Readmissions following ambulatory pediatric endoscopic sinus surgery.

Laryngoscope. 2019 Mar 01;:

Authors: McKeon M, Medina G, Kawai K, Cunningham M, Adil E

Abstract
OBJECTIVES/HYPOTHESIS: Endoscopic sinus surgery (ESS) is indicated in select pediatric patients with medically refractory sinus disease. Our objectives were to examine indications and rates of readmission following ambulatory pediatric ESS and identify specific subgroups that may benefit from inpatient admission.
STUDY DESIGN: Retrospective database review.
METHODS: The Pediatric Health Information Systems (PHIS) 2004-2016 database was retrospectively reviewed for patients age <18 years who underwent ambulatory ESS between January 2011 and December 2016 and were readmitted within 30 days postoperatively. Data regarding demographics, extent of surgery, comorbidities, adjunctive procedures, and cost were collected. A multivariable mixed-effects logistic regression model was employed for analysis.
RESULTS: We identified 3,669 unique pediatric ESS cases with 128 readmissions within 30 days (3.5%; 95% confidence interval [CI]: 2.9%-4.1%). Median cost of readmission was $980 (mean, $5,890; standard deviation, $13,421). The most common indication for readmission was epistaxis (17.2%), followed by nausea/abdominal pain (14.1%). Respiratory infection (13.3%) and sinusitis (10.2%) presented a combined readmission rate exceeding that of epistaxis alone. Multivariable analysis indicated age <3 years (odds ratio [OR]: 3.41, 95% CI: 1.96-5.93) and a prior diagnosis of asthma (OR: 2.88, 95% CI: 1.99-4.18) or cystic fibrosis (OR: 1.57, 95% CI: 1.00-2.44) significantly increased the risk of readmission. Extent of ESS and simultaneous adenoidectomy, septoplasty, or turbinate reduction had no significant impact on readmission rates.
CONCLUSIONS: ESS is a relatively safe outpatient surgical procedure in pediatric patients, with an overall readmission rate of 3.5%. Clinicians should consider careful preoperative evaluation of very young patients and those with cystic fibrosis or asthma to optimize perioperative management and determine if postoperative admission is warranted, given their significantly higher readmission rates.
LEVEL OF EVIDENCE: NA Laryngoscope, 2019.

PMID: 30821352 [PubMed - as supplied by publisher]

Aquagenic Wrinkling of Skin: A Screening Test for Cystic Fibrosis.

Indian Pediatr. 2019 Feb 15;56(2):109-113

Authors: Singh A, Lodha R, Shastri S, Sethuraman G, Sreedevi KN, Kabra M, Kabra SK

Abstract
OBJECTIVE: To study the utility of aquagenic wrinkling as screening test for children with cystic fibrosis.
DESIGN: Evaluation of diagnostic test.
SETTING: Pediatric Chest Clinic, and Pediatric Wards of a tertiary care hospital in New Delhi.
PARTICIPANTS: Three groups (children with cystic fibrosis, carriers of cystic fibrosis, and controls).
METHODS: Time taken to develop aquagenic wrinkling was measured. The test was performed by asking the enrolled subject to put their one hand in water and was checked for development of wrinkling every minute, and a photograph was also taken every minute.
RESULTS: A total of 64 children with cystic fibrosis, 64 controls and 64 carriers were enrolled in the study. Median (IQR) time to develop aquagenic wrinkling in the three groups was 2 (2.5,3) minutes, 4 (3,5) minutes and 8 (5,11) minutes, respectively. The optimal cut-off was calculated as 3 minutes by Receiver operating characteristic curve with a sensitivity and specificity for identification of children with cystic fibrosis as 81% and 57%, respectively. The area under curve was 76.5%. The 3 minute cut-off for development of aquagenic wrinkling was applied to 54 children referred for sweat test. 20 children had sweat chloride values of ≥60 mEq/l and diagnosed as cystic fibrosis. 15 of these developed aquagenic wrinkling at ≤3 minutes, giving a sensitivity of 75%.
CONCLUSIONS: In places with no facility for sweat test, children with phenotype compatible with cystic fibrosis who develop aquagenic wrinkling in 3 minutes may be diagnosed as probable cystic fibrosis and referred for confirmation by sweat test.

PMID: 30819988 [PubMed - in process]

A Simple Screening Test for Cystic Fibrosis?

Indian Pediatr. 2019 Feb 15;56(2):105-106

Authors: Davies G, Aurora P

Abstract

PMID: 30819986 [PubMed - in process]

Hyperpolarised 129Xe MRI to monitor treatment response in children with cystic fibrosis.

Eur Respir J. 2019 Feb 28;:

Authors: Rayment JH, Couch MJ, McDonald N, Kanhere N, Manson D, Santyr G, Ratjen F

Abstract
Pulmonary magnetic resonance imaging using hyperpolarised 129Xe gas (XeMRI) can quantify ventilation inhomogeneity by measuring the percentage of unventilated lung volume (ventilation defect percent; VDP). While previous studies have demonstrated its sensitivity to detect early cystic fibrosis (CF) lung disease, the utility of XeMRI to monitor response to therapy in CF is unknown. The aim of this study was to assess the ability of XeMRI to capture treatment response in paediatric CF patients undergoing inpatient antibiotic treatment for a pulmonary exacerbation.15 CF patients age 8-18 years underwent XeMRI, spirometry, plethysmography, and multiple breath nitrogen washout at the beginning and end of inpatient treatment of a pulmonary exacerbation. VDP was calculated from XeMRI images obtained during a static breath hold using semi-automated k-means clustering and linear binning approaches.XeMRI was well tolerated. VDP, lung clearance index and the forced expiratory volume in one second all improved with treatment, however, response was not uniform in individual patients. Of all outcome measures, VDP showed the largest relative improvement (-42.1%; 95%CI -52.1, -31.9, p<0.0001).These data support further investigation of XeMRI as a tool to capture treatment response in CF lung disease.

PMID: 30819815 [PubMed - as supplied by publisher]

Exhaled NO in stable adult cystic fibrosis patients, during exacerbation and following CFTR-modifying treatment.

Eur Respir J. 2019 Feb 28;:

Authors: Vincken S, Verbanck S, De Wachter E, Vanderhelst E

PMID: 30819814 [PubMed - as supplied by publisher]

Quantitative multivolume proton-MRI in patients with cystic fibrosis lung disease: comparison with clinical indicators.

Eur Respir J. 2019 Feb 28;:

Authors: Pennati F, Salito C, Borzani I, Cervellin G, Gambazza S, Guarise R, Russo MC, Colombo C, Aliverti A

Abstract
OBJECTIVES: The present cross-sectional study aims to verify the relationship between quantitative multivolume magnetic resonance imaging (MRI) and clinical indicators of ventilatory abnormalities in cystic fibrosis (CF) lung disease.
METHODS: 28 patients (10-27 years) with CF lung disease performed non-enhanced chest MRI, spirometry and multiple breath washout (MBW). Images acquired at end-inspiration and end-expiration were registered by optical flow to estimate expiratory-inspiratory proton density change (Δ1H-MRI) as a measure of regional ventilation. MR images were also evaluated using a CF-specific scoring system.
RESULTS: Biomarkers of CF ventilation impairment were defined from Δ1H-MRI: Δ1H-MRI median, Δ1H-MRI quartile coefficient of variation (QCV) and percent low-ventilation volume (%LVV). Imaging biomarkers correlate to all the clinical measures of ventilation abnormalities, with the strongest correlation between Δ1H-MRI median and forced expiratory volume in one second (FEV1) (r2=0.44, p<0.001), Δ1H-MRI QCV and lung clearance index (LCI) (r2=0.51, p<0.001) and %LVV and LCI (r2=0.66, p<0.001). Correlations were also found between imaging biomarkers of ventilation and morphological scoring.
CONCLUSION: The study showed a significant correlation between quantitative multivolume-MRI and clinical indicators of CF lung disease. MRI, as a non-ionizing imaging technique, may be particularly attractive in CF care for longitudinal evaluation, providing a new imaging biomarker to detect early ventilator abnormalities.

PMID: 30819810 [PubMed - as supplied by publisher]

Mucus penetrating properties of soft, distensible lipid nanocapsules.

Eur J Pharm Biopharm. 2019 Feb 25;:

Authors: Chen H, Mansfield EDH, Woods A, Khutoryanskiy VV, Forbes B, Jones SA

Abstract
Designing nanomaterials to release their drug pay-load upon exposure to an exogenous trigger can help to direct drug delivery, but how the triggered release, which often modifies the nanomaterial properties, influences the biological fate of these systems is currently unknown. The aim of this study was to investigate how the triggered drug release from PEG coated, soft, 50 nm distensible lipid nanocapsules (LNC) influenced their diffusion across a mucus barrier. The translocation speed of the non-triggered LNC across a 35 µm thick purified gastric mucin (PGM) barrier was 3 times faster (30.08 ± 2.49 x 10-10 cm2 s-1) compared to equivalent-sized negatively charged polystyrene particles (9.87 ± 0.61 x 10-10 cm2 s-1, p < 0.05). In cystic fibrosis mucus (CFM), harvested from patient primary cells, the non-triggered LNC translocation speed was similar to the PGM, but the polystyrene particles diffusion was so slow it could not be measured. The trigger induced LNC distension process had no effect on the particle diffusion rate in both PGM and CFM (p > 0.05) in a static mucus barrier, but when shear was applied to the barrier the distended LNCs diffused more slowly (3.97 ± 1.38 x 10-8 cm2s-1, p < 0.05) compared to the non-distended materials (4.94 ± 0.04 x 10-8 cm2s-1). This data suggested the rapid mucus penetration of the distended LNCs, despite their increased size, was a consequence of their capacity to take a less tortious path through the barrier, i.e., they experienced less steric hinderance, compared to the non-distended LNC.

PMID: 30818012 [PubMed - as supplied by publisher]

Minocycline and silver dual-loaded polyphosphoester-based nanoparticles for treatment of resistant Pseudomonas aeruginosa.

Mol Pharm. 2019 Feb 28;:

Authors: Chen Q, Shah KN, Zhang F, Salazar AJ, Shah PN, Li R, Sacchettini JC, Wooley KL, Cannon CL

Abstract
Pseudomonas aeruginosa has been detected in the lungs of about 50% of patients with cystic fibrosis (CF) patients, including 20% of adult CF patients. The majority of these adult patients harbor multi-drug resistant (MDR) strains limiting the available treatment options. Silver has long been used as a broad-spectrum antimicrobial agent with a low incidence of resistance. Despite low toxicity, poor availability of silver cations mandates a high dosage to effectively eradicate infections. To address these shortcomings of silver, nanoparticles have been used as delivery devices to improve treatment outcomes. Furthermore, studies have demonstrated that synergistic combinations with careful dose calibrations and efficient delivery systems result in superior antimicrobial activity, while avoiding potential side-effects of both therapeutics. Here, 4-epi-minocycline, a metabolite of minocycline, was identified as an active antimicrobial against P. aeruginosa using a high-throughput screen. The antimicrobial activities of 4-epi-minocycline, minocycline and silver acetate against clinical isolates of P. aeruginosa obtained from CF patients were evaluated in vitro. Next, the synergistic activity of the silver/minocycline combination against P. aeruginosa isolates was investigated using checkerboard assays and identified with end-point colony forming unit (CFU) determination assays. Finally, nanoparticles co-loaded with minocycline and silver were evaluated in vitro for antimicrobial activity. The results demonstrated that both silver and minocycline are potent antimicrobials alone, and that the combination allows reduced dosage of both therapeutics to achieve the same antimicrobial effect. Furthermore, the proposed synergistic silver/minocycline combination can be co-loaded into nanoparticles as a next-generation antibiotic to combat the threats presented by MDR pathogens.

PMID: 30817887 [PubMed - as supplied by publisher]

Aspergillus colonization and antifungal immunity in cystic fibrosis patients.

Med Mycol. 2019 Apr 01;57(Supplement_2):S118-S126

Authors: Warris A, Bercusson A, Armstrong-James D

Abstract
Cystic fibrosis (CF), caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, is the most common inherited life-limiting disease in North European people affecting 90,000 people worldwide. Progressive lung damage caused by recurrent infection and chronic airway inflammation is the major determinant of survival with a median age at death of 29 years. Approximately 60% of CF patients are infected with Aspergillus fumigatus, a ubiquitous environmental fungus, and its presence has been associated with accelerated lung function decline. Half of the patients infected with Aspergillus are <18 years of age. Yet time of acquisition of this fungus and determinants of CF-related Aspergillus disease severity and progression are not known. CFTR expression has been demonstrated in cells of the innate and adaptive immune system and has shown to be critical for normal function. Research delineating the role of CFTR-deficient phagocytes in Aspergillus persistence and infection in the CF lung, has only recently received attention. In this concise review we aim to present the current understanding with respect to when people with CF acquire infection with A. fumigatus and antifungal immune responses by CF immune cells.

PMID: 30816976 [PubMed - in process]

Aspergillus-Pseudomonas interaction, relevant to competition in airways.

Med Mycol. 2019 Apr 01;57(Supplement_2):S228-S232

Authors: Sass G, Nazik H, Penner J, Shah H, Ansari SR, Clemons KV, Groleau MC, Dietl AM, Visca P, Haas H, Déziel E, Stevens DA

Abstract
In airways of immunocompromised patients and individuals with cystic fibrosis, Pseudomonas aeruginosa and Aspergillus fumigatus are the most common opportunistic bacterial and fungal pathogens. Both pathogens form biofilms and cause acute and chronic illnesses. Previous studies revealed that P. aeruginosa is able to inhibit A. fumigatus biofilms in vitro. While numerous P. aeruginosa molecules have been shown to affect A. fumigatus, there never has been a systematic approach to define the principal causative agent. We studied 24 P. aeruginosa mutants, with deletions in genes important for virulence, iron acquisition, or quorum sensing, for their ability to interfere with A. fumigatus biofilms. Cells, planktonic or biofilm culture filtrates of four P. aeruginosa mutants, pvdD-pchE-, pvdD-, lasR-rhlR-, and lasR-, inhibited A. fumigatus biofilm metabolism or planktonic A. fumigatus growth significantly less than P. aeruginosa wild type. The common defect of these four mutants was a lack in the production of the P. aeruginosa siderophore pyoverdine. Pure pyoverdine affected A. fumigatus biofilm metabolism, and restored inhibition by the above mutants. In lungs from cystic fibrosis patients, pyoverdine production and antifungal activity correlated. The key inhibitory mechanism for pyoverdine was iron-chelation and denial of iron to A. fumigatus. Further experiments revealed a counteracting, self-protective mechanism by A. fumigatus, based on A. fumigatus siderophore production.

PMID: 30816973 [PubMed - in process]

Acid Sphingomyelinase-Ceramide System in Bacterial Infections.

Cell Physiol Biochem. 2019;52(2):280-301

Authors: Li C, Wang A, Wu Y, Gulbins E, Grassmé H, Zhao Z

Abstract
Acid sphingomyelinase hydrolyzes sphingomyelin to ceramide and phosphorylcholine. Ceramide molecules spontaneously interact with each other and generate ceramide-enriched membrane domains. These ceramide-enriched domains further fuse, forming large ceramideenriched platforms that participate in the organization of receptors and in the amplification of signaling molecules. Recent studies have suggested several bacteria and bacterial toxins that stimulate the activation and the translocation of acid sphingomyelinase, which leads to the release of ceramide. The acid sphingomyelinase/ceramide system also regulates the internalization of bacteria into the host cell, the subsequent cytokine release, inflammatory response, and initiation of host cell apoptosis. In addition, ceramide has been implicated in the fusion of phagosomes and lysosomes upon bacterial infection. Thus, this system modulates the reorganization of cell membrane receptors and intracellular signaling molecules during bacteria-host interactions. The acid sphingomyelinase and ceramide system may thus serve as a novel therapeutic target for treating infections.

PMID: 30816675 [PubMed - in process]

A data-driven evaluation of the size and content of expanded carrier screening panels.

Genet Med. 2019 Feb 28;:

Authors: Ben-Shachar R, Svenson A, Goldberg JD, Muzzey D

Abstract
PURPOSE: The American College of Obstetricians and Gynecologists (ACOG) proposed seven criteria for expanded carrier screening (ECS) panel design. To ensure that screening for a condition is sufficiently sensitive to identify carriers and reduce residual risk of noncarriers, one criterion requires a per-condition carrier rate greater than 1 in 100. However, it is unestablished whether this threshold corresponds with a loss in clinical detection. The impact of the proposed panel design criteria on at-risk couple detection warrants data-driven evaluation.
METHODS: Carrier rates and at-risk couple rates were calculated in 56,281 patients who underwent a 176-condition ECS and were evaluated for panels satisfying various criteria. Condition-specific clinical detection rates were estimated via simulation.
RESULTS: Different interpretations of the 1-in-100 criterion have variable impact: a compliant panel would include between 3 and 38 conditions, identify 11-81% fewer at-risk couples, and detect 36-79% fewer carriers than a 176-condition panel. If the carrier rate threshold must be exceeded in all ethnicities, ECS panels would lack prevalent conditions like cystic fibrosis. Simulations suggest that the clinical detection rate remains >84% for conditions with carrier rates as low as 1 in 1000.
CONCLUSION: The 1-in-100 criterion limits at-risk couple detection and should be reconsidered.

PMID: 30816298 [PubMed - as supplied by publisher]

Carriage of a single strain of non-toxigenic Corynebacterium diphtheriae biovar Belfanti (Corynebacterium belfantii) in four patients with cystic fibrosis.

J Clin Microbiol. 2019 Feb 27;:

Authors: Pivot D, Fanton A, Badell-Ocando E, Benouachkou M, Astruc K, Huet F, Amoureux L, Neuwirth C, Criscuolo A, Aho S, Toubiana J, Brisse S

Abstract
Cystic fibrosis (CF) patients are commonly colonized by bacterial pathogens, which can induce persistent lung inflammation and may contribute to clinical deterioration. Colonization of CF patients and cross-transmission by Corynebacterium diphtheriae has not been reported so far. The aim of this article was to investigate the possibility of a cross transmission of C. diphtheriae biovar Belfanti between four patients of a CF center. C. diphtheriae biovar belfanti (now formally called C. belfantii) isolates were collected from four patients in a single CF care center over a 6 years period and analyzed by microbiological methods and whole genome sequencing. Epidemiological links among patients were investigated. Ten isolates were collected from 4 patients. Whole genome sequencing of one isolate from each patient showed that a single strain was shared among them. In addition, one patient had the same strain on two consecutive samplings nine months apart. The strain was non-toxigenic and was susceptible to most antimicrobial agents. Ciprofloxacin resistance was observed in one patient. Transmission of the strain among patients was supported by the occurrence of same-day visits to the CF center. This study demonstrates colonization of CF patients by C. diphtheriae biovar Belfanti (C. belfantii) and suggests persistence and transmission of a unique strain during at least six years in a single CF patient care center.

PMID: 30814269 [PubMed - as supplied by publisher]

Progression of Cystic Fibrosis Lung Disease from Childhood to Adulthood: Neutrophils, Neutrophil Extracellular Trap (NET) Formation, and NET Degradation.

Genes (Basel). 2019 Feb 26;10(3):

Authors: Khan MA, Ali ZS, Sweezey N, Grasemann H, Palaniyar N

Abstract
Genetic defects in cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene cause CF. Infants with CFTR mutations show a peribronchial neutrophil infiltration prior to the establishment of infection in their lung. The inflammatory response progressively increases in children that include both upper and lower airways. Infectious and inflammatory response leads to an increase in mucus viscosity and mucus plugging of small and medium-size bronchioles. Eventually, neutrophils chronically infiltrate the airways with biofilm or chronic bacterial infection. Perpetual infection and airway inflammation destroy the lungs, which leads to increased morbidity and eventual mortality in most of the patients with CF. Studies have now established that neutrophil cytotoxins, extracellular DNA, and neutrophil extracellular traps (NETs) are associated with increased mucus clogging and lung injury in CF. In addition to opportunistic pathogens, various aspects of the CF airway milieux (e.g., airway pH, salt concentration, and neutrophil phenotypes) influence the NETotic capacity of neutrophils. CF airway milieu may promote the survival of neutrophils and eventual pro-inflammatory aberrant NETosis, rather than the anti-inflammatory apoptotic death in these cells. Degrading NETs helps to manage CF airway disease; since DNAse treatment release cytotoxins from the NETs, further improvements are needed to degrade NETs with maximal positive effects. Neutrophil-T cell interactions may be important in regulating viral infection-mediated pulmonary exacerbations in patients with bacterial infections. Therefore, clarifying the role of neutrophils and NETs in CF lung disease and identifying therapies that preserve the positive effects of neutrophils, while reducing the detrimental effects of NETs and cytotoxic components, are essential in achieving innovative therapeutic advances.

PMID: 30813645 [PubMed]

Transcriptome Profiling and Molecular Therapeutic Advances in Cystic Fibrosis: Recent Insights.

Genes (Basel). 2019 Feb 26;10(3):

Authors: Ideozu JE, Zhang X, McColley S, Levy H

Abstract
In cystic fibrosis (CF), mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene disrupt the capacity of the encoded protein to function as a channel to transport chloride ions and water across cell membranes. The consequences are deleterious, system-wide, and immensely variable, even among patients with the same CFTR genotype. This underscores the need to characterize the mechanisms contributing to CF pathophysiology. Gene replacement and gene editing therapies have been pursued intensively and are expected to provide a one-time treatment for CF. However, gene replacement therapy is limited by the lack of efficient vectors to deliver functional copies of CFTR to cells without immunological complications, while gene editing technologies such as CRISPR/Cas9 are still in their infancy, mainly useful in somatic cells and limited by off-target insertions. Small molecule treatments targeted at potentiating or correcting CFTR have shown clinical benefits, but they are limited to a few CFTR mutations and insufficient to overcome challenges related to clinical heterogeneity. Transcriptome profiling approaches have emerged as robust tools capable of characterizing phenotypic variability and revealing novel molecular targets with therapeutic potential for CF. We summarize current insights gained through transcriptome profiling approaches in CF studies and recent advances in molecular therapeutics.

PMID: 30813620 [PubMed]

Chronic Rhinosinusitis in Cystic Fibrosis: Diagnosis and Medical Management.

Med Sci (Basel). 2019 Feb 22;7(2):

Authors: Safi C, Zheng Z, Dimango E, Keating C, Gudis DA

Abstract
Chronic rhinosinusitis (CRS) is nearly ubiquitous in patients with cystic fibrosis (CF). CF CRS is a challenging entity to define, diagnose, and treat, as patients often have severe refractory sinus disease in addition to complex medical comorbidities. The purpose of this article is to review the literature on the medical management of CF CRS and determine how to best identify, diagnose, and manage CF CRS. Ultimately, the treatment of these patients requires a multi-disciplinary approach involving the pulmonologist and otolaryngologist.

PMID: 30813317 [PubMed]

The Changing Prevalence of Lower Airway Infections in Young Children with Cystic Fibrosis.

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

Authors: Breuer O, Schultz A, Turkovic L, de Klerk N, Keil AD, Brennan S, Harrison J, Robertson C, Robinson PJ, Sly PD, Ranganathan S, Stick SM, Caudri D, AREST CF

Abstract
RATIONALE: Historical studies suggest that airway infection in cystic fibrosis (CF) initiates with Staphylococcus aureus and Haemophilus influenzae with later emergence of Pseudomonas aeruginosa. Aspergillus species are regarded as relatively infrequent, late occurring infections.
OBJECTIVES: To assess the prevalence and change in prevalence of early lower airway infections in a modern cohort of children with CF.
METHODS: All infants diagnosed with CF after newborn screening, participating in the AREST-CF cohort study between 2000-2018, were included. Participants prospectively underwent bronchoalveolar lavage (BAL) at 3-6 months,1 year and annually up to 6 years of age. Lower airway infection prevalence was described. Changes in prevalence patterns were assessed longitudinally using generalized estimating equations controlling for age and repeated visits.
MEASUREMENTS AND MAIN RESULTS: A total of 380 infants underwent 1,759 BALs. The overall prevalence and median age of first acquisition of the most common infections were: S. aureus 11%, 2.5yrs, P. aeruginosa 8%, 2.4yrs, Aspergillus species 11%, 3.2yrs, H. influenzae 9%, 3.1yrs. During the study, a significant decrease in prevalence of P. aeruginosa (p<0.001) and S. aureus (p<0.001) was observed with significant change towards more aggressive treatment. Prevalence of Aspergillus infections did not significantly change (p=0.669).
CONCLUSION: Aspergillus species and P. aeruginosa are commonly present in the lower airways from infancy. The decrease in prevalence of P. aeruginosa and S. aureus since 2000, coinciding with more aggressive therapeutic approach, has resulted in Aspergillus becoming the most commonly isolated pathogen in young children. Further research is warranted to understand the implication of these findings.

PMID: 30811949 [PubMed - as supplied by publisher]

Enhancing the Expression of CFTR Using Antisense Molecules Against MicroRNA miR-145-5p.

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

Authors: Finotti A, Gasparello J, Fabbri E, Tamanini A, Corradini R, Dechecchi MC, Cabrini G, Gambari R

PMID: 30811944 [PubMed - as supplied by publisher]

Phenazine Antibiotic Inspired Discovery of Bacterial Biofilm-Eradicating Agents.

Chembiochem. 2019 Feb 27;:

Authors: Huigens Iii RW, Abouelhassan Y, Yang H

Abstract
Bacterial biofilms are surface-attached communities of slow-growing and non-replicating persister cells that demonstrate high levels of antibiotic tolerance. Biofilms occur in nearly 80% of infections and present unique challenges to our current arsenal of antibiotic therapies, all of which were initially discovered for their abilities to target rapidly-dividing, free-floating planktonic bacteria. Bacterial biofilms are credited as the underlying cause of chronic and recurring bacterial infections. Innovative approaches are required to identify new small molecules that operate through bacterial growth-independent mechanisms to effectively eradicate biofilms. One source of inspiration comes from within the lungs of young Cystic Fibrosis (CF) patients, who often endure persistent Staphylococcus aureus infections. As these CF patients age, Pseudomonas aeruginosa co-infects the lungs and utilize phenazine antibiotics to eradicate the established S. aureus infection. Our group has taken a special interest in this microbial competition strategy and we are investigating the potential of phenazine antibiotic-inspired compounds and synthetic analogues thereof to eradicate persistent bacterial biofilms. To discover new biofilm-eradicating agents, we have established an interdisciplinary research program involving synthetic medicinal chemistry, microbiology and molecular biology. From these efforts, we have identified a series of halogenated phenazines (HP) that potently eradicate bacterial biofilms and future work aims to translate these preliminary findings into groundbreaking clinical advances for the treatment of persistent biofilm infections.

PMID: 30811834 [PubMed - as supplied by publisher]

Expanding the phenotypic and genetic spectrum of Chinese patients with congenital absence of vas deferens bearing CFTR and ADGRG2 alleles.

Andrology. 2019 Feb 27;:

Authors: Yuan P, Liang ZK, Liang H, Zheng LY, Li D, Li J, Zhang J, Tian J, Lai LH, Zhang K, He ZY, Zhang QX, Wang WJ

Abstract
BACKGROUND: Congenital absence of vas deferens (CAVD) is a major cause of obstructive azoospermia. Mutations in CFTR and ADGRG2 are responsible for this disease. However, until now the genetic spectrum of the CFTR and ADGRG2 genes in Chinese population and the reasons of the differences from Caucasian cohorts were not clear.
OBJECTIVES: (i) To study the characteristic and functional consequences of CFTR and ADGRG2 mutations in Chinese CAVD patients. (ii) To describe the genetic spectrum of Chinese CAVD patients and explain the reasons of the differences from Caucasian cohorts and Chinese cystic fibrosis (CF) patients.
MATERIALS AND METHODS: Patients were screened for mutations in CFTR by Sanger sequencing. Patients with only one or no mutations were further investigated by multiplex ligation-dependent probe amplification analysis and direct sequencing of ADGRG2 gene. Bioinformatic analysis and structural modeling of proteins were performed.
RESULTS: A total of 28 mutations in CFTR were identified in 72 patients, of which five mutations were novel. Fifty-five patients (76.39%) had CFTR mutations but no indels, among which 80.00% CBAVD patients have at least one CFTR mutation and 66.67% CUAVD have at least one CFTR mutation. Two novel mutations (p.Lys818* and p.Arg1008Gln) in ADGRG2 were detected. These novel mutations were predicted to be damaging by bioinformatics and were absent or extremely low frequency among our controls and databases. The genetic spectrum of Chinese CAVD patients revealed that the most common mutations were c.1210-12T[5], p.Ile556Val and p.Gln1352His, the last two of which were predicted to reduce the domains' contacts and weaken adenosine triphosphate binding.
DISCUSSION AND CONCLUSION: This study illustrates the significance of all exon sequencing in CFTR and ADGRG2. A picture of the genetic spectrum of Chinese CAVD patients and the most common mutations can be described, which are different from Caucasian cohorts and Chinese CF patients.

PMID: 30811104 [PubMed - as supplied by publisher]