THE PHOSPHODIESTERASE INHIBITOR ENSIFENTRINE REDUCES PRODUCTION OF PRO-INFLAMMATORY MEDIATORS IN WELL-DIFFERENTIATED BRONCHIAL EPITHELIAL CELLS BY INHIBITING PDE4.

J Pharmacol Exp Ther. 2020 Oct 04;:

Authors: Turner M, Dauletbaev N, Lands L, Hanrahan JW

Abstract
Cystic fibrosis (CF) is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) anion channel that impair airway salt and fluid secretion. Excessive release of pro-inflammatory cytokines and chemokines by CF bronchial epithelium during airway infection leads to chronic inflammation and a slow decline in lung function, thus there is much interest in finding safe and effective treatments that reduce inflammation in CF. We showed previously that the cyclic nucleotide phosphodiesterase (PDE) inhibitor ensifentrine (RPL554; Verona Pharma) stimulates the channel function of CFTR mutants with abnormal gating and also those with defective trafficking that are partially rescued using a clinically approved corrector drug. PDE inhibitors also have known anti-inflammatory effects, therefore we examined whether ensifentrine alters the production of pro-inflammatory cytokines in CF bronchial epithelial cells. Ensifentrine reduced the production of monocyte chemoattractant protein-1 (MCP-1) and granulocyte monocyte colony stimulating factor (GM-CSF) during challenge with Interleukin-1β. Comparing the effect of ensifentrine with milrinone and roflumilast, selective PDE3 and PDE4 inhibitors respectively, demonstrated that the anti-inflammatory effect of ensifentrine was mainly due to inhibition of PDE4. Beneficial modulation of GM-CSF was further enhanced when ensifentrine was combined with low concentrations of the β2-adrenergic agonist isoproterenol or the corticosteroid dexamethasone. The results indicate ensifentrine may have beneficial anti-inflammatory effects in CF airways particularly when used in combination with β2-adrenergic agonists or corticosteroids. Significance Statement Airways inflammation that is disproportionate to the burden of chronic airway infection causes much of the pathology in the Cystic Fibrosis (CF) lung. We show here that ensifentrine beneficially modulates the release of pro-inflammatory factors in well-differentiated CF bronchial epithelial cells that is further enhanced when combined with β2-adrenergic agonists or low-concentration corticosteroids. The results encourage further clinical testing of ensifentrine, alone and in combination with β2-adrenergic agonists or low-concentration corticosteroids, as a novel anti-inflammatory therapy for CF.

PMID: 33012706 [PubMed - as supplied by publisher]

"By Time's Fell Hand": Shakespeare and Emotional Lockdown.

Mayo Clin Proc. 2020 Oct;95(10):2073-2075

Authors: Craik KA, Chapman SJ

PMID: 33012339 [PubMed - in process]

Chronic rhinitis in South Africa - more than just allergy!

S Afr Med J. 2020 Jul 07;110(7):594-598

Authors: Green RJ, Hockman M, Friedman R, Van Niekerk A, Feldman C, Vardas E, Quitter C, Els C, Van Bruwaene L, Nanan A, Peter J, Seedat RY, Levin M, Bateman On Behalf Of The South African Allergic Rhinitis Working Group Saarwg C

Abstract
Chronic rhinitis is a troublesome condition for sufferers. It is tempting to label all patients with chronic nasal symptoms as having allergic rhinitis (AR), but many such patients have other causes of chronic rhinitis that need a specific diagnosis and management strategy. Even when the patient fully fits the definition of AR, their condition will be best served by combining medication with ongoing patient education.

PMID: 32880327 [PubMed - indexed for MEDLINE]

Safety and efficacy of lenabasum in a phase 2 randomized, placebo-controlled trial in adults with cystic fibrosis.

J Cyst Fibros. 2020 Sep 30;:

Authors: Chmiel JF, Flume P, Downey DG, Dozor AJ, Colombo C, Mazurek H, Sapiejka E, Rachel M, Constantine S, Conley B, Dgetluck N, Dinh Q, White B, Elborn JS, Lenabasum JBT101-CF-001 Study Group

Abstract
BACKGROUND: Few therapies specifically address the chronic airway inflammation in cystic fibrosis (CF) that contributes to progressive destruction of lung tissue and loss of lung function. Lenabasum is a cannabinoid type 2 receptor (CB2) agonist that resolves inflammation in a number of in vitro and in vivo models.
METHODS: A Phase 2 double-blind, randomized, placebo-controlled study assessed the safety and tolerability of lenabasum in adults with CF. Subjects with FEV1% (ppFEV1) ≥40% predicted were randomized to lenabasum 1 or 5 mg or placebo once daily (QD) (Weeks 1-4), then 20 mg QD, 20 mg twice daily (BID) or placebo (Weeks 5-12), with follow-up at Week 16. Pulmonary exacerbations (PEx) were recorded and biomarkers of blood and lung inflammation were measured.
RESULTS: Of 89 subjects randomized, 51 lenabasum and 23 placebo-only subjects completed the study. No deaths or serious or severe adverse events (AE) were considered related to lenabasum. Most AEs were mild/moderate, and the most common were PEx, hemoptysis, dry mouth, and upper respiratory infection. Three lenabasum and one placebo-only subjects discontinued the study for a treatment related AE. New PEx were treated with intravenous antibiotics in 4.0% of lenabasum-treated vs. 11.4% of placebo-treated subjects, during Weeks 1-4 and 5.2% compared to 13.0% during Weeks 5-12 (p<0.2). No significant differences in ppFEV1 were observed between treatment groups. Sputum neutrophils, eosinophils, and neutrophil elastase were numerically reduced, and significant (p<0.05) reductions in IL-8 and immunoglobulin G levels occurred with lenabasum.
CONCLUSIONS: The safety findings of lenabasum, coupled with biomarker data, support further testing in a larger study with a longer duration.

PMID: 33011099 [PubMed - as supplied by publisher]

Combined Single Lung and Liver Transplantation in a Cystic Fibrosis Patient With Previous Contralateral Pneumonectomy: A Case Report.

Transplant Proc. 2020 Sep 30;:

Authors: Roquet G, Maury JM, Mabrut JY, Flamens C, Senechal A, Mornex JF, Tronc F

Abstract
Combined lung-liver transplantation is a rare life-saving procedure to treat concomitant end-stage lung and liver failure. In this report, we describe the first published case of single lung and liver transplantation in a cystic fibrosis patient who had previously undergone a pneumonectomy for the treatment of an infected and destroyed right lung. We detail the lung first, sequential transplant procedure and surgical difficulties due to mediastinal shift. Emergent intraoperative renal replacement therapy was carried out before liver transplantation to overcome pulmonary edema in the transplanted lung. After fluid balance equilibration, liver transplantation was performed in good conditions. The patient is currently alive with no signs of rejection 8 years after the procedure.

PMID: 33010935 [PubMed - as supplied by publisher]

Sit-to-stand test in children with bronchiectasis: Does it measure functional exercise capacity?

Heart Lung. 2020 Sep 30;49(6):796-802

Authors: Zeren M, Gurses HN, Denizoglu Kulli H, Ucgun H, Cakir E

Abstract
BACKGROUND: Similar to six-minute walk test (6MWT), sit-to-stand test (STST) is a self-paced test which elicits sub-maximal effort; therefore, it is suggested as an alternative measurement for functional exercise capacity in various pulmonary conditions including COPD and cystic fibrosis. We aimed to investigate the association between 30-second STST (30s-STST) and 6MWT in both children with bronchiectasis (BE) and their healthy counterparts, as well as exploring cardiorespiratory burden and discriminative properties of both tests.
METHODS: Sixty children (6 to 18-year-old) diagnosed with non-cystic fibrosis BE and 20 age-matched healthy controls were included. Both groups performed 30s-STST and 6MWT. Test results, and heart rate, SpO2 and dyspnea responses to tests were recorded.
RESULTS: Univariate analysis revealed that 30s-STST was able to explain 52% of variance in 6MWT (r = 0.718, p<0.001) in BE group, whereas 20% of variance in healthy controls (r = 0.453, p = 0.045). 6MWT elicited higher changes in heart rate and dyspnea level compared to 30s-STST, indicating it was more physically demanding. Both 30s-STST (21.65±5.28 vs 26.55±3.56 repetitions) and 6MWT (538±85 vs 596±54 m) were significantly lower in BE group compared to healthy controls (p<0.01). Receiver operating characteristic (ROC) curve analysis revealed an area under the ROC curve (UAC) of 0.765 for 30s-STST and 0.693 for 6MWT in identifying the individuals with or without BE (p<0.05). Comparison between AUCs of 30s-STST and 6MWT yielded no significant difference (p = 0.466), indicating both tests had similar discriminative properties.
CONCLUSIONS: 30s-STST is found to be a valid alternative measurement for functional exercise capacity in children with BE.

PMID: 33010517 [PubMed - as supplied by publisher]

Inhibitory activities of curzerenone, curdione, furanodienone, curcumol and germacrone on Ca2+-activated chloride channels.

Fitoterapia. 2020 Sep 30;:104736

Authors: Zhu X, Zhang W, Jin L, Zhang G, Yang H, Yu B

Abstract
Calcium-activated chloride channels (CaCCs) as a kind of widely expressed ion channels play crucial roles in a variety of physiological regulation. TMEM16A has been identified as the molecular basis of CaCCs in numerous cell types and is considered a new drug target for many diseases. Regulating the function of TMEM16A through small molecule modulators has become a new strategy to improve respiratory and digestive dysfunction and even tumor therapy. Herein, we obtained 5 sesquiterpenoids, named curzerenone, curdione, furanodienone, curcumol and germacrone with TMEM16A inhibition and revealed their mechanism of action by fluorescent and electrophysiological assays. Cell-based YFP fluorescence data demonstrated that 5 compounds inhibited TMEM16A-mediated I- influx in a dose-dependent manner. To explore the mechanism of 5 compounds on CaCCs, FRT cells with high expression of TMEM16A, HBE, HT-29 and T84 cells and mouse colons were used in short-circuit current assay. Our results showed that 5 compounds inhibited the Ca2+-activated Cl- currents generated by the Eact, ATP and UTP stimulation, and this inhibitory effect was related not only to the direct inhibition of channel opening, but also the inhibition of intracellular Ca2+ concentration and K+ channel activity. In addition to CaCCs, these 5 compounds also had definite inhibitory activities against cystic fibrosis transmembrane regulator (CFTR) at the cellular level. In summary, these compounds have the potential to regulate the activites of TMEM16A/CaCCs and CFTR channels in vitro, providing a new class of lead compounds for the development of drugs for diseases related to chloride channel dysfunction.

PMID: 33010370 [PubMed - as supplied by publisher]

Impulse oscillometry and spirometry measurements relative to personal best values at the time of acute exacerbations of cystic fibrosis in adults.

Clin Physiol Funct Imaging. 2020 Oct 03;:

Authors: Blin T, Flament T, Mankikian J, Chambellan A, Marchand-Adam S, Plantier L

Abstract
BACKGROUND: Diagnosis of acute exacerbation (AE) of cystic fibrosis (CF) must be precise because both under- and over-prescription of antibiotics may be detrimental. How lung function tests contribute to diagnose AE is unclear. We aimed to describe variation of spirometry and oscillometry measurements, at Stable state and at AE in adults with CF.
METHODS: Patients were included in a retrospective single-centre study when both spirometry (FEV1, FVC) and oscillometry (X5, R5, R5-R20 and AX) data were available for at least one Stable and one AE visit between December 2016 and July 2019. For each visit, we calculated variation (Δ) in spirometry and oscillometry indices in comparison with personal best values. Measurements were expressed as % of predicted values and Z-scores when applicable. Areas under ROC curves (AUC) were computed.
RESULTS: Forty-two patients (28±9 years, FEV1 64±21%) were included; 80 AE and 104 Stable visits were analysed. FEV1 (L, %pred and Z-score) and FVC (%pred and Z-score) varied significantly between AE and Stable visits (p<0.05), although differences were small (80 ml/2.7%pred for FEV1). Among oscillometry indices, X5 (kPa.s.L-1), R5-R20 (kPa.s.L-1) and AX (kPa/L) varied significantly. The AUCs for the variation in spirometry indices ranged from 0.601 (ΔFVC L) to 0.635 (ΔFEV1 %pred). They were not significantly different from the AUCs for ΔX5 (0.589), ΔR5-R20 (0.649) and ΔAX (0.598).
CONCLUSIONS: Performance of both spirometry and oscillometry to discriminate AE from Stable state was poor. Variation of oscillometry indices (X5, R5-R20, AX) may be helpful when spirometry is unreliable or uncomfortable.

PMID: 33010097 [PubMed - as supplied by publisher]

Immunological and virological profile of children with chilblain-like lesions and SARS-CoV-2.

J Eur Acad Dermatol Venereol. 2020 Oct 03;:

Authors: Fertitta L, Welfringer A, Ouedrani A, Polivka L, Chhun S, Chatenoud L, Fourgeaud J, Hadj-Rabia S, Temmam S, Eloit M, Sermet-Gaudelus, Bodemer C

Abstract
The link between SARS-CoV-2 and the reported cutaneous manifestations has not been established. We assessed a possible correlation between the paediatric dermatological manifestations and the biological investigations, using for the first time 3 different SARS-CoV-2 tests.

PMID: 33010072 [PubMed - as supplied by publisher]

Are cystic fibrosis mutation carriers a potentially highly vulnerable group to COVID-19?

J Cell Mol Med. 2020 Oct 03;:

Authors: Sarantis P, Koustas E, Papavassiliou AG, Karamouzis MV

Abstract
Undoubtedly, the new SARS-CoV-2 virus poses a grave health threat, plaguing the health and socio-economic sectors. COVID-19 disease must be treated quickly and effectively as soon as possible. The main axes in this direction are establishing vaccines, drugs, diagnostic tests, as well as identifying the most vulnerable groups. Probably, there is a correlation between COVID-19 and cystic fibrosis. Our interest is focused on cystic fibrosis carriers that, due to limited tests, remain undetectable. There is an activation of the inflammatory response in the carriers, as well as in cystic fibrosis patients. First of all, a striking similarity lies between the inflammatory response in COVID-19 and cystic fibrosis carriers. Notably, ACE-2 plays the same role in both cases and a similar geographical distribution is observed in both diseases. In conclusion, we suggest that cystic fibrosis mutation carriers are potential members of a certain vulnerable group and the detection of such mutations in the population might be vital for the prevention of SARS-CoV-2 virus, and more specifically to limit its serious complications.

PMID: 33009727 [PubMed - as supplied by publisher]

Cystic Fibrosis in the PICU-More of a Zebra Than a Horse.

Pediatr Crit Care Med. 2020 Oct;21(10):904-905

Authors: Hartmann SM, McGuire JK

PMID: 33009302 [PubMed - as supplied by publisher]

Prolonged infusion of beta-lactam antibiotics for Gram-negative infections: rationale and evidence base.

Curr Opin Infect Dis. 2020 Sep 29;:

Authors: Abdul-Aziz MH, Portunato F, Roberts JA

Abstract
PURPOSE OF REVIEW: The aim of this review is to discuss the rationale of and current evidence for prolonged beta-lactam infusion in the management of Gram-negative infections.
RECENT FINDINGS: Pharmacokinetic/pharmacodynamic (PK/PD) data from various in-vitro and in-vivo experimental studies conclusively support prolonged infusion over intermittent infusion in terms of achieving effective beta-lactam exposure for maximal bacterial killing. Superior PK/PD target attainment has been demonstrated with prolonged beta-lactam infusion in patient populations that are more likely to have less susceptible Gram-negative infections. These populations include critically ill patients, cystic fibrosis patients and patients with malignant diseases. The clinical impact of prolonged beta-lactam infusion is likely to be the greatest in these patient groups: critically ill patients with a high level of illness severity who are not receiving renal replacement therapy; patients with nonfermenting Gram-negative bacilli infection and patients with respiratory infection. Critically ill patients with augmented renal clearance may not achieve effective beta-lactam exposure even with the use of prolonged infusion. Maximizing the effectiveness of prolonged beta-lactam infusion via therapeutic drug monitoring is becoming a more common strategy in the management of critically ill patients with Gram-negative infection.
SUMMARY: Prolonged beta-lactam infusion may not benefit all patients but only for those who are critically ill and/or immunocompromised, who are also more likely to have less susceptible Gram-negative infections.

PMID: 33009140 [PubMed - as supplied by publisher]

Intravenous versus oral antibiotics for eradication of Pseudomonas aeruginosa in cystic fibrosis (TORPEDO-CF): a randomised controlled trial.

Lancet Respir Med. 2020 Oct;8(10):975-986

Authors: Hewer SCL, Smyth AR, Brown M, Jones AP, Hickey H, Kenna D, Ashby D, Thompson A, Williamson PR, TORPEDO-CF study group

Abstract
BACKGROUND: Chronic pulmonary infection with Pseudomonas aeruginosa is one of the most important causes of mortality and morbidity in cystic fibrosis. If antibiotics are commenced promptly, infection can be eradicated. The aim of the trial was to compare the effectiveness and safety of intravenous ceftazidime and tobramycin versus oral ciprofloxacin in the eradication of P aeruginosa.
METHODS: We did a multicentre, parallel group, open-label, randomised controlled trial in 72 cystic fibrosis centres (70 in the UK and two in Italy). Eligible participants were older than 28 days with an isolate of P aeruginosa (either the first ever isolate or a new isolate after at least 1 year free of infection). Participants were excluded if the P aeruginosa was resistant to, or they had a contraindication to, one or more of the trial antibiotics; if they were already receiving P aeruginosa suppressive therapy; if they had received any P aeruginosa eradication therapy within the previous 9 months; or if they were pregnant or breastfeeding. We used web-based randomisation to assign patients to 14 days intravenous ceftazidime and tobramycin or 12 weeks oral ciprofloxacin. Both were combined with 12 weeks inhaled colistimethate sodium. Randomisation lists were generated by a statistician, who had no involvement in the trial, using a computer-generated list. Randomisation was stratified by centre and because of the nature of the interventions, blinding was not possible. Our primary outcome was eradication of P aeruginosa at 3 months and remaining free of infection to 15 months. Primary analysis used intention to treat (powered for superiority). Safety analysis included patients who received at least one dose of study drug. TORPEDO-CF was registered on the ISRCTN register, ISRCTN02734162, and EudraCT, 2009-012575-10.
FINDINGS: Between Oct 5, 2010, and Jan 27, 2017, 286 patients were randomly assigned to treatment: 137 to intravenous antibiotics and 149 to oral antibiotics. 55 (44%) of 125 participants in the intravenous group and 68 (52%) of 130 participants in the oral group achieved the primary outcome. Participants randomly assigned to the intravenous group were less likely to achieve the primary outcome, although the difference between groups was not statistically significant (relative risk 0·84, 95% CI 0·65-1·09; p=0·18). 11 serious adverse events occurred in ten (8%) of 126 participants in the intravenous antibiotics group and 17 serious adverse events in 12 (8%) of 146 participants in the oral antibiotics group.
INTERPRETATION: Compared with oral therapy, intravenous antibiotics did not achieve sustained eradication of P aeruginosa in a greater proportion of patients with cystic fibrosis and was more expensive. Although there were fewer hospitalisations in the intravenous group than the oral group during follow-up, this confers no advantage over oral treatment because intravenous eradication frequently requires hospitalisation. These results do not support the use of intravenous antibiotics to eradicate P aeruginosa in cystic fibrosis.
FUNDING: National Institute for Health Research Health Technology Assessment Programme.

PMID: 33007285 [PubMed - as supplied by publisher]

Diagnostic Value of Sputum Cultures in Children under 2 Years of Age with Chronic Suppurative Lung Diseases.

Pediatr Pulmonol. 2020 Oct 02;:

Authors: Stafler P, Zaks-Hoffer G, Scheuerman O, Ben Zvi H, Mussaffi H, Mei-Zahav M, Steuer G, Levine H, Bar-On O, Mantin H, Prais D, Blau H

Abstract
BACKGROUND: Acquiring sputum cultures from infants is considered challenging. We describe their yield in infants with CF and other chronic suppurative lung diseases (CSLD).
METHODS: Retrospective medical record review over a 4 year period, for infants aged 0-2 years with ≥ 2 airway bacterial cultures acquired by deep suction or induced sputum ≥ 4 weeks apart. Data included demographics, culture results and clinical status.
RESULTS: 98 infants (16 CF) were evaluated and 534 sputum cultures acquired, 201 in CF and 333 in CSLD. There were 12 (2-23), median (range) cultures/ CF infant, and 3 (2-21)/ CSLD infant. Age at first culture was 3.8 (1-19.5) months for CF and 10.4 (0.5-22) months for CSLD, p=0.016. 360 cultures (67%) were positive for any bacteria, with 170/234 (73%) positive during exacerbations, compared to 190/300 (63%) during routine visits, p=0.05. More infants with CF than CSLD had cultures positive for Staphylococcus aureus (SA) (75% vs 34%, p=0.004) throughout the period. Pseudomonas aeruginosa (PA) was common in both CF and CSLD (56% and 44% respectively, p=0.42) and increased over time for CF but was high throughout for CSLD. Number of hospital days prior to PA acquisition was 6 (10.2) for CF and 28.8 (38.7) for CSLD (p=0.003). No CF but 6/82 (7%) CSLD infants had chronic PA (p=0.56).
CONCLUSIONS: Sputum cultures showed that infection, in particular PA, is common in CF and CSLD whereas SA is more common in CF. Prospective studies are warranted to elucidate the role of active surveillance in guiding antibiotic therapy. This article is protected by copyright. All rights reserved.

PMID: 33006230 [PubMed - as supplied by publisher]

A case of reversible toxic optic neuropathy from tacrolimus (FK506).

Am J Ophthalmol Case Rep. 2020 Dec;20:100932

Authors: Gokoffski KK, Patel VR

Abstract
Purpose: To report a rare case of reversible vision loss from tacrolimus-associated toxic optic neuropathy.
Observations: A 30-year-old man with cystic fibrosis requiring bilateral lung transplantation developed painless, bilateral, gradual onset central vision loss with dyschromatopsia two years after starting tacrolimus. Visual fields revealed bilateral cecocentral scotomas. Fundoscopy demonstrated bilateral temporal pallor of the optic nerves. Testing for nutritional deficiencies was unremarkable. Tacrolimus was switched to cyclosporine and the patient was started on idebenone. Two months later, the patient demonstrated marked improvement in his visual acuity and dyschromatopsia.
Conclusionsand Importance: Neurotoxicity is a rare but major potential side effect of tacrolimus. Idebenone should be considered as a potential, low-risk supplement for transplant patients who are immunosuppressed in whom toxic optic neuropathy is a concern.

PMID: 33005819 [PubMed]

Alleviation of depression-like behavior in a cystic fibrosis mouse model by Hdac6 depletion.

Sci Rep. 2020 Oct 01;10(1):16278

Authors: Corey DA, Rymut SM, Kelley TJ

Abstract
Cystic fibrosis (CF) patients experience heightened levels of anxiety and depression. Stress from dealing with chronic disease and rigorous treatment regimens certainly are primary contributors to these outcomes. We previously have demonstrated that microtubule alterations in CF are linked to a number of CF phenotypes including growth regulation and inflammatory responses to airway bacterial challenge. Deletion of histone deactelyase 6 (HDAC6), a cytosolic deacetylase that regulates tubulin acetylation, in CF mice restores growth and inflammatory phenotypes to wild type (WT) profiles. In this study, the hypothesis that Hdac6 depletion in CF mice would impact behaviors since Hda6 inhibition has been previously reported to have anti-depressive properties. Data demonstrate that CF mice exhibit reduced activity and reduced open arm time in an elevated plus maze test which can be consistent with anxiety-like behavior. CF mice also exhibit depression-like behaviors compared to WT mice in an age dependent manner. By eight weeks of age, CF mice exhibit significantly more immobile time in the tail-suspension test, however, Hdac6 depletion reverses the depressive phenotype. These data demonstrate that loss of CFTR function may predispose patients to experience depression and that this behavior is Hdac6 dependent.

PMID: 33004910 [PubMed - in process]

Asthma in children and adolescents: the ControL'Asma project.

Acta Biomed. 2020 Sep 15;91(11-S):e2020002

Authors: Licari A, Ciprandi G, Marseglia GL, Silvestri M, Tosca MA, Anastasio E, Brambilla I, Caffarelli C, Castagnoli R, Chini L, Ciprandi R, De Vittori V, Duse M, Di Cicco ME, Indinnimeo L, Kantar A, Leone M, Marinelli G, Moschese V, Olcese R, Peroni DG, Pistorio A, Salmaso C, Zicari AM

Abstract
The control of asthma is the objective of asthma management. However, it is difficult to obtain in clinical practice. The Italian Society of Allergy and Clinical Immunology promoted the nationwide project "ControL'Asma" to investigate the real situation in a group of children and adolescents with asthma. The preliminary outcomes demonstrated that many asthmatic subjects do not achieve adequate asthma control. Moreover, asthma in Italian children and adolescents was usually more frequent in males, had an early onset and allergic phenotype with very frequent rhinitis comorbidity, uncontrolled and partly controlled asthma affected about the half of subjects. However, this project suggested that the assessment of asthma symptom perception by VAS could be a reliable tool in the asthma management.

PMID: 33004772 [PubMed - in process]

Qualitative exploration of health professionals' experiences of communicating positive newborn bloodspot screening results for nine conditions in England.

BMJ Open. 2020 Oct 01;10(10):e037081

Authors: Chudleigh J, Chinnery H, Bonham JR, Olander E, Moody L, Simpson A, Morris S, Ulph F, Bryon M, Southern K

Abstract
OBJECTIVE: To explore health professionals' experiences of communicating positive newborn bloodspot screening (NBS) results, highlight differences, share good practice and make recommendations for future research.
DESIGN: Qualitative exploratory design was employed using semi-structured interviews SETTING: Three National Health Service provider organisations in England PARTICIPANTS: Seventeen health professionals involved in communicating positive newborn bloodspot screening results to parents for all nine conditions currently included in the newborn bloodspot screening programme in England.
RESULTS: Findings indicated variation in approaches to communicating positive newborn bloodspot screening results to parents, largely influenced by resources available and the lack of clear guidance. Health professionals emphasised the importance of communicating results to families in a way that is sensitive to their needs. However, many challenges hindered communication including logistical considerations; difficulty contacting the family and other health professionals; language barriers; parental reactions; resource considerations; lack of training; and insufficient time.
CONCLUSION: Health professionals invest a lot of time and energy trying to ensure communication of positive newborn bloodspot screening results to families is done well. However, there continues to be great variation in the way these results are communicated to parents and this is largely influenced by resources available but also the lack of concrete guidance. How best to support health professionals undertaking this challenging and emotive task requires further exploration. We recommend evaluation of a more cohesive approach that meets the needs of parents and staff while being sensitive to the subtleties of each condition.
TRIAL REGISTRATION NUMBER: ISRCTN15330120.

PMID: 33004391 [PubMed - in process]

A systematic review of patient-reported outcome measures (PROMs) in cystic fibrosis.

BMJ Open. 2020 Oct 01;10(10):e033867

Authors: Ratnayake I, Ahern S, Ruseckaite R

Abstract
BACKGROUND: To determine patient-reported outcome measures (PROMs) which may be suitable for incorporation into the Australian Cystic Fibrosis Data Registry (ACFDR) by identifying PROMs administered in adult and paediatric cystic fibrosis (CF) populations in the last decade.
METHODS: We searched MEDLINE, EMBASE, Scopus, CINAHL, PsycINFO and Cochrane Library databases for studies published between January 2009 and February 2019 describing the use of PROMs to measure health-related quality of life (HRQoL) in adult and paediatric patients with CF. Validation studies, observational studies and qualitative studies were included. The search was conducted on 13 February 2019. The COnsensus-based Standards for the selection of health Measurement INstruments Risk of Bias Checklist was used to assess the methodological quality of included studies.
RESULTS: Twenty-seven different PROMs were identified. The most commonly used PROMs were designed specifically for CF. Equal numbers of studies were conducted on adult (32%, n=31), paediatric (35%, n=34) and both (27%, n=26) populations. No PROMs were used within a clinical registry setting previously. The two most widely used PROMs, the Cystic Fibrosis Questionnaire-Revised (CFQ-R) and the Cystic Fibrosis Quality of Life Questionnaire (CFQoL), demonstrated good psychometric properties and acceptability in English-speaking populations.
DISCUSSION: We found that although PROMs are widely used in CF, there is a lack of reporting on the efficacy of methods and timepoints of administration. We identified the CFQ-R and CFQoL as the most suitable for incorporation in the ACFDR as they captured significant effects of CF on HRQoL and were reliable and valid in CF populations. These PROMs will be used in a further qualitative study assessing patients' with CF and clinicians' perspectives toward the acceptability and feasibility of incorporating a PROM in the ACFDR.
PROSPERO REGISTRATION NUMBER: CRD42019126931.

PMID: 33004381 [PubMed - in process]

Heterozygous Cystic Fibrosis Transmembrane Regulator Gene Missense Variants Are Associated With Worse Cardiac Function in Patients With Duchenne Muscular Dystrophy.

J Am Heart Assoc. 2020 Oct 02;:e016799

Authors: Jiang X, Shao Y, Araj FG, Amin AA, Greenberg BM, Drazner MH, Xing C, Mammen PPA

Abstract
Background Duchenne muscular dystrophy (DMD) is a neuromuscular disorder caused by mutations within the dystrophin gene. DMD is characterized by progressive skeletal muscle degeneration and atrophy and progressive cardiomyopathy. It has been observed the severity of cardiomyopathy varies in patients with DMD. Methods and Results A cohort of male patients with DMD and female DMD carriers underwent whole exome sequencing. Potential risk factor variants were identified according to their functional annotations and frequencies. Cardiac function of 15 male patients with DMD was assessed by cardiac magnetic resonance imaging, and various cardiac magnetic resonance imaging parameters and circulating biomarkers were compared between genotype groups. Five subjects carrying potential risk factor variants in the cystic fibrosis transmembrane regulator gene demonstrated lower left ventricular ejection fraction, larger left ventricular end-diastolic volume, and higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels compared with 10 subjects who did not carry the potential risk factor variants (P=0.023, 0.019 and 0.028, respectively). Conclusions This study revealed heterozygous cystic fibrosis transmembrane regulator gene missense variants were associated with worse cardiac function in patients with DMD. The cystic fibrosis transmembrane regulator gene may serve as a genetic modifier that accounts for more severe cardiomyopathy in patients with DMD, who would require more aggressive management of the cardiomyopathy.

PMID: 33003980 [PubMed - as supplied by publisher]