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Mircea Gabriel Stoleriu,1,2,&ast; Michael Pienn,3,4,&ast; Rudolf A Joerres,5 Peter Alter,6 Tamas Fero,7 Martin Urschler,8 Gabor Kovacs,3,9 Horst Olschewski,3,9 Hans-Ulrich Kauczor,7,10 Mark Wielpütz,7,10 Bertram Jobst,7,10 Tobias Welte,11 Jürgen Behr,2,12 Franziska C Trudzinski,10,13 Robert Bals,14,15 Henrik Watz,16 Claus F Vogelmeier,6 Jürgen Biederer,10,17,18,&ast; Kathrin Kahnert2,12,19,&ast; On behalf of the COSYCONET Study Group1Division for Thoracic Surgery Munich, Ludwig-Maximilians-University of Munich (LMU) and Asklepios Medical Center; Munich-Gauting, Gauting, 82131, Germany; 2Institute for Lung Health and Immunity and Comprehensive Pneumology Center with the CPC-M bioArchive; Helmholtz Center Munich; Member of the German Lung Research Center (DZL), Munich, 81377, Germany; 3Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; 4Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; 5Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Hospital of Ludwig-Maximilians-University Munich (LMU), Munich, 80336, Germany; 6Department of Medicine, Pulmonary and Critical Care Medicine, University of Marburg (UMR), Member of the German Center for Lung Research (DZL), Marburg, 35033, Germany; 7Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany; 8Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria; 9University Clinic for Internal Medicine, Medical University of Graz, Division of Pulmonology, Graz, Austria; 10Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research DZL, Heidelberg, Germany; 11Department of Respiratory Medicine and Infectious Disease, Member of the German Center of Lung Research, Hannover School of Medicine, Hannover, Germany; 12Department of Medicine V, LMU University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany; 13Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Heidelberg, Germany; 14Department of Internal Medicine V-Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Homburg, 66421, Germany; 15Helmholtz Institute for Pharmaceutical Research, Saarbrücken, 66123, Germany; 16Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Centre North, German Centre for Lung Research, Großhansdorf, Germany; 17Faculty of Medicine, Christian-Albrechts-Universität Zu Kiel, Kiel, Germany; 18University of Latvia, Faculty of Medicine, Riga, LV-1586, Latvia; 19MediCenterGermering, Germering, Germany&ast;These authors contributed equally to this workCorrespondence: Mircea Gabriel Stoleriu, Division of Thoracic Surgery Munich, Ludwig-Maximilians-University of Munich (LMU) and Asklepios Lung Clinic Munich-Gauting, Marchioninistr. 15, 81377 Munich and Robert-Koch-Allee 2, Gauting, 82131, Germany, Tel +49 89 85791 4201, Email gabriel.stoleriu@helmholtz-munich.dePurpose: The aim of this study was to evaluate the association between computed tomography (CT) quantitative pulmonary vessel morphology and lung function, disease severity, and mortality risk in patients with chronic obstructive pulmonary disease (COPD).Patients and Methods: Participants of the prospective nationwide COSYCONET cohort study with paired inspiratory-expiratory CT were included. Fully automatic software, developed in-house, segmented arterial and venous pulmonary vessels and quantified volume and tortuosity on inspiratory and expiratory scans. The association between vessel volume normalised to lung volume and tortuosity versus lung function (forced expiratory volume in 1 sec [FEV1]), air trapping (residual volume to total lung capacity ratio [RV/TLC]), transfer factor for carbon monoxide (TLCO), disease severity in terms of Global Initiative for Chronic Obstructive Lung Disease (GOLD) group D, and mortality were analysed by linear, logistic or Cox proportional hazard regression.Results: Complete data were available from 138 patients (39% female, mean age 65 years). FEV1, RV/TLC and TLCO, all as % predicted, were significantly (p < 0.05 each) associated with expiratory vessel characteristics, predominantly venous volume and arterial tortuosity. Associations with inspiratory vessel characteristics were absent or negligible. The patterns were similar for relationships between GOLD D and mortality with vessel characteristics. Expiratory venous volume was an independent predictor of mortality, in addition to FEV1.Conclusion: By using automated software in patients with COPD, clinically relevant information on pulmonary vasculature can be extracted from expiratory CT scans (although not inspiratory scans); in particular, expiratory pulmonary venous volume predicted mortality.Trial Registration: NCT01245933.Keywords: COPD, computed tomography, pulmonary vasculature, vessel volume, vessel tortuosity, lung function

Background: Nitrous oxide (N2O), often known as ''laughing gas,'' ranks as a widely used recreational drug among young people in the UK, with 3.9 % of young adults aged 16–24 reporting its use in 2021–2022. Besides its known neurological risks, there is emerging evidence linking N2O misuse to serious haematological issues, including arterial and venous thrombosis. Aims/objectives: The project aimed to elucidate the prevalence of N2O usage in young adults (18–35 years) with unprovoked venous thromboembolism (VTE) between January 2021 and July 2023. Method: Patient records from three East London emergency departments (ED), coded with a SNOMED code for VTE upon ED discharge between January 2021 and June 2023, were compiled using Qliksense. The data extracted from electronic patient records (EPR) encompassed demographics, confirmed cases of VTE at discharge, and history of N2O usage. Criteria for exclusion included age restrictions, established provoking factors for VTE, and unconfirmed reports of N2O use. Results: We found 26 patients, out of which 8 patients (31 %) reported N2O use. Among these, a majority of 7 patients (88 %) reported regular N2O at the time of admission for VTE. Furthermore, 6 patients (75 %) reported regular N2O use for at least 12 months. The quantity of N2O usage varied widely, ranging from 7 to 210 (mean = 61.9, ∼495g) small canisters per week with each canister containing 8 g of N2O. The duration of N2O use varied significantly ranging from 7 to 59 months (mean = 29.25). This group of young adults (18–35; mean = 25) was 88 % male and 12 % female. The ethnic distribution among the cohort was 62 % Asian or Asian British, 25 % Black or Black British, and 12 % White. Stratified by the index of multiple deprivation 25 % were in quintile 1–2, 50 % were 3–4, 12 % were 5–6, and 12 % were in 7–8 range (0 % 9–10). Conclusion: Healthcare providers, particularly those in Acute Medicine and EDs, should consider implementing VTE screening protocols for young adults aged 18–35 presenting to ED with reported N2O misuse and neurological problems. A thorough assessment of N2O usage patterns is essential, alongside the provision of culturally sensitive health education that addresses the unique needs of marginalised communities. Ongoing research is necessary to elucidate the pathophysiological pathways connecting N2O use to VTE incidents, particularly its link to increased homocysteine levels.

Background The study aimed to elucidate the prevalence of nitrous oxide (N2O) usage in patients with unexplained venous thromboembolism (VTE), highlighting the potential association with hyperhomocysteinaemia (HHcy).Methods We conducted a retrospective study at the Royal London Hospital, examining cases of N2O-related VTE from March to August 2023. Among 50 patients identified, four (8%) had recent unprovoked VTE. Patient data were collected based on N2O ambulatory emergency care pathway admissions.Results Among the 50 patients identified, four (8%) had recent or concurrent VTE. Three were male (75%), with an ethnic distribution of 50% Asian or Asian British and 50% Black or Black British. Patients were distributed across quintiles of the index of multiple deprivation. All had actual or functional vitamin B12 deficiency.Discussion The association between N2O use and VTE requires further investigation, though a plausible mechanism involving HHcy has been proposed. Clinicians should be vigilant for VTE in N2O users, especially those presenting with unexplained symptoms. VTE prophylaxis may be worth considering, particularly if continued exposure to nitrous oxide is anticipated.Conclusion N2O misuse may increase the risk of VTE, warranting attention from healthcare providers. Further research is needed to elucidate this association and inform preventive strategies. Public awareness about the risks of N2O remains essential.

Antibiotic combination therapies are an approach used to counter the evolution of resistance; their purported benefit is they can stop the successive emergence of independent resistance mutations in the same genome. Here, we show that bacterial populations with 'mutators', organisms with defects in DNA repair, readily evolve resistance to combination antibiotic treatment when there is a delay in reaching inhibitory concentrations of antibiotic-under conditions where purely wild-type populations cannot. In populations of Escherichia coli subjected to combination treatment, we detected a diverse array of acquired mutations, including multiple alleles in the canonical targets of resistance for the two drugs, as well as mutations in multi-drug efflux pumps and genes involved in DNA replication and repair. Unexpectedly, mutators not only allowed multi-resistance to evolve under combination treatment where it was favoured, but also under single-drug treatments. Using simulations, we show that the increase in mutation rate of the two canonical resistance targets is sufficient to permit multi-resistance evolution in both single-drug and combination treatments. Under both conditions, the mutator allele swept to fixation through hitch-hiking with single-drug resistance, enabling subsequent resistance mutations to emerge. Ultimately, our results suggest that mutators may hinder the utility of combination therapy when mutators are present. Additionally, by raising the rates of genetic mutation, selection for multi-resistance may have the unwanted side-effect of increasing the potential to evolve resistance to future antibiotic treatments.

Cardiac autonomic modulation of heart rate, assessed by heart rate variability (HRV), is commonly used to monitor training status. HRV is usually measured in athletes after awakening in the morning in the supine position. Whether recording during standing reveals additional information compared to supine remains unclear. We aimed to evaluate the association between short-duration HRV, assessed both in the supine and standing position, and a low-intensity long-duration performance (walking ultramarathon), as well as training experience. Twenty-five competitors in a 100 km walking ultramarathon underwent pre-race supine (12 min) and standing (6 min) HR recordings, whereas performance and subjective training experience were assessed post-race. There were no significant differences in both supine and standing HRV between finishers (n = 14) and non-finishers (n = 11, mean distance 67 km). In finishers, a slower race velocity was significantly correlated with a higher decrease in parasympathetic drive during position change [larger decrease in High Frequency power normalized units (HFnu: r = −0.7, p = 0.01) and higher increase in the detrended fluctuation analysis alpha 1 index (DFA1: r = 0.6, p = 0.04)]. Highly trained athletes accounted for higher HFnu during standing compared to poorly trained competitors (+11.5, p = 0.01). Similarly, greater training volume (total km/week) would predict higher HFnu during standing (r = 0.5, p = 0.01). HRV assessment in both supine and standing position may provide additional information on the dynamic adaptability of cardiac autonomic modulation to physiologic challenges and therefore be more valuable for performance prediction than a simple assessment of supine HRV. Self-reported training experience may reliably associate with parasympathetic drive, therefore indirectly predicting long-term aerobic performance in ultramarathon walking races.