1183/13993003.00432-2021. Online ahead of print.

ABSTRACT

BACKGROUND: The lung clearance index (LCI) assesses global ventilation inhomogeneity and is a sensitive biomarker of airway function in cystic fibrosis (CF) lung disease.

OBJECTIVES: We examined the association of LCI with the risk of death or lung transplantation (LTX) in individuals with CF.

METHODS: We performed a retrospective analysis in a cohort of individuals with CF aged≥5 years with LCI and FEV1 measurements performed between 1980 and 2006. The outcome was time until death or LTX. We used the earliest available LCI and FEV1 values in a Cox proportional hazard regression adjusted for demographic and clinical variables. For sensitivity analyses, we used the mean of the first three LCI and FEV1 measurements, stratified the cohort based on age, and investigated individuals with normal FEV1.

RESULTS: In total, 237 individuals with CF with a mean (range) age of 13.9 (5.6-41.0) years were included. The time-to-event analysis accrued 3813 person-years and 94 (40%) individuals died or received LTX. Crude hazard ratios [95% CI] were 1.04 [1.01-1.06] per one z-score increase in LCI and 1.25 [1.11-1.41] per one z-score decrease in FEV1. After adjusting LCI and FEV1 mutually in addition to sex, age, BMI and the number of hospitalisations, hazard ratios were 1.04 [1.01-1.07] for LCI, and 1.12 [0.95-1.33] for FEV1. Sensitivity analyses yielded similar results and using the mean LCI strengthened the associations.

CONCLUSIONS: Increased ventilation inhomogeneity is associated with greater risk of death or LTX. Our data support LCI as novel surrogate of survival in individuals with CF.

PMID:34289977 | DOI:10.1183/13993003.00432-2021

J Cyst Fibros. 2021 Jul 19:S1569-1993(21)01300-X. doi: 10.1016/j.jcf.2021.07.003. Online ahead of print.

ABSTRACT

BACKGROUND: People with cystic fibrosis (CF) heterozygous for F508del-CFTR and a minimal function CFTR mutation (F/MF) that results in no CFTR protein or results in CFTR protein that is not responsive to tezacaftor, ivacaftor, and tezacaftor/ivacaftor in vitro comprise a sizeable percentage of the US CF population. This retrospective, cross-sectional, observational study aimed to characterize CF burden in this subpopulation.

METHODS: People ≥2 years of age in the US CF Foundation Patient Registry with a CF diagnosis, F/MF genotype, and ≥1 encounters in 2017 were included. Descriptive analyses assessed lung function, nutritional parameters, microbiology, hospitalization and pulmonary exacerbation rates, and CF-related complications. Results were stratified by age group; select characteristics were summarized by percent predicted FEV1 (ppFEV1) and ethnicity.

RESULTS: 5348 people met inclusion criteria. Rates of positive bacterial cultures, pulmonary exacerbations, and hospitalizations were generally higher in older age groups. Prevalence of prescribed symptomatic CF therapies was substantial and also generally higher in older age groups. ppFEV1 was lower in older age groups. A greater percentage of adolescents and adults reported complications, including cirrhosis, osteoporosis, osteopenia, and sinus disease, than younger age groups. Increased prevalence of cultured Pseudomonas aeruginosa and prescribed chronic therapy was seen with decreasing ppFEV1. In each age group, ppFEV1 was slightly higher in the non-Hispanic cohort than in the Hispanic cohort.

CONCLUSIONS: People with F/MF genotypes have substantial disease burden that worsened in older age groups consistent with the progressive nature of CF, indicating need for additional treatment options in this subpopulation.

PMID:34289939 | DOI:10.1016/j.jcf.2021.07.003

Zhonghua Wei Chang Wai Ke Za Zhi. 2021 Jul 25;24(7):638-643. doi: 10.3760/cma.j.cn.441530-20200422-00236.

ABSTRACT

Intestinal organoids, also named "mini-guts", reconstitute sophisticated three-dimensional architecture recapitulating diversified intestinal epithelial cell types and physiology, which is driven by the proliferative and self-assembling characteristics of crypt stem cells. The initiation of organoids study relies on the identification of Lgr5+ crypt stem cells from different intestinal segments and the key role of EGF, Wnt, BMP/TGF-β, Notch signal pathways within the microenvironment during the cultivation process. Besides constituting polarized crypt-villus structures, these "mini-guts" exhibit various effective functions of intestinal epithelium. Since 2009 when the culture system of small intestinal organoids was established by Sato et al, intestinal organoids excel conventional intestinal models depending on genetical mutation in multiple aspects and thus have become the hotspot among the research on intestinal diseases. Combined with genomics, material science and engineering, "mini-guts" have been widely applied to the research on intestinal development, intestinal transport physiology, epithelial barrier, pathogen-host interaction and the study on cystic fibrosis, infectious diarrhea, ulcerative colitis, Crohn's disease, intestinal cancer, etc. In this review, we summarize the new insights introduced by organoid into the research on intestinal diseases, and related research advances and applications.

PMID:34289550 | DOI:10.3760/cma.j.cn.441530-20200422-00236

Allergy. 2021 Jul 21. doi: 10.1111/all.15016. Online ahead of print.

ABSTRACT

BACKGROUND: Food allergen immunotherapy (FA-AIT) practice is known to vary globally. This project aims to identify and characterise European centres performing FA-AIT.

METHODS: An EAACI task force conducted an online survey to gather relevant information regarding FA-AIT practice and setting-specific resources after reviewing the published literature and congress abstracts throughout Europe.

RESULTS: We identified 102 FA-AIT centres in 18 countries; only Spain (n=39) and France (n=16) had ≥10 such centres. Overall, most facilities were hospital-based (77.5%), publicly funded (80.4%), and delivered FA-AIT as routine clinical care (80.4%). On average, departments had 3 allergists/paediatric allergists and 2 nurses. Surveyed centres had provided FA-AIT for a median of 9 years [1-24] to a median of 105 [5-2415] patients. The estimated total number of treated patients was 24875, of whom 41.3% received AIT for milk, 34.2% egg, 12.8% peanut, and 11.7% other foods. Anaphylaxis to AIT doses requiring over 4-6 hours of observation was reported by 70.6% of centres, ICU admissions by 10.8%, and eosinophilic esophagitis by 45.1%. Quality of life and sustained unresponsiveness were evaluated in 20.6% and 54.9% of centres, respectively. The main contraindications for food AIT were severe asthma(57%-63%), eosinophilic esophagitis (56%-48%), and age below 5 years (47%-41%).

CONCLUSIONS: In Europe, FA-AIT is provided mostly in clinical practice. Significant variation is seen in the number of centres per country, facility characteristics, inclusion/exclusion criteria, and in certain aspects of protocols. Potential inequality in access to AIT has been identified as well as the need for education and guidance for treatment standardization.

PMID:34289131 | DOI:10.1111/all.15016

Physiol Rep. 2021 Jul;9(14):e14978. doi: 10.14814/phy2.14978.

ABSTRACT

Hepatobiliary disease causes significant morbidity and mortality in people with cystic fibrosis (CF), yet this problem remains understudied. Previous studies in the newborn CF pig demonstrated decreased bile flow into the small intestine and a microgallbladder with increased luminal mucus and fluid secretion defects. In this study, we examined the intrahepatic bile ducts of the newborn CF pig. We assessed whether our findings from the gallbladder are present elsewhere in the porcine biliary tract and if CF pig cholangiocytes have fluid secretion defects. Immunohistochemistry demonstrated apical CFTR expression in non-CF pig intrahepatic bile ducts of a variety of sizes; CF pig intrahepatic bile ducts lacked CFTR expression. Assessment of serum markers did not reveal significant signs of hepatobiliary disease except for an elevation in direct bilirubin. Quantitative histology demonstrated that CF pigs had smaller bile ducts that more frequently contained luminal mucus. CF intrahepatic cholangiocyte organoids were smaller and lacked cAMP-mediated fluid secretion. Together these data suggest that cholangiocyte fluid secretion is decreased in the CF pig, contributing to structural changes in bile ducts and decreased biliary flow.

PMID:34288572 | DOI:10.14814/phy2.14978

J Eur Acad Dermatol Venereol. 2021 Aug;35(8):1608. doi: 10.1111/jdv.17445.

NO ABSTRACT

PMID:34288141 | DOI:10.1111/jdv.17445

Eur J Nutr. 2021 Jul 21. doi: 10.1007/s00394-021-02637-6. Online ahead of print.

ABSTRACT

BACKGROUND: Adequate intake of choline is essential for growth and homeostasis, but its supply does often not meet requirements. Choline deficiency decreases phosphatidylcholine (PC) and betaine synthesis, resulting in organ pathology, especially of liver, lung, and brain. This is of particular clinical importance in preterm infants and cystic fibrosis patients. We compared four different choline supplements for their impact on plasma concentration and kinetics of choline, betaine as a methyl donor and trimethylamine oxide (TMAO) as a marker of bacterial degradation prior to absorption.

METHODS: Prospective randomized cross-over study (1/2020-4/2020) in six healthy adult men. Participants received a single dose of 550 mg/d choline equivalent in the form of choline chloride, choline bitartrate, α-glycerophosphocholine (GPC), and egg-PC in randomized sequence at least 1 week apart. Blood was taken from t = - 0.1-6 h after supplement intake. Choline, betaine, TMAO, and total PC concentrations were analyzed by tandem mass spectrometry. Results are shown as medians and interquartile range.

RESULTS: There was no difference in the AUC of choline plasma concentrations after intake of the different supplements. Individual plasma kinetics of choline and betaine differed and concentrations peaked latest for PC (at ≈3 h). All supplements similarly increased plasma betaine. All water-soluble supplements rapidly increased TMAO, whereas egg-PC did not.

CONCLUSION: All supplements tested rapidly increased choline and betaine levels to a similar extent, with egg-PC showing the latest peak. Assuming that TMAO may have undesirable effects, egg-PC might be best suited for choline supplementation in adults.

STUDY REGISTRATION: This study was registered at "Deutsches Register Klinischer Studien" (DRKS) (German Register for Clinical Studies), 17.01.2020, DRKS00020454.

PMID:34287673 | DOI:10.1007/s00394-021-02637-6

Genet Med. 2021 Jul 20. doi: 10.1038/s41436-021-01203-z. Online ahead of print.

ABSTRACT

Carrier screening began 50 years ago with screening for conditions that have a high prevalence in defined racial/ethnic groups (e.g., Tay-Sachs disease in the Ashkenazi Jewish population; sickle cell disease in Black individuals). Cystic fibrosis was the first medical condition for which panethnic screening was recommended, followed by spinal muscular atrophy. Next-generation sequencing allows low cost and high throughput identification of sequence variants across many genes simultaneously. Since the phrase "expanded carrier screening" is nonspecific, there is a need to define carrier screening processes in a way that will allow equitable opportunity for patients to learn their reproductive risks using next-generation sequencing technology. An improved understanding of this risk allows patients to make informed reproductive decisions. Reproductive decision making is the established metric for clinical utility of population-based carrier screening. Furthermore, standardization of the screening approach will facilitate testing consistency. This practice resource reviews the current status of carrier screening, provides answers to some of the emerging questions, and recommends a consistent and equitable approach for offering carrier screening to all individuals during pregnancy or preconception.

PMID:34285390 | DOI:10.1038/s41436-021-01203-z

Chest. 2021 Jul 17:S0012-3692(21)01352-0. doi: 10.1016/j.chest.2021.07.024. Online ahead of print.

ABSTRACT

People with Cystic fibrosis (pwCF) have experienced increased survival and wellbeing in recent decades, such that more than half of those living with CF are adults. Consequently, sexual and reproductive health is increasingly important for pwCF as many are considering parenthood. Most men and some women with CF (wwCF) will have reduced fertility, which in both sexes is multifactorial. However, unplanned pregnancies in women are not rare, and contraception and its interaction with CF complications need to be addressed by the CF team. Reduced fertility may be overcome in most pwCF through use of assisted reproductive technologies; however, the risk of having offspring with CF must be considered. Most wwCF will have normal pregnancies, but premature birth is common especially in the setting of reduced lung function and CF related diabetes (CFRD); optimization of treatment is recommended during pregnancy planning. Parenting imposes an increased burden on pwCF, with the challenges of caring for the newborn, postpartum physiologic changes and maintaining CF treatments. Most drugs used to treat CF are considered safe in pregnancy and lactation, but exceptions need to be acknowledged, including the limited data regarding safety of CF transmembrane conductance regulator (CFTR) modulators during conception, pregnancy, and lactation. As most pwCF are eligible for highly effective CFTR modulators, fertility, contraception, and pregnancy in people with CF is changing. Prospective studies regarding these issues in people treated with CFTR modulators are paramount to provide evidence-based guidance for management in the current era of CF care.

PMID:34284004 | DOI:10.1016/j.chest.2021.07.024

Am J Respir Crit Care Med. 2021 Jul 20. doi: 10.1164/rccm.202102-0278OC. Online ahead of print.

ABSTRACT

RATIONALE: Previous cross-sectional studies demonstrated that chest magnetic resonance imaging (MRI) is sensitive to detect early lung disease in infants and preschool children with cystic fibrosis (CF) without radiation exposure. However, the ability of MRI to detect progression of lung disease and the impact of early diagnosis in preschool children with CF remains unknown.

OBJECTIVES: To investigate the potential of MRI to detect progression of early lung disease and impact of early diagnosis by CF newborn screening (NBS) in preschool children with CF.

METHODS: Annual MRI was performed from diagnosis over four years in a cohort of 96 preschool children with CF (age 0-4 yr) that were concurrently diagnosed based on NBS (n=28) or clinical symptoms (n=68). MRI scans were evaluated using a dedicated morphofunctional score and the relationship between longitudinal MRI scores and respiratory symptoms, pulmonary exacerbations, upper airway microbiology and mode of diagnosis were determined.

MEASUREMENTS AND MAIN RESULTS: The MRI global score increased in the total cohort of children with CF during preschool years (P<0.001) which was associated with cough, pulmonary exacerbations (P<0.0001), and detection of Staphylococcus aureus and Haemophilus influenzae (P<0.05). MRI-defined abnormalities in lung morphology, especially airway wall thickening/bronchiectasis, were lower in NBS compared to clinically diagnosed children with CF throughout the observation period (P<0.01).

CONCLUSIONS: MRI detected progression of early lung disease and benefits of early diagnosis by NBS in preschool children with CF. These findings support MRI as sensitive outcome measure for diagnostic monitoring and early intervention trials in preschool children with CF.

PMID:34283704 | DOI:10.1164/rccm.202102-0278OC

J Antimicrob Chemother. 2021 Jul 20:dkab222. doi: 10.1093/jac/dkab222. Online ahead of print.

ABSTRACT

OBJECTIVES: To determine the activity of murepavadin in comparison with tobramycin, colistin and aztreonam, against cystic fibrosis (CF) Pseudomonas aeruginosa isolates growing in biofilms. The biofilm-epidemiological cut-off (ECOFF) values that include intrinsic resistance mechanisms present in biofilms were estimated.

METHODS: Fifty-three CF P. aeruginosa isolates from respiratory samples were tested using the Calgary (closed system) device, while 4 [2 clinical (one smooth, one mucoid) and 2 reference strains] were tested using the BioFlux, a microfluidic open model of biofilm testing. Biofilm was stained with SYTO9® and propidium iodide. The minimal biofilm inhibitory concentration (MBIC) and the minimal biofilm eradication concentration (MBEC) were determined. The MBIC-ECOFF and the MBEC-ECOFF were calculated.

RESULTS: Colistin, tobramycin and murepavadin presented similar MBIC50/MBIC90 values (4/32, 8/64 and 2/32, respectively). Murepavadin exhibited the lowest MBEC90 (64 mg/L). Aztreonam MBIC and MBEC values were higher than those of the other antibiotics tested. Tobramycin and murepavadin had the lowest MBEC-ECOFF (64 and 128 mg/L, respectively), while those of aztreonam and colistin exceeded 512 mg/L. Using the BioFlux, for the PAO1, PAO mutS and the smooth clinical strain, a significant difference (P < 0.0125) was observed when comparing the fluorescence of treated and untreated biofilms. For the mucoid strain, only the biofilm treated with aztreonam (MBIC and MBEC) and tobramycin (MBEC) showed differences with respect to the untreated biofilm.

CONCLUSIONS: Murepavadin demonstrated good activity against P. aeruginosa biofilms both in open and closed systems. The MBIC-ECOFF and the MBEC-ECOFF are proposed as new parameters to estimate the activity of antibiotics on biofilms.

PMID:34283223 | DOI:10.1093/jac/dkab222

Nanomedicine (Lond). 2021 Jul 20. doi: 10.2217/nnm-2021-0179. Online ahead of print.

ABSTRACT

The aim of this study was to investigate the distribution, tolerance, and anticancer and antiviral activity of Zn-based physiometacomposites (PMCs). Manganese, iron, nickel and cobalt-doped ZnO, ZnS or ZnSe were synthesized. Cell uptake, distribution into 3D culture and mice, and biochemical and chemotherapeutic activity were studied by fluorescence/bioluminescence, confocal microscopy, flow cytometry, viability, antitumor and virus titer assays. Luminescence and inductively coupled plasma mass spectrometry analysis showed that nanoparticle distribution was liver >spleen >kidney >lung >brain, without tissue or blood pathology. Photophysical characterization as ex vivo tissue probes and LL37 peptide, antisense oligomer or aptamer delivery targeting RAS/Ras binding domain (RBD) was investigated. Treatment at 25 μg/ml for 48 h showed ≥98-99% cell viability, 3D organoid uptake, 3-log inhibition of β-Galactosidase and porcine reproductive respiratory virus infection. Data support the preclinical development of PMCs for imaging and delivery targeting cancer and infectious disease.

PMID:34282923 | DOI:10.2217/nnm-2021-0179

BMJ Open Respir Res. 2021 Jul;8(1):e000927. doi: 10.1136/bmjresp-2021-000927.

ABSTRACT

INTRODUCTION: Improvements in the treatment of cystic fibrosis (CF) have resulted in longer survival and an increased focus on optimising daily functioning with the condition. Patient-reported outcome measures (PROMs) are valuable tools in evaluating the health-related quality of life of persons with chronic diseases. PROMs may be incorporated into clinical registries to assess and provide feedback regarding the health-related quality of life of the affected population. This study uses qualitative methodology to describe the views of patients with CF, caregivers and clinicians on the usefulness and practicality of incorporating a PROM in the Australian Cystic Fibrosis Data Registry (ACFDR).

METHODS: We conducted semistructured interviews with a convenience sample of patients with CF (n=5), caregivers (n=7) and clinicians (n=13) on their opinions on incorporating the Cystic Fibrosis Questionnaire-Revised or the Cystic Fibrosis Quality of Life Questionnaire into the ACFDR. We analysed data into topics and subtopics using conventional content analysis.

RESULTS: Participants believed that PROMs could generate useful aggregate health-related quality of life data to support better understanding of the experiences of the modern CF population. Participants emphasised that implementation must be supported by processes to feedback data to patients and clinicians. Most participants preferred electronic PROMs administration for easy integration into existing systems and the potential to support feedback.

CONCLUSION: Patients, caregivers and clinicians in this study generally supported the usefulness and practicality of PROM implementation in the ACFDR.

PMID:34281916 | DOI:10.1136/bmjresp-2021-000927