tbuckley/cabot-search huggingface dataset:
Human scalp hair follicles can “taste”: Chemosensory signalling via the bitter taste receptor, TAS2R4, inhibits hair growth <i>ex vivo</i>
Authors: Jennifer Gherardini, Thomas Rouillé, Rivka C Stone, Markus Fehrholz, Wolfgang Funk, Jose Rodríguez-Feliz, Alan J Bauman, Tamás Bíró, Jérémy Chéret, Ralf Paus
Journal: British Journal of Dermatology (2025)

Abstract Background Taste receptors (TRs) exert many ‘non-gustatory’ chemosensory functions beyond the sensation of taste. Recently, human keratinocytes were found to express some bitter TRs, whose physiological functions remain unknown. Since we had discovered that human scalp hair follicles (HFs) use olfactory receptors to regulate their growth, we hypothesized that some bitter TRs may exert a similar function. Objectives To explore whether human scalp HFs express the bitter TR, TAS2R4, whether its stimulation with cognate agonists or its selective knockdown impacts key human HF functions and, if yes, how. Methods TAS2R4 mRNA and protein expression were assessed in situ, and organ-cultured scalp HFs were stimulated with the TAS2R4-agonistic natural sweetener, rebaudioside A (Reb A), in the presence/absence of TAS2R4 siRNA. Subsequently, changes in hair growth, growth factor expression, and HF gene expression were assessed ex vivo. Results TAS2R4 mRNA and protein are mainly expressed in the outer root sheath and matrix of human anagen scalp HFs. Stimulating these with Reb-A ex vivo initially inhibits hair matrix keratinocyte proliferation, followed by enhanced intrafollicular production of catagen-promoting TGF-β2. This leads to TGF-β-driven premature catagen entry, which can be antagonized by TGF-β-neutralizing antibodies. Premature catagen induction is also seen with other known TAS2R4 agonists, while TAS2R4 knockdown in the presence of Reb-A promotes hair growth, thus documenting the TAS2R4-dependence of the observed HF effects of Reb-A. Gene expression profiling (RNA-seq) revealed differential transcriptional signatures consistent with TAS2R4-mediated changes in cell cycle control and TGF-β pathway signalling. Conclusion Our study uncovers that human scalp HFs engage in chemosensation via bitter TRs to regulate their growth, matrix keratinocyte proliferation, growth factor production, and overall gene expression. Specifically, we demonstrate that a simple tastant like Reb-A can promote the anagen-catagen switch of human scalp HFs, their TGF-β2 production, and modulate both HF keratinocyte proliferation and intrafollicular gene transcription in a TAS2R4-dependent manner. This expands our understanding of bitter TR-mediated chemosensation in human skin and invites a novel, drug-free strategy for inhibiting unwanted hair growth (hirsutism, hypertrichosis) by targeting TAS2R4, e.g. via topical Reb-A.
Biomarkers of histological response in lanifibranor-treated patients with metabolic dysfunction-associated steatohepatitis
Authors: Jérôme Boursier, Hugo Hervé, Marine Roux, Manal F Abdelmalek, Sven M Francque, Pierre Broqua, Jean-Louis Junien, Jean-Louis Abitbol, Philippe Huot-Marchand, Lucile Dzen, Michael P Cooreman, Sanjaykumar Patel
Journal: Clinical Gastroenterology and Hepatology (2025)
Alpha synuclein co-pathology is associated with accelerated amyloid-driven tau accumulation in Alzheimer’s disease
Authors: Nicolai Franzmeier, Sebastian Niclas Roemer-Cassiano, Alexander Maximilian Bernhardt, Amir Dehsarvi, Anna Dewenter, Anna Steward, Davina Biel, Lukas Frontzkowski, Zeyu Zhu, Johannes Gnörich, Julia Pescoller, Fabian Wagner, Fabian Hirsch, Hannah de Bruin, Rik Ossenkoppele, Carla Palleis, Felix Strübing, Michael Schöll, Johannes Levin, Matthias Brendel, Günter U. Höglinger
Journal: Molecular Neurodegeneration (2025)

Aggregated alpha-Synuclein (αSyn) is a hallmark pathology in Parkinson's disease but also one of the most common co-pathologies in Alzheimer's disease (AD). Preclinical studies suggest that αSyn can exacerbate tau aggregation, implying that αSyn co-pathology may specifically contribute to the Aβ-induced aggregation of tau that drives neurodegeneration and cognitive decline in AD. To investigate this, we combined a novel CSF-based seed-amplification assay (SAA) to determine αSyn positivity with amyloid- and tau-PET neuroimaging in a large cohort ranging from cognitively normal individuals to those with dementia, examining whether αSyn co-pathology accelerates Aβ-driven tau accumulation and cognitive decline. In 284 Aβ-positive and 308 Aβ-negative subjects, we employed amyloid-PET, Flortaucipir tau-PET, and a CSF-based αSyn seed-amplification assay (SAA) to detect in vivo αSyn aggregation. CSF p-tau181 measures were available for 384 subjects to assess earliest tau abnormalities. A subset of 155 Aβ-positive and 135 Aβ-negative subjects underwent longitudinal tau-PET over approximately 2.5 years. Using linear regression models, we analyzed whether αSyn SAA positivity was linked to stronger Aβ-related increases in baseline fluid and PET tau biomarkers, faster Aβ-driven tau-PET increase, and more rapid cognitive decline. αSyn SAA positivity was more common in Aβ + vs. Aβ- subjects and increased with clinical severity (p < 0.001). Most importantly, αSyn positivity was also associated with greater amyloid-associated CSF p-tau181 increases (p = 0.005) and higher tau-PET levels in AD-typical brain regions (p = 0.006). Longitudinal analyses confirmed further that αSyn positivity was associated with faster amyloid-related tau accumulation (p = 0.029) and accelerated amyloid-related cognitive decline, potentially driven driven by stronger tau pathology. Our findings suggest that αSyn co-pathology, detectable via CSF-based SAAs, is more prevalent in advanced AD and contributes to the development of aggregated tau pathology thereby driving faster cognitive decline. This highlights that a-Syn co-pathology may specifically accelerate amyloid-driven tau pathophysiology in AD, underscoring the need to consider αSyn in AD research and treatment strategies.
A multi-metabolite signature robustly predicts long-term mortality in the PREDIMED trial and several US cohorts
Authors: Gonzalo Fernández-Duval, Cristina Razquin, Fenglei Wang, Huan Yun, Jie Hu, Marta Guasch-Ferré, Kathryn Rexrode, Raji Balasubramanian, Jesús García-Gavilán, Miguel Ruiz-Canela, Clary B Clish, Dolores Corella, Enrique Gómez-Gracia, Miquel Fiol, Ramón Estruch, José Lapetra, Montse Fitó, Luis Serra-Majem, Emilio Ros, Liming Liang, Courtney Dennis, Eva M Asensio, Olga Castañer, Francis Planes, Jordi Salas-Salvadó, Frank B Hu, Estefanía Toledo, Miguel Ángel Martínez-González
Journal: Metabolism (2025)
Multi-task benchmarking of spatially resolved gene expression simulation models
Authors: Xiaoqi Liang, Marni Torkel, Yue Cao, Jean Yee Hwa Yang
Journal: Genome biology (2025)

Abstract Background Computational methods for spatially resolved transcriptomics (SRT) are often developed and assessed using simulated data. The effectiveness of these evaluations relies on the ability of simulation methods to accurately reflect experimental data. However, a systematic evaluation framework for spatial simulators is currently lacking. Results Here, we present SpatialSimBench, a comprehensive evaluation framework that assesses 13 simulation methods using ten distinct STR datasets. We introduce simAdaptor, a tool that extends single-cell simulators by incorporating spatial variables, enabling them to simulate spatial data. SimAdaptor ensures SpatialSimBench is backwards compatible, facilitating direct comparisons between spatially aware simulators and existing non-spatial single-cell simulators through the adaption. Using SpatialSimBench, we demonstrate the feasibility of leveraging existing single-cell simulators for SRT data and highlight performance differences among methods. Additionally, we evaluate the simulation methods based on a total of 35 metrics across data property estimation, various downstream analyses, and scalability. In total, we generated 4550 results from 13 simulation methods, ten spatial datasets, and 35 metrics. Conclusions Our findings reveal that model estimation can be influenced by distribution assumptions and dataset characteristics. In summary, our evaluation framework provides guidelines for selecting appropriate methods for specific scenarios and informs future method development.
Genitourinary Pathology Society and International Society of Urological Pathology White Paper on Defining Indolent Prostate Cancer: Call for a Multidisciplinary Approach
Authors: Rajal B Shah, Gladell P Paner, Liang Cheng, Angelo M De Marzo, Cristina Magi-Galluzzi, Murali Varma, Ming Zhou, Ali Amin, Mahul B Amin, Manju Aron, Isabela W Cunha, Jonathan I Epstein, Samson W Fine, Aiman Haider, Kenneth A Iczkowski, James G Kench, Lakshmi Priya Kunju, Sambit K Mohanty, Rodolfo Montironi, George J Netto, Chin-Chen Pan, Priya Rao, John R Srigley, Guido Sauter, Puay Hoon Tan, Toyonori Tsuzuki, Theodorus H van der Kwast, Geert J van Leenders, Glen Kristiansen
Journal: European Urology (2025)
Reply to Alexandra Masson-Lecomte. Bladder Cancer Recurrence Following Management of Upper Tract Urothelial Carcinoma: Balancing Prevention and Iatrogenicity. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2025.01.004
Authors: Thomas van Doeveren, Katja K H Aben, Pim J van Leeuwen, Joost L Boormans
Journal: European Urology (2025)
Efficacy and Safety of High- vs Low-Dose Sirolimus in Patients with Kaposiform Hemangioendothelioma: A Randomized Clinical Trial
Authors: Jiangyuan Zhou, Yuru Lan, Tong Qiu, Zixin Zhang, Xue Gong, Xuepeng Zhang, Congxia Yang, Zilong Zhou, Yujia Zhang, Min Yang, Jianlei Fu, Chunshui He, Qiang Peng, Fan Hu, Chunchao Xia, Feiteng Kong, Siyuan Chen, Yi Ji
Journal: Journal of the American Academy of Dermatology (2025)
Electro-ion Therapy for Xanthelasma Palpebrarum: Potential as a Low-Recurrence and Cost-Effective Treatment
Authors: Xiaowen Huang, Siqi Zheng, Keshav Raj Gyawali, Pingjiao Chen, Qian Li, Menghua Zhu, Jia Guo, Sijin He, Yue Zheng
Journal: Journal of the American Academy of Dermatology (2025)
Continued year-on-year improvement in hair density with systemic minoxidil in women with female pattern hair loss: A case series
Authors: Daniella Kushnir-Grinbaum, Daranporn Triwongwaranat, Bevin Bhoyrul, John Frewen, Nicole Yoong, Blake R C Smith, Rodney Sinclair
Journal: Journal of the American Academy of Dermatology (2025)
Patient-reported quality of life and aesthetic satisfaction continues to improve for 1-year after Mohs surgery: A Multicenter Prospective Cohort Study
Authors: Inge J Veldhuizen, Stephen W Dusza, Alyce Kuo, Abdullah Aleisa, Elliot Blue, Sushmita Adhikari, Umer Nadir, Kim Le, Soroush Kazemi, Adam V Sutton, Rajiv I Nijhawan, Daniel B Eisen, Anthony M Rossi, Divya Srivastava, Ashley Wysong, Kishwer S Nehal, Erica H Lee
Journal: Journal of the American Academy of Dermatology (2025)
A cisplatin prodrug-based self-assembling ozone delivery nanosystem sensitizes radiotherapy in triple-negative breast cancer
Authors: Tianyue Xu, Dan Zheng, Meixu Chen, Linlin Song, Zhihui Liu, Yan Cheng, Yujie Zhao, Liwen Huang, Yixuan Li, Zhankun Yang, Cong Li, Biao Dong, Jing Jing, Hubing Shi
Journal: Acta Pharmaceutica Sinica B (2025)
Factors predicting disordered eating and the prevalence of eating disorders in adolescent elite athletes, trained athletes and a reference group: a prospective controlled two-step study
Authors: Christine Sundgot-Borgen, Jorunn Sundgot-Borgen, Nina Sølvberg, Monica Klungland Torstveit, Margo Mountjoy, Therese Fostervold Mathisen
Journal: British Journal of Sports Medicine (2025)

Objective To prospectively examine the prevalence of diagnosed eating disorders (ED-diagnosis), ED-symptoms and factors predicting ED-symptoms in three male and female high school student groups: elite athletes, trained athletes and a non-athlete reference group at baseline (T1) and 1-year follow-up (T2). Methods A survey was administered at baseline (T1) (n=1186) and 1-year follow-up (T2) (n=1144) (step-one). Participants classified with ED-symptoms by the Eating Disorder Examination Questionnaire (EDEQ 6.0) at T2 were invited to a diagnostic interview (step-two). Results Prevalence of ED-diagnosis for males and females were 6.9% and 9.3% in elite athletes, 5.9% and 11.2% in trained athletes and 3.0% and 11.9% in references, respectively. No group differences were statistically significant. Male references had more ED-symptoms compared with elite and trained male athletes (EDEQ-global score 0.81 vs &lt;0.55), while elite female athletes had fewer ED-symptoms compared with trained female athletes and female references (EDEQ-global score 1.14 vs &gt;1.59). Trained female athletes increased ED-symptoms over time, whereas elite female athletes consistently had fewer ED-symptoms in comparison. High ED-symptom presentation was predicted by high body mass index and more psychological distress in males, whereas for females, ED-symptoms were predicted by lower resilience, more psychological distress and being a non-athlete reference. Conclusion No statistically significant group differences in the prevalence of ED-diagnosis were observed between elite athletes, trained athletes and a non-athlete reference group. Female elite athletes had fewer ED-symptoms compared with other female groups, and male references had more ED-symptoms compared with male athlete groups. Preventive measures that address psychological resilience and distress should be considered. Trial registration number NCT04003675 .
Progression of Cerebral Small Vessel Disease Among Neurologically Asymptomatic Middle-Aged Individuals With Type 1 Diabetes
Authors: Aleksi Tarkkonen, Iiris Kyläheiko, Jussi Inkeri, Marika I. Eriksson, Lena M. Thorn, Paula A. Summanen, Turgut Tatlisumak, Per-Henrik Groop, Jukka Putaala, Daniel Gordin, Juha Martola
Journal: Diabetes Care (2025)

OBJECTIVE To investigate the potential progression rate of cerebral small vessel disease (CSVD) in brain MRI among neurologically asymptomatic middle-aged individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS A total of 172 individuals with type 1 diabetes were re-examined with brain MRI 7.5 years after their initial visit. Baseline predictors of changes in CSVD, particularly cerebral microbleeds (CMBs) and white matter hyperintensities (WMHs) were analyzed. RESULTS The proportion of individuals with type 1 diabetes with CSVD increased from 36% to 70% (P &amp;lt; 0.001), CMBs increased from 17% to 33% (P &amp;lt; 0.001), and WMHs from 23% to 63% (P &amp;lt; 0.001) at follow-up. The increase in CMBs was associated with baseline systolic blood pressure, HbA1c, and preexisting CMBs. The increases in CSVD and WMHs were associated only with age. CONCLUSIONS The prevalence of CSVD doubled over a 7.5-year period in middle-aged individuals with type 1 diabetes.
TOP-1 Priority: Advancing Biomarker-Driven Patient Selection for the use of ADCs
Authors: William R. Gwin, Sara A. Hurvitz
Journal: Clinical Cancer Research (2025)

Abstract A recent study reports the emergence of TOP1 mutations as a potential mechanism of resistance to topoisomerase inhibitor-ADCs in advanced breast cancer. This is a crucial first step in identifying biomarkers to guide ADC therapy selection and underscores the need for caution when sequencing ADCs with similar payloads.
Evaluation of instruments assessing peripheral arthritis in spondyloarthritis: an analysis of the ASAS-PerSpA study
Authors: Dafne Capelusnik, Clementina Lopez-Medina, Désirée van der Heijde, Robert Landewé, Maxime Dougados, Joachim Sieper, Anna Molto, Sofia Ramiro
Journal: Annals of the Rheumatic Diseases (2025)

To assess construct validity, including known-group discrimination, of the currently available disease activity instruments assessing peripheral arthritis in spondyloarthritis (SpA). In this analysis from the Assessment of SpondyloArthritis International Society (ASAS)-PerSpA study, patients with a diagnosis of axial SpA, peripheral SpA, or psoriatic arthritis (PsA) were included. The disease activity instruments evaluated were the Patient Global Assessment (PGA), Bath Ankylosing Spondylitis Disease Activity Index, Axial Spondyloarthritis Disease Activity Score, Disease Activity Index for PsA (DAPSA), Swollen Joint Count (SJC), Tender Joint Count, Disease Activity Score (DAS) 28, DAS44, and C-reactive protein (CRP). Construct validity was assessed through correlations with external constructs (Bath Ankylosing Spondylitis Functional Index, ASAS Health Index, and Euro Quality of Life 5 Dimensions) and known-group discrimination (active/inactive disease based on a combination of PGA [≥5/<5]), and SJC (≥1/0 and ≥2/<2) was analysed using standardised mean differences (SMDs). In total, 4121 patients were included (mean age 45 [SD, 14] years, 61% males). When assessing the construct validity through correlations with external constructs, all instruments performed excellently (100% hypotheses confirmed). When assessing known-group discrimination, all disease activity measures, except CRP, presented SMDs ≥ 0.8 (good discrimination), with higher SMDs observed for DAS28 followed by DAPSA. Results were similar across disease phenotypes. Considering all combinations of PGA and SJC to discriminate between active/inactive disease, a better performance was observed for the composite scores, including joint counts. In our construct validity analysis, all disease activity instruments assessing peripheral arthritis had a good performance as reflected in the correlations with external constructs and the known-group discrimination. The highest discriminatory capacity to distinguish between 'active/inactive disease' was observed for composite scores, including joint counts, like DAS28 and DAPSA.
Retinal fundus imaging as biomarker for ADHD using machine learning for screening and visual attention stratification
Authors: Hangnyoung Choi, JaeSeong Hong, Hyun Goo Kang, Min-Hyeon Park, Sungji Ha, Junghan Lee, Sangchul Yoon, Daeseong Kim, Yu Rang Park, Keun-Ah Cheon
Journal: npj Digital Medicine (2025)

Attention-deficit/hyperactivity disorder (ADHD), characterized by diagnostic complexity and symptom heterogeneity, is a prevalent neurodevelopmental disorder. Here, we explored the machine learning (ML) analysis of retinal fundus photographs as a noninvasive biomarker for ADHD screening and stratification of executive function (EF) deficits. From April to October 2022, 323 children and adolescents with ADHD were recruited from two tertiary South Korean hospitals, and the age- and sex-matched individuals with typical development were retrospectively collected. We used the AutoMorph pipeline to extract retinal features and used four types of ML models for ADHD screening and EF subdomain prediction, and we adopted the Shapely additive explanation method. ADHD screening models achieved 95.5%-96.9% AUROC. For EF function stratification, the visual and auditory subdomains showed strong (AUROC > 85%) and poor performances, respectively. Our analysis of retinal fundus photographs demonstrated potential as a noninvasive biomarker for ADHD screening and EF deficit stratification in the visual attention domain.
Activated T cells break tumor immunosuppression by macrophage re-education
Authors: Rosa Trotta, Silvia Rivis, Shikang Zhao, Marie-Pauline Orban, Sarah Trusso Cafarello, Iris Charatsidou, Joanna Pozniak, Jonas Dehairs, Lotte Vanheer, Carlos A. Pulido Vicuna, Veerle Boecxstaens, Oliver Bechter, Francesca M. Bosisio, Johannes V. Swinnen, Jean-Christophe Marine, Massimiliano Mazzone
Journal: Cancer Discovery (2025)

Abstract Here, we observe that in human and murine melanomas, T-cell activation abates hematopoietic prostaglandin-D2 synthase (HPGDS) transcription in tumor-associated macrophages (TAMs) through TNFα signaling. Mechanistically, HPGDS installs a Prostaglandin-D2 (PGD2) autocrine loop in TAMs via DP1 and DP2 activation that sustains their pro-tumoral phenotype and promotes paracrine inhibition of CD8+ T cells via a PGD2-DP1 axis. Genetic or pharmacologic HPGDS targeting induces anti-tumoral features in TAMs and favors CD8+ T-cell recruitment, activation, and cytotoxicity, altogether sensitizing tumors to αPD1. Conversely, HPGDS overexpression in TAMs or systemic TNFα blockade sustains a pro-tumoral environment and αPD1-resistance, preventing the downregulation of HPGDS by T cells. Congruently, patients and mice resistant to αPD1 fail to suppress HPGDS in TAMs, reinforcing the evidence that circumventing HPGDS is necessary for efficient αPD1 treatment. Overall, we disclose a mechanism whereby T-cell activation controls the innate immune system, and we suggest HPGDS/PGD2 targeting to overcome immunotherapy resistance.
Finerenone Reduces New-Onset Atrial Fibrillation across the Spectrum of Cardio-Kidney-Metabolism: the FINE-HEART Pooled Analysis
Authors: Maria A Pabon, Gerasimos Filippatos, Brian L Claggett, Michael Zi Miao, Akshay S Desai, Pardeep S Jhund, Alasdair Henderson, Meike Brinker, Patrick Schloemer, Lucas Hofmeister, Li Li, Carolyn S P Lam, Michele Senni, Sanjiv J Shah, Adriaan A Voors, Faiez Zannad, Peter Rossing, Luis M Ruilope, Stefan D Anker, Bertram Pitt, Rajiv Agarwal, John J V McMurray, Scott D Solomon, Muthiah Vaduganathan
Journal: Journal of the American College of Cardiology (2025)
Impact of Heart Failure Severity on Vutrisiran Efficacy in Transthyretin Amyloidosis with Cardiomyopathy
Authors: Mathew S Maurer, Ronald M Witteles, Pablo Garcia-Pavia, Farooq H Sheikh, Caroline Morbach, Daniel Rodriguez Duque, Emre Aldinc, Satish A Eraly, Julian D Gillmore
Journal: Journal of the American College of Cardiology (2025)
Use of Cardiac Rehabilitation in Older Patients with Myocardial Infarction Complicated by Cardiogenic Shock
Authors: Mohammed Essa, Sérgio R R Decker, Lichen Liang, Yang Song, Merilyn S Varghese, Jose F Figueroa, Laurence Sperling, Gregg C Fonarow, Steven J Keteyian, Michael P Thompson, Alexis Beatty, Dhruv S Kazi
Journal: Journal of the American College of Cardiology (2025)
Managing Cardiogenic Shock Caused by Acute Myocardial Infarction
Authors: Eric P Cantey, Aaron Lopacinski, Milan Seth, David E Hamilton, Elias J Dayoub, Siddharth Gandhi, Mir B Basir, Amir Kaki, Ryan D Madder, Devraj Sukul, Hitinder S Gurm
Journal: Journal of the American College of Cardiology (2025)
Effect of Targeting apoC-III with Plozasiran on Lipoprotein Particle Size and Number in Hypertriglyceridemia
Authors: Christie M Ballantyne, Daniel Gaudet, Robert S Rosenson, Robert A Hegele, Rong Zhou, Stacey Melquist, Jennifer Hellawell, Nicholas J Leeper
Journal: Journal of the American College of Cardiology (2025)
Large language model agents can use tools to perform clinical calculations
Authors: Alex J. Goodell, Simon N. Chu, Dara Rouholiman, Larry F. Chu
Journal: npj Digital Medicine (2025)

Large language models (LLMs) can answer expert-level questions in medicine but are prone to hallucinations and arithmetic errors. Early evidence suggests LLMs cannot reliably perform clinical calculations, limiting their potential integration into clinical workflows. We evaluated ChatGPT's performance across 48 medical calculation tasks, finding incorrect responses in one-third of trials (n = 212). We then assessed three forms of agentic augmentation: retrieval-augmented generation, a code interpreter tool, and a set of task-specific calculation tools (OpenMedCalc) across 10,000 trials. Models with access to task-specific tools showed the greatest improvement, with LLaMa and GPT-based models demonstrating a 5.5-fold (88% vs 16%) and 13-fold (64% vs 4.8%) reduction in incorrect responses, respectively, compared to the unimproved models. Our findings suggest that integration of machine-readable, task-specific tools may help overcome LLMs' limitations in medical calculations.
Respiratory Syncytial Virus and Incidence of Cardiovascular Events
Authors: Mats C Højbjerg Lassen, Daniel Modin, Niklas Dyrby Johansen, Pradeesh Sivapalan, Anders Hviid, Tyra Grove Krause, Jens Ulrik Stæhr Jensen, Tor Biering-Sørensen
Journal: Journal of the American College of Cardiology (2025)