Average rate of lung function decline in adults with cystic fibrosis in the United Kingdom: Data from the UK CF registry.

J Cyst Fibros. 2020 May 04;:

Authors: Caley L, Smith L, White H, Peckham DG

Abstract
BACKGROUND: Rate of change in lung function is used as a measure of disease progression and a predictor of mortality in individuals with cystic fibrosis (CF). The aim of this study was to determine the national rate of decline in percent predicted Forced Expiratory Volume in 1 second (ppFEV1) in adults in the UK accounting for age, sex and pancreatic status.
METHODS: Data on ppFEV1 for adults with CF, excluding those post lung transplantation, was extracted from the UK CF registry between 2015 and 2017. Multilevel modelling was conducted to calculate the annual rate of change in ppFEV1 accounting for age, sex and pancreatic status.
RESULTS: Overall annual ppFEV1 decline was -1.52% (95% CI: -1.66 to -1.38%) and -0.55% (95% CI: -0.86 to -0.23%) in pancreatic insufficient (PI) and sufficient (PS) adults respectively. In PI individuals, females had a greater rate of decline in ppFEV1. There were differences between age groups. The fastest rate of decline was observed in the 18-28 years group, declining -1.76% (95% CI: -2.06 to -1.46) and -1.61% (95% CI: -1.91 to -1.31) per year in PI females and males respectively. The pattern between the sexes and age categories was more inconsistent in the PS group.
CONCLUSIONS: The average annual rates of decline in lung function in adults with CF in the UK are similar to reports from other large international cohorts. Pancreatic status has a marked impact on average rate of decline. Younger adults, especially females, have a faster rate of decline and need close monitoring.

PMID: 32381400 [PubMed - as supplied by publisher]

Royal Society of Medicine Cystic Fibrosis Symposium 2019.

Paediatr Respir Rev. 2020 Apr 15;:

Authors: Jones AM

PMID: 32381344 [PubMed - as supplied by publisher]

End-of-Life Care in Cystic Fibrosis: Comparing Provider Practices Based on Lung Transplant Candidacy.

J Palliat Med. 2020 May 07;:

Authors: Lange AV, Rueschhoff A, Terauchi S, Cohen L, Reisch J, Jain R, Finklea JD

Abstract
Background: The optimal timing to introduce palliative care (PC) and end-of-life (EOL) conversations into the lives of people with cystic fibrosis (CF) has not been established. Objective: Compare EOL care practices for people with CF who died without a lung transplant (LT), are living without an LT, and those who received an LT. Design: Retrospective chart review. Setting/Subjects: People with CF who received care from 2012 to 2017 at the University of Texas Southwestern Medical Center. Measurements: Primary outcomes were (1) EOL discussion with a pulmonologist, (2) time of EOL discussion before death or LT, (3) evaluation by PC, and (4) documentation of advanced directive or medical power of attorney. Results: Twenty-three patients died without LT, 40 patients received an LT, and 222 were living without an LT. Among LT recipients, 10% had EOL conversations compared with 74% of deceased patients and 5% of living patients without LT (p = 0.001). Among deceased patients, 39% had EOL conversations more than six months before death, while 5% of transplanted patients had EOL conversation more than six months before LT (p < 0.001). Deceased patients were more likely to have seen PC (57%) than either patients who received LT (2%) or those living without LT (3%, p = 0.0001). Conclusions: Patients who died without LT were more likely to have seen PC and had an EOL conversation than patients who received LT or who are living without LT. Further research should explore the optimal timing to discuss EOL care and the best timing to involve PC.

PMID: 32380886 [PubMed - as supplied by publisher]

Regulation of TMEM16A by CK2 and Its Role in Cellular Proliferation.

Cells. 2020 May 05;9(5):

Authors: Pinto MC, Schreiber R, Lerias J, Ousingsawat J, Duarte A, Amaral M, Kunzelmann K

Abstract
Casein kinase 2 (CK2) is a highly ubiquitous and conserved serine/threonine kinase that forms a tetramer consisting of a catalytic subunit (CK2α) and a regulatory subunit (CK2β). Despite being ubiquitous, CK2 is commonly found at higher expression levels in cancer cells, where it inhibits apoptosis, and supports cell migration and proliferation. The Ca2+-activated chloride channel TMEM16A shows similar effects in cancer cells: TMEM16A increases cell proliferation and migration and is highly expressed in squamous cell carcinoma of the head and neck (HNSCC) as well as other malignant tumors. A microscopy-based high-throughput screening was performed to identify proteins that regulate TMEM16A. Within this screen, CK2 was found to be required for proper membrane expression of TMEM16A. small interfering (si) RNA-knockdown of CK2 reduced plasma membrane expression of TMEM16A and inhibited TMEM16A whole cell currents in (cystic fibrosis bronchial epithelial) CFBE airway epithelial cells and in the head and neck cancer cell lines Cal33 and BHY. Inhibitors of CK2, such as TBB and the preclinical compound CX4549 (silmitasertib), also blocked membrane expression of TMEM16A and Ca2+-activated whole cell currents. siRNA-knockout of CK2 and its pharmacological inhibition, as well as knockdown or inhibition of TMEM16A by either niclosamide or Ani9, attenuated cell proliferation. Simultaneous inhibition of CK2 and TMEM16A strongly potentiated inhibition of cell proliferation. Although membrane expression of TMEM16A is reduced by inhibition of CK2, our data suggest that the antiproliferative effects by inhibition of CK2 are mostly independent of TMEM16A. Simultaneous inhibition of TMEM16A by niclosamide and inhibition of CK2 by silmitasertib was additive with respect to blocking cell proliferation, while cytotoxicity was reduced when compared to solely blockade of CK2. Therefore, parallel blockade TMEM16A by niclosamide may assist with anticancer therapy by silmitasertib.

PMID: 32380794 [PubMed - in process]

Is extracorporeal membrane oxygenation withdrawal a safe option after double-lung transplantation?

Ann Thorac Surg. 2020 May 04;:

Authors: Fessler J, Sage E, Roux A, Feliot E, Gayat E, Pirracchio R, Parquin F, Cerf C, Fischler M, Le Guen M

Abstract
BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is commonly used during double-lung transplantation. ECMO can be Planned or Unplanned, and used only during the procedure or extended postoperatively (Intraoperative or Extended). Our practice is to limit its use and duration as much as possible. We conducted this retrospective single-center study to assess prognoses of patients undergoing Unplanned-Intraoperative ECMO.
METHODS: From among 436 patients who underwent double-lung transplantation from 2012 to 2018, we excluded those who underwent bridge-to-transplantation, multiorgan transplantation, repeated transplantation during the study period, and cardiopulmonary bypass. Unplanned-Intraoperative ECMO group was compared to No-ECMO and Planned-Intraoperative ECMO groups.
RESULTS: Two hundred nine patients did not require ECMO, 77 underwent Unplanned-Intraoperative ECMO, and 14 underwent Planned-Intraoperative ECMO. One and three-year survival were lower in Unplanned-Intraoperative ECMO group than in No-ECMO group (p=0.043 and p=0.032, respectively). The only independent protective factor related to one-year mortality was history of cystic fibrosis (p=0.013). Lung allocation score (p=0.001), grade 3 pulmonary graft dysfunction at end-surgery status (p=0.014), and estimated intraoperative blood loss (p=0.031) were risk factors.
CONCLUSIONS: Patients who underwent Unplanned-Intraoperative ECMO showed poorer prognoses than patients who did not require ECMO. This finding may be explained by differences in initial condition severity, by long-term consequences of the intraoperative complications leading to ECMO pump implantation, or by flaws in our weaning protocol.

PMID: 32380057 [PubMed - as supplied by publisher]

Risks associated with animal-assisted intervention programs: A literature review.

Complement Ther Clin Pract. 2020 May;39:101145

Authors: Dalton KR, Waite KB, Ruble K, Carroll KC, DeLone A, Frankenfield P, Serpell JA, Thorpe RJ, Morris DO, Agnew J, Rubenstein RC, Davis MF

Abstract
The benefits of animal-assisted interventions (AAI), to utilize companion animals as an adjunctive treatment modality, is well-established and a burgeoning research field. However, few studies have evaluated the potential hazards of these programs, such as the potential for therapy animals to transfer hospital-associated pathogens between individuals and the hospital environment. Here we review the current literature on the possible risks of hospital-based AAI programs, including zoonotic pathogen transmission. We identified twenty-nine articles encompassing reviews of infection control guidelines and epidemiological studies on zoonotic pathogen prevalence in AAI. We observed substantial heterogeneity in infection control practices among hospital AAI programs. Few data confirmed pathogen transmission between therapy animals and patients. Given AAI's known benefits, we recommend that future research utilize a One Health framework to evaluate microbial dynamics among therapy animals, patients, and hospital environments. This framework may best promote safe practices to ensure the sustainability of these valuable AAI programs.

PMID: 32379677 [PubMed - as supplied by publisher]

An organoid model to assay the role of CFTR in the human epididymis epithelium.

Cell Tissue Res. 2020 May 06;:

Authors: Leir SH, Yin S, Kerschner JL, Xia S, Ahmadi S, Bear C, Harris A

Abstract
Organoid cultures derived from primary human tissues facilitate the study of disease processes and the development of new therapeutics. Most men with cystic fibrosis (CF) are infertile due to defects in the epididymis and vas deferens; however, the causative mechanisms are still unclear. We used human epididymis epithelial cell (HEE) organoids and polarized HEE cell cultures to assay the CF transmembrane conductance regulator (CFTR) in the human epididymis. 3D HEE organoids and polarized 2D HEE cell cultures on membrane inserts were established from human caput epididymis. Single-cell RNA sequencing (scRNA-seq) was performed to map cell type-specific gene expression in the organoids. Using forskolin (FSK) to activate CFTR and inhibitor CFTRinh172 to block its activity, we assessed how CFTR contributes to organoid swelling and epithelial barrier function. The scRNA-seq data showed key caput epididymis cell types present in HEE organoid cultures. FSK at 10 μM induced HEE organoid swelling by 20% at 16 h, while 5 and 10 μM CFTRinh172 treatment significantly reduced HEE organoid size. In transepithelial resistance (TER) measurements, FSK reduced TER, while inhibition of CFTR increased TER; also, depletion of CFTR with specific siRNAs significantly increased TER. FSK treatment significantly increased the flux of 4-kDa but not 70-kDa dextran, suggesting activation of CFTR mainly enhances transcellular diffusion. We have demonstrated that CFTR contributes to the maintenance of HEE cell TER and that cultured HEE organoids are a useful model to investigate human epididymis function. These results facilitate progress in elucidating how CFTR-dependent cellular processes impair fertility in CF.

PMID: 32377875 [PubMed - as supplied by publisher]

A multinational report to characterise SARS-CoV-2 infection in people with cystic fibrosis.

J Cyst Fibros. 2020 Apr 25;:

Authors: Cosgriff R, Ahern S, Bell SC, Brownlee K, Burgel PR, Byrnes C, Corvol H, Cheng SY, Elbert A, Faro A, Goss CH, Gulmans V, Marshall BC, McKone E, Middleton PG, Ruseckaite R, Stephenson AL, Carr SB

Abstract
Information is lacking on the clinical impact of the novel coronavirus, SARS-CoV-2, on people with cystic fibrosis (CF). Our aim was to characterise SARS-CoV-2 infection in people with cystic fibrosis.
METHODS: Anonymised data submitted by each participating country to their National CF Registry was reported using a standardised template, then collated and summarised.
RESULTS: 40 cases have been reported across 8 countries. Of the 40 cases, 31 (78%) were symptomatic for SARS-CoV-2 at presentation, with 24 (60%) having a fever. 70% have recovered, 30% remain unresolved at time of reporting, and no deaths have been submitted.
CONCLUSIONS: This early report shows good recovery from SARS-CoV-2 in this heterogeneous CF cohort. The disease course does not seem to differ from the general population, but the current numbers are too small to draw firm conclusions and people with CF should continue to strictly follow public health advice to protect themselves from infection.

PMID: 32376098 [PubMed - as supplied by publisher]

Antibiotic resistance in Pseudomonas aeruginosa and adaptation to complex dynamic environments.

Microb Genom. 2020 Apr 29;:

Authors: Sommer LM, Johansen HK, Molin S

Abstract
Antibiotic resistance has become a serious threat to human health (WHO Antibacterial Agents in Clinical Development: an Analysis of the Antibacterial Clinical Development Pipeline, Including Tuberculosis. Geneva: World Health Organization; 2017), and the ability to predict antibiotic resistance from genome sequencing has become a focal point for the medical community. With this genocentric prediction in mind, we were intrigued about two particular findings for a collection of clinical Pseudomonas aeruginosa isolates (Marvig et al. Nature Genetics 2015;47:57-64; Frimodt-Møller et al. Scientific Reports 2018;8:12512; Bartell et al. Nature Communications 2019;10:629): (i) 15 out of 52 genes found to be frequently targeted by adaptive mutations during the initial infection stage of cystic fibrosis airways ('candidate pathoadaptive genes') (Marvig et al. Nature Genetics 2015;47:57-64) were associated with antibiotic resistance (López-Causapé et al. Fronters in Microbiology 2018;9:685; López-Causapé et al. Antimicrobal Agents and Chemotherapy 2018;62:e02583-17); (ii) there was a parallel lack of resistance development and linkage to the genetic changes in these antibiotic-resistance-associated genes (Frimodt-Møller et al. Scientific Reports 2018;8:12512; Bartell et al. Nature Communications 2019;10:629). In this review, we highlight alternative selective forces that potentially enhance the infection success of P. aeruginosa and focus on the linkage to the 15 pathoadaptive antibiotic-resistance-associated genes, thereby showing the problems we may face when using only genomic information to predict and inform about relevant antibiotic treatment.

PMID: 32375975 [PubMed - as supplied by publisher]

The Italian External Quality Assessment Program for Cystic Fibrosis Sweat Chloride Test: Does Active Participation Improve the Quality?

Int J Environ Res Public Health. 2020 May 04;17(9):

Authors: Salvatore M, Amato A, Floridia G, Censi F, Ferrari G, Tosto F, Padoan R, Raia V, Cirilli N, Castaldo G, Capoluongo E, Caruso U, Corbetta C, Taruscio D

Abstract
(1) Background: Diagnostic testing for cystic fibrosis (CF) is based on a sweat chloride test (SCT) considering the appropriate signs and symptoms of the disease and results of a gene mutation analysis. In 2014, the Istituto Superiore di Sanità (ISS) established a pilot Italian external quality assessment program for CF SCT (Italian EQA-SCT), which is now a third party service carried out by the ISS. (2) Methods: The ongoing scheme is prospective, enrollment is voluntary, and the payment of a fee is required. Results are shared through a dedicated web-facility. Assessment covers the analysis, interpretation, and reporting of results. (3) Results: Thirteen, fifteen, sixteen, and fifteen different laboratories, respectively, participated from 2015 to 2016 and from 2018 to 2019 in the Italian EQA-SCT scheme. Eleven different laboratories participated each year in all four rounds of the Italian EQA-SCT. (4) Conclusions: The overall results obtained from the laboratories participating constantly clearly show that their qualitative and quantitative performance improved significantly. This is due to the opportunity-after receiving the EQA results-to constantly review their performance and address any inconsistencies. We firmly believe that participation in the EQA program will improve the quality of participating laboratories and that EQA participation should become mandatory as a fundamental requirement for laboratory accreditation.

PMID: 32375358 [PubMed - in process]

General Asymmetric Synthesis of Densely Functionalized Pyrrolidines via Endo-Selective [3+2] Cycloaddition of β-Quaternary-Substituted Nitroalkenes and Azomethine Ylides.

J Org Chem. 2020 May 06;:

Authors: Greszler SN, Zhao G, Buchman M, Searle XB, Liu B, Voight EA

Abstract
A scalable endo-selective synthesis of 2,3,4,5-tetrasubstituted pyrrolidines via cycloaddition of nitroalkenes and azome-thine ylides is reported using a P,N-type ferrocenyl ligand and [Cu(OTf)]2·C6H6. The robust method is tolerant of a wide range of functionalities, including rarely-reported quaternary nitroalkene substitution and heteroaromatic and hindered ortho-substituted arenes on the azomethine ylide. Subsequent transformations highlight the utility of the method in the synthesis of densely-functionalized small molecules suitable for fragment-based drug discovery and the cystic fibrosis C2-corrector clinical candidate ABBV-3221.

PMID: 32374998 [PubMed - as supplied by publisher]

Airway Remodeling in Ferrets with Cigarette Smoke Induced COPD using µCT Imaging.

Am J Physiol Lung Cell Mol Physiol. 2020 May 06;:

Authors: Stanford D, Kim H, Bodduluri S, LaFontaine J, Byzek SA, Schoeb TR, Harris ES, Nath HP, Bhatt SP, Raju SV, Rowe SM

Abstract
RATIONALE: Structural changes to airway morphology such as increased bronchial wall thickness (BWT) and airway wall area are cardinal features of chronic obstructive pulmonary disease (COPD). Ferrets are a recently established animal model uniquely exhibiting similar clinical and pathological characteristics of COPD as humans, including chronic bronchitis.
OBJECTIVES: Develop a µCT method for evaluating structural changes to the airways in ferrets, and assess whether the effects of smoking induce changes consistent with chronic bronchitis in humans.
METHODS: Ferrets were exposed to mainstream cigarette smoke or air control twice daily for 6 months. µCT was conducted in vivo at 6 months; a longitudinal cohort was imaged monthly. Manual measurements of BWT, luminal diameter (LD), and BWT:LD ratio were conducted, and confirmed by a semi-automated algorithm. The square root of bronchial wall area (WA) vs. luminal perimeter was determined on an individual ferret basis.
MEASUREMENTS AND MAIN RESULTS: Smoke exposed ferrets reproducibly demonstrated 34% increased BWT (P<0.001); along with increased LD, and BWT:LD ratio vs. air controls. Regression indicated the effect of smoking on BWT persisted despite controlling for covariates. Semi-automated measurements replicated findings. WA for the theoretical median airway luminal perimeter of 4 mm (Pi4) was elevated 4.4% in smoke exposed ferrets (P=0.015). Increased BWT and Pi4 developed steadily over time.
CONCLUSIONS: µCT-based airway measurements in ferrets are feasible and reproducible. Smoke exposed ferrets develop increased BWT and Pi4, changes similar to humans with chronic bronchitis. µCT can be used as a significant translational platform to measure dynamic airway morphological changes.

PMID: 32374671 [PubMed - as supplied by publisher]

Novel Therapy of Bicarbonate, Glutathione and Ascorbic Acid Improves Cystic Fibrosis Mucus Transport.

Am J Respir Cell Mol Biol. 2020 May 06;:

Authors: Adewale AT, Falk Libby E, Fu L, Lenzie A, Boitet ER, Birket SE, Petty CF, Johns JD, Mazur M, Tearney GJ, Copeland D, Durham C, Rowe SM

Abstract
Defective airway mucus clearance is a defining characteristic of CF lung disease, and improvements to current mucolytic strategies are needed. Novel approaches targeting a range of contributing mechanisms are in various stages of preclinical and clinical development. ARINA-1 is a new, nebulized product comprised of ascorbic acid, glutathione, and bicarbonate. Using micro-optical coherence tomography, we tested the effect of ARINA-1 on central features of mucociliary clearance in F508del/F508del primary human bronchial epithelial cells to assess its potential as a mucoactive therapy in CF. We found that ARINA-1 significantly augmented mucociliary transport (MCT) rates, both alone and with CFTR modulator therapy, whereas airway hydration and ciliary beating were largely unchanged compared to PBS vehicle control. Analysis of mucus reflectivity and particle tracking microrheology indicated that ARINA-1 restores mucus clearance by principally reducing mucus layer viscosity. The combination of bicarbonate and glutathione elicited increases to MCT rate comparable to those seen with ARINA-1, indicating the importance of this interaction to the impact of ARINA-1 on mucus transport; this effect was not recapitulated with bicarbonate alone or bicarbonate combined with ascorbic acid. Assessment of CFTR chloride transport revealed an increase in CFTR-mediated chloride secretion in response to ARINA-1 in CFBE41o- cells expressing wild-type CFTR, driven by CFTR activity stimulation by ascorbate. This response was absent in CFBE41o- F508del cells treated with VX-809 and primary HBE cells, implicating CFTR-independent mechanisms for the effect of ARINA-1 on CF mucus. Together, these studies indicate that ARINA-1 is a novel potential therapy for the treatment of impaired mucus clearance in CF.

PMID: 32374624 [PubMed - as supplied by publisher]

Cystic fibrosis transmembrane conductance receptor modulator therapy in cystic fibrosis, an update.

Curr Opin Pediatr. 2020 Jun;32(3):384-388

Authors: Egan ME

Abstract
PURPOSE OF REVIEW: Cystic fibrosis transmembrane conductance receptor (CFTR) modulators are a new class of drugs that treat the underlying cause of cystic fibrosis. To date, there are four approved medications, which are mutation-specific. Although the number of mutations that respond to these agents is expanding, effective CFTR modulators are not available to all cystic fibrosis patients. The purpose of this article is to review the approved CFTR modulators and discuss the mutations that can be treated with these agents, as well as, review the long-term benefits of modulator therapy.
RECENT FINDINGS: More people with cystic fibrosis can be effectively treated with CFTR modulators. The new, highly effective triple therapy, elexacaftor/tezacaftor/ivacaftor is indicated for more than 90% of patients with cystic fibrosis and ivacaftor is now approved for children as young as 6 months of age with 1 of 30 CFTR mutations. Long-term use of modulator therapy is associated with fewer pulmonary exacerbations, maintenance of lung function, improved weight gain, and quality of life.
SUMMARY: CFTR modulators are the first therapies developed to treat the underlying defect in cystic fibrosis. Their use is associated with preserved lung function and improved health in patients with cystic fibrosis.

PMID: 32374578 [PubMed - as supplied by publisher]

Patient-Reported Outcome Measures in Cystic Fibrosis: Protocol for a Systematic Review.

JMIR Res Protoc. 2020 May 06;9(5):e15467

Authors: Ratnayake I, Ahern S, Ruseckaite R

Abstract
BACKGROUND: Patients with cystic fibrosis (CF) can struggle with burdensome symptoms and treatment regimens that negatively affect every aspect of their life. As physiological parameters can fail to capture these complications, the assessment of health-related quality of life (HRQOL) has gained prominence. HRQOL can be measured using standardized patient questionnaires called patient-reported outcome measures (PROMs). The Australian Cystic Fibrosis Data Registry (ACFDR) collects clinical data on adult and pediatric patients with CF. The incorporation of PROMs into the ACFDR would enable monitoring of HRQOL trends, benchmarking of HRQOL outcomes, and support of HRQOL research in CF.
OBJECTIVE: Prior to incorporation of a PROM in the ACFDR, this systematic review was planned to evaluate whether any suitable PROMs are currently being used for CF.
METHODS: This systematic review will be conducted in compliance with the PRISMA-P (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols) guidelines. MEDLINE, EMBASE, Scopus, CINAHL (Cumulative Index of Nursing and Allied Health Literature), PsycINFO, and Cochrane Library databases were searched for articles published between January 2009 and February 2019 on the use of PROMs to measure HRQOL in adult and pediatric patients with CF. Study designs such as observational studies, reviews and validation studies were included. Studies describing randomized controlled trials, dissertations, books, guideline statements, and abstracts were excluded. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) risk of bias checklist was used to assess the methodological quality of included studies. A descriptive synthesis of the results will be undertaken in line with the outcomes of this study.
RESULTS: As of July 2019, the search has been conducted and 4530 records were screened. After two phases of screening, 97 studies were included in the final review and subjected to data extraction. Reviewers are currently in the process of critical appraisal.
CONCLUSIONS: This review will identify any PROM(s) that may be used to measure HRQOL in the ACFDR.
TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42019126931; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=126931.

PMID: 32374269 [PubMed - as supplied by publisher]

Synergistic interactions of cadmium-free quantum dots embedded in a photosensitised polymer surface: efficient killing of multidrug-resistant strains at low ambient light levels.

Nanoscale. 2020 May 06;:

Authors: Owusu EGA, Yaghini E, Naasani I, Parkin IP, Allan E, MacRobert AJ

Abstract
Cadmium-free quantum dots (QD) were combined with crystal violet photosensitising dye and incorporated into medical grade polyurethane via a non-covalent dipping process known as 'swell-encapsulation-shrink'. The antibacterial efficacy of the prepared quantum dot-crystal violet polyurethane substrates (QD + CV PU) was investigated under low power visible light illumination at similar intensities (500 lux) to those present in clinical settings. The antibacterial performance of QD + CV PU was superior to the constituent polymer substrates, eliminating ∼99.9% of an environmental P. aeruginosa strain, a clinical P. aeruginosa strain from a cystic fibrosis patient and a clinical E. coli strain. The nature of the reactive oxygen species (ROS) involved in antibacterial activity of the QD + CV PU surface was investigated using ROS inhibitors and time-resolved optical spectroscopy. The photo-physical interactions of the green-emitting QDs with CV lead to a combination of Type I and II electron transfer and energy transfer processes, with the highly potent ROS singlet oxygen playing a dominant role. This study is the first to demonstrate highly efficient synergistic killing of clinical and environmental strains of intrinsically resistant and multi-drug resistant Gram-negative bacteria using light-activated surfaces containing biocompatible cadmium-free QDs and crystal violet dye at ambient light levels.

PMID: 32373810 [PubMed - as supplied by publisher]

iPSC-Derived Intestinal Organoids from Cystic Fibrosis Patients Acquire CFTR Activity upon TALEN-Mediated Repair of the p.F508del Mutation.

Mol Ther Methods Clin Dev. 2020 Jun 12;17:858-870

Authors: Fleischer A, Vallejo-Díez S, Martín-Fernández JM, Sánchez-Gilabert A, Castresana M, Del Pozo A, Esquisabel A, Ávila S, Castrillo JL, Gaínza E, Pedraz JL, Viñas M, Bachiller D

Abstract
Cystic fibrosis (CF) is the main genetic cause of death among the Caucasian population. The disease is characterized by abnormal fluid and electrolyte mobility across secretory epithelia. The first manifestations occur within hours of birth (meconium ileus), later extending to other organs, generally affecting the respiratory tract. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR encodes a cyclic adenosine monophosphate (cAMP)-dependent, phosphorylation-regulated chloride channel required for transport of chloride and other ions through cell membranes. There are more than 2,000 mutations described in the CFTR gene, but one of them, phenylalanine residue at amino acid position 508 (p.F508del), a recessive allele, is responsible for the vast majority of CF cases worldwide. Here, we present the results of the application of genome-editing techniques to the restoration of CFTR activity in p.F508del patient-derived induced pluripotent stem cells (iPSCs). Gene-edited iPSCs were subsequently used to produce intestinal organoids on which the physiological activity of the restored gene was tested in forskolin-induced swelling tests. The seamless restoration of the p.F508del mutation resulted in normal expression of the mature CFTR glycoprotein, full recovery of CFTR activity, and a normal response of the repaired organoids to treatment with two approved CF therapies: VX-770 and VX-809.

PMID: 32373648 [PubMed]

Primary immunodeficiency disorders in children with Non-Cystic Fibrosis Bronchiectasis.

Eur Ann Allergy Clin Immunol. 2020 May 06;:

Authors: Cagdas D, Pehlivanturk Kyzylkan M, Tagiyev A, Emiralioglu N, Keleþ A, Yalcyn E, Dogru D, OzCelik U, Kiper N, Tezcan Y

Abstract
Summary: Introduction.Primary Immunodeficiency diseases(PID) are common in patients with non-cystic fibrosis bronchiectasis(NCFB). Our objective was to determine ratio/types of PID in NCFB. Patients.Seventy NCFB patients followed up in a two-year period were enrolled. Results.Median age was 14 years (min.-max., 6-30). Patients had their first pulmonary infection at a median age of 6 months(min.-max., 0.5-84), were diagnosed with bronchiectasis at about 9 years(114 months)(min.-max., 2-276)). Male/female ratio was 39/31; parental consanguinity, 38.6%. PID, primary ciliary dyskinesis (PCD), bronchiolitis obliterans, rheumatic/autoimmune diseases, severe congenital heart disease and tuberculosis were evaluated as the most common causes of NCFB. About 40% of patients (n=16) had bronchial hyperreactivity(BH) and asthma. Twenty-nine patients(41.4%) had a PID, and nearly all (n=28) had primary antibody deficiency, including patients with combined T and B cell deficiency. PID and non-PID groups did not differ according to gender, parental consanguinity, age at first pneumonia, age of onset of chronic pulmonary symptoms, bronchiectasis, presence of gastroesophageal reflux disease(GERD), bronchial hyperreactivity(BH) and asthma (p>0.05). Admission to immunology clinic was about 3 years later in PID compared with non-PID group(p less than 0.001). Five patients got molecular diagnosis, X-linked agammaglobulinemia(n=2), LRBA deficiency(n=1), RASGRP1 deficiency(n=1), MHC Class II deficiency(n=1). They were given monthly IVIG and HSCT was performed for three patients. Conclusions.PID accounted for about 40% of NCFB. Early diagnosis/appropriate treatment have impact on clinical course of a PID patient. Thus, follow-up in also immunology clinics should be a routine for patients who experience pneumonia in the first year of their lives and those with NCFB. Most patients with NCFB (84.28%) had their first pulmonary infection within the first year of their lives.

PMID: 32372587 [PubMed - as supplied by publisher]

Manifestations of pulmonary aspergillosis in pediatrics.

Curr Opin Pediatr. 2020 Jun;32(3):389-394

Authors: Chacko A, Moss RB

Abstract
PURPOSE OF REVIEW: Aspergillus spp. cause a clinical spectrum of disease with severity of disease dependent on degree of immune compromise, nature and intensity of inflammatory host response, and/or underlying lung disease. Chronic pulmonary aspergillosis encompasses a spectrum of diseases including aspergilloma, Aspergillus nodules, chronic cavitary pulmonary aspergillosis, chronic fibrosing pulmonary aspergillosis, and subacute invasive pulmonary aspergillosis. Allergic bronchopulmonary aspergillosis (ABPA) paradoxically is an immune hypersensitivity manifestation in the lungs that almost always occurs in the setting of underlying asthma or cystic fibrosis. These chronic Aspergillus conditions are now becoming more prevalent than invasive Aspergillus, thus it is important to be aware of the current literature of these conditions.
RECENT FINDINGS: High-level research assessing the clinical significance and treatment options of these chronic diseases are lacking. Recent literature suggests colonization is antecedent for local airway infection (Aspergillus bronchitis), chronic or allergic bronchopulmonary disease, or invasive and potentially disseminated disease. There have been few advances in assessment of treatment of ABPA.
SUMMARY: Research assessing the clinical significance and treatment options is currently needed.

PMID: 32371841 [PubMed - in process]

Keep cystic fibrosis patients out of the hospital.

Cleve Clin J Med. 2020 May 05;:

Authors: Dasenbrook E

Abstract
No specific data exists regarding management of patients with cystic fibrosis (CF) who are infected with COVID-19. Based on expert opinion, strategies for outpatient management include use of elexacaftor-tezacaftor-ivacaftor to reduce pulmonary exacerbations, telemedicine, adherence to prescribed regimens, prompt and aggressive treatment of CF exacerbations, and communication about COVID-19 with patients with CF. Strategies for inpatient management may vary due to special precautions to avoid the aerosolization of COVID-19 with the use of nebulized medications and other therapies.

PMID: 32371562 [PubMed - as supplied by publisher]