Sci Rep. 2021 Oct 20;11(1):20722. doi: 10.1038/s41598-021-99467-7.

ABSTRACT

In Cystic Fibrosis (CF), a rapid and standardized definition of chronic infection would allow a better management of Pseudomonas aeruginosa (Pa) infections, as well as a quick grouping of patients during clinical trials allowing better comparisons between studies. With this purpose, we compared the metabolic profiles of 44 in vitro cultures of Pa strains isolated from CF patients at different stages of infection in order to identify metabolites differentially synthetized according to these clinical stages. Compounds produced and secreted by each strain in the supernatant of a liquid culture were analysed by metabolomic approaches (UHPLC-DAD-ESI/QTOF, UV and UPLC-Orbitrap, MS). Multivariate analyses showed that first colonization strains could be differentiated from chronic colonization ones, by producing notably more Alkyl-Quinolones (AQs) derivatives. Especially, five AQs were discriminant: HQC5, HQNOC7, HQNOC7:1, db-PQS C9 and HQNOC9:1. However, the production of HHQ was equivalent between strain types. The HHQ/HQNOC9:1 ratio was then found to be significantly different between chronic and primo-colonising strains by using both UV (p = 0.003) and HRMS data (p = 1.5 × 10-5). Our study suggests that some AQ derivatives can be used as biomarkers for an improved management of CF patients as well as a better definition of the clinical stages of Pa infection.

PMID:34671079 | DOI:10.1038/s41598-021-99467-7

Emerg Infect Dis. 2021 Nov;27(11):2836-2846. doi: 10.3201/eid2711.210124.

ABSTRACT

Mycobacterium avium complex (MAC) species constitute most mycobacteria infections in persons with cystic fibrosis (CF) in the United States, but little is known about their genomic diversity or transmission. During 2016-2020, we performed whole-genome sequencing on 364 MAC isolates from 186 persons with CF from 42 cystic fibrosis care centers (CFCCs) across 23 states. We compared isolate genomes to identify instances of shared strains between persons with CF. Among persons with multiple isolates sequenced, 15/56 (27%) had >1 MAC strain type. Genomic comparisons revealed 18 clusters of highly similar isolates; 8 of these clusters had patients who shared CFCCs, which included 27/186 (15%) persons with CF. We provide genomic evidence of highly similar MAC strains shared among patients at the same CFCCs. Polyclonal infections and high genetic similarity between MAC isolates are consistent with multiple modes of acquisition for persons with CF to acquire MAC infections.

PMID:34670648 | DOI:10.3201/eid2711.210124

Mol Ecol Resour. 2021 Oct 20. doi: 10.1111/1755-0998.13535. Online ahead of print.

ABSTRACT

Microbes interact in natural communities in a spatially structured manner, particularly in biofilms and polymicrobial infections. While next generation sequencing approaches provide powerful insights into diversity, metabolic capacity, and mutational profiles of these communities, they generally fail to recover in situ spatial proximity between distinct genotypes in the interactome. Hi-C is a promising method that has assisted in analyzing complex microbiomes, by creating chromatin cross-links in cells, that aid in identifying adjacent DNA, to improve de novo assembly. This study explored a modified Hi-C approach involving an initial lysis phase prior to DNA cross-linking, to test whether adjacent cell chromatin can be cross-linked, anticipating that this could provide a new avenue for study of spatial-mutational dynamics in structured microbial communities. An artificial polymicrobial mixture of Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli was lysed for 1 to 18 hours, then prepared for Hi-C. A murine biofilm infection model was treated with sonication, mechanical lysis, or chemical lysis before Hi-C. Bioinformatic analyses of resulting Hi-C interspecies chromatin links showed that while microbial species differed from one another, generally lysis significantly increased links between species and increased the distance of Hi-C links within species, while also increasing novel plasmid-chromosome links. The success of this modified lysis-Hi-C protocol in creating extracellular DNA links is a promising first step toward a new lysis-Hi-C based method to recover genotypic microgeography in polymicrobial communities, with potential future applications in diseases with localized resistance, such as cystic fibrosis lung infections and chronic diabetic ulcers.

PMID:34669257 | DOI:10.1111/1755-0998.13535

Eur Radiol. 2021 Oct 20. doi: 10.1007/s00330-021-08236-7. Online ahead of print.

ABSTRACT

OBJECTIVES: To compare the diagnostic value of ultrashort echo time (UTE) magnetic resonance imaging (MRI) for the lung versus the gold standard computed tomography (CT) and two T1-weighted MRI sequences in children.

METHODS: Twenty-three patients with proven oncologic disease (14 male, 9 female; mean age 9.0 + / - 5.4 years) received 35 low-dose CT and MRI examinations of the lung. The MRI protocol (1.5-T) included the following post-contrast sequences: two-dimensional (2D) incoherent gradient echo (GRE; acquisition with breath-hold), 3D volume interpolated GRE (breath-hold), and 3D high-resolution radial UTE sequences (performed during free-breathing). Images were evaluated by considering image quality as well as distinct diagnosis of pulmonary nodules and parenchymal areal opacities with consideration of sizes and characterisations.

RESULTS: The UTE technique showed significantly higher overall image quality, better sharpness, and fewer artefacts than both other sequences. On CT, 110 pulmonary nodules with a mean diameter of 4.9 + / - 2.9 mm were detected. UTE imaging resulted in a significantly higher detection rate compared to both other sequences (p < 0.01): 76.4% (84 of 110 nodules) for UTE versus 60.9% (67 of 110) for incoherent GRE and 62.7% (69 of 110) for volume interpolated GRE sequences. The detection of parenchymal areal opacities by the UTE technique was also significantly higher with a rate of 93.3% (42 of 45 opacities) versus 77.8% (35 of 45) for 2D GRE and 80.0% (36 of 45) for 3D GRE sequences (p < 0.05).

CONCLUSION: The UTE technique for lung MRI is favourable in children with generally high diagnostic performance compared to standard T1-weighted sequences as well as CT. Key Points • Due to the possible acquisition during free-breathing of the patients, the UTE MRI sequence for the lung is favourable in children. • The UTE technique reaches higher overall image quality, better sharpness, and lower artefacts, but not higher contrast compared to standard post-contrast T1-weighted sequences. • In comparison to the gold standard chest CT, the detection rate of small pulmonary nodules small nodules ≤ 4 mm and subtle parenchymal areal opacities is higher with the UTE imaging than standard T1-weighted sequences.

PMID:34668994 | DOI:10.1007/s00330-021-08236-7

Am J Physiol Lung Cell Mol Physiol. 2021 Oct 20. doi: 10.1152/ajplung.00563.2020. Online ahead of print.

ABSTRACT

Aberrant anion secretion across the bronchial epithelium is associated with airway disease, most notably in cystic fibrosis. While the cystic fibrosis transmembrane conductance regulator (CFTR) is recognized as the primary source of airway anion secretion, alternative anion transport mechanisms play a contributing role. An alternative anion transporter of growing interest is SLC26A9, a constitutively active chloride channel which has been shown to interact with CFTR and may also contribute to bicarbonate secretion. Interest in SLC26A9 has been fueled by genome-wide association studies which suggest it is a significant modifier of CF disease severity. In spite of this growing evidence that SLC26A9 plays an important role in the airway, its presence and function in bronchial epithelia remains poorly understood, in part because its activity is difficult to separate from the activity of CFTR. Here we present results using primary, human bronchial epithelia (HBE) from multiple patient sources to confirm that SLC26A9 mRNA is present in HBE, and that its constitutive channel activity is unaffected by knock down of CFTR. Furthermore, SLC26A9 and CFTR show differential responses to common inhibitors of anion secretion. Finally, we assess the impact of bicarbonate on the activity of SLC26A9 and CFTR. These results confirm that SLC26A9 is the primary source of constitutive anion secretion across HBE, and should inform future studies focused on activation of SLC26A9 as an alternative anion channel in CF. These results should provide a strong foundation to investigate how single nucleotide polymorphisms in SLC26A9 modulate airway disease.

PMID:34668421 | DOI:10.1152/ajplung.00563.2020

Clin Chem Lab Med. 2021 Oct 19. doi: 10.1515/cclm-2021-0724. Online ahead of print.

ABSTRACT

OBJECTIVES: Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators have revolutionized the therapeutic landscape in CF treatment. These vital drugs are extensively metabolized via CYP3A, so caution must be exercised in multimodal CF therapy because of the risk of adverse drug interactions. Our goal was to develop a highly sensitive assay for the purpose of therapeutic drug monitoring (TDM) in diagnostic laboratories.

METHODS: After protein precipitation, the CFTR modulators ivacaftor, lumacaftor, tezacaftor, elexacaftor, and their metabolites ivacaftor-M1, ivacaftor-M6, and tezacaftor-M1 were separated with a two-dimensional chromatography setup within 5 min, and quantified with stable isotope-labeled internal standards. The method was validated according to the European Medicines Agency (EMA) guideline on bioanalytical method validation and applied to CF patient samples.

RESULTS: Inaccuracy was ≤7.0% and the imprecision coefficient of variation (CV) was ≤8.3% for all quality controls (QCs). The method consistently compensated for matrix effects, recovery, and process efficiency were 105-115 and 96.5-103%, respectively. Analysis of CF serum samples provided concentrations comparable to the pharmacokinetic profile data reported in the EMA assessment report for the triple combination therapy Kaftrio.

CONCLUSIONS: We hereby present a robust and highly selective isotope dilution liquid chromatography tandem mass spectrometry (ID-LC-MS/MS) assay for the simultaneous quantification of the so far approved CFTR modulators and their metabolites in human serum. The assay is suitable for state-of-the-art pharmacovigilance of CFTR modulator therapy in CF patients, in order to maximize safety and efficacy, and also to establish dose-response relationships in clinical trials.

PMID:34668357 | DOI:10.1515/cclm-2021-0724

Environ Microbiol. 2021 Oct 19. doi: 10.1111/1462-2920.15816. Online ahead of print.

ABSTRACT

Cryptic prophages are not genomic junk but instead enable cells to combat myriad stresses as an active stress response. How these phage fossils affect persister cell resuscitation has, however, not been explored. Persister cells form as a result of stresses such as starvation, antibiotics and oxidative conditions, and resuscitation of these persister cells likely causes recurring infections such as those associated with tuberculosis, cystic fibrosis and Lyme disease. Deletion of each of the nine Escherichia coli cryptic prophages has no effect on persister cell formation. Strikingly, elimination of each cryptic prophage results in an increase in persister cell resuscitation with a dramatic increase in resuscitation upon deleting all nine prophages. This increased resuscitation includes eliminating the need for a carbon source and is due to activation of the phosphate import system resulting from inactivating the transcriptional regulator AlpA of the CP4-57 cryptic prophage. Deletion of alpA increases persister resuscitation, and AlpA represses phosphate regulator PhoR. Both phosphate regulators PhoP and PhoB stimulate resuscitation. This suggests a novel cellular stress mechanism controlled by cryptic prophages: regulation of phosphate uptake which controls the exit of the cell from dormancy and prevents premature resuscitation in the absence of nutrients.

PMID:34668292 | DOI:10.1111/1462-2920.15816

Acta Reumatol Port. 2021 Jul-Sep;46(3):283-285.

ABSTRACT

INTRODUCTION: Long-term survivors of cystic fibrosis (CF) have a dramatic increase in the risk of osteoporosis and incident fracture. The objective of this work is to characterize a CF related bone disease in a Portuguese cohort of CF patients.

METHODS: We performed a cross-sectional, observational study on a cohort of CF adult patients. Clinical status, laboratory parametres, nutrition, lung function tests, genetics and bone mineral density (BMD) data were collected from a CF reference centre.

RESULTS: Of 30 patients, 53.3% were males (n=16). Median age was 32.5 (27.0; 32,5) and median body mass index (BMI) was 22,04 (19,85; 24,55), with 4 patients (13.3%) being underweight (BMI<18.5 kg/m²). Four patients (13.3 %) were diagnosed with osteoporosis and 15 patients (50%) has low BMD. Among them, 2 (6.7%) had fragility fractures. A moderate correlation was found between the lumbar spine (LS) BMD and BMI and, as expected, femural neck BMD and LS BMD has moderate to strong correlations with BMD Z scores.

CONCLUSION: Despite the young middle age we found a high prevalence of low BMD and osteoporosis in patients with CF. Early recognition and treatment are the most effective strategies for reducing the morbidity due to osteoporosis in these patients.

PMID:34667140

J Cyst Fibros. 2021 Oct 16:S1569-1993(21)01425-9. doi: 10.1016/j.jcf.2021.09.020. Online ahead of print.

ABSTRACT

BACKGROUND: Pharmacotherapies for people with cystic fibrosis (pwCF) who have premature termination codons (PTCs) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are under development. Thus far, clinical studies focused on compounds that induce translational readthrough (RT) at the mRNA PTC location. Recent studies using primary airway cells showed that PTC functional restoration can be achieved through combining compounds with multiple mode-of-actions. Here, we assessed induction of CFTR function in PTC-containing intestinal organoids using compounds targeting RT, nonsense mRNA mediated decay (NMD) and CFTR protein modulation.

METHODS: Rescue of PTC CFTR protein was assessed by forskolin-induced swelling of 12 intestinal organoid cultures carrying distinct PTC mutations. Effects of compounds on mRNA CFTR level was assessed by RT-qPCRs.

RESULTS: Whilst response varied between donors, significant rescue of CFTR function was achieved for most donors with the quintuple combination of a commercially available pharmacological equivalent of the RT compound (ELX-02-disulfate or ELX-02ds), NMD inhibitor SMG1i, correctors VX-445 and VX-661 and potentiator VX-770. The quintuple combination of pharmacotherapies reached swelling quantities higher than the mean swelling of three VX-809/VX-770-rescued F508del/F508del organoid cultures, indicating level of rescue is of clinical relevance as VX-770/VX-809-mediated F508del/F508del rescue in organoids correlate with substantial improvement of clinical outcome.

CONCLUSIONS: Whilst variation in efficacy was observed between genotypes as well as within genotypes, the data suggests that strong pharmacological rescue of PTC requires a combination of drugs that target RT, NMD and protein function.

PMID:34666947 | DOI:10.1016/j.jcf.2021.09.020

Respir Res. 2021 Oct 19;22(1):267. doi: 10.1186/s12931-021-01865-y.

ABSTRACT

BACKGROUND: The non-cancerous functions of Akt in the airway are understudied. In some tissues, Akt phosphorylates and activates endothelial nitric oxide synthase (eNOS) to produce nitric oxide (NO) that has anti-inflammatory effects. NO production has antibacterial and antiviral effects in the airway, and increasing NO may be a useful anti-pathogen strategy. Akt also stimulates the nuclear factor erythroid 2-related factor 2 (Nrf-2) transcription factor, which transcribes antioxidant genes. Therefore, we hypothesized that activation of the Akt/eNOS pathway, which also activates Nrf-2, may have protective effects in human airway cells against injury.

METHODS: To directly test the effects of Akt signaling in the airway, we treated A549 and 16HBE cells as well as primary bronchial, nasal, and type II alveolar epithelial cells with small molecule Akt activator SC79. We examined the effects of SC79 on eNOS activation, NO production, Nrf-2 target levels, and interleukin-8 (IL-8) transcription during exposure to TNF-α or Pseudomonas flagellin (TLR5 agonist). Additionally, air-liquid interface bronchial cultures were treated with cadmium, an oxidative stressor that causes airway barrier breakdown.

RESULTS: SC79 induced a ~ twofold induction of p-eNOS and Nrf-2 protein levels blocked by PI3K inhibitor LY294002. Live cell imaging revealed SC79 increased acute NO production. Quantitative RT-PCR showed a ~ twofold increase in Nrf-2 target gene transcription. TNF-α or flagellin-induced IL-8 levels were also significantly reduced with SC79 treatment. Moreover, the transepithelial electrical resistance decrease observed with cadmium was ameliorated by SC79, likely by an acute increase in tight junction protein ZO-1 levels.

CONCLUSIONS: Together, the data presented here demonstrate SC79 activation of Akt induces potentially anti-pathogenic NO production, antioxidant gene transcription, reduces IL-8 transcription, and may protect against oxidative barrier dysfunction in a wide range of airway epithelial cells.

PMID:34666758 | DOI:10.1186/s12931-021-01865-y

BMC Pulm Med. 2021 Oct 19;21(1):326. doi: 10.1186/s12890-021-01689-y.

ABSTRACT

BACKGROUND: Handheld oscillating positive expiratory pressure (OPEP) devices have been a mainstay of treatment for patients with hypersecretory conditions such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) since the 1970s. Current devices are reusable and require regular cleaning and disinfection to prevent harbouring potentially pathogenic organisms. Adherence to cleaning regimens for respiratory devices is often poor and in response to this, a prototype disposable OPEP device-the 'UL-OPEP' (University of Limerick-Oscillating Positive Expiratory Pressure device)-was developed to mitigate the risk of contamination by pathogens. The device was previously evaluated successfully in a group of paediatric CF patients. The aim of the current study was to initially evaluate the safety of the prototype in patients with COPD over a period of 1 month to ensure no adverse events, negative impacts on lung function, exercise tolerance, or quality of life. Data on user experience of the device were also collected during post-study follow-up.

METHODS: A sample of 50 volunteer participants were recruited from pulmonary rehabilitation clinics within the local hospital network. The patients were clinically stable, productive, and not current or previous users of OPEP devices. Participants were invited to use a prototype disposable OPEP device daily for a period of 1 month. Pre- and post-study lung function was assessed with standard spirometry, and exercise tolerance with the 6-min-walk-test (6MWT). Quality of life was assessed using the St. George's Respiratory Questionnaire (SGRQ), and user experience of the prototype device evaluated using a post-study questionnaire.

RESULTS: 24 Participants completed the study: 9 were female. Overall median age was 67.5 years, range 53-85 years. Lung function, 6-min walk test, and SGRQ scores showed no significant change post-study. User feedback was positive overall.

CONCLUSIONS: The results indicate that the UL-OPEP is safe to use in patients with COPD. No adverse events were recorded during the study or in the follow-up period of 2 weeks. The device did not negatively impact patients' lung function, exercise tolerance, or quality of life during short term use (1 month), and usability feedback received was generally positive. Larger, longer duration studies will be required to evaluate efficacy. Registration The study was approved as a Clinical Investigation by the Irish Health Products Regulatory Authority (CRN-2209025-CI0085).

PMID:34666748 | DOI:10.1186/s12890-021-01689-y

Chron Respir Dis. 2021 Jan-Dec;18:14799731211041506. doi: 10.1177/14799731211041506.

ABSTRACT

BackgroundCurrent evidence suggests that interval exercise training (IET) and continuous exercise training (CET) produce comparable benefits in exercise capacity, cardiorespiratory fitness and symptoms in patients with chronic obstructive pulmonary disease (COPD). However, the effects of these modalities have only been reviewed in patients with COPD. This meta-analysis compares the effectiveness of IET versus CET on exercise capacity, cardiorespiratory fitness and exertional symptoms in patients with chronic respiratory diseases (CRDs). Methods: PubMed, CINHAL, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL) and Nursing and Allied health were searched for randomised controlled trials from inception to September 2020. Eligible studies included the comparison between IET and CET, reporting measures of exercise capacity, cardiorespiratory fitness and symptoms in individuals with CRDs. Results: Thirteen randomised control trials (530 patients with CRDs) with fair to good quality on the PEDro scale were included. Eleven studies involved n = 446 patients with COPD, one involved n = 24 patients with cystic fibrosis (CF) and one n = 60 lung transplantation (LT) candidates. IET resulted in greater improvements in peak work rate (WRpeak) (2.40 W, 95% CI: 0.83 to 3.97 W; p = 0.003) and lower exercise-induced dyspnoea (-0.47, 95% CI: -0.86 to 0.09; p = 0.02) compared to CET; however, these improvements did not exceed the minimal important difference for these outcomes. No significant differences in peak values for oxygen uptake (VO2peak), heart rate (HRpeak), minute ventilation (VEpeak), lactate threshold (LAT) and leg discomfort were found between the interventions. Conclusions: IET is superior to CET in improving exercise capacity and exercise-induced dyspnoea sensations in patients with CRDs; however, the extent of the clinical benefit is not considered clinically meaningful.

PMID:34666528 | DOI:10.1177/14799731211041506

Klin Lab Diagn. 2021 Oct 18;66(10):629-634. doi: 10.51620/0869-2084-2021-66-10-629-634.

ABSTRACT

Cystic fibrosis (CF) is a common genetic disease, manifested by airway obstruction and chronic respiratory infection. The most prevalent infectious agent in airways of CF patients is Pseudomonas aeruginosa. This study aimed to determine sequence-types, antimicrobial resistance phenotypes and genes defining adaptive antibiotic resistance in P. aeruginosa isolates recovered from CF patients in Russia. In total, 84 P. aeruginosa strains from 64 CF patients were analyzed. Susceptibility to antibiotics was determined by disk diffusion test. Whole-genome sequencing (WGS) was performed on MGISEQ-2000 platform. SPAdes software, Galaxy, ResFinder, PubMLST were used for analysis of WGS data. Examined P. aeruginosa isolates belonged to 53 different sequence-types (STs), including 6 new STs. High-risk epidemic clone ST235 (10%) and clonal CF P. aeruginosa strains ST17, ST242, ST274 (7%) were detected. Non-susceptibility to ticarcillin-clavulanate, cefepime, imipenem was observed in 63%, 12% and 25% of isolates, respectively; to tobramycin - in 24%, to amikacin - in 35%; to ciprofloxacin, levofloxacin - in 35% and 57% of strains, respectively. Multidrug-resistant phenotype was detected in 18% of isolates. In examined strains, genes of beta-lactamases VIM-2 (5 ST235 strains), VEB-1 (two ST2592 strains), GES-1 (1 ST235 strain), PER-1 (1 ST235 strain) were found. Ciprofloxacin-modifying enzyme CrpP gene was detected in 67% of isolates, aminoglycoside-modifying enzymes AAD, ANT, AAC genes - in 7%, 4%, 12% of strains, respectively. P. aeruginosa isolates from CF patients in Russia demonstrate a high clonal diversity, which is similar to other P. aeruginosa infections. The isolates of high-risk clone and clonal CF P. aeruginosa strains are detected.

PMID:34665950 | DOI:10.51620/0869-2084-2021-66-10-629-634

Am J Gastroenterol. 2021 Oct 19. doi: 10.14309/ajg.0000000000001527. Online ahead of print.

ABSTRACT

INTRODUCTION: Acute pancreatitis (AP) occurs among patients with pancreas-sufficient cystic fibrosis (PS-CF) but is reportedly less common among patients with pancreas-insufficient cystic fibrosis (PI-CF). The incidence of AP may be influenced by cystic fibrosis transmembrane conductance regulator (CFTR) modulator use. We hypothesized that CFTR modulators would reduce AP hospitalizations, with the greatest benefit in PS-CF.

METHODS: MarketScan (2012-2018) was queried for AP hospitalizations and CFTR modulator use among patients with CF. Multivariable Poisson models that enabled crossover between CFTR modulator treatment groups were used to analyze the rate of AP hospitalizations on and off therapy. Pancreas insufficiency was defined by the use of pancreas enzyme replacement therapy.

RESULTS: A total of 10,417 patients with CF were identified, including 1,795 who received a CFTR modulator. AP was more common in PS-CF than PI-CF (2.9% vs 0.9%, P = 0.007). Overall, the observed rate ratio of AP during CFTR modulator use was 0.33 (95% confidence interval [CI] 0.10, 1.11, P = 0.07) for PS-CF and 0.38 (95% CI 0.16, 0.89, P = 0.03) for PI-CF, indicating a 67% and 62% relative reduction in AP hospitalizations, respectively. In a subset analysis of 1,795 patients who all had some CFTR modulator use, the rate ratio of AP during CFTR modulator use was 0.36 (95% CI 0.13, 1.01, P = 0.05) for PS-CF and 0.53 (95% CI 0.18, 1.58, P = 0.26) for PI-CF.

DISCUSSION: CFTR modulator use is associated with a reduction in AP hospitalizations among patients with CF. These observational data support the prospective study of CFTR modulators to reduce AP hospitalizations among patients with CF.

PMID:34665155 | DOI:10.14309/ajg.0000000000001527

Am J Rhinol Allergy. 2021 Oct 19:19458924211046719. doi: 10.1177/19458924211046719. Online ahead of print.

ABSTRACT

Background: Comorbid chronic rhinosinusitis (CRS) of adulthood is increasing among patients with cystic fibrosis (CF) due to improved median survival. However, little is known about the natural history of endoscopic sinus surgery (ESS) in this cohort. The objective of this study was to evaluate the revision rate of ESS and associated risk factors among adults with CRS and CF (CRSwCF). Methods: The Utah Population Database was queried for patients age >18 with CRS who underwent at least one ESS between 1996 and 2018. Demographic information and ESS history were collected and compared for CRSwCF versus CRS without CF (CRSsCF) using chi-square and t-tests. Risk factors for revision were analyzed using Cox proportional hazard models and logistic regression analysis. Results: A total of 34 050 patients (33 639 CRSsCF and 411 CRSwCF) were included in the final analysis. The mean duration of follow-up was 9.3 and 9.3 years, respectively (P = .98). Adult patients with CF were significantly more likely to undergo revision ESS (18.7%) than those without CF (13.4%; P < .01). Logistic regression analysis indicated that a diagnosis of CF independently elevated the risk for revision ESS in the absence of nasal polyps (odds ratio [OR] 2.18, confidence interval [CI] 1.34-3.54), asthma (OR 1.36, CI 0.94-1.98), and allergies (OR 1.29, CI 0.90-1.73). Conclusion: In the era before highly effective modulator therapies, the mean revision rate of ESS among adults with CRSwCF was 18.7%, significantly greater than that of adults with CRSsCF. CF was an independent risk factor for revision ESS in the absence of nasal polyps, asthma, and allergies.

PMID:34665045 | DOI:10.1177/19458924211046719

Clin Otolaryngol. 2021 Oct 18. doi: 10.1111/coa.13875. Online ahead of print.

ABSTRACT

OBJECTIVES: Undetected cystic fibrosis transmembrane regulator (CFTR) mutations may predispose individuals to develop CRS independent of formal CF diagnosis. The objective of this study was to determine the prevalence of CFTR mutations among individuals with CRS.

DESIGN: A systematic search following PRISMA guidelines was performed. A meta-analysis was performed to calculate pooled estimates for the prevalence of any CFTR mutation and for the DF508 mutation.

SETTING AND PARTICIPANTS: The systematic search included all studies identifying adults diagnosed with CRS, with no limitation to region or publication date. Studies had to identify a sample of patients previously diagnosed with CRS but not with CF and reporting testing for the prevalence of CF or the CFTR gene mutation MAIN OUTCOME MEASURES: Prevalence of CFTR mutations among the general CRS population, with subgroup analysis of individuals with the dF508 mutation.

RESULTS AND CONCLUSIONS: The 6 included studies represented five countries: the US, the UK, France, Poland, and Finland. The pooled prevalence of CFTR mutations of any kind in CRS subjects without CF was 5.65% (RE 95% CI 2.99 - 10.41). The overall prevalence for the dF508 mutation was 4.22% (RE 95% CI 1.71 - 10.07). These estimates were significantly higher than the baseline estimated prevalence of CFTR carrier status of 3-4% in the general population. However, the clinical relevance of the presence of CFTR mutations in CRS patients who have not been diagnosed with CF is currently unclear. Future studies should include sweat chloride testing as a measure of CFTR function.

PMID:34664411 | DOI:10.1111/coa.13875

Sci Rep. 2021 Oct 18;11(1):20607. doi: 10.1038/s41598-021-99747-2.

ABSTRACT

The development of computational methods to assess pathogenicity of pre-messenger RNA splicing variants is critical for diagnosis of human disease. We assessed the capability of eight algorithms, and a consensus approach, to prioritize 249 variants of uncertain significance (VUSs) that underwent splicing functional analyses. The capability of algorithms to differentiate VUSs away from the immediate splice site as being 'pathogenic' or 'benign' is likely to have substantial impact on diagnostic testing. We show that SpliceAI is the best single strategy in this regard, but that combined usage of tools using a weighted approach can increase accuracy further. We incorporated prioritization strategies alongside diagnostic testing for rare disorders. We show that 15% of 2783 referred individuals carry rare variants expected to impact splicing that were not initially identified as 'pathogenic' or 'likely pathogenic'; one in five of these cases could lead to new or refined diagnoses.

PMID:34663891 | DOI:10.1038/s41598-021-99747-2

Adv Virus Res. 2021;111:63-110. doi: 10.1016/bs.aivir.2021.07.004. Epub 2021 Sep 2.

ABSTRACT

Phages are viruses that specifically infect bacteria, and their biodiversity contributes to historical and current development of phage therapy to treat myriad bacterial infections. Phage therapy holds promise as an alternative to failing chemical antibiotics, but there are benefits and costs of this technology. Here, we review the rich history of phage therapy, highlighting reasons (often political) why it was widely rejected by Western medicine until recently. One longstanding idea involves mixing different phages together in cocktails, to increase the probability of killing target pathogenic bacteria without pre-screening for phage susceptibility. By challenging 30 lytic phages to infect 14 strains of the bacteria Pseudomonas aeruginosa, we showed that some phages were "generalists" with broad host-ranges, emphasizing that extreme host-specificity of phages was not necessarily a liability. Using a "greedy algorithm" analysis, we identified the best cocktail mixture of phages to achieve broad bacteria killing. Additionally, we review how virus host-range can evolve and connect lessons learned from virus emergence-including contributions of elevated virus mutation rates in promoting emergence and virus evolutionary transitions from specialized to generalized host-use-as cautionary tales for avoiding risk of "off-target" phage emergence on commensal bacteria in microbiomes. Throughout, we highlight how fundamental understanding of virus ecology and evolution is vital for developing phage therapy; heeding these principles should help in designing therapeutic strategies that do not recapitulate consequences of virus selection to emerge on novel hosts.

PMID:34663499 | DOI:10.1016/bs.aivir.2021.07.004

Vasc Endovascular Surg. 2021 Oct 18:15385744211051812. doi: 10.1177/15385744211051812. Online ahead of print.

ABSTRACT

Bronchial artery (BA) pseudoaneurysm is an uncommon vascular complication of tuberculosis (TB), and early diagnosis is crucial due to risk of rupture and life-threatening hemorrhage. Immediate intervention is warranted in massive hemoptysis due to high mortality. Various causes of massive hemoptysis are TB, bronchiectasis, aspergilloma, lung abscess, lung cancer, necrotizing pneumonia, and cystic fibrosis. Active pulmonary TB as well as chronic pulmonary TB can manifest with massive hemoptysis. Hemoptysis in active TB occurs due to ulceration in bronchiolar wall, eroding the wall of the adjacent BA or pulmonary artery, and in chronic TB due to hypertrophied bronchial arteries, or bronchiectasis, or aspergilloma. Herein, we report a case of pulmonary TB causing intrapulmonary BA pseudoaneurysm in a young male patient who presented with acute massive hemoptysis. The BA pseudoaneurysm as well as other hypertrophied bronchial arteries were embolized using polyvinyl alcohol (PVA) particles.

PMID:34663143 | DOI:10.1177/15385744211051812

Diagn Microbiol Infect Dis. 2021 Sep 23;102(1):115559. doi: 10.1016/j.diagmicrobio.2021.115559. Online ahead of print.

ABSTRACT

Methicillin-resistant Staphylococcus aureus (MRSA) detection in cystic fibrosis (CF) is challenging. We compared different phenotypic methods among 157 S. aureus from 136 CF-patients: cefoxitin (FOX) and oxacillin (OXA) broth-microdilution; MicroScan-WalkAway®; FOX and OXA disk-diffusion (DD), and PBP2a-latex agglutination. PCR detection of mecA/mecC was the gold standard. Growth on ChromIDTM-MRSA agar was evaluated and compared with that of 157 blood culture (BC) isolates. ChromIDTM-MRSA was also tested on sputa from 111 CF-patients. 32 isolates (20%) were mecA-positive. Both FOX DD and MicroScan-WalkAway® (FOX/OXA) showed the highest sensitivity and specificity (100% and 100%, 96.9% and 99.2%, 96.9% and 100%). ChromIDTM-MRSA showed an excellent sensitivity for BC and CF-isolates (100% and 96.9%) but a poorer specificity for CF ones (95.5% vs. 73.7%), which was also observed when samples were seeded on this medium. FOX DD and MicroScan-WalkAway® are suitable for MRSA detection among CF-isolates and should be used to confirm ChromIDTM-MRSA positive CF-cultures.

PMID:34662789 | DOI:10.1016/j.diagmicrobio.2021.115559