Aerosolizable Lipid Nanoparticles for Pulmonary Delivery of mRNA through Design of Experiments.

Pharmaceutics. 2020 Oct 30;12(11):

Authors: Zhang H, Leal J, Soto MR, Smyth HDC, Ghosh D

Abstract
Messenger RNA is a class of promising nucleic acid therapeutics to treat a variety of diseases, including genetic diseases. The development of a stable and efficacious mRNA pulmonary delivery system would enable high therapeutic concentrations locally in the lungs to improve efficacy and limit potential toxicities. In this study, we employed a Design of Experiments (DOE) strategy to screen a library of lipid nanoparticle compositions to identify formulations possessing high potency both before and after aerosolization. Lipid nanoparticles (LNPs) showed stable physicochemical properties for at least 14 days of storage at 4 °C, and most formulations exhibited high encapsulation efficiencies greater than 80%. Generally, upon nebulization, LNP formulations showed increased particle size and decreased encapsulation efficiencies. An increasing molar ratio of poly-(ethylene) glycol (PEG)-lipid significantly decreased size but also intracellular protein expression of mRNA. We identified four formulations possessing higher intracellular protein expression ability in vitro even after aerosolization which were then assessed in in vivo studies. It was found that luciferase protein was predominately expressed in the mouse lung for the four lead formulations before and after nebulization. This study demonstrated that LNPs hold promise to be applied for aerosolization-mediated pulmonary mRNA delivery.

PMID: 33143328 [PubMed]

Classical Drug Digitoxin Inhibits Influenza Cytokine Storm, With Implications for Covid-19 Therapy.

In Vivo. 2020 Nov-Dec;34(6):3723-3730

Authors: Pollard BS, BLANCOl JC, Pollard JR

Abstract
BACKGROUND/AIM: Influenza viruses, corona viruses and related pneumotropic viruses cause sickness and death partly by inducing cytokine storm, a hyper-proinflammatory host response by immune cells and cytokines in the host airway. Based on our in vivo experience with digitoxin as an inhibitor of TNFα-driven NFĸB signaling for cytokine expression in prostate cancer in rats and in cystic fibrosis in humans, we hypothesize that this drug will also block a virally-activated cytokine storm. Materials Methods: Digitoxin was administered intraperitoneally to cotton rats, followed by intranasal infection with 107TCID50/100 g of cotton rat with influenza strain A/Wuhan/H3N2/359/95. Daily digitoxin treatment continued until harvest on day 4 of the experiment.
RESULTS: The cardiac glycoside digitoxin significantly and differentially suppressed levels of the cytokines TNFα, GRO/KC, MIP2, MCP1, and IFNγ, in the cotton rat lung in the presence of influenza virus.
CONCLUSION: Since cytokine storm is a host response, we suggest that digitoxin may have a therapeutic potential not only for influenza and but also for coronavirus infections.

PMID: 33144490 [PubMed - in process]

Copper and Copper/Zinc Ratio in a Series of Cystic Fibrosis Patients.

Nutrients. 2020 Oct 30;12(11):

Authors: Escobedo-Monge MF, Barrado E, Alonso Vicente C, Escobedo-Monge MA, Torres-Hinojal MC, Marugán-Miguelsanz JM, Redondo Del Río MP

Abstract
Cystic fibrosis (CF) patients require a stable and sufficient supply of micronutrients. Since copper is an essential micronutrient for human development, a cross-sectional study was carried out to investigate the serum copper levels, serum copper/zinc (Cu/Zn) ratios, and their relationship with nutritional indicators in a group of CF patients. Anthropometric, biochemical, and dietary measurements, an abdominal ultrasound, and respiratory and pancreatic tests were conducted. Seventeen CF patients were studied (10 females, 59%), 76.5% of whom were ∆F580. Their mean serum copper (113 ± 23 μg/dL) was normal, and there was only one teenager with hypocupremia (6%) and two children with hypercupremia (18%). A significant association between serum copper and zinc levels was discovered. The Cu/Zn ratio was higher than 1.00 for 94% of patients, which is an indicator of an inflammation status. There was no significant correlation between the serum copper concentrations and respiratory and pancreatic function, respiratory colonization, and the results of the abdominal ultrasound. Linear regression analysis showed that serum copper had a positive association with both the Z-score body mass index (BMI) and mean bone conduction speed (BCS). Therefore, since 94% of CF patients had a Cu/Zn ratio > 1.00, this factor must alert us to consider the risk of zinc deficiency and high inflammatory response. The measurement of serum zinc alone does not show one's zinc status. However, the Cu/Zn ratio may be an indicator of zinc deficiency and the inflammatory status of CF patients.

PMID: 33143143 [PubMed - in process]

Chest computed tomography outcomes in a randomized clinical trial in cystic fibrosis: Lessons learned from the first ataluren phase 3 study.

PLoS One. 2020;15(11):e0240898

Authors: Tiddens HAWM, Andrinopoulou ER, McIntosh J, Elborn JS, Kerem E, Bouma N, Bosch J, Kemner-van de Corput M

Abstract
A phase 3 randomized double blind controlled, trial in 238 people with cystic fibrosis (CF) and at least one nonsense mutation (nmCF) investigated the effect of ataluren on FEV1. The study was of 48 weeks duration and failed to meet its primary endpoint. Unexpectedly, while FEV1 declined, chest computed tomography (CT) scores using the Brody-II score as secondary outcome measures did not show progression in the placebo group. Based on this observation it was concluded that the role of CT scans in CF randomized clinical trials was limited. However, more sensitive scoring systems were developed over the last decade warranting a reanalysis of this unique dataset. The aim of our study was to reanalyse all chest CT scans, obtained in the ataluren phase 3 study, using 2 independent scoring systems to characterize structural lung disease in this cohort and to compare progression of structural lung disease over the 48 weeks between treatment arms. 391 study CT scans from 210 patients were reanalysed in random order by 2 independent observers using the CF-CT and Perth-Rotterdam Annotated Grid Morphometric Analysis for CF (PRAGMA-CF) scoring systems. CF-CT and PRAGMA-CF subscores were expressed as %maximal score and %total lung volume, respectively. PRAGMA-CF subscores %Disease (p = 0.008) and %Mucus Plugging (p = 0.029) progressed over 48 weeks. CF-CT subscores did not show progression. There was no difference in progression of structural lung disease between treatment arm and placebo independent of tobramycin use. PRAGMA-CF Chest CT scores can be used as an outcome measure to study the effect of potential disease modifying drugs in CF on lung structure.

PMID: 33141825 [PubMed - as supplied by publisher]

COVID-19 in Lung Transplant Recipients.

Transplantation. 2020 Oct 30;:

Authors: Messika J, Eloy P, Roux A, Hirschi S, Nieves A, Le Pavec J, Sénéchal A, Saint Raymond C, Carlier N, Demant X, Le Borgne A, Tissot A, Debray MP, Beaumont L, Renaud-Picard B, Reynaud-Gaubert M, Mornex JF, Falque L, Boussaud V, Jougon J, Mussot S, Mal H, French Group of Lung Transplantation.

Abstract
BACKGROUND: A concern about the susceptibility of immunocompromised patients to the worldwide pandemic of coronavirus disease 2019 (COVID-19) has been raised. We aimed at describing COVID-19 infections in the French cohort of lung transplant (LT) patients.
METHODS: Multicenter nationwide cohort study of all LT recipients with COVID-19 diagnosed from March 1 to May 19, 2020. Recipient main characteristics and their management were retrieved. Hospitalization characteristics, occurrence of complications and survival were analyzed.
RESULTS: Thirty-five LT patients with a COVID-19 infection were included. Median age was 50.4 [40.6-62.9] years, 16 (45.7%) were female, and 80% were double-LT recipients. Infection was community-acquired in 25 (71.4%). Thirty-one (88.6%) required hospitalization, including 13 (41.9%) in the intensive care unit. The main symptoms of COVID-19 were fever, cough, and diarrhea, present in 71.4%, 54.3%, and 31.4% of cases, respectively. Extension of pneumonia on chest CT was moderate to severe in 51.4% of cases. Among the 13 critically ill patients, 7 (53.9%) received invasive mechanical ventilation. Thrombotic events occurred in 4 patients. Overall survival rate was 85.7% after a median follow-up of 50 days [41.0-56.5]. Four of 5 nonsurvivors had had bronchial complications or intensification of immunosuppression in the previous weeks. On univariate analysis, overweight was significantly associated with risk of death (odds ratio 16.0 [95% confidence interval1.5-170.6], p=0.02).
CONCLUSION: For the 35 LT recipients with COVID-19, the presentation was severe, requiring hospitalization in most cases, with a survival rate of 85.7%.

PMID: 33141808 [PubMed - as supplied by publisher]

Machine learning evaluates improvement in sinus computed tomography opacification with CFTR modulator therapy.

Int Forum Allergy Rhinol. 2020 Nov 02;:

Authors: Beswick DM, Humphries SM, Balkissoon CD, Vladar EK, Ramakrishnan VR, Lynch DA, Taylor-Cousar JL

PMID: 33140564 [PubMed - as supplied by publisher]

Sputum microbiota in adults with CF associates with response to inhaled tobramycin.

Thorax. 2020 Nov 02;:

Authors: Heirali A, Thornton C, Acosta N, Somayaji R, Laforest Lapointe I, Storey D, Rabin H, Waddell B, Rossi L, Arrieta MC, Surette M, Parkins MD

Abstract
BACKGROUND: Inhaled tobramycin powder/solution (TIP/S) use has resulted in improved clinical outcomes in patients with cystic fibrosis (CF) with chronic Pseudomonas aeruginosa. However, TIP/S effect on the CF sputum microbiome has not been explored. We hypothesised that TIP/S has additional 'off-target' effects beyond merely P. aeruginosa and that baseline microbiome prior to initiation of therapy is associated with subsequent patient response.
METHODS: We drew sputum samples from a prospectively collected biobank. Patients were included if they had one sputum sample in the 18 months before and after TIP/S. Bacterial 16S rRNA gene profiling was used to characterise the sputum microbiome.
RESULTS: Forty-one patients met our inclusion criteria and 151 sputum samples were assessed. At baseline, median age was 30.4 years (IQR 24.2-35.2) and forced expiratory volume in 1 (FEV1) second was 57% predicted (IQR 44-74). Nineteen patients were defined a priori as responders having no net decrease in FEV1 in the year following TIP/S. No significant changes were observed in key microbiome metrics of alpha (within-sample) or beta (between-sample) diversity for samples collected before and after TIP/S. However, significant beta-diversity (Bray-Curtis) differences were noted at baseline between patients based on response status. Notably, responders were observed to have a higher abundance of Staphylococcus in pretherapy baseline samples.
CONCLUSIONS: Our longitudinal study demonstrates that the sputum microbiome of patients with CF is relatively stable following inhaled tobramycin over many months. Intriguingly, our findings suggest that baseline microbiome may associate with patient response to TIP/S-suggesting the sputum microbiome could be used to personalise therapy.

PMID: 33139451 [PubMed - as supplied by publisher]

Airway microbiome studies challenge simplistic models of inhaled tobramycin benefit.

Thorax. 2020 Nov 02;:

Authors: Rogers GB

PMID: 33139450 [PubMed - as supplied by publisher]

Acid ceramidase rescues cystic fibrosis mice from pulmonary infections.

Infect Immun. 2020 Nov 02;:

Authors: Becker KA, Verhaegh R, Verhasselt HL, Keitsch S, Soddemann M, Wilker B, Wilson GC, Buer J, Ahmad SA, Edwards MJ, Gulbins E

Abstract
Previous studies have shown that sphingosine kills a variety of pathogenic bacteria, including Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus Sphingosine concentrations are decreased in airway epithelial cells of cystic fibrosis (CF) mice and this defect has been linked to the infection susceptibility of these mice. Here, we tested whether genetic overexpression of the acid ceramidase rescues cystic fibrosis mice from pulmonary infections with P. aeruginosa We demonstrate that transgenic overexpression of the acid ceramidase in CF mice corresponds to an overexpression of the acid ceramidase in bronchial and tracheal epithelial cells and normalizes ceramide and sphingosine levels in bronchial and tracheal epithelial cells. In addition, expression of β1-integrin, which is ectopically expressed on the luminal surface of airway epithelial cells in cystic fibrosis mice - an alteration that is very important for mediating pulmonary P. aeruginosa infections of cystic fibrosis, is normalized in cystic fibrosis airways upon overexpression of acid ceramidase. Most importantly, overexpression of acid ceramidase protects cystic fibrosis mice from pulmonary P. aeruginosa infections. Infection of CF mice or CF mice that were inhaled with sphingosine with P. aeruginosa or a P. aeruginosa mutant that is resistant to sphingosine indicate that sphingosine and not a metabolite kills P. aeruginosa upon pulmonary infection. These studies further support the use of acid ceramidase and its metabolite sphingosine as a potential treatment of cystic fibrosis.

PMID: 33139382 [PubMed - as supplied by publisher]

LC-MS detection of antibiotic agents in sputum from persons with cystic fibrosis.

Antimicrob Agents Chemother. 2020 Nov 02;:

Authors: Gallagher T, Riedel S, Kapcia J, Caverly LJ, Carmody L, Kalikin LM, Lu J, Phan J, Gargus M, Kagawa M, Leemans SW, Rothman JA, Grun F, LiPuma JJ, Whiteson KL

Abstract
Antibiotic therapy is expected to impact host microbial communities considerably, yet many studies focused on microbiome and health are often confounded by limited information about antibiotic exposure. Given that antibiotics have diverse pharmacokinetic and antimicrobial properties, investigating the type and concentration of these agents in specific host specimens would provide much needed insight into their impact on the microbes therein. Here, we developed liquid chromatography mass spectrometry (LC-MS) methods to detect 18 antibiotic agents in sputum from persons with cystic fibrosis. Antibiotic spike-in control samples were used to compare three liquid extraction methods on the Waters Acquity Quattro Premier XE. Extraction with dithiothreitol captured the most antibiotics and was used to detect antibiotics in sputum samples from 11 people with cystic fibrosis, with results being compared to the individuals' self-reported antibiotic use. For the sputum samples, two LC-MS assays were used; the Quattro Premier detected nanomolar or micromolar concentrations of 16 antibiotics, whereas the Xevo TQ-XS detected all 18 antibiotics, most at sub-nanomolar levels. In 45% of tested sputum samples (71/158), at least one antibiotic that was not reported by the subject was detected by both LC-MS methods, a discordance largely explained by the thrice weekly administration and long half-life of azithromycin. For ∼37% of samples, antibiotics reported as taken by the individual were not detected by either instrument. Our results provide an approach for detecting a variety of antibiotics at the site of infection, thereby providing a means to include antibiotic usage data into microbiome studies.

PMID: 33139284 [PubMed - as supplied by publisher]

Complement activation and endothelial perturbation parallel COVID-19 severity and activity.

J Autoimmun. 2020 Oct 29;:102560

Authors: Cugno M, Meroni PL, Gualtierotti R, Griffini S, Grovetti E, Torri A, Lonati P, Grossi C, Borghi MO, Novembrino C, Boscolo M, Uceda Renteria SC, Valenti L, Lamorte G, Manunta M, Prati D, Pesenti A, Blasi F, Costantino G, Gori A, Bandera A, Tedesco F, Peyvandi F

Abstract
BACKGROUND: Animal models and few clinical reports suggest the involvement of the complement system in the onset of severe manifestations of coronavirus disease-2019 (COVID-19). However, complement contribution to endotheliopathy and hypercoagulability has not been elucidated yet.
OBJECTIVE: To evaluate the association among complement activation, endothelial damage and disease severity or activity in COVID-19 patients.
METHODS: In this single-centre cohort study, 148 patients with COVID-19 of different severity were evaluated upon hospital admission and 30 days later. Markers of complement activation (SC5b-9 and C5a) and endothelial perturbation (von Willebrand factor [vWF], tissue-type plasminogen activator [t-PA], plasminogen activator inhibitor-1 [PAI-1], soluble thrombomodulin [sTM], and soluble endothelial selectin [sE-selectin]) were measured in plasma.
RESULTS: The patients had high plasma levels of SC5b-9 and C5a (p = 0.0001 for both) and vWF, t-PA and PAI-1 (p = 0.0001 for all). Their SC5b-9 levels correlated with those of vWF (r = 0.517, p = 0.0001) and paralleled disease severity (severe vs mild p = 0.0001, severe vs moderate p = 0.026 and moderate vs mild p = 0.001). The levels of sE-selectin were significantly increased only in the patients with severe disease. After 30 days, plasma SC5b-9, C5a and vWF levels had significantly decreased (p = 0.0001 for all), and 43% of the evaluated patients had normal levels.
CONCLUSIONS: Complement activation is boosted during the progression of COVID-19 and dampened during remission, thus indicating its role in the pathophysiology of the disease. The association between complement activation and the biomarkers of endothelial damage suggests that complement may contribute to tissue injury and could be the target of specific therapy.

PMID: 33139116 [PubMed - as supplied by publisher]

NGS-based expanded carrier screening for genetic disorders in North Indian population reveals unexpected results - a pilot study.

BMC Med Genet. 2020 Nov 02;21(1):216

Authors: Singh K, Bijarnia-Mahay S, Ramprasad VL, Puri RD, Nair S, Sharda S, Saxena R, Kohli S, Kulshreshtha S, Ganguli I, Gujral K, Verma IC

Abstract
BACKGROUND: To determine the carrier frequency and pathogenic variants of common genetic disorders in the north Indian population by using next generation sequencing (NGS).
METHODS: After pre-test counselling, 200 unrelated individuals (including 88 couples) were screened for pathogenic variants in 88 genes by NGS technology. The variants were classified as per American College of Medical Genetics criteria. Pathogenic and likely pathogenic variants were subjected to thorough literature-based curation in addition to the regular filters. Variants of unknown significance were not reported. Individuals were counselled explaining the implications of the results, and cascade screening was advised when necessary.
RESULTS: Of the 200 participants, 52 (26%) were found to be carrier of one or more disorders. Twelve individuals were identified to be carriers for congenital deafness, giving a carrier frequency of one in 17 for one of the four genes tested (SLC26A4, GJB2, TMPRSS3 and TMC1 in decreasing order). Nine individuals were observed to be carriers for cystic fibrosis, with a frequency of one in 22. Three individuals were detected to be carriers for Pompe disease (frequency one in 67). None of the 88 couples screened were found to be carriers for the same disorder. The pathogenic variants observed in many disorders (such as deafness, cystic fibrosis, Pompe disease, Canavan disease, primary hyperoxaluria, junctional epidermolysis bullosa, galactosemia, medium chain acyl CoA deficiency etc.) were different from those commonly observed in the West.
CONCLUSION: A higher carrier frequency for genetic deafness, cystic fibrosis and Pompe disease was unexpected, and contrary to the generally held view about their prevalence in Asian Indians. In spite of the small sample size, this study would suggest that population-based carrier screening panels for India would differ from those in the West, and need to be selected with due care. Testing should comprise the study of all the coding exons with its boundaries in the genes through NGS, as all the variants are not well characterized. Only study of entire coding regions in the genes will detect carriers with adequate efficiency, in order to reduce the burden of genetic disorders in India and other resource poor countries.

PMID: 33138774 [PubMed - in process]

Molecular Docking and QSAR Studies as Computational Tools Exploring the Rescue Ability of F508del CFTR Correctors.

Int J Mol Sci. 2020 Oct 29;21(21):

Authors: Righetti G, Casale M, Liessi N, Tasso B, Salis A, Tonelli M, Millo E, Pedemonte N, Fossa P, Cichero E

Abstract
Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. Different mutations involving the cystic fibrosis transmembrane regulator protein (CFTR) gene, which encodes the CFTR channel, are involved in CF. A number of life-prolonging therapies have been conceived and deeply investigated to combat this disease. Among them, the administration of the so-called CFTR modulators, such as correctors and potentiators, have led to quite beneficial effects. Recently, based on QSAR (quantitative structure activity relationship) studies, we reported the rational design and synthesis of compound 2, an aminoarylthiazole-VX-809 hybrid derivative exhibiting promising F508del-CFTR corrector ability. Herein, we explored the docking mode of the prototype VX-809 as well as of the aforementioned correctors in order to derive useful guidelines for the rational design of further analogues. In addition, we refined our previous QSAR analysis taking into account our first series of in-house hybrids. This allowed us to optimize the QSAR model based on the chemical structure and the potency profile of hybrids as F508del-CFTR correctors, identifying novel molecular descriptors explaining the SAR of the dataset. This study is expected to speed up the discovery process of novel potent CFTR modulators.

PMID: 33138251 [PubMed - in process]

Cystic Fibrosis Lung Function Decline after Within-Host Evolution Increases Virulence of Infecting Pseudomonas Aeruginosa.

Am J Respir Crit Care Med. 2020 Nov 02;:

Authors: Jorth P, Durfey S, Rezayat A, Garudathri J, Ratjen A, Staudinger BJ, Genatossio A, McNamara S, Radey MC, Cook DA, Aitken ML, Gibson RL, Yahr TL, Singh PK

PMID: 33137262 [PubMed - as supplied by publisher]

Factors influencing medical practitioner participation in population carrier screening for cystic fibrosis.

Aust N Z J Obstet Gynaecol. 2020 Nov 02;:

Authors: Valente GM, Amor DJ, Ioannou LJ, Archibald AD

Abstract
BACKGROUND: Cystic fibrosis (CF) carrier screening should be offered to people planning a pregnancy or in early pregnancy, according to current recommendations. However, research indicates rates of offering CF carrier screening are low. Health professionals (HPs) play an important role in offering population carrier screening.
AIMS: To determine the opinions, knowledge and practice patterns of HPs with regard to the routine offering of population carrier screening for CF.
MATERIALS AND METHODS: Five key informant interviews informed the development of an online questionnaire which was distributed to a select group of HPs involved in prenatal care in Victoria, Australia.
RESULTS: Of the participants who completed the questionnaire (n = 87), 35.6% reported offering CF carrier screening to all patients attending for preconception or early pregnancy consultations. High referrers of CF carrier screening were more likely to be female, work in the private sector, in metropolitan areas and specialise as an obstetrician. High referrers demonstrated a greater level of knowledge of CF and carrier screening than low referrers (t = -3.779, P < 0.001). Low referrers perceived more barriers to offering carrier screening than high referrers (t = 2.125, P = 0.037). Low referrers were more likely to perceive lack of community awareness and HP knowledge as a barrier to offering CF carrier screening, compared to high referrers, who were more likely to perceive time constraints as a barrier.
CONCLUSIONS: To promote routine offering of population CF carrier screening, resources are needed to improve knowledge and provide clinical support thereby reducing perceived barriers.

PMID: 33135161 [PubMed - as supplied by publisher]

Organoid based personalized medicine: from bench to bedside.

Cell Regen. 2020 Nov 02;9(1):21

Authors: Li Y, Tang P, Cai S, Peng J, Hua G

Abstract
Three-dimensional cultured organoids have become a powerful in vitro research tool that preserves genetic, phenotypic and behavioral trait of in vivo organs, which can be established from both pluripotent stem cells and adult stem cells. Organoids derived from adult stem cells can be established directly from diseased epithelium and matched normal tissues, and organoids can also be genetically manipulated by CRISPR-Cas9 technology. Applications of organoids in basic research involve the modeling of human development and diseases, including genetic, infectious and malignant diseases. Importantly, accumulating evidence suggests that biobanks of patient-derived organoids for many cancers and cystic fibrosis have great value for drug development and personalized medicine. In addition, organoids hold promise for regenerative medicine. In the present review, we discuss the applications of organoids in the basic and translational research.

PMID: 33135109 [PubMed]

Management of paediatric IBD after the peak of COVID-19 pandemic in Italy: A position paper on behalf of the SIGENP IBD working group.

Dig Liver Dis. 2020 Oct 22;:

Authors: Arrigo S, Alvisi P, Banzato C, Bramuzzo M, Civitelli F, Corsello A, D'Arcangelo G, Lillo AD, Dipasquale V, Felici E, Fuoti M, Gatti S, Giusti Z, Knafelz D, Lionetti P, Mario F, Marseglia A, Martelossi S, Moretti C, Norsa L, Nuti F, Panceri R, Rampado S, Renzo S, Romano C, Romeo E, Strisciuglio C, Martinelli M

Abstract
Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2, spreading in Italy during the first months of 2020, abruptly changed the way of practicing medicine in this country. As a consequence of the lockdown, the diagnostic and therapeutic management of paediatric chronic conditions, such as inflammatory bowel disease (IBD) has been affected. During the peak of COVID-19 pandemic, elective visits, endoscopies and infusions have been postponed, with potential clinical and psychological impact on disease course and a high likelihood of increasing waiting lists. While slowly moving back towards normality, clinicians need to recognize the best ways to care for patients with IBD, carefully avoiding risk factors for new potential epidemic outbreaks. In this uncertain scenario until the development and spread of COVID-19 vaccine, it is necessary to continue to operate with caution. Hereby we provide useful indications for a safer and gradual restarting of routine clinical activities after COVID-19 peak in Italy.

PMID: 33132063 [PubMed - as supplied by publisher]

Reply to Olschewski et al.: TMEM16A Potentiation: Possible Drawbacks.

Am J Respir Crit Care Med. 2020 09 15;202(6):905-906

Authors: Danahay HL, Morris DG, Gosling M

PMID: 32464067 [PubMed - indexed for MEDLINE]

TMEM16A Potentiation: Possible Drawbacks.

Am J Respir Crit Care Med. 2020 09 15;202(6):904-905

Authors: Olschewski A, Nagaraj C, Zabini D, Nagy BM, Kwapiszewska G, Olschewski H

PMID: 32464066 [PubMed - indexed for MEDLINE]

Cystic fibrosis: physiopathology and the latest pharmacological treatments.

Pharmacol Res. 2020 Oct 27;:105267

Authors: Fonseca C, Bicker J, Alves G, Falcão A, Fortuna A

Abstract
Cystic fibrosis (CF) is a lethal autosomal recessive genetic disease, which primarily affects the lungs and digestive system, caused by a mutation in the cystic fibrosis transmembrane conductance regulator gene (CFTR). This gene encodes the CFTR protein, a distinctive membrane transporter of the ATP-binding cassette (ABC) superfamily. It functions as a chloride channel, allowing the balance and transport of chloride through the apical membrane of epithelial cells. Due to its ubiquitous location, mutations in the CFTR gene trigger multiple changes in ion transport and metabolic pathways, affecting various organs, as it will be herein explained. Pulmonary impairment is the most characteristic comorbidity of CF and respiratory failure is the main cause of death. This review presents the importance of an early diagnosis of CF to establish, as soon as possible, a primary therapy for symptomatic prevention and relief. It is also mentioned the new therapeutic approaches, that include CFTR modulators. They are correctors and/or potentiators of the deficient CFTR channel. In an attempt to overcome the disadvantages of CFTR modulators, the application of biotechnology techniques is addressed, such as gene therapy, gene editing, RNA therapy and therapeutic microRNAs. The potential of the intranasal administration route is another aspect presented.

PMID: 33127556 [PubMed - as supplied by publisher]