Air care: an 'aerography' of breath, buildings and bugs in the cystic fibrosis clinic.

Sociol Health Illn. 2020 May 13;:

Authors: Brown N, Buse C, Lewis A, Martin D, Nettleton S

Abstract
With significant relevance to the Covid-19 pandemic, this paper contributes to emerging 'aerographic' research on the socio-materialities of air and breath, based on an in-depth empirical study of three hospital-based lung infection clinics treating people with cystic fibrosis. We begin by outlining the changing place of atmosphere in hospital design from the pre-antibiotic period and into the present. We then turn to the first of three aerographic themes where air becomes a matter of grasping and visualising otherwise invisible airborne infections. This includes imagining patients located within bodily spheres or 'cloud bodies', conceptually anchored in Irigaray's thoughts on the 'forgetting of the air' and Sloterdijk's immunitary 'spherology' of the body. Our second theme explores the material politics of air, air conditioning, window design and the way competing 'air regimes' come into conflict with each other at the interface of buildings, bodies and the biotic. Our final theme attends to the 'cost of air', the aero-economic problem of atmospheric scarcity within modern high-rise, deep-density healthcare architectures.

PMID: 32406081 [PubMed - as supplied by publisher]

[Radicality of maxillary sinus surgery and size of the maxillary sinus ostium].

HNO. 2020 May 13;:

Authors: Sommer F, Hoffmann T, Lindemann J, Hahn J, Theodoraki MN

Abstract
Until the 1990s, radical sinus surgery was considered a standard procedure for maxillary sinus diseases, but it is no longer favored due to the high morbidity. Today, functional endoscopic sinus surgery (FESS) is considered the gold standard in sinus surgery. Modifications of surgical approaches also allow access to regions of the maxillary sinus that were previously difficult to reach. Depending on anatomy and pathology, different methods for widening the maxillary ostium can be selected. In type I sinusotomy, the natural ostium is widened dorsally by a maximum of 1 cm. Sinusotomy type II involves widening the natural ostium up to a maximum diameter of 2 cm. In sinusotomy type III, the natural ostium is widened dorsally to the posterior wall of the maxillary sinus and caudally to the base of the inferior turbinate. Beside the prelacrimal approach, more invasive approaches are the medial maxillectomy, in which the dorsal part of the inferior turbinate and the adjacent medial wall of the maxillary sinus is resected, as well as its modifications "mega antrostomy" and "extended maxillary antrostomy." Correct selection of the size of the maxillary sinus window is prerequisite for successful treatment and long-term postoperative success. Isolated purulent maxillary sinusitis can usually be treated by a type I sinusotomy. Sinusotomy type II addresses nasal polyps with involvement of the mucosa of the ostium, recurrent stenosis after previous surgery, chronic maxillary sinusitis due to cystic fibrosis, and purulent maxillary sinusitis with involvement of other adjacent sinuses. Sinusotomy type III is required for choanal polyps with attachment to the floor of the maxillary sinus, for extensive polyposis and fungal sinusitis, and for inverted papilloma. Particularly for (recurrent) disease and extensive interventions in the maxillary sinus, medial maxillectomy or a modification thereof may be required.

PMID: 32405682 [PubMed - as supplied by publisher]

CFTR variant testing: a technical standard of the American College of Medical Genetics and Genomics (ACMG).

Genet Med. 2020 May 14;:

Authors: Deignan JL, Astbury C, Cutting GR, Del Gaudio D, Gregg AR, Grody WW, Monaghan KG, Richards S, ACMG Laboratory Quality Assurance Committee

Abstract
Pathogenic variants in the CFTR gene are causative of classic cystic fibrosis (CF) as well as some nonclassic CF phenotypes. In 2001, CF became the first target of pan-ethnic universal carrier screening by molecular methods. The American College of Medical Genetics and Genomics (ACMG) recommended a core panel of 23 disease-causing variants as the minimal set to be included in pan-ethnic carrier screening of individuals with no family history of the disease, and these variants were usually assessed using targeted methods. The original recommendation also left open the option for laboratories to offer expanded CFTR variant panels; however, at the time, expanded CFTR variant panels were met with some controversy on the basis of the available technologies and the limited phenotypic knowledge of rare variants. Both of those aspects have now evolved, prompting this update of the ACMG technical standards for CFTR variant testing.

PMID: 32404922 [PubMed - as supplied by publisher]

Probiotics may be considered for children and adults with cystic fibrosis.

Evid Based Nurs. 2020 May 13;:

Authors: Hill J, Smith C, Clegg A

PMID: 32404349 [PubMed - as supplied by publisher]

Optimal management of acute kidney injury in critically ill patients with invasive fungal infections being treated with liposomal amphotericin B.

BMJ Case Rep. 2020 May 12;13(5):

Authors: Armstrong-James D, Koh M, Ostermann M, Cockwell P

Abstract
Critically ill patients are at risk of developing both acute kidney injury (AKI) and invasive fungal infections (IFIs). Prompt and efficient treatment of the IFI is essential for the survival of the patient. This article examines three distinct clinical situations where liposomal amphotericin B, a broad-spectrum antifungal agent, was successfully used in the setting of AKI. The first was Aspergillus infection in a 63-year-old man with bleeding oesophageal varices related to advanced liver disease. The second was gastrointestinal mucormycosis in a 74-year-old man who developed a small bowel obstruction following an autologous stem cell transplant for mantle cell lymphoma. The third was a Fusarium infection in a 32-year-old woman on immunosuppression for a bilateral lung transplant for cystic fibrosis. In all three cases, liposomal amphotericin B was required for urgent management of the patient's IFI. We discuss the rationale for treatment with a potentially nephrotoxic agent in this setting.

PMID: 32404321 [PubMed - in process]

Bronchial Infection due to Pseudomonas Aeruginosa in Patients with Cystic Fibrosis Diagnosed in Neonatal Screening.

Arch Bronconeumol. 2020 May 11;:

Authors: Ayats Vidal R, Bosque García M, García González M, Asensio de la Cruz Ó

PMID: 32404239 [PubMed - as supplied by publisher]

The Microbiome in Cystic Fibrosis Pulmonary Disease.

Genes (Basel). 2020 May 11;11(5):

Authors: Françoise A, Héry-Arnaud G

Abstract
Cystic fibrosis (CF) is a genetic disease with mutational changes leading to profound dysbiosis, both pulmonary and intestinal, from a very young age. This dysbiosis plays an important role in clinical manifestations, particularly in the lungs, affected by chronic infection. The range of microbiological tools has recently been enriched by metagenomics based on next-generation sequencing (NGS). Currently applied essentially in a gene-targeted manner, metagenomics has enabled very exhaustive description of bacterial communities in the CF lung niche and, to a lesser extent, the fungi. Aided by progress in bioinformatics, this now makes it possible to envisage shotgun sequencing and opens the door to other areas of the microbial world, the virome, and the archaeome, for which almost everything remains to be described in cystic fibrosis. Paradoxically, applying NGS in microbiology has seen a rebirth of bacterial culture, but in an extended manner (culturomics), which has proved to be a perfectly complementary approach to NGS. Animal models have also proved indispensable for validating microbiome pathophysiological hypotheses. Description of pathological microbiomes and correlation with clinical status and therapeutics (antibiotic therapy, cystic fibrosis transmembrane conductance regulator (CFTR) modulators) revealed the richness of microbiome data, enabling description of predictive and follow-up biomarkers. Although monogenic, CF is a multifactorial disease, and both genotype and microbiome profiles are crucial interconnected factors in disease progression. Microbiome-genome interactions are thus important to decipher.

PMID: 32403302 [PubMed - in process]

Novel bacterial topoisomerase inhibitors derived from isomannide.

Eur J Med Chem. 2020 Apr 28;199:112324

Authors: Okumu A, Lu Y, Dellos-Nolan S, Papa JL, Koci B, Cockroft NT, Gallucci J, Wozniak DJ, Yalowich JC, Mitton-Fry MJ

Abstract
A series of Novel Bacterial Topoisomerase Inhibitors (NBTIs) employing a linker derived from isomannide were synthesized and evaluated. Reduced hERG inhibition was observed compared to structure-matched analogues with different linkers, and compound 6 showed minimal proarrhythmic potential using an in vitro panel of cardiac ion channels. Compound 6 also displayed excellent activity against fluoroquinolone-resistant MRSA (MIC90 = 2 μg/mL) and other Gram-positive pathogens.

PMID: 32402932 [PubMed - as supplied by publisher]

COVID-19 in lung-transplanted and cystic fibrosis patients: Be careful.

J Cyst Fibros. 2020 May 10;:

Authors: Farfour E, Picard C, Beaumont L, Lesprit P, Ballester MC, Ackermann F, Galliot R, Colin de Verdiere S, Cerf C, Vasse M, Sars-Cov-2 Foch Hospital study group

PMID: 32402680 [PubMed - as supplied by publisher]

Highly Efficient Gene Editing of Cystic Fibrosis Patient-Derived Airway Basal Cells Results in Functional CFTR Correction.

Mol Ther. 2020 Apr 29;:

Authors: Suzuki S, Crane AM, Anirudhan V, Barillà C, Matthias N, Randell SH, Rab A, Sorscher EJ, Kerschner JL, Yin S, Harris A, Mendel M, Kim K, Zhang L, Conway A, Davis BR

Abstract
There is a strong rationale to consider future cell therapeutic approaches for cystic fibrosis (CF) in which autologous proximal airway basal stem cells, corrected for CFTR mutations, are transplanted into the patient's lungs. We assessed the possibility of editing the CFTR locus in these cells using zinc-finger nucleases and have pursued two approaches. The first, mutation-specific correction, is a footprint-free method replacing the CFTR mutation with corrected sequences. We have applied this approach for correction of ΔF508, demonstrating restoration of mature CFTR protein and function in air-liquid interface cultures established from bulk edited basal cells. The second is targeting integration of a partial CFTR cDNA within an intron of the endogenous CFTR gene, providing correction for all CFTR mutations downstream of the integration and exploiting the native CFTR promoter and chromatin architecture for physiologically relevant expression. Without selection, we observed highly efficient, site-specific targeted integration in basal cells carrying various CFTR mutations and demonstrated restored CFTR function at therapeutically relevant levels. Significantly, Omni-ATAC-seq analysis revealed minimal impact on the positions of open chromatin within the native CFTR locus. These results demonstrate efficient functional correction of CFTR and provide a platform for further ex vivo and in vivo editing.

PMID: 32402246 [PubMed - as supplied by publisher]

APPEAL-1: A multiple country European survey assessing the psychosocial impact of peanut allergy.

Allergy. 2020 May 13;:

Authors: DunnGalvin A, Blumchen K, Timmermans F, Regent L, Schnadt S, Podestà M, Sánchez Á, Couratier P, Feeney M, Hjorth B, Patel R, Lush T, Ryan R, Vereda A, Fernández-Rivas M, Fisher HR

Abstract
BACKGROUND: Peanut allergy (PA) is a common, potentially life-threatening, and typically lifelong condition with a significant burden of illness. However, information is lacking on how persons with PA (PwPA) and their caregivers perceive the psychosocial impact of living with PA. The Allergy to Peanuts imPacting Emotions And Life study 1 (APPEAL-1) survey, conducted across Europe, investigated the experience and impact of living with PA. Here, we report data evaluating the psychosocial impact of PA on PwPA and their caregivers.
METHODS: APPEAL-1 was an online survey conducted in 8 European countries. Representatives of 8 patient advocacy groups and 5 healthcare-research specialists developed the survey. Eligible respondent groups included: adults diagnosed with PA (self-report); parent/nonparent caregivers (proxy-report for a child with PA); and parent/nonparent caregivers (self-report of PA impact on themselves).
RESULTS: Of 1846 total study respondents, 419 were adults with PA (self-report); 546 were parents/ caregivers (proxy-report) ; 881 were parents/caregivers (self-report). Most respondents reported lifestyle restrictions regarding food (84-93%) and additional domains including parties and socializing, holiday activities and destinations, and taking public transport (53-89%). Approximately 40% rated themselves as "very" frustrated and "very" stressed. Two-thirds (65%) felt socially isolated; 43% were bullied. Less than half felt confident in knowing when to use an adrenaline autoinjector. Several intercountry differences were observed such as high levels of uncertainty and stress in respondents from Ireland, highest rates of anxiety in respondents from Germany, and social exclusion and isolation most common in respondents from France.
CONCLUSIONS: PA imposes an adverse psychosocial impact on patients and caregivers, leading to frustration, stress, and isolation. Attention to the impact of PA is needed in research and clinical practice to improve PA healthcare and public education programs.

PMID: 32400915 [PubMed - as supplied by publisher]

Improved Fmoc-solid-phase peptide synthesis of an extracellular loop of CFTR for antibody selection by the phage display technology.

J Pept Sci. 2020 May 12;:e3253

Authors: Ferreira VFC, Correia JDG, Farinha CM, Mendes F

Abstract
Cystic fibrosis (CF), a life-shortening genetic disease, is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that codes for the CFTR protein, the major chloride channel expressed at the apical membrane of epithelial cells. The development of an imaging probe capable of non-invasively detect CFTR at the cell surface could be of great advantage for the management of CF. With that purpose, we synthesized the first extracellular loop of CFTR protein (ECL1) through fluorenylmethyloxycarbonyl (Fmoc)-based microwave-assisted solid-phase peptide synthesis (SPPS), according to a reported methodology. However, aspartimide formation, a well-characterized side reaction in Fmoc-SPPS, prompted us to adopt a different side-chain protection strategy for aspartic acid residues present in ECL1 sequence. The peptide was subsequently modified via PEGylation and biotinylation, and cyclized through disulfide bridge formation, mimicking the native loop conformation in CFTR protein. Herein, we report improvements in the synthesis of the first extracellular loop of CFTR, including peptide modifications that can be used to improve antigen presentation in phage display for selection of novel antibodies against plasma membrane CFTR.

PMID: 32400108 [PubMed - as supplied by publisher]

Development of bacterial resistance during treatment with topical gentamicin for chronic rhinosinusitis in patients with cystic fibrosis and primary ciliary dyskinesis. Retrospective case series.

Otolaryngol Pol. 2020 Jan 28;74(3):33-40

Authors: Kisiel M, Sjölander I, Klar A, Asplund Stenkvist M, Laurell G

Abstract
BACKGROUND: The management of chronic rhinosinusitis (CRS) in patients with cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) is still a challenge. At our institution we have used gentamycin nasal spray, extemporaneously produced, for prophylactic treatment of moderate-to-severe CRS. The aim of this study was to investigate the gentamycin susceptibility of bacteria in sputum samples in CF and PCD patients treated for CRS.
METHODOLOGY: Patients with CF and PCD who were prescribed gentamycin nasal spray for CRS and had sputum bacterial cultures taken pre-treatment and followed-up at least once after ≥6 months were retrospectively included. Microbiological data were descriptively analysed in terms of bacterial species and resistance to gentamycin.
RESULTS: A case series of 17 CF and 12 PCD patients passed the inclusion criteria. Of those cases, three (18%) CF patients and one (8%) PCD patient developed resistance to gentamycin during treatment with gentamycin nasal spray. In all four cases, the resistant bacterial isolates were <i>P. aeruginosa</i>. Additionally, two CF patients already had <i>P. aeruginosa </i> isolates resistant to gentamycin in the pre-treatment culture. In further two CF patients, the multi-resistant <i>Burgdorferi cepacia </i>complex, including gentamycin resistance, was identified. <i>P. aeruginosa </i> and <i>S. aureus </i> in CF and <i>P. aeruginosa</i> and <i>H. influenza </i> in PCD were the predominant bacterial species.
CONCLUSIONS: The study showed that there was moderate incidence of gentamycin resistance in CF and PCD patients at our institution. However, further prospective studies are needed to confirm the outcomes.

PMID: 32398382 [PubMed - in process]

Morbidity and mortality in carriers of the cystic fibrosis mutation CFTR Phe508del in the general population.

Eur Respir J. 2020 May 12;:

Authors: Çolak Y, Nordestgaard BG, Afzal S

Abstract
Cystic fibrosis is caused by autosomal-recessive inheritance of a dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR), up to 90% due to Phe508del mutation in the CFTR gene. We tested the hypothesis that CFTR Phe508del carriers versus non-carriers in the general population have increased morbidity and mortality.We genotyped 108 035 randomly selected white Danish individuals aged 20-100 from the Copenhagen General Population Study for CFTR Phe508del (rs113993960). We assessed risk of chronic bronchitis and airflow limitation cross-sectionally, and overall survival and risk of bronchiectasis, lung cancer, pneumonia, chronic rhinosinusitis, airway bleeding, spontaneous pneumothorax, respiratory failure, acute and chronic pancreatitis, liver cirrhosis, ileus, gastric and colorectal cancer, and male infertility prospectively during up to 15 years follow-up (median:9 years). A single individual was excluded due to homozygosity for CFTR Phe508del and known cystic fibrosis. No other individuals had diagnosed cystic fibrosis at baseline examination or during follow-up.Among 108 034 individuals, 105 176(97%) were non-carriers and 2858(3%) were carriers, i.e. heterozygous for CFTR Phe508del. Overall survival was similar between carriers and non-carriers. Compared to non-carriers and multivariable adjusted, carriers had odds ratio of 1.31(95% confidence interval:1.16-1.48) for chronic bronchitis, hazard ratio of 1.88(1.03-3.45) for bronchiectasis, and hazard ratio of 1.52(1.12-2.08) for lung cancer. Carriers did not differ from non-carriers concerning lung function or any other morbidity outcomes as mentioned above.In the general population, carriers of CFTR Phe508del have a normal lifespan but an increased risk of chronic bronchitis by 1.3-fold, bronchiectasis by 1.9-fold, and lung cancer by 1.5-fold.

PMID: 32398304 [PubMed - as supplied by publisher]

Blood eosinophils predict inhaled fluticasone response in bronchiectasis.

Eur Respir J. 2020 May 12;:

Authors: Aliberti S, Sotgiu G, Blasi F, Saderi L, Posadas T, Martinez Garcia MA

PMID: 32398295 [PubMed - as supplied by publisher]

Cathepsin S: investigating an old player in lung disease pathogenesis, comorbidities, and potential therapeutics.

Respir Res. 2020 May 12;21(1):111

Authors: Brown R, Nath S, Lora A, Samaha G, Elgamal Z, Kaiser R, Taggart C, Weldon S, Geraghty P

Abstract
Dysregulated expression and activity of cathepsin S (CTSS), a lysosomal protease and a member of the cysteine cathepsin protease family, is linked to the pathogenesis of multiple diseases, including a number of conditions affecting the lungs. Extracellular CTSS has potent elastase activity and by processing cytokines and host defense proteins, it also plays a role in the regulation of inflammation. CTSS has also been linked to G-coupled protein receptor activation and possesses an important intracellular role in major histocompatibility complex class II antigen presentation. Modulated CTSS activity is also associated with pulmonary disease comorbidities, such as cancer, cardiovascular disease, and diabetes. CTSS is expressed in a wide variety of immune cells and is biologically active at neutral pH. Herein, we review the significance of CTSS signaling in pulmonary diseases and associated comorbidities. We also discuss CTSS as a plausible therapeutic target and describe recent and current clinical trials examining CTSS inhibition as a means for treatment.

PMID: 32398133 [PubMed - in process]

Exposure of Mycobacterium abscessus to Environmental Stress and Clinically Used Antibiotics Reveals Common Proteome Response among Pathogenic Mycobacteria.

Microorganisms. 2020 May 09;8(5):

Authors: Rojony R, Danelishvili L, Campeau A, Wozniak JM, Gonzalez DJ, Bermudez LE

Abstract
Mycobacterium abscessus subsp. abscessus (MAB) is a clinically important nontuberculous mycobacterium (NTM) causing pulmonary infection in patients such as cystic fibrosis and bronchiectasis. MAB is naturally resistant to the majority of available antibiotics. In attempts to identify the fundamental response of MAB to aerobic, anaerobic, and biofilm conditions (as it is encountered in patients) and during exposure to antibiotics, we studied bacterial proteome using tandem mass tag mass spectrometry sequencing. Numerous de novo synthesized proteins belonging to diverse metabolic pathways were found in anaerobic and biofilm conditions, including glycolysis/gluconeogenesis, tricarboxylic acid (TCA) cycle, oxidative phosphorylation, nitrogen metabolism, and glyoxylate and dicarboxylate metabolism. Upon exposure to amikacin and linezolid under stress environments, MAB displayed metabolic enrichment for glycerophospholipid metabolism and oxidative phosphorylation. By comparing proteomes of two significant NTMs, MAB and M. avium subsp. hominissuis, we found highly synthesized shared enzymes of oxidative phosphorylation, TCA cycle, glycolysis/gluconeogenesis, glyoxylate/dicarboxylate, nitrogen metabolism, peptidoglycan biosynthesis, and glycerophospholipid/glycerolipid metabolism. The activation of peptidoglycan and fatty acid biosynthesis pathways indicates the attempt of bacteria to modify the cell wall, influencing the susceptibility to antibiotics. This study establishes global changes in the synthesis of enzymes promoting the metabolic shift and enhancing the pathogen resistance to antibiotics within different environments.

PMID: 32397563 [PubMed]

Synthesis and Therapeutic Applications of Iminosugars in Cystic Fibrosis.

Int J Mol Sci. 2020 May 09;21(9):

Authors: Esposito A, D'Alonzo D, Fenza M, Gregorio E, Tamanini A, Lippi G, Dechecchi MC, Guaragna A

Abstract
Iminosugars are sugar analogues endowed with a high pharmacological potential. The wide range of biological activities exhibited by these glycomimetics associated with their excellent drug profile make them attractive therapeutic candidates for several medical interventions. The ability of iminosugars to act as inhibitors or enhancers of carbohydrate-processing enzymes suggests their potential use as therapeutics for the treatment of cystic fibrosis (CF). Herein we review the most relevant advances in the field, paying attention to both the chemical synthesis of the iminosugars and their biological evaluations, resulting from in vitro and in vivo assays. Starting from the example of the marketed drug NBDNJ (N-butyl deoxynojirimycin), a variety of iminosugars have exhibited the capacity to rescue the trafficking of F508del-CFTR (deletion of F508 residue in the CF transmembrane conductance regulator), either alone or in combination with other correctors. Interesting results have also been obtained when iminosugars were considered as anti-inflammatory agents in CF lung disease. The data herein reported demonstrate that iminosugars hold considerable potential to be applied for both therapeutic purposes.

PMID: 32397443 [PubMed - in process]

Immunomodulation in Cystic Fibrosis: Why and How?

Int J Mol Sci. 2020 May 08;21(9):

Authors: Giacalone VD, Dobosh BS, Gaggar A, Tirouvanziam R, Margaroli C

Abstract
Cystic fibrosis (CF) lung disease is characterized by unconventional mechanisms of inflammation, implicating a chronic immune response dominated by innate immune cells. Historically, therapeutic development has focused on the mutated cystic fibrosis transmembrane conductance regulator (CFTR), leading to the discovery of small molecules aiming at modulating and potentiating the presence and activity of CFTR at the plasma membrane. However, treatment burden sustained by CF patients, side effects of current medications, and recent advances in other therapeutic areas have highlighted the need to develop novel disease targeting of the inflammatory component driving CF lung damage. Furthermore, current issues with standard treatment emphasize the need for directed lung therapies that could minimize systemic side effects. Here, we summarize current treatment used to target immune cells in the lungs, and highlight potential benefits and caveats of novel therapeutic strategies.

PMID: 32397175 [PubMed - in process]

Mycobacterium abscessus and Antibiotic Resistance: Same As It Ever Was.

Clin Infect Dis. 2019 10 30;69(10):1687-1689

Authors: Griffith DE

PMID: 30689764 [PubMed - indexed for MEDLINE]