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During the last few decades, important efforts and developments in the computational modeling of geo-materials have contributed to an increase in the accuracy of the predictions of the dynamic responses of soil systems. Due to their catastrophic consequences, special emphasis has been placed on liquefaction-induced ground failures. However, the numerical tools for liquefaction modeling need to be continually assessed and validated in order to enhance their reliability and enable them to be included in design practices.Within that context, the main objective of this paper was to present a complete validation exercise that explores the capabilities of the numerical predictions to simulate the lateral spreading phenomenon in clean sands under a diverse range of densities and input motions. The validation exercise used the “Strain Space Multiple Mechanism Model” to simulate the lateral spreading phenomenon (although the methodology presented here might be applicable for the validation of other numerical tools as well), and was based on multiple, cross-checked, and high-quality physical models (centrifuge models) and element tests (hollow cylinder cyclic shear tests).Special focus was placed on the quantification of the median response and the associated variability of both physical and numerical models, including an analysis of the importance of the proper selection of validation metrics.The comparison showed that the numerical model is able to predict the displacements for the median trend and the 95% probability confidence bounds for PGA

Background: Women are underrepresented in major atrial fibrillation (AF) trials. In addition, data regarding clinical profile and outcome in young AF patients is limited. Therefore we aimed to investigate the clinical profile, AF progression rate and cardiovascular outcome between sexes in patients with young-onset AF. Methods: A total of 497 patients with AF-onset

Background: FGFR2/3, MTAP and ERBB2 genomic alterations have treatment targets in advanced urothelial carcinoma (aUC). These alterations may affect tumor microenvironment and outcomes with immune checkpoint inhibitors (ICIs) in aUC., Patients and Methods: We identified patients with available genomic data in our multi-institution cohort of patients with aUC treated with ICI. Outcomes (observed response rate [ORR], progression-free and overall survival [PFS, OS]) with ICI were compared between patients with and without FGFR 2/3, MTAP, ERBB2 alterations. We compared ORR using logistic regression and PFS/OS using Cox proportional hazards., Results: Out of 1,514 patients, 276 (18%), 174 (11%) and 208 (14%) patients had known FGFR2/3, MTAP and ERBB2 alteration status, respectively. and were treated with ICI in 1L or 2 + L. In patients with (vs. without) FGFR2/3 alteration, ORR with ICI was 21% vs. 32% (OR 0.54; [95%CI 0.32-0.91]), PFS was significantly shorter in patients with FGFR2/3 alterations (HR = 1.36 [95%CI 1.03-1.80]; P=0.03); OS was not significantly different (HR = 1.22 [95%CI 0.86-1.47]). In patients with (vs. without) MTAP alteration, ORR with ICI was 25% versus 40% (OR 0.52 [95%CI 0.20-1.38]); PFS and OS were nonsignificantly different. In patients with (vs. without) ERBB2 alteration, ORR with ICI was similar (37% vs. 35%; OR 1.06; 95%CI 0.57-1.97); PFS and OS were significantly longer in patients with ERBB2 alteration [HR 0.63 (95%CI 0.41-0.95); P=0.03; HR 0.66, [95% CI 0.44-0.97]), respectively., Conclusion: Our results support further evaluation of FGFR2/3, MTAP and ERBB2 alterations as putative biomarkers in patients with aUC treated with ICI., Competing Interests: Disclosure Rafee Talukder, Dimitra Rafailia Bakaloudi, Dimitrios Makrakis, Leonidas N. Diamantopoulos, Thomas Enright, Jacob Leary, Ruben Raychaudhuri, Nishita Tripathi, Tanya Jindal, Charles B. Nguyen, Roubini Zakopoulou, Aristotelis Bamias, David Marmorejo, David J Pinato, James Korolewicz,Lucia Alonso Buznego, Clara Castro Carballeira, Tyler F. Stewart, Pedro Barata, Vadim S. Koshkin: No conflicts to disclosure. Neeraj Agarwal (lifetime disclosures): No personal COIs since April 15, 2021. Consultancy to Astellas, Astra Zeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics. Research funding to Neeraj Agarwal's institution: Arnivas, Astellas, Astra Zeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Crispr, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Glaxo Smith Kline, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon. Jason R. Brown: Received funding from EMD–Serono for a Speaker's Bureau. Yousef Zakharia: Advisory Board: Bristol Myers Squibb, Amgen, Roche Diagnostics, Novartis, Janssen, Eisai, Exelixis, Castle Bioscience, Genzyme Corporation, Astrazeneca, Array, Bayer, Pfizer, Clovis, EMD serono, Myovant. Grant/research support from: Institution clinical trial support from NewLink Genetics, Pfizer, Exelixis, Eisai. DSMC: Janssen Research and Development.Consultant honorarium: Pfizer, Novartis. Alexandra Drakaki has served as consultant for Bristol–Myers Squibb, AstraZeneca, RADMETRIX, Seattle Genetics, Janssen, PACT Pharma, Merck, Roche/Genentech, Exelixis, Dyania Health, has received research funding from Kite/Gilead, AstraZeneca, Genentech/Roche, BMS, Merck Sharp & Dohme, Jounce Therapeutics, Infinity Pharmaceuticals, Seattle Genetics/Astellas, and has received travel expenses from Lilly, AstraZeneca and Seattle Genetics. Ignacio Duran: Research Grant to institution: Roche, AstraZeneca, Honoraria: Bristol Myers Squibb, MSD, Ipsen, Roche–Genentech, Janssen, Astellas Pharma, EUSA Pharma, Bayer, Novartis, Gilead, Bayer. Support for attending meetings and/or travel: Merck–Pfizer, Ipsen, Jansen, Bayer, AstraZeneca. Advisory board: Bristol Myers Squibb, MSD, Ipsen, Roche–Genentech, Astellas Pharma, EUSA Pharma, Bayer, Novartis, Eisai, Debio Pharma, Pharmacyclycs, Gilead. Rafael Morales–Barrera has served as consultant/advisor for Sanofi, AstraZeneca, Astellas Pharma and MSD, has been in the speaker's Bureau for Astellas Pharma, Merck/Pfizer and MSD Oncology, and has received travel accommodations from Sanofi, Pfizer, MSD, Astellas Pharma, Astra Zeneca, Bayer, Roche/Genentech. Macarena Rey–Cárdenas: Pfizer, Bayer. Pfizer; Pierre Fabre; Ipsen; BMS; AstraZeneca; MSD; Roche; Kyowa Kirin; Accord. Daniel Castellano: Consulting or Advisory Role: Janseen Oncology, Roche/Genentech, Astellas Pharma, AstraZeneca, Pfizer, Novartis, Ipsen, Bristol–Myers Squibb, MSD Oncology, Bayer, Lilly, Sanofi, Pierre Fabre, Bpehringer Ingelheim. Research funding: Janseen Oncology. Travel, Accomondations, Expenses: Pfizer, Roche, Bristol–Myers Squibb, AstraZeneca Spain. Ajjai Alva: Dr. Ajjai Alva serves as a consultant for Merck, AstraZeneca, Bristol–Myers Squibb, and Pfizer/EMD Serono. Dr. Ajjai Alva receives research funding through the University of Michigan from Merck, Genentech, Prometheus Laboratories, Mirati Therapeutics, Roche, Bayer, Progenics, Astellas Pharma, Arcus Biosciences, AstraZeneca, Bristol–Myers Squibb, and Clovis Oncology. Rana R. McKay: Consulting/Advisory Board – Aveo, AstraZeneca, Bayer, Bristol Myers Squib, Calithera, Caris, Denderon, Exelixis, Esiai, Janssen, Lilly, Merck, Myovant, Novartis, Pfizer, Sanofi, SeaGen, Sorrento Therapeutics, Telix, Tempus. Institutional Research Funding – Bayer, Tempus, AstraZeneca, Oncternal, Exelixis, BMS. Tyler Stewart: Advisory Board/Consulting- Seagen/Astellas, AstraZeneca and received research support from GRAIL. Shilpa Gupta has received personal fees from Bristol Myers Squibb, Merck, Janssen, Seattle Genetics, EMD Sorono and Pfizer, and has received grants from Astellas, BMS and Bristol Myers Squibb. Evan Yu: Consulting fees from Aadi Bioscience, Advanced Accelerator Applications, Bayer, Janssen, Merck, Oncternal. Research funding to institution from Bayer, Blue Earth, Daiichi–Sankyo, Dendreon, Lantheus, Merck, Seagen, Surface, Taiho, Tyra Ali Raza Khaki has received institutional research funding from 23andMe, Janssen, and Pfizer. Petros Grivas: consulting for Aadi Bioscience, Abbvie, Asieris Pharmaceuticals, Astellas, AstraZeneca, Bicycle Therapeutics, Bristol Myers Squibb, CG Oncology, Daiichi Sankyo, EMD Serono, Fresenius Kabi, Gilead, G1 Therapeutics, ImmunityBio, Janssen, MSD, Pfizer, Replimune, Roche, Strata Oncology; research funding: Acrivon Therapeutics, ALX Oncology, Bristol Myers Squibb, EMD Serono, Genentech, Gilead, G1 Therapeutics, Mirati Therapeutics, MSD, QED Therapeutics., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To assess the association of being overweight or obese with Nonmuscle invasive bladder cancer (NMIBC) recurrence, stage progression, and grade progression., Methods: Patients with NMIBC were included and categorized into 3 groups based on their body mass index (BMI): normal weight, overweight, and obese. Recurrence was defined as any histologically proven bladder cancer on subsequent transurethral resection of bladder tumor (TURBT). Progression was defined as upgrading from low to high grade, upstaging to pT1 from pTa, or to muscle-invasion from pT1 disease., Results: A total of 457 patients were analyzed, 135 (29.5%) had normal weight, 192 (42.6%) were overweight, and 130 (28.4%) were obese, with a median BMI of 27.1 (24.4-30.7) Kg/m2. The study found no significant difference in the time to recurrence, stage progression, and grade progression within the BMI categories (P < .05). Additionally, no increased risk was observed in BMI categories (Obesity recurrence HR: 1.067, CI 95%: 0.783-1.453; Obesity stage progression HR: 1.315, 95% CI: 0.635-2.724; Obesity grade progression HR: 0.586, 95% CI: 0.195-1.760)., Conclusions: In our cohort, body weight category showed no association with NMIBC recurrence, stage progression, or grade progression. These findings highlight the need to identify other potential risk factors that could improve NMIBC risk stratification. Further studies are warranted to validate our results and explore additional predictors of NMIBC outcomes., Competing Interests: Disclosure All authors have no conflict of interests to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: von Willebrand disease (VWD) is the most common inherited bleeding disorder caused by quantitative or qualitative defects in von Willebrand factor (VWF). The p.M771V VWF variant leads to a severe bleeding phenotype in homozygous patients. However, the exact molecular mechanism remains unclear, which prevents personalized treatment of those VWD patients., Objectives: This study aimed to characterize the underlying molecular mechanisms of the p.M771V variant in multiple representative ex vivo cell models., Methods: Endothelial colony-forming cells (ECFCs) were isolated from venous blood of VWD patients from the Willebrand in the Netherlands cohort carrying homozygous and heterozygous p.M771V VWF variants. The p.M771V variant was also introduced in cord blood-derived ECFCs (CB-ECFCs) through adenine base editing and was overexpressed in HEK293 cells. Biosynthesis, storage, and secretion of VWF was studied using biochemical methods and confocal microscopy., Results: Two unrelated homozygous p.M771V patients presented with very low VWF activity and antigen levels in plasma. Patient ECFCs showed impaired uncleaved VWF processing into mature VWF, with secreted VWF being severely reduced when compared to ECFCs of healthy donors. Multimer analysis of p.M771V ECFCs showed a deficiency of high molecular weight VWF multimers. Immunofluorescent staining revealed VWF retention in the endoplasmic reticulum; this was confirmed in various populations of base-edited CB-ECFCs harboring the p.M771V variant., Conclusion: The severe endothelial phenotype observed in patient-derived p.M771V ECFCs, HEK293 cells, and an original base-edited CB-ECFC modeling system show that endoplasmic reticulum retention of VWF and failure to undergo subsequent proteolytic processing underpins the severe bleeding phenotype of patients with homozygous variants at M771., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cardiac digital twins are computational tools capturing key functional and anatomical characteristics of patient hearts for investigating disease phenotypes and predicting responses to therapy. When paired with large-scale computational resources and large clinical datasets, digital twin technology can enable virtual clinical trials on virtual cohorts to fast-track therapy development. Here, we present an open-source automated pipeline for personalising ventricular electrophysiological function based on routinely acquired magnetic resonance imaging (MRI) data and the standard 12-lead electrocardiogram (ECG). Using MRI-based anatomical models, a sequential Monte-Carlo approximate Bayesian computational inference method is extended to infer electrical activation and repolarisation characteristics from the ECG. Fast simulations are conducted with a reaction-Eikonal model, including the Purkinje network and biophysically-detailed subcellular ionic current dynamics for repolarisation. For each patient, parameter uncertainty is represented by inferring an envelope of plausible ventricular models rather than a single one, which means that parameter uncertainty can be propagated to therapy evaluation. Furthermore, we have developed techniques for translating from reaction-Eikonal to monodomain simulations, which allows more realistic simulations of cardiac electrophysiology. The pipeline is demonstrated in three healthy subjects, where our inferred pseudo-diffusion reaction-Eikonal models reproduced the patient's ECG with a median Pearson's correlation coefficient of 0.9, and then translated to monodomain simulations with a median correlation coefficient of 0.84 across all subjects. We then demonstrate our digital twins for virtual evaluation of Dofetilide with uncertainty quantification. These evaluations using our cardiac digital twins reproduced dose-dependent QTc and T peak to T end prolongations that are in keeping with large population drug response data. The methodologies for cardiac digital twinning presented here are a step towards personalised virtual therapy testing and can be scaled to generate virtual populations for clinical trials to fast-track therapy evaluation. The tools developed for this paper are open-source, documented, and made publicly available., 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. Published by Elsevier B.V.)

Desmopressin (DDAVP) can be used to prevent or stop bleeding. However, large inter-individual variability is observed in DDAVP response and determinants are largely unknown. In this systematic review and meta-analysis we aim to identify the response to DDAVP, and the factors that determine DDAVP response in patients. We included studies with patients with any bleeding disorder receiving DDAVP. First and second screening round and risk of bias assessment were performed by independent reviewers. The main outcome was proportion of patients with complete (factor level > 50 U/dL), or partial (30-50 U/dL) response to DDAVP. Determinants of response including disease type, age, sex, Von Willebrand factor (VWF) and factor VIII (FVIII) mutations, and baseline factor levels were investigated. In total, 591 articles were found and 103 were included. Of these, 71 articles (1772 patients) were suitable for the study's definition of response. Meta-analysis showed a pooled response proportion of 0·71 [0·64;0·78] and a significant difference in response between disease subtypes. For hemophilia A, baseline FVIII:C was a borderline significant determinant of response. In von Willebrand disease (VWD) type 1 patients, VWF:Ag, VWF:Act and FVIII:C were significant determinants. A large variation in response was observed for specific mutations in VWF and F8. Response to DDAVP varied between disease subtypes, and was largely determined by the baseline levels of FVIII:C for hemophilia A and VWF:Ag for VWD. Our findings highlight the significant differences in response and emphasize the need for a standardized response definition and further research into response mechanisms., (Copyright © 2025 American Society of Hematology.)

Clean air is a requirement for life, and the quality of indoor air is a health determinant since people spend most of their daily time indoors. The aim of this study was to systematically review the available evidence regarding the sources, determinants and concentrations of indoor air pollutants in a set of scenarios under study in K-HEALTHinAIR project. To this end, a systematic review was performed to review the available studies published between the years 2013-2023, for several settings (schools, homes, hospitals, lecture halls, retirement homes, public transports and canteens), conducted in Europe, where sources and determinants of the indoor pollutants concentrations was assessed. After a two-stage screening in abstract and full-text, 148 papers were included for data extraction. For particulate matter, carbon dioxide and volatile organic compounds, several emission sources were identified (occupancy, human activities, resuspension, cleaning products, disinfectants, craft activities, cooking, smoking), with ventilation, number of occupants, building characteristics, being considered as important determinants. This review made also possible to discuss some of the actions that are already in place or should be implemented in the future to prevent and control the presence of pollutants indoors., 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 © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: This study investigates the association of loneliness during the COVID-19 pandemic and the course of depressive, anxiety and sleep symptoms after psychological treatment in older adults., Methods: During the first wave of the pandemic in 2020, we assessed additional, original data of 132 participants aged ≥60 years who had completed psychological treatment for late-life depression (LLD) in the context of a multicenter, randomized controlled trial (CBT-late). We measured loneliness using the UCLA Loneliness Scale. Depression, anxiety and sleep symptoms were assessed using the Geriatric Depression Scale (GDS), Geriatric Anxiety Inventory (GAI), and Insomnia Severity Index (ISI)., Results: Participants with higher loneliness scores (n = 44) experienced a significant worsening of depressive and anxiety symptoms during the pandemic (estimated marginal mean difference (emmd) of change in GDS between post-treatment and COVID-19 visit: GDS emmd = -4.61, [95% CI: -6.97 to -2.26], GAI emmd = -2.21, [95% CI: -3.76 to -0.65]), while those with low to moderate loneliness (n = 72) maintained stable mild symptoms (GDS emmd = -1.39, [95% CI: -3.00 to 0.22], GAI emmd = -0.49, [95% CI: -1.69 to 0.72]). All patients reported increased sleep disturbances during the pandemic regardless of loneliness, while remaining in the range for sub-threshold insomnia., Conclusions: Our results suggest an association of significant loneliness during the COVID-19 pandemic and a clinically relevant worsening of depressive and anxiety symptoms in older adults. Loneliness assessments and interventions may be incorporated into treatments for LLD, particularly during pandemics or other crises., Competing Interests: DISCLOSURES The initial randomized controlled trial was funded by grant BMBF01KG1716 from the German Federal Ministry of Education and Research (BMBF). The analysis of the additional COVID-19 visit was partially funded by the BMBF Network of University Medicine 2.0 (NUM 2.0, 01KX2121, Project: CollPan). The authors have no disclosures to report., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

In this study, we propose a continuous assay that provides a high-throughput, efficient method for screening the regioselectivity of lipases at the sn-1,3 and sn-2 positions on triacylglycerols (TAGs). This assay measures the specific hydrolysis rates at the primary and secondary positions of TAGs derivates containing oleic (O) and punicic (P) acids. The method is based on the absorbance ratio of released punicic acid from the hydrolysis of sn-POP (sn-1,3 regiospecific lipases) and sn-OPO (sn-2 regiospecific lipases). The method was validated using pure lipases with known and unknown regioselectivity. Unexpectedly, we found that recombinant Lipase 4 from Candida rugosa (rCRLip4) exhibited significant sn-2 regioselectivity, indicating greater regioselectivity than recombinant lipase A from Candida antarctica (rCALA). In silico analysis and molecular docking studies were conducted to elucidate the main structural differences between CRLip4 and the non-regioselective isoform CRLip1. This continuous regioselective lipase assay on TAGs is versatile and can be used to screen for sn-1,3, sn-2 or non-regioselective lipases. It holds significant potential applications in the biocatalytic production of structured lipids and other industrial processes where regioselectivity is crucial., 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 © 2025 Elsevier Inc. All rights reserved.)

Corn wet milling (CWM) and corn starch flash drying processing conditions reduce undesirable microorganisms, such as Salmonella. Finished products are historically safe, with intrinsic properties such as low water activity inhibiting microbial growth. Corn processors could use quantified levels of reduction in this study of Salmonella surrogate Enterococcus faecium (E. faecium) to update their food safety plans. Industry-relevant conditions for CWM processes were recreated at pilot or lab scale for 3 unit operations: (1) steeping treatment in sulfur dioxide (SO 2 ) with low (750 ppm SO 2 , 20 h, 43.3 °C), medium (1,500 ppm SO 2 , 30 h, 48.9 °C), and high (2,200 ppm SO 2 , 40 h, 53.3 °C) treatment conditions; (2) hydrogen peroxide (H 2 O 2 ) treatment tested on bench scale with a factorial design (pH 3.5, 4.0, and 4.5), H 2 O 2 concentrations (0.05%, 0.10%, 0.15% (w/w)), and temperatures (32, 38, and 46 °C) for 3 and 6 h; (3) flash drying treatment at 4 different temperatures (149, 177, 204, and 232 °C) with 2 different inoculation methods. E. faecium was reduced during each of these unit operations. By the end of each steeping treatment, E. faecium was consistently below the limit of quantitation (LOQ), meaning >6.5 log CFU/mL reduction in steep water, and >3.7 log CFU/g reduction in ground corn. The peroxide step had a reduction range from 0.03 log CFU/mL in the control group (0% H 2 O 2 added) to >6 log CFU/mL observed in the high-intensity treatment of corn starch slurry. Flash drying had a reduction range from 1.7 to 2.7 log CFU/g. There was also no biologically meaningful change (<1 log CFU/g reduction) of E. faecium counts during an 8-week survival study of the dried final product. This hurdle approach study shows that existing CWM conditions are effective for Salmonella surrogate reduction through processing into finished starch and provides quantified E. faecium reductions for use in food safety plans., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: “Matthew J Stasiewicz reports financial support was provided by Corn Refiners Association. Gordon Shetley reports a relationship with Ingredion Incorporated that includes: employment. David Stenger reports a relationship with Archer Daniels Midland Company that includes: employment. Kirk A Perreau reports a relationship with Cargill Inc that includes: employment. Allison Cooke reports a relationship with Corn Refiners Association that includes: employment. 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 Author(s). Published by Elsevier Inc. All rights reserved.)

Methane (CH 4 ) spatial distribution and its trends in the Atlantic-Mediterranean transition region of southwestern Europe were studied using TROPOMI and GOSAT observations. TROPOMI XCH 4 provided insights into the distribution across the entire Iberian Peninsula, highlighting the high XCH 4 mixing ratios in the two main valleys and the southern sub-plateau, characterized by agricultural and livestock activities. The marine-continental region in the southwestern Iberian Peninsula was identified as a major CH 4 hot spot. Focusing on this region, the seasonal distribution of CH 4 and its trends were studied. The lowest XCH 4 levels were recorded in a semi-natural landscape in a mountain range with an average mixing ratio of 1871.9 ± 18.5 nmol mol -1 , while the highest trend was recorded at 10.9 ± 0.7 nmol mol -1  year -1 for the period 2019-2023. Conversely, the highest XCH 4 levels were obtained over an inland wetland, averaging 1888.7 ± 15.8 nmol mol -1 ; while recording the lowest regional trend, 6.4 ± 0.9 nmol mol -1  year -1 . Aiming to identify potential regional changes in the XCH 4 trend, GOSAT observations were used, revealing a long-term trend of 8.7 ± 0.3 nmol mol -1  year -1 from 2009 to 2023. Focusing on the first and last five years of the series, trends of 6.5 ± 0.9 nmol mol -1  year -1 and 14.9 ± 1.2 nmol mol -1  year -1 were detected, indicating a trend acceleration ratio of 2.3. An analogous pattern was found in the Atlantic Ocean and central Mediterranean at the same latitude, with ratios of 2.7 and 2.4 respectively. Furthermore, these outcomes were corroborated by ground-based observations from the Azores and Lampedusa stations, which belong to the NOAA network. Despite CH 4 increasing globally and its trend accelerating, this work highlights the complexity of its dynamics, with regional variations in its mixing ratios, horizontal distribution, and temporal trends., 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 B.V. All rights reserved.)

Objectives: To evaluate the role of systemic arterial embolization in patients with primary and metastatic lung tumors presenting with hemoptysis requiring emergent management., Patients and Methods: This retrospective single-center study evaluated patients undergoing transarterial embolization for emergent hemoptysis. Endpoints included technical success, clinical success and overall survival. Clinical success was divided into partial or complete, and defined as absence (complete) or subtotal (partial) reduction in frequency and/or volume of hemoptysis in the first 24-hours following embolization. Predictive factors for clinical outcomes were evaluated using univariate analysis. Adverse events were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0., Results: Thirty-seven patients were identified, including 21/37 (56.8%) patients with primary lung cancer. Clinical success was achieved in 31/37 (83.8%) patients. Median overall survival was 18 days (95% CI, 10-95). Median hemoptysis-free survival was 270 days (95% CI 7 to not reached). No significant predictors of hemoptysis-free survival were identified. Prior chemotherapy (HR 2.69, 95% CI, 1.08-6.67; P = .03) was associated with poorer overall survival. History of primary lung tumor (vs. metastatic tumor) was associated with improved overall survival (HR 0.45, 95% CI, 0.21-0.95; P = 0.04). No serious adverse events (CTCAE Grade ≥ 3) were found to be directly attributable to the embolization., Conclusion: Hemoptysis requiring emergent management in patients with lung malignancy carries a poor prognosis. Transarterial embolization is feasible, safe and may be an effective management option, although further research is warranted to identify which patients are likely to derive the greatest benefit., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), hold notable significance due to their pharmaceutical relevance. Obtaining PUFAs from diverse sources like vegetables, fish oils, and algae poses challenges due to the mixed fatty acid (FA) composition. Therefore, focusing on particular FAs necessitates purification and resolution processes. To address this, we propose a continuous assay for screening lipases selective for ethyl EPA (E-EPA) or ethyl DHA (E-DHA). Utilizing microplate spectrophotometry, the method enables quantification of liberated fatty acids from ethyl esters (E-EPA or E-DHA). This involves assessing enzyme selectivity by measuring the release of FAs through p-nitrophenolate protonation, either separately for each substrate or in competition with a reference substrate, resorufin acetate. Ten lipases underwent screening, revealing Burkholderia cepacia lipase's (BCL) preference for ethyl DHA hydrolysis (E-EPA/E-DHA = 0.82 ± 0.07 and the lipase selectivity ratio (S) for E-EPA/E-DHA = 0.13 ± 0.04) and Candida antarctica lipase B's (CALB) high specific activity towards both E-EPA and E-DHA (531.14 ± 37.76 and 281.79 ± 2.79 U/mg, respectively) and E-EPA preference (E-EPA/E-DHA = 1.86 ± 0.15 and S E-EPA/E-DHA = 2.59±0.15). Candida rugosa recombinant isoform 4 (rCRLip4) and commercial Candida rugosa lipase (CRL) exhibited significant preference for E-EPA hydrolysis (E-EPA/E-DHA = 2.18 ±0.51 and 2.26 ±0.36, respectively; and S E-EPA/E-DHA = 7.59 ± 1.59 and 7.88 ± 2.13, respectively). Docking analyses of rCRLip4, BCL, and CALB demonstrated no statistically significant differences in activation energies or distances to the catalytic serine; however, they agreed with the experimental results. These findings suggest potential mutagenesis or directed evolution strategies for CALB to enhance E-EPA selectivity, with rCRLip4 emerging as a promising candidate for further investigation. This assay offers a valuable tool for identifying lipases with desired substrate selectivity, with broad implications for pharmaceutical and biotechnological applications., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The ability to discriminate quantities is crucial for humans and other animals, by allowing individuals to maximize food intake and successfully navigate in their social environment. Here, we used a comprehensive approach to compare quantity discrimination abilities (i.e. ability to compare sets with different quantities of identical items, reliance on item size and spatial distribution, existence of irrational biases) in 9 different species of ungulates and provide novel insight into the socio-ecological conditions that might favor their emergence. We tested a total of 37 captive subjects including goats (Capra aegagrus hircus), llamas (Lama glama), guanacos (Lama guanicoe), Grevy's zebras (Equus grevyi), Chapman's zebras (Equus burchelli chapmanni), rhinos (Diceros bicornis michaeli), giraffes (Giraffa camelopardalis rothschildi), bison (Bison bonasus) and buffalos (Syncerus caffer nanus). Our results revealed that subjects were able to discriminate quantities when presented with two sets of food items that could differ in number, size and partially density. When presented with sets containing a different number of identical food items, subjects successfully selected the set with more items, with performance overall decreasing when sets had higher ratios (e.g., 1:3 vs 1:5). In addition, subjects could successfully maximize their food intake when both sets had the same number of items, but items had different sizes. However, performance decreased at chance levels when varying both the number of items and their size or distribution. Giraffes performed better than other species in most conditions, and we found no evidence for an irrational bias toward sets with more, smaller items or denser distributions. Overall, our study provides a first comparative assessment of quantity discrimination skills in several ungulate species., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Artificial intelligence (AI) has shown promising results for computational pathology tasks. However, one of the limitations in clinical practice is that these algorithms are optimised for the distribution represented by the training data. For out-of-distribution (OOD) data, they often deliver predictions with equal confidence, even though these often are incorrect. In the pursuit of OOD detection in digital pathology, this study evaluates the state-of-the-art (SOTA) in computational pathology OOD detection, based on diffusion probabilistic models, specifically by adapting the latent diffusion model (LDM) for this purpose (AnoLDM). We compare this against post-hoc methods based on the latent space of foundation models, which are SOTA in general computer vision research. The approaches are not only evaluated on data from the same medical centres as the training set, but also on several datasets with data distribution shifts. The results show that AnoLDM performs similarly well or better than diffusion model based approaches published in previous studies in computational pathology but with reduced computational costs. However, our optimal configuration of an approach based on foundation models (kang&#95;residual) outperforms AnoLDM on OOD detection on data not experiencing any covariate shifts, with an AUROC of 96.17 versus 91.86. Interestingly, AnoLDM is more successful at handling the data distribution shifts investigated in this study. However, both AnoLDM and kang&#95;residual suffer substantial loss in the performance under the data distribution shifts, hence future work should focus on improving the generalisation of OOD detection for computational pathology applications., 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. Published by Elsevier Ltd.)

Sustainable lignin-based materials are becoming increasingly valuable in agriculture, where climate change and nutrient deficiencies threaten crop productivity. We developed lignin-derived cryogels using waste biomass to improve soil nutrients, seed germination, water retention, and photosynthetic pigment levels. These cryogels were synthesized with gum Arabic (GA), keratin (K), and N-vinylpyrrolidone at lignin concentrations of 0.02 wt% (LbC 1 ), and 0.1 wt% (LbC 2 ), along with a control (NLC), through low-temperature polymerization at -20 °C. The cryogels exhibited high thermal stability and water retention, exceeding 170 %, due to their network structure. Functional groups like carboxyl and hydroxyl enhanced nutrient assimilation, accelerating germination and plant growth, with keratin providing bioavailable amino acids through microbial degradation. After 5 days, the cryogel treatments significantly improved early germination rates (100 %, 100 %, and 99 % for wheat, maize, and rapeseed, respectively), while boosting chlorophyll (a, b, and total), sugar, and soluble protein levels. Treated plants showed increased leaf numbers, plant height, and root length, with a 98.4 % improvement in water uptake compared to controls, mitigating the effect of soil salinity. LbC 1 and LbC 2 also notably increased chlorophyll pigments, soluble sugars, and total protein across all crops compared to the NLC. Additionally, the cryogel exhibited a 33 % biodegradation rate after 130 days in soil, confirming their environmental compatibility. In conclusion, the developed lignin-based cryogels represent a sustainable, effective solution to enhance nutrient availability and resilience in agriculture, repurposing industrial lignin waste to address climate-driven challenges in crop production., 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 B.V. All rights reserved.)

Objective: This paper aims to introduce and assess KeyGAN, a generative modeling-based keystroke data synthesizer. The synthesizer is designed to generate realistic synthetic keystroke data capturing the nuances of fine motor control and cognitive processes that govern finger-keyboard kinematics, thereby paving the way to support biomarker development for psychomotor impairment due to neurodegeneration., Methods: KeyGAN is designed with two primary objectives: (i) to ensure high realism in the synthetic distributions of the keystroke features and (ii) to analyze its ability to replicate the subtleties of natural typing for enhancing biomarker development. The quality of synthetic keystroke data produced by KeyGAN is evaluated against two keystroke-based applications, TypeNet and nQiMechPD, employed as'referee' controls. The performance of KeyGAN is compared with a reference random Gaussian generator, testing its ability to fool the biometric authentication method TypeNet, and its ability to characterize fine motor impairment in Parkinson's Disease using nQiMechPD., Results: KeyGAN outperformed the reference comparator in fooling the biometric authentication method TypeNet. It also exhibited a superior approximation to real data than the reference comparator when using nQiMechPD, showcasing its adaptability and versatility in mimicking early signs of Parkinson's Disease in natural typing. KeyGAN's synthetic data demonstrated that almost 20% of real PD samples could be replaced in the training set without a decline in classification performance on the real test set. Low Fréchet Distance (<0.03) and Kullback-Leibler Divergence (<700) between KeyGAN outputs and real data distributions underline the high performance of KeyGAN., Conclusion: KeyGAN presents strong potential as a realistic keystroke data synthesizer, displaying impressive capability to reproduce complex typing patterns relevant to biomarkers for neurological disorders, like Parkinson's Disease. The ability of its synthetic data to effectively supplement real data for training algorithms without affecting performance implies significant promise for advancing research in digital biomarkers for neurodegenerative and psychomotor disorders., Competing Interests: Declaration of competing interest A.A., and T. A.-G. are employees at Area2 Inc. and received a regular salary while contributing to the work. L.G. is an inventor on a patent currently licensed to Area2 Inc. in the same general research area of this work., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To evaluate the role of salvage local treatment in managing recurrent PCa following FT, focusing on oncological and functional outcomes., Methods: A systematic review and meta-analysis were performed following the PRISMA framework. A comprehensive literature search using the PubMed/MEDLINE and EMBASE databases was performed until July 2023. Eligible studies included patients with clinically localised PCa initially treated with FT, who experienced relapse during surveillance and subsequently underwent salvage radical prostatectomy (sRP), salvage external beam radiation therapy (sEBRT) or salvage focal therapy (sFT). The primary endpoint was the biochemical recurrence rate post-salvage treatment. The secondary endpoints were functional outcomes, including urinary incontinence and erectile dysfunction rates., Results: In 26 retrospective studies including 990 patients, the overall pooled biochemical recurrence rate postsalvage treatment was 26%. The subgroup analysis revealed a biochemical recurrence rate of 20%, 22%, and 42% after sRP, sEBRT, and sFT, respectively. The overall pooled rate of urinary incontinence was 20%. Salvage FT had the lowest prevalence of urinary incontinence, followed by sRP and sEBRT. The overall pooled rate of erectile dysfunction was 43%. Salvage RP had the highest prevalence of erectile dysfunction, followed by sFT and sEBRT. Substantial heterogeneity was observed among the studies, primarily due to different sample sizes. Meta-regression analysis revealed no to low contributions of salvage treatment modalities, extent of ablation, age, prostatic specific antigen level before salvage treatment, proportion of patients with Gleason score ≥7 at recurrence, and time between the primary and salvage therapies to heterogeneity., Conclusion: Salvage local treatment for recurrent PCa after FT is feasible, and it provides acceptable oncological and functional outcomes. Among all treatment modalities, sRP and sEBRT appeared to have the lowest biochemical recurrence rates, whereas sFT was associated with improved functional outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Freshwater snails act as obligate intermediate hosts for trematode parasites that cause trematodiases threatening public and veterinary health, and biodiversity conservation. While interest in snail control for trematodiases has re-emerged, their ecology remains poorly understood. We examined the relationship between ecosystem indicators - such as environmental variables, macroinvertebrates, macrophytes, and land use - and their correlation with snail abundance, diversity, and infection prevalence in 19 man-made ponds in eastern Zimbabwe. In total, 926 freshwater snails from 10 species were collected, with 547 individuals belonging to five schistosome-competent species: Bulinus tropicus, Bulinus truncatus, Bulinus globosus, Bulinus forskalii, and Biomphalaria pfeifferi. The remaining 379 snails comprised Radix natalensis, Gyraulus sp., and the exotic invasive species Melanoides tuberculata, Pseudosuccinea columella, and Physella acuta. Six cercarial types - mammalian schistosomes, avian schistosomes, longifurcate pharyngeates, echinostomes, amphistomes, and xiphidiocercariae - were isolated from 104 out of 926 snails (11.2 %). PCR revealed a significantly higher infection rate, with 70.2 % of snails testing positive for trematodes. Snail taxon diversity and infection rate significantly varied across land use types, with the lowest values observed in the commercial tobacco farm section, highlighting the potential adverse effects of agriculture on biodiversity. Ponds with extensive Lagarosiphon major (oxygen weed) coverage appeared to facilitate the presence and abundance of P. acuta and P. columella. Schistosome-competent snails such as B. truncatus and B. tropicus seemed to favor shallow water depths and more eutrophic sites characterized by high levels of nitrates, phytoplankton biomass, turbidity, and phycocyanin. These ponds were predominantly associated with the emergent macrophyte Cladium mariscus, revealing a potential association with important intermediate snail hosts. In conclusion, our study emphasizes the complex interplay among environmental factors, macrophyte composition, land use, and the abundance, diversity, and infection prevalence of freshwater snails, offering insights into potential strategies for targeted snail control and disease management in man-made waterbodies., 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 B.V. All rights reserved.)

Background/purpose: Testicular torsion(TT) with unsalvageable testis has a significant psychosocial impact. Orchiectomy can be performed with optional testicular prosthesis(TP) placement, commonly deferred(dTP). Orchiectomy and simultaneous testicular prosthesis placement(sTP) may be a feasible and safe option and has been implemented in our department since 2018., Aim: The authors aim to perform a reflective analysis of the patient's experience and assess the feasibility, safety, and satisfaction of the sTP, by comparing it with the dTP., Methods: All patients with TT and unsalvageable testis submitted to orchiectomy were included in the study. An anonymous questionnaire assessed the patients' experience. Those submitted to orchiectomy and TP placement were divided in sTP and dTP groups and their clinical details, satisfaction and quality-of-life were analyzed and compared., Results: Scrotal exploration due to TT was performed in 185 patients, 54 were submitted to orchiectomy and 37 placed a TP(17 sTP, 20 dTP). All dTP patients and 66.7% of those without TP, would prefer having a prosthesis placed at the time of the orchiectomy. No significant differences in clinical details and outcomes were found, except prosthesis position (higher in dTP, p = 0.011) and operative time (13 min longer in sTP, p = 0.015). Both groups reported being satisfied with the prosthesis. Only one patient regretted placing a prosthesis(in dTP)., Conclusion: The sTP approach is as safe and effective as dTP. The patients preferred the sTP, as it avoids a second operation and possibly by having a lower psychological impact., Levels of Evidence: Level III., Competing Interests: Conflict of interest None., (Copyright © 2024 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Endothelial cells deliver a vital contribution to the maintenance of hemostasis by constituting an anatomical as well as functional barrier between the blood and the rest of the body. Apart from the physical barrier function, endothelial cells maintain the hemostatic equilibrium by their pro- and anticoagulant functions. An important part of their procoagulant contribution is the production of von Willebrand factor (VWF), which is a carrier protein for coagulation factor VIII and facilitates the formation of a platelet plug. Thus, VWF is indispensable for both primary and secondary hemostasis, which is exemplified by the bleeding disorder von Willebrand disease that results from qualitative or quantitative deficiencies in VWF. A cellular model that was found to accurately reflect the endothelium and its secretory organelles are endothelial colony-forming cells, which can be readily isolated from peripheral blood and constitute a robust ex vivo model to investigate the donor's endothelial cell function. This review summarizes some of the valuable insights on biology of VWF and pathogenic mechanisms of von Willebrand disease that have been made possible using studies with endothelial colony-forming cells derived from patients with bleeding disorders., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Abstract: Drug development for chronic myelomonocytic leukemia (CMML) has failed to parallel the recent success observed in related myeloid neoplasms. To address these shortcomings, the US Food and Drug Administration (FDA) held a "Mini-symposium on CMML: Current State of the Art and Trial Design" in September 2023. This symposium brought together a panel of key FDA regulators and academic experts in CMML drug development to discuss challenges and provide perspectives on future drug development for this disease. The panel explored unique challenges that underlie the lack of therapeutic advances in CMML to date and discussed relevant topics such as clinical trial design, study end points, and key regulatory considerations. This article summarizes the key points of discussion from this symposium to facilitate advancements in the field.

Importance: Ligamentous ankle lesions are among the most frequent sports injuries. One of the key intrinsic stabilizers of the ankle joint is the incisura fibularis (IF), as it interlocks the distal tibia and fibula. Despite an abundant amount of studies related to ligamentous ankle injuries, scant attention has been given to the specific role of the IF morphology., Objective: We systematically reviewed all literature focused on the relation between ligamentous ankle lesions and IF morphology., Evidence Review: A systematic literature search was conducted on PubMed, Embase, and Web of Science according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and registered on the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42021282862). In general, search terms were related to ankle and syndesmosis trauma/instability in combination with morphology parameters of the IF. Studies categorizable as original research (randomized controlled trial or observational) were included. Studies concerning degenerative ankle disease and cadavers were excluded., Findings: Thirteen studies were confirmed eligible and consisted of a prospective cohort (n ​= ​1), retrospective comparative (n ​= ​10), and observational (n ​= ​2) study design. Several studies have found an increased number of ankle ligament injuries and a higher incidence of chronic ankle instability in association with a shallow IF depth. In addition, statistically significant differences in incisura height and angle were also noted: a shorter incisura and more obtuse angle were more present in patients with ankle ligament injuries., Conclusion and Relevance: Most studies found distinct characteristics of the IF morphology associated with ligamentous ankle lesions, potentially due to lower osseous resistance against tibiofibular displacement. However, not all studies could identify this association and presented a heterogeneous methodological quality. Therefore, further prospective studies are warranted to clarify the relationship between the IF morphology and ligamentous ankle injuries., Lever of Evidence: Level III, systematic review., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest related to this study., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The human body represents the habitat of trillions of symbiotic microorganisms, collectively known as human microbiota, approximately half of which residing in the gut. The development of next-generation sequencing techniques has boosted the profiling of human microbiota in recent years. A growing body of evidence seems to support a strict relationship between the disruption of the mutualistic relationship between the microbiota and the host (i.e., dysbiosis) and the development of several diseases, including breast malignancies. Breast cancer still represents the most frequent cause of cancer-related death in women. Its complex relationship with gut microbiota is the object of a growing body of evidence. In fact, the interaction with the host immune system and a direct impact of gut microbiota on estrogen, lipid and polyphenols metabolism, seem to potentially affect breast tumor development, progression and response to treatments. In this review, in an attempt to help oncologists navigating this rapidly-evolving research field, we provide an essential overview on the taxonomy, main analytical techniques and terminology most commonly adopted. We discuss what is currently known regarding the interaction between gut microbiota and breast cancer and potential efforts to harness this complex interplay for therapeutic purposes, and revise main ongoing studies. We also briefly provide an overview on breast cancer intratumoral microbiota and its potential role beyond gut microbiota., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Francesco Schettini reports honoraria from Novartis, Gilead and Daiichy-Sankyo for educational events/materials and travel expenses from Novartis, Gilead and Daiichy-Sankyo. Daniele Generali declares personal fees for educational events by Novartis, Lilly, Pfizer, Daiichy-Sankyo, Roche; research funds from Astrazeneca, Novartis and LILT. The other authors have nothing to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Intraductal oncocytic papillary neoplasms (IOPNs) of the pancreas are now considered a separate entity to intraductal papillary mucinous neoplasms (IPMN). Invasive IOPNs are extremely rare, and their recurrence patterns, response to adjuvant chemotherapy and long-term survival outcomes are unknown., Methods: Consecutive patients undergoing pancreatic resection (2010-2020) for invasive IOPNs or adenocarcinoma arising from IPMN (A-IPMN) from 18 academic pancreatic centers worldwide were included. Outcomes of invasive IOPNs were compared with A-IPMN invasive subtypes (ductal and colloid A-IPMN)., Results: 415 patients were included: 20 invasive IOPN, 331 ductal A-IPMN and 64 colloid A-IPMN. After a median follow-up of 6-years, 45% and 60% of invasive IOPNs had developed recurrence and died, respectively. There was no significant difference in recurrence or overall survival between invasive IOPN and ductal A-IPMN. Overall survival of invasive IOPNs was inferior to colloid A-IPMNs (median time of survival 24.4 months vs. 86.7, months, p = 0.013), but the difference in recurrence only showed borderline significance (median time to recurrence, 22.5 months vs. 78.5 months, p = 0.132). Adjuvant chemotherapy, after accounting for high-risk features, did not reduce rates of recurrence in invasive IOPN (p = 0.443), ductal carcinoma (p = 0.192) or colloid carcinoma (p = 0.574)., Conclusions: Invasive IOPNs should be considered an aggressive cancer with a recurrence rate and prognosis consistent with ductal type A-IPMN., (Copyright © 2024 International Hepato-Pancreato-Biliary Association Inc. All rights reserved.)

Background: Obesity confers higher risks of cardiac arrhythmias. The extent to which weight loss reverses subclinical proarrhythmic adaptations in arrhythmia-free obese individuals is unknown., Objective: The purpose of this study was to study structural, electrophysiological, and autonomic remodeling in arrhythmia-free obese patients and their reversibility with bariatric surgery using electrocardiographic imaging (ECGi)., Methods: Sixteen arrhythmia-free obese patients (mean age 43 ± 12 years; 13 (81%) female participants; BMI 46.7 ± 5.5 kg/m 2 ) had ECGi pre-bariatric surgery, of whom 12 (75%) had ECGi postsurgery (BMI 36.8 ± 6.5 kg/m 2 ). Sixteen age- and sex-matched lean healthy individuals (mean age 42 ± 11 years; BMI 22.8 ± 2.6 kg/m 2 ) acted as controls and had ECGi only once., Results: Obesity was associated with structural (increased epicardial fat volumes and left ventricular mass), autonomic (blunted heart rate variability), and electrophysiological (slower atrial conduction and steeper ventricular repolarization time gradients) remodeling. After bariatric surgery, there was partial structural reverse remodeling, with a reduction in epicardial fat volumes (68.7 cm 3 vs 64.5 cm 3 ; P = .0010) and left ventricular mass (33 g/m 2.7 vs 25 g/m 2.7 ; P < .0005). There was also partial electrophysiological reverse remodeling with a reduction in mean spatial ventricular repolarization gradients (26 mm/ms vs 19 mm/ms; P = .0009), although atrial activation remained prolonged. Heart rate variability, quantified by standard deviation of successive differences in R-R intervals, was also partially improved after bariatric surgery (18.7 ms vs 25.9 ms; P = .017). Computational modeling showed that presurgical obese hearts had a larger window of vulnerability to unidirectional block and had an earlier spiral-wave breakup with more complex reentry patterns than did postsurgery counterparts., Conclusion: Obesity is associated with adverse electrophysiological, structural, and autonomic remodeling that is partially reversed after bariatric surgery. These data have important implications for bariatric surgery weight thresholds and weight loss strategies., Competing Interests: Disclosures The authors have no conflicts to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Abstract: With emerging new drugs in myelofibrosis (MF), a robust and harmonized framework for defining the severity of anemia and response to treatment will enhance clinical investigation and facilitate interstudy comparisons. Accordingly, the lead authors on the 2013 edition of the International Working Group-European LeukemiaNet (IWG-ELN) response criteria in MF were summoned to revise their document with the intent to (1) account for gender-specific differences in determining hemoglobin levels for eligibility criteria; (2) revise the definition of transfusion-dependent anemia (TDA) based on current restrictive transfusion practices; and (3) provide a structurally simple and easy to apply response criteria that are sensitive enough to detect efficacy signals (minor response) and also account for major responses. The initial draft of the 2024 IWG-ELN proposed criteria was subsequently circulated around a wider group of international experts and their feedback incorporated. The proposed articles include new definitions for TDA (≥3 units in the 12 weeks before study enrollment) and hemoglobin thresholds for eligibility criteria (<10 g/dL for women and <11 g/dL for men). The revised document also provides separate (TDA vs non-TDA) and graded (major vs minor response) response criteria while preserving the requirement for a 12-week period of screening and observation on treatment., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Competing Interests: Disclosures The authors have no conflicts of interest to disclose.

Purpose: Anemia is a cardinal feature of myelofibrosis often managed with red blood cell (RBC) transfusions, which may contribute to negative prognostic, quality-of-life, and healthcare-related economic impacts. The Janus kinase (JAK) 1/JAK2/activin A receptor type 1 inhibitor momelotinib was approved for the treatment of patients with myelofibrosis and anemia based on clinical trial evidence of anemia, spleen, and symptom benefits illustrated using binomial response/nonresponse endpoints. In the present post hoc, descriptive analyses, the impact of momelotinib on RBC transfusion burden over time was further characterized across JAK inhibitor-naive and -experienced patients., Methods: All RBC units transfused were collected during the baseline and 24-week treatment periods, initially in a single-arm phase 2 study as proof-of-concept analysis, and then versus comparators (ruxolitinib, best available therapy [BAT], and danazol) in the phase 3 SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM studies, respectively., Results: In the phase 2 study, mean transfusion requirement changed by -1.5 units/28 days, with 85% of patients (35/41) achieving numeric transfusion reduction. Across SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM, mean transfusion requirements decreased with momelotinib (-0.1, -0.36, and -0.86 units/28 days), while mean requirements with ruxolitinib, BAT, and danazol changed by +0.39, 0, and ‒0.28 units/28 days, respectively. Overall, 87% (185/213), 77% (79/103), and 85% (110/130) of patients had improved or stable transfusion intensities with momelotinib versus 54% (117/216), 62% (32/52), and 63% (41/65) with ruxolitinib, BAT, and danazol., Conclusion: These novel time-dependent transfusion burden analyses demonstrate that momelotinib is associated with anemia-related benefits in most patients and greater transfusion burden reduction versus comparators., Trial Registration: ClinicalTrials.gov identifiers: NCT02515630, NCT01969838, NCT02101268, NCT04173494., Competing Interests: Disclosure CNH has received institutional research funding from BMS/Celgene, Constellation Pharmaceuticals Inc (a MorphoSys Company), and Novartis; consulting fees from AOP, Galecto, GSK, Keros, SOBI, and Roche; advisory role and speaker funding from AbbVie, AOP Pharma, BMS/Celgene, Constellation Pharmaceuticals Inc (a MorphoSys Company), CTI BioPharma, Galecto, Geron, GSK, Jannsen, Novartis, Roche, and Promedior; and support from Novartis for attending meetings. RM reports consulting fees from AbbVie, Blueprint, BMS, CTI Biopharma, Genentech, Geron, GSK, Incyte, MorphoSys, Novartis, and Sierra Oncology. MT reports research funding from BMS and advisory board participation for BMS, Kyowa Kirin, and SDP/Sumitomo. VG reports consulting fees from AbbVie, BMS Celgene, Daiichi Sankyo, GSK, and Pfizer and participation in a data safety monitoring/advisory board for AbbVie, BMS Celgene, and Daiichi Sankyo. ATG reports consulting fees from AbbVie, BMS, Constellation/MorphoSys, CTI Biopharma, Imago Biosciences/Merck, Incyte, PharmaEssentia, Sierra Oncology, and Telios. AP reports payment of honoraria from and participation in advisory board work with AbbVie, CTI BioPharma, GSK, Incyte, Kartos, and Novartis. YTG reports consulting fees from Amgen, Antengene, Astellas, AstraZeneca, GSK, Janssen, Pfizer, and Roche; and payment or honoraria from AbbVie, DKSH, and Recordati. MLF reports consulting fees from AbbVie, GSK, Novartis, Sanofi, and Sierra Oncology and participation in a Keros Therapeutics steering committee. DM reports grants from Imago Biosciences; payment or honoraria from AbbVie, Jazz Pharmaceuticals, and Novartis; participation in a data safety monitoring board for the UK ALL RIC trial; and a leadership role with the European Society for Blood and Marrow Transplantation. JP reports payment or honoraria from CTI Biopharma and participation in a data safety monitoring/advisory board for MorphoSys. LF reports honoraria from GSK and Novartis and advisory board participation with GSK, Medison, and Novartis. AV reports payment or honoraria from AbbVie, AOP, BMS, GSK, Incyte, Novartis, and Roche. SK reports research funding, consulting fees, honoraria, and/or travel grants from AbbVie, AOP Pharma, BMS/Celgene, CTI Biopharma, Geron, GSK, Incyte, Imago Biosciences, iOMEDICO, Janssen, Kartos, MPN Hub, MSD, Novartis, Pfizer, PharmaEssentia, and Sierra Oncology and intellectual property with RWTH Aachen University. FP reports grants from BMS; consulting fees from AbbVie, AOP Health, BMS/Celgene, Karo Pharma, Kyowa Kirin, MEI, Novartis, Roche, Sierra Oncology, and Sumitomo; and payment or honoraria from AbbVie, AOP Health, BMS/Celgene, Novartis, and Roche. STO reports consulting fees from AbbVie, Constellation, BMS, Cogent, CTI Biopharma, Geron, Incyte, Protagonist, and Sierra Oncology. CE, BS, and FJGC report employment with and stock/stock options at GSK. SEL declares no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Thawing permafrost forms "thaw ponds" that accumulate and transport organic carbon (OC), redox-active iron (Fe), and other elements. Although Fe has been shown to act as a control on the microbial degradation of OC in permafrost soils, the role of iron in carbon cycling in thaw ponds remains poorly understood. Here, we investigated Fe-OC interactions in thaw ponds in partially and fully thawed soils ("bog" and "fen" thaw ponds, respectively) in a permafrost peatland complex in Abisko, Sweden, using size separation (large particulate fraction (LPF), small particulate fraction (SPF), and dissolved fraction (DF)), acid extractions, scanning electron microscopy (SEM), Fe K-edge X-ray absorption spectroscopy (XAS), and Fourier Transform Infrared (FTIR) spectroscopy. The bulk total Fe (total suspended Fe) in the bogs ranged from 135 mg/L (mean = 13 mg/L) whereas the fens exhibited higher total Fe (1.5 to 212 mg/L, mean = 30 mg/L). The concentration of bulk total OC (TOC) in the bog thaw ponds ranged from 50 to 352 mg/L (mean = 170 mg/L), higher than the TOC concentration in the fen thaw ponds (8.5 to 268 mg/L, mean = 17 mg/L). The concentration of 1 M HCl-extractable Fe in the bog ponds was slightly lower than that in the fens (93 ± 1.2 and 137 ± 3.5 mg/L Fe, respectively) with Fe predominantly (>75 %) in the DF in both thaw stages. Fe K-edge XAS analysis showed that while Fe(II) was the predominant species in LPF, Fe(III) was more abundant in the DF, indicating that the stage of thawing and particle size may control Fe redox state. Furthermore, Fe(II) and Fe(III) were partially complexed with natural organic matter (NOM, 8 to 80 %) in both thaw ponds. Results of our work suggest that Fe and OC released during permafrost thaw into thaw ponds (re-)associate, potentially protecting OC from microbial decomposition while also stabilizing the redox state of Fe., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Ageing may cause a progressive pro-inflammatory environment and alter functionality of different immune-cell populations. The aim of the present study is to examine the influence of certain serum immunological parameters on hospitalization stay and complications in patients who have suffered a hip fracture., Patients and Methods: A prospective study was carried out with 87 patients (63 women) presenting with either trochanteric femoral fracture or Garden IV displaced subcapital fracture. The average age was 84.43 ± 9, ranging from 65 to 104 years old. Data regarding different comorbidities were recorded at the time of arrival. The morning after patient's admission peripheral blood samples were obtained and a series of immunological parameters were determined: leukocyte formula, platelets count, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), IL-6 and IL-10 levels, T-lymphocytes count, number of cells/mm3 and percentages of CD3, CD4, CD8, CD3-/CD16/56+ (NK cells), and CD 3 -/CD19+ (B cells)., Results: IL-6 serum levels presented a positive and significant correlation with higher levels of CRP (p < 0.001), IL-10 (p = 0.002), and higher percentages of NK CD56+ cells (p = 0.046). IL-6 serum levels at hospitalization presented a positive and significant correlation with a longer hospitalization stay (p = 0.037). Hospitalization increased by 0.231 days for every 1 pg/mL above the IL-6 mean value (40.43 pg/mL). Lower serum IL-10 levels on admission were associated with the appearance of symptomatic urinary tract infection during hospitalization (p = 0.032). Higher number of CD19+ cells/mm 3 presented a significant relationship with pneumonia (p = 0.018) and symptomatic urinary tract infection (p = 0.0019)., Conclusions: IL-6 serum levels on admission showed a positive and significant correlation with a longer hospitalization stay in elderly patients presenting with hip fracture. Lower levels of IL-10 in peripheral blood on admission were associated with symptomatic urinary tract infections. A higher number of CD19+ cells/mm³ was significantly associated with pneumonia and symptomatic urinary tract infection. These immunological variables on admission may serve as risk indicators of complications during hospitalization., Competing Interests: Declaration of competing interest The authors declare there is no conflict of interests., (Copyright © 2024. Published by Elsevier Ltd.)

Objectives: Human babesiosis is an emerging and potentially fatal tick-borne disease caused by intraerythrocytic parasites of the Babesia genus. Among these, Babesia duncani is particularly notable for causing severe and life-threatening illness in humans. Accurate diagnosis and effective disease management hinge on the detection of active B. duncani infections. While molecular assays are available to detect the parasite in blood, a reliable method for identifying biomarkers of active infection remains elusive., Methods: We developed the first B. duncani antigen capture assays, targeting two immunodominant antigens, BdV234 and BdV38. These assays were validated using established in vitro and in vivo B. duncani infection models, and following drug treatment., Results: The assays demonstrated no cross-reactivity with other species such as B. microti, B. divergens, Babesia MO1, or Plasmodium falciparum, and can detect as few as 115 infected erythrocytes/µl of blood. Screening of 1731 blood samples from various biorepositories, including samples previously identified as Lyme and/or B. microti-positive, as well as new specimens from wild mice, revealed no evidence of B. duncani infection or cross-reactivity., Conclusions: These assays hold significant promise for various applications, including point-of-care testing for the early detection of B. duncani in patients, field tests for screening reservoir hosts, and high-throughput screening of blood samples intended for transfusion., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

By replicating damaged nucleotides, error-prone DNA translesion synthesis (TLS) enables the completion of replication, albeit at the expense of fidelity. TLS of helix-distorting DNA lesions, that usually have reduced capacity of basepairing, comprises insertion opposite the lesion followed by extension, the latter in particular by polymerase ζ (Pol ζ). However, little is known about involvement of Pol ζ in TLS of non- or poorly-distorting, but miscoding, lesions such as O 6 -methyldeoxyguanosine (O 6 -medG). Using purified Pol ζ we describe that the enzyme can misincorporate thymidine opposite O 6 -medG and efficiently extend from terminal mismatches, suggesting its involvement in the mutagenicity of O 6 -medG. Surprisingly, O6-medG lesions induced by the methylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) appeared more, rather than less, mutagenic in Pol ζ-deficient mouse embryonic fibroblasts (MEFs) than in wild type MEFs. This suggested that in vivo Pol ζ participates in non-mutagenic TLS of O 6 -medG. However, we found that the Pol ζ-dependent misinsertions at O 6 -medG lesions are efficiently corrected by DNA mismatch repair (MMR), which masks the error-proneness of Pol ζ. We also found that the MNNG-induced mutational signature is determined by the adduct spectrum, and modulated by MMR. The signature mimicked single base substitution signature 11 in the catalogue of somatic mutations in cancer, associated with treatment with the methylating drug temozolomide. Our results unravel the individual roles of the major contributors to methylating drug-induced mutagenesis. Moreover, these results warrant caution as to the classification of TLS as mutagenic or error-free based on in vitro data or on the analysis of mutations induced in MMR-proficient cells., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Combined distal interphalangeal joint (DIP) arthrodesis with proximal interphalangeal joint (PIP) arthroplasty or arthrodesis presents unique challenges. Although less common than isolated surgery for the DIP and PIP joints, with an aging population, combined DIP and PIP procedures are an increasingly encountered occurrence. Anatomical and morphological studies have provided length and width measurement standards for the middle and distal phalanges, allowing for planning to assess the compatibility of strategies. Besides reviewing anatomical studies to provide length and width guidelines for hardware placement, we will also discuss optimal hardware combinations for combined surgical intervention in the DIP and PIP joints. Conflict may exist between hardware used for the DIP arthrodesis and implants used for the PIP arthroplasty. As an example, if K-wires are used for DIP arthrodesis, any intervention in the PIP joint will be compatible. However, if headless screws are used for DIP arthrodesis, these should ideally not reach proximal to the midpoint of the middle phalanx. Other techniques, such as single or multiple oblique screws, and tension bands are compatible with PIP arthroplasty. Hence, options for management of the PIP joint are dependent on the technique used for DIP arthrodesis., Competing Interests: Conflicts of Interest No benefits in any form have been received or will be received related directly to this article., (Copyright © 2024 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Background: Left ventricular outflow tract (LVOT) obstruction in obstructive hypertrophic cardiomyopathy (HCM) is caused by a constellation of abnormalities. This study reviewed outcomes of a comprehensive approach to correct these abnormalities during surgery., Methods: This was a single-institution study of patients with HCM who underwent septal myectomy from 2016 to 2023. Their New York Heart Association functional classification and most recent echocardiogram that estimated LVOT gradient and mitral valve function were tracked., Results: The study included 103 patients with a mean age of 54 years (interquartile range, 40-67 years) and common comorbidities: hypertension (50%) and atrial fibrillation (25%). On average, the preprocedure resting echocardiogram showed an LVOT gradient of 36.4 mm Hg and moderate or severe mitral regurgitation in 50.5% of patients. All patients underwent septal myectomy, and associated abnormalities contributing to LVOT obstruction were addressed. Elongation of the anterior leaflet of the mitral valve was typically treated with papillary muscle realignment (72%). Aberrant papillary muscle heads and elongated secondary chordae tendineae contributing to systolic anterior motion were resected (66%). Myocardial bands, including apicoseptal bands contributing to LVOT obstruction, were resected (68%). With an average follow-up of 4 years, 91% of patients were considered to be in New York Heart Association functional class I or II. Long-term echocardiographic follow-up showed a mean peak LVOT gradient of 11 mm Hg (interquartile range, 4-13 mm Hg). Only 1 patient had more than mild mitral regurgitation., Conclusions: A comprehensive surgical approach to HCM that addresses the entire constellation of abnormalities associated with HCM, including mitral valve anterior leaflet elongation, aberrant or displaced mitral valve subvalvular apparatus, and myocardial bands, leads to outstanding midterm outcomes., Competing Interests: Disclosures Gurion Lantz reports a relationship with Medtronic that includes: consulting or advisory. Ahmad Masri reports a relationship with Attralus that includes: consulting or advisory; with BioMarin Pharmaceutical that includes: consulting or advisory; with Bristol Myers Squibb that includes: consulting or advisory; with BridgeBio Pharma that includes: consulting or advisory; with Cytokinetics that includes: consulting or advisory; with Ionis Pharmaceuticals that includes: consulting or advisory; with Lexicon Pharmaceuticals that includes: consulting or advisory; with Pfizer that includes: consulting or advisory; and with Tenaya Therapeutics that includes: consulting or advisory. Howard K. Song reports a relationship with Medtronic that includes: consulting or advisory. All other authors declare that they have no conflicts of interest., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of the study was to describe how physical exercise affects metabolic control, insulin requirements and carbohydrate intake in children who use hybrid closed-loop systems., Methods: Cross-sectional study design. The sample included 21 children and adolescents diagnosed with type 1 diabetes. During the study, participants were monitored for a period of 7 days to gather comprehensive data on these factors., Results: Nine participants (42.9%) had switched to exercise mode to raise the target glucose temporarily to 150 mg/dL. The HbA1c values ranged from 5.5% to 7.9% (median, 6.5%; IQR, 0.75). The percentage of time within the target range of 70-180 mg/dL was similar; however, there was an increased duration of hyperglycaemia and more autocorrections on exercise days. The time spent in severe hyperglycaemia (>250 mg/dL) increased by 2.7% in exercise compared to non-exercise days (P = .02). It is worth noting that hypoglycaemic episodes did not increase during the exercise days compared with non-exercise days., Conclusion: The hybrid closed-loop system was effective and safe in children and adolescents with type 1 diabetes during the performance of competitive sports in real life., (Copyright © 2024 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.)

Objective: To assess the efficacy and safety of combined High-Intensity Focused Ultrasound (HIFU) and Holmium Laser Enucleation of the Prostate (HoLEP) in treating patients with both localized prostate cancer (PCa) and prostate > 60 g., Methods: All patients who underwent HIFU for treatment of localized PCa were prospectively enrolled in our study. We reviewed records of patients undergoing procedures from January 2016 to January 2023. For patients with prostate sizes > 60 g, HoLEP was offered before HIFU to prevent worsened urinary symptoms post-treatment. Oncological outcomes-prostatic-specific (PSA) kinetics, recurrence rates, treatment failure - and functional results-Sexual Health Inventory for Men (SHIM), International Prostate Symptoms Score (IPSS), and urinary complications were compared between patients undergoing combined HoLEP and HIFU with those underwent HIFU-monotherapy., Results: Among 100 patients, 74 underwent HIFU-monotherapy and 26 underwent the combined HoLEP and HIFU. The majority had intermediate-risk PCa (67%). Pathologic assessment of HoLEP specimens showed no tumor evidence in 57% of cases. In comparison to the HIFU-only group, the combined group exhibited significantly lower PSA metrics across various intervals, however, no differences were found regarding overall and infield recurrences and treatment failure rates. While the combined treatment initially resulted in higher incontinence rates and shorter catheterization durations (P < 0.001), no significant difference in IPSS was observed during subsequent follow-ups., Conclusion: HoLEP and HIFU can be safely combined for the treatment of PCa in patients with >60 g prostate volume without compromising early oncological outcomes thereby expanding the therapeutic scope of HIFU in treating patients with localized PCa and large adenomas., 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.)

Background: Intima proliferation and in-stent restenosis is a challenging situation in interventional treatment of small vessel obstruction. Al/Al 2 O 3 nanowires have been shown to accelerate vascular endothelial cell proliferation and migration in vitro, while suppressing vascular smooth muscle cell growth. Moreover, surface modification of Al/Al 2 O 3 nanowires with poly[bis(2,2,2-trifluoromethoxy)phosphazene (PTFEP) coating enables further advantages such as reduced platelet adhesion. Therefore, the study's goal was to compare the biocompatibility of novel Al/Al 2 O 3  + PTFEP coated nanowire bare-metal stents to uncoated control stents in vivo using optical coherence tomography (OCT), quantitative angiography and histomorphometric assessment., Methods: 15 Al/Al 2 O 3  + PTFEP coated and 19 control stents were implanted in the cervical arteries of 9 Aachen minipigs. After 90 days, in-stent stenosis, thrombogenicity, and inflammatory response were assessed. Scanning electron microscopy was used to analyse the stent surface., Results: OCT analysis revealed that neointimal proliferation in Al/Al 2 O 3  + PTFEP coated stents was significantly reduced compared to control stents. The neointimal area was 1.16 ± 0.77 mm 2 in Al/Al 2 O 3  + PTFEP coated stents vs. 1.98 ± 1.04 mm 2 in control stents (p = 0.004), and the neointimal thickness was 0.28 ± 0.20 vs. 0.47 ± 0.10 (p = 0.003). Quantitative angiography showed a tendency to less neointimal growth in coated stents. Histomorphometry showed no significant difference between the two groups and revealed an apparent inflammatory reaction surrounding the stent struts., Conclusions: At long-term follow-up, Al/Al 2 O 3  + PTFEP coated stents placed in peripheral arteries demonstrated good tolerance with no treatment-associated vascular obstruction and reduced in-stent restenosis in OCT. These preliminary in vivo findings indicate that Al/Al 2 O 3  + PTFEP coated nanowire stents may have translational potential to be used for the prevention of in-stent restenosis., Competing Interests: Declaration of competing interest The following co-authors hold a patent which is related to the contents of the manuscript: Ayman Haidar, Michael Veith, Cenk Aktas, Hashim Abdul-Khaliq, Ali Awadelkareem. Patent title: Beschichtung oder mit einer Beschichtung versehener Körper sowie Verfahren zu deren Herstellung. DAKZ 10 2017 113 7580. 2018; Deutsches Patent- und Markenamt. https://register.dpma.de/DPMAregister/pat/register?AKZ=1020171137580. In addition to this we declare that we have no conflicts of interest to disclose regarding this publication. If any conflicts of interest arise during the course of the publication, we will promptly disclose them to the editor of the publication or to the appropriate parties., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Clinical prediction models provide risks of health outcomes that can inform patients and support medical decisions. However, most models never make it to actual implementation in practice. A commonly heard reason for this lack of implementation is that prediction models are often not externally validated. While we generally encourage external validation, we argue that an external validation is often neither sufficient nor required as an essential step before implementation. As such, any available external validation should not be perceived as a license for model implementation. We clarify this argument by discussing 3 common misconceptions about external validation. We argue that there is not one type of recommended validation design, not always a necessity for external validation, and sometimes a need for multiple external validations. The insights from this paper can help readers to consider, design, interpret, and appreciate external validation studies., Competing Interests: Declaration of competing interest There are no competing interests for any author., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Chronic Chagas cardiomyopathy (CCC) has unique pathogenic and clinical features with worse prognosis than other causes of heart failure (HF), despite the fact that patients with CCC are often younger and have fewer comorbidities. Patients with CCC were not adequately represented in any of the landmark HF studies that support current treatment guidelines. PARACHUTE-HF (Prevention And Reduction of Adverse outcomes in Chagasic Heart failUre Trial Evaluation) is an active-controlled, randomized, phase IV trial designed to evaluate the effect of sacubitril/valsartan 200 mg twice daily vs enalapril 10 mg twice daily added to standard of care treatment for HF. The study aims to enroll approximately 900 patients with CCC and reduced ejection fraction at around 100 sites in Latin America. The primary outcome is a hierarchical composite of time from randomization to cardiovascular death, first HF hospitalization, or relative change from baseline to week 12 in NT-proBNP levels. PARACHUTE-HF will provide new data on the treatment of this high-risk population. (Efficacy and Safety of Sacubitril/Valsartan Compared With Enalapril on Morbidity, Mortality, and NT-proBNP Change in Patients With CCC [PARACHUTE-HF]; NCT04023227)., Competing Interests: Funding Support and Author Disclosures PARACHUTE-HF is funded by Novartis Pharma AG. Dr Bocchi has received consulting fees from Servier, AstraZeneca, and Boehringer Ingelheim; has received travel/hotel/registration fees from Servier; has served as a member of the steering committee for Servier, Novartis, Boehringer Ingelheim; has received research grant support through the Heart Institute (Incor) from Janssen, Bayer/Merck, AstraZeneca, Boehringer Ingelheim, Pfizer, and Novartis; and has received honoraria from Servier, Novartis, AstraZeneca, and Boehringer Ingelheim. Dr Echeverria has received research support from Pfizer, Novartis, and Boehringer Ingelheim; has received consulting fees from Novartis and Boehringer Ingelheim, AstraZeneca, and Bayer. Drs Demacq, Chiang, Ferrari, and Gimpelewicz are Novartis employees. Dr de Barros e Silva has received research support from Pfizer, Bayer, and Roche Diagnostics; and has received consulting fees from Pfizer, Bayer, and Roche Diagnostics. Dr Morillo has received research support from Abbott, Medtronic, and Novartis; and has received consulting fees from Abbott, Medtronic, Novartis, and Pfizer. Dr Ramires has received speaker fees from AstraZeneca, Amgen, Pfizer, Novartis, and Bristol; and has received consulting fees from Novartis and Bristol. Dr Bahit has received honoraria (modest) from Merck Sharp & Dohme, Pfizer, Bristol Myers Squibb, CSL Behring, Janssen, and Boehringer Ingelheim. Dr Chavez-Mendoza has received a speaker fee from Novartis. Dr McMurray has received payments through Glasgow University from work on clinical trials, consulting, and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GlaxoSmithKline, KBP Biosciences, and Novartis; has received personal consultancy fees from Alnylam Pharma, Bayer, Bristol Myers Squibb, George Clinical PTY Ltd, Ionis Pharma, Novartis, Regeneron Pharma, and River 2 Renal Corporation; has received personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharma. Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica health, Intas Pharma, J.B. Chemicals and Pharma Ltd, Lupin Pharma, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharma, The Corpus, Translation Research Group, and Translational Medicine Academy; and is a director of Global Clinical Trial Partners Ltd. Dr Lopes has received research support from Bristol Myers Squibb, GlaxoSmithKline, Medtronic, and Pfizer; and has received consulting fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer, and Portola. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: Unlike high-income countries (HICs), there are few early intervention services for psychosis in low-and middle-income countries (LAMICs). In HICs, research spurred the growth of such services. Little is known about the state of EIP research in LAMICs, which we address by examining their research output and collaborations vis-à-vis that of HICs., Methods: We conducted a search in Scopus database for early psychosis publications in scientific journals since 1980. Data from each record, including title, author affiliation, and date, were downloaded. For HIC-LAMIC collaborations, data on first, corresponding and last authors' affiliations, and funding were manually extracted. Descriptive statistics and social network analysis were conducted., Results: Globally, early psychosis publications increased from 24 in 1980 to 1297 in 2022. Of 16,942 included publications, 16.1 % had LAMIC authors. 71.3 % involved authors from a single country (regardless of income level). 21.9 % were collaborations between HICs, 6.6 % between HICs and LAMICs, and 0.2 % among LAMICs. For research conducted in LAMICs and involving HIC-LAMIC collaborations, the first, last, and corresponding authors were LAMIC-based in 71.8 %, 60.7 %, and 63.0 %, respectively. These positions were dominated (80 %) by authors from four LAMICs. 29.4 % of the HIC-LAMIC subset was funded solely by LAMIC funders, predominantly two LAMICs., Conclusions: LAMICs are starkly underrepresented in the otherwise flourishing body of early psychosis research. They have far fewer collaborations and less funding than HICs. Closing these gaps in LAMICs where most of the world's youth live is imperative to generate the local knowledge needed to strengthen early psychosis services that are known to improve outcomes., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by a CTG repeat expansion in the 3' untranslated region of the DM1 protein kinase gene. Characteristic degenerative muscle symptoms include myotonia, atrophy, and weakness. We previously proposed an Musashi homolog 2 (MSI2)>miR-7>autophagy axis whereby MSI2 overexpression repressed miR-7 biogenesis that subsequently de-repressed muscle catabolism through excessive autophagy. Because the DM1 HSA LR mouse model expressing expanded CUG repeats shows weak muscle-wasting phenotypes, we hypothesized that MSI2 overexpression was sufficient to promote muscle dysfunction in vivo., Methods: By means of recombinant AAV murine MSI2 was overexpressed in neonates HSA LR mice skeletal muscle to induce DM1-like phenotypes., Results: Sustained overexpression of the murine MSI2 protein in HSA LR neonates induced autophagic flux and expression of critical autophagy proteins, increased central nuclei and reduced myofibers area, and weakened muscle strength. Importantly, these changes were independent of MBNL1, MBNL2, and Celf1 protein levels, which remained unchanged upon Msi2 overexpression., Conclusions: Globally, molecular, histological, and functional data from these experiments in the HSA LR mouse model confirms the pathological role of MSI2 expression levels as an atrophy-associated component that impacts the characteristic muscle dysfunction symptoms in DM1 patients., Competing Interests: Declaration of competing interest M.S-A., R.A., and A.B. are inventors in patent PCT/EP2022/054129., (© 2023 The Authors. Published by Elsevier B.V. on behalf of Chang Gung University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).)

In recent years, owing to advances in our understanding of hepatocarcinogenesis, rare primary liver cancers (PLCs), including combined hepatocellular-cholangiocarcinoma, fibrolamellar carcinoma, and hepatic epithelioid hemangioendothelioma have garnered increased attention. In this position paper, an international panel of experts representing oncology, hepatology, pathology, radiology, surgery, and molecular biology has summarised the available information and evidence on the pathogenesis, diagnosis, and treatment of rare PLCs. While clinical trials of systemic treatments are underway for some rare PLCs, it is evident that more research, involving national and international collaboration, is required., (Copyright © 2024. Published by Elsevier B.V.)

While numerous membrane-bound complement inhibitors protect the body's cells from innate immunity's autoaggression, soluble inhibitors like complement factor I (FI) are rarely produced outside the liver. Previously, we reported the expression of FI in non-small cell lung cancer (NSCLC) cell lines. Now, we assessed the content of FI in cancer biopsies from lung cancer patients and associated the results with clinicopathological characteristics and clinical outcomes. Immunohistochemical staining intensity did not correlate with age, smoking status, tumor size, stage, differentiation grade, and T cell infiltrates, but was associated with progression-free survival (PFS), overall survival (OS) and disease-specific survival (DSS). Multivariate Cox analysis of low vs. high FI content revealed HR 0.55, 95 % CI 0.32-0.95, p=0.031 for PFS, HR 0.51, 95 % CI 0.25-1.02, p=0.055 for OS, and HR 0.32, 95 % CI 0.12-0.84, p=0.021 for DSS. Unfavorable prognosis might stem from the non-canonical role of FI, as the staining pattern did not correlate with C4d - the product of FI-supported degradation of active complement component C4b. To elucidate that, we engineered three human NSCLC cell lines naturally expressing FI with CRISPR/Cas9 technology, and compared the transcriptome of FI-deficient and FI-sufficient clones in each cell line. RNA sequencing revealed differentially expressed genes engaged in intracellular signaling pathways controlling proliferation, apoptosis, and responsiveness to growth factors. Moreover, in vitro colony-formation assays showed that FI-deficient cells formed smaller foci than FI-sufficient NSCLC cells, but their size increased when purified FI protein was added to the medium. We postulate that a non-canonical activity of FI influences cellular physiology and contributes to the poor prognosis of lung cancer patients., Competing Interests: Declaration of Competing Interest MO and AMB are named as inventors in patent WO2016038055A1 for the anti-C4d antibody used in this study. The other authors declare no conflict of interest. All authors have read the journal's policy on disclosure of potential conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)