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Medically important pathogenic fungi invade vertebrate tissue and are considered primary when part of their nature life cycle is associated with an animal host and are usually able to infect immunocompetent hosts. Opportunistic fungal pathogens complete their life cycle in environmental habitats or occur as commensals within or on the vertebrate body, but under certain conditions can thrive upon infecting humans. The extent of host damage in opportunistic infections largely depends on the portal and modality of entry as well as on the host's immune and metabolic status. Diseases caused by primary pathogens and common opportunists, causing the top approximately 80% of fungal diseases [D. W. Denning, Lancet Infect Dis, 24:e428-e438, 2024, https://doi.org/10.1016/S1473-3099(23)00692-8], tend to follow a predictive pattern, while those by occasional opportunists are more variable. For this reason, it is recommended that diseases caused by primary pathogens and the common opportunists are named after the etiologic agent, for example, histoplasmosis and aspergillosis, while this should not be done for occasional opportunists that should be named as [causative fungus] [clinical syndrome], for example, Alternaria alternata cutaneous infection. The addition of a descriptor that identifies the location or clinical type of infection is required, as the general name alone may cover widely different clinical syndromes, for example, "rhinocerebral mucormycosis." A list of major recommended human and animal disease entities (nomenclature) is provided in alignment with their causative agents. Fungal disease names may encompass several genera of etiologic agents, consequently being less susceptible to taxonomic changes of the causative species, for example, mucormycosis covers numerous mucormycetous molds., Competing Interests: The authors declare no conflict of interest.

Background: Reversible short-term fluctuations in the frailty index (FI) are often thought of as representing only noise or error. Here, we assess (i) the size and source of short-term FI fluctuations, (ii) variation across sociodemographic characteristics, (iii) association with chronic diseases, (iv) correlation with age, frailty level, frailty change, and mortality, and (v) whether fluctuations reflect discrete health transitions., Methods: Nationwide, biweekly longitudinal data from 426 community-dwelling older adults (70+) were collected in the FRequent health Assessment In Later life (FRAIL70+) study using a measurement burst design (5 122 repeated observations, median of 13 repeated observations per person). We calculated the intraindividual standard deviation of the FI and used location-scale mixed regression models., Results: Mean intraindividual standard deviation was 0.04 (standard deviation = .03). Fluctuations were driven foremost by cognitive problems, somatic symptoms, and limitations in instrumental and mobility-related activities of daily living. Short-term fluctuations correlated with higher FI levels (r = 0.62), 1-year FI change (r = 0.26), and older age (+3% per year). Older adults who took to bed due to a health problem (+50%), those who had an overnight hospital stay (+50%), and those who died during follow-up (+44%) exhibited more FI fluctuations., Conclusions: Short-term FI fluctuations were neither small nor random. Instead, as older adults become frailer, their measured health also becomes more unstable; hence, short-term fluctuations in overall health status can be seen as a concomitant phenomenon of the aging process. Researchers and clinicians should be aware of the existence of reversible fluctuations in the FI over weeks and months and its consequences for frailty monitoring., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Invasive aspergillosis (IA) is a life-threatening infection. Early and specific diagnosis is pivotal to ensure adequate therapy. Antigen testing from blood is a widespread and convenient diagnostic approach. Various tests for the detection of Aspergillus antigen as well as for the panfungal antigen β-1,3-D-glucan (BDG) are available, for which comprehensive comparisons are still lacking. Blood samples of 82 proven/probable (11/71) IA patients and 52 controls were tested using two enzyme-linked immunosorbent assays (ELISAs) (Bio-Rad and Euroimmun), one chemiluminescent immunoassay (CLIA) (Vircell), one BDG assay (Fujifilm Wako), and two point of care (PoC) assays (Immy sōna and OLM). PoC assays were evaluated visually and used automated read out systems. Of the 82 IA patients, 37 had received solid organ transplantation (SOT) and 25 hematopoietic stem cell transplant (HSCT). Sensitivities and specificities for the eight test systems ranged from 27% to 71% and from 64% to 100%. Estimating a 10% prevalence of IA, test performance would have resulted in positive and negative predictive values of 14%-100% and 91%-95%. Areas under the curve (AUCs) for all tests except GM were below 0.7. When the cut-off values for quantitative tests were normalized to a specificity close to 95%, sensitivities ranged from 14% to 40%. The use of automated read out systems for the PoC assays had a significant impact. Combining different tests did not result in better test strategies. Sensitivity of Aspergillus antigen testing from single serum samples is low. Due to specificity issues, the majority of tests is not suited for screening purposes. The different assays can meet different needs in different diagnostic settings., Competing Interests: J.W. received financial support (research grant) from Pfizer outside of this study, technical and financial support by Fujifilm Wako Chemicals Europe and Euroimmun Medizinische Labordiagnostika for past projects outside this study, and speaker fees from Pfizer, Wako, und Gilead. J.P. serves as President of the Austrian Society of Medical Mycology, received speaker fees from Gilead, Pfizer, Swedish Orphan BioVitrum, and Associates of Cape Cod, and holds stock in AbbVie Inc. and Novo Nordisk, all unrelated to the submitted work. M.H. received research funding from Gilead, Astellas, MSD, IMMY, Mundipharma, Scynexis, F2G, and Pfizer, all outside of the submitted work. J.H. received speaker fees from Pfizer, Gilead, Associates of Cape Cod, BD, and Biomerieux, research funding from Pfizer and Gilead, and technical support for projects outside this study from Associates of Cape Cod, Vircell, Virion\Serion, IMMY, and OLM. K.D. received technical and financial support by Fujifilm Wako Chemicals Europe and by Euroimmun Medizinische Labordiagnostika for past projects outside this study and technical support by Vircell, OLM, and IMMY for past projects outside this study. T.S., I.K., and S.S. have no conflicts of interest.

Aims: Understanding heart failure (HF) characteristics is essential to improve patient outcomes. Categorizing HF beyond left ventricular ejection fraction (LVEF) is challenging due to heterogeneous clinical presentation and aetiologies. Despite global studies on HF, the role of LVEF on mortality remains controversial. We explored the association of LVEF with mortality, considering sex differences and comorbidities in a cohort from the largest tertiary cardiovascular centre in Switzerland., Methods: HF patients admitted to the University Hospital of Bern from January 2015 to December 2019 were evaluated. LVEF was used to classify patients into HF with preserved ejection fraction (HFpEF), HF with mid-range ejection fraction (HFmrEF) and HF with reduced preserved ejection fraction (HFrEF) categories. Cox proportional hazard models and time-stratified analyses adjusted for potential confounders were employed., Results: A total of 5824 HF patients were included, and 2912 died over a median follow-up time of 3.39 years. Mortality rates across LVEF categories showed no significant differences, while overall, women showed significantly higher mortality; 30 day mortality was lower in the HFpEF category [hazard ratio (HR) 0.67, 95% confidence interval (CI): 0.52-0.88, P = 0.003], with persistent effects upon stratification in males (HR 0.59, 95% CI: 0.42-0.81, P < 0.001) and non-diabetics (HR 0.62, 95% CI: 0.44-0.87, P = 0.005). An isolated reduction in HFpEF mortality was observed in females after 1 year (HR 0.72, 95% CI: 0.53-0.98, P = 0.035)., Conclusions: The prognostic role of LVEF on all-cause mortality remains unclear, while differences in mortality rate distribution between women and men mirror established HF pathophysiological sex differences. Future HF studies should focus on HF aetiology and include measures beyond LVEF for comprehensive characterization., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: The relationship between angiographic findings and fractional flow reserve (FFR) according to gender is currently unknown., Aims: To examine gender-based differences in the concordance between angiographic and functional assessment of coronary stenosis severity., Methods: We examined 3770 coronary stenoses of stable patients undergoing both quantitative coronary angiography and FFR measurements in at least one coronary stenosis., Results: Median FFR values were higher in female as compared with male patients (0.84 vs. 0.81, p < 0.001) in the overall cohort and in the first three quartiles of diameter stenosis (DS). At receiver operator characteristics (ROC) analysis, DS was effective in predicting ischemic FFR values in both men and women. A 50% DS was the optimal cut off to identify functionally significant stenoses in the entire cohort and in male patients. In females, a higher DS threshold (≥ 59%) significantly improved lesions classification (69.4% vs. 72.4%, p = 0.034), yet at the cost of an increased false negatives rate (10.5% vs. 20.8%, p < 0.001). A lower cut-off of 50% showed a superior diagnostic accuracy for ischemic FFR values (i.e., FFR values ≤ 0.80, AUC: 0.697 vs. 0.661, p = 0.006). Female gender was independently associated with a reduced risk of ischemic FFR (OR 0.51 95% CI [0.43-0.61])., Conclusions: Female patients show higher FFR values across different DS thresholds compared to male patients. A DS ≥ 50% is the best threshold to identify ischemic FFR in both males and females. A higher threshold of DS (≥ 59%) is associated with a significant improvement in lesion classification, despite leading to increased false negatives rate., (© 2024 Wiley Periodicals LLC.)

Regular physical activity and exercise (PA) are cornerstones of diabetes care for individuals with type 1 diabetes. In recent years, the availability of automated insulin delivery (AID) systems has improved the ability of people with type 1 diabetes to achieve the recommended glucose target ranges. PA provides additional health benefits but can cause glucose fluctuations, which challenges current AID systems. While an increasing number of clinical trials and reviews are being published on different AID systems and PA, it seems prudent at this time to collate this information and develop a position statement on the topic. This joint European Association for the Study of Diabetes (EASD)/International Society for Pediatric and Adolescent Diabetes (ISPAD) position statement reviews current evidence on AID systems and provides detailed clinical practice points for managing PA in children, adolescents and adults with type 1 diabetes using AID technology. It discusses each commercially available AID system individually and provides guidance on its use in PA. Additionally, it addresses different glucose responses to PA and provides stratified therapy options to maintain glucose levels within the target ranges for these age groups., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Pulmonary hypertension (PH) is a frequent complication of chronic lung disease (CLD). However, PH is difficult to diagnose early since accompanying symptoms overlap and are similar to those of the underlying CLD. In most cases the PH is mild to moderate and therefore physical signs may be absent or subtle. This consensus paper provides insight into the clues that might suggest the presence of occult PH in patients with CLD. An overview of current diagnostic tools and emerging diagnostic technologies is provided as well as guidance for the work-up and diagnosis of PH in patients with CLD., Competing Interests: Dr. Vitulo has consulted for MSD and AOP and has received support for attending congresses from MSD, Janssen all of which not related to this manuscript. Dr. Piccari has received research funding from and served as a speaker for Janssen and Ferrer, advised Janssen, Ferrer and United Therapeutics as well as received support for attending congresses from Janssen, MSD and Ferrer, all of which not related to this manuscript. Dr. S. John Wort received honoraria from Janssen, MSD, Bayer, Ferrer and Acceleron for advisory boards, received honoraria from Janssen for educational activity, received unrestricted research grants from Janssen, Ferrer and Bayer, and travel grants, conference registration and accommodation from Janssen and Ferrer. Dr. Shlobin has consulted for UT, Bayer, ALtavant, Aerovate, Jenssen&Jenssen Jenssen& Jenssen and Merck, and is on the speaker bureau for UT, Bayer, and J&J; Dr. Stockbridge has no conflict of interest. Dr. Kovacs reports personal fees and nonfinancial support from Actelion, Janssen, Bayer, GSK, MSD, Boehringer Ingelheim, Novartis, Chiesi, Vitalaire, Ferrer, and AOP outside the submitted work. Dr. Vizza has no conflict of interest regarding this topic. Dr. Hassoun serves on a scientific advisory board for Merck, an activity unrelated to the current work. Dr. Olschewski received funding from Actelion, AOP, Astra Zeneca, Bayer, Boehringer, Chiesi, GSK, Iqvia, Janssen, Menarini, MSD, Novartis, Ludwig Boltzmann Society, Ferrer, MedUpdate, and Mondial not related to this work. Dr. Girgis received honoraria from Boehringer Ingelheim and research funding from UT. Dr. Nikkho is an employee of Bayer AG.Dr. Nathan is a consultant for United Therapeutics, Bellerophon, Third Pole, Roche, Boehringer‐Ingelheim, Insmed, Roivant, Merck and Daewoong. He is on the speakers bureau for United Therapeutics and Boehringer‐Ingelheim. He is also on the Gossamer Bio Board of Directors., (© 2024 The Author(s). Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Regular physical activity and exercise (PA) are cornerstones of diabetes care for individuals with type 1 diabetes. In recent years, the availability of automated insulin delivery (AID) systems has improved the ability of people with type 1 diabetes to achieve the recommended glucose target ranges. PA provide additional health benefits but can cause glucose fluctuations, which challenges current AID systems. While an increasing number of clinical trials and reviews are being published on different AID systems and PA, it seems prudent at this time to collate this information and develop a position statement on the topic. This joint European Association for the Study of Diabetes (EASD)/International Society for Pediatric and Adolescent Diabetes (ISPAD) position statement reviews current evidence on AID systems and provides detailed clinical practice points for managing PA in children, adolescents and adults with type 1 diabetes using AID technology. It discusses each commercially available AID system individually and provides guidance on their use in PA. Additionally, it addresses different glucose responses to PA and provides stratified therapy options to maintain glucose levels within the target ranges for these age groups., Competing Interests: Acknowledgements: We would like to thank the nine reviewers (three experts in the field of PA, AID and type 1 diabetes; three people with type 1 diabetes using AID systems; and three parents of children/adolescents with type 1 diabetes using AID systems) for critical assessment of this manuscript prior to submission to the EASD CCA. We also want to thank K. Moser for support with the production of the figures and tables. We extend our gratitude to all individuals living with type 1 diabetes who have generously contributed their time and participated in research trials. Finally, we would like to acknowledge the following individuals who have contributed to clinical trials, data collection and advancing the field of exercise and type 1 diabetes research: D. Morrison (University of Melbourne, Australia), B. Paldus (University of Melbourne, Australia), O. McCarthy, (Steno Diabetes Center Copenhagen, Denmark), G. Ash (Yale University, USA), L. Nally (Yale University, USA), M. Clements (Children’s Mercy, Kansas City, USA), R. Gal (Jaeb Center for Health Research, USA), S. Patton (Nemours Children's Health, USA), N. Bratina (University of Ljubljana, Slovenia), F. Annan (University College London Hospitals NHS Foundation Trust, UK), C. Smart (John Hunter Children’s Hospital, Australia), E. Heyman (University of Lille, France) and S. Tagougui (University of Lille, France). Data availability: All data used within this position statement are included in the manuscript. Funding: Open Access funding enabled and organized by Projekt DEAL. OM has received research funding from Sêr Cymru II COFUND Fellowship/European Union, Novo Nordisk, Abbott Diabetes Care, Sanofi, Dexcom, Team Novo Nordisk, SAIL, Brauerei Maisel, Medtronic, European Foundation for the Study of Diabetes (EFSD)/EASD, Falke, BISp., Ypsomed, DiabetesDE and Perfood. DPZ has received an ISPAD-JDRF Research Fellowship and research support from Insulet and the Leona M. and Harry B. Helmsley Charitable Trust. PA has received research grants from Medtronic and Novo Nordisk. KD has received an ISPAD-JDRF Research Fellowship. TB’s institution has received research grant support from Abbott, Medtronic, Novo Nordisk, Sanofi, Novartis, Sandoz, Zealand Pharma, the Slovenian Research Agency, the National Institutes of Health (NIH) and the European Union. Yale School of Medicine has received research support for JLS from Abbott Diabetes, the Jaeb Center for Health Research, JDRF, Insulet, Medtronic, NIH and Provention Bio. JEY has received in-kind research support from Dexcom and LifeScan Canada and support from Medtronic, Dexcom and Abbott. KN’s institution has received research funding from Zealand Pharma, Novo Nordisk, Medtronic and Dexcom. HS has received research support from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, the European Union, the Austrian Research Promotion Agency (FFG) and the Austrian Science Fund (KLP3413324). BAB has received research support from the NIDDK and Breakthrough T1D. KU Leuven has received research support for CM from Medtronic, Novo Nordisk, Sanofi and ActoBio Therapeutics. MCR has received research grants and/or contract research support from the Jaeb Center for Health Research, Sanofi, Novo Nordisk, Eli Lilly, Dexcom, Insulet and Zucara Therapeutics. GPF has received research funding from NIH, JDRF/BT1D, NSF, Medtronic, Dexcom, Abbott, Tandem, Insulet, Beta Bionics and Lilly. EAD’s institution has received research support from Medtronic, Dexcom and Tandem. NSO has received research support from Dexcom, Medtronic, Roche Diabetes, Diabetes UK, Imperial College NIHR BRC, the Leona M. and Harry B. Helmsley Charitable Trust and UKRI EME. For PG, KU Leuven has received research grants from Dexcom (financial and non-financial support), Medtronic, Novo Nordisk, Roche, Sanofi and Tandem. PG is the recipient of a senior clinical research fellowship from FWO, the Flemish Research Council (1861924N). RMB has received research funding or product supply from Medtronic, Novo Nordisk, Sêr Cymru II COFUND European Union, Abbott Diabetes Care, Sanofi, Dexcom, Team Novo Nordisk, Supersapiens and Beneo. RH reports receiving speaker honoraria from Eli Lilly, Dexcom and Novo Nordisk and license and/or consultancy fees from B. Braun and Abbott Diabetes Care, patents related to closed-loop, and being director at CamDiab. TD serves as Chief Medical Officer of Breakthrough T1D (formerly JDRF). None of the funders played a role in the development of this position paper. Authors’ relationships and activities: OM has received lecture fees from Medtronic, Eli Lilly, Novo Nordisk, Sanofi, TAD Pharma, Theras, Diatec, Ypsomed, Dexcom, AstraZeneca, Insulet and Perfood; and is on the advisory board for Sanofi, TAD Pharma, Glaice, Perfood, Medtronic and Dexcom. DPZ has received honoraria for speaking engagements from Ascensia Diabetes Care, Insulet Canada, Dexcom Canada and Medtronic; is on an advisory board for Dexcom and the Diabetes Research Hub; PA has taken part in advisory boards of Eli Lilly, Insulet, Medtronic, Novo Nordisk, Roche and Sanofi. KD has received honoraria for speaking engagements from Abbott, Eli Lilly, Medtronic, Novo Nordisk and Pfizer; is on an advisory board for Medtronic and Novo Nordisk. SEH has received speaker’s honoraria from Eli Lilly, Sanofi, Medtronic, Insulet, Dexcom and Ypsomed. JP has received speaker’s honoraria from Dexcom and Abbott and sits on the advisory board for Roche. TB has served on advisory panels of Novo Nordisk, Sanofi, Eli Lilly, Boehringer, Medtronic, Abbott and Indigo Diabetes and has received honoraria for participating on the speakers bureaus of Eli Lilly, Novo Nordisk, Medtronic, Abbott, Sanofi, Dexcom, Aventis, AstraZeneca and Roche. JLS reports serving, or having served, on advisory panels for Cecelia Health, Insulet, Medtronic Diabetes, StartUp Health Diabetes Moonshot and Vertex and having served as a consultant to Abbott Diabetes, Insulet, Medtronic Diabetes, Vertex and Zealand. RR-L has received consulting/advisory panel honoraria from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Dexcom, Eli Lilly, HLS Therapeutics, INESSS, Insulet, Janssen, Medtronic, Merck, Novo Nordisk, Pfizer and Sanofi-Aventis; honoraria for conferences from Abbott, AstraZeneca, Boehringer Ingelheim, CPD Network, Dexcom, CMS Canadian Medical & Surgical Knowledge Translation Research Group, Eli Lilly, Janssen, Medtronic, Merck, Novo Nordisk, Sanofi-Aventis, Tandem and Vertex Pharmaceutical; consumable gifts (in kind) from Eli Lilly and Medtronic; and purchase fees from Eli Lilly in the field of automated insulin delivery. JEY has received speaker’s fees from Dexcom and Abbott. JKM is a member of the advisory boards of Abbott Diabetes Care, Becton-Dickinson/Embecta, Biomea, Eli Lilly, Medtronic, Novo Nordisk, Pharmasens, Roche Diabetes Care, Sanofi and Viatris; has received speaker honoraria from Abbott Diabetes Care, A. Menarini Diagnostics, Becton-Dickinson/Embecta, Boehringer Ingelheim, Eli Lilly, MedTrust, Novo Nordisk, Roche Diabetes Care, Sanofi, Servier and Ypsomed; and is a shareholder of decide Clinical Software and elyte Diagnostics. MT has received honoraria for speaking engagements from Ely Lilly, Medtronic and Ypsomed and is on advisory boards for Abbott Diabetes Care and Sanofi. KN owns shares in Novo Nordisk and has been a paid consultant for Novo Nordisk and Medtronic and has received speaker and advisory board honorarium for her institution from Abbott, Medtronic, Novo Nordisk, Insulet and Convatec. HS has received speaker’s honoraria or is on the advisory board for Amgen, Amarin, Boehringer Ingelheim, Cancom, Eli Lilly, Daiichi Sankyo and Novo Nordisk. MCR serves on advisory panels for Zealand Pharma, Zucara Therapeutics and Indigo Diabetes; acts as a consultant for the Jaeb Center for Health Research; has given lectures sponsored by Dexcom, Novo Nordisk and Sanofi; and is a shareholder, or holds stocks in, Supersapiens and Zucara Therapeutics. BAB has received consulting fees from Ypsomed, Arecor and Medtronic. CM serves or has served on the advisory panel for Novo Nordisk, Sanofi, Eli Lilly, Novartis, Dexcom, Boehringer Ingelheim, Bayer, Roche, Medtronic, Insulet, Biomea Fusion, SAB Bio and Vertex. Financial compensation for these activities has been received by KU Leuven. CM serves or has served on the speakers bureau for Novo Nordisk, Sanofi, Eli Lilly, Medtronic and Boehringer Ingelheim. Financial compensation for these activities has been received by KU Leuven. CM is president of EASD. All external support provided to EASD can be found at http://www.easd.org/. DNO has received honoraria from Medtronic, Insulet, Abbott Diabetes Care, Novo Nordisk and Sanofi, and research support from Medtronic, Insulet, Dexcom, Roche, GlySens, BioCapillary and Endogenex, and is on advisory boards for Medtronic, Insulet, Abbott Diabetes Care, Ypsomed, Novo Nordisk and Sanofi. GPF has served as a speaker/consultant/ad board member for Medtronic, Dexcom, Abbott, Tandem, Insulet, Beta Bionics, Sequel and Lilly. EAD’s institution has received speaker honorariums from Eli Lilly and EAD has sat on an advisory panel for Tandem. NSO has participated in advisory groups for Dexcom, Medtronic and Roche Diabetes and received fees for speaking from Astra Zeneca, Sanofi, Dexcom, Tandem, Medtronic and Roche Diabetes. PG has served on the advisory board for Insulet and Ypsomed. PG reports consulting fees from Abbott, Bayer and Medtronic, and honoraria for speaking from Abbott, Bayer, Dexcom, Insulet, Medtronic, Novo Nordisk, Vitalaire and Ypsomed (financial compensation received by KU Leuven). PG has received support for attending (virtual) conferences/meetings from Medtronic, Novo Nordisk, Roche and Sanofi (financial compensation received by KU Leuven). RMB has received lecture fees from Abbott Diabetes Care, Novo Nordisk, Medtronic, Eli Lilly and Sanofi. TD has received speaker, advisory panel or research support from Abbott, Dexcom, Eli Lilly, Insulet, Medtronic, Novo Nordisk, Roche, Sanofi, Ypsomed and Vitalaire. He is a shareholder of DreaMed Ltd. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: All authors of this joint EASD/ISPAD position statement substantially contributed to conception and design, acquisition of data or analysis and interpretation of data, drafted the article or revised it critically for important intellectual content and approved the final version to be published., (© 2024. The Author(s).)

Mechanosensation is essential for endothelial cell (EC) function, which is compromised in early-onset preeclampsia (EPE), impacting offspring health. The ion channels Piezo-type mechanosensitive ion channel component 1 (Piezo1) and Transient receptor potential cation channel subfamily V member 4 (TRPV4) are co-regulated mechanosensors in ECs. Current evidence suggests that both channels could mediate aberrant placental endothelial function in EPE. Using isolated feto-placental ECs (fpECs) from early control (EC) and EPE pregnancies, we show functional co-expression of both channels and that Ca 2+ influx and membrane depolarization in response to chemical channel activation is reduced in EPE fpECs. Downstream of channel activation, Piezo1 alone can induce phosphorylation of endothelial nitric oxide synthase (eNOS) in fpECs, while combined activation of Piezo1 and TRPV4 only affects eNOS phosphorylation in EPE fpECs. Additionally, combined activation reduces the barrier integrity of fpECs, also with a stronger effect on EPE fpECs. This implies altered Piezo1-TRPV4 co-regulation in EPE. Mechanistically, we suggest this to be driven by changes in the arachidonic acid metabolism in EPE fpECs as identified by RNA-Seq. Targeting of Piezo1 and TRPV4 might hold potential for EPE treatment options in the future.

A 63-year-old woman with a history of acute myeloid leukemia followed by stem cell transplantation presented with acute heart failure. Transthoracic echocardiography revealed a preserved left ventricular ejection fraction with severe ventricular hypertrophy and signs of elevated filling pressures indicating infiltrative cardiomyopathy. She died from cardiac arrest due to cardiogenic shock. The autopsy revealed an enlarged heart with a fish-flesh appearance. Here, we describe a rare case of a myeloid sarcoma of the heart., Competing Interests: Declarations. Conflict of interest: K. Skok, M. Zacharias, N. Verheyen, S. Hatzl, L. Scholz, C. Langner, G. Hoefler and F.R. Vagena declare that they have no competing interests. Ethical standards: All procedures performed in studies involving human participants or on human tissue were in accordance with the ethical standards of the institutional and/or national research committee. The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Ethics Committee of the Medical University of Graz (No. 1073/2024)., (© 2024. The Author(s).)

Thrombocytopenia is a frequent complication in patients with cancer, mostly due to the myelosuppressive effects of antineoplastic therapies. The risk of venous thromboembolism (VTE) in patients with cancer is increased despite low platelet counts. The management of cancer-associated VTE in patients with thrombocytopenia is challenging, as the risk of both recurrent VTE and bleeding complications is high. Moreover, the time-dependent nature of thrombocytopenia over the course of antineoplastic therapies further complicates the management of patients in clinical practice. In the absence of evidence from high-quality studies, the management of anticoagulation therapy for VTE must be personalized, balancing the individual risk of VTE progression and recurrence against the risk of hemorrhage. In the present case-based review, we highlight the clinical challenges that arise upon managing cancer-associated VTE in the setting of present or anticipated thrombocytopenia, summarize the available evidence, and provide a comparative overview of available guidelines., (Copyright © 2024 by The American Society of Hematology.)

Ongoing innovation in diabetes technologies has led to the development of advanced tools such as automated insulin delivery (AID) systems that adjust insulin delivery in response to current and predicted glucose levels, residual insulin action, and other inputs (eg, meal and exercise announcements). However, infusion sets continue to be the "Achilles heel" of accurate and precise insulin delivery and continued device use. A recent study by Kalus et al (DERMIS Study) revealed higher vessel density and signals of inflammation by optical coherence tomography (OCT), in addition to increased inflammation, fat necrosis, fibrosis, and eosinophilic infiltration by histopathology. Although the study provided a comprehensive description of what was happening, the results raise important questions that require additional research. On February 29, 2024, the Leona M. and Harry B. Helmsley Charitable Trust sponsored a conference to begin addressing these issues. This article summarizes the DERMIS study findings and testing methodologies discussed at the conference and proposes the next steps for developing insulin infusion sets that reduce the variability in insulin delivery and extend wear., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Autophagy is a highly conserved metabolic process that regulates cellular homeostasis and energy supply by degrading dysfunctional and excess cell constituents and reserve materials into products that are reused in metabolic and biosynthetic pathways. Macroautophagy is the best studied form of autophagy in invertebrates. Starvation is a common stress factor triggering autophagy in overwintering animals. In arachnids, the midgut diverticula cells perform many vital metabolic functions and are therefore critically involved in the response to starvation. Here we studied macroautophagy in three species which apply different modes for overwintering in caves: the harvestmen Gyas annulatus in diapause, Amilenus aurantiacus with ongoing ontogenesis under fasting conditions, and the spider Meta menardi, which feeds opportunistically even in winter. The main goal was to find eventual qualitative and quantitative differences in autophagic processes by inspecting TEM micrographs. In all three species, the rates of midgut epithelial cells with autophagic structures gradually increased during overwintering, but were significantly lower in G. annulatus in the middle and at the end of overwintering than in the other two species, owing to metabolic activity having been more suppressed. Decomposition of mitochondria and glycogen took place in autophagic structures in all three species. Moreover, spherite disintegration in A. aurantiacus and a special form of lipid disintegration through "lipid bubbly structures" in M. menardi indicate the crucial involvment of selective autophagy, while no specific autophagy was observed in G. annulatus. We conclude that autophagic activities support overwintering in different ways in the species studied., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Physical exercise has been shown to induce positive reactions in bone healing but next to nothing is known about how it affects the nanostructure, in particular around implants. In this study, we established this link by using small-angle X-ray scattering tensor tomography (SASTT) to investigate nanostructural parameters in 3D such as mineral particle orientation and thickness. As a model system, rat femoral bone with a bio-resorbable implant (ultra-high purity magnesium) was used. One half of the rats underwent treadmill exercise while the other half were moving freely in a cage. At two- and six-weeks post-surgery rats were sacrificed, and samples were taken. Our results point to an earlier start and stronger remodeling when physical exercise is applied and to a stronger reorientation of the mineralized collagen fibers around the implant. This study reveals the nanostructural response of bone with bio-resorbable implants to physical exercise. Understanding this response is very important for designing post-surgery treatments. STATEMENT OF SIGNIFICANCE: Physical exercise is known to have beneficial effects on the human body and is often incorporated into the recovery process following orthopedic surgeries. While the response of bone to physical exercise is well-documented, the structural response of bone to early exercise after implant placement, particularly its impact on the nanostructure, has not been extensively studied. In this study, we identify the effects of physical exercise on the bone nanostructure and the remodeling process around a bioresorbable implant. These findings could help develop tailored physical exercise strategies for post-surgery recovery in patients., Competing Interests: Declaration of interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Annelie M Weinberg is a shareholder of Bioretec Ltd. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Plastic particles smaller than 5 mm, referred to as Microplastics, pose health risks, like metabolic, immunological, neurological, reproductive, and carcinogenic effects, after being ingested. Smaller plastic particles are more likely to be absorbed by human cells, with nanoplastics showing higher potential for cellular damage, including DNA fragmentation and altered protein functions. Micro- and nanoplastics (MNPs) affect the gastrointestinal tract by altering the microbial composition, they could influence digestive enzymes, and possibly disrupt mucus layers. In the stomach, they potentially interfere with digestion and barrier functions, while in the intestines, they could increase permeability via inflammation and tissue disruption. MNPs can lead to microbial dysbiosis, leading to gastrointestinal symptoms. By activating inflammatory pathways, altering T cell functions and affecting dendritic cells and macrophages, immune system homeostasis could possibly be disrupted. Probiotics offer potential strategies to alleviate plastic effects, by either degrading plastic particles or directly countering health effects. We compared genetic sequences of probiotics to the genome of known plastic degraders and concluded that no probiotic bacteria could serve the role of plastic degradation. However, probiotics could directly mitigate MNP-health effects. They can restore microbial diversity, enhance the gut barrier, regulate bile acid metabolism, reduce inflammation, regulate insulin balance, and counteract metabolic disruptions. Antioxidative properties protect against lipid peroxidation and MNP-related reproductive system damage. Probiotics can also bind and degrade toxins, like heavy metals and bisphenol A. Additionally, bacteria could be used to aggregate MNPs and reduce their impact. Therefore, probiotics offer a variety of strategies to counter MNP-induced health effects., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: N.S. is employee of Institut AllergoSan (Institut AllergoSan manufactures and markets probiotics). M.H. and W.M. are employees of Winclove Probiotics (Winclove Probiotics manufactures and markets probiotics). The content of this study was neither influenced nor constrained by this fact. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Appropriate glycemic control is paramount for people with type 1 diabetes (PwT1D) by the effective delivery of exogenous insulin. However, glycemic variability and the risk of severe hypoglycemia must be reliably controlled., Methods: COMET-T is a prospective, multicenter, observational study conducted in Germany, Austria, and Switzerland during 2021-2022 to assess the effectiveness and safety of insulin glargine 300 U/ml (Gla-300) after switching from other basal insulins. Out of 135 PwT1D, data of 94 patients were analyzed. The primary endpoint was the change in time in range (TIR) approximately 12 and 24 weeks after switching to Gla-300. Secondary endpoints were: change in HbA 1c , fasting plasma glucose (FPG), coefficient of variation (CV%) of plasma glucose, body weight (BW) and insulin dose., Results: Patients had mean age of 48.6 ± 16.5 years, included 39.4% males and had 18.2 ± 15.5 years T1D duration. From baseline (54.3%), TIR changed at week 12 (mean change 0.3% [± 14.3]; p = 0.8383) and at week 24 (+ 4.5% [± 14.9], p = 0.078). At week 24, TIR significantly increased in patients with body mass index > 30 kg/m 2 (8.4% [± 12.8] p = 0.0057) and patients who previously received insulin detemir (10.5%; [± 12.93]; p = 0.0005). At week 24, there was a significant reduction in the HbA 1c value (8.1 ± 0.6% vs. 7.7 ± 0.9%; p < 0.001), a reduction in the CV% of plasma glucose (36.1 ± 12.4% vs. 32.8 ± 9.6%, p = 0.056), and increase in bolus insulin dose (26.5 ± 16.3 vs. 27.9 ± 16.6 U/day; p = 0.042). FPG, BW, and basal insulin doses were not significantly changed., Conclusions: Although switching to Gla-300 in poorly controlled PwT1D did not significantly reduce TIR, it significantly decreased HbA 1c values and glycemic variability without changes in BW and basal insulin dose., Competing Interests: Declarations. Conflict of Interest: Thomas Danne has received speaker fees and research support from or has consulted for Abbott, AstraZeneca, Boehringer Ingelheim, Dexcom, Eli Lilly, Medtronic, Novo Nordisk, Provention Bio, Roche, Sanofi, and Vertex and is a shareholder of DreaMed Ltd. Stefan Gölz has received speaker fees and research support from or has consulted for Abbott, Ascencia, Novo Nordisk, Novartis, Sanofi, Astra Zeneca, MSD, Berlin Chemia, Lilly, Boehringer Ingelheim, Johnson & Johnson, Medical Tribune, Dexcom, Roche, Menarini, Santis, EvivaMed. Julia Mader has received research support from A. Menarini Diagnostics, Novo Nordisk, Sanofi; Advisory Board: Abbott Diabetes Care, Becton–Dickinson/Embecta, Eli Lilly, Medtronic, Novo Nordisk, PharmaSens, Roche Diabetes Care, Sanofi, Viatris; speaker fees from Abbott Diabetes Care, A. Menarini Diagnostics, Becton Dickinson/Embecta, Boehringer-Ingelheim, Eli Lilly, MedTrust, Novo Nordisk, Roche Diabetes Care, Sanofi, Servier, Ypsomed; Shareholder of decide Clinical Software GmbH. Stefan Bilz has received speaker’s fees from or consulted for Amgen, Sanofi, Novartis, Bayer, Daiichi-Sankyo, Novo Nordisk; travel support from Novo Nordisk. Julia Kenzler is an employee of Sanofi-Aventis Deutschland GmbH. Ethical Approval: The study was conducted in accordance with the Helsinki Declaration of 1964. The study received approval from the institutional review board or ethics committee at each participating center. Approval reference numbers were BASEC-Nr. 2020-01997, F-2020-106, 32-605 ex 19/2. A formal written informed consent was obtained from all patients prior to their enrolment in the study. Permissions were obtained to use the DTSQ questionnaire in this study., (© 2024. The Author(s).)

Reasoning is the ability to formulate inferences or conclusions from available information. The two major types, deductive and inductive, are thought to rely on distinct cognitive mechanisms and recruit separate brain areas. Neuroimaging studies yield mixed results; some found the left inferior frontal gyrus (IFG) activations for deductive reasoning and the left dorsolateral prefrontal cortex (DLPFC) for inductive reasoning. This assumption was put to the test in the present study. In two double-blinded, sham-controlled experiments, high-definition transcranial direct current stimulation (HD-tDCS) was used to systematically explore the left IFG's and DLPFC's causal role in deductive and inductive reasoning. Participants with no formal training in logic judged deductive and inductive arguments before and after 10 minutes of anodal, cathodal, or sham tDCS of the left IFG (Experiment 1, n = 20) or left DLPFC (Experiment 2, n = 21). Left IFG anodal tDCS impairs reaction times (RTs) for easy categorical (p = < .001) and propositional (p = .025) deductive arguments and the accuracy for easy inductive propositional arguments (p = .003). Meanwhile, regardless of the active stimulation conditions, left DLPFC tDCS shortens RTs (anodal: p = < .001, cathodal: p = .014) and increases accuracy (anodal: p = .029, cathodal: p = .001) for difficult categorical inductive arguments, but decreases accuracy (anodal: p = .027, cathodal: p = < .001) for difficult propositional inductive arguments. The overall results showed a partial dissociation of the left frontal lobe areas subserving the two types of reasoning and argument difficulty-dependent stimulation effects. This study extends knowledge of the neural basis of reasoning and hopefully inspires interventions that could augment reasoning impairments associated with normal aging and brain lesions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Fresnoza et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: To assess outcomes of continence and complications after implantation of Adjustable TransObturator Male System (ATOMS) for the treatment of male stress urinary incontinence (SUI)., Materials and Methods: Data of 80 patients receiving an ATOMS implatation between 2010 and 2021 at a tertiary academic referral centre were retrospectively analyzed. Primary endpoints were outcomes of continence and complications. Implant survival rate was estimated by the Kaplan-Meier method, risk factors for explantation were analyzed by univariable Cox regression., Results: During a median follow-up of three yrs. the number of pads decreased significantly from four to two pads per day (p<0.001). After five yrs., 17 patients experienced an explantation, eight of them during the first year following ATOMS implantation, resulting in one- and five-year-implant-survival rates of 0.89 (95%CI:0.80-0.95) and 0.71 (95%CI:0.56-0.81), respectively. During the total observation time, ATOMS was explanted in 22 (27.5%) patients (Kaplan-Meier estimate for explantation: 0.35 [95%CI:0.09-0.64]) after a median time of 2.3 (0.1, 10.2) yrs. The risk for explantation was higher in patients after previous incontinence surgery (HR=3.4, 95%CI:1.4-8.2, p=0.007), ISUP (International Society of Urological Pathology) > 4 (Gleason score >8) in surgery specimens (HR=4.4, 95%CI:1.03-27.1 compared to ISUP 1, p=0.046), and a preoperative daily pad weight >250g (HR=3.1, 95%CI:1.18-8.17, p=0.022)., Conclusion: ATOMS lead to a significant reduction of pad usage. During the intermediate-term follow-up approximately every 3 rd patient experienced device explantation. In particular, patients with recurrent SUI and patients with severe SUI have to be warned about a relevant risk of explantation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The incidence of one-year venous thromboembolism (VTE) after cancer diagnosis is reported to be increasing for several types of cancer. The introduction of targeted anti-cancer therapies and immunotherapy into the therapeutic armamentarium of medical oncologists contributed to the significantly improved response rates and survival times of cancer patients. In recent years, a potential prothrombotic effect of several targeted anti-cancer agents and immunotherapy drugs has been suggested; however, the methodological limitations of clinical trials evaluating the possible role of these classes of drugs on the VTE risk often make the interpretation of their results difficult. It is still not clear whether the increased risk of VTE is more closely correlated to the expression of specific oncogenic profiles than to the administration of specific therapies against these mutations. Furthermore, the increased survival rates observed with these agents could influence the prevalence of VTE events in cancer patients by the competing risk mortality on the risk of VTE. To date, the available data have suggested that the risk of VTE varies among different categories of targeted therapy, being most reported for anti-vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), monoclonal antibodies and immune checkpoint inhibitors, and less reported for tyrosine kinase inhibitors (TKI). The risk of VTE seems to significantly increase when targeted therapy is administered in combination with traditional anti-cancer agents. Considering the uncertainties in estimating the rate of thrombotic complications associated with targeted therapy, the need for antithrombotic prophylaxis in cancer patients receiving targeted therapies still needs to be specifically assessed. In this review, we examine available evidence of the literature and the methodological limitations of clinical trials, and we discuss the potential future perspectives.

Aim: A recent European Heart Rhythm Association (EHRA) practical guide provides guidance on the use of novel digital devices for heart rhythm analysis using either electrocardiogram (ECG) or photoplethysmography (PPG) technology for the diagnosis of atrial fibrillation (AF). This survey assesses physicians' preferences to use digital devices in patients with possible AF and their impact on clinical decision-making., Methods and Results: Participants of the DAS-CAM III initiated and distributed an online survey assessing physician preferences in using digital devices for the management of AF in different clinical scenarios. A total of 505 physicians (median age: 38 [IQR 33-46] years) from 30 countries completed the survey. A third of respondents were electrophysiologists, the others were cardiologists, cardiology residents, or general practitioners. Electrophysiologists were more likely to have experience with both ECG-based (92% vs. 68%, p < 0.001) and PPG-based (60% vs. 34%, p < 0.001) digital devices. The initial diagnostic approach to each scenario (symptomatic low-risk, symptomatic high-risk, or asymptomatic high-risk patient) was heterogeneous. Electrophysiologists preferred intermittent single-lead ECG monitoring to traditional Holter ECGs to screen for AF. Both electrophysiologists and non-electrophysiologists would rarely use PPG-based devices to diagnose and screen for AF (8.2%-9.8%). Electrophysiologists and non-electrophysiologists use ECG-based technology to confirm PPG-documented tracings suggestive of AF., Conclusion: While PPG-based digital devices are rarely used for diagnosis and screening for AF, intermittent ECG-based digital devices are beginning to be implemented in clinical practice. More education on the potential of novel digital devices is required to achieve diagnostic pathways as suggested by the EHRA practical guide., (© 2024 The Author(s). Clinical Cardiology published by Wiley Periodicals, LLC.)

Background: Advances in haemolytic disease of the fetus and newborn have led to numerous treatment options. We report practice variations in the management and outcomes of haemolytic disease of the fetus and newborn in at-risk pregnancies., Methods: In this international, retrospective, observational cohort study, data from cases with moderate or severe haemolytic disease of the fetus and newborn were retrieved from 31 centres in 22 countries. Eligible participants had pregnancies with haemolytic disease of the fetus that led to fetal death at 16 + 0 weeks or later, those treated antenatally with intrauterine transfusion or intravenous immunoglobulins, or neonates without antenatal treatment who were treated with intensive phototherapy, exchange transfusion, or red blood cell transfusions. All patients had confirmed maternal alloantibodies and an antigen-positive fetus incompatible with the maternal alloantibody. Patients with ABO-incompatibility only were excluded. We assessed serological diagnostics and referrals, antenatal treatment and timing, complications, delivery route, and gestational age at birth. Outcomes were analysed in all eligible participants who had complete data available., Findings: 2443 pregnancies with haemolytic disease of the fetus and newborn treated between Jan 1, 2006, and July 1, 2021, were shared by the centres and analysed between Dec 1, 2021, and March 1, 2023. 23 pregnancies were excluded due to missing information and we included 2420 for further analysis. 1764 (72·9%) of 2420 pregnancies were affected by D-antibodies. 95 (3·9%) of 2420 pregnancies resulted in fetal death. Of the 2325 liveborn neonates, 1349 (58·1%) received any form of antenatal treatment and 976 (41·9%) were only treated postnatally. Median gestational age at referral was 20·4 weeks (IQR 14·9-28·0) and ranged between medians of 10·0 and 26·3 weeks between centres. Severe hydrops at first intrauterine transfusion was present in 185 (14·5%) of 1276 pregnancies, with proportions ranging between 0 and 42% between centres. A median of two intrauterine transfusions (IQR 1-4) were done per pregnancy. The fetal access sites used in intrauterine transfusions varied widely between centres. Non-lethal complications in intrauterine transfusions by transfusion site occurred at a lower rate in intrahepatic approaches (2·0%, 95% CI 1·1-3·3) than in placental insertion (6·9%, 5·8-8·0) and free loop (13·3%, 8·9-18·9). The use and indication for intravenous immunoglobulin administration varied widely. Neonates with intrauterine transfusion were born at a median gestational age of 35·6 weeks (IQR 34·0-36·7), ranging between medians of 33·2 and 37·3 weeks between centres, while neonates without antenatal treatment were born at a median gestational age of 37·3 (IQR 36·3-38·1), ranging between medians of 34·9 and 38·9 weeks between centres., Interpretation: We found considerable variation in antenatal management and outcomes in haemolytic disease of the fetus and newborn between sites in different countries. Our study shows the capacity of the field to gather valuable data on a rare disease and to optimise care., Funding: None., Competing Interests: Declaration of interests DPdW is doing a PhD programme partly funded by Momenta Pharmaceuticals, which was acquired by Johnson & Johnson, and is an investigator for a phase 2 trial (NCT03842189) of a new drug for the treatment of haemolytic disease of the fetus and newborn. EL is a sub-investigator for a phase 2 trial (NCT03842189) of a new drug for the treatment of haemolytic disease of the fetus and newborn, which is sponsored by Janssen Pharmaceuticals. RD reports paid lectures and participation in studies for Janssen Pharmaceuticals. PM received payment for a lecture from CSL Behrin. PM and J-MJ reports participation in an advisory board for haemolytic disease of the fetus and newborn of Janssen Pharmaceuticals in December, 2023, and both report participation in a phase 3 trial (NCT05912517) of a new drug for the treatment of haemolytic disease of the fetus and newborn, which is sponsored by Janssen Pharmaceuticals. ET is the principal investigator for Janssen-sponsored trials Unity and Clarity in Sweden and an advisory Board Member and Steering Committee member for Janssen Pharmaceutical on haemolytic disease of the fetus and newborn and FNAIT programmes. TPS is a member of the board of the International Society of The Fetus as a Patient and member of the expert committee for Gynaecology and Obstetrics at Ministry of Health, Republic of Slovenia. EJTV is the principal investigator for a phase 2 trial (NCT03842189) and phase 3 trial (NCT05912517) of a new drug for the treatment of haemolytic disease of the fetus and newborn, which is sponsored by Janssen Pharmaceuticals. All other authors report no competing interests or financial disclosures., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Intracerebral haemorrhage (ICH) is a devastating condition associated with high mortality and substantial residual disability among survivors. Effective treatments for the acute stages of ICH are limited. However, promising findings from randomized trials of therapeutic strategies, including acute care bundles that target anticoagulation therapies, blood pressure control and other physiological parameters, and trials of minimally invasive neurosurgical procedures have led to renewed optimism that patient outcomes can be improved. Currently ongoing areas of research for acute treatment include anti-inflammatory and haemostatic treatments. The implementation of effective secondary prevention strategies requires an understanding of the aetiology of ICH, which involves vascular and brain parenchymal imaging; the use of neuroimaging markers of cerebral small vessel disease improves classification with prognostic relevance. Other data underline the importance of preventing not only recurrent ICH but also ischaemic stroke and cardiovascular events in survivors of ICH. Ongoing and planned randomized controlled trials will assess the efficacy of prevention strategies, including antiplatelet agents, oral anticoagulants or left atrial appendage occlusion (in patients with concomitant atrial fibrillation), and optimal management of long-term blood pressure and statin use. Together, these advances herald a new era of improved understanding and effective interventions to reduce the burden of ICH., Competing Interests: Competing interests: DJW reports speaking honoraria from Bayer; speaking and chairing honoraria from Alexion and NovoNordisk; and consultancy fees from Alnylam, Bayer and NovoNordisk. He is Co-Chief Investigator for the PROHIBIT-ICH trial. He has participated as a member of the LACI-2, TICH-2, TICH-3, RESTART, MACE-ICH and PLINTH Trial Steering Committees. The other authors declare no competing interests., (© 2024. Springer Nature Limited.)

Background: Langerhans cell histiocytosis (LCH) is a rare malignant disorder of epidermal antigen presenting cells. It is characterized by infiltration of various tissues with dendritic cells (Langerhans cells, LC) that express CD1a or CD207 (langerin), often leading to organ dysfunction. A patient with LCH required liver transplantation (LT) for LCH-associated biliary-tract disease. Cholangiopathy developed after LT. The question arose: In this patient, did LC in damaged liver-allograft biliary epithelium signify acute cellular rejection (ACR) or recurrent LCH?, Methods: We evaluated immunohistochemical identification of LC (CD1a, CD207) in the proposita and in 14 ACR patient samples as distinguishing between ACR and recurrent LCH., Results: Among 15 patient samples, 3 (20%) marked with neither antibody. Among the remaining 12 samples (80%), 4 (26.7%)-including that from the proposita-had cells marking for both antigens within bile-duct epithelium as well as in surrounding portal-tract connective tissue, 2 (13.3%) had cells marking for both antigens in one region or the other, but not in both, and 6 (40%) had cells marking for only one antigen in one region or the other., Conclusions: Immunostaining for CD1a and CD207/langerin in the setting of ACR without suspicion of LCH identifies LC in damaged bile ducts. This biomarker pairing proved not to be LCH-specific. Our findings indicate that the presence of these cells alone is insufficient to identify recurrent LCH in the allograft liver., (© 2024 The Author(s). Pediatric Transplantation published by Wiley Periodicals LLC.)

Malignant melanoma, a rapidly spreading form of skin cancer, is becoming more prevalent worldwide. While surgery is successful in treating early-stage melanoma, patients with advanced disease have only a 20 % chance of surviving beyond five years. Melanomas with mutations in the NRAS gene are characterized for a more aggressive tumor biology, poorer prognosis and shorter survival. Hence, new therapeutic strategies are needed, especially for this specific group of patients. Novel approaches, such as cancer vaccines, offer promising solutions by stimulating the anti-tumor immune response. Nevertheless, their clinical efficacy is still modest and more effective approaches are required. Herein, we propose the systemic administration of the adenovirus-based cancer vaccine complexed in extracellular vesicles (EVs) with the aim of achieving a targeted therapeutic effect. The vaccine was based on previously tested oncolytic adenovirus Ad5/3-D24-ICOSL-CD40L in combination with melanoma-specific antigens targeting NRAS mutations to enhance the anticancer effect. The antineoplastic properties of the oncolytic vaccine were evaluated in xenograft MUG Mel-2 melanoma BALB/c nude mice. Moreover, to mimic the tumor microenvironment, while investigating at the same time immune cell infiltration and drug penetration, we established a 3D co-culture model based on human NRAS mutated MUG Mel-2 spheroids and PBMCs (HLA matched), which displayed a synergistic effect when treated with the cancer vaccine compared to relative controls. Subsequently, we investigated the systemic delivery of the vaccine in EV formulations in a humanized NSG MUG Mel-2 melanoma mouse model. Our study provides a promising strategy for a tumor-targeted vaccine delivery by EVs, resulting in improved anticancer efficacy and increased infiltration of tumor-infiltrating lymphocytes. This study explores the potential of EVs for the selective delivery of cancer vaccines against malignancies, such as NRAS melanoma. Overall, this research could pave the way for applying autologous EVs as a safe and efficacious tool for targeted cancer therapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Author LK is an employee and/or shareholder of Valo Therapeutics. The other authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: A sizeable minority of commercially available blood glucose monitoring (BGM) systems fail to satisfy regulatory accuracy requirements, such as ISO 15197:2013, after approval. This study assessed whether the BGMs tested could consistently meet these ISO requirements by investigating their accuracy in a non-standardized setting., Methods: In this 18-month post-market performance study, using the ISO criteria, healthcare professionals tested the accuracy of four CE-marked BGM systems (Roche Diabetes Care, Mannheim, Germany) on European adults with diabetes mellitus. ISO criteria included 95% of blood glucose (BG) values being within ± 15 mg/dl of a reference measurement for BG < 100 mg/dl or ± 15% for BG ≥ 100 mg/dl and, in the Parkes Consensus Error grid for type 1 diabetes comparing capillary BGM measurements versus reference method, 99% of BG values falling within zone A (no effect on clinical action or outcome) and zone B (altered clinical action with little or no effect on clinical outcome)., Results: BGM readings were obtained from 1650 participants, and the number of readings per BGM system was between 1712 and 2376. The percentage of BGM readings that fell within ISO 15197:2013 limits ranged from 99.4 to 99.9%. For all meter types, 100% of data points fell within zone A or zone B, and most data points for each meter (≥ 99.9%) were in zone A., Conclusion: All four CE-marked BGM models showed results within the accuracy limits defined by ISO 15197 in a non-standardized setting and thus consistently met regulatory accuracy requirements., Competing Interests: Declarations Conflict of interest Julia K. Mader is a member of advisory boards of Abbott Diabetes Care, Becton-Dickinson, Boehringer Ingelheim, Eli Lilly, Embecta, Medtronic, NovoNordisk A/S, Roche Diabetes Care, Sanofi-Aventis, and Viatris. She has received speaker honoraria from A. Menarini Diagnostics, Abbott Diabetes Care, AstraZeneca, Boehringer Ingelheim, Dexcom, Eli Lilly, Medtrust, MSD, NovoNordisk A/S, Roche Diabetes Care, Sanofi, Servier, Viatris, and Ypsomed. Julia K. Mader is a shareholder of decide Clinical Software GmbH and elyte Diagnostics and serves as CMO of elyte Diagnostics. Annette Baumstark is an employee of the Institut für Diabetes-Technologie, Forschungs- und Entwicklungsgesellschaft mbH an der Universität Ulm (IfDT), which carries out clinical studies, for example, with medical devices for diabetes therapy on its own initiative and on behalf of various companies. Johannes Tüting and Günter Sokol have no conflicts of interest to declare. Robbert J. Slingerland is chair of the Clinical Chemistry Department of Isala, which carries out clinical studies, for example, with medical devices for diabetes therapy on its own initiative and on behalf of various companies. Robbert J. Slingerland has received speakers’ honoraria or consulting fees in the last three years from Roche and Menarini. Ruth Schuebel, Yuhong Tong, and Julia Roetschke are employees of Roche. Ethical Approval The study protocol was approved by the appropriate health authorities according to local guidelines and by an Institutional Review Board/Independent Ethics Committee. The Ethics Committees included: Ethikkommission of the State Medical Association of Baden-Wuerttemberg, Stuttgart (AZ MP-2018-10) for the center in Ulm, Germany; and the Ethikkommission of the Medical Association of Lower Saxony, Hanover (AZ Bo/05/2018) for the center in Cloppenburg, Germany. Approval for conducting the study at the centers in Vienna and Graz in Austria was given by the Austrian Agency for Health and Food Safety (AGES). Study approval for the center in Zwolle, The Netherlands, was given by the local authority. The study was conducted in accordance with the Declaration of Helsinki of 1964 and its later amendments. Study participants provided written informed consent., (© 2024. The Author(s).)

Objective: We aimed to evaluate the longer-term safety and efficacy of hybrid closed-loop (CL) therapy in very young children with type 1 diabetes (T1D)., Research Design and Methods: Following a 16-week multinational, randomized crossover trial comparing hybrid CL with sensor-augmented pump (SAP) therapy in 74 very young children aged 1-7 years with T1D, participants were invited to an extension phase using CL for a further 18 months. Outcomes were compared with the primary-phase SAP period and primary-phase CL period., Results: After the primary study phase, 60 participants were eligible to enroll in the extension. Of these, 49 consented (mean ± SD age 6.6 ± 1.5 years) to continue use of CL for 18 months. Percentage time in range (TIR) 3.9-10.0 mmol/L was 8.4 percentage points (95% CI 6.7-10.1; P < 0.001) higher, while HbA1c was 0.4% ([5.0 mmol/mol], 95% CI 0.3-0.6 [3.7-6.2]; P < 0.001) lower during the CL extension phase compared with primary-phase SAP period. At 18 months, mean HbA1c was 6.7 ± 0.5% and TIR was 70 ± 7%, compared with 6.7 ± 0.5% and 71 ± 6% in the primary-phase CL period. Time in hypoglycemia (<3.9 mmol/L) was similar between CL extension phase and both primary-phase SAP (P = 0.31) and CL periods (P = 0.70). There were two severe hypoglycemia events and one other serious adverse event during the extension phase. One unexpected serious adverse device effect occurred., Conclusions: Use of the Cambridge hybrid CL system led to sustained improvements in glycemic control lasting more than 18 months in very young children with T1D., (© 2024 by the American Diabetes Association.)

Background: Despite the emerging interest in phase angle (PhA), a non-invasive marker of cell hydration and nutritional status, no previous study has reported the prospective association between PhA and incident sarcopenia. Therefore, the aim of our study was to evaluate the association of baseline PhA in older subjects without sarcopenia with the development of new sarcopenia as outcome., Methods: Six-hundred ninety-six subjects without sarcopenia aged ≥75 years enrolled in an international multicenter observational study were included. Sarcopenia was assessed according to the revised EWGSOP2 criteria at baseline and in follow-up visits at 12 and 24 months. Muscle strength was assessed through the handgrip strength test using a hydraulic grip strength dynamometer, muscle mass was assessed by bioimpedance analysis (BIA) and appendicular skeletal muscle mass (ASMM) was estimated. Physical performance was assessed by Short Physical Performance Battery (SPPB)., Results: Participants who developed sarcopenia were older, less educated, had higher prevalence of osteoporosis, and lower baseline cognitive function, SPPB, handgrip strength and ASMM than those without sarcopenia. Baseline PhA was significantly lower in subjects developing sarcopenia. Nevertheless, after adjusting for all potential covariates including baseline components of sarcopenia in multiple logistic regression, neither PhA as continuous variable nor different levels of PhA were any more significant predictors of sarcopenia., Conclusions: As an indicator of cells function, PhA could be a potential useful early marker in identifying older people at risk of developing sarcopenia but its practical applicability remains uncertain with the present data., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: The clinical relevance of cardiac troponin (cTn) elevation in takotsubo syndrome (TTS) remains uncertain. The present study sought to investigate the role of cardiac troponin (cTn) elevations in mortality prediction of patients with Takotsubo syndrome (TTS)., Methods: Patients enrolled in the International Takotsubo (InterTAK) Registry from January 2011 to February 2020 with available data on peak cTn levels were included in the analysis. Peak cTn levels during the index hospitalization were used to define clinically relevant myocardial injury. The threshold at which clinically relevant myocardial injury drives mortality at 1 year was identified using restricted cubic spline analysis., Results: Out of 2'938 patients, 222 (7.6%) patients died during 1-year follow-up. A more than 28.8-fold increase of cTn above the upper reference limit was identified as threshold for clinically relevant myocardial injury. The presence of clinically relevant myocardial injury was significantly associated with an increased risk of mortality at 5 years (adjusted HR 1.58, 95% CI 1.18-2.12, p =.002). Clinically relevant myocardial injury was related to an increased 5-year mortality risk in patients with apical TTS (adjusted HR 1.57, 95% CI 1.21-2.03, p =.001), in presence of physical stressors (adjusted HR 1.60, 95% CI 1.22-2.11, p =.001), and in absence of emotional stressors (adjusted HR 1.49, 95% CI, 1.17-1.89, p =.001)., Conclusion: This study for the first time determined a troponin threshold for the identification of TTS patients at excess risk of mortality. These findings advance risk stratification in TTS and assist in identifying patients in need for close monitoring and follow-up., (© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

The aging process is a complex phenomenon characterised by a gradual decline in physiological functions and an increased susceptibility to age-related diseases. An important factor in aging is mitochondrial dysfunction, which leads to an accumulation of cellular damage over time. Mitochondrial Sirtuin 3 (Sirt3), an important regulator of energy metabolism, plays a central role in maintaining mitochondrial function. Loss of Sirt3 can lead to reduced energy levels and an impaired ability to repair cellular damage, a hallmark of the aging process. In this study we investigated the impact of Sirt3 loss on mitochondrial function, metabolic responses and cellular aging processes in male and female mouse embryonic fibroblasts (MEF) exposed to etoposide-induced DNA damage, which is commonly associated with cellular dysfunction and senescence. We found that Sirt3 contributes to the sex-specific metabolic response to etoposide treatment. While male MEF exhibited minimal damage suggesting potential prior adaptation to stress due to Sirt3 loss, female MEF lacking Sirt3 experienced higher vulnerability to genotoxic stress, implying a pivotal role of Sirt3 in their resistance to such challenges. These findings offer potential insights into therapeutic strategies targeting Sirt3- and sex-specific signalling pathways in diseases associated with DNA damage that play a critical role in the aging process., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Current guidelines for pain treatment recommend a personalized, multimodal and interdisciplinary approach as well as the use of a combination of drug and non-drug therapies. Risk factors for chronification should already be reduced in patients with acute pain, e.g., after surgery or trauma. Auricular vagus nerve stimulation (aVNS) could be an effective non-drug therapy in the multimodal treatment of chronic and acute pain. The aim of this systematic review and meta-analysis is to evaluate the clinical efficacy and safety of aVNS in treating chronic and acute pain conditions., Methods: A systematic literature search was performed regarding the application of auricular electrical stimulation in chronic and acute pain. Studies were classified according to their level of evidence (Jadad scale), scientific validity and risk of bias (RoB 2 tool) and analyzed regarding indication, method, stimulation parameters, duration of treatment and efficacy and safety. A meta-analysis on (randomized) controlled trials (using different comparators) was performed for chronic and acute pain conditions, respectively, including subgroup analysis for percutaneous (pVNS-needle electrodes) and transcutaneous (tVNS-surface electrodes) aVNS. The visual analog pain scale (VAS) was defined as primary efficacy endpoint., Results: A total of n = 1496 patients were treated with aVNS in 23 identified and analyzed studies in chronic pain, 12 studies in acute postoperative pain and 7 studies in experimental acute pain. Of these, seven studies for chronic pain and six studies for acute postoperative pain were included in the meta-analysis. In chronic pain conditions, including back pain, migraine and abdominal pain, a statistically significant reduction in VAS pain intensity for active compared to sham aVNS or control treatment with an effect size Hedges' g/mean difference of - 1.95 (95% confidence interval [CI]: - 3.94 to 0.04, p = 0.008) could be shown and a more favorable effect in pVNS compared to tVNS (- 5.40 [- 8.94; - 1.85] vs. - 1.00 [- 1.55; - 0.44]; p = 0.015). In acute pain conditions, single studies showed significant improvements with aVNS, e.g., in kidney donor surgery or tonsillectomy but, overall, a non-statistically significant reduction in VAS pain intensity for active compared to sham aVNS or control with - 0.70 [- 2.34; 0.93] (p = 0.15) could be observed in the meta-analysis. In acute pain results vary greatly between studies depending especially on co-medication and timepoints of assessment after surgery. A significant reduction in analgesics or opiate intake was documented in most studies evaluating this effect in chronic and acute pain. In 3 of the 12 randomized controlled trials in patients with chronic pain, a sustainable pain reduction over a period of up to 12 months was shown. Overall, aVNS was very well tolerated., Conclusion: This systematic review and meta-analysis indicate that aVNS can be an effective and safe non-drug treatment in patients with specific chronic and acute postoperative pain conditions. Further research is needed to identify the influence of simulation parameters and find optimal and standardized treatment protocols while considering quality-of-life outcome parameters and prolonged follow-up periods. A more standardized approach and harmonization in study designs would improve comparability and robustness of outcomes., (© 2024. The Author(s).)

Introduction: Severe burn trauma damages resting and exercise cardiac function that may affect long term cardiovascular health. The implementation of rehabilitation exercise training (RET) soon after hospital discharge improves cardiorespiratory fitness; however, it does not fully restore aerobic capacity and presents large inter-individual variability. We tested the hypothesis that the inter-individual variability of aerobic capacity for responders (R) compared to nonresponders (NR) would differ for exercise frequency and intensity., Methods: Thirty-three children (11 female, [mean±SD] 12 ± 3 years, 145 ± 18 cm, 40 ± 11 kg, 49 ± 31 BMI percentile) with severe burns (49 ± 15 % total body surface area burned, with 35 ± 22 % third-degree burns) completed a 6-week RET program. Cardiorespiratory fitness (peak VO 2 ) was measured before and after RET. Frequency (session days/week), intensity (% peak heart rate), time (min/session), and volume (min/week) were compared between responders and non-responders. Significance was set at p < 0.05., Results: Sixty-four percent of the study population improved peak VO2 after RET whereas 36 % showed no improvements. Using a 2-way factorial ANOVA (group [G] × week [WK]), we found that exercise frequency and session time were similar and increased slightly over 6 weeks between R and NR (main effect for WK; P < 0.002). Exercise volume was significantly lower on week 2 for NR compared to R (G × WK interaction, P < 0.028). Exercise intensity over 6-weeks was significantly lower in the NR compared to the R group (G × WK interaction, P < 0.022)., Conclusions: Exercise intensity and volume may be important contributors for improving the interindividual response to exercise training for peak VO 2 . These data suggest that the appropriate dose-response requirement for exercise intensity may be > 80 % peak heart rate and exercise volume of > 150 min per week. Further understanding of the exercise prescription will provide insights important for cardiovascular rehabilitation in children with severe burns., Subject Code: Inter-individual Variability, Exercise, Pediatrics, Exercise Training., Competing Interests: Declaration of Competing Interest All authors have read and agree to the publication of the manuscript, and that the manuscript has not been submitted elsewhere. The authors have no conflict of interest., (Copyright © 2024 International Society of Burns Injuries. All rights reserved.)

Purpose: To report a rare case of isolated lumbar vertebral body infarction following lumbar artery embolization for suspected retroperitoneal haemorrhage., Methods: We present the case of a 75-year-old male who underwent lumbar artery embolization due to a suspected retroperitoneal haemorrhage post-surgery. Magnetic resonance imaging (MRI) was performed to monitor post-embolization severe lumbar pain., Results: Initial MRI two days post-embolization showed no osseous signal changes or epidural abscess. A subsequent MRI 26 days post-embolization was performed because of increasing lumbar back pain and it revealed a new bone infarction at the L3 vertebral body. CT showed embolization deposits within the vertebral body, not present before the procedure., Conclusion: This unique case underscores the importance of considering vertebral body infarction as a potential complication following lumbar artery embolization. MRI was critical in early detection of the bone infarction, while CT confirmed the presence of embolization material. Awareness of this rare complication is crucial for prompt diagnosis and management., Competing Interests: Statements and Declarations. The authors did not receive support from any organization for the submitted work. The authors have no relevant financial or non-financial interests to disclose. All authors attest that they meet the current International Committee of Medical Journals Editors (ICMJE) criteria for authorship. The authors declare that the work described has been performed in accordance with the Declaration of Helsinki of the World Medical Association. The local ethics committee of the Medical University Graz approved this case report (EK Nr. 1022/2024). A written informed consent was obtained from the patient to participate in this study and publication of its results. The authors declare that this report does not contain any personal information that could lead to the identification of the patient. Disclosure: During the preparation of this work, the authors used ChatGPT4 (OpenAI) in order to refine language. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Circulating tumor cells (CTCs) are an established prognostic marker in metastatic prostate cancer (PrC) but have received little attention in localized high-risk disease. Peripheral blood was obtained from patients with early intermediate and high-risk PrC (n = 15) at baseline, after radiotherapy, and during follow-up, as well as from metastatic PrC patients (n = 23). CTCs were enriched using the microfluidic Parsortix ® technology. CTC-related marker were quantified with qPCR and RNA in-situ hybridization (ISH). Positivity and associations to clinical parameters were assessed using McNemar test, Fisher Exact test or log-rank test. The overall positivity was high in both cohorts (87.0% metastatic vs. 66.7% early at baseline). A high concordance of qPCR and RNA ISH was achieved. In metastatic PrC, PSA and PSMA were prognostic for shorter overall survival. In early PrC patients, an increase of positive transcripts per blood sample was observed from before to after radiation therapy, while a decrease of positive markers was observed during follow-up. CTC analysis using the investigated qPCR marker panel serves as tool for achieving high detection rates of PrC patient samples even in localized disease. RNA ISH offers the advantage of confirming these markers at the single cell level. Employing the clinically relevant marker PSMA, our CTC approach can be used for diagnostic purposes to screen patients profiting from PSMA-directed PET-CT or PSMA-targeted therapy., Competing Interests: Declarations. Competing interest: The authors have no competing interest to declare., (© 2024. The Author(s).)

The ESPA Pain Management Ladder Initiative is a clinical practice advisory based upon expert consensus supported by the current literature to help ensure a basic standard of perioperative pain management for all children. In 2018 the perioperative pain management of six common pediatric surgical procedures was summarised. The current Pain Management Ladder recommendations focus on five more complex pediatric surgical procedures and suggest basic, intermediate, and advanced pain management methods. The aim of this paper is to encourage best possible pain management practice and to support institutions to create their own pain management concepts according to their financial and human resources due to the diversity of clinical settings in Europe. Furthermore, the authors underline that these recommendations are intended for inpatients only., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is considered multifactorial with a number of predisposing gene polymorphisms known., Methods: The occurrence of MASLD in 7 and 10 year old siblings, one without classical risk factors and one with type 2 diabetes suggested a monogenic etiology and prompted next-generation sequencing. Exome sequencing was performed in the proband, both parents and both siblings. The impact of a likely disease-causing DNA variant was assessed on the transcript and protein level., Results: Two siblings have hepatomegaly, elevated serum transaminase activity, and steatosis and harbor a homozygous DECR1 splice-site variant, c.330+3A>T. The variant caused DECR1 transcript decay. Immunostaining demonstrated lack of DECR1 in patient liver., Conclusions: These patients may represent the first individuals with DECR1 deficiency, then defining within MASLD an autosomal-recessive entity, well corresponding to the reported steatotic liver disease in Decr1 knockout mice. DECR1 may need to be considered in the genetic work-up of MASLD., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: All methods were performed in accordance with the relevant guidelines and regulations. Human subjects: Genetic studies were approved by the Institutional Review Boards of the Medical University of Innsbruck (No. UN4501), Innsbruck, Austria. The parents provided written informed consent for their participation and that of their children in the study, with clinical data and specimen collection, genetic analysis, and publication of relevant findings., (© 2024. The Author(s).)

Anorectal malformations (ARM) encompass a spectrum of rare congenital defects of the rectum and anus, requiring specialized reconstructive surgery. To improve epidemiological and clinical research in rare diseases such as ARM, collaborative efforts and patient registries are key. This retrospective study pools clinical data over a 30-year period from two ARM patient registries (The Royal Children's Hospital (RCH) in Melbourne, Australia, and the ARM-Network Consortium in Europe). It aims to draw comparisons on demographics, management, and outcomes between ARM patients in Australia and Europe. A total of 2947 ARM patients were included in the analyses. The RCH cohort had more complex ARM types (including rectal atresia and recto-vaginal fistula) and more associated anomalies, specifically skeletal, cardiac, and/or trachea-esophageal, than ARM-Net patients. Other patient characteristics were similar. Treatments clearly differed between the groups. European surgeons favoured the PSARP approach for both less complex and more complex ARM types, where Australian surgeons opted more often for cutback surgery in less complex, and laparoscopic assistance in more complex types. Complications were differently distributed, with less complications after LAARP and more after PSARP at RCH, compared to ARM-Net. While RCH patients more often required a redo, ARM-Net patients more commonly underwent anal dilatations. Anorectal malformation patients in Australia and Europe had minor differences in disease characteristics, and both operative and medical approaches differed. Joint efforts such as the present study emphasize the importance of collaboration to elucidate areas of improvement where surgeons may learn from each other across the world, ultimately improving patient outcomes. TYPE OF STUDY: Original Research. LEVEL OF EVIDENCE: III., Competing Interests: Conflict of interest None to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Metastatic renal cell carcinoma (mRCC) carrying sarcomatoid features (sRCC) has aggressive biology and poor prognosis. First-line immunotherapy (IO)-based combinations have improved the outcome of clear cell RCC patients, including that of sRCC. Real-world data confirming the adequate first-line management of sRCC is largely lacking. We investigated the clinical features and the outcome of sRCC patients treated with IO-based combinations within the ARON-1 study population (NCT05287464). The primary objective was to define the incidence and baseline clinical characteristics of sRCC compared with non-sRCC patients. The secondary objective was to describe the outcome of sRCC patients based on type of first-line treatment (IO + IO vs. IO + tyrosin kinase inhibitor [TKI]). We identified 1362 mRCC patients with IMDC intermediate or poor risk, 226 sRCC and 1136 non-sRCC. These two subgroups did not differ in terms of baseline characteristics. The median overall survival (OS) was 26.8 months (95%CI 21.6-44.2) in sRCC and 35.3 months (95%CI 30.2-40.4) in non-sRCC patients (p = .013). The median progression-free survival (PFS) was longer in non-sRCC patients compared to sRCC (14.5 vs. 12.3 months, p = .064). In patients treated with first-line IO + TKI the median OS was 34.4 months compared to 26.4 months of those who received IO + IO (p = .729). The median PFS was 12.4 months with IO + TKI and 12.3 months with IO + IO (p = .606). In conclusion, we confirm that sRCC are aggressive tumors with poor prognosis. IO-based combinations improve survival outcomes of sRCC patients, regardless from the type of strategy (IO + IO versus IO + TKI) adopted., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: There is a little evidence regarding long-term safety and efficacy for atrial shunt devices in heart failure (HF)., Methods: The REDUCE LAP-HF I (n = 44) and II (n = 621) trials (RCT-I and -II) were multicenter, randomized, sham-controlled trials of patients with HF and ejection fraction >40%. Outcome data were analyzed from RCT-I, a mechanistic trial with 5-year follow-up, and RCT-II, a pivotal trial identifying a responder group (n = 313) defined by exercise PVR <1.74 WU and no cardiac rhythm management device with 3-year follow-up., Results: At 5 years in RCT I, there were no differences in cardiovascular (CV) mortality, HF events, embolic stroke, or new-onset atrial fibrillation between groups. After 3 years in RCT II, there was no difference in the primary outcome (hierarchical composite of CV mortality, stroke, HF events, and KCCQ) between shunt and sham in the overall trial. Compared to sham, those with responder characteristics in RCT-II had a better outcome with shunt (win ratio 1.6 [95% CI 1.2-2.2], P = .006; 44% reduction in HF events [shunt 9 vs. control 16 per 100 patient-years], P = .005; and greater improvement in KCCQ overall summary score [+17.9 ± 20.0 vs. +7.6 ± 20.4], P < .001), while nonresponders had significantly more HF events. Shunt treatment at 3 years was associated with a higher rate of ischemic stroke (3.2% vs. 0%, 95% CI 2%-6.1%, P = .032) and lower incidence of worsening kidney dysfunction (10.7% vs. 19.3%, P = .041)., Conclusions: With up to 5 years of follow up, adverse events were low in patients receiving atrial shunts. In the responder group, atrial shunt treatment was associated with a significantly lower HF event rate and improved KCCQ compared to sham through 3 years of follow-up., Gov Registration: NCT02600234, NCT03088033., Competing Interests: Conflict of Interest None., (Published by Elsevier Inc.)

Acute nutrient deprivation (fasting) causes an immediate increase in spermidine biosynthesis in yeast, flies, mice and humans, as corroborated in four independent clinical studies. This fasting-induced surge in spermidine constitutes the critical first step of a phylogenetically conserved biochemical cascade that leads to spermidine-dependent hypusination of EIF5A (eukaryotic translation initiation factor 5A), which favors the translation of the pro-macroautophagic/autophagic TFEB (transcription factor EB), and hence an increase in autophagic flux. We observed that genetic or pharmacological inhibition of the spermidine increase by inhibition of ODC1 (ornithine decarboxylase 1) prevents the pro-autophagic and antiaging effects of fasting in yeast, nematodes, flies and mice. Moreover, knockout or knockdown of the enzymes required for EIF5A hypusination abolish fasting-mediated autophagy enhancement and longevity extension in these organisms. Of note, autophagy and longevity induced by rapamycin obey the same rule, meaning that they are tied to an increase in spermidine synthesis. These findings indicate that spermidine is not only a "caloric restriction mimetic" in the sense that its supplementation mimics the beneficial effects of nutrient deprivation on organismal health but that it is also an obligatory downstream effector of the antiaging effects of fasting and rapamycin. Abbreviation : EIF5A: eukaryotic translation initiation factor 5A; IGF1: insulin like growth factor 1; MTOR: mechanistic target of rapamycin kinase; ODC1: ornithine decarboxylase 1; TFEB: transcription factor EB.

In this study, the European Academy of Dermatology and Venereology (EADV) Task Forces on Quality of Life and Patient-Oriented Outcomes and Urticaria and Angioedema has examined the Health-Related Quality of Life (HRQoL) measurement in the treatment of urticaria. The Dermatology Life Quality Index was the most frequently used HRQoL instrument in clinical trials on urticaria. Many reports of clinical trials of urticaria gave no exact numeric results related to HRQoL changes, making clear conclusions and comparisons with other studies impossible. The interpretation of HRQoL impairment data is more difficult when assessed by instruments without severity stratification systems. The minimal clinically significant difference (MCID) is a more clinically oriented and relevant parameter than depending on statistically significant changes in HRQoL scores. Therefore, using HRQoL instruments with established MCID data in clinical trials and clinical practice is preferred., (© 2024 the International Society of Dermatology.)

Background: The adverse effects of high air pollution levels on childhood lung function are well-known. Limited evidence exists on the effects of moderate exposure levels during early life on childhood lung function. We investigated the association of exposure to moderate air pollution during pregnancy, infancy, and preschool time with lung function at school age in a Swiss population-based study., Methods: Fine-scale spatiotemporal model estimates of particulate matter with a diameter <2.5 µm (PM 2.5 ) and nitrogen dioxide (NO 2 ) were linked with residential address histories. We compared air pollution exposures within different time windows (whole pregnancy, first, second, and third trimester of pregnancy, first year of life, preschool age) with forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC) measured cross-sectionally using linear regression models adjusted for potential confounders., Results: We included 2182 children, ages 6-17 years. Prenatal air pollution exposure was associated with reduced lung function at school age. In children aged 12 years, per 10 µg·m -3 increase in PM 2.5 during pregnancy, FEV 1 was 55 mL lower (95% CI -84 to -25 mL) and FVC 62 mL lower (95% CI -96 to -28 mL). Associations were age-dependent since they were stronger in younger and weaker in older children. PM 2.5 exposure after birth was not associated with reduced lung function. There was no association between NO 2 exposure and lung function., Conclusion: In utero lung development is most sensitive to air pollution exposure, since even modest PM 2.5 exposure during the prenatal time was associated with reduced lung function, most prominent in younger children., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Cerebrospinal fluid (CSF) leaks originating from defects within the anterior and middle cranial fossa typically manifest as unilateral clear watery rhinorrhea. Continuous CSF leakage mandates surgical repair due to the risk of meningitis and brain abscess. It can be categorized based on its underlying etiology into traumatic, iatrogenic and non-traumatic CSF leaks.

Purpose: Patients with unilateral treatment-naïve exudative neovascular age-related macular degeneration (nAMD) were examined for the presence of nonexudative macular neovascularization (neMNV) in their fellow eye using a multimodal imaging approach. This is intended to determine the sensitivity of individual imaging methods, namely, indocyanine green angiography (ICGA) and optical coherence tomography angiography (OCTA)., Methods: In this retrospective cross-sectional study, ICGA images of the nonexudative eye were analyzed for the presence of plaques. SS-OCTA outer retinal segmentations were evaluated for neovascular flow in en-face scans and/or color-coded flow in B-scans. The findings were matched with a double-layer sign (DLS) or pigment epithelium detachment (PED) on conventional OCT., Results: In total, neMNV was diagnosed in the fellow eye of 40 of 241 patients (17%) using a multimodal imaging approach employing both ICGA and SS-OCTA. 25 eyes (10%) showed neMNV in both modalities, while 7 (3%) were only detected by ICGA and 8 (3%) by OCTA alone. The sensitivities of ICGA therefore were 80% (32/40) and 83% (33/40) for OCTA. Of the 40 eyes with neMNV, OCT revealed DLS in 25/40 (63%) and PED in 17/40 (43%) of the cases., Conclusion: None of the modalities alone could detect all neMNV in the partner eye of Caucasians with unilateral treatment-naïve exudative nAMD. ICGA and OCTA showed comparable sensitivity. The combination of ICGA, OCTA, and OCT provides the most comprehensive screening for this AMD subtype., Competing Interests: Declarations. Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the Viennese ethics committee and with the 1964 Helsinki declaration and its later amendments. Informed consent: This study was approved by the Viennese ethics committee, City of Vienna, approval number EK-17-083-0517. Due to its retrospective nature, the study has been granted an exemption from requiring written informed consent by the Viennese ethics committee. Conflict of interest: All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: To establish reference ranges of peripheral-muscle regional oxygen saturation (prSO 2 ) and peripheral fractional tissue oxygen extraction (pFTOE) during the first 15 min after birth in stable term neonates., Methods: Secondary outcome parameters of prospective observational studies in healthy term neonates delivered by Caesarean section were analysed. prSO 2 was measured on the right forearm using the INVOS 5100C monitor. pFTOE was calculated out of prSO 2 and arterial oxygen saturation (SpO 2 ). Centile charts (10th-90th) of prSO 2 and pFTOE were defined during the first 15 min after birth., Results: Three-hundred-five term neonates with a mean gestational age and birth weight of 39.0 ± 0.9 weeks and 3321 ± 454 g, respectively, were included. The 50th centiles of prSO 2 were 39% (minute two), 52% (minute five), 71% (minute 10), and 73% (minute 15). The 50th centiles of pFTOE were 0.529 (minute two), 0.378 (minute five), 0.237 (minute 10), and 0.231 (minute 15)., Conclusion: Reference ranges of prSO 2 and pFTOE were established for term neonates delivered by Caesarean section during the immediate transition after birth. These reference ranges increase knowledge of physiological processes taking place immediately after birth and are necessary for possible future clinical applications., (© 2024 The Author(s). Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Introduction: A decade ago, a comprehensive study was conducted to investigate the reasons for revision surgeries and their respective frequencies in cases of total hip arthroplasty (THA) and total knee arthroplasty (TKA) based on a complication-based analysis of joint replacement registries. The aim of the present study was to determine whether the causes and risks of their occurrence have changed over the last ten years and to present an updated analysis., Materials and Methods: A systematic review of national arthroplasty registries from seven countries examined the causes and rates of revisions of THA and TKA. The study focused on a descriptive analysis that provided an updated overview without statistical significance values., Results: The most common causes for revisions of THA were aseptic loosening (35.1%), deep infection (18.2%), dislocation/instability (15.9%), and periprosthetic fractures (11.4%). The most common causes for revisions of TKA were deep infection (21.6%), aseptic loosening (18.3%), instability (14.1%), and pain (10.9%)., Conclusion: The findings of this study revealed significant shifts in the underlying causes of revision surgeries in the last decade. Notably, septic complications emerged as the predominant reason for revision of primary TKA, while they also gained prominence as a cause of failure of THA. Although aseptic loosening remains the primary cause for re-operation of THA, the relative risk has decreased for both THA and TKA., Competing Interests: Declarations. Conflict of interest: Author A.L and P.S have received institutional grants from Medtronic, Alphamed, Johnson & Johnson not directly related to this study. The other authors declare that they have no conflict of interest., (© 2024. The Author(s).)

Objective Real-life management of patients with hypertension and chronic kidney disease (CKD) among European Society of Hypertension Excellence Centres (ESH-ECs) is unclear : we aimed to investigate it. Methods A survey was conducted in 2023. The questionnaire contained 64 questions asking ESH-ECs representatives to estimate how patients with CKD are managed. Results Overall, 88 ESH-ECS representatives from 27 countries participated. According to the responders, renin-angiotensin system (RAS) blockers, calcium-channel blockers and thiazides were often added when these medications were lacking in CKD patients, but physicians were more prone to initiate RAS blockers (90% [interquartile range: 70-95%]) than MRA (20% [10-30%]), SGLT2i (30% [20-50%]) or (GLP1-RA (10% [5-15%]). Despite treatment optimisation, 30% of responders indicated that hypertension remained uncontrolled (30% (15-40%) vs 18% [10%-25%]) in CKD and CKD patients, respectively). Hyperkalemia was the most frequent barrier to initiate RAS blockers, and dosage reduction was considered in 45% of responders when kalaemia was 5.5-5.9 mmol/L. Conclusions RAS blockers are initiated in most ESH-ECS in CKD patients, but MRA and SGLT2i initiations are less frequent. Hyperkalemia was the main barrier for initiation or adequate dosing of RAS blockade, and RAS blockers' dosage reduction was the usual management.