The social life of microbes in chronic infection.

Curr Opin Microbiol. 2020 Mar 04;53:44-50

Authors: Ibberson CB, Whiteley M

Abstract
Chronic infections place a significant burden on healthcare systems, requiring over $25 billion in treatment annually in the United States alone [1,2]. Notably, the majority of chronic infections, which include cystic fibrosis (CF), chronic wounds, otitis media, periodontitis, urinary tract infections, and osteomyelitis, are considered polymicrobial and are often recalcitrant to antibiotic treatment [1-9]. Although we know that diverse communities of microbes comprise these infections, how microbes interact and the impacts of these interactions on human disease are less understood. Here, we discuss recent advances in our understanding of how bacteria communicate in chronic infection, with a focus on Staphylococcus aureus and Pseudomonas aeruginosa, and we highlight outstanding questions and controversies in the field.

PMID: 32145635 [PubMed - as supplied by publisher]

[Cystic fibrosis and pregnancy:outcome, prognostic factors and obstetrical management].

Gynecol Obstet Fertil Senol. 2020 Mar 04;:

Authors: Fijean AL, Chamagne M, Billon Y, Morel O, Dahlhoff S

Abstract
As a result of improvements in life expectancy and therapies, increasing numbers of patients with cystic fibrosis become pregnant. The first studies were pessimistic and report adverse outcomes on the fetus and the mother. In the recent publications, long-term outcome for women with cystic fibrosis does not appear to be negatively impacted by pregnancy. Furthermore, the number of women successfully completing pregnancy continues to rise. The aim of this review is to assess the outcome of pregnancy in women with cystic fibrosis and the impact of pregnancy on the disease. It is hoped it will improve the counseling for pregnant women with cystic fibrosis and their obstetrical management.

PMID: 32145451 [PubMed - as supplied by publisher]

Selective Binding of HSC70 and its Co-Chaperones to Structural Hotspots on CFTR.

Sci Rep. 2020 Mar 06;10(1):4176

Authors: Baaklini I, Gonçalves CC, Lukacs GL, Young JC

Abstract
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) channel cause cystic fibrosis. Chaperones, including HSC70, DNAJA1 and DNAJA2, play key roles in both the folding and degradation of wild-type and mutant CFTR at multiple cellular locations. DNAJA1 and HSC70 promote the folding of newly synthesized CFTR at the endoplasmic reticulum (ER), but are required for the rapid turnover of misfolded channel at the plasma membrane (PM). DNAJA2 and HSC70 are also involved in the ER-associated degradation (ERAD) of misfolded CFTR, while they assist the refolding of destabilized channel at the PM. These outcomes may depend on the binding of chaperones to specific sites within CFTR, which would be exposed in non-native states. A CFTR peptide library was used to identify binding sites for HSC70, DNAJA1 and DNAJA2, validated by competition and functional assays. Each chaperone had a distinct binding pattern, and sites were distributed between the surfaces of the CFTR cytosolic domains, and domain interfaces known to be important for channel assembly. The accessibility of sites to chaperones will depend on the degree of CFTR folding or unfolding. Different folded states may be recognized by unique combinations of HSC70, DNAJA1 and DNAJA2, leading to divergent biological effects.

PMID: 32144307 [PubMed - as supplied by publisher]

A qualitative study of design stakeholders' views of developing and implementing a registry-based learning health system.

Implement Sci. 2020 Mar 06;15(1):16

Authors: Dixon-Woods M, Campbell A, Chang T, Martin G, Georgiadis A, Heney V, Chew S, Van Citters A, Sabadosa KA, Nelson EC

Abstract
BACKGROUND: New opportunities to record, collate, and analyze routine patient data have prompted optimism about the potential of learning health systems. However, real-life examples of such systems remain rare and few have been exposed to study. We aimed to examine the views of design stakeholders on designing and implementing a US-based registry-enabled care and learning system for cystic fibrosis (RCLS-CF).
METHODS: We conducted a two-phase qualitative study with stakeholders involved in designing, implementing, and using the RCLS-CF. First, we conducted semi-structured interviews with 19 program personnels involved in design and delivery of the program. We then undertook 11 follow-up interviews. Analysis of interviews was based on the constant comparative method, supported by NVivo software.
RESULTS: The organizing principle for the RCLS-CF was a shift to more partnership-based relationships between patients and clinicians, founded in values of co-production, and facilitated by technology-enabled data sharing. Participants proposed that, for the system to be successful, the data it collects must be both clinically useful and meaningful to patients and clinicians. They suggested that the prerequisites included a technological infrastructure capable of supporting data entry and joint decision-making in an accessible way, and a set of social conditions, including willingness from patients and clinicians alike to work together in new ways that build on the expertise of both parties. Follow-up interviews highlighted some of the obstacles, including technical challenges and practical constraints on refiguring relationships between clinicians and patients.
CONCLUSIONS: The values and vision underlying the RCLS-CF were shared and clearly and consistently articulated by design stakeholders. The challenges to realization were often not at the level of principle, but were both practical and social in character. Lessons from this study may be useful to other systems looking to harness the power of "big data" registries, including patient-reported data, for care, research, and quality improvement.

PMID: 32143678 [PubMed - as supplied by publisher]

Clinical, genetic and microbiological characterization of pediatric patients with cystic fibrosis in a public Hospital in Ecuador.

BMC Pediatr. 2020 Mar 06;20(1):111

Authors: Lascano-Vaca Y, Ortiz-Prado E, Gomez-Barreno L, Simbaña-Rivera K, Vasconez E, Lister A, Arteaga-Espinosa ME, Perez GF

Abstract
BACKGROUND: To carry out a complete clinical, pathological, genetic and microbiological characterization of pediatric patients with molecular confirmed cystic fibrosis (CF) attending the Carlos Andrade Marín Hospital (HCAM) within the study period.
METHODS: A cross-sectional analysis of the pediatric population with a confirmed diagnosis of CF disease who attended HCAM, one of the largest tertiary-level hospitals in Ecuador, between 2017 and 2018 was performed. All demographic, clinical and genetic variables were obtained from the electronic medical records (EMR) stored by the hospital.
RESULTS: Forty seven patients with CF were included in the study. Gender distribution was similar between male (48.9%, n = 23) and female patients (51.1%, n = 24). The Tiffeneau-Pinelli index (FEV1/FVC) changed significantly after nine months post-diagnosis (85.55 ± 13.26; p < 0.05). The most common pathogenic genetic variants were F508del, found in 52.78% of the cohort (n = 19); H609R, found in 36.11% (n = 13); g.204099A > C, found in 14.1% (n = 7), followed by G85E and the N1303K with 11.11% (n = 3) each.
CONCLUSIONS: To our best knowledge, this is the first study exploring the clinical, genetic and bacteriological profile of CF's patients in Ecuador. Within the cohort of patients, an important and unique genetic feature was characterized by the presence of the g.204099A > C and the c.206359C > A homozygous polymorphism as well as the presence of the H609R variant, a mutation only reported among Ecuadorians.

PMID: 32143663 [PubMed - as supplied by publisher]

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Aetiological agents for pulmonary exacerbations in children with cystic fibrosis: An observational study from a tertiary care centre in northern India.

Indian J Med Res. 2020 Jan;151(1):65-70

Authors: Arvind B, Medigeshi GR, Kapil A, Xess I, Singh U, Lodha R, Kabra SK

Abstract
Background & objectives: Pulmonary disease is the main cause of morbidity and mortality in cystic fibrosis (CF). The infection occurs with a unique spectrum of bacterial pathogens that are usually acquired in an age-dependent fashion. The objective of this study was to find out the aetiological agents in respiratory specimens from children with CF during pulmonary exacerbation and relate with demographic variables.
Methods: In this observational study, airway secretions from children (n=104) with CF presenting with pulmonary exacerbations were collected and tested for bacteria, fungi, mycobacteria and viral pathogens using appropriate laboratory techniques. The frequencies of isolation of various organisms were calculated and associated with various demographic profiles.
Results: Bacteria were isolated in 37 (35.5%) and viral RNA in 27 (29.3%) children. Pseudomonas was the most common bacteria grown in 31 (29.8%) followed by Burkholderia cepacia complex (Bcc) in three (2.8%) patients. Among viruses, Rhinovirus was the most common, identified in 16 (17.4%) samples followed by coronavirus in four (4.3%). Fungi and mycobacteria were isolated from 23 (22.1%) and four (3.8%) children, respectively. Aspergillus flavus was the most common fungus isolated in 13 (12.5%) children.
Interpretation & conclusions: Pseudomonas was the most common organism isolated during exacerbation. Non-tuberculous mycobacteria were not isolated, whereas infection with Bcc and Mycobacterium tuberculosis was observed, which could probably have a role in CF morbidity. Polymicrobial infections were associated with severe exacerbations.

PMID: 32134016 [PubMed - in process]

When gastroenterology meets radiology: air under right diaphragm.

Frontline Gastroenterol. 2020 Mar;11(2):176

Authors: Gurvits GE

PMID: 32133121 [PubMed]

Secretin-Stimulated Magnetic Resonance Imaging Reveals Variable Diagnostic Accuracy According to Etiology in Pancreatic Disease.

Pancreas. 2020 Mar 02;:

Authors: Engjom T, Tjora E, Erchinger F, Madzak A, Dimcevski G, Frøkjær JB, Haldorsen IS

Abstract
OBJECTIVES: Secretin-stimulated magnetic resonance imaging (s-MRI) is the best validated radiological modality assessing pancreatic exocrine secretion. In this prospective observational study, we compare the diagnostic accuracy of s-MRI for exocrine pancreatic failure due to different pancreatic diseases and healthy controls.
METHODS: We performed s-MRI in 21 cystic fibrosis (CF) patients, 78 patients with chronic pancreatitis (CP) and 20 healthy controls. Exocrine failure was defined by fecal elastase-1 of less than 200 μg/g or bicarbonate concentration from endoscopic secretin test of less than 80 mmol/L.
RESULTS: Eleven CF and 61 CP patients were exocrine insufficient. Insufficient CF patients had lower s-MRI volume output compared with all other groups (P < 0.05). Insufficient CP patients had reduced volume output compared with controls and sufficient CF (P < 0.05). Secretin-stimulated MRI yielded overall accuracy of 0.78 (95% confidence interval [CI], 0.70-0.86) for exocrine failure. When divided according to etiology, the test yielded accuracy of 0.95 (95% CI, 0.90-1) in CF and 0.73 (95% CI, 0.64-0.82) in CP.
CONCLUSIONS: The accuracy of s-MRI volume output measures to diagnose exocrine failure was higher in CF than in CP. Differences in s-MRI volume output in patients with exocrine failure may be due to different etiological and pathogenic mechanisms in CF and CP.

PMID: 32132505 [PubMed - as supplied by publisher]

Lung transplant referral practice patterns: a survey of cystic fibrosis physicians and general pulmonologists.

BMC Pulm Med. 2020 Mar 04;20(1):58

Authors: Bartley BL, Schwartz CE, Stark RB, Georgiopoulos AM, Friedman D, Richards CJ, Dorkin HL, Kinane TB, Neuringer IP, Yonker LM

Abstract
BACKGROUND: Many individuals with cystic fibrosis (CF) die from respiratory failure without referral for lung transplant. Physician practices that may expedite, delay, or preclude referral, are poorly understood.
METHODS: Two parallel, web-based surveys focusing on lung transplant referral triggers and barriers, as well as pre-referral evaluation, were emailed to pulmonologists practicing in the New England region. One questionnaire was sent to CF providers (n = 61), and the second to general pulmonary providers practicing at the same institutions (n = 61).
RESULTS: There were 43 (70%) responses to the CF provider survey, and 25 (41%) responses to the general pulmonary ('non-CF') provider survey. Primary reasons for CF providers to refer their patients included: rapidly declining lung function (91%) and a forced expiratory volume in 1 s (FEV1) below 30% predicted (74%). The greatest barriers to referral for both CF and non-CF providers included active tobacco use (65 and 96%, respectively, would not refer), and active alcohol or other substance use or dependence (63 and 80%). Furthermore, up to 42% of CF providers would potentially delay their referral if triple-combination therapy or other promising new, disease-specific therapy were anticipated. In general, non-CF providers perform a more robust pre-referral medical work-up, while CF providers complete a psychosocial evaluation in higher numbers. Across both groups, communication with lung transplant programs was reported to be inadequate.
CONCLUSIONS: Physician-level barriers to timely lung transplant referral exist and need to be addressed. Enhanced communication between lung transplant programs and pulmonary providers may reduce these barriers.

PMID: 32131782 [PubMed - in process]

Genome-wide analysis of MicroRNA-messenger RNA interactome in ex-vivo gill filaments, Anguilla japonica.

BMC Genomics. 2020 Mar 04;21(1):208

Authors: Ng HM, Ho JCH, Nong W, Hui JHL, Lai KP, Wong CKC

Abstract
BACKGROUND: Gills of euryhaline fishes possess great physiological and structural plasticity to adapt to large changes in external osmolality and to participate in ion uptake/excretion, which is essential for the re-establishment of fluid and electrolyte homeostasis. The osmoregulatory plasticity of gills provides an excellent model to study the role of microRNAs (miRs) in adaptive osmotic responses. The present study is to characterize an ex-vivo gill filament culture and using omics approach, to decipher the interaction between tonicity-responsive miRs and gene targets, in orchestrating the osmotic stress-induced responses.
RESULTS: Ex-vivo gill filament culture was exposed to Leibovitz's L-15 medium (300 mOsmol l- 1) or the medium with an adjusted osmolality of 600 mOsmol l- 1 for 4, 8 and 24 h. Hypertonic responsive genes, including osmotic stress transcriptional factor, Na+/Cl--taurine transporter, Na+/H+ exchange regulatory cofactor, cystic fibrosis transmembrane regulator, inward rectifying K+ channel, Na+/K+-ATPase, and calcium-transporting ATPase were significantly upregulated, while the hypo-osmotic gene, V-type proton ATPase was downregulated. The data illustrated that the ex-vivo gill filament culture exhibited distinctive responses to hyperosmotic challenge. In the hyperosmotic treatment, four key factors (i.e. drosha RNase III endonuclease, exportin-5, dicer ribonuclease III and argonaute-2) involved in miR biogenesis were dysregulated (P < 0.05). Transcriptome and miR-sequencing of gill filament samples at 4 and 8 h were conducted and two downregulated miRs, miR-29b-3p and miR-200b-3p were identified. An inhibition of miR-29b-3p and miR-200b-3p in primary gill cell culture led to an upregulation of 100 and 93 gene transcripts, respectively. Commonly upregulated gene transcripts from the hyperosmotic experiments and miR-inhibition studies, were overlaid, in which two miR-29b-3p target-genes [Krueppel-like factor 4 (klf4), Homeobox protein Meis2] and one miR-200b-3p target-gene (slc17a5) were identified. Integrated miR-mRNA-omics analysis revealed the specific binding of miR-29b-3p on Klf4 and miR-200b-3p on slc17a5. The target-genes are known to regulate differentiation of gill ionocytes and cellular osmolality.
CONCLUSIONS: In this study, we have characterized the hypo-osmoregulatory responses and unraveled the modulation of miR-biogenesis factors/the dysregulation of miRs, using ex-vivo gill filament culture. MicroRNA-messenger RNA interactome analysis of miR-29b-3p and miR-200b-3p revealed the gene targets are essential for osmotic stress responses.

PMID: 32131732 [PubMed - in process]

Lung cancer in a CF patient: combination of bad luck or is there more to say?

Acta Clin Belg. 2020 Mar 05;:1-2

Authors: Vekens K, Vincken S, Hanon S, Demuynck K, Stylemans D, Vanderhelst E

Abstract
Patients with cystic fibrosis have increased risk for gastrointestinal cancer, lymphoid leukemia and testicular carcinomas. Chronic inflammation does not seem to be the only contributing factor. Mutations and epigenetic alterations in the CFTR gene may alter susceptibility to develop cancer. Lung cancer is up to now not frequently observed in CF patients. In lung cancer patients without CF low CFTR expression is significantly associated with advanced staging, lymph node metastasis. As the management and life expectancy of patients with cystic fibrosis have improved substantially in recent years, we expect an increased number of these patients diagnosed with lung cancer. In addition, it is possible that they, as a result of CFTR-dysfunction, will present with more aggressive lung tumors. Treating cancer in CF patients is a challenge because of multi-organ involvement and chronic colonization by resistant pathogens. The effectiveness and safety of immunotherapy in this population needs to be further evaluated.

PMID: 32131717 [PubMed - as supplied by publisher]

Role of phosphodiesterase-4 inhibitors in chronic obstructive pulmonary disease.

Korean J Intern Med. 2020 Mar;35(2):276-283

Authors: Rhee CK, Kim DK

Abstract
Phosphodiesterase-4 inhibitors (PDE4Is) are potent anti-inf lammatory agents and roflumilast has been used to prevent acute exacerbation of chronic obstructive pulmonary disease (COPD). Roflumilast decreases neutrophil migration, restores cystic fibrosis transmembrane conductance regulator activity, and recovers glucocorticoid effects. A forced expiratory volume in 1 second of < 50%, a chronic bronchitis phenotype, high blood eosinophil levels, and a history of hospitalization are biomarkers for predicting responses to roflumilast. Adverse effects are common in clinical practice. An inhaled PDE4I has recently been developed and is under clinical trial. CHF6001 and RPL554 exhibit promise and may be future treatment options for COPD.

PMID: 32131571 [PubMed - in process]

Burkholderia cenocepacia H111 Produces a Water-Insoluble Exopolysaccharide in Biofilm: Structural Determination and Molecular Modelling.

Int J Mol Sci. 2020 Mar 02;21(5):

Authors: Bellich B, Jou IA, Caterino M, Rizzo R, Ravenscroft N, Fazli M, Tolker-Nielsen T, Brady JW, Cescutti P

Abstract
Biofilms are a multicellular way of life, where bacterial cells are close together and embedded in a hydrated macromolecular matrix which offers a number of advantages to the cells. Extracellular polysaccharides play an important role in matrix setup and maintenance. A water-insoluble polysaccharide was isolated and purified from the biofilm produced by Burkholderia cenocepacia strain H111, a cystic fibrosis pathogen. Its composition and glycosidic linkages were determined using Gas-Liquid Chromatography-Mass Spectrometry (GLC-MS) on appropriate carbohydrate derivatives while its complete structure was unraveled by 1D and 2D NMR spectroscopy in deuterated sodium hydroxide (NaOD) aqueous solutions. All the collected data demonstrated the following repeating unit for the water-insoluble B. cenocepacia biofilm polysaccharide: [3)-α-d-Galp-(1→3)-α-d-Glcp-(1→3)-α-d-Galp-(1→3)-α-d-Manp-(1→]n Molecular modelling was used, coupled with NMR Nuclear Overhauser Effect (NOE) data, to obtain information about local structural motifs which could give hints about the polysaccharide insolubility. Both modelling and NMR data pointed at restricted dynamics of local conformations which were ascribed to the presence of inter-residue hydrogen bonds and to steric restrictions. In addition, the good correlation between NOE data and calculated interatomic distances by molecular dynamics simulations validated potential energy functions used for calculations.

PMID: 32131450 [PubMed - in process]

Antibacterial and Antivirulence Activity of Glucocorticoid PYED-1 against Stenotrophomonas maltophilia.

Antibiotics (Basel). 2020 Mar 02;9(3):

Authors: Esposito A, Vollaro A, Esposito EP, D'Alonzo D, Guaragna A, Zarrilli R, De Gregorio E

Abstract
Stenotrophomonas maltophilia, an environmental Gram-negative bacterium, is an emerging nosocomial opportunistic pathogen that causes life-threatening infections in immunocompromised patients and chronic pulmonary infections in cystic fibrosis patients. Due to increasing resistance to multiple classes of antibiotics, S. maltophilia infections are difficult to treat successfully. This makes the search for new antimicrobial strategies mandatory. In this study, the antibacterial activity of the heterocyclic corticosteroid deflazacort and several of its synthetic precursors was tested against S. maltophilia. All compounds were not active against standard strain S. maltophilia K279a. The compound PYED-1 (pregnadiene-11-hydroxy-16α,17α-epoxy-3,20-dione-1) showed a weak effect against some S. maltophilia clinical isolates, but exhibited a synergistic effect with aminoglycosides. PYED-1 at sub-inhibitory concentrations decreased S. maltophilia biofilm formation. Quantitative real-time polymerase chain reaction (RT-qPCR) analysis demonstrated that the expression of biofilm- and virulence- associated genes (StmPr1, StmPr3, sphB, smeZ, bfmA, fsnR) was significantly suppressed after PYED-1 treatment. Interestingly, PYED-1 also repressed the expression of the genes aph (3´)-IIc, aac (6´)-Iz, and smeZ, involved in the resistance to aminoglycosides.

PMID: 32131413 [PubMed]

Cost of precision medicine at a referral center for cystic fibrosis.

J Bras Pneumol. 2020 Mar 02;46(2):e20190308

Authors: Marson FAL

PMID: 32130336 [PubMed - as supplied by publisher]

Airway submucosal glands from cystic fibrosis swine suffer from abnormal ion transport across the serous acini, collecting duct and ciliated duct.

Am J Physiol Lung Cell Mol Physiol. 2020 Mar 04;:

Authors: Luan X, Tam JS, Jagadeeshan S, Grishchenko N, Hassan N, Gioino P, Shipley AM, Machen TE, Ianowski JP

Abstract
The human airway is protected by an efficient innate defence mechanism that requires healthy secretion of airway surface liquid (ASL) to clear pathogens from the lungs. Most of the ASL in the upper airway is secreted by submucosal glands. In cystic fibrosis (CF), the function of airway submucosal glands is abnormal, and these abnormalities are attributed to anomalies in ion transport across the epithelia lining the different sections of the glands that function coordinately to produce the ASL. However, the ion transport properties of most of the anatomical regions of the gland have never been measured, and there is controversy regarding which segments express CFTR. This makes it difficult to determine the glandular abnormalities that may contribute to CF lung disease. Using a non-invasive, extracellular self-referencing ion selective electrode technique, we characterized ion transport properties in all four segments of submucosal glands from wild-type and CFTR-/- swine. In wild-type airways the serous acini, mucus tubules, and collecting ducts secrete Cl- and Na+ into the lumen in response to carbachol and forskolin stimulation. The ciliated duct also transports Cl- and Na+ but in the opposite direction, i.e. reabsorption from the ASL, which may contribute to lowering Na+ and Cl- activities in the secreted fluid. In CFTR-/- airways the serous acini, collecting ducts, and ciliated ducts fail to transport ions after forskolin stimulation, resulting in the production of smaller volumes of ASL with normal Cl-, Na+ and K+ concentration.

PMID: 32130033 [PubMed - as supplied by publisher]

Outcome according to subspecies following lung transplantation in cystic fibrosis paediatric patients infected with mycobacterium abscessus.

Transpl Infect Dis. 2020 Mar 04;:e13274

Authors: Kavaliunaite E, Harris KA, Aurora P, Dixon G, Shingadia D, Muthialu N, Spencer H

Abstract
BACKGROUND: Mycobacterium abscessus infection has been associated with variable outcomes following lung transplantation. M. abscessus comprises three subspecies (M. abscessus subsp abscessus, M. abscessus subsp massiliense, and M. abscessus subsp bolletii). We investigated whether lung transplantation outcome in cystic fibrosis (CF) patients in a single centre was related to the M. abscessus subspecies and genetic cluster.
METHODS: CF patients with chronic M. abscessus infection transplanted at Great Ormond Street Hospital between 2004 and 2017 were retrospectively examined. All M. abscessus isolates were identified to subspecies level by polymerase chain reaction (PCR) and sequencing. Genetic cluster was determined by variable number tandem repeat (VNTR) profiling and whole genome sequencing (WGS), sequence type (ST) inferred from WGS.
RESULTS: 13 patients with chronic M. abscessus infection underwent heart/lung or lung transplantation. Subspecies identification showed n=1 with M. abscessus bolletii, n=5 with M. abscessus massiliense and n=7 with M. abscessus abscessus infection. Eight (62%) patients (one with M.abscessus massiliense and 7 with M. abscessus abscessus) died post lung transplant. The patient with M. abscessus bolletii and three patients with M. abscessus massiliense did well post-transplant. One patient with M. abscessus massiliense is receiving on-going treatment.
CONCLUSIONS: Dramatically worse outcomes are observed in patients infected with M. abscessus subspecies abscessus, the majority of whom were infected with ST-1 and ST-26 strains. Patients infected with other M. abcsessus strains can have acceptable outcomes.

PMID: 32129923 [PubMed - as supplied by publisher]

Predictive value of computed tomography scoring systems evolution in adults with cystic fibrosis.

Eur Radiol. 2020 Mar 03;:

Authors: Zorzo C, Caballero P, Diab L, Pastor MT, Gómez-Punter RM, Girón RM

Abstract
OBJECTIVES: To assess whether the evolution of two consecutive high-resolution computed tomography (HRCT) scores in patients with cystic fibrosis (CF) has prognostic value.
METHODS: A longitudinal retrospective study was performed to research adult patients with CF. Two consecutive HRCT studies were scored using Bhalla and Brody II scoring scales by two senior radiologists. Annual scoring changes for each scale were calculated and correlated with annual FEV1% decline, with pulmonary exacerbations and number of antibiotic treatments.
RESULTS: We selected sixty-four adult patients. The median interval between the two HRCTs was 3.88 ± 1.59 years. The mean spirometric values showed dynamic lung volumes lower than the general population; globally, there was a worsening of respiratory function over time. The change in the annual HRCT scores was positive on both scales, indicating a worse structural situation over time. The Brody II scale annual change showed a significant statistical correlation with a decline in the annual FEV1%, exacerbations and number of oral antibiotic treatments. In contrast, for the Bhalla scale, the relationship was moderately inverse with exacerbations and with the number of oral treatments. No statistically significant relationships were found for the change in the annual FEV1% and exacerbations or number of antibiotic treatments. The interobservational and intraobservational agreements were very strong in both scales.
CONCLUSIONS: The annual evolution of the Brody II HRCT scoring system demonstrated a predictive value and correlated with FEV1% decline, pulmonary exacerbations and oral antibiotic treatments.
KEY POINTS: • HRCT evolution has prognostic value in cystic fibrosis. • Temporal evolution for the Brody II score is useful for clinical follow-up. • Brody II score changes correlate with FEV1% decline, pulmonary exacerbations and number of antibiotic treatments.

PMID: 32128619 [PubMed - as supplied by publisher]

Discovery of a picomolar potency pharmacological corrector of the mutant CFTR chloride channel.

Sci Adv. 2020 Feb;6(8):eaay9669

Authors: Pedemonte N, Bertozzi F, Caci E, Sorana F, Di Fruscia P, Tomati V, Ferrera L, Rodríguez-Gimeno A, Berti F, Pesce E, Sondo E, Gianotti A, Scudieri P, Bandiera T, Galietta LJV

Abstract
F508del, the most frequent mutation causing cystic fibrosis (CF), results in mistrafficking and premature degradation of the CFTR chloride channel. Small molecules named correctors may rescue F508del-CFTR and therefore represent promising drugs to target the basic defect in CF. We screened a carefully designed chemical library to find F508del-CFTR correctors. The initial active compound resulting from the primary screening underwent extensive chemical optimization. The final compound, ARN23765, showed an extremely high potency in bronchial epithelial cells from F508del homozygous patients, with an EC50 of 38 picomolar, which is more than 5000-fold lower compared to presently available corrector drugs. ARN23765 also showed high efficacy, synergy with other types of correctors, and compatibility with chronic VX-770 potentiator. Besides being a promising drug, particularly suited for drug combinations, ARN23765 represents a high-affinity probe for CFTR structure-function studies.

PMID: 32128418 [PubMed - in process]