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  • Journal article
    Stanford GE, Jones M, Charman SC, Bilton D, Usmani OS, Davies JC, Simmonds NJet al., 2022,

    Clinimetric analysis of outcome measures for airway clearance in people with cystic fibrosis: a systematic review

    , Therapeutic Advances in Respiratory Disease, Vol: 16, Pages: 1-12, ISSN: 1753-4666

    Background:Airway clearance techniques (ACTs) are integral to cystic fibrosis (CF) management. However, there is no consensus as to which outcome measures (OMs) are best for assessing ACT efficacy.Objectives:To summarise OMs that have been assessed for their clinimetric properties (including validity, feasibility, reliability, and reproducibility) within the context of ACT research in CF.Design and Methods:A systematic review was conducted according to Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA) standards. Any parallel or cross-over randomised controlled trial (RCT) investigating outcome measures for ACT in the CF population were eligible for inclusion. The search was performed in five medical databases, clinicaltrials.gov, and abstracts from international CF conferences. The authors planned to independently assess study quality and risk of bias using the COnsensus-based Standards for the selection of health status Measurement InstrumeNts (COSMIN) risk of bias checklist with external validity assessment based upon study details (participants and study intervention). Two review authors (GS and MJ) independently screened search results against inclusion criteria, and further data extraction were planned but not required.Results:No completed RCTs from the 187 studies identified met inclusion criteria for the primary or post hoc secondary objective. Two ongoing trials were identified.Discussion and conclusion:This empty systematic review highlights that high-quality RCTs are urgently needed to investigate and validate the clinimetric properties of OMs used to assess ACT efficacy. With the changing demographics of CF combined with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies, an accurate assessment of the current benefit of ACT or the effect of ACT withdrawal is a high priority for clinical practice and future research; OMs which have been validated for this purpose are essenti

  • Journal article
    Jones MP, Krexner T, Bismarck A, 2022,

    Repurposing Fischer-Tropsch and natural gas as bridging technologies for the energy revolution

    , Energy Conversion and Management, Vol: 267, ISSN: 0196-8904

    Immediate and widespread changes in energy generation and use are critical to safeguard our future on this planet. However, while the necessity of renewable electricity generation is clear, the aviation, transport and mobility, chemical and material sectors are challenging to fully electrify. The age-old Fischer-Tropsch process and natural gas industry could be the bridging solution needed to accelerate the energy revolution in these sectors – temporarily powering obsolete vehicles, acting as renewable energy's battery, supporting expansion of hydrogen fuel cell technologies and the agricultural and waste sectors as they struggle to keep up with a full switch to biofuels. Natural gas can be converted into hydrogen, synthetic natural gas, or heat during periods of low electricity demand and converted back to electricity again when needed. Moving methane through existing networks and converting it to hydrogen on-site at tanking stations also overcomes hydrogen distribution, storage problems and infrastructure deficiencies. Useful co-products include carbon nanotubes, a valuable engineering material, that offset emissions in the carbon nanotube and black industries. Finally, excess carbon can be converted back into syngas if desired. This flexibility and the compatibility of natural gas with both existing and future technologies provides a unique opportunity to rapidly decarbonise sectors struggling with complex requirements.

  • Journal article
    Lee CT, Feary J, Johannson KA, 2022,

    Environmental and occupational exposures in interstitial lung disease

    , CURRENT OPINION IN PULMONARY MEDICINE, Vol: 28, Pages: 414-420, ISSN: 1070-5287
  • Journal article
    Hine C, Desai M, Davies J, Sapey E, Nagakumar Pet al., 2022,

    A systematic review of lung clearance index in non-cystic fibrosis, non-primary ciliary dyskinesia bronchiectasis

    , Respiratory Medicine, Vol: 201, Pages: 1-8, ISSN: 0954-6111

    BackgroundNon cystic fibrosis, non primary ciliary dyskinesia bronchiectasis (nCFnPCD-BE) results in significant morbidity with few evidence-based treatments.Objectiveassessments are required to assess severity and evaluate treatment. Lung clearance index (LCI) measures ventilation inhomogeneity and is a sensitive test of disease in CF; its use in nCFnPCD-BE is unclear.MethodsA systematic review of LCI in nCFnPCD-BE was performed using standard methodology (protocol registered on PROSPERO, University of York).ResultsOf 276 records identified, 12 articles, describing 519 adult and paediatric patients in cross-sectional studies were included, addressing several domains.1: What is the utility of LCI in detecting disease and severity?LCI detected disease in adults, differentiating bronchiectasis from controls (AUC 0.90 to 0.96) and mild from moderate/severe bronchiectasis on CT (AUC 0.73).2: Does LCI correlate with spirometry and imaging?LCI correlated with spirometry in adult (r = −0.37 to −0.61) and paediatric (r = −0.6) groups, signs of bronchiectasis on CT, and CT scoring systems (modified Reiff).3: Does LCI relate to subjective scores of severity?In adults, LCI correlated with St. George's Respiratory Questionnaire (r = 0.18) and Bronchiectasis Severity Index (r = 0.45).4: Does LCI identify response to intervention?LCI did not change in studies examining LCI pre-post intervention (adults treated for exacerbation and undergoing physiotherapy).Overall study quality was variable.ConclusionContrary to data in CF, the review did not identify good quality studies defining the role of LCI in children with bronchiectasis. In adults, LCI was a sensitive measure of disease severity and correlated with clinical assessment tools.

  • Journal article
    Ledesma Amaro R, Ellis T, Shaw W, Studena L, Roy K, Mccarty N, Graham A, Hapeta Pet al., 2022,

    Inducible expression of large gRNA arrays for multiplexed CRISPRai applications

    , Nature Communications, Vol: 13, ISSN: 2041-1723

    CRISPR gene activation and inhibition (CRISPRai) has become a powerful synthetic tool for influencing the expression of native genes for foundational studies, cellular reprograming, and metabolic engineering. Here we develop a method for near leak-free, inducible expression of a polycistronic array containing up to 24 gRNAs from two orthogonal CRISPR/Cas systems to increase CRISPRai multiplexing capacity and target gene flexibility. To achieve strong inducibility, we created a technology to silence gRNA expression within the array in the absence of the inducer, since we found that long gRNA arrays for CRISPRai can express themselves even without promoter. Using this method, we create a highly tuned and easy-to-use CRISPRai toolkit in the industrially relevant yeast, Saccharomyces cerevisiae, establishing the first system to combine simultaneous activation and repression, large multiplexing capacity, and inducibility. We demonstrate this platform by targeting 11 genes in central metabolism in a single transformation, achieving a 45-fold increase in succinic acid, which could be precisely controlled in an inducible manner. Our method offers a highly effective way to regulate genes and rewire metabolism in yeast, with principles of gRNA array construction and inducibility that should extend to other chassis organisms.

  • Journal article
    Farne H, Lin L, Jackson D, Rattray M, Simpson A, Custovic A, Joshi S, Wilson P, Williamson R, Edwards M, Singanayagam A, Johnston Set al., 2022,

    In vivo bronchial epithelial interferon responses are augmented in asthma on day 4 following experimental rhinovirus infection

    , Thorax, Vol: 77, Pages: 929-932, ISSN: 0040-6376

    Despite good evidence of impaired innate antiviral responses in asthma, trials of inhaled interferon-β given during exacerbations showed only modest benefits in moderate/severe asthma. Using human experimental rhinovirus infection, we observe robust in vivo induction of bronchial epithelial interferon response genes four days after virus inoculation in 25 subjects with asthma but not 11 control subjects. This signature correlated with virus loads and lower respiratory symptoms. Our data indicate that the in vivo innate antiviral response is dysregulated in asthma and open up the potential that prophylactic rather than therapeutic interferon therapy may have greater clinical benefit.

  • Journal article
    Allen RJ, Oldham JM, Jenkins DA, Leavy OC, Guillen-Guio B, Melbourne CA, Ma S-F, Jou J, Kim JS, CleanUP-IPF Investigators of the Pulmonary Trials Cooperative, Fahy WA, Oballa E, Hubbard RB, Navaratnam V, Braybrooke R, Saini G, Roach KM, Tobin MD, Hirani N, Whyte MKB, Kaminski N, Zhang Y, Martinez FJ, Linderholm AL, Adegunsoye A, Strek ME, Maher TM, Molyneaux PL, Flores C, Noth I, Gisli Jenkins R, Wain LVet al., 2022,

    Longitudinal lung function and gas transfer in individuals with idiopathic pulmonary fibrosis: a genome-wide association study

    , The Lancet Respiratory Medicine, ISSN: 2213-2600

    BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an incurable lung disease characterised by progressive scarring leading to alveolar stiffness, reduced lung capacity, and impeded gas transfer. We aimed to identify genetic variants associated with declining lung capacity or declining gas transfer after diagnosis of IPF. METHODS: We did a genome-wide meta-analysis of longitudinal measures of forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) in individuals diagnosed with IPF. Individuals were recruited to three studies between June, 1996, and August, 2017, from across centres in the US, UK, and Spain. Suggestively significant variants were investigated further in an additional independent study (CleanUP-IPF). All four studies diagnosed cases following American Thoracic Society/European Respiratory Society guidelines. Variants were defined as significantly associated if they had a meta-analysis p<5 × 10-8 when meta-analysing across all discovery and follow-up studies, had consistent direction of effects across all four studies, and were nominally significant (p<0·05) in each study. FINDINGS: 1329 individuals with a total of 5216 measures were included in the FVC analysis. 975 individuals with a total of 3361 measures were included in the DLCO analysis. For the discovery genome-wide analyses, 7 611 174 genetic variants were included in the FVC analysis and 7 536 843 in the DLCO analysis. One variant (rs115982800) located in an antisense RNA gene for protein kinase N2 (PKN2) showed a genome-wide significant association with FVC decline (-140 mL/year per risk allele [95% CI -180 to -100]; p=9·14 × 10-12). INTERPRETATION: Our analysis identifies a genetic variant associated with disease progression, which might highlight a new biological mechanism for IPF. We found that PKN2, a Rho and Rac effector protein, is the most likely gene of interest fro

  • Journal article
    Pugashetti JV, Adegunsoye A, Wu Z, Lee CT, Srikrishnan A, Ghodrati S, Vo V, Renzoni EA, Wells AU, Garcia CK, Chua F, Newton CA, Molyneaux PL, Oldham JMet al., 2022,

    Validation of proposed criteria for progressive pulmonary fibrosis.

    , American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X

    RATIONALE: Criteria for progressive pulmonary fibrosis (PPF) have been proposed, but their prognostic value beyond categorical decline in forced vital capacity (FVC) remains unclear. OBJECTIVE: To determine whether proposed PPF criteria predict transplant-free survival (TFS) in patients with non-idiopathic pulmonary fibrosis (IPF) forms of interstitial lung disease (ILD). METHODS: A retrospective, multi-center cohort analysis was performed. Patients diagnosed with fibrotic connective tissue disease associated ILD, fibrotic hypersensitivity pneumonitis and non-IPF idiopathic interstitial pneumonia from three US centers and one UK center comprised test and validation cohorts, respectively. Cox proportional hazards regression was used to test the association between five-year TFS and 10% FVC decline, followed by thirteen additional PPF criteria satisfied in the absence of >=10% FVC decline. MAIN RESULTS: One thousand three hundred forty-one patients met inclusion criteria. A >=10% relative FVC decline was the strongest predictor of reduced TFS and showed consistent TFS association across cohorts, ILD subtypes and treatment groups, resulting in a phenotype that closely resembled IPF. Ten additional PPF criteria satisfied in the absence of >=10% relative FVC decline were also associated with reduced TFS in the US test cohort, with six maintaining TFS association in the UK validation cohort. Validated PPF criteria requiring a combination of physiologic, radiologic, and symptomatic worsening performed similarly to their stand-alone components but captured a smaller number of patients. CONCLUSIONS: An FVC decline of >=10% and six additional PPF criteria satisfied in the absence of such decline identify non-IPF ILD patients at increased risk of death or lung transplant.

  • Journal article
    Hewitt RJ, Bartlett EC, Ganatra R, Butt H, Kouranos V, Chua F, Kokosi M, Molyneaux PL, Desai SR, Wells AU, Jenkins RG, Renzoni EA, Kemp S, Devaraj A, George PMet al., 2022,

    Lung cancer screening provides an opportunity for early diagnosis and treatment of interstitial lung disease

    , THORAX, ISSN: 0040-6376
  • Journal article
    Park Y-K, Ledesma-Amaro R, 2022,

    What makes Yarrowia lipolytica well suited for industry?

    , Trends in Biotechnology, ISSN: 0167-7799

    Yarrowia lipolytica possesses natural and engineered traits that make it a good host for the industrial bioproduction of chemicals, fuels, foods, and pharmaceuticals. In recent years, academic and industrial researchers have assessed its potential, developed synthetic biology techniques, improved its features, scaled its processes, and identified its limitations. Both publications and patents related to Y. lipolytica have shown a drastic increase during the past decade. Here, we discuss the characteristics of this yeast that make it suitable for industry and the remaining challenges for its wider use at large scale. We present evidence herein that shows the importance and potential of Y. lipolytica in bioproduction such that it may soon be one of the preferred choices of industry.

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