Effects of the SARS-CoV2-Lockdown on Pediatric Care in the Rhine-Main Area.

Klin Padiatr. 2021 Jan;233(1):31-36

Authors: Donath H, Zielen S, Wittekindt B, Klingebiel T, Graf J, Eckrich M, Walter C, Blümchen K

Abstract
BACKGROUND: The effects of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and lockdown on pediatric diseases and care are not well characterized in Germany.
PATIENTS AND METHODS: To investigate the effects of the lockdown on pediatric medical care in the Rhine-Main area, a survey asking 115 pediatricians and an analysis of the inpatient admissions at the Department for Children and Adolescents Goethe-University, Frankfurt in April 2020 compared to April 2019 was performed.
RESULTS: 65/115 (56.5%) pediatricians answered the survey. Pediatricians estimated the reduction of patient consultations in April 2020 vs. 2019 by 40% (median), however, according to their practice administration software, patient visits decreased by 30%. The median number of cases with the diagnosis J21 (acute bronchitis) were significantly less in April 2020 vs. April 2019 (50 vs. 10 cases per pediatrician; p<0.001). Simultaneously, hospital admissions decreased by 43.7% from 402 total cases in April 2019 to 226 cases in April 2020. Hospital admissions due to acute respiratory tract infections or asthma exacerbations as well as neonatal and oncological disorders were significantly reduced compared to the previous year (83.7; 38.1 and 22.1% respectively less to 2019).
CONCLUSION: The lockdown in April 2020 resulted in significantly fewer visits to pediatricians in general practice and hospital admissions, especially for acute respiratory tract infections. The health and economic consequences are discussed.

PMID: 33184805 [PubMed - indexed for MEDLINE]

Extracellular cyclic dinucleotides induce polarized responses in barrier epithelial cells by adenosine signaling.

Proc Natl Acad Sci U S A. 2020 11 03;117(44):27502-27508

Authors: Chang D, Whiteley AT, Bugda Gwilt K, Lencer WI, Mekalanos JJ, Thiagarajah JR

Abstract
Cyclic dinucleotides (CDNs) are secondary messengers used by prokaryotic and eukaryotic cells. In mammalian cells, cytosolic CDNs bind STING (stimulator of IFN gene), resulting in the production of type I IFN. Extracellular CDNs can enter the cytosol through several pathways but how CDNs work from outside eukaryotic cells remains poorly understood. Here, we elucidate a mechanism of action on intestinal epithelial cells for extracellular CDNs. We found that CDNs containing adenosine induced a robust CFTR-mediated chloride secretory response together with cAMP-mediated inhibition of Poly I:C-stimulated IFNβ expression. Signal transduction was strictly polarized to the serosal side of the epithelium, dependent on the extracellular and sequential hydrolysis of CDNs to adenosine by the ectonucleosidases ENPP1 and CD73, and occurred via activation of A2B adenosine receptors. These studies highlight a pathway by which microbial and host produced extracellular CDNs can regulate the innate immune response of barrier epithelial cells lining mucosal surfaces.

PMID: 33087577 [PubMed - indexed for MEDLINE]

A Murine Model for Chronic A. fumigatus Airway Infections.

Methods Mol Biol. 2021;2260:215-224

Authors: Ralph B, Sheppard DC

Abstract
In addition to causing acute invasive infections in immunocompromised patients, the mold Aspergillus fumigatus causes chronic infections in patients with chronic pulmonary conditions such as cystic fibrosis. Here we describe a non-lethal model of chronic pulmonary aspergillosis in which immunocompetent mice are endotracheally infected with A. fumigatus conidia embedded in agar beads. This approach results in the establishment of hyphal infection within the airways of mice for up to a 28-day period and is amenable to the study of innate and adaptive antifungal responses, fungal mutant strains, and antifungal agents.

PMID: 33405041 [PubMed - as supplied by publisher]

Carbapenem-Resistant Pseudomonas aeruginosa in Chronic Lung Infection: Current Resistance Profile and Hypermutability in Patients with Cystic Fibrosis.

Curr Microbiol. 2021 Jan 06;:

Authors: Almeida MM, Freitas MT, Folescu TW, Firmida MC, Carvalho-Assef APD, Marques EA, Leão RS

Abstract
Pseudomonas aeruginosa is associated with chronic and progressive lung disease and is closely related to increased morbidity and mortality in cystic fibrosis (CF) patients. Hypermutable (HPM) P. aeruginosa isolates have been described in these patients and are usually associated with antibiotic resistance. This study aimed to investigate the occurrence of carbapenem resistance and hypermutable phenotype in 179 P. aeruginosa isolates from 8 chronically CF patients assisted at two reference centers in Rio de Janeiro, Brazil. Using disk diffusion test, non-susceptible (NS) rates higher than 40% were observed for imipenem, amikacin, and gentamicin. A total of 79 isolates (44.1%), 71 (39.6%), and 8 (4.4%) were classified as carbapenem-resistant (CR resistance to at least one carbapenem), multidrug-resistant (MDR), and extensively drug-resistant (XDR), respectively. Minimal inhibitory concentration was determined for 79 CR P. aeruginosa and showed the following variations: 4 and 128 μg/mL to imipenem, 4 and 64 µg/mL to meropenem, and 4 and ≥ 32 µg/mL to doripenem. We have found only four (2.23%) HPM isolates from 4 patients. Analyzing the genetic relationship among the HPM isolates, 3 pulsed-field gel electrophoresis/pulsotypes (D, M, and J) were observed. Only M pulsotype was recovered from two patients in different years. Polymerase chain reaction screening for blaGES, blaIMP, blaKPC, blaNDM, blaOXA-48, blaSPM, and blaVIM genes was performed for all CR isolates and none of them were positive. Our results demonstrate a high occurrence of CR and MDR P. aeruginosa of CF patients follow-up in both centers studied, while the presence of HPM is still unusual.

PMID: 33404752 [PubMed - as supplied by publisher]

Erratum to "Epithelial vectorial ion transport in cystic fibrosis: Dysfunction, measurement, and pharmacotherapy to target the primary deficit".

SAGE Open Med. 2020;8:2050312120974970

Authors:

Abstract
[This corrects the article DOI: 10.1177/2050312120933807.].

PMID: 33403112 [PubMed]

Preliminary national report on cystic fibrosis epidemiology in Tunisia: the actual state of affairs.

Afr Health Sci. 2020 Mar;20(1):444-452

Authors: Hamouda S, Fredj SH, Hilioui S, Khalsi F, Ameur SB, Bouguila J, Boussoffara R, Besbes H, Ajmi H, Mattoussi N, Messaoud T, Mehrezi A, Hachicha M, Boughamoura L, Sfar MT, Gueddiche N, Abroug S, Becheur SB, Barsaoui S, Tebib N, Samoud A, Gandoura N, Tinsa F, Boussetta K

Abstract
Aim: To establish a preliminary national report on clinical and genetic features of cystic fibrosis (CF) in Tunisian children as a first measure for a better health care organization.
Methods: All children with CF diagnosed by positive sweat tests between 1996 and 2015 in children's departments of Tunisian university hospitals were included. Data was recorded at diagnosis and during the follow-up from patients' medical records.
Results: In 12 departments, 123 CF children were collected. The median age at diagnosis was 5 months with a median diagnosis delay of 3 months. CF was revealed mostly by recurrent respiratory tract infections (69.9%), denutrition (55.2%), and/or chronic diarrhea (41.4%). The mean sweat chloride concentration was 110.9mmol/L. At least one mutation was found in 95 cases (77.2%). The most frequent mutations were Phe508del (n=58) and E1104X (n=15). Fifty-five patients had a Pseudomonas Aeruginosa chronic colonization at a median age of 30 months. Cirrhosis and diabetes appeared at a mean age of 5.5 and 12.5 years respectively in 4 patients each. Sixty-two patients died at a median age of 8 months. Phe508del mutation and hypotrophy were associated with death (p=0.002 and p<0.001, respectively).
Conclusion: CF is life-shortening in Tunisia. Setting-up appropriate management is urgent.

PMID: 33402933 [PubMed - in process]

SARS-CoV-2 Entry Genes Expression in Relation with Interferon Response in Cystic Fibrosis Patients.

Microorganisms. 2021 Jan 03;9(1):

Authors: Bitossi C, Frasca F, Viscido A, Oliveto G, Scordio M, Belloni L, Cimino G, Pietropaolo V, Gentile M, d'Ettorre G, Midulla F, Trancassini M, Antonelli G, Pierangeli A, Scagnolari C

Abstract
The expression rate of SARS-CoV-2 entry genes, angiotensin-converting enzyme 2 (ACE2), the main viral receptor and the proteases, furin and transmembrane serine protease 2 (TMPRSS2) in cystic fibrosis (CF) individuals is poorly known. Hence, we examined their levels in upper respiratory samples of CF patients (n = 46) and healthy controls (n = 45). Moreover, we sought to understand the interplay of type I interferon (IFN-I) with ACE2, furin and TMPRSS2 by evaluating their gene expression with respect to ISG15, a well-known marker of IFN activation, in upper respiratory samples and after ex vivo IFNβ exposure. Lower ACE2 levels and trends toward the reduction of furin and TMPRSS2 were found in CF patients compared with the healthy controls; decreased ACE2 amounts were also detected in CF individuals with pancreatic insufficiency and in those receiving inhaled antibiotics. Moreover, there was a strong positive correlation between ISG15 and ACE2 levels. However, after ex vivo IFNβ stimulation of nasopharyngeal cells, the truncated isoform (dACE2), recently demonstrated as the IFN stimulated one with respect to the full-length isoform (flACE2), slightly augmented in cells from CF patients whereas in those from healthy donors, dACE2 levels showed variable levels of upregulation. An altered expression of SARS-COV-2 entry genes and a poor responsiveness of dACE2 to IFN-I stimulation might be crucial in the diffusion of SARS-CoV-2 infection in CF.

PMID: 33401565 [PubMed]

Optimizations of In Vitro Mucus and Cell Culture Models to Better Predict In Vivo Gene Transfer in Pathological Lung Respiratory Airways: Cystic Fibrosis as an Example.

Pharmaceutics. 2020 Dec 31;13(1):

Authors: Ghanem R, Laurent V, Roquefort P, Haute T, Ramel S, Le Gall T, Aubry T, Montier T

Abstract
The respiratory epithelium can be affected by many diseases that could be treated using aerosol gene therapy. Among these, cystic fibrosis (CF) is a lethal inherited disease characterized by airways complications, which determine the life expectancy and the effectiveness of aerosolized treatments. Beside evaluations performed under in vivo settings, cell culture models mimicking in vivo pathophysiological conditions can provide complementary insights into the potential of gene transfer strategies. Such models must consider multiple parameters, following the rationale that proper gene transfer evaluations depend on whether they are performed under experimental conditions close to pathophysiological settings. In addition, the mucus layer, which covers the epithelial cells, constitutes a physical barrier for gene delivery, especially in diseases such as CF. Artificial mucus models featuring physical and biological properties similar to CF mucus allow determining the ability of gene transfer systems to effectively reach the underlying epithelium. In this review, we describe mucus and cellular models relevant for CF aerosol gene therapy, with a particular emphasis on mucus rheology. We strongly believe that combining multiple pathophysiological features in single complex cell culture models could help bridge the gaps between in vitro and in vivo settings, as well as viral and non-viral gene delivery strategies.

PMID: 33396283 [PubMed]

Pseudomonas aeruginosa associated with severity of non-cystic fibrosis bronchiectasis measured by the modified bronchiectasis severity score (BSI) and the FACED: The US bronchiectasis and NTM Research Registry (BRR) study.

Respir Med. 2020 Dec 24;177:106285

Authors: Choate R, Aksamit TR, Mannino D, Addrizzo-Harris D, Barker A, Basavaraj A, Daley CL, Daniels MLA, Eden E, DiMango A, Fennelly K, Griffith DE, Johnson MM, Knowles MR, McShane PJ, Metersky ML, Noone PG, O'Donnell AE, Olivier KN, Salathe MA, Schmid A, Thomashow B, Tino G, Winthrop KL, Stone G

Abstract
RATIONALE: Non-cystic fibrosis bronchiectasis (NCFB) is characterized by dilated bronchi, poor mucus clearance and susceptibility to bacterial infection. Pseudomonas aeruginosa (PA) is one of the most frequently isolated pathogens in patients with NCFB. The purpose of this study was to evaluate the association between presence of PA and disease severity in patients within the US Bronchiectasis and Nontuberculous mycobacteria (NTM) Research Registry (BRR).
METHODS: Baseline US BRR data from adult patients with NCFB collected between 2008 and 2018 was used for this study. The presence of PA was defined as one or more positive PA cultures within two years prior to enrollment. Modified Bronchiectasis Severity Index (m-BSI) and modified FACED (m-FACED) were computed to evaluate severity of bronchiectasis. Unadjusted and multivariable multinomial regression models were used to assess the association between presence of PA and severity of bronchiectasis.
RESULTS: Average age of the study participants (n = 1831) was 63.7 years (SD = 14.1), 91.5% white, and 78.8% female. Presence of PA was identified in 25.4% of the patients. Patients with presence of PA had significantly lower mean pre-bronchodilator FEV1% predicted compared to those without PA (62.8% vs. 73.7%, p < .0001). In multivariate analyses, patients with presence of PA had significantly greater odds for having high (ORadj = 6.15 (95%CI:3.98-9.50) and intermediate (ORadj = 2.06 (95%CI:1.37-3.09) severity vs. low severity on m-BSI.
CONCLUSION: The presence of PA is common in patients with NCFB within the Bronchiectasis and NTM Research Registry. Severity of bronchiectasis is significantly greater in patients with PA which emphasizes high burden of the disease.

PMID: 33401148 [PubMed - as supplied by publisher]

Repurposing calcium sensing receptor agonist cinacalcet for treatment of CFTR-mediated secretory diarrheas.

JCI Insight. 2021 Jan 05;:

Authors: Oak AA, Chhetri PD, Rivera A, Verkman AS, Cil O

Abstract
Diarrhea is a major cause of global mortality, and outbreaks of secretory diarrhea such as cholera remain an important problem in the developing world. Current treatment of secretory diarrhea primarily involves supportive measures such as fluid replacement. The calcium-sensing receptor (CaSR) regulates multiple biological activities in response to changes in extracellular Ca+2. The FDA-approved drug cinacalcet is an allosteric activator of CaSR used for treatment of hyperparathyroidism. Here, we found by short-circuit current measurements in human colonic T84 cells that CaSR activation by cinacalcet reduced forskolin-induced Cl- secretion by greater than 80%. Cinacalcet also reduced Cl- secretion induced by cholera toxin, heat-stable E. coli enterotoxin, and vasoactive intestinal peptide (VIP). The cinacalcet effect primarily involved indirect inhibition of cystic fibrosis transmembrane conductance regulator (CFTR)-mediated Cl- secretion following activation of CaSR, and downstream phospholipase C and phosphodiesterases. In mice, cinacalcet reduced fluid accumulation by more than 60% in intestinal closed-loop models of cholera and Traveler's diarrhea. The cinacalcet effect involved both inhibition of CFTR-mediated secretion and stimulation of sodium-hydrogen exchanger 3 (NHE3)-mediated absorption. These findings support the therapeutic utility of the safe and commonly used drug cinacalcet in CFTR-dependent secretory diarrheas including cholera, Traveler's diarrhea and VIPoma.

PMID: 33400691 [PubMed - as supplied by publisher]

Recurrent massive hemoptysis in a patient with cystic fibrosis: balloon assisted Onyx embolization after bronchial artery coil recanalization.

CVIR Endovasc. 2021 Jan 05;4(1):4

Authors: Mattay RR, Shlansky-Goldberg R, Pukenas BA

Abstract
BACKGROUND: Although not standard of care, Cystic Fibrosis patients with recurrent hemoptysis occasionally have coil embolization of bronchial arteries. In the event of recanalization of these arteries in this specific subset of patients, the presence of indwelling coils makes the prospect of conventional particle embolization more difficult, preventing both adequate catheterization of the coiled segment and reflux of the particles.
CASE PRESENTATION: In this report, we describe a case of bronchial artery embolization of a complex Cystic Fibrosis patient with massive hemoptysis from recanalized coiled bronchial arteries utilizing a Scepter Balloon Catheter® (Microvention Terumo, USA) in administration of the liquid embolic agent Onyx® (Medtronic, USA).
CONCLUSIONS: The Scepter occlusion balloon catheter allowed for careful placement of the tip within the interstices of the pre-existing coils, allowing for Onyx injection directly into the coil mass without reflux, reconfirming the benefits of Onyx embolization in bronchial artery embolization and providing evidence that the Scepter occlusion balloon catheter should be added to the armamentarium of devices used in complex bronchial artery embolization for Cystic Fibrosis patients with massive hemoptysis.

PMID: 33400002 [PubMed - as supplied by publisher]

Discovery of GLPG2451, a Novel Once Daily Potentiator for the Treatment of Cystic Fibrosis.

J Med Chem. 2021 Jan 05;:

Authors: Van der Plas SE, Kelgtermans H, Mammoliti O, Menet C, Tricarico G, De Blieck A, Joannesse C, De Munck T, Lambin D, Cowart M, Dropsit S, Martina SLX, Gees M, Wesse AS, Conrath K, Andrews M

Abstract
Cystic fibrosis (CF) is a life-threatening recessive genetic disease caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Lumacaftor, it has been shown that administration of one or more small molecules can partially restore the CFTR function. Correctors are small molecules that enhance the amount of CFTR on the cell surface, while potentiators improve the gating function of the CFTR channel. Herein, we describe the discovery and optimization of a novel potentiator series. Scaffold hopping, focusing on retaining the different intramolecular contacts, was crucial in the whole discovery process to identify a novel series devoid of genotoxic liabilities. From this series, the clinical candidate GLPG2451 was selected based on its pharmacokinetic properties, allowing QD dosing and based on its low CYP induction potential.

PMID: 33399458 [PubMed - as supplied by publisher]

Comparison of respiratory pathogen colonization and antimicrobial susceptibility in people with cystic fibrosis bronchiectasis versus non-cystic fibrosis bronchiectasis: a protocol for a systematic review.

Syst Rev. 2021 Jan 04;10(1):7

Authors: Verma S, Mathew JL, Ray P

Abstract
BACKGROUND: Both cystic fibrosis (CF) and non-cystic fibrosis bronchiectasis are characterized by permanent bronchial dilation, impaired mucociliary clearance, and development of chronic colonization and infection. Although the major airway microbiota in both CF and non-CF bronchiectasis may be similar, there are some differences in clinical and microbiologic features. There may also be differences in antibiotic susceptibility patterns between the CF and non-CF populations. Therefore, analysis and comparison of the microbiota and antibiotic susceptibility pattern in CF bronchiectasis versus non-CF bronchiectasis would help to improve the management of both conditions.
METHODS: Two authors will independently search the electronic databases PubMed, EMBASE, the Cochrane Library, and LIVIVO, for studies reporting bacterial colonization of the respiratory tract in adults and children diagnosed with bronchiectasis in either CF or non-CF. We will include studies examining any respiratory tract specimen, using conventional bacterial culture or other specialized techniques such as molecular methods. We will also examine the antimicrobial susceptibility patterns in people with CF bronchiectasis versus non-CF bronchiectasis. The authors will independently assess the risk of bias in each included study using the Newcastle Ottawa Scale (NOS). We will present the data with descriptive statistics and provide pooled estimates of outcomes, wherever it is feasible to perform meta-analysis. Heterogeneity in studies will be explored by visual inspection of forest plots as well as using the Higgins and Thompson I2 method. We will contact the corresponding authors of studies where data is/are missing and try to obtain the missing data. We will undertake sensitivity analysis to explore the impact of study quality and subgroup analysis based on pre-set criteria. We will prepare a summary of findings' table and assess the confidence in the evidence using the GRADE methodology.
DISCUSSION: To date, there are no locally applicable evidence-based guidelines for antimicrobial treatment of non-CF bronchiectasis patients. In general, treatment is based on extrapolation of evidence in people with CF bronchiectasis. An insight into the microbiota and antimicrobial susceptibility patterns in the two conditions would facilitate appropriate rather than empiric antimicrobial therapy and hopefully reduce the burden of antimicrobial resistance created by rampant usage of antibiotics.
SYSTEMATIC REVIEW REGISTRATION: The protocol has been registered in PROSPERO on July 26, 2020 (PROSPERO registration number: CRD42020193859 ).

PMID: 33397475 [PubMed - in process]

Synergy between Readthrough and Nonsense Mediated Decay Inhibition in a Murine Model of Cystic Fibrosis Nonsense Mutations.

Int J Mol Sci. 2020 Dec 31;22(1):

Authors: McHugh DR, Cotton CU, Hodges CA

Abstract
Many heritable genetic disorders arise from nonsense mutations, which generate premature termination codons (PTCs) in transcribed mRNA. PTCs ablate protein synthesis by prematurely terminating the translation of mutant mRNA, as well as reducing mutant mRNA quantity through targeted degradation by nonsense-mediated decay (NMD) mechanisms. Therapeutic strategies for nonsense mutations include facilitating ribosomal readthrough of the PTC and/or inhibiting NMD to restore protein function. However, the efficacy of combining readthrough agents and NMD inhibitors has not been thoroughly explored. In this study, we examined combinations of known NMD inhibitors and readthrough agents using functional analysis of the CFTR protein in primary cells from a mouse model carrying a G542X nonsense mutation in Cftr. We observed synergy between an inhibitor of the NMD component SMG-1 (SMG1i) and the readthrough agents G418, gentamicin, and paromomycin, but did not observe synergy with readthrough caused by amikacin, tobramycin, PTC124, escin, or amlexanox. These results indicate that treatment with NMD inhibitors can increase the quantity of functional protein following readthrough, and that combining NMD inhibitors and readthrough agents represents a potential therapeutic option for treating nonsense mutations.

PMID: 33396210 [PubMed - in process]

Surgery-Related Quality of Life of Pediatric Patients With Crohn's Disease.

Front Pediatr. 2020;8:608370

Authors: Dipasquale V, Antonelli E, Cannavò L, Cavatoi G, Romeo C, Trimarchi G, Navarra G, Romano C

Abstract
Objective: Up to 30% of pediatric patients with Crohn's disease (CD) require surgery. The aim of the study was to evaluate long-term health-related quality of life (HRQoL) outcome in children with CD who have had ileocolonic resection. Materials and methods: This was a retrospective cross-sectional study on all pediatric patients who had undergone surgery for CD between January 2015 and December 2017 in the Pediatric Surgery and Gastroenterology Units of the University Hospital of Messina. Surgical treatment was represented by laparoscopic ileocecal resection with latero-lateral anastomosis. Patients were asked to fill in a modified version of the IMPACT III questionnaire made up of 15 closed questions before and after surgery. The questionnaire was scored on a five-point scale with 5 reporting "not a problem" and 1 "a very severe problem." The total score ranged from 15 (worst HRQoL) to 75 (best HRQoL). Frequency of relapses, reoperations, complications during follow-up, and postoperative bowel function were also studied. Results: Data were obtained in 10 patients (9 males), who underwent surgery at a median age of 13.5 years (range 13-18), after a median post-diagnosis period of 2.5 years (range 0-8). Preoperative scores were low in all 4 domains of the questionnaire. Postoperatively, HRQoL measures improved significantly (p < 0.05) about symptoms, school attendance, social and emotional functioning. Overall, nearly all patients were completely satisfied with the surgical outcome. Conclusions: HRQoL is low in CD children referred for possible operation, and surgery may positively affect the overall HRQoL. Collecting HRQoL data provides insight into the impact of treatment on children health status.

PMID: 33392119 [PubMed]

The Interplay Between Respiratory Microbiota and Innate Immunity in Flavor E-Cigarette Vaping Induced Lung Dysfunction.

Front Microbiol. 2020;11:589501

Authors: Quinones Tavarez Z, Li D, Croft DP, Gill SR, Ossip DJ, Rahman I

Abstract
Global usage of electronic nicotine delivery systems (ENDS) has been increasing in the last decade. ENDS are non-combustible tobacco products that heat and aerosolize a liquid containing humectants, with added flavorings and often nicotine. Though ENDS are promoted as a less harmful alternative to smoking, current evidence links their use to a wide range of deleterious health effects including acute and chronic lung damage. ENDS can elicit an inflammatory response and impair the innate immune response in the lungs. Exposure to ENDS flavorings results in abnormal activation of the lung epithelial cells and β-defensins, dysfunction of the macrophage phagocytic activity, increased levels of mucin (MUC5AC) and abnormal activation of the neutrophilic response (NETosis). ENDS menthol flavorings disrupt innate immunity and might be associated with allergies and asthma through activation of transient receptor potential ankyrin 1 (TRAP1). Recent studies have expanded our understanding of the relationship between the homeostasis of lung innate immunity and the immunomodulatory effect of the host-microbiota interaction. Alterations of the normal respiratory microbiota have been associated with chronic obstructive pulmonary disease (COPD), asthma, atopy and cystic fibrosis complications which are strongly associated with smoking and potentially with ENDS use. Little is known about the short-and long-term effects of ENDS on the respiratory microbiota, their impact on the innate immune response and their link to pulmonary health and disease. Here we review the interaction between the innate immune system and the respiratory microbiota in the pathogenesis of ENDS-induced pulmonary dysfunction and identify future areas of research.

PMID: 33391205 [PubMed]

A Novel G542X CFTR Rat Model of Cystic Fibrosis Is Sensitive to Nonsense Mediated Decay.

Front Physiol. 2020;11:611294

Authors: Sharma J, Abbott J, Klaskala L, Zhao G, Birket SE, Rowe SM

Abstract
Nonsense mutations that lead to the insertion of a premature termination codon (PTC) in the cystic fibrosis transmembrane conductance regulator (CFTR) transcript affect 11% of patients with cystic fibrosis (CF) worldwide and are associated with severe disease phenotype. While CF rat models have contributed significantly to our understanding of CF disease pathogenesis, there are currently no rat models available for studying CF nonsense mutations. Here we created and characterized the first homozygous CF rat model that bears the CFTR G542X nonsense mutation in the endogenous locus using CRISPR/Cas9 gene editing. In addition to displaying severe CF manifestations and developmental defects such as reduced growth, abnormal tooth enamel, and intestinal obstruction, CFTR G542X knockin rats demonstrated an absence of CFTR function in tracheal and intestinal sections as assessed by nasal potential difference and transepithelial short-circuit current measurements. Reduced CFTR mRNA levels in the model further suggested sensitivity to nonsense-mediated decay, a pathway elicited by the presence of PTCs that degrades the PTC-bearing transcripts and thus further diminishes the level of CFTR protein. Although functional restoration of CFTR was observed in G542X rat tracheal epithelial cells in response to single readthrough agent therapy, therapeutic efficacy was not observed in G542X knockin rats in vivo. The G542X rat model provides an invaluable tool for the identification and in vivo validation of potential therapies for CFTR nonsense mutations.

PMID: 33391025 [PubMed]

Development of an intervention to increase adherence to nebuliser treatment in adults with cystic fibrosis: CFHealthHub.

Pilot Feasibility Stud. 2021 Jan 04;7(1):1

Authors: Arden MA, Hutchings M, Whelan P, Drabble SJ, Beever D, Bradley JM, Hind D, Ainsworth J, Maguire C, Cantrill H, O'Cathain A, Wildman M

Abstract
BACKGROUND: Cystic fibrosis (CF) is a life-limiting genetic condition in which daily therapies to maintain lung health are critical, yet treatment adherence is low. Previous interventions to increase adherence have been largely unsuccessful and this is likely due to a lack of focus on behavioural evidence and theory alongside input from people with CF. This intervention is based on a digital platform that collects and displays objective nebuliser adherence data. The purpose of this paper is to identify the specific components of an intervention to increase and maintain adherence to nebuliser treatments in adults with CF with a focus on reducing effort and treatment burden.
METHODS: Intervention development was informed by the Behaviour Change Wheel (BCW) and person-based approach (PBA). A multidisciplinary team conducted qualitative research to inform a needs analysis, selected, and refined intervention components and methods of delivery, mapped adherence-related barriers and facilitators, associated intervention functions and behaviour change techniques, and utilised iterative feedback to develop and refine content and processes.
RESULTS: Results indicated that people with CF need to understand their treatment, be able to monitor adherence, have treatment goals and feedback and confidence in their ability to adhere, have a treatment plan to develop habits for treatment, and be able to solve problems around treatment adherence. Behaviour change techniques were selected to address each of these needs and were incorporated into the digital intervention developed iteratively, alongside a manual and training for health professionals. Feedback from people with CF and clinicians helped to refine the intervention which could be tailored to individual patient needs.
CONCLUSIONS: The intervention development process is underpinned by a strong theoretical framework and evidence base and was developed by a multidisciplinary team with a range of skills and expertise integrated with substantial input from patients and clinicians. This multifaceted development strategy has ensured that the intervention is usable and acceptable to people with CF and clinicians, providing the best chance of success in supporting people with CF with different needs to increase and maintain their adherence. The intervention is being tested in a randomised controlled trial across 19 UK sites.

PMID: 33390191 [PubMed]

New Therapeutic Approaches in Cystic Fibrosis.

Turk J Pharm Sci. 2020 Dec 23;17(6):686-697

Authors: Fakıoğlu DM, Altun B

Abstract
Cystic fibrosis (CF) is a hereditary, multisystemic disease caused by different mutations in the CFTR gene encoding CF transmembrane conductance regulator. CF is mainly characterized by pulmonary dysfunction as a result of deterioration in the mucociliary clearance and anion transport of airways. Mortality is mostly caused by bronchiectasis, bronchiole obstruction, and progressive respiratory dysfunction in the early years of life. Over the last decade, new therapeutic strategies rather than symptomatic treatment have been proposed, such as the small molecule approach, ion channel therapy, and pulmonary gene therapy. Due to considerable progress in the treatment options, CF has become an adult disease rather than a pediatric disease in recent years. Pulmonary gene therapy has gained special attention due to its mutation type independent aspect, therefore being applicable to all CF patients. On the other hand, the major obstacle for CF treatment is to predict the drug response of patients due to genetic complexity and heterogeneity. The advancement of 3D culture systems has made it possible to extrapolate the disease modeling and individual drug response in vitro by producing mini adult organs called "organoids" obtained from rectal cell biopsies. In this review, we summarize the advances in the novel therapeutic approaches, clinical interventions, and precision medicine concept for CF.

PMID: 33389985 [PubMed]

Noninvasive Ventilatory Support of COVID-19 Patients Outside the Intensive Care Units (WARd-COVID).

Ann Am Thorac Soc. 2021 Jan 04;:

Authors: Bellani G, Grasselli G, Cecconi M, Antolini L, Borelli M, De Giacomi F, Bosio G, Latronico N, Filippini M, Gemma M, Giannotti C, Antonini B, Petrucci N, Zerbi SM, Maniglia P, Castelli GP, Marino G, Subert M, Citerio G, Radrizzani D, Mediani TS, Lorini FL, Russo FM, Faletti A, Beindorf A, Covello RD, Greco S, Bizzarri MM, Ristagno G, Mojoli F, Pradella A, Severgnini P, Da Macallè M, Albertin A, Ranieri VM, Rezoagli E, Vitale G, Magliocca A, Cappelleri G, Docci M, Aliberti S, Serra F, Rossi E, Valsecchi MG, Pesenti A, Foti G, COVID-19 Lombardy ICU Network

Abstract
RATIONALE: Treatment with non-invasive ventilation (NIV) in COVID-19 is frequent. Shortage of Intensive care unit (ICU) beds led clinicians to deliver NIV also outside intensive care units (ICUs). Data about the use of NIV in COVID-19 is limited.
OBJECTIVE: To describe the prevalence and clinical characteristics of patients with COVID-19 treated with NIV outside the ICUs. To investigate the factors associated with NIV failure (need for intubation or death).
METHODS: In this prospective single day observational study, we enrolled adult COVID-19 patients, treated with NIV outside the ICU from thirty-one hospitals in Lombardy, Italy.
RESULTS: We collected data on demographic, clinical characteristics, ventilatory management and patients' outcome. Of 8753 COVID-19 patients present in the hospitals on the study day, 909 (10%) were receiving NIV outside the ICU. 778/909 (85%) patients were treated with Continuous Positive Airway Pressure (CPAP), delivered by helmet in 617 (68%). NIV failed in 300 patients (37.6%), while 498 (62.4%) were discharged alive without intubation. Overall mortality was 25%. NIV failure occurred in 152/284 (53%) patients with a PaO2/FiO2 ratio < 150 mmHg. Higher C-reactive protein, lower PaO2/FiO2, and platelet counts were independently associated with increased risk of NIV failure.
CONCLUSIONS: The use of NIV outside the ICUs, in COVID-19 was common, with a predominant use of helmet CPAP, with a rate of success greater than 60% and close to 75% in full treatment patients. C-reactive protein, PaO2/FiO2, platelet counts were independently associated with increased risk of NIV failure. Clinical trial registered with ClinicalTrials.gov (NCT04382235).

PMID: 33395553 [PubMed - as supplied by publisher]