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The electroweak sector of the Standard Model can be tested either via precision measurements of fundamental observables or via direct tests of its underlying gauge structure. The ATLAS collaboration has recently released a measurement of the effective leptonic weak mixing angle using data collected at a centre-of-mass energy of 8 TeV. The result has a precision similar to that of the most precise individual measurements. The high integrated luminosity delivered by the LHC during Run-2 has allowed ATLAS to measure integrated and differential cross-sections for several kinematic observable of W±Z production in pp collisions and to observe vector boson scattering processes with WZ and same-sign WW final states. The results from these milestone analyses as well as their interpretation in the context of the Standard Model are presented in this proceeding.

Background: Squamous cell carcinoma has a stronger association with tobacco smoking than other non-small cell lung cancers (NSCLC). A study was undertaken to determine whether chronic obstructive pulmonary disease (COPD) is a risk factor for the squamous cell carcinoma histological subtype in smokers with surgically resectable NSCLC. Methods: Using a case-control design, subjects with a surgically confirmed diagnosis of squamous cell carcinoma were enrolled from smokers undergoing lung resection for NSCLC in the District Hospital of Ferrara, Italy. Control subjects were smokers who underwent lung resection for NSCLC in the same hospital and had a surgically confirmed diagnosis of NSCLC of any histological type other than squamous cell. Results: Eighty six cases and 54 controls (mainly adenocarcinoma, n = 50) were enrolled. The presence of COPD was found to increase the risk for the squamous cell histological subtype by more than four times. Conversely, the presence of chronic bronchitis was found to decrease the risk for this histological subtype by more than four times. Among patients with chronic bronchitis (n = 77), those with COPD had a 3.5 times higher risk of having the squamous cell histological subtype. Conclusions: These data suggest that, among smokers with surgically resectable NSCLC, COPD is a risk factor for the squamous cell histological subtype and chronic bronchitis, particularly when not associated with COPD, is a risk factor for the adenocarcinoma histological subtype.

Background:Chronic obstructive pulmonary disease (COPD) is often associated with other chronic diseases. These patients are often admitted to hospital based rehabilitation programmes.Objectives:To determine the prevalence of chronic comorbidities in patients with COPD undergoing pulmonary rehabilitation and to assess their influence on outcome.Design:Observational retrospective cohort study.Setting:A single rehabilitation centre.Patients:2962 inpatients and outpatients with COPD (73% male, aged 71 (SD 8) years, forced expiratory volume in 1 s (FEV1) 49.3 (SD 14.8)% of predicted), graded 0, 1 or ⩾2 according to the comorbidity categories and included in a pulmonary rehabilitation programme.Measurements:The authors analysed the number of self-reported comorbidities and recorded the Charlson Index. They then calculated the percentage of patients with a predefined positive response to pulmonary rehabilitation (minimum clinically important difference (MCID)), as measured by improvement in exercise tolerance (6 min walking distance test (6MWD)), dyspnoea (Medical Research Council scale) and/or health related quality of life (St George’s Respiratory Questionnaire (SGRQ)).Results:51% of the patients reported at least one chronic comorbidity added to COPD. Metabolic (systemic hypertension, diabetes and/or dyslipidaemia) and heart diseases (chronic heart failure and/or coronary heart disease) were the most frequently reported comorbid combinations (61% and 24%, respectively) among the overall diseases associated with COPD. The prevalence of patients with MCID was different across the comorbidity categories and outcomes. In a multiple categorical logistic regression model, the Charlson Index (OR 0.72 (96% CI 0.54 to 0.98) and 0.51 (96% CI 0.38 to 0.68) vs 6MWD and SGRQ, respectively), metabolic diseases (OR 0.57 (96% CI 0.49 to 0.67) vs 6MWD) and heart diseases (OR 0.67 (96% CI 0.55 to 0.83) vs SGRQ) reduced the probability to improve outcomes of rehabilitation.Conclusions:Most patients with COPD undergoing pulmonary rehabilitation have one or more comorbidities. Despite the fact that the presence of comorbidities does not preclude access to rehabilitation, the improvement in exercise tolerance and quality of life after rehabilitation may be reduced depending on the comorbidity.

Summary This randomized and controlled study evaluated the effect of therapy with strontium ranelate on callus formation in wrist fractures and its incidence in wrist recovery. Radiographic healing, progression of clinical recovery, and callus quality with ultrasound were evaluated. No statistically significant benefit of therapy was found. Introduction Fracture prevention is the main goal of any therapy for osteoporosis. Various drugs used in osteoporosis treatment have the theoretical premises to promote fracture healing and osseointegration. In this study, the effect of strontium ranelate on callus formation in wrist fractures was evaluated and whether it could lead to clinically relevant modification of wrist recovery; having strontium ranelate osteoinductive properties, it could be used, if effective, as an adjunct in fracture healing for a faster and functionally better recovery and, at the same time, in starting proper therapy in osteoporotic patients with fragility fractures. Methods We considered only patients older than 60 years who had suffered wrist fracture and received nonoperative treatment with manual reduction of the fracture and cast for 35 days. Forty patients were included and randomly assigned to one of two groups: group A [patients treated with calcium (1200 mg/day) and vitamin D (800 IU/day)] and group B [patients treated with calcium (1200 mg/day) and vitamin D (800 IU/day) associated with strontium ranelate 2 g daily]. Radiographic healing was evaluated through the bone callus formation, cortical continuity, and density of the callus. A clinical evaluation using Castaing’s criteria was carried out 2 and 3 months following the fracture together with an ultrasound study of callus density and vessels. Results A parametric analysis of the X-ray data, clinical evaluation, and ultrasonography results showed that there were no statistically significant differences in the two groups ( p  > 0.05 for all data). Conclusion In analyzing the data obtained, we concluded that strontium ranelate administered in acute phase did not improve nor accelerate wrist fracture healing in our population.

Background:Sjögren’s disease (SjD) is an autoimmune condition marked by lymphocytic infiltration of exocrine glands, where salivary gland epithelial cells (SGECs) play a crucial role in initiating and amplifying inflammation. To address dysfunction, understanding the mechanisms behind pro-inflammatory signaling in SGECs is vital. Epitranscriptomics, a recent field, highlights RNA modifications’ impact on gene expression regulation. Writers such as METTL3/14 add methyl groups to RNA, while erasers like FTO remove them. Collectively, these modifications influence various aspects of RNA function.Objectives:To evaluate the expression of m6A machinery components in SGEC of controls and SjD. Additionally, we aim to define the mechanisms through which this newly identified post-transcriptional regulation controls inflammatory signal transduction in SGECs.Methods:We retrieved RNA-seq data from SGEC sorted from minor salivary gland biopsies of controls and SjD. We specifically looked at the expression of the m6A machinery by qPCR in sorted SGEC and by immunohistochemistry (IHC). Additionally, we determined the functional role of m6A writers in SGEC by performing knockdown experiments and by using pharmacological inhibitors. We assessed the expression of pro-inflammatory cytokines and chemokines, conducted transwell assays, and established SGEC/B cell co-cultures to comprehensively explore the impact of RNA m6A methylation on B cell survival and activation. Finally, we used immunofluorescence and flow cytometry techniques to detect the presence of dsRNA, and to explore their link with RNA methylation.Results:METTL14 showed increased expression in sorted SGECs from SjD subjects, and both METTL3 and METTL14 proteins increased in SGECs per IHC. Knockdown experiments targeting m6A writers demonstrated elevated CXCL10 and TNFSF13B expression upon SGEC activation by Poly(I:C) or IFNα, suggesting a protective effect of m6A against inflammation. Pharmacological inhibition of METTL3 increased CXCL10 expression, while inhibiting FTO decreased it, emphasizing RNA m6A’s role in modulating the inflammatory response. RNA-seq and pathway analysis upon METTL3 inhibition revealed interferon signature gene induction. Mechanistically, blocking METTL3 heightened the presence of dsRNA, as confirmed by immunofluorescence and flow cytometry. In parallel, inhibiting METTL3 not only increased the capacity of SGECs to attract immune cells in transwell assays, but also elevated the expression of CD38 on B cells in co-culture assays. Conversely, blocking FTO resulted in the opposite phenotype.Conclusion:Our findings highlight the role of RNA m6A pathway as a protector of SGECs in response to pro-inflammatory triggers. We hypothesize that the observed elevation of METTL3 and METTL14 in SGECs from SjD patients may not be sufficiently effective or significant in efficiently regulating the inflammatory response. Ongoing research is assessing the effectiveness of post-transcriptional regulation through the m6A pathway in preventing dsRNA accumulation in SGECs from SjD patients compared to controls.REFERENCES:NIL.Figure 1.A) RNA m6A methylation involves writers (METTL3/14), erasers (FTO, ALKBH5), and readers (YTH, IGF2BP families). B) SGECs, stimulated with Poly(I:C) (10 mg/mL), were treated with METTL3 inhibitor (STM2457), nonfunctional inhibitor (STM2120), or FTO inhibitor (FB23-2) to assess CXCL10 expression. C) Enrichment pathway analysis compared STM2457 and Poly(I:C)-treated SGECs vs. Poly(I:C)-treated SGECs. D) Transwell experiments studied SGECs pre-treated with STM2457, with or without Poly(I:C), in the lower compartment. PBMCs were added to the upper compartment. E) Coculture experiments where SGEC were preteated or not with STM2457 in the presence or not of Poly(I:C) and co-cultured with B cells.Acknowledgements:NIL.Disclosure of Interests:None declared.

Exacerbations represent an important feature of the clinical manifestation and natural history of chronic obstructive pulmonary disease (COPD). Nuclear localisation of p65 is a signal of nuclear factor-kappaB (NF-kappaB) activation. A study was undertaken to evaluate whether NF-kappaB activation is modified in sputum cells during COPD exacerbations. Total and nuclear p65 immunoreactivity was measured by immunocytochemistry in the sputum cells of 11 smokers with moderate COPD during an exacerbation and after 6-8 weeks of clinical stability. Total sputum cell count was significantly increased during exacerbations from a median (IQR) of 880 (510-1865) to 1914.5 (1065-3205) x 10(3)/ml (p<0.05). The main inflammatory cells in the sputum were neutrophils (83.2 (75.4-92.3)%) and macrophages (14.7 (2.6-21.6)%) and their relative proportion did not change during exacerbations. Nuclear staining for p65 was absent in sputum neutrophils, both during exacerbations and in the stable phase. In contrast, the percentage of macrophages expressing nuclear p65 increased significantly during exacerbations from a median (IQR) of 16 (7-24)% to 41.4 (6-69)% (p<0.05). NF-kappaB appears to be activated in sputum macrophages but not in sputum neutrophils during exacerbations of COPD

Background: The predominant emphysema phenotype is associated with more severe airflow limitation in patients with chronic obstructive pulmonary disease (COPD). A study was undertaken to investigate whether COPD patients, with or without emphysema quantitatively confirmed by high resolution computed tomography (HRCT), have different COPD severity as assessed by the BODE index (body mass index, airflow obstruction, dyspnoea, exercise performance) and inspiratory capacity to total lung capacity ratio (IC/TLC), and by different biological markers of lung parenchymal destruction. Methods: Twenty six outpatients with COPD and eight healthy non-smokers were examined. Each subject underwent HRCT scanning, pulmonary function tests, cell counts, and measurements of neutrophil elastase, matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1 in induced sputum, as well as measurement of desmosine, a marker of elastin degradation in urine, plasma and sputum. Results: Patients with HRCT confirmed emphysema had a higher BODE index and lower IC/TLC ratio than subjects without HRCT confirmed emphysema and controls. Forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity ratio, and carbon monoxide transfer coefficient were lower, whereas the number of eosinophils, MMP-9, and the MMP-9/TIMP-1 ratio in sputum were higher in patients with emphysema. In COPD patients the number of sputum eosinophils was the biological variable that correlated positively with the HRCT score of emphysema (p = 0.04). Conclusions: These results suggest that COPD associated with HRCT confirmed emphysema is characterised by more severe lung function impairment, more intense airway inflammation and, possibly, more serious systemic dysfunction than COPD not associated with HRCT confirmed emphysema.

Background: COPD is an inflammatory disorder characterised by chronic airflow limitation, but the extent to which airway inflammation is related to functional abnormalities is still uncertain. The interaction between inflammatory cells and airway smooth muscle may have a crucial role. Methods: To investigate the microlocalisation of inflammatory cells within the airway smooth muscle in COPD, surgical specimens obtained from 26 subjects undergoing thoracotomy (eight smokers with COPD, 10 smokers with normal lung function, and eight non-smoking controls) were examined. Immunohistochemical analysis was used to quantify the number of neutrophils, macrophages, mast cells, CD4+ and CD8+ cells localised within the smooth muscle of peripheral airways. Results: Smokers with COPD had an increased number of neutrophils and CD8+ cells in the airway smooth muscle compared with non-smokers. Smokers with normal lung function also had a neutrophilic infiltration in the airway smooth muscle, but to a lesser extent. When all the subjects were analysed as one group, neutrophilic infiltration was inversely related to forced expiratory volume in 1 second (% predicted). Conclusions: Microlocalisation of neutrophils and CD8+ cells in the airway smooth muscle in smokers with COPD suggests a possible role for these cells in the pathogenesis of smoking induced airflow limitation.

Recently, two \"fixed triple\" single-inhaler combinations of an inhaled corticosteroid (ICS), a long-acting β -agonist (LABA), and a long-acting muscarinic antagonist (LAMA) have become available for patients with COPD. This review presents the clinical evidence that led to the approval of these triple therapies, discusses the role of ICS in patients with COPD, and presents data on the relative efficacy of \"fixed triple\" (ICS/LAMA/LABA) therapy vs LAMA, ICS/LABA, and LAMA/LABA combinations, and summarizes studies in which ICS/LABAs were combined with LAMAs to form \"open triple\" combinations. Of the five main fixed triple studies completed so far, three evaluated the efficacy and safety of an extrafine formulation of beclometasone dipropionate, formoterol fumarate, and glycopyrronium; the other two studies evaluated fluticasone furoate, vilanterol, and umeclidinium. Overall, compared to LAMA, ICS/LABA, or LAMA/LABA, triple therapy decreased the risk of exacerbations and improved lung function and health status, with a favorable benefit-to-harm ratio. Furthermore, triple therapy showed a promising signal in terms of improved survival. The evidence suggests that triple therapy is the most effective treatment in moderate/severe symptomatic patients with COPD at risk of exacerbations, with marginal if any risk of side effects including pneumonia. Ongoing studies are examining the role of triple therapy in less severe symptomatic patients with COPD and asthma-COPD overlap.

Substantial epidemiologic and clinical evidence indicates that agents inhaled at work can induce asthma. In industrialized countries, occupational factors have been implicated in 9 to 15% of all cases of adult asthma. Work-related asthma includes (1) immunologic occupational asthma (OA), characterized by a latency period before the onset of symptoms; (2) nonimmunologic OA, which occurs after single or multiple exposures to high concentrations of irritant materials; (3) work-aggravated asthma, which is preexisting or concurrent asthma exacerbated by workplace exposures; and (4) variant syndromes. Assessment of the work environment has improved, making it possible to measure concentrations of several high- and low-molecular-weight agents in the workplace. The identification of host factors, polymorphisms, and candidate genes associated with OA is in progress and may improve our understanding of mechanisms involved in OA. A reliable diagnosis of OA should be confirmed by objective testing early after its onset. Removal of the worker from exposure to the causal agent and treatment with inhaled glucocorticoids lead to a better outcome. Finally, strategies for preventing OA should be implemented and their cost-effectiveness examined.