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Vicky Kritikos,1,2 David Price,3– 5 Alberto Papi,6 Antonio Infantino,7 Björn Ställberg,8 Dermot Ryan,3,9 Federico Lavorini,10 Henry Chrystyn,11 John Haughney,12 Karin Lisspers,8 Kevin Gruffydd-Jones,13 Miguel Román Rodríguez,14 Svein Høegh Henrichsen,15 Thys van der Molen,16 Victoria Carter,3,4 Sinthia Bosnic-Anticevich1,17,18 1Quality Use of Respiratory Medicines Group, Woolcock Institute of Medical Research, University of Sydney, Sydney, NSW, Australia; 2Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Sydney, NSW, Australia; 3Optimum Patient Care, Cambridge, UK; 4Observational and Pragmatic Research Institute, Singapore, Singapore; 5Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; 6Respiratory Medicine, University of Ferrara, Ferrara, Italy; 7Special Interest Respiratory Area, Italian Interdisciplinary Society for Primary Care, Bari, Italy; 8Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden; 9Usher Institute, University of Edinburgh, Edinburgh, UK; 10Department Experimental and Clinical Medicine, University of Florence, Florence, Italy; 11Inhalation Consultancy Ltd, Leeds, UK; 12NHS Greater Glasgow & Clyde R&D, Glasgow, UK; 13Box Surgery, Box, UK; 14Primary Care Respiratory Research Unit Instituto De Investigación Sanitaria De Baleares (IdISBa), Palma, Spain; 15Department of Primary Health Care Services, Norwegian Directorate of Health, Oslo, Norway; 16Department of Primary Care, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands; 17Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; 18Central Sydney Local Area Health District, Sydney, NSW, AustraliaCorrespondence: Vicky KritikosWoolcock Institute of Medical Research, Glebe, Sydney, NSW, AustraliaTel +61 4 0299 5125Fax +61 2 9114 0014Email vicky.kritikos@sydney.edu.auPurpose: There is a dearth of research regarding the prevalence and nature of patient-reported rhinitis and its relationship with risk of asthma exacerbations. The aim of this study was to (i) determine the prevalence, severity and treatment of self-reported rhinitis symptoms among adults aged ≥ 18 years with asthma treated at Global Initiative for Asthma (GINA) Step 3 and above and (ii) compare the demographics, clinical characteristics, medication use, side-effects and healthcare practitioner review between patients who report rhinitis symptoms and those who do not and (iii) determine whether patient-reported rhinitis is associated with risk of asthma exacerbations in the total patient sample.Patients and Methods: This analysis used data from the iHARP (Initiative Helping Asthma in Real-life Patients) asthma review service – a cross-sectional observational study (2011 and 2014) in seven countries that captured data on patient demographics, rhinitis symptoms, asthma symptoms, indicators of exacerbations, medication use, oropharyngeal effects and side-effects, using practitioner- and patient-reported questionnaires. Comparisons between patients with and without rhinitis were tested. Univariate logistic regression was used to identify variables associated with risk of exacerbations for entry into multivariable logistic regression.Results: This report contains data from 4274 patients: 67.4% (2881/4274) reported rhinitis symptoms and of which 65.7% (1894/2881) had not received a doctor diagnosis; 36.5% (1052/2881) had moderate-severe rhinitis, 12.4% (358/2881) had used intranasal corticosteroids and 19.8% (569/2881) oral antihistamines. Patients with coexisting moderate-severe rhinitis were more likely to have GINA-defined uncontrolled asthma than those with mild rhinitis or no rhinitis. Moderate-severe rhinitis was associated with 40% increased risk of asthma exacerbations (OR=1.40, 95% CI: 1.02– 1.90).Conclusion: This study identified a major gap in the diagnosis and management of rhinitis in a cohort of people with asthma treated at GINA Step 3 and above who are managed in general practice. It highlights the need for practitioners to identify, evaluate and optimally treat rhinitis in adults with asthma, which is a significant factor associated with exacerbation risk.Keywords: asthma symptom control, comorbidities, oral steroids, preventer, reliever, side-effects

Kevin Gruffydd-Jones,1 Mike Thomas,2 Miguel Roman-Rodríguez,3 Antonio Infantino,4 J Mark FitzGerald,5 Ian Pavord,6 Jennifer M Haddon,7 Ulrich Elsasser,8 Christian Vogelberg91Box Surgery, Box, Wiltshire, UK; 2Primary Care and Population Sciences, University of Southampton, Southampton, UK; 3Son Pisà Primary Health Care Centre, Balearic Health Centre, Palma de Mallorca, Spain; 4Società Italiana Interdisciplinare per le Cure Primarie (SIICP), Bari, Italy; 5Institute for Heart and Lung Health, University of British Columbia, Vancouver, British Columbia, Canada; 6Respiratory Medicine Unit and Oxford Respiratory NIHR Biomedical Research Centre, Nuffield Department of Medicine, University of Oxford, Oxford, UK; 7TA Dig Excellence + Healthcare Inno Med, Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany; 8Biostatistics and Data Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany; 9Department of Pediatric Pneumology and Allergology, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, GermanyBackground: Asthma affects millions of people worldwide, with many patients experiencing symptoms that affect their daily lives despite receiving long-term controller medication.Purpose: Work is a large part of most people’s lives, hence this study investigated the impact of uncontrolled asthma on work productivity in adults receiving asthma maintenance therapy.Patients and methods: An online survey was completed by employed adults in Brazil, Canada, Germany, Japan, Spain and the UK. Participants were confirmed as symptomatic using questions from the Royal College of Physicians’ 3 Questions for Asthma tool. The survey contained the Work Productivity and Activity Impairment – Specific Health Problem questionnaire and an open-ended question on the effect of asthma at work.Results: Of the 2,055 patients on long-term maintenance therapy screened, 1,598 were symptomatic and completed the survey. The average percentage of work hours missed in a single week due to asthma symptoms was 9.3%, ranging from 3.5% (UK) to 17.4% (Brazil). Nearly three-quarters of patients reported an impact on their productivity at work caused by asthma. Overall work productivity loss (both time off and productivity whilst at work) due to asthma was 36%, ranging from 21% (UK) to 59% (Brazil). When asked how asthma made participants feel at work, many respondents highlighted how their respiratory symptoms affect them. Tiredness, weakness and mental strain were also identified as particular challenges, with respondents describing concerns about the perception of colleagues and feelings of inferiority.Conclusions: This study emphasizes the extent to which work time is adversely affected by asthma in patients despite the use of long-term maintenance medication, and provides unique personal insights. Strategies to improve patients’ lives may include asthma education, optimizing asthma management plans and running workplace well-being programs. Clinicians, employers and occupational health teams should be more aware of the impact of asthma symptoms on employees, and work together to help overcome these challenges.Keywords: work productivity, asthma, burden, costs

Pulmonary sclerosing pneumocytoma (PSP) is a quite rare tumor outside Eastern countries. This rarity, together with a wide histological appearance, makes its correct identification a diagnostic challenge for pathologists under the microscope. Historically, PSP was considered a vascular-derived neoplasm (sclerosing hemangioma), but its immunohistochemical profile clearly supports its epithelial origin. No specific molecular fingerprint has been detected so far. This short narrative revisits the clinical, histological, immunohistochemical, and molecular aspects of this tumor, paying special attention to some controversial points still not well clarified, i.e., clinical aggressiveness and metastatic spread, multifocality, the supposed development of sarcomatoid change in a subset of cases, and tumor associations with lung adenocarcinoma and/or well-differentiated neuroendocrine hyperplasia/tumors. The specific diagnostic difficulties on fine-needle aspiration cytology/biopsy and perioperative frozen sections are also highlighted. Finally, a teaching case of tumor concurrence of lung adenocarcinoma, neuroendocrine lesions, and PSP, paradigmatic of tumor association in this context, is also presented.

Abstract Background Despite extensive studies on the neurobiological correlates of traumatic brain injury (TBI), little is known about its molecular determinants on long-term consequences, such as dementia and Alzheimer’s disease (AD). Methods Here, we carried out behavioural studies and an extensive biomolecular analysis, including inflammatory cytokines, gene expression and the combination of LC-HRMS and MALDI-MS Imaging to elucidate the targeted metabolomics and lipidomics spatiotemporal alterations of brains from wild-type and APP-SWE mice, a genetic model of AD, at the presymptomatic stage, subjected to mild TBI. Results We found that brain injury does not affect cognitive performance in APP-SWE mice. However, we detected an increase of key hallmarks of AD, including Aβ1-42 levels and BACE1 expression, in the cortices of traumatized transgenic mice. Moreover, significant changes in the expanded endocannabinoid (eCB) system, or endocannabinoidome (eCBome), occurred, including increased levels of the endocannabinoid 2-AG in APP-SWE mice in both the cortex and hippocampus, and N-acylserotonins, detected for the first time in the brain. The gene expression of enzymes for the biosynthesis and inactivation of eCBs and eCB-like mediators, and some of their main molecular targets, also underwent significant changes. We also identified the formation of heteromers between cannabinoid 1 (CB1) and serotonergic 2A (5HT2A) receptors, whose levels increased in the cortex of APP-SWE mTBI mice, possibly contributing to the exacerbated pathophysiology of AD induced by the trauma. Conclusions Mild TBI induces biochemical changes in AD genetically predisposed mice and the eCBome may play a role in the pathogenetic link between brain injury and neurodegenerative disorders also by interacting with the serotonergic system.

We describe an approach to calibrate Single Event Effect (SEE)-based detectors in monoenergetic fields and apply the resulting semi-empiric responses to more general mixed-field cases in which a broad variety of particle species and energy spectra are present. The calibration of the response functions is based both on experimental proton (30–200 MeV) and neutron (5–300 MeV) data and considerations derived from Monte Carlo simulations using the FLUKA Monte Carlo code. The application environments include the quasi-monoenergetic neutrons at RCNP, the atmospheric-like VESUVIO spallation spectrum and the CHARM high-energy accelerator test facility. The agreement between the mixed-field response and that predicted through the mono-energetic calibration is within ±30% for the broad variety of cases considered and thus regarded as highly successful for mixed-field monitoring applications.

This paper focuses on Monte Carlo simulations aimed at calculating the dose response of the RadFET dosimeter, when exposed to the complex CHARM mixed-fields, at CERN. We study how the dose deposited in the gate oxide (SiO2) of the RadFET is affected by the energy threshold variation in the Monte Carlo simulations as well as the materials and sizes of scoring volumes. Also the characteristics of the input spectra will be taken into account and their impact on the final simulated dose will be studied. Dose variation as a function of the position of the RadFET in the test facility will be then examined and comparisons with experimental results will be shown. The contribution to the total dose due to all particles of the mixed-field, under different target-shielding configurations, is finally presented, aiming at a complete characterization of the RadFETs dose response in the CHARM mixed-fields.

This paper focuses on Monte Carlo simulations aiming at calculating the dose response of the Rad- FET dosimeter, when exposed to the complex CHARM mixed-fields, at CERN. We study how the dose deposited in the Gate Oxide (SiO2) of the RadFET is a_ected by the energy threshold variation in the Monte Carlo simulations as well as the materials and sizes of scoring volumes. Also the characteristics of the input spectra will be taken into account and their impact on the final simulated dose will be studied. Dose variation as a function of the position of the RadFET in the test facility will be then examined and comparisons with experimental results will be shown. The contribution to the total dose due to every single particles of the mixed-field, under di_erent target-shielding configurations, will be finally presented, aiming at a complete characterization of the RadFETs dose response in the CHARM mixed-fields.

As part of its post-LHC high energy physics program, CERN is conducting a study for a new proton-proton collider, called Future Circular Collider (FCC-hh), running at center-of-mass energies of up to 100 TeV in a new 100 km tunnel. The study includes a 90-350 GeV lepton collider (FCC-ee) as well as a lepton-hadron option (FCC-he). In this work, FLUKA Monte Carlo simulation was extensively used to perform a first evaluation of the radiation environment in critical areas for electronics in the FCC-hh tunnel. The model of the tunnel was created based on the original civil engineering studies already performed and further integrated in the existing FLUKA models of the beam line. The radiation levels in critical areas, such as the racks for electronics and cables, power converters, service areas, local tunnel extensions was evaluated.

Background Advanced atrioventricular block (AVB), that is, higher than second‐degree Mobitz‐1, is an abnormal finding in athletes. Despite intensive investigation, in several cases the pathogenesis remains unknown, but frequently pacemaker implantation is still indicated. Increasing evidence points to circulating anti‐Ro/Sjögren syndrome–related antigen A (SSA) antibodies cross‐reacting with L‐type calcium channel and inhibiting the related current as an epidemiologically relevant and potentially reversible cause of isolated AVB in adults. The aim of the study was to determine the prevalence of anti‐Ro/SSA‐associated advanced AVBs in a large sample of young athletes. Methods and Results A total of 2536 consecutive athletes aged

There is a growing evidence suggesting the association of vitamin D deficiency (VDD) and cognitive impairment. In this study we evaluated the possible involvement of gut microbiota in the cognitive impairments mediated by VDD and investigated the effects of pharmacological treatment with the oxazoline derivative of the aliamide palmitoylethanolamide, 2-Pentadecyl-2-oxazoline (PEA-OXA). Mice were submitted to behavioural, biochemical and electrophysiological analysis to assess whether their vitamin D status affected cognitive performance together with gut microbiota composition. In VDD mice we found cognitive malfunctioning associated with reduced neuroplasticity, indicated by impaired long term potentiation, and neuroinflammation at the hippocampal level. Importantly, PEA-OXA counteracted the cognitive impairments and modified the biochemical and functional changes induced by VDD. Additionally, PEA-OXA treatment enhanced gut microbiota diversity, which tended to be decreased by VDD only in female mice, elevated the relative abundance of lactic and butyric acid-producing families, i.e. Aerococcaceae and Butyricicoccaceae, and reversed the VDD-induced decrease of butyrate-producing beneficial genera, such as Blautia in female mice, and Roseburia in male mice. These data provide novel insights for a better understanding of the cognitive decline induced by VDD and related gut dysbiosis and its potential therapeutic treatment.

Abstract The Scattering and Neutrino Detector at the LHC (SND@LHC) started taking data at the beginning of Run 3 of the LHC. The experiment is designed to perform measurements with neutrinos produced in proton-proton collisions at the LHC in an energy range between 100 GeV and 1 TeV. It covers a previously unexplored pseudo-rapidity range of $$7.2

Macrophages represent primary players of the innate immune system. Macrophage activation triggers several signaling pathways and is tightly associated with metabolic changes, which drive different immune subsets. Recent studies unveil the role of various metabolic enzymes in macrophage activation. Here, we show that malic enzyme 1 (ME1) is overexpressed in LPS-induced macrophages. Through chromatin immunoprecipitation, we demonstrate that ME1 transcriptional regulation is under control of NF-κB. Furthermore, ME1 activity is also increased in activated human PBMC-derived macrophages. Notably, ME1 gene silencing decreases nitric oxide as well as reactive oxygen species and prostaglandin E2 inflammatory mediators. Therefore, modulating ME1 provides a potential approach for immunometabolic regulation and in turn macrophage function.

Objectives: Coronavirus disease 2019 (COVID-19) has a wide spectrum of clinical severity. A cytokine storm is associated with COVID-19 severity. Of these, IL-6 is significantly associated with higher mortality and is also a marker for predicting disease prognosis. IL-6 may act as a target for therapeutics and, a blockade of IL-6 function by Tocilizumab has been described as a treatment of the inflammatory process COVID-19-related. This study aims to describe our experience comparing two different methods, in detail Human IL-6 Instant ELISA and the Elecsys IL-6 based on ECLIA, for the IL-6 assessment. Design and methods: IL-6 levels from serum samples of 104 COVID-19 patients, admitted to the AOU Careggi (Hospital in Florence -Italy), were assessed by using the two above-mentioned methods, and the results were analysed through Passing-Bablok regression fit and Bland-Altman plot. Results: The regression exhibited a linear relation between the methods with a regression equation (y = - 0.13 + 0.63 x; 95 % C.I. intercept = − 0.13 to 4.55; 95 % C.I. slope = 1.03 to 1.26 with R2 = 0.89, p > 0.05), showing a positive slope. The agreement of the two methods reported a bias of −25.0 pg/mL. Thus, the two methods correlate but do not agree in terms of numeric results. Conclusions: The two assays showed good comparability. However, because of the extremely wide linear range of the ECLIA, its throughput and its capacity for immune profiling, it represents an interesting emerging technology in the immunology field.

ABSTRACT Background: Proton pump inhibitors (PPIs) are widely prescribed worldwide, often resulting in their overuse. Consequently, it is essential to identify the likely causes of this overuse to facilitate their appropriate prescription. Objective: This study aims to assess physician prescribing patterns, their knowledge of PPIs, and factors affecting their knowledge. Methods: An online survey was conducted among Latin American and Spanish physicians, collecting the following data: professional information, patterns of PPI usage, familiarity with published evidence, and the management approach in three hypothetical case-scenarios. Participant knowledge was categorized as sufficient or insufficient based on the results of the case scenarios. Subsequently, subgroup analysis was performed based on physician training level, years in practice, specialty, and time since the last PPI literature review. Results: A total of 371 physicians participated in the survey. Thirty-eight percent frequently prescribe PPIs, primarily for prophylactic purposes (57.9%). Eighty percent were unfamiliar with PPI deprescribing strategies, and 54.4% rarely reviewed the ongoing indication of patients taking a PPI. Sixty-four percent demonstrated sufficient knowledge in the case-scenarios. A significant association was observed between specialty type (medical vs surgical: 69.4% vs 46.8%, P5 years: 71.4% vs 58.7%, P=0.010), and sufficient knowledge. Conclusion: While most participants prescribed PPIs regularly and for prophylaxis purposes, the majority were unfamiliar with deprescribing strategies and rarely reviewed ongoing indications. Sufficient knowledge is correlated with recent literature reviews and medical specialty affiliation.

Cyclic-nucleotide phosphodiesterases (PDEs) represent a superfamily of enzymes playing a pivotal role in cell signaling by controlling cAMP and cGMP levels in response to receptor activation. PDE activity and expression are linked to many diseases including inflammatory diseases. In light of their specific biochemical properties, PDE inhibition has attracted the interest of several researrs In this context, PDE4 inhibition induces anti-inflammatory effects. Piclamilast and rolipram, well-known PDE4 inhibitors, are endowed with common side effects. The selective phosphodiesterase 4B (PDE4B) inhibitors could be a promising approach to overcome these side effects. In the present study, six potential PDE4B inhibitors have been investigated. Through this study, we identified three PDE4B inhibitors in human macrophages activated by lipopolysaccharide. Interestingly, two of them reduced reactive oxygen species production in pro-inflammatory macrophages.

After rapid approval and installation, the SND@LHC Collaboration was able to gather data successfully in 2022 and 2023. Neutrino interactions from νμs originating at the LHC IP1 were observed. Since muons constitute the major background for neutrino interactions, the muon flux entering the acceptance was also measured. To improve the rejection power of the detector and to increase the fiducial volume, a third Veto plane was recently installed. The energy resolution of the calorimeter system was measured in a test beam. This will help with the identification of νe interactions that can be used to probe charm production in the pseudo-rapidity range of SND@LHC (7.2 < η < 8.4). Events with three outgoing muons have been observed and are being studied. With no vertex in the target, these events are very likely from muon trident production in the rock before the detector. Events with a vertex in the detector could be from trident production, photon conversion, or positron annihilation. To enhance SND@LHC’s physics case, an upgrade is planned for HL-LHC that will increase the statistics and reduce the systematics. The installation of a magnet will allow the separation of νμ from ν¯μ