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  • Journal article
    Muxworthy A, Lam C, Green D, Cowan A, Maher B, Gonet Tet al., 2022,

    Magnetic characterisation of London’s airborne nanoparticulate matter

    , Atmospheric Environment, Vol: 287, Pages: 1-8, ISSN: 1352-2310

    Iron-bearing particulate matter produced by vehicle emissions is known to be toxic. To better quantify potential health risks, we have conducted the first magnetic study of a time-series of London's inhalable particulate matter (<10 μm, PM10), captured by three monitoring stations in central London (Marylebone Road, Earl's Court Road and Oxford Street) through 2010 and 2012. We conducted room-temperature analysis on all the samples, and a limited number of samples were analysed at both high and low temperatures. The high-temperature measurements identified magnetite as the dominant magnetic phase. The low-temperature measurements revealed high numbers of nanoparticles, which, assuming magnetite, are in the grain-size range 1–4 nm. It is estimated that as much as ∼40% of the total magnetic signal at 10 K is from particles <4 nm, that are magnetically ‘invisible’ at room-temperature and are being routinely under-estimated in room temperature-based magnetic studies. From the low-temperature measurements, the total concentration of magnetite was estimated at ∼7.5%, significantly higher than previously reported. The room-temperature magnetic data were compared with other pollution data, e.g., NOX and PM10, and meteorological data. Mass-dependent terms like the saturation magnetisation were found to display a strong correlation with NOX and PM10, indicating a common source for these pollutants, i.e., vehicle emissions. Magnetic coercivity measurements, which are independent of abundance, and provide information on grain-size, were consistent across all three sampling localities, again suggesting a major dominant source. Relatively small variations in coercivity were correlated with meteorological events, e.g., temperature and precipitation, suggesting preferential removal of larger airborne grains, i.e., >50 nm.

  • Journal article
    Allen RJ, Stockwell A, Oldham JM, Guillen-Guio B, Schwartz DA, Maher TM, Flores C, Noth I, Yaspan BL, Jenkins RG, Wain Let al., 2022,

    Genome-wide association study across five cohorts identifies five novel loci associated with idiopathic pulmonary fibrosis

    , THORAX, Vol: 77, Pages: 829-833, ISSN: 0040-6376
  • Journal article
    Kraven LM, Taylor AR, Molyneaux PL, Maher T, McDonough J, Mura M, Yang I, Schwartz DA, Huang Y, Noth I, Ma SF, Yeo AJ, Fahy WA, Jenkins G, Wain Let al., 2022,

    Cluster analysis of transcriptomic datasets to identify endotypes of idiopathic pulmonary fibrosis

    , Thorax, ISSN: 0040-6376

    Background Considerable clinical heterogeneity in idiopathic pulmonary fibrosis (IPF) suggests the existence of multiple disease endotypes. Identifying these endotypes would improve our understanding of the pathogenesis of IPF and could allow for a biomarker-driven personalised medicine approach. We aimed to identify clinically distinct groups of patients with IPF that could represent distinct disease endotypes.Methods We co-normalised, pooled and clustered three publicly available blood transcriptomic datasets (total 220 IPF cases). We compared clinical traits across clusters and used gene enrichment analysis to identify biological pathways and processes that were over-represented among the genes that were differentially expressed across clusters. A gene-based classifier was developed and validated using three additional independent datasets (total 194 IPF cases).Findings We identified three clusters of patients with IPF with statistically significant differences in lung function (p=0.009) and mortality (p=0.009) between groups. Gene enrichment analysis implicated mitochondrial homeostasis, apoptosis, cell cycle and innate and adaptive immunity in the pathogenesis underlying these groups. We developed and validated a 13-gene cluster classifier that predicted mortality in IPF (high-risk clusters vs low-risk cluster: HR 4.25, 95% CI 2.14 to 8.46, p=3.7×10−5).Interpretation We have identified blood gene expression signatures capable of discerning groups of patients with IPF with significant differences in survival. These clusters could be representative of distinct pathophysiological states, which would support the theory of multiple endotypes of IPF. Although more work must be done to confirm the existence of these endotypes, our classifier could be a useful tool in patient stratification and outcome prediction in IPF.

  • Journal article
    Gudoshava M, Wainwright C, Hirons L, Endris HS, Segele ZT, Woolnough S, Atheru Z, Artan Get al., 2022,

    Atmospheric and oceanic conditions associated with early and late onset for Eastern Africa short rains

    , International Journal of Climatology, ISSN: 0899-8418

    Timing of the rainy season is essential for a number of climate sensitive sectors over Eastern Africa. This is particularly true for the agricultural sector, where most activities depend on both the spatial and temporal distribution of rainfall throughout the season. Using a combination of observational and reanalysis datasets, the present study investigates the atmospheric and oceanic conditions associated with early and late onset for Eastern Africa short rains season (October–December). Our results indicate enhanced rainfall in October and November during years with early onset and rainfall deficit in years with late onset for the same months. Early onset years are found to be associated with warmer sea surface temperatures (SSTs) in the western Indian Ocean, and an enhanced moisture flux and anomalous low-level flow into Eastern Africa from as early as the first dekad of September. The late onset years are characterized by cooler SSTs in the western Indian Ocean, anomalous westerly moisture flux and zonal flow limiting moisture supply to the region. The variability in onset date is separated into the interannual and decadal components, and the links with SSTs and low-level circulation over the Indian Ocean basin are examined separately for both timescales. Significant correlations are found between the interannual variability of the onset and the Indian Ocean dipole mode index. On decadal timescales the onset is shown to be partly driven by the variability of the SSTs over the Indian Ocean. Understanding the influence of these potentially predictable SST and moisture patterns on onset variability has huge potential to improve forecasts of the East African short rains. Improved prediction of the variability of the rainy season onset has huge implications for improving key strategic decisions and preparedness action in many sectors, including agriculture.

  • Journal article
    Fabbri L, Moss S, Khan FA, Chi W, Xia J, Robinson K, Smyth AR, Jenkins G, Stewart Iet al., 2022,

    Parenchymal lung abnormalities following hospitalisation for COVID-19 and viral pneumonitis: a systematic review and meta-analysis

    , Thorax, ISSN: 0040-6376

    Introduction Persisting respiratory symptoms in COVID-19 survivors may be related to development of pulmonary fibrosis. We assessed the proportion of chest CT scans and pulmonary function tests consistent with parenchymal lung disease in the follow-up of people hospitalised with COVID-19 and viral pneumonitis.Methods Systematic review and random effects meta-analysis of proportions using studies of adults hospitalised with SARS-CoV-2, SARS-CoV, MERS-CoV or influenza pneumonia and followed up within 12 months. Searches performed in MEDLINE and Embase. Primary outcomes were proportion of radiological sequelae on CT scans; restrictive impairment; impaired gas transfer. Heterogeneity was explored in meta-regression.Results Ninety-five studies (98.9% observational) were included in qualitative synthesis, 70 were suitable for meta-analysis including 60 SARS-CoV-2 studies with a median follow-up of 3 months. In SARS-CoV-2, the overall estimated proportion of inflammatory sequelae was 50% during follow-up (0.50; 95% CI 0.41 to 0.58; I2=95%), fibrotic sequelae were estimated in 29% (0.29; 95% CI 0.22 to 0.37; I2=94.1%). Follow-up time was significantly associated with estimates of inflammatory sequelae (−0.036; 95% CI −0.068 to –0.004; p=0.029), associations with fibrotic sequelae did not reach significance (−0.021; 95% CI −0.051 to 0.009; p=0.176). Impaired gas transfer was estimated at 38% of lung function tests (0.38 95% CI 0.32 to 0.44; I2=92.1%), which was greater than restrictive impairment (0.17; 95% CI 0.13 to 0.23; I2=92.5%), neither were associated with follow-up time (p=0.207; p=0.864).Discussion Sequelae consistent with parenchymal lung disease were observed following COVID-19 and other viral pneumonitis. Estimates should be interpreted with caution due to high heterogeneity, differences in study casemix and initial severity.

  • Journal article
    Khan F, Howard L, Hearson G, Edwards C, Barber C, Jones S, Wilson AM, Maher TM, Saini G, Stewart I, Jenkins Get al., 2022,

    Clinical utility of home versus hospital spirometry in fibrotic ILD: evaluation following INJUSTIS interim analysis

    , Annals of the American Thoracic Society, Vol: 19, Pages: 506-510, ISSN: 1546-3222
  • Journal article
    Dechezleprêtre A, Gennaioli C, Martin R, Muûls M, Stoerk Tet al., 2021,

    Searching for carbon leaks in multinational companies

    , Journal of Environmental Economics and Management, Vol: 112, ISSN: 0095-0696

    Does a unilateral climate change policy cause companies to shift the location of production, thereby creating carbon leakage? In this paper, we analyze the effect of the European Union Emissions Trading System (EU ETS) on the geographic distribution of carbon emissions by multinational companies. The empirical evidence is based on unique data for the period 2007-2014 from the Carbon Disclosure Project, which tracks the emissions of multinational businesses by geographic region within each company. Because they already operate from multiple locations, multinational firms should be the most prone to carbon leakage. Our data includes the regional emissions of 1,122 companies, of which 261 are subject to EU ETS regulation. We find no evidence that the EU ETS has led to a displacement of carbon emissions from Europe toward the rest of the world, including to countries with lax climate policies and within energy-intensive companies. A large number of robustness checks confirm this finding. Overall, the paper suggests that modest differences in carbon prices between countries do not induce carbon leakage.

  • Journal article
    Wilkinson AL, John AE, Barrett JW, Gower E, Morrison VS, Man Y, Pun KT, Roper JA, Luckett JC, Borthwick LA, Barksby BS, Burgoyne RA, Barnes R, Fisher AJ, Procopiou PA, Hatley RJD, Barrett TN, Marshall RP, Macdonald SJF, Jenkins RG, Slack RJet al., 2021,

    Pharmacological characterisation of GSK3335103, an oral alpha v beta 6 integrin small molecule RGD-mimetic inhibitor for the treatment of fibrotic disease

    , European Journal of Pharmacology, Vol: 913, Pages: 1-10c, ISSN: 0376-6357

    Fibrosis is the formation of scar tissue due to injury or long-term inflammation and is a leading cause of morbidity and mortality. Activation of the pro-fibrotic cytokine transforming growth factor-β (TGFβ) via the alpha-V beta-6 (αvβ6) integrin has been identified as playing a key role in the development of fibrosis. Therefore, a drug discovery programme to identify an orally bioavailable small molecule αvβ6 arginyl-glycinyl-aspartic acid (RGD)-mimetic was initiated. As part of a medicinal chemistry programme GSK3335103 was identified and profiled in a range of pre-clinical in vitro and in vivo systems. GSK3335103 was shown to bind to the αvβ6 with high affinity and demonstrated fast binding kinetics. In primary human lung epithelial cells, GSK3335103-induced concentration- and time-dependent internalisation of αvβ6 with a rapid return of integrin to the cell surface observed after washout. Following sustained engagement of the αvβ6 integrin in vitro, lysosomal degradation was induced by GSK3335103. GSK3335103 was shown to engage with the αvβ6 integrin and inhibit the activation of TGFβ in both ex vivo IPF tissue and in a murine model of bleomycin-induced lung fibrosis, as measured by αvβ6 engagement, TGFβ signalling and collagen deposition, with a prolonged duration of action observed in vivo. In summary, GSK3335103 is a potent αvβ6 inhibitor that attenuates TGFβ signalling in vitro and in vivo with a well-defined pharmacokinetic/pharmacodynamic relationship. This translates to a significant reduction of collagen deposition in vivo and therefore GSK3335103 represents a potential novel oral therapy for fibrotic disorders.

  • Journal article
    Slack RJ, Macdonald SJF, Roper JA, Jenkins RG, Hatley RJDet al., 2021,

    Emerging therapeutic opportunities for integrin inhibitors

    , NATURE REVIEWS DRUG DISCOVERY, Vol: 21, Pages: 60-78, ISSN: 1474-1776
  • Journal article
    Khan FA, Stewart I, Fabbri L, Moss S, Robinson K, Smyth AR, Jenkins Get al., 2021,

    Systematic review and meta-analysis of anakinra, sarilumab, siltuximab and tocilizumab for COVID-19

    , Thorax, Vol: 76, Pages: 907-919, ISSN: 0040-6376

    Background There is accumulating evidence for an overly activated immune response in severe COVID-19, with several studies exploring the therapeutic role of immunomodulation. Through systematic review and meta-analysis, we assess the effectiveness of specific interleukin inhibitors for the treatment of COVID-19.Methods Electronic databases were searched on 7 January 2021 to identify studies of immunomodulatory agents (anakinra, sarilumab, siltuximab and tocilizumab) for the treatment of COVID-19. The primary outcomes were severity on an Ordinal Scale measured at day 15 from intervention and days to hospital discharge. Key secondary endpoints included overall mortality.Results 71 studies totalling 22 058 patients were included, 6 were randomised trials. Most studies explored outcomes in patients who received tocilizumab (60/71). In prospective studies, tocilizumab was associated with improved unadjusted survival (risk ratio 0.83, 95% CI 0.72 to 0.96, I2=0.0%), but conclusive benefit was not demonstrated for other outcomes. In retrospective studies, tocilizumab was associated with less severe outcomes on an Ordinal Scale (generalised OR 1.34, 95% CI 1.10 to 1.64, I2=98%) and adjusted mortality risk (HR 0.52, 95% CI 0.41 to 0.66, I2=76.6%). The mean difference in duration of hospitalisation was 0.36 days (95% CI −0.07 to 0.80, I2=93.8%). There was substantial heterogeneity in retrospective studies, and estimates should be interpreted cautiously. Other immunomodulatory agents showed similar effects to tocilizumab, but insufficient data precluded meta-analysis by agent.Conclusion Tocilizumab was associated with a lower relative risk of mortality in prospective studies, but effects were inconclusive for other outcomes. Current evidence for the efficacy of anakinra, siltuximab or sarilumab in COVID-19 is insufficient, with further studies urgently needed for conclusive findings.

  • Journal article
    Bui LT, Winters NI, Chung M-I, Joseph C, Gutierrez AJ, Habermann AC, Adams TS, Schupp JC, Poli S, Peter LM, Taylor CJ, Blackburn JB, Richmond BW, Nicholson AG, Rassl D, Wallace WA, Rosas IO, Jenkins RG, Kaminski N, Kropski JA, Banovich NEet al., 2021,

    Chronic lung diseases are associated with gene expression programs favoring SARS-CoV-2 entry and severity

    , NATURE COMMUNICATIONS, Vol: 12
  • Journal article
    Hopkinson NS, Jenkins G, Hart N, 2021,

    COVID-19 and what comes after?

    , THORAX, Vol: 76, Pages: 324-325, ISSN: 0040-6376
  • Journal article
    Brand C, Dons E, Anaya-Boig E, Avila-Palencia I, Clark A, de Nazelle A, Gascon M, Gaupp-Berghausen M, Gerike R, Gotschi T, Iacorossi F, Kahlmeier S, Laeremans M, Nieuwenhuijsen MJ, Orjuela JP, Racioppi F, Raser E, Rojas-Rueda D, Standaert A, Stigell E, Sulikova S, Wegener S, Panis LIet al., 2021,

    The climate change mitigation effects of daily active travel in cities

    , Transportation Research Part D: Transport and Environment, Vol: 93, Pages: 1-18, ISSN: 1361-9209

    Active travel (walking or cycling for transport) is considered the most sustainable form of personal transport. Yet its net effects on mobility-related CO2 emissions are complex and under-researched. Here we collected travel activity data in seven European cities and derived life cycle CO2 emissions across modes and purposes. Daily mobility-related life cycle CO2 emissions were 3.2 kgCO2 per person, with car travel contributing 70% and cycling 1%. Cyclists had 84% lower life cycle CO2 emissions than non-cyclists. Life cycle CO2 emissions decreased by −14% per additional cycling trip and decreased by −62% for each avoided car trip. An average person who ‘shifted travel modes’ from car to bike decreased life cycle CO2 emissions by 3.2 kgCO2/day. Promoting active travel should be a cornerstone of strategies to meet net zero carbon targets, particularly in urban areas, while also improving public health and quality of urban life.

  • Journal article
    Dhindsa RS, Mattsson J, Nag A, Wang Q, Wain L, Allen R, Wigmore EM, Ibanez K, Vitsios D, Deevi SVV, Wasilewski S, Karlsson M, Lassi G, Olsson H, Muthas D, Monkley S, Mackay A, Murray L, Young S, Haefliger C, Maher TM, Belvisi MG, Jenkins G, Molyneaux PL, Platt A, Petrovski Set al., 2021,

    Identification of a missense variant in SPDL1 associated with idiopathic pulmonary fibrosis

    , Communications Biology, Vol: 4, ISSN: 2399-3642

    Idiopathic pulmonary fibrosis (IPF) is a fatal disorder characterised by progressive, destructive lung scarring. Despite substantial progress, the genetic determinants of this disease remain incompletely defined. Using whole genome and whole exome sequencing data from 752 individuals with sporadic IPF and 119,055 UK Biobank controls, we performed a variant-level exome-wide association study (ExWAS) and gene-level collapsing analyses. Our variant-level analysis revealed a novel association between a rare missense variant in SPDL1 and IPF (NM_017785.5:g.169588475 G > A p.Arg20Gln; p = 2.4 × 10−7, odds ratio = 2.87, 95% confidence interval: 2.03–4.07). This signal was independently replicated in the FinnGen cohort, which contains 1028 cases and 196,986 controls (combined p = 2.2 × 10−20), firmly associating this variant as an IPF risk allele. SPDL1 encodes Spindly, a protein involved in mitotic checkpoint signalling during cell division that has not been previously described in fibrosis. To the best of our knowledge, these results highlight a novel mechanism underlying IPF, providing the potential for new therapeutic discoveries in a disease of great unmet need.

  • Journal article
    Brand C, Gotschi T, Dons E, Gerike R, Anaya-Boig E, Avila-Palencia I, de Nazelle A, Gascon M, Gaupp-Berghausen M, Iacorossi F, Kahlmeier S, Panis LI, Racioppi F, Rojas-Rueda D, Standaert A, Stigell E, Sulikova S, Wegener S, Nieuwenhuijsen MJet al., 2021,

    The climate change mitigation impacts of active travel: Evidence from a longitudinal panel study in seven European cities

    , GLOBAL ENVIRONMENTAL CHANGE-HUMAN AND POLICY DIMENSIONS, Vol: 67, Pages: 1-15, ISSN: 0959-3780

    Active travel (walking or cycling for transport) is considered the most sustainable and low carbon form of getting from A to B. Yet the net effects of changes in active travel on changes in mobility-related CO2 emissions are complex and under-researched. Here we collected longitudinal data on daily travel behavior, journey purpose, as well as personal and geospatial characteristics in seven European cities and derived mobility-related lifecycle CO2 emissions over time and space. Statistical modelling of longitudinal panel (n = 1849) data was performed to assess how changes in active travel, the ‘main mode’ of daily travel, and cycling frequency influenced changes in mobility-related lifecycle CO2 emissions.We found that changes in active travel have significant lifecycle carbon emissions benefits, even in European urban contexts with already high walking and cycling shares. An increase in cycling or walking consistently and independently decreased mobility-related lifecycle CO2 emissions, suggesting that active travel substituted for motorized travel – i.e. the increase was not just additional (induced) travel over and above motorized travel. To illustrate this, an average person cycling 1 trip/day more and driving 1 trip/day less for 200 days a year would decrease mobility-related lifecycle CO2 emissions by about 0.5 tonnes over a year, representing a substantial share of average per capita CO2 emissions from transport. The largest benefits from shifts from car to active travel were for business purposes, followed by social and recreational trips, and commuting to work or place of education. Changes to commuting emissions were more pronounced for those who were younger, lived closer to work and further to a public transport station.Even if not all car trips could be substituted by active travel the potential for decreasing emissions is considerable and significant. The study gives policy and practice the empirical evidence needed to assess climate

  • Journal article
    Corada K, Woodward H, Alaraj H, Collins CM, de Nazelle Aet al., 2021,

    A systematic review of the leaf traits considered to contribute to removal of airborne particulate matter pollution in urban areas

    , Environmental Pollution, Vol: 269, Pages: 1-13, ISSN: 0269-7491

    Global urban planning has promoted green infrastructure (GI) such as street trees, shrubs or other greenspace in order to mitigate air pollution. Although considerable attention has been paid to understanding particulate matter (PM) deposition on GI, there has been little focus on identifying which leaf traits might maximise airborne PM removal. This paper examines existing literature to synthesize the state of knowledge on leaf traits most relevant to PM removal. We systematically reviewed measurement studies that evaluated particulate matter accumulated on leaves on street trees, shrubs green roofs, and green walls, for a variety of leaf traits. Our final selection included 62 papers, most from field studies and a handful from wind tunnel studies. The following were variously promoted as useful traits: coniferous needle leaves; small, rough and textured broadleaves; lanceolate and ovate shapes; waxy coatings, and high-density trichomes. Consideration of these leaf traits, many of which are also associated with drought tolerance, may help to maximise PM capture. Although effective leaf traits were identified, there is no strong or consistent evidence to identify which is the most influential leaf trait in capturing PM. The diversity in sampling methods, wide comparison groups and lack of background PM concentration measures in many studies limited our ability to synthesize results. We found that several ancillary factors contribute to variations in the accumulation of PM on leaves, thus cannot recommend that selection of urban planting species be based primarily on leaf traits. Further research into the vegetation structural features and standardization of the method to measure PM on leaves is needed.

  • Journal article
    Leavy OC, Ma S-F, Molyneaux PL, Maher TM, Oldham JM, Flores C, Noth I, Jenkins RG, Dudbridge F, Wain LV, Allen RJ, Leavy OC, Ma S-F, Molyneaux PL, Maher TM, Oldham JM, Flores C, Noth I, Jenkins RG, Dudbridge F, Wain LV, Allen RJet al., 2020,

    Proportion of idiopathic pulmonary fibrosis risk explained by known Common genetic loci in European populations

    , American Journal of Respiratory and Critical Care Medicine, Vol: 203, Pages: 775-778, ISSN: 1073-449X

    Genome-wide association studies have identified 14 genetic loci associated with susceptibility to idiopathic pulmonary fibrosis (IPF), a devastating lung disease with poor prognosis. Of these, the variant with the strongest association, rs35705950, is located in the promoter region of the MUC5B gene and has a risk allele (T) frequency of 30-35% in IPF cases. Here we present estimates of the proportion of disease liability explained by each of the 14 IPF risk variants as well as estimates of the proportion of cases that can be attributed to each variant. We estimate that rs35705950 explains 5.9-9.4% of disease liability, which is much lower than previously reported estimates. Of every 100,000 individuals with the rs35705950_GG genotype we estimate 30 will have IPF, whereas for every 100,000 individuals with the rs35705950_GT genotype 152 will have IPF. Quantifying the impact of genetic risk factors on disease liability improves our understanding of the underlying genetic architecture of IPF and provides insight into the impact of genetic factors in risk prediction modelling.

  • Journal article
    George PM, Barratt SL, Condliffe R, Desai SR, Devaraj A, Forrest I, Gibbons MA, Hart N, Jenkins RG, McAuley DF, Patel BV, Thwaite E, Spencer LGet al., 2020,

    Respiratory follow-up of patients with COVID-19 pneumonia

    , Thorax, Vol: 75, Pages: 1009-1016, ISSN: 0040-6376

    The COVID-19 pandemic has led to an unprecedented surge in hospitalised patients with viral pneumonia. The most severely affected patients are older men, individuals of black and Asian minority ethnicity and those with comorbidities. COVID-19 is also associated with an increased risk of hypercoagulability and venous thromboembolism. The overwhelming majority of patients admitted to hospital have respiratory failure and while most are managed on general wards, a sizeable proportion require intensive care support. The long-term complications of COVID-19 pneumonia are starting to emerge but data from previous coronavirus outbreaks such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) suggest that some patients will experience long-term respiratory complications of the infection. With the pattern of thoracic imaging abnormalities and growing clinical experience, it is envisaged that interstitial lung disease and pulmonary vascular disease are likely to be the most important respiratory complications. There is a need for a unified pathway for the respiratory follow-up of patients with COVID-19 balancing the delivery of high-quality clinical care with stretched National Health Service (NHS) resources. In this guidance document, we provide a suggested structure for the respiratory follow-up of patients with clinicoradiological confirmation of COVID-19 pneumonia. We define two separate algorithms integrating disease severity, likelihood of long-term respiratory complications and functional capacity on discharge. To mitigate NHS pressures, virtual solutions have been embedded within the pathway as has safety netting of patients whose clinical trajectory deviates from the pathway. For all patients, we suggest a holistic package of care to address breathlessness, anxiety, oxygen requirement, palliative care and rehabilitation.

  • Journal article
    John AE, Graves RH, Pun KT, Vitulli G, Forty EJ, Mercer PF, Morrell JL, Barrett JW, Rogers RF, Hafeji M, Bibby LI, Gower E, Morrison VS, Man Y, Roper JA, Luckett JC, Borthwick LA, Barksby BS, Burgoyne RA, Barnes R, Le J, Flint DJ, Pyne S, Habgood A, Organ LA, Joseph C, Edwards-Pritchard RC, Maher TM, Fisher AJ, Gudmann NS, Leeming DJ, Chambers RC, Lukey PT, Marshall RP, Macdonald SJF, Jenkins RG, Slack RJet al., 2020,

    Translational pharmacology of an inhaled small molecule alpha v beta 6 integrin inhibitor for idiopathic pulmonary fibrosis

    , Nature Communications, Vol: 11, ISSN: 2041-1723

    The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK3008348 binds to αvβ6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.

  • Journal article
    Leavy O, Ma S-F, Molyneaux P, Maher T, Oldham J, Flores C, Noth I, Jenkins G, Dudbridge F, Wain L, Allen Ret al., 2020,

    Proportion of idiopathic pulmonary fibrosis risk explained by known genetic loci

    Genome-wide association studies have identified 14 genetic loci associated with susceptibility to idiopathic pulmonary fibrosis (IPF), a devastating lung disease with poor prognosis. Of these, the variant with the strongest association, rs35705950, is located in the promoter region of the MUC5B gene and has a risk allele (T) frequency of 30-35% in IPF cases. Here we present estimates of the proportion of disease liability explained by each of the 14 IPF risk variants as well as estimates of the proportion of cases that can be attributed to each variant. We estimate that rs35705950 explains 5.9-9.4% of disease liability, which is much lower than previously reported estimates. Of every 100,000 individuals with the rs35705950_GG genotype we estimate 30 will have IPF, whereas for every 100,000 individuals with the rs35705950_GT genotype 152 will have IPF. Quantifying the impact of genetic risk factors on disease liability improves our understanding of the underlying genetic architecture of IPF and provides insight into the impact of genetic factors in risk prediction modelling.

  • Journal article
    Kia A, Wong H, Cheeseman C, 2019,

    High-strength clogging resistant permeable pavement

    , International Journal of Pavement Engineering, Vol: 22, Pages: 271-282, ISSN: 1029-8436

    Permeable pavement is utilised in order to alleviate flooding in towns, cities and other urban areas, but it is prone to clogging, has relatively low strength and requires regular maintenance. We have developed a novel permeable pavement with low tortuosity pore structure that can be cast on-site that is not only resistant to clogging, but also has high permeability and strength. This high strength clogging resistant permeable pavement (CRP) was prepared by introducing straight pore channels of varying size and number into self-compacting mortar. Samples with porosity ranging from 2 to 32% were tested. In all cases, permeability and compressive strength were substantially higher than conventional permeable concrete. More significantly, CRP can be engineered with low porosity (5%), high strength (> 50 MPa) and high permeability (> 2 cm/s), but does not clog despite extensive cyclic exposure to flow containing sand and clay. A simple method to model the permeability of CRP from the pore structure is described. We report for the first time a high strength clogging resistant permeable pavement capable of retaining sufficient porosity and permeability for storm-water infiltration without requiring frequent maintenance. This innovative system will help alleviate urban flooding and contribute towards a more sustainable urbanisation.

  • Journal article
    Gschwend F, Chambon C, Biedka M, Brandt-Talbot A, Fennell P, Hallett Jet al., 2019,

    Quantitative glucose release from softwood after pretreatment with low-cost ionic liquids

    , Green Chemistry, Vol: 21, Pages: 692-703, ISSN: 1463-9262

    Softwood is an abundantly available feedstock for the bio-based industry, however, achieving cost-effective sugar release is particularly challenging owing to its guaiacyl-only lignin. Here, we report the highly effective pretreatment of the softwood pine (Pinus sylvestris) using ionoSolv pretreatment, a novel ionic liquid-based lignocellulose fractionation technology. Three protic, low-cost ionic liquids, 1-butylimidazolium hydrogen sulfate, triethylammonium hydrogen sulfate and N,N-dimethylbutylammonium hydrogen sulfate, were used to fractionate the biomass into a carbohydrate-rich pulp and a lignin. The carbohydrate-rich pulp was hydrolysed into fermentable sugars by enzymatic saccharification. Under the most successful pretreatment conditions, quantitative glucose release from the pulp was achieved, which equates to a projected glucose release of 464 mg per gram of pine wood entering the process. We further intensified the process by increasing the solid to solvent ratio up to 1:2 g/g while maintaining saccharification yields of 75% of the theoretical maximum. We also demonstrate for the first time that N,N-dimethylbutylammonium hydrogen sulfate, [DMBA][HSO4] is an excellent low-cost pretreatment solvent, surpassing the pretreatment effectiveness of its symmetrically substituted analogue triethylammonium hydrogen sulfate. This shows that ionoSolv pretreatment with protic hydrogen sulfate ionic liquids is a truly feedstock-independent pretreatment option, further increasing the commercial potential of this pretreatment technology.

  • Journal article
    Vineis P, Fecht D, 2018,

    Environment, cancer and inequalities-The urgent need for prevention

    , European Journal of Cancer, Vol: 103, Pages: 317-326, ISSN: 0959-8049

    The proportion of total deaths attributable to environmental factors is estimated to be 23% of global deaths and 22% of global disability-adjusted life years (DALYs) according to one review. These estimates encompass all environmental agents including infectious agents but excluding behavioural factors. The authors of the review also estimated that 16% (95% CI: 7-41%) of cancer deaths are attributable to environmental risk factors (and 36% [95% CI: 17-52%] for lung cancer). In this article, we focus on the reasons why epidemiology is often unable to account for the whole burden of environmental carcinogens. The experience of air pollution is particularly instructive. While in the 1970s and early 1980s, air pollution was considered as a relatively marginal exposure in terms of attributable risks, the most recent estimate is that it accounts for 7.6% of global deaths and 4.2% of global DALYs world-wide (with East and South Asia accounting for 59% of the total). According to a review, ambient fine particulate matter air pollution contributed to 17.1% of ischaemic heart disease, 14.2% of cerebrovascular disease, 16.5% of lung cancer, 24.7% of low respiratory infections, and 27.1% of COPD mortality in 2015. Estimates for cancer as a whole are not available. The change in appreciation of the role of air pollution has been mainly due to the refinement of exposure assessment methods and the new generations of longitudinal studies. Mechanistic evidence via omic technologies is now rapidly increasing, thus lending credibility to previous epidemiological ('black box') associations. Much less is known about other environmental contaminants, some of which are widespread and pervasive, thus suggesting the need for the same rigourous methods as those applied to air pollution. Finally, a crucial issue remains inequality across different population groups, with uneven exposure to hazards and acquired susceptibilities due to multiple concomitant exposures and poorer health status.

  • Journal article
    Bull R, Romanowicz J, Jennings N, Laskari M, Stuart G, Everitt Det al., 2018,

    Competing priorities: lessons in engaging students to achieve energy savings in universities

    , International Journal of Sustainability in Higher Education, Vol: 19, ISSN: 1467-6370

    PurposeThis paper aims to present findings from an EU-funded international student-led energy saving competition (SAVES) on a scale previously unseen. There are multiple accounts of short-term projects and energy saving competitions encouraging pro-environmental behaviour change amongst students in university dormitories, but the purpose of this research is to provide evidence of consistent and sustained energy savings from student-led energy savings competitions, underpinned by practical action.Design/methodology/approachA mixed-methods approach (pre- and post-intervention surveys, focus groups and analysis of energy meter data) was used to determine the level of energy savings and quantifiable behaviour change delivered by students across participating university dormitories.FindingsThis research has provided further insight into the potential for savings and behaviour change in university dormitories through relatively simple actions. Whilst other interventions have shown greater savings, this project provided consistent savings over two years of 7 per cent across a large number of university dormitories in five countries through simple behaviour changes.Research limitations/implicationsAn energy dashboard displaying near a real-time leaderboard was added to the engagement in the second year of the project. Whilst students were optimistic about the role that energy dashboards could play, the evidence is not here to quantify the impact of dashboards. Further research is required to understand the potential of dashboards to contribute to behavioural change savings and in constructing competitions between people and dormitories that are known to each other.Social implicationsSAVES provided engagement with students, enabling, empowering and motivating them to save energy – focusing specifically on the last stage of the “Awareness, Interest, Desire, Action” framework. Automated meter reading data was used in the majority of participating dormitories

  • Journal article
    Chambon C, Mkhize T, Reddy P, Brandt-Talbot A, Deenadayalu N, Fennell P, Hallett Jet al., 2018,

    Pretreatment of South African sugarcane bagasse using a low-cost protic ionic liquid: a comparison of whole, depithed, fibrous and pith bagasse fractions

    , Biotechnology for Biofuels, Vol: 11, ISSN: 1754-6834

    BackgroundSugarcane bagasse is an abundant and geographically widespread agro-industrial residue with high carbohydrate content, making it a strong candidate feedstock for the bio-based economy. This study examines the use of the low-cost protic ionic liquid triethylammonium hydrogen sulfate ([TEA][HSO4]) to fractionate a range of South African sugarcane bagasse preparations into a cellulose-rich pulp and lignin. The study seeks to optimize pretreatment conditions and examine the necessity of applying a depithing step on bagasse prior to pretreatment.ResultsPretreatment of five bagasse preparations, namely whole, industrially depithed, laboratory depithed (short and long fiber) and pith bagasse with [TEA][HSO4]:[H2O] (4:1 w/w) solutions produced highly digestible cellulose-rich pulps, as assessed by residual lignin analysis and enzymatic hydrolysis. Pretreatment under the optimized condition of 120 °C for 4 h produced a pretreated cellulose pulp with up to 90% of the lignin removed and enabled the release of up to 69% glucose contained in the bagasse via enzymatic hydrolysis. Glucose yields from whole and depithed bagasse preparations were very similar. Significant differences in lignin recovery were obtained for laboratory depithed bagasse compared with whole and industrially depithed bagasse. The silica-rich ash components of bagasse were seen to partition mainly with the pulp, from where they could be easily recovered in the post-hydrolysis solids.ConclusionsThe five bagasse preparations were compared but did not show substantial differences in composition or cellulose digestibility after pretreatment. Evidence was presented that a depithing step appears to be unnecessary prior to ionoSolv fractionation, potentially affording significant cost and energy savings. Instead, lignin re-deposition onto the pulp surface (and, in turn, particle size and shape) appeared to be major factors affecting the conditioning of bagasse with the applied IL. We show that pith ba

  • Journal article
    Pierotti L, Schofield SJ, Collett D, Fecht D, De Hoogh K, Hansell AL, Dark J, Cullinan Pet al., 2018,

    Traffic-related air pollution and solid organ transplant failure in Great Britain: A retrospective cohort study

    , Journal of Transport and Health, Vol: 10, Pages: 124-131, ISSN: 2214-1405

    Background: Limited evidence suggests that exposure to traffic related air pollution is associated with graft failure among lung transplant recipients. We explored associations between pollution and transplant failure among lung and other solid organ transplant recipients in Great Britain through a retrospective cohort study. Methods: All patients who received a lung, heart, liver, or kidney transplant between 2000 and 2008 in Great Britain were included, as recorded in the National Health Service Blood and Transplant (NHSBT) register and followed to March 2015. Using residential addresses at time of transplant we calculated distance to nearest (major) road and modelled annual average exposures to airborne nitrogen oxides and particulate matter of diameter ≤10µm and ≤2.5µm for each transplant recipient. All-cause mortality or graft failure (kidney) during follow up was the main outcome; median follow-up was around 10 years for each organ type. We fitted Cox regression models with adjustment for age, sex, year of transplant and donor age/smoking status. Results: 780 lung, 1213 heart, 3650 liver and 11966 graft kidney transplant patients were analysed. We did not find any consistent associations between mortality or graft failure and any of the analysed air pollutants or road metrics. Although, exposure to particulate matter was associated with renal transplant failure in univariable analyses but not after adjustment for confounders. Conclusions: Our analysis does not confirm previously reported associations between traffic-related air pollution exposure and the risk of transplant failure.

  • Journal article
    Yunus IS, Wichmann J, Wördenweber R, Lauersen KJ, Kruse O, Jones PRet al., 2018,

    Synthetic metabolic pathways for photobiological conversion of CO2 into hydrocarbon fuel

    , Metabolic Engineering, Vol: 49, Pages: 201-211, ISSN: 1096-7176

    Liquid fuels sourced from fossil sources are the dominant energy form for mobile transport today. The consumption of fossil fuels is still increasing, resulting in a continued search for more sustainable methods to renew our supply of liquid fuel. Photosynthetic microorganisms naturally accumulate hydrocarbons that could serve as a replacement for fossil fuel, however productivities remain low. We report successful introduction of five synthetic metabolic pathways in two green cell factories, prokaryotic cyanobacteria and eukaryotic algae. Heterologous thioesterase expression enabled high-yield conversion of native fatty acyl-acyl carrier protein (ACP) into free fatty acids (FFA) in Synechocystis sp. PCC 6803 but not in Chlamydomonas reinhardtii where the polar lipid fraction instead was enhanced. Despite no increase in measurable FFA in Chlamydomonas, genetic recoding and over-production of the native fatty acid photodecarboxylase (FAP) resulted in increased accumulation of 7-heptadecene. Implementation of a carboxylic acid reductase (CAR) and aldehyde deformylating oxygenase (ADO) dependent synthetic pathway in Synechocystis resulted in the accumulation of fatty alcohols and a decrease in the native saturated alkanes. In contrast, the replacement of CAR and ADO with Pseudomonas mendocina UndB (so named as it is responsible for 1-undecene biosynthesis in Pseudomonas) or Chlorella variabilis FAP resulted in high-yield conversion of thioesterase-liberated FFAs into corresponding alkenes and alkanes, respectively. At best, the engineering resulted in an increase in hydrocarbon accumulation of 8- (from 1 to 8.5 mg/g cell dry weight) and 19-fold (from 4 to 77 mg/g cell dry weight) for Chlamydomonas and Synechocystis, respectively. In conclusion, reconstitution of the eukaryotic algae pathway in the prokaryotic cyanobacteria host generated the most effective system, highlighting opportunities for mix-and-match synthetic metabolism. These studies describe functioning synt

  • Journal article
    Yunus IS, Jones PR, 2018,

    Photosynthesis-dependent biosynthesis of medium chain-length fatty acids and alcohols

    , Metabolic Engineering, Vol: 49, Pages: 59-68, ISSN: 1096-7176

    Cyanobacteria can directly channel atmospheric CO2 into a wide range of versatile carbon products such as fatty acids and fatty alcohols with applications including fuel, cosmetics, and health products. Works on alcohol production in cyanobacteria have so far focused on either long (C12-C18) or short (C2-C4) chain-length products. In the present work, we report the first synthetic pathway for 1-octanol (C8) biosynthesis in Synechocystis sp. PCC 6803, employing a carboxylic acid reductase and C8-preferring fatty acyl-ACP thioesterase. The first engineered strain produced 1-octanol but exhibited poor productivity and cellular health issues. We therefore proceeded to systematically optimize the strain and cultivation conditions in order to understand what the limiting factors were. The identification of optimal promoters and ribosomal binding sites, in combination with isopropyl myristate solvent overlay, resulted in a combined (C8-OH and C10-OH) titer of more than 100 mg/L (a 25-fold improvement relative to the first engineered strain) and a restoration of cellular health. Additionally, more than 905 mg/L 1-octanol was produced when the strain expressing sfp (phosphopantetheinyl transferase) and car (carboxylic acid reductase) was fed with octanoic acid. A combination of feeding experiments and protein quantification indicated that the supply of octanoic acid from the introduced thioesterase, and possibly also native fatty acid synthesis pathway, were the main bottlenecks of the pathway.

  • Journal article
    Gschwend FJV, Brandt-Talbot A, Malaret FJ, Shinde S, Hallett JPet al., 2018,

    Rapid pretreatment of Miscanthus using the low-cost ionic liquid triethylammonium hydrogen sulfate at elevated temperatures

    , Green Chemistry, Vol: 20, Pages: 3486-3498, ISSN: 1463-9262

    Deconstruction with low-cost ionic liquids (ionoSolv) is a promising method to pre-condition lignocellulosic biomass for the production of renewable fuels, materials and chemicals. This study investigated process intensification strategies for the ionoSolv pretreatment of Miscanthus X giganteus using the low-cost ionic liquid triethylammonium hydrogen sulfate ([TEA][HSO4]) in the presence of 20 wt% water, using high temperatures and a high solid to solvent loading of 1:5 g/g. The temperatures investigated were 150, 160, 170 and 180°C. We discuss the effect of pretreatment temperature on lignin and hemicellulose removal, cellulose degradation and enzymatic saccharification yields. We report that very good fractionation can be achieved across all investigated temperatures, including an enzymatic saccharification yield exceeding 75% of the theoretical maximum after only 15 min of treatment at 180°C. We further characterised the recovered lignins which established some tunability of the hydroxyl group content, subunit composition, connectivity and molecular weight distribution in the isolated lignin while maintaining maximum saccharification yield. This drastic reduction of pretreatment time at increased biomass loading without a yield penalty is promising for the development of a commercial ionoSolv pretreatment process.

  • Journal article
    Tonne C, Milà C, Fecht D, Alvarez M, Gulliver J, Smith J, Beevers S, Ross Anderson H, Kelly Fet al., 2018,

    Socioeconomic and ethnic inequalities in exposure to air and noise pollution in London

    , Environment International, Vol: 115, Pages: 170-179, ISSN: 0160-4120

    BACKGROUND: Transport-related air and noise pollution, exposures linked to adverse health outcomes, varies within cities potentially resulting in exposure inequalities. Relatively little is known regarding inequalities in personal exposure to air pollution or transport-related noise. OBJECTIVES: Our objectives were to quantify socioeconomic and ethnic inequalities in London in 1) air pollution exposure at residence compared to personal exposure; and 2) transport-related noise at residence from different sources. METHODS: We used individual-level data from the London Travel Demand Survey (n = 45,079) between 2006 and 2010. We modeled residential (CMAQ-urban) and personal (London Hybrid Exposure Model) particulate matter <2.5 μm and nitrogen dioxide (NO2), road-traffic noise at residence (TRANEX) and identified those within 50 dB noise contours of railways and Heathrow airport. We analyzed relationships between household income, area-level income deprivation and ethnicity with air and noise pollution using quantile and logistic regression. RESULTS: We observed inverse patterns in inequalities in air pollution when estimated at residence versus personal exposure with respect to household income (categorical, 8 groups). Compared to the lowest income group (<£10,000), the highest group (>£75,000) had lower residential NO2 (-1.3 (95% CI -2.1, -0.6) μg/m3 in the 95th exposure quantile) but higher personal NO2 exposure (1.9 (95% CI 1.6, 2.3) μg/m3 in the 95th quantile), which was driven largely by transport mode and duration. Inequalities in residential exposure to NO2 with respect to area-level deprivation were larger at lower exposure quantiles (e.g. estimate for NO2 5.1 (95% CI 4.6, 5.5) at quantile 0.15 versus 1.9 (95% CI 1.1, 2.6) at quantile 0.95), reflecting low-deprivation, high residential NO2 areas in the city centre. Air pollution exposure at residence consistently overestimated personal exposure; this overestimation varied with age

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