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Abstract Defect-engineered and even amorphous two-dimensional (2D) materials have recently gained interest due to properties that differ from their pristine counterparts. Since these properties are highly sensitive to the exact atomic structure, it is crucial to be able to characterize them at atomic resolution over large areas. This is only possible when the imaging process is automated to reduce the time spent on manual imaging, which at the same time reduces the observer bias in selecting the imaged areas. Since the necessary datasets include at least hundreds if not thousands of images, the analysis process similarly needs to be automated. Here, we introduce disorder into graphene and monolayer hexagonal boron nitride (hBN) using low-energy argon ion irradiation, and characterize the resulting disordered structures using automated scanning transmission electron microscopy annular dark field imaging combined with convolutional neural network-based analysis techniques. We show that disorder manifests in these materials in a markedly different way, where graphene accommodates vacancy-type defects by transforming hexagonal carbon rings into other polygonal shapes, whereas in hBN the disorder is observed simply as vacant lattice sites with very little rearrangement of the remaining atoms. Correspondingly, in the case of graphene, the highest introduced disorder leads to an amorphous membrane, whereas in hBN, the highly defective lattice contains a large number of vacancies and small pores with no indication of amorphisation. Overall, our study demonstrates that combining automated imaging and image analysis is a powerful way to characterize the structure of disordered and amorphous 2D materials, while also illustrating some of the remaining shortcomings with this methodology.

Abstract Tuberculosis (TB) remains one of the leading infectious disease killers in the world. The ongoing development of novel anti-TB medications has yielded potent compounds that often target single sites with well-defined mechanisms of action. However, despite the identification of resistance-associated mutations through target deconvolution studies, comparing these findings with the diverse Mycobacterium tuberculosis populations observed in clinical settings is often challenging. To address this gap, we constructed an open-access database encompassing genetic variations from > 50,000 clinical isolates, spanning the entirety of the M. tuberculosis protein-encoding genome. This resource offers a valuable tool for investigating the prevalence of target-based resistance mutations in any drug target within clinical contexts. To demonstrate the practical application of this dataset in drug discovery, we focused on drug targets currently undergoing phase II clinical trials. By juxtaposing genetic variations of these targets with resistance mutations derived from laboratory-adapted strains, we identified multiple positions across three targets harbouring resistance-associated mutations already present in clinical isolates. Furthermore, our analysis revealed a discernible correlation between genetic diversity within each protein and their predicted essentiality. This meta-analysis, openly accessible via a dedicated dashboard, enables comprehensive exploration of genetic diversity pertaining to any drug target or resistance determinant in M. tuberculosis.

Abstract We evaluated the utility of transmission electron microscopy (TEM) in transbronchial lung cryobiopsy (TBLC) samples from 16 consecutive patients undergoing routine evaluation of fibrotic interstitial lung disease (ILD). Next to routine pathology examination, 1 to 2 TBLC samples were prepared for TEM analysis and evaluated using a Zeiss LEO EM 910. Subpleural cryobiopsies and unfrozen excision biopsies from fresh lobectomy tissue of non-ILD lung cancer patients served as controls. TEM provided high-quality images with only minor cryoartifacts as compared to controls. Furthermore, in several ILD patients we found marked microvascular endothelial abnormalities like luminal pseudopodia-like protrusions and inner surface defects. These were extensively present in four (25%), moderately present in seven (43.8%), and largely absent in five (31.3%) patients. A higher degree of TEM endothelial abnormalities was associated with younger age, non-specific interstitial pneumonia pattern, higher broncho-alveolar lavage lymphocyte count, positive autoantibodies, and lower spirometry, diffusion capacity and oxygenation biomarkers. We conclude that TEM evaluation of TBLC samples from ILD patients is feasible, while the observed microvascular alterations warrant further evaluation.

Abstract EphrinB2 regulates synaptic transmission and morphology however its role in memory formation is unknown. Here we show that deleting ephrinB2 from excitatory neurons in the basolateral amygdala (BLA) of male mice impairs long-term (LTM), but not short-term (STM), fear memory formation. Deleting ephrinB2 from astrocytes in the BLA impairs fear LTM but not STM. Removing ephrinB2 from astrocytes in the BLA reduces the level of the excitatory amino acid transporter 1 (EAAT1) in these cells. Inhibiting EAAT1 activity in the BLA during fear conditioning, by its specific inhibitor UCPH-101, impairs fear LTM showing that EAAT1 in the BLA is needed for fear LTM formation. The administration of ephrinB2 into the BLA during fear conditioning training enhances fear LTM. Moreover, ephrinB2 increases the ability of fear conditioning to activate cells in the BLA as detected by c-Fos labeling. EphrinB2 therefore determines the threshold for fear memory formation. In contrast to mature neurons, we show that ephrinB2 in neural stem cells (NSCs) is not needed for fear LTM. Our study shows that ephrinB2 in the BLA determines the strength of long-term memory consolidation.

Abstract Functional electrical stimulation (FES) can support functional restoration of a paretic limb post-stroke. Hebbian plasticity depends on temporally coinciding pre- and post-synaptic activity. A tight temporal relationship between motor cortical (MC) activity associated with attempted movement and FES-generated visuo-proprioceptive feedback is hypothesized to enhance motor recovery. Using a brain–computer interface (BCI) to classify MC spectral power in electroencephalographic (EEG) signals to trigger FES-delivery with detection of movement attempts improved motor outcomes in chronic stroke patients. We hypothesized that heightened neural plasticity earlier post-stroke would further enhance corticomuscular functional connectivity and motor recovery. We compared subcortical non-dominant hemisphere stroke patients in BCI-FES and Random-FES (FES temporally independent of MC movement attempt detection) groups. The primary outcome measure was the Fugl-Meyer Assessment, Upper Extremity (FMA-UE). We recorded high-density EEG and transcranial magnetic stimulation-induced motor evoked potentials before and after treatment. The BCI group showed greater: FMA-UE improvement; motor evoked potential amplitude; beta oscillatory power and long-range temporal correlation reduction over contralateral MC; and corticomuscular coherence with contralateral MC. These changes are consistent with enhanced post-stroke motor improvement when movement is synchronized with MC activity reflecting attempted movement.

Purpose: This study addresses the complex risks of implementing prescriptive analytics in vineyard management. It focusses on integrating diverse, previously isolated data resources into operational decisions in irrigation, nutrition and pest management. Aligning with the United Nations’ Sustainable Development Goals (SDGs), this integration is crucial for optimising vineyard growth and production, and advancing precision agriculture techniques within the framework of sustainable agriculture. In this context, it introduces a Control Risk Template (CRT) to manage these risks effectively. Design/methodology/approach: The study uses an exploratory research design and grounded theory methodology to conduct a comprehensive systematic literature review. Findings/results: The findings demonstrate how the CRT can effectively identify, assess and manage the risks of deploying prescriptive analytics in vineyard management. This approach minimises risks and significantly improves decision-making and operational efficiencies in vineyard management, contributing to the advancement of sustainable agricultural practices. Practical implications: This research offers valuable insights for vineyard managers and information technology (IT) governance leaders. It provides a robust model for enhancing vineyard management through advanced data-driven decisions. Implementing the CRT facilitates better resource allocation and improved crop health management, fostering a transition towards more sustainable agricultural practices. Originality/value: This research suggests a comprehensive approach to integrating IT governance with practical agricultural operations, significantly contributing to academic research and industry practices. Moreover, the study delivers essential insights into the effective integration of prescriptive analytics in vineyard management, underscoring the transformative potential of IT governance frameworks in enhancing the sustainability and efficiency of vineyard management.

Background: Perianal rhabdomyosarcoma ((P)RMS) are rare and have a poor prognosis. Data in young children are limited and local therapy is not well defined. Combined brachytherapy and surgery is routinely being used for RMS at other sites in children as it provides good oncologic outcomes and allows for organ-sparing surgery. The objective of this study was to evaluate this combination treatment for local tumor control and organ-sparing surgery in young children with (P)RMS. Methods: A retrospective review of the medical records of all children who underwent surgery and brachytherapy for (P)RMS at our institution since 2009 was conducted. Results: Surgery for (P)RMS was performed in 6 patients at a median age of 19 months (range 8–50). Embryonal RMS was diagnosed in 4 patients and alveolar RMS in 2 patients, of which 1 patient had FOXO1 fusion-positive RMS. All patients underwent postoperative high-dose rate (HDR) brachytherapy. Organ-preserving surgery was achieved in 5 of 6 patients (83 %). In 1 patient, the entire sphincter was infiltrated, making organ-preserving resection impossible. 5 of 6 patients (83 %) exhibited an event-free and overall survival at a median follow-up of 26 months (range 8–107). One patient died due to locoregional recurrence. Complications were urethral leakage in 1 patient followed by urethral stenosis and delayed wound healing and vaginal stenosis in another patient. No patient reported fecal incontinence. Conclusions: Combined treatment with surgery and HDR brachytherapy is feasible in very young children with (P)RMS and leads to a favorable oncologic outcome. Preliminary data show a good functional preservation.

BackgroundMalnutrition is a common complication in chronic pancreatitis and associated with reduced quality of life and life expectancy. Nutritional support is considered mandatory in malnourished patients with chronic pancreatitis but there is only scarce evidence on optimal treatment modalities and the efficacy of nutrition therapy. Here, we investigated the feasibility and efficacy of an intensified nutritional intervention in malnourished patients with chronic pancreatitis and aimed to identify suitable indicators for monitoring nutritional status.MethodsWe performed a single-arm feasibility study, in which malnourished patients with chronic pancreatitis received an intensified trans-sectoral nutritional intervention for 6 months. Multimodal treatment comprised face-to-face dietary counseling, oral nutritional supplementation, and a complementary telephone-based nutrition and exercise coaching. Patients underwent follow-up examinations after 28, 90, and 180 days, when we assessed changes in anthropometric and body composition measures, muscle function, Chronic Pancreatitis Prognosis Score (COPPS), as well as blood parameters and intestinal microbiota composition.ResultsEleven out of 73 patients initially screened for study participation were enrolled in the trial of which 9 subjects (age (mean ± SD): 56.2 (±14.8) years; male: 67%; alcoholic etiology: 44%) underwent the complete intervention. Patients gained a median of 5.3 kg (8.6%) body weight, including 1.6 kg skeletal muscle mass, and significantly increased gait speed (p

The anthropogenic and biogenic contributions of isoprene, monoterpenes, sesquiterpenes and methanol in an urban area were estimated based on direct eddy covariance flux observations during four campaigns between 2018 and 2021. While these compounds are typically thought to be dominated by biogenic sources on regional and global scales, the role of potentially significant anthropogenic emissions in urban areas has been recently debated. Typical fluxes of isoprene, monoterpenes and sesquiterpenes were on the order of 0.07 ± 0.02, 0.09 and 0.003 nmol m−2 s−1 during spring. During summer, emission fluxes of isoprene, monoterpenes and sesquiterpenes were higher on the order of 0.85 ± 0.09, 0.11 and 0.004 nmol m−2 s−1. It was found that the contribution of the anthropogenic part is strongly seasonally dependent. For isoprene, the anthropogenic fraction can be as high as 64 % in spring but is typically very low < 18 % during the summer season. For monoterpenes, the anthropogenic fraction was estimated to be between 43 % in spring and less than 20 % in summer. With values of 2.8 nmol m−2 s−1 in spring and 3.2 nmol m−2 s−1 in summer, methanol did not exhibit a significant seasonal variation of observed surface fluxes. However, there was a difference in emissions between weekdays and weekends (about 2.3 times higher on weekdays in spring). This suggests that methanol emissions are likely influenced by anthropogenic activities during all seasons.

Abstract Background Reference values for lung volumes are necessary to identify and diagnose restrictive lung diseases and hyperinflation, but the values have to be validated in the relevant population. Our aim was to investigate the Global Lung Function Initiative (GLI) reference equations in a representative healthy Austrian population and create population-derived reference equations if poor fit was observed. Methods We analysed spirometry and body plethysmography data from 5371 respiratory healthy subjects (6–80 years) from the Austrian LEAD Study. Fit with the GLI equations was examined using z-scores and distributions within the limits of normality. LEAD reference equations were then created using the LMS method and the generalized additive model of location shape and scale package according to GLI models. Results Good fit, defined as mean z-scores between + 0.5 and -0.5,was not observed for the GLI static lung volume equations, with mean z-scores > 0.5 for residual volume (RV), RV/TLC (total lung capacity) and TLC in both sexes, and for expiratory reserve volume (ERV) and inspiratory capacity in females. Distribution within the limits of normality were shifted to the upper limit except for ERV. Population-derived reference equations from the LEAD cohort showed superior fit for lung volumes and provided reproducible results. Conclusion GLI lung volume reference equations demonstrated a poor fit for our cohort, especially in females. Therefore a new set of Austrian reference equations for static lung volumes was developed, that can be applied to both children and adults (6–80 years of age).

Abstract Malnutrition is a common complication of chronic pancreatitis (CP) and liver cirrhosis (LC). Inadequate food intake is considered a relevant driver of malnutrition in both entities. However, the contribution of habitual diet to impaired nutritional status is unclear. In a prospective, multicenter cross-sectional study, we recruited patients with confirmed CP or LC and healthy volunteers as a control group. Malnutrition was diagnosed according to the Global Leadership Initiative on Malnutrition criteria. We comprehensively investigated habitual dietary intake on nutrient, food group, and dietary pattern level applying two validated food frequency questionnaires. We included 144 patients (CP: n = 66; LC: n = 78) and 94 control subjects. Malnutrition was prevalent in 64% and 62% of patients with CP or LC, respectively. In both CP and LC, despite slightly altered food group consumption in malnourished and non-malnourished patients there were no differences in energy or nutrient intake as well as dietary quality. Compared to controls patients showed distinct dietary food group habits. Patients consumed less alcohol but also lower quantities of fruits and vegetables as well as whole grain products (p

Rebekka Wlassits,1 Mathias Müller,2 Karl H Fenzl,1 Thomas Lamprecht,3 Ludwig Erlacher3 1Karl Landsteiner Institut für Autoimmunerkrankungen und Rheumatologie, Vienna, Austria; 2Department für Biomedizinische Wissenschaften, Institut für Tierzucht und Genetik, Veterinärmedizinische Universität Wien, Vienna, Austria; 3Ludwig Erlacher, Karl Landsteiner Institut für Autoimmunerkrankungen und Rheumatologie, Vienna, AustriaCorrespondence: Rebekka Wlassits, Karl Landsteiner Institut für Autoimmunerkrankungen und Rheumatologie, Vienna, Kundratstraße 3, 1100 Wien, Austria, Tel +43 1 60910 72238, Email rebekka.wlassits@gesundheitsverbund.atAbstract: Rheumatoid arthritis (RA) is a systemic, chronic, immune-mediated inflammatory condition. Treatments options encompass conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), biologic disease-modifying antirheumatic drugs (bDMARDs) like tumor necrosis factor (TNF) inhibitors (TNFis) and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) including Janus Kinase inhibitors (JAKinibs). Orally administered JAKinibs have demonstrated comparable or, in specific cases, superior efficacy compared to bDMARDs in inflammatory conditions. However, the escalating clinical utilization has been accompanied by the emergence of serious adverse effects, including major adverse cardiac events (MACE), malignancies and venous thrombotic episodes (VTE), leading to regulatory restrictions imposed by health authorities in both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).Keywords: rheumatoid arthritis, treatment, safety restrictions, major adverse cardiac events, malignancies, venous thrombotic episodes

ObjectivesIn 2008, an analysis investigating health impact assessment (HIA) practice found that only 6% of HIA-related peer-reviewed publications had a focus on low- and medium-developed countries, whereas 94% were conducted in countries with a high or very high development state. We aimed to update and deepen these observations.MethodsWe conducted a systematic review, searching PubMed and Web of Science for HIA-related papers published in the scientific literature from June 2007 to January 2023. Only applied HIA and papers with HIA as a subject were included.ResultsThe search yielded 3,036 publications and the final selection consisted of 1,019 publications. The annual number of total publications increased considerably over the past 15 years. Whereas research-driven HIA (n = 460) showed a steep increase, step-by-step HIA (n = 71) did not show a clear trend.ConclusionThe gap between the number of HIA-related peer-reviewed publications focusing on low/medium and high/very high developed countries has diminished from 6/94 to 11/89. There is a growing tendency to apply the terminology HIA for health impact modelling studies and quantitative health risk assessments.

Andreas Horner,1 Horst Olschewski,2 Sylvia Hartl,3 Arschang Valipour,4 Georg-Christian Funk,5 Michael Studnicka,6 Monika Merkle,7 Bernhard Kaiser,1 Eva Maria Wallner,8 Stephan Brecht,8 Bernd Lamprecht1 1Johannes Kepler University Linz, Kepler University Hospital, Department of Pulmonology, Linz, Austria; 2Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, and Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; 3Department of Respiratory and Critical Care Medicine, Klinik Penzing and Sigmund Freud University, Medical School, Vienna, Austria; 4Karl-Landsteiner-Institute for Lung Research and Pulmonary Oncology, Klinik Floridsdorf, Vienna, Austria; 5Department of Internal and Respiratory Medicine, Klinik Ottakring, Vienna, Austria; 6Department of Pulmonary Medicine, Paracelsus Medical University, Salzburg, Austria; 7Specialist Office for Pulmonology Dr. Merkle, Vienna, Austria; 8A. Menarini Pharma GmbH, Vienna, AustriaCorrespondence: Andreas Horner, Johannes Kepler University Linz, Kepler University Hospital, Department of Pulmonology, Altenberger Strasse, 69, 4040 Linz and Krankenhausstrasse 9, 4020 Linz, Austria, Email Andreas.Horner@kepleruniklinikum.atBackground: Symptoms of depression, pain and limitations in physical activity may affect quality of life in COPD patients independent from their respiratory burden. We aimed to analyze the associations of these factors in outpatients with COPD in Austria in a stable phase of disease.Methods: We conducted a national, cross-sectional study among patients with COPD. For depression, the Patient Health Questionnaire-9 (PHQ-9) and for respiratory symptoms the St. George’s Respiratory Questionnaire for COPD patients (SGRQ-C) were used along with 10-point scales for physical activity and pain.Results: After exclusion of 211 patients due to non-obstructive spirometry or missing data, 630 patients (62.5% men; mean age 66.8 ± 8.6 (SD) years; mean FEV1%pred. 54.3 ± 16.5 (SD)) were analyzed. Of these, 47% reported one or more exacerbations in the previous year, 10.4% with hospitalization. A negative depression score was found in 54% and a score suggesting severe depression (PHQ-9 score ≥ 15) in 4.7%. In a multivariate linear regression model, self-reported pain, dyspnea, and number of exacerbations were predictors for higher PHQ-9-scores. A negative pain score was found in 43.8%, and a score suggesting severe pain in 2.9% (8– 10 points of 10-point scale). Patients reporting severe pain were more often female, had more exacerbations, and reported more respiratory and depressive symptoms, a lower quality of life, and less physical activity. About 46% of patients rated their physical activity as severely impaired. These patients were significantly older, had more exacerbations, concomitant heart disease, a higher pain and depression score, and a lower quality of life (SGRQ-C – total score and all subscores).Conclusions: In Austria, nearly half of stable COPD outpatients reported symptoms of depression, which were associated with lower levels of self-reported physical activity, more pain, and respiratory symptoms. The associations were particularly strong for depression with SGRQ-C.Keywords: chronic obstructive pulmonary disease, depression, PHQ-9, pain, quality of life, St. George’s Respiratory Questionnaire, physical activity

Abstract Background Parenchymal accumulation of beta-amyloid (Aβ) characterizes Alzheimer’s disease (AD). Aβ homeostasis is maintained by two ATP-binding cassette (ABC) transporters (ABCC1 and ABCB1) mediating efflux, and the receptor for advanced glycation end products (RAGE) mediating influx across the blood-brain barrier (BBB). Altered transporter levels and disruption of tight junctions (TJ) were linked to AD. However, Aβ transport and the activity of ABCC1, ABCB1 and RAGE as well as the functionality of TJ in AD are unclear. Methods ISMICAP, a BBB model involving microperfusion of capillaries, was used to assess BBB properties in acute cortical brain slices from Tg2576 mice compared to wild-type (WT) controls using two-photon microscopy. TJ integrity was tested by vascularly perfusing biocytin-tetramethylrhodamine (TMR) and quantifying its extravascular diffusion as well as the diffusion of FM1-43 from luminal to abluminal membranes of endothelial cells (ECs). To assess ABCC1 and ABCB1 activity, calcein-AM was perfused, which is converted to fluorescent calcein in ECs and gets actively extruded by both transporters. To probe which transporter is involved, probenecid or Elacridar were applied, individually or combined, to block ABCC1 and ABCB1, respectively. To assess RAGE activity, the binding of 5-FAM-tagged Aβ by ECs was quantified with or without applying FPS-ZM1, a RAGE antagonist. Results In Tg2576 mouse brain, extravascular TMR was 1.8-fold that in WT mice, indicating increased paracellular leakage. FM1-43 staining of abluminal membranes in Tg2576 capillaries was 1.7-fold that in WT mice, indicating reduced TJ integrity in AD. While calcein was undetectable in WT mice, its accumulation was significant in Tg2576 mice, suggesting lower calcein extrusion in AD. Incubation with probenecid or Elacridar in WT mice resulted in a marked calcein accumulation, yet probenecid alone had no effect in Tg2576 mice, implying the absence of probenecid-sensitive ABC transporters. In WT mice, Aβ accumulated along the luminal membranes, which was undetectable after applying FPS-ZM1. In contrast, marginal Aβ fluorescence was observed in Tg2576 vessels, and FPS-ZM1 was without effect, suggesting reduced RAGE binding activity. Conclusions Disrupted TJ integrity, reduced ABCC1 functionality and decreased RAGE binding were identified as BBB alterations in Tg2576 mice, with the latter finding challenging the current concepts. Our results suggest to manage AD by including modulation of TJ proteins and Aβ-RAGE binding.

Formulations designed to address ocular conditions and diseases are predominantly administered topically. While in vitro test systems have been developed to assess corneal permeation under extended contact conditions, methods focusing on determining the penetration depth and kinetics of a substance within the cornea itself rather than through it, are scarce. This study introduces a method for time-dependent penetration depth analysis (10 and 60 min) by means of a semiquantitative imaging method in comparison with a quantitative corneal depth-cut technique, employing fluorescein sodium at concentrations of 0.2 and 0.4 mg/mL as a small molecule model substance and sheep cornea as a human surrogate. Excised tissues exhibited sustained viability in modified artificial aqueous humor and maintained thickness (746 ± 43 µm) and integrity (electrical resistance 488 ± 218 Ω∙cm2) under the experimental conditions. Both methods effectively demonstrated the expected concentration- and time-dependent depth of penetration of fluorescein sodium, displaying a significantly strong correlation. The traceability of the kinetic processes was validated with polysorbate 80, which acted as a penetration enhancer. Furthermore, the imaging-based method enabled detecting the retention of larger structures, such as hyaluronic acid and nanoemulsions from the commercial eyedrop formulation NEOVIS® TOTAL multi, inside the lacrimal layer.

Background: The clinical spectrum of fibrotic interstitial lung diseases (ILDs) is highly heterogeneous. We aimed to evaluate the prognostic value of widely available baseline biomarkers for the improvement of lung function in patients with fibrotic ILDs. Methods: This registry-based study included 142 patients with fibrotic ILDs as defined by the presence of reticulation, traction bronchiectasis or honeycombing on initial high-resolution computed tomography (HRCT). Functional improvement at 1 year was defined as a relative increase of 5% in forced vital capacity (FVC) or of 10% in diffusion capacity for carbon monoxide (DLCO). The prognostic value of baseline biomarkers was evaluated for all patients and the subgroup with anti-inflammatory treatment. Results: At one year, 44 patients showed improvement while 73 showed disease progression. Multivariate analyses found prognostic significance for age < 60 years (OR 5.4; 95%CI 1.9–15.4; p = 0.002), lactate dehydrogenase (LDH) >250 U/L (OR 2.5; 95%CI 1.1–5.8; p = 0.043) and blood monocyte count < 0.8 G/L (OR 3.5; 95%CI 1.1–11.3; p = 0.034). In 84 patients undergoing anti-inflammatory treatment, multivariate analysis revealed age < 60 years (OR 8.5 (95%CI 2.1–33.4; p = 0.002) as the only significant variable. Conclusion: Younger age, a higher LDH and lower blood monocyte count predicted functional improvement in fibrotic ILD patients, while in those treated with anti-inflammatory drugs, only age had significant implications.

Abstract Background Ageing is a process characterised by chronic low-grade inflammation and oxidative stress which could lead to increased prevalence of both physical and mental age-related chronic conditions. A healthy balanced diet, rich in fruit and vegetables as well as omega-3 polyunsaturated fatty acids (n3 PUFA), could reduce oxidative stress and improve markers of low-grade inflammation. Nonetheless, considering that a large part of the population struggles to meet current guidelines on fruit and vegetable and n3 PUFA recommendations, fruit and vegetable concentrate supplements and mixed omega fatty acid supplements could be an effective strategy to bridge the gap between actual and recommended intakes. Methods In this randomised, controlled, open-labelled, parallel-grouped clinical trial, 112 participants will be allocated to one of four arms (n = 28 on each arm): an encapsulated juice powder concentrate, a plant-based omega fatty acid supplement, both or a control group. We aim to investigate whether long-term separate or combined ingestion of the two can affect biomarkers of cardiovascular health, low-grade inflammation and indicators of ageing, including cognitive function, in middle-aged and elderly people. We will additionally explore the effect of the different supplementations on plasma levels of vitamins, carotenoids and fatty acids. Intervention will last 2 years and participants will be assessed at baseline and at follow-up visits at 6, 12, 18 and 24 months. Discussion This study will provide evidence whether long-term, plant-based dietary supplementation can support cardiovascular health, anti-inflammatory processes, immunity and nutritional status in ageing. Trial registration This trial was registered at ClinicalTrials.gov (NCT04763291) on February 21, 2021.

Glucocorticoids represent a key element in the treatment of pediatric acute lymphoblastic leukemia (ALL) and lead to adrenal suppression. We aimed to ass ess the differential response profile of adrenal steroids in children with ALL during BFM (Berlin–Frankfurt– Münster) induction treatment. Therefore, we performed liquid chromatography tandem– mass spectrometry (LC–MS/MS)-based steroid profiling of up to se ven consecutive leftover morning serum samples derived from 11 patients (pts) with ALL before (day 0) and during induction therapy at days 1–5, 6–12, 13–26, 27–29, 30–35 and 36–40. 17-hydroxyprogesterone (17OHP), 11-deoxycortisol (11S), cortisol, 11-deoxycorticosterone (DOC), corticosterone and aldosterone were determined in parallel. Subsequently, steroid concentrations were normalized by multiples of median (MOM) to adequately consider pediatric age- and sex-specific reference ranges. MOM-cortisol a nd its precursors MOM– 11S and MOM–17OHP were significantly suppressed by glucocorticoi d treatment until day 29 (P < 8.06 × 10−10, P < 5.102 × 10−5, P < 0.0076, respectively). Cortisol recovered in one of four pts at days 27–29 and in two of five pts at days 36–40. Amo ng the mineralocorticoids, corticosterone was significantly suppressed (P < 3.115 × 10−6). Aldosterone and DOC showed no significant changes when comparing day 0 to the treatm ent time points. However, two ALL patients with ICU treatment due to the sepsis showed significantly lower MOM–DOC (P = 0.006436) during that time and almost always the lowest aldost erone compared to all other time points. Suppression of mineralocorticoid precursors under high-dose glucocorticoid therapy suggests a functional cross talk of central glucocorticoid regulation and adrenal mineralocorticoid synthesis. Our data should stimulate prospective investigation to assess potential clinical relevance.

ABSTRACTThe World Health Organization’s goal to combat tuberculosis (TB) is hindered by the emergence of anti-microbial resistance, therefore necessitating the exploration of new drug targets. Multidrug regimens are indispensable in TB therapy as they provide synergetic bactericidal effects, shorten treatment duration, and reduce the risk of resistance development. The research within our European RespiriTB consortium explores Mycobacterium tuberculosis energy metabolism to identify new drug candidates that synergize with bedaquiline, with the aim of discovering more efficient combination drug regimens. In this study, we describe the development and validation of a luminescence-coupled, target-based assay for the identification of novel compounds inhibiting Mycobacterium tuberculosis mycothione reductase (MtrMtb), an enzyme with a role in the protection against oxidative stress. Recombinant MtrMtb was employed for the development of a highly sensitive, robust high-throughput screening (HTS) assay by coupling enzyme activity to a bioluminescent readout. Its application in a semi-automated setting resulted in the screening of a diverse library of ~130,000 compounds, from which 19 hits were retained after an assessment of their potency, selectivity, and specificity. The selected hits formed two clusters and four fragment molecules, which were further evaluated in whole-cell and intracellular infection assays. The established HTS discovery pipeline offers an opportunity to deliver novel MtrMtb inhibitors and lays the foundation for future efforts in developing robust biochemical assays for the identification and triaging of inhibitors from high-throughput library screens.IMPORTANCEThe growing anti-microbial resistance poses a global public health threat, impeding progress toward eradicating tuberculosis. Despite decades of active research, there is still a dire need for the discovery of drugs with novel modes of action and exploration of combination drug regimens. Within the European RespiriTB consortium, we explore Mycobacterium tuberculosis energy metabolism to identify new drug candidates that synergize with bedaquiline, with the aim of discovering more efficient combination drug regimens. In this study, we present the development of a high-throughput screening pipeline that led to the identification of M. tuberculosis mycothione reductase inhibitors.

Summary: Background: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19. Methods: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care). Findings: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61–1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64–1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09–0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality. Interpretation: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19. Funding: Hellenic Foundation for Research and Innovation.

Introduction The Swiss Sports Observatory has been conducting the national club survey since 1996. Every six years, the club managers of all sports clubs belonging to an association affiliated to Swiss Olympic are asked to complete a questionnaire. The survey is supported by Swiss Olympic, the Federal Office of Sport and other partners and provides information on the development of Swiss sports clubs, their structures and performance, as well as their strategies and prospects. The latest club survey was published at the end of 2023 (Bürgi et al., 2023). Methods The 2023 club survey is based on an online survey of 6,782 sports clubs. With a total of 18,229 sports clubs contacted, this results in a participation rate of 37.2%. The results were validated and their representativeness checked through various comparisons with other surveys (survey of the associations and the population surveys "Sport Schweiz 2020" and "Freiwilligen-Monitor"). Results The number of sports clubs - but not the number of active members - has fallen slightly in recent years. However, the large number of small clubs continues to characterize the Swiss club system. The high density of clubs ensures a wide range of activities, but also ties up a lot of resources and leads to increased fluctuation among members. The vast majority of active members as well as children and young people are active in medium-sized and large clubs. The number of active club members has remained stable for many years. There has been no decline in club memberships, but the clubs cannot profit from population growth and the sports boom. There are also significant changes in the club structure: clubs are growing among children but losing members among adults. This development has an impact on the recruitment of volunteers. Voluntary work therefore remains the foundation of club sport, but also the number one challenge. The problem cannot be solved with increased professionalization. Although there is more paid work in clubs today, the need for volunteers is still growing. Club budgets also place limits on professionalization. Staff cost is already the largest expense item today. The financial situation of Swiss sports clubs has not generally deteriorated in recent years. However, it has not been possible to tap into new sources of income either and membership fees cannot be increased at will. Discussion/Conclusion Overall, Swiss sports clubs have coped well with the various challenges of recent years. At the same time, the proportion of clubs facing problems that threaten their existence is increasing. Only with the active further development of club work and differentiated approaches to solutions, which help to meet the growing demands placed on clubs and the associated increased need for volunteers and paid staff, will clubs remain a central pillar of Swiss sport in the future (Lamprecht & Nagel, 2022). References Bürgi, R., Lamprecht, M., Gebert, A. & Stamm, H. P. (2023). Sportvereine in der Schweiz 2022. Entwick­lungen, Herausforderungen und Perspektiven [Sports clubs in Switzerland in 2022: Developments, challenges and prospects]. Swiss Olympic. Lamprecht, M. & Nagel, S. (2022). Sportsoziologie: Einführung [Sociology of sport: Introduction]. Nomos.

Summary: Background: Chronic cough is a common respiratory symptom with an impact on daily activities and quality of life. Global prevalence data are scarce and derive mainly from European and Asian countries and studies with outcomes other than chronic cough. In this study, we aimed to estimate the prevalence of chronic cough across a large number of study sites as well as to identify its main risk factors using a standardised protocol and definition. Methods: We analysed cross-sectional data from 33,983 adults (≥40 years), recruited between Jan 2, 2003 and Dec 26, 2016, in 41 sites (34 countries) from the Burden of Obstructive Lung Disease (BOLD) study. We estimated the prevalence of chronic cough for each site accounting for sampling design. To identify risk factors, we conducted multivariable logistic regression analysis within each site and then pooled estimates using random-effects meta-analysis. We also calculated the population attributable risk (PAR) associated with each of the identifed risk factors. Findings: The prevalence of chronic cough varied from 3% in India (rural Pune) to 24% in the United States of America (Lexington,KY). Chronic cough was more common among females, both current and passive smokers, those working in a dusty job, those with a history of tuberculosis, those who were obese, those with a low level of education and those with hypertension or airflow limitation. The most influential risk factors were current smoking and working in a dusty job. Interpretation: Our findings suggested that the prevalence of chronic cough varies widely across sites in different world regions. Cigarette smoking and exposure to dust in the workplace are its major risk factors. Funding: Wellcome Trust.