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The EarlyCDT-Lung test is a high-specificity blood-based autoantibody biomarker that could contribute to predicting lung cancer risk. We report on the results of a phase IV biomarker evaluation of whether using the EarlyCDT-Lung test and any subsequent computed tomography (CT) scanning to identify those at high risk of lung cancer reduces the incidence of patients with stage III/IV/unspecified lung cancer at diagnosis compared with the standard clinical practice at the time the study began.The Early Diagnosis of Lung Cancer Scotland (ECLS) trial was a randomised controlled trial of 12 208 participants at risk of developing lung cancer in Scotland in the UK. The intervention arm received the EarlyCDT-Lung test and, if test-positive, low-dose CT scanning 6-monthly for up to 2 years. EarlyCDT-Lung test-negative and control arm participants received standard clinical care. Outcomes were assessed at 2 years post-randomisation using validated data on cancer occurrence, cancer staging, mortality and comorbidities.At 2 years, 127 lung cancers were detected in the study population (1.0%). In the intervention arm, 33 out of 56 (58.9%) lung cancers were diagnosed at stage III/IV compared with 52 out of 71 (73.2%) in the control arm. The hazard ratio for stage III/IV presentation was 0.64 (95% CI 0.41-0.99). There were nonsignificant differences in lung cancer and all-cause mortality after 2 years.ECLS compared EarlyCDT-Lung plus CT screening to standard clinical care (symptomatic presentation) and was not designed to assess the incremental contribution of the EarlyCDT-Lung test. The observation of a stage shift towards earlier-stage lung cancer diagnosis merits further investigations to evaluate whether the EarlyCDT-Lung test adds anything to the emerging standard of low-dose CT., Competing Interests: Conflict of interest: F.M. Sullivan reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. Conflict of interest: F.S. Mair reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. Conflict of interest: W. Anderson has nothing to disclose. Conflict of interest: P. Armory reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. Conflict of interest: A. Briggs reports grants from the Scottish Government Health and Social Care Directorate of the Chief Scientist Office and Oncimmune, during the conduct of the study. Conflict of interest: C. Chew has nothing to disclose. Conflict of interest: A. Dorward has nothing to disclose. Conflict of interest: J. Haughney has nothing to disclose. Conflict of interest: F. Hogarth reports grants from the Scottish Government Health and Social Care Directorate of the Chief Scientist Office and from Oncimmune, during the conduct of the study. Conflict of interest: D. Kendrick has nothing to disclose. Conflict of interest: R. Littleford reports grants from the Scottish Government Health and Social Care Directorate of the Chief Scientist Office and Oncimmune, during the conduct of the study. Conflict of interest: A. McConnachie reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. Conflict of interest: C. McCowan has nothing to disclose. Conflict of interest: N. McMeekin reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. Conflict of interest: M. Patel has nothing to disclose. Conflict of interest: P. Rauchhaus reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. Conflict of interest: L. Ritchie has nothing to disclose. Conflict of interest: C. Robertson reports personal fees and other funding from Oncimmune, outside the study. Conflict of interest: J. Robertson reports other funding from Oncimmune, during the conduct of the study; and other funding from Oncimmune, outside the study. J. Robertson was a founder of Oncimmune, a company spun out from the University of Nottingham based on his academic research. Between 2003 and 2013 he was Chief Scientific Officer of Oncimmune and a Director of the company. During this time, he was responsible for the original drafting of the ECLS protocol. Since 2013 he has had no involvement in the science or management of the company. He has been and remains a shareholder in the company. Conflict of interest: J. Robles-Zurita reports grants from the Scottish Government Health and Social Care Directorate of the Chief Scientist Office and Oncimmune, during the conduct of the study. Conflict of interest: J. Sarvesvaran has nothing to disclose. Conflict of interest: H. Sewell reports other funding from Oncimmune, outside the submitted work; and was an external member of the Oncimmune Scientific Advisory Board from 2006 to 2013. Conflict of interest: M. Sproule has nothing to disclose. Conflict of interest: T. Taylor reports grants, nonfinancial support and other funding from Oncimmune, grants and personal fees from the Chief Scientist Office for Scotland, and grants and nonfinancial support from the Scottish Government, outside the submitted work. Conflict of interest: A. Tello reports grants from Oncimmune, during the conduct of the study. Conflict of interest: S. Treweek reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. Conflict of interest: K. Vedhara has nothing to disclose. Conflict of interest: S. Schembri reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study; and nonfinancial support from GlaxoSmithKline and AstraZeneca, outside the submitted work., (Copyright ©ERS 2021.)

Background: Cigarette smoking is associated with worse symptoms in asthma and abnormal segmental airways in healthy subjects. We tested the hypothesis that current symptom control in smokers with asthma is associated with altered segmental airway dimensions measured by CT scan., Methods: In 93 subjects with mild, moderate, and severe asthma (smokers and never smokers), we recorded Asthma Control Questionnaire-6 (ACQ-6) score, spirometry (FEV1; forced expiratory flow rate, midexpiratory phase [FEF(25%-75%)]), residual volume (RV), total lung capacity (TLC), and CT scan measures of the right bronchial (RB) and left bronchial (LB) segmental airway dimensions (wall thickness, mm; lumen area, mm²) in the RB3/LB3, RB6/LB6, and RB10/LB10 (smaller) airways., Results: The CT scan segmental airway (RB10 and LB10) lumen area was reduced in smokers with asthma compared with never smokers with asthma; RB10, 16.6 mm² (interquartile range, 12.4-19.2 mm²) vs 19.6 mm² (14.7-24.2 mm²) (P = .01); LB10, 14.8 mm² (12.1-19.0 mm²) vs 19.9 mm² (14.5-25.0 mm²) (P = .003), particularly in severe disease, with no differences in wall thickness or in larger airway (RB3 and LB3) dimensions. In smokers with asthma, a reduced lumen area in fifth-generation airways (RB10 or LB10) was associated with poor symptom control (higher ACQ-6 score) (-0.463 [-0.666 to -0.196], P = .001, and -0.401 [-0.619 to -0.126], P = .007, respectively) and reduced postbronchodilator FEF(25%-75%) (0.521 [0.292-0.694], P < .001, and [0.471 [0.236-0.654], P = .001, respectively) and higher RV/TLC %., Conclusions: The CT scan segmental airway lumen area is reduced in smokers with asthma compared with never smokers with asthma, particularly in severe disease, and is associated with worse current symptom control and small airway dysfunction.

Transcription factors are known to play multiple roles in cellular function. Investigators report that factors such as early growth response (Egr) protein and nuclear factor kappa B (NF-κB) are activated in the brain during cancer, brain injury, inflammation, and/or memory. To explore NF-κB activity further, we investigated the transcriptomes of hippocampal slices following electrical stimulation of NF-κB p50 subunit knockout mice (p50-/-) versus their controls (p50+/+). We found that the early growth response gene Egr-2 was upregulated by NF-κB activation, but only in p50+/+ hippocampal slices. We then stimulated HeLa cells and primary cortical neurons with tumor necrosis factor alpha (TNFα) to activate NF-κB and increase the expression of Egr-2. The Egr-2 promoter sequence was analyzed for NF-κB binding sites and chromatin immunoprecipitation (ChIP) assays were performed to confirm promoter occupancy in vivo. We discovered that NF-κB specifically binds to an NF-κB consensus binding site within the proximal promoter region of Egr-2. Luciferase assay demonstrated that p50 was able to transactivate the Egr-2 promoter in vitro. Small interfering RNA (siRNA)-mediated p50 knockdown corroborated other Egr-2 expression studies. We show for the first time a novel link between NF-κB activation and Egr-2 expression with Egr-2 expression directly controlled by the transcriptional activity of NF-κB., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Asthmatic smokers have poor symptom control and accelerated decline in lung function. A reduced ratio of matrix metalloproteinase (MMP)-9/tissue inhibitors of metalloproteinases (TIMPs) in nonsmokers with asthma has been implicated in airway remodelling. We tested the hypothesis that sputum MMP-9 activity/TIMPs ratios are reduced in smokers compared with never-smokers with asthma and are associated with reduced lung function and altered computed tomography (CT) measures of airway wall dimensions. Lung function, airway dimensions by CT, and induced sputum concentrations (and activity) of MMP-9 and TIMP-1 and -2 were measured in 81 asthmatics and 43 healthy subjects (smokers and never-smokers). Respiratory epithelial MMP9 and TIMP mRNA was quantified in 31 severe asthmatics and 32 healthy controls. Sputum MMP-9 activity/TIMP-1 and TIMP-2 ratios, and nasal epithelial MMP9/TIMP1 and MMP9/TIMP2 expression ratios were reduced in smokers with asthma compared with never-smokers with asthma. Low sputum ratios in asthmatic smokers were associated with reduced post-bronchodilator forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity ratio and segmental airway lumen area. The association of a low sputum MMP-9 activity/TIMP-1 ratio with persistent airflow obstruction and reduced CT airway lumen area in smokers with asthma may indicate that an imbalance of MMP-9 and TIMPs contributes to structural changes to the airways in this group., (©ERS 2014.)

Background: Matrix-metalloproteinase (MMP)-9 has been implicated in the pathogenesis of COPD, although its link to disease severity is unclear. The purpose of the study was to examine the relationship between disease severity assessed by lung function and computed tomography (CT) and sputum MMP-9 expression, concentration and activity in patients with COPD., Findings: In 53 COPD subjects, smokers and ex-smokers; 46 healthy controls, smokers and never smokers, we measured sputum MMP-9 concentrations (ELISA) and enzyme activity (FRET), sputum MMP-9 mRNA expression, spirometry, diffusing capacity for carbon monoxide (DLco) and CT assessment of emphysema (% low attenuation areas below-950 Hounsfield units). Sputum MMP-9 concentrations and mRNA expression in COPD subjects were significantly greater than in healthy never-smokers (p = 0.007 and p = 0.001 respectively) and similar to those in healthy smokers. Disease severity when assessed by the extent of emphysema measured by CT, but not by spirometry or DLco values, was directly associated with sputum MMP-9 concentrations [r = 0.442 (0.171, 0.634), p = 0.020], and MMP-9 activity [r = 0.447 (0.219, 0.643), p = 0.010]. In moderate to severe COPD, increased MMP-9 mRNA expression levels were associated with reduced post-bronchodilator FEV1 [r = -0.530 (-0.686, -0.327), p < 0.001], FEV1/FVC ratio [r = -0.551 (-0.701, -0.354), p < 0.001] and reduced DLco [r = -0.399 (-539, -0.102), p = 0.048]., Conclusions: Sputum MMP-9 concentrations in COPD are directly associated with the extent of emphysema measured by CT and MMP-9 expression levels are inversely associated with DLco. These findings support a role for MMP-9 in the pathogenesis of COPD.

Background: Chronic cough and sputum production (chronic mucus hypersecretion) is a poorly described clinical feature of asthma. Our objective was to identify clinical, immunological and computed tomography (CT) measures of airway wall dimensions associated with these symptoms in smokers and never smokers with asthma., Methods: Cross-sectional data was analysed from 120 smokers and never smokers with asthma. Participants with and without a history of chronic mucus hypersecretion were compared for clinical outcomes, sputum differential cell counts and CT measures of airway dimensions (wall thickness, luminal area and percent wall area)., Results: Chronic mucus hypersecretion occurred in a higher proportion of smokers with asthma (56%) than never smokers with asthma (20%), (p < 0.001) and the proportion of patients with these symptoms increased with asthma severity (p = 0.003). Smokers with asthma and chronic mucus hypersecretion had worse current clinical control than smokers without those symptoms [ACQ score 2.3 versus 1.6, p = 0.002]. A greater proportion of never smokers with chronic mucus hypersecretion required short courses of oral corticosteroids in the last year (58% versus 19%, p = 0.011). Sputum neutrophil and eosinophil counts were similar in asthma patients with or without chronic mucus hypersecretion. Of those with severe asthma and chronic mucus hypersecretion, a CT measure of airway lumen area was reduced in smokers compared to never smokers (11.4 mm(2) versus 18.4 mm(2); p = 0.017)., Conclusions: Chronic mucus hypersecretion occurs frequently in adults with stable asthma, particularly in smokers with severe disease and is associated with worse current clinical control in smokers and more exacerbations in never smokers., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Matrix metalloproteinase (MMP)-12 has been implicated in the pathogenesis of both chronic obstructive pulmonary disease (COPD) and asthma. The influence of disease severity on sputum MMP-12 concentrations and activity is not known., Objectives: We sought to examine the relationship between disease severity assessed by means of lung function and computed tomography (CT) and induced sputum MMP-12 concentrations and activity in patients with asthma and COPD., Methods: In 208 subjects (109 asthmatic patients, smokers and never smokers, mild, moderate, and severe; 53 patients with COPD, smokers and exsmokers, mild, moderate, and severe; and 46 healthy control subjects, smokers and never smokers), we measured induced sputum MMP-12 concentrations (ELISA) and enzyme activity (fluorescence resonance energy transfer), sputum cell MMP12 mRNA expression (quantitative PCR [qPCR]), diffusing capacity for carbon monoxide (Dlco), and CT assessment of emphysema (percentage of low-attenuation areas at less -950 Hounsfield units)., Results: Sputum MMP-12 concentrations are greater in patients with COPD and smokers with asthma than in healthy nonsmokers (P = .003 and P = .035, respectively) but similar to those seen in healthy smokers. In patients with COPD, disease severity, when measured by means of CT-assessed emphysema, but not by means of spirometry or Dlco values, is directly associated with sputum MMP-12 concentrations and activity. In the asthma groups there is no significant association between disease severity and sputum MMP-12 concentrations or activity., Conclusions: Sputum MMP-12 concentrations and activity in patients with COPD are directly associated with the extent of emphysema measured by means of CT. This finding supports a role for MMP-12 in the pathogenesis of COPD and might suggest that blocking MMP-12 activity in patients with COPD could prevent the further development of emphysema., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Electroretinographic (ERG) abnormalities have been reported in multiple sclerosis (MS), as well as the presence of circulating antiretinal antibodies. We and others have reported cases of impaired vision and diminished ERGs in MS patients with alpha-enolase autoantibodies. Anti-enolase antibodies have been implicated in autoimmune retinopathy. We performed this study to further explore the relationship between antiretinal antibodies and ERG changes in patients with MS., Methods: Patients with clinically definite MS and normal visual acuity were recruited for this study, along with healthy controls. All patients and controls had ERG testing done according to ISCEV standards. Patient and control sera were analyzed for the presence of antiretinal antibodies using Western blot and ELISA techniques, and HLA class II typing was performed using polymerase chain reaction., Results: We found a statistically significant difference between MS patients and controls in the rod-cone b-wave implicit time (p < 0.005). We found autoantibodies against alpha-enolase in 38% of MS patients and 11% of controls (p < 0.02). There was no statistically significant difference between ERG parameters of MS patients with alpha-enolase autoantibodies compared to those without alpha-enolase antibodies. Furthermore, the presence of alpha-enolase did not associate with a particular HLA haplotype., Conclusions: Factors affecting the retina other than alpha-enolase antibodies may account for the delayed rod-cone b-wave implicit times observed in MS patients in this study. Anti-enolase antibodies are likely an epiphenomenon of autoimmune disease, and are not causing retinopathy in MS patients with normal visual acuity. However, the possibility of rare cases of patients with pathogenic alpha-enolase autoantibodies can not be excluded. The pathogenic contribution of these antibodies in MS patients with visual impairment deserves further investigation.

Background: Multiple sclerosis (MS) has been associated with inflammation of the uveal tract, suggesting an immunological link between the uvea and central nervous system (CNS) in this disease. The retina is embryologically derived from the CNS, and it is conceivable that retinal antigens may also be recognized by the immune system in MS. Electroretinographic abnormalities, as well as retinal autoantibodies, have previously been described in MS. We performed this study to further explore the possibility of retinal autoimmunity in MS., Methods: Thirty-four patients with clinically definite MS and thirty-seven healthy controls were recruited. All patients and controls had standard electroretinographic (ERG) testing done, as well as a brightflash ERG protocol to isolate rod photoreceptor function. Patient and control sera were analyzed for the presence of antiretinal antibodies using Western blot techniques., Results: We found statistically significant differences between MS patients and controls in four ERG parameters. In the MS group, implicit times of the rod-cone b-wave response, cone b-wave response, and rod photoreceptor response were increased. The amplitudes of the photopic oscillatory potentials were reduced in the MS group. Patients with the highest titres of retinal autoantibodies had delayed rod-cone b-wave implicit times and diminished photopic oscillatory potential amplitudes., Conclusions: We report ERG evidence of retinal dysfunction in patients with MS. We also report the first use of the brightflash ERG protocol in MS, which demonstrated rod photoreceptor dysfunction. Patients with the highest antiretinal antibody titres had abnormal ERG recordings. Retinal autoimmunity is a possible explanation for these observed ERG abnormalities in MS patients.

Purpose: To investigate the utility of the 25-Item National Eye Institute Visual Function Questionnaire (VFQ-25) in assessing visual function in a heterogeneous group of multiple sclerosis (MS) patients and to identify correlations of VFQ-25 scores with clinically relevant objective visual parameters., Design: Comparative cohort study., Methods: The VFQ-25 was distributed to 34 patients with clinically definite MS. Patients underwent a comprehensive ophthalmic examination, including Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (V(A)), Pelli-Robson contrast sensitivity (CS), Humphrey visual field 30 to 2 (HVF), and Farnsworth-Munsell 100-Hue color vision (100-Hue). Expanded Disability Status Scores (EDSS) were recorded for each patient. Comparative analyses using chi2 tests and t tests were performed. Spearman rank correlation coefficients were computed to identify relationships between VFQ-25 scores and the aforementioned visual parameters., Results: In comparison with a published reference group without ocular disease, MS patients had considerably worse VFQ-25 composite scores (P < .01), being similar to published cohorts of glaucoma and cataract patients. VFQ-25 composite scores were found to be modestly and significantly correlated with several clinical parameters, including: V(A) (r = -0.63, P < .001), CS (r = 0.60, P < .001), HVF (r = 0.53, P = .003), and 100-Hue (r = -0.48, P = .01). EDSS scores, the use of disease modifying agents, and having a history of previous optic neuritis did not correlate significantly with VFQ-25 composite scores., Conclusions: The VFQ-25 questionnaire is a sensitive and useful tool in assessing visual function in MS patients. Such patients have quality of life indices similar to glaucoma and cataract patients, underscoring the significance of visual symptoms in MS.

Purpose: The purpose of our study was to evaluate CT findings during respiratory syncytial virus (RSV) infection in lung transplant recipients and to identify sequelae., Method: Thirty-nine CT scans prior to, during, and following acute infection in 10 lung transplant recipients were reviewed. Abnormalities that were new from baseline observations and occurred within 4 weeks of diagnosis were defined as acute. Chronic findings were defined as those present >4 weeks after diagnosis., Results: Findings in nine patients were ground-glass (seven), air-space (five), and tree-in-bud (four) opacities and acute bronchial dilatation (four) and wall thickening (four). Patients lacked pleural effusions or lymph node enlargement. Five of seven patients with follow-up exams had new air trapping (three), persistent bronchial dilatation (three), and thickening (two). Three and 2 of the 10 patients developed bronchiolitis obliterans syndrome and obliterative bronchiolitis, respectively., Conclusion: During acute infection, patients commonly had ground-glass opacities but lacked pleural effusions and lymph node enlargement. There can be chronic sequelae after infection.

The prevalence of venous thromboembolism (VTE) in cancer patients has been estimated as up to 15% antemortem, and higher (over 50% in pancreatic tumours) postmortem owing to the asymptomatic nature of many episodes of VTE. We investigated the prevalence of deep venous thrombosis (DVT) in a population of 298 hospice inpatients with advanced cancer. They were screened for the presence of DVT using light reflection rheography; 258 (86.6%) patients were evaluable for DVT, which was found in 135 (52%; 95% confidence interval 46-58). Factors associated (multivariate analysis) with the presence of DVT were: poor mobility, reduced serum albumin level and higher serum urea. A DVT risk assessment index was calculated using these variables. The three highest categories all had significant rates of DVT and, although the lowest category had a low rate of DVT, it accounted for less than 10% of all patients tested. DVT is common in patients with advanced cancer. It was found to be significantly associated with the above variables, but a combined index was of limited clinical application. In view of the number of patients identified with DVT, repeated small pulmonary emboli may be responsible for more symptoms than previously recognized in cancer patients.

A long-term, comparison-group outcome trial with a partial crossover design was carried out on the effects of electromyographic biofeedback (EMGBF) plus physiotherapy (PT) versus PT alone in the treatment of the hemiplegic upper limb in stroke patients who were at least six months beyond the onset of their disability. Both the experimental and the control groups benefited from their treatment, but EMGBF was shown to have an additional effect, both in the experimental patients, and in the control patients when they switched over to the experimental treatment condition.