Background Alice in Wonderland syndrome (AIWS) is a neuropsychiatric disorder characterized by sensory perception distortions, including altered body image perception and distortions of shape, size, motion, color, and speed. Migraine and infectious diseases are among the most common etiologies of AIWS. However, it has not been studied in individuals with persistent headache after COVID-19. Methods This cross-sectional study included a subset of individuals with AIWS symptoms derived from a survey conducted in Latin America to identify adults with persistent headache after COVID-19. For data analysis, AIWS individuals were characterized by sex and analyzed using univariable tests. Subsequently, the entire study cohort was stratified into two groups: the AIWS group and the non-AIWS group. Binomial logistic regression using the backward stepwise selection method was performed to identify the factors associated with AIWS after COVID-19. Results Out of 421 participants with persistent headache after COVID-19, 106 (25.2%) reported at least one AIWS symptom. The AIWS group was significantly younger (median age 36 vs. 39 years, p = 0.011) and had a higher proportion of pre-existing migraine (40.6% vs. 29.5%, p = 0.035) compared to the non-AIWS group. The most common post-COVID-19 AIWS symptoms were time distortion (32.1%), derealization/depersonalization (24.5%), and hyperchromatopsia (20.8%). Logistic regression analysis revealed that experiencing any AIWS symptom during acute COVID-19 was the strongest predictor for post-acute AIWS (OR = 9.937, 95% CI = 5.603–17.62, p <0.001). Other significant predictors included phonophobia (OR = 2.322, 95% CI = 1.288–4.185, p = 0.005) and depressive symptoms (OR = 1.937, 95% CI = 1.099–3.413, p = 0.022) during acute COVID-19. Conclusion In this cohort, AIWS was a notable feature in adults with persistent headache after COVID-19, particularly in younger individuals with a history of migraine. Experiencing AIWS symptoms during acute infection increased the odds of post-acute AIWS symptoms nearly tenfold, suggesting SARS-CoV-2 may be a potent trigger. Clinicians should be aware of this association and screen for perceptual disturbances in patients with post-COVID-19 neurological sequelae.

This study introduces an explainable deep learning framework for the accurate classification of wild poisonous mushroom species, contributing to food safet

In this study, we applied microarray, bioinformatics, and qRT-PCR techniques to identify miRNAs and their target genes in plasma obtained from acute ischem

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuron loss and the accumulation of misfolded α-synuclein, yet the underlying mechanisms remain incompletely understood. Over the past two decades, genetic discoveries have highlighted the convergence of multiple familial PD genes on the autophagy-lysosome pathway (ALP), a key cellular system responsible for the degradation and recycling of intracellular components. Recent studies have further revealed that components of the ALP not only mediate the clearance of α-synuclein aggregates but also, under certain pathological conditions, contribute to their propagation via lysosomal exocytosis or secretory autophagy. The precise functions of autophagy are highly context-dependent, with neuronal and glial cells exhibiting distinct ALP dynamics that shift with development, stress, and aging. In this review, we summarize current knowledge on the physiological regulation of autophagy in the brain and critically examine its involvement in PD pathogenesis, incorporating mechanistic insights from familial models and emerging evidence from sporadic PD. We also explore translational implications, focusing on efforts to identify ALP-related biomarkers in cerebrospinal fluid and urine, and on the therapeutic potential of modulating ALP activity. Although the causality between ALP dysfunction and PD remains elusive, mounting evidence supports its contribution to disease progression, particularly through impaired lysosomal homeostasis and disrupted intracellular trafficking. Future research should aim to define cell type-specific ALP alterations, clarify the bidirectional interactions between α-synuclein and autophagic machinery, and develop in vivo tools to monitor autophagy activity and secretory signatures. A deeper understanding of these processes will be crucial for refining PD models, discovering robust fluid biomarkers, and designing targeted therapies capable of modifying disease trajectory.

Background Cetacean morbillivirus, herpesvirus, avian influenza virus (AIV) and Brucella spp. have been linked to numerous cetacean strandings in the Northeast (NE) Atlantic. Yet, their prevalence in free-living cetaceans remains insufficiently investigated, particularly in northern regions. Methods Between 2016 and 2025, humpback whales (Megaptera novaeangliae), sperm whales (Physeter macrocephalus) and, opportunistically, fin whales (Balaenoptera physalus) and a long-finned pilot whale (Globicephala melas), were sampled in two foraging grounds in northern Norway (Skjervøy and Andenes), in Iceland and in Cape Verde. Blow samples (n = 76), skin biopsies (n = 45), and organ samples from one stranded pilot whale were collected and screened for cetacean morbillivirus, herpesvirus, AIV and Brucella spp, via polymerase chain reaction (PCR). Results In northern Norway, cetacean morbillivirus, identified as the dolphin morbillivirus (DMV) strain, was detected in the blows of two asymptomatic groups of humpback whales, in the blow of one sperm whale in poor health and in the kidney of a stranded pilot whale. An alphaherpesvirus was detected in the blows of five humpback whale groups sampled in Norway, Iceland, and Cape Verde, while a gammaherpesvirus was detected in one humpback whale skin biopsy, sampled in Norway. No other samples tested positive to any of the pathogens, including AIV or Brucella spp. Conclusion Our results demonstrate that minimally invasive sampling, particularly blow sampling, can be used for pathogen surveillance in free-ranging cetaceans. They also provide new insights into the circulation of cetacean morbillivirus and herpesviruses in cetaceans from the NE Atlantic. Continuous monitoring of pathogen exposure, alongside other stressors, will be crucial to assess the cumulative health implications for these cetaceans.

Background Cardiometabolic risk (CMR) is a monotonic if not linear continuum where, over time, incremental rises in biological risk can herald large increases in absolute disease risk and thus incident cardiometabolic disease (CMD). The built environment (BE)—green/open space, walkability, and food environment—may influence biological risk. Assessing the biological plausibility and temporal direction of such associations by linking BE features to the progression of biological indicators of CMR is essential for stronger causal inference. This review summarised longitudinal studies assessing BE factors and continuously expressed biological indicators of CMR. Methods Six databases were searched for longitudinal studies examining associations between BE features and continuous CMR factors, including fasting plasma glucose (FPG), triglycerides, lipoproteins, total cholesterol, glycated haemoglobin (HbA1c), systolic blood pressure (SBP), and diastolic blood pressure (DBP). Four authors screened the titles and abstracts, assessed the full text for inclusion, extracted data, and conducted quality appraisals. Associations were synthesised qualitatively, and a weighted z-score meta-analysis, incorporating study quality and sample size scores, was used to estimate the strength of the pooled evidence. Results Sixteen longitudinal studies met inclusion criteria, with four studies examining multiple BE features. Green/open space was the most frequently examined feature (n = 9), followed by walkability (n = 8), and food environments (n = 3). Pooled weighted z-score meta-analyses showed that greater availability of green/open space environment was associated with lesser increases over time in SBP (n = 4/5, weighted z = 3.43, p < 0.001) and DBP (n = 3/3, weighted z = 2.89, p < 0.01), but findings were inconsistent for triglycerides (n = 1/2), HDL-C (n = 1/2), and FPG (n = 0/2). There was strong evidence for an association between greater walkability and lesser increases over time in SBP (n = 3/5, weighted z = 2.95, p < 0.01) and HbA1c (n = 2/2), but associations with DBP and FPG were inconsistent. Healthful food sources were associated with lesser increases over time in blood pressure, FPG and HbA1c levels (n = 1/1 for each outcome). Conclusions This review provides evidence for the role of the built environment in shaping CMR over time, particularly blood pressure and HbA1c, dependent on BE feature. Greater availability of green/open space environment and healthful food environment were reliably associated with a lesser progression of CMR. Evidence for walkability was inconsistent.

Background One of the major challenges in late-stage cancer research is studying the direct interactions between cancer cells and the metastatic tissue. Metastasis is an inefficient multistep process in which only a small subset of cancer cells successfully colonizes the new microenvironment. Bone is the most common tissue for breast and prostate cancer metastasis and the third most common site across all cancer types. We present an ex vivo co-culture protocol for modeling bone metastasis that enables direct investigation of cancer cell interactions with the native bone and marrow microenvironment. Methods The procedure involves the extraction and preparation of mouse long bones (femurs and tibiae), injection of cancer cells into the bone marrow cavity, maintenance of the co-culture, and sample processing for downstream analysis. The protocol supports functional readouts, including bioluminescence imaging of tumor cell viability, conditioned media sampling, and downstream tissue analysis, such as immunohistochemistry or micro-computed tomography (µCT). The culture setup procedure can be completed in a single day, and daily media maintenance thereafter requires minimal time. Final sample processing times vary, depending on the analysis completed. Discussion The system maintains viable and metabolically active bone, marrow, and cancer cells for up to four weeks and preserves the heterogeneity of the bone microenvironment. It is highly adaptable for various cancer types and bone genotypes and enables high-throughput functional interrogation of cancer colonization in a complex microenvironment. The protocol requires basic expertise in mammalian cell culture and mouse dissection and is suitable for researchers studying metastasis, tumor–stroma interactions, or preclinical therapeutic screening in the bone microenvironment. Clinical trial number Not applicable.

Background CAR-T therapy has revolutionized treatments for many hematologic malignancies, but it has shown far less efficacy against solid tumors. One reason for this lower efficacy in solid tumors is increased antigen heterogeneity. This study utilizes a ligand-based CAR-T approach, which allows targeting of multiple receptors by a single ligand. A high expression of the ligand oncostatin M’s (OSM) receptors, oncostatin M receptor (OSMR), and/or leukemic inhibitory factor receptor (LIFR) were noted in osteosarcoma cell lines and patient samples. Osteosarcoma is a bone cancer where treatment options have been stagnant for close to 40 years. Thus, this study explores the therapeutic potential of OSM ligand-based CAR-T cells against osteosarcoma. Methods Third-generation CAR-T cells expressing human OSM on their surface were created, with the surface expression of OSM confirmed by flow cytometry. Co-incubation of OSM CARs and osteosarcoma in vitro was performed, with cell death assessed via Incucyte and PI detection by flow cytometry. CAR-Ts were injected i.v. into mice with osteosarcoma cell line xenografts, and metastatic osteosarcoma. New patient-derived samples were tested for OSMR and LIFR expression and vulnerability to OSM CAR T cells. A new PDX model (named KKOS) from a patient with metastatic treatment-resistant osteosarcoma was characterized and tested for its susceptibility to OSM CAR T cells. All cytotoxic in vivo experiments were performed with n=3–6 mice per group per experiment. Results OSM-CAR-T cells displayed cytotoxicity against osteosarcoma cell lines and patient samples expressing either one of OSM’s receptors in vitro and in vivo. Large increases in cytokine release, specifically IFNγ, were noted in a target-specific manner. One injection of OSM-CAR-T cells intravenously reduced tumor burden in two different mouse xenograft models. A similar anti-tumor effect was also noted in a metastatic model and a mouse model with multiple implanted KKOS tumors. Conclusions Human ligand-based OSM CAR-T cells displayed anti-tumor effects against multiple osteosarcoma cell lines and patient samples. These effects were demonstrated in vitro, in xenograft models, and against a model simulating metastatic disease. Overall, this data supports the continued study of OSM-CAR-T cells as a new therapeutic avenue for osteosarcoma.

Background Growing evidence implicates gut microbiota (GM) dysbiosis in Alzheimer’s disease (AD) pathogenesis via the gut-brain axis. Dysbiosis contributes to neuroinflammation, amyloid-β deposition, tau hyperphosphorylation, blood-brain barrier disruption, and cognitive decline. Synbiotics (combinations of probiotics and prebiotics) offer a promising strategy to modulate GM, potentially ameliorating these AD hallmarks through multiple mechanisms including enhanced production of neuroprotective short-chain fatty acids (SCFAs), reduced inflammation, improved gut barrier integrity, and immunomodulation. Objective This review critically evaluates the current evidence on the therapeutic potential of synbiotics for AD. It aims to synthesize findings from preclinical and clinical studies regarding the efficacy of synbiotics in improving cognitive function and AD pathology, elucidate the underlying biological mechanisms including GM modulation, SCFA production, immune regulation, and gut-brain signaling, and identify key challenges and future research directions for translating GM-targeted interventions into effective AD therapies. Conclusion Synbiotics demonstrate significant potential, particularly in early AD, by improving cognitive domains, reducing neuroinflammation and AD biomarkers, and modulating beneficial microbial metabolites. However, challenges include confounding factors, unresolved questions about causality, inconsistent results in advanced disease, and insufficient large-scale human trials. Future success hinges on rigorous longitudinal randomized controlled trials integrating multi-omics approaches, advanced in vitro models, and personalized strategies considering baseline microbiota and host genetics. While not a standalone cure, synbiotics represent a valuable component within multi-target therapeutic approaches aimed at modulating the gut-brain axis to slow AD progression.

Background Endocannabinoid (eCB) signaling has been implicated in the physiological and affective responses to endurance exercise, including phenomena such as the runner’s high. However, although humans have the capacity to run for several hours and even days, evidence regarding eCB signaling is largely limited to exercise bouts shorter than 60 min. Consequently, the temporal dynamics of eCB signaling during prolonged running and the accompanying acute affective responses remain unclear. Methods This study investigated eCB signaling during long-distance running and following a 45-minute break. Two studies were conducted: In Study 1, 19 trained runners completed both a marathon and a duration-matched walking session, with repeated blood sampling every 14 km during the marathon and after a 45-minute recovery. In Study 2, 36 ultramarathon runners completed races of 100 km, 160 km, or 230 km and provided blood samples before and after their respective races. Plasma concentrations of anandamide (AEA), 2-arachidonoylglycerol (2-AG), 1-AG, arachidonic acid (AA), and palmitoylethanolamide (PEA) were quantified by a standardized liquid chromatography/multiple reaction monitoring assay. Euphoria, anxiety, and pain were assessed as core features of the runner’s high using visual analog scales. Results AEA increased progressively throughout the marathon and remained elevated after 45 min, whereas walking elicited only modest changes. In line, after all ultramarathon distances AEA levels were increased compared with baseline. By contrast, an increase in 2-AG during exercise was observed only in the regular marathon, where concentrations rose significantly during the later stages of running and into early recovery. Elevated post-race 2-AG levels were also observed following all ultramarathon distances, consistent with a delayed, recovery-related response. Marathon running was associated with higher euphoria and lower anxiety than walking, while pain increased after 28 km of running. Ultramarathon running increased pain, reduced anxiety, and did not significantly alter euphoria post-exercise. Conclusions Together, these findings show robust, time-dependent changes in circulating eCB concentrations during and after prolonged endurance running, as well as gradual increases in AEA during walking. These eCB dynamics occurred alongside acute affective changes during sustained endurance exercise.

Celiac disease (CeD) is an autoimmune disease triggered by dietary gluten in genetically predisposed individuals. Deamidation of gluten peptides by the CeD

Background Food literacy is a multidimensional construct encompassing the knowledge, skills, and attitudes needed to make informed food choices and support healthy eating. Food literacy education is important for fostering lifelong positive eating behaviours. However, evidence on intensive experiential, culinary education interventions for school-aged children remains limited. The objective of this study was to assess changes in food literacy skills following a one-week experiential culinary education intervention among school-aged children attending a university-based culinary summer camp. Methods A theory-informed, child-centered culinary intervention was developed using a competency-based framework to support structured skill development. A single-arm, baseline-to-endpoint study design was used to evaluate change in food literacy skills among children aged 8–12 attending a one-week culinary summer camp. Food literacy skills were assessed using an observational scoring rubric informed by a competency framework and the Experiential Learning Theory, measuring six domains: autonomy, ease and safety, measuring, hygiene, working with others, and confidence. Each domain was scored on a 12-point scale, with higher scores indicating greater skill proficiency. Paired-samples t-tests were conducted to evaluate changes. Effect sizes (Cohen’s dz) and 95% confidence intervals were calculated. Results Eighty-eight children participated in the culinary intervention. Significant improvements were observed across all six food literacy domains following the intervention (p< .001). Mean score increases ranged from 1.46 to 2.47 points, with effect sizes ranging from moderate to large (dz = 0.62–1.36), indicating meaningful improvements in observed food literacy skills over the one-week period. Improvements were particularly notable for the ease and safety, measuring, and confidence domains. Conclusions This intensive experiential culinary education intervention was associated with significant improvements in food literacy skills among school-aged children. These findings support the potential of immersive, skills-based food literacy programs and highlight the value of experiential learning approaches for supporting children’s food literacy development.

Although promising results have been obtained for anaplastic thyroid cancer (ATC) therapy, this therapy still needs to be improved. In addition to the currently approved therapies, radiotherapy alone or combined with adjuvant immunotherapy could be beneficial for patients affected by ATC. The patients affected by this aggressive solid malignancy could benefit from the modulation of autophagy in cancer cells. This study focused on detecting autophagy players in ATCs and bursting autophagy process via photon irradiation to induce decay in irradiated ATCs. The transcript expression of autophagy genes was detected in tumor tissue resected from 19 patients and in C643 cells, four primary ATC cell lines and primary follicular thyroid cell line (Nthy-ori-3–1) photons irradiated with 4 or 6 Gy. The protein level of Beclin1 was detected by immunofluorescence in 10/19 patients. The levels of autophagy markers were detected by RT‒qPCR and western blotting in irradiated cells. Autophagy and maturation of autophagosome vesicles were monitored in C643 cells stably transfected with the GFP-RFP-LC3B plasmid. All patients included in the study exhibited significant overexpression of autophagy transcripts. Additionally, the Beclin1 protein was expressed in resected tumor tissue. Furthermore, the analysis of autophagy-related gene transcripts revealed significant increases in the expression of these genes in C643, Patient 2 and Patient 3 cells irradiated with 4 or 6 Gy. Additionally, irradiation with 4 or 6 Gy downregulated the expression of all the proteins involved in the autophagy process. Thus, the ongoing catabolic process was confirmed. Interestingly, the levels of AMPKα and its active phosphorylated form were strongly downregulated, which excluded its involvement in autophagy activation. 6 Gy photon irradiation caused an increase in both green and red fluorescence in C643-derived spheroids. An increase in fluorescence was detectable for up to 28 days. The spheroids gradually exhibited an increase in fluorescence, which probably caused the dismantling of their ultrastructure. This finding provides evidence of the bursting of autophagy and its ability to affect spheroid integrity. Photon irradiation exacerbates autophagy in anaplastic thyroid cancer cells and could represent a valid target for focused therapy against this aggressive malignancy.

Background Breast cancer is one of the most common cancers among women, with improved therapies reducing mortality. Antiresorptive (AR) therapy is crucial for managing bone loss and skeletal complications in patients with cancer. However, high-dose AR therapy may carry a significant risk of medication-related osteonecrosis of the jaw (MRONJ). This study aimed to investigate the incidence of MRONJ and its risk factors in patients with diagnosed breast cancer undergoing either biannual postoperative bisphosphonate therapy or high-dose AR therapy. Methods This study followed 220 female patients receiving AR therapy in Sweden, from 2015 to 2020. Oral health status was assessed before and during AR therapy, collecting data on MRONJ incidence, dental procedures, and data on breast cancer characteristics. Statistical analyses included Fisher’s exact tests, and group differences in Kaplan-Meier curves were assessed using the log-rank test. p < 0.05 was considered statistically significant. Results The cohort comprised 119 patients on biannual AR therapy and 101 patients on high-dose AR therapy. Nine patients (4.0%) developed bone metastases and transitioned to high-dose AR therapy after a mean interval of 237 days; of these, 55.5% subsequently switched from bisphosphonates to denosumab. MRONJ cumulative incidence was 5.5% in the overall cohort and 11.9% in the high-dose group (p < 0.001); no MRONJ cases occurred in the biannual group. Tooth extractions (30.5%, p < 0.001), localisation to the mandible (83.3%, p = 0.039) and number of AR doses (p = 0.004) were significantly associated with the development of MRONJ. Notably, spontaneous MRONJ accounted for 41.7% of cases. Baseline DMFT did not differ, but MRONJ patients had a higher DMFT increment during follow-up. Conclusions This study identifies a significant association between high-dose AR therapy and the development of MRONJ in breast cancer patients, with tooth extractions, mandibular localisation, and cumulative AR exposure identified as risk factors. MRONJ was not observed in the biannual AR therapy group. These findings underscore the importance of comprehensive dental assessments and early risk stratification.

Antarctica, though remote and sparsely inhabited, faces significant ecological risks due to human activities and settlements that generate, among others, f

Background Peritoneal metastatic gastric cancer (PMGC) is associated with a dismal prognosis and limited benefit from immune checkpoint inhibitors (ICIs). Although PD-1/PD-L1 blockade has improved outcomes in selected patients, therapeutic responses remain highly heterogeneous, even among PD-L1-high tumors. The lack of preclinical models that functionally recapitulate tumor-immune interactions in a three-dimensional (3D) context has hindered the investigation of immune susceptibility and resistance mechanisms in PMGC. Methods We established a standardized allogeneic 3D co-culture platform integrating patient-derived PMGC organoids with pooled peripheral blood mononuclear cells (PBMCs) from healthy donors. An optimized Matrigel-embedded configuration was used to enable sustained immune cell infiltration and tumor-immune contact. Immune-mediated cytotoxicity, organoid susceptibility phenotypes, and responses to PD-1 blockade with pembrolizumab were functionally assessed. Comparative proteomic profiling was performed, and differential expression between groups was evaluated using appropriate statistical tests with false discovery rate correction. Group comparisons were conducted using Student’s t-test. Results The optimized 3D embedded system enabled dynamic infiltration of activated T cells into organoid structures. PMGC organoids exhibited heterogeneous susceptibility to immune-mediated cytotoxicity, classifying them into cytolytic and noncytolytic phenotypes independent of HLA mismatching. Comparative proteomic profiling revealed that cytolytic lines were enriched in metabolic pathways, whereas noncytolytic lines showed enrichment of immune-related signaling. Notably, response to pembrolizumab varied even among PD-L1-high organoids. Nonresponsive PD-L1-high lines were characterized by elevated baseline expression of alternative immune checkpoint ligands, specifically CD112 (TIGIT ligand) and galectin-9 (TIM-3 ligand). Conclusions We established a robust pooled PBMC-organoid co-culture platform that enables functional assessment of tumor-immune dynamics in PMGCs. This system serves as a functional ex vivo tool for evaluating immunotherapy responses and for examining the expression patterns of alternative immune checkpoint ligands associated with differential PD-1 blockade response. These findings support the utility of this ex vivo PMGC co-culture system for evaluating heterogeneous responses to PD-1 blockade and associated baseline differences in alternative immune checkpoint ligand expression among PD-L1-high organoids.

Although promising results have been obtained for anaplastic thyroid cancer (ATC) therapy, this therapy still needs to be improved. In addition to the currently approved therapies, radiotherapy alone or combined with adjuvant immunotherapy could be beneficial for patients affected by ATC. The patients affected by this aggressive solid malignancy could benefit from the modulation of autophagy in cancer cells. This study focused on detecting autophagy players in ATCs and bursting autophagy process via photon irradiation to induce decay in irradiated ATCs. The transcript expression of autophagy genes was detected in tumor tissue resected from 19 patients and in C643 cells, four primary ATC cell lines and primary follicular thyroid cell line (Nthy-ori-3–1) photons irradiated with 4 or 6 Gy. The protein level of Beclin1 was detected by immunofluorescence in 10/19 patients. The levels of autophagy markers were detected by RT‒qPCR and western blotting in irradiated cells. Autophagy and maturation of autophagosome vesicles were monitored in C643 cells stably transfected with the GFP-RFP-LC3B plasmid. All patients included in the study exhibited significant overexpression of autophagy transcripts. Additionally, the Beclin1 protein was expressed in resected tumor tissue. Furthermore, the analysis of autophagy-related gene transcripts revealed significant increases in the expression of these genes in C643, Patient 2 and Patient 3 cells irradiated with 4 or 6 Gy. Additionally, irradiation with 4 or 6 Gy downregulated the expression of all the proteins involved in the autophagy process. Thus, the ongoing catabolic process was confirmed. Interestingly, the levels of AMPKα and its active phosphorylated form were strongly downregulated, which excluded its involvement in autophagy activation. 6 Gy photon irradiation caused an increase in both green and red fluorescence in C643-derived spheroids. An increase in fluorescence was detectable for up to 28 days. The spheroids gradually exhibited an increase in fluorescence, which probably caused the dismantling of their ultrastructure. This finding provides evidence of the bursting of autophagy and its ability to affect spheroid integrity. Photon irradiation exacerbates autophagy in anaplastic thyroid cancer cells and could represent a valid target for focused therapy against this aggressive malignancy.

When a Thalamic Hemorrhage Is Not a Primary Hemorrhage

Background Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and disproportionately affects women, with neuroinflammation emerging as a key driver of disease onset and progression. Beyond amyloid-β (Aβ) and hyperphosphorylated tau protein accumulation, chronic activation of microglia and astrocytes amplifies synaptic dysfunction and neuronal loss. Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) represent a promising translational strategy due to their capacity to modulate inflammation and promote neuroprotection. Here, we investigated whether intranasal administration of extracellular vesicles derived from human amniotic membrane MSCs (hAMSC-EVs) could counteract cognitive decline, neuroinflammation, and synaptic alterations in experimental and human cellular models of AD. Methods hAMSC-EVs were isolated and characterized for size, markers, and biodistribution. Female 3 × Tg-AD mice received chronic intranasal hAMSC-EV administration from 3 to 9 months of age. Cognitive performance was assessed using novel object recognition, object place recognition, and Y-maze tests. Hippocampal Aβ levels, tau phosphorylation, glial density, microglial morphology, cytokine profiles, and synaptic protein expression were analyzed by immunoblotting, ELISA, immunofluorescence, and morphometric analyses. Bioinformatic analyses were performed to investigate the miRNA cargoes of hAMSC-EVs. Translational relevance of the hAMSC-EV effects was assessed in glutamatergic neurons differentiated from induced pluripotent stem cells derived from sporadic AD patients. Results The hAMSC-EVs delivered intranasally reached the hippocampus and were internalized by neurons and microglia. hAMSC-EV treatment significantly improved cognitive performance of female 3 × Tg-AD mice and reduced hippocampal Aβ levels without affecting tau phosphorylation. The hAMSC-EVs attenuated neuroinflammation by reducing microglial and astrocytic density, inducing microglial structural remodeling, and downregulating TMEM119 and TREM2 expression. We also detected a shift toward an anti-inflammatory cytokine profile and increased expression of neuroplasticity-related proteins, including BDNF, GluA1, and ARC in the hippocampus of 3 × Tg-AD mice. Bioinformatic analyses identified EV miRNA cargoes enriched in immunomodulatory and neuroprotective pathways. In human AD neurons, hAMSC-EVs prevented neurite atrophy and rescued synaptic protein expression without affecting the cell viability. Conclusions hAMSC-EVs exert robust anti-inflammatory and neuroprotective effects in both murine and human AD models, improving cognition, modulating glial activation, and restoring synaptic integrity. These findings highlight the translational potential of intranasal hAMSC-EVs as an adjuvant therapeutic strategy targeting neuroinflammation and neurodegeneration in AD.

When Cytopenia Changes the Diagnosis: Anti-MDA5 Dermatomyositis, Rapidly Progressive Interstitial Lung Disease, and Macrophage Activation

Antarctica, though remote and sparsely inhabited, faces significant ecological risks due to human activities and settlements that generate, among others, f

Background Endocannabinoid (eCB) signaling has been implicated in the physiological and affective responses to endurance exercise, including phenomena such as the runner’s high. However, although humans have the capacity to run for several hours and even days, evidence regarding eCB signaling is largely limited to exercise bouts shorter than 60 min. Consequently, the temporal dynamics of eCB signaling during prolonged running and the accompanying acute affective responses remain unclear. Methods This study investigated eCB signaling during long-distance running and following a 45-minute break. Two studies were conducted: In Study 1, 19 trained runners completed both a marathon and a duration-matched walking session, with repeated blood sampling every 14 km during the marathon and after a 45-minute recovery. In Study 2, 36 ultramarathon runners completed races of 100 km, 160 km, or 230 km and provided blood samples before and after their respective races. Plasma concentrations of anandamide (AEA), 2-arachidonoylglycerol (2-AG), 1-AG, arachidonic acid (AA), and palmitoylethanolamide (PEA) were quantified by a standardized liquid chromatography/multiple reaction monitoring assay. Euphoria, anxiety, and pain were assessed as core features of the runner’s high using visual analog scales. Results AEA increased progressively throughout the marathon and remained elevated after 45 min, whereas walking elicited only modest changes. In line, after all ultramarathon distances AEA levels were increased compared with baseline. By contrast, an increase in 2-AG during exercise was observed only in the regular marathon, where concentrations rose significantly during the later stages of running and into early recovery. Elevated post-race 2-AG levels were also observed following all ultramarathon distances, consistent with a delayed, recovery-related response. Marathon running was associated with higher euphoria and lower anxiety than walking, while pain increased after 28 km of running. Ultramarathon running increased pain, reduced anxiety, and did not significantly alter euphoria post-exercise. Conclusions Together, these findings show robust, time-dependent changes in circulating eCB concentrations during and after prolonged endurance running, as well as gradual increases in AEA during walking. These eCB dynamics occurred alongside acute affective changes during sustained endurance exercise.

Background Fc-gamma receptors (FcγRs) regulate IgG antibody activity, and Fc-engineering is a proven method to improve the efficacy of tumor-targeting antibodies. Here, we explore tailored FcγR blockade to enhance the therapeutic efficacy and tolerability of immune checkpoint-blocking (ICB) antibodies. Methods Mechanistically matched murine surrogate and human lead FcγR-blocking and immune checkpoint-blocking antibodies were used to study whether tailored FcγR-blockade, targeting FcγRIIB selectively or all FcγRs, can enhance the efficacy and overcome resistance to immune checkpoint therapy in vivo and in vitro. Mechanistic studies were performed with clinical reagents, including ipilimumab, nivolumab, pembrolizumab, and human FcγRIIB-selective (BI-1607) and pan-FcγR-blocking (BI-1206) antibodies, using human cells and transgenic animals with clinically relevant expression of immune checkpoint receptors. Results We demonstrate that FcγRIIB-selective and pan-FcγR-blocking antibodies increase the in vivo efficacy of αCTLA-4 and αPD-1 antibodies, respectively. FcγRIIB-selective antibody enhancement of αCTLA-4 was associated with increased intratumoral Treg depletion, myeloid reprogramming, interferon-γ and CXCL10-induction, and increased activated effector CD8+ T cells, correlating with higher activating-to-inhibitory (A:I) FcγR engagement ratios. Conversely, pan-FcγR blockade protected αPD-1-coated T cells from macrophage phagocytosis, increasing intratumoral activated CD8+ T cells by decreasing activating and inhibitory FcγRs. Conclusions Our studies provide in vivo proof of concept that tailored FcγR blockade enhances immune checkpoint therapy and overcomes resistance through mechanistically distinct pathways. Clinical trials with tailored human FcγRIIB-blocking antibodies are ongoing. Graphical Abstract FcγRIIB-selective blockade enhances αCTLA-4-mediated Treg depletion, myeloid reprogramming, and effector CD8+ T cell activation by increasing the activating-to-inhibitory (A:I) FcγR engagement ratio. Conversely, pan-FcγR blockade protects αPD-1-coated T cells from macrophage phagocytosis and from αPD-1 removal via trogocytosis, thereby increasing intratumoral activated CD8+ T cells by decreasing activating and inhibitory FcγRs.

Biomolecular condensates control key cellular processes, from gene expression to signal transduction, by organizing molecules through selective compartmentalization. Increasing evidence links their dysregulation to cancer, neurodegeneration, and other diseases, positioning condensates as promising therapeutic targets. This review explores emerging strategies that go beyond dissolving pathological condensates, including approaches that induce, redirect, or reprogram their dynamics, composition, and physical state. Rather than inhibiting individual proteins, these interventions reshape the cellular organization itself. By targeting the material and functional properties of condensates, such strategies offer a new conceptual framework for therapeutic design in complex, dysregulated biological systems.

Predation pressure shapes ecosystems via selection on locomotor form and function. To explore this link, we grouped 48 species of predatory mammals into five hunting-strategy clusters: Anteaters, Opportunistic Grapplers, Large Grapplers, Opportunistic Pouncers, and Social Hunters, and asked whether their locomotor shape (limb posture through the stride) reliably distinguished these clusters. We digitised 115 side-view stride sequences across these species, performed Procrustes alignment and principal component analysis on per-stride shapes, and analysed symmetrical (walking) and asymmetrical (galloping/bounding) gaits. In symmetrical gaits, phylogeny accounted for the largest share of locomotor variation, but hunting strategy still explained a significant portion, whereas gait type made only a weak contribution and body mass was not significant. These slower, more economical gaits showed relatively broad overlap among hunting groups, although Social Hunters tended to use more upright limb postures and Grappling species more crouched and extended forelimb configurations. In asymmetrical gaits, differences among hunting strategies were stronger, while gait type and body mass again contributed little. Social Hunters showed larger limb and spinal excursions, whereas Opportunistic Pouncers occupied a more restricted region of locomotor space. The stronger separation among hunting groups during asymmetrical gaits suggests that ecological specialization is expressed most clearly in high-performance behaviours such as acceleration, manoeuvring, and prey capture, rather than in economical walking. We then placed the extinct marsupial predator, the thylacine (Thylacinus cynocephalus), within this framework using archival footage of walking. Its symmetrical-gait centroid was predominantly associated to Opportunistic Pouncer across classifiers. These results show that locomotor biomechanics are associated with hunting ecology, but that these ecological patterns are embedded within substantial phylogenetic structure; they also suggest that this relationship may help inform ecological inference in extinct species.

Background As longevity increases and the population over age 65 expands, advancing age remains the most reliable predictor of cognitive decline, highlighting the need to identify biological mechanisms that support exceptional cognitive aging. We tested whether lower inherited risk of Alzheimer’s disease (AD) dementia predicts SuperAger status (adults ≥ 80 years with episodic memory at least as good as middle-age adults) using prospectively enrolled SuperAgers and Cognitively Average Controls (Controls) from the multisite SuperAging Research Initiative. Methods We studied 231 participants (SuperAgers n = 142; Controls n = 89). We confirmed that the genetic ancestry structure across groups was comparable. We evaluated whether APOE status (ε2, ε3, ε4) and three AD polygenic risk scores (PRS) derived from large contemporary Genome-Wide Association Studies (GWAS) (PRSLambert, PRSWightman, PRSBellenguez) predicted SuperAging status using logistic regression models adjusted for age, sex, and education, considering ancestry interactions. Results APOE allele and genotype distributions did not differ between groups, and neither APOE nor any of the three PRS predicted SuperAger status. Results were unchanged when accounting for global non-European or African ancestry or principal components. In this well-characterized cohort, neither APOE nor contemporary PRS explained SuperAger status. Conclusions These findings suggest that the exceptional late-life memory phenotype that is characteristic of SuperAging is not explained by common-variant AD genetic risk captured by APOE or contemporary AD PRS, motivating a deeper investigation of potential rare genetic variations and experiential factors contributing to exceptional cognitive aging.

Background Systemic lupus erythematosus (SLE) is a systemic autoimmune disease targeting multiple organ systems, including the nervous system. The cerebellum may be involved in prevalent neuropsychiatric manifestations, such as depression and cognitive dysfunction, alongside other prevalent SLE manifestations such as pain and fatigue. We aim to compare cerebellar volumes in SLE patients and healthy individuals (HI) and assess the correlation between cerebellar volumes and cognitive impairment, fatigue, pain, and depression in SLE. Methods 72 female SLE patients and 25 age- and sex-matched HI underwent 3 tesla magnetic resonance imaging (MRI), clinical evaluations, and cognitive testing. T1-weighted MRI scans were segmented using CEREbellum Segmentation (CERES) volBrain automatic segmentation. Extracted cerebellar lobule volumes (normalized to total cerebellar volume) were compared between SLE and HI using analyses of covariance (ANCOVA). In regions showing significant volume changes between SLE and HI, the relationship between volume and clinical scores for cognitive impairment, fatigue, pain, and depression was analyzed using either ANCOVAs or partial correlation analyses. Results Lobular analysis of the cerebellum revealed significant (p < 0.05) region-specific volume alterations in SLE compared with HI. Bilateral and left lobule IV volumes were larger, while bilateral, right, and left lobule VIIB volumes were smaller in SLE compared to HI. Smaller white matter volumes in right lobule VIIIA, and right lobule X and larger white matter volumes in lobule crus I were observed in SLE compared to HI. In SLE, smaller VIIB volumes were significantly correlated with poorer cognitive performance (both complex attention and cognitive flexibility), and with higher fatigue scores. Conclusion The findings suggest that the cerebellum, and particularly lobule VIIB, is involved in SLE and may contribute to both cognitive dysfunction and fatigue in patients with systemic lupus erythematosus. Trial registration Not applicable.

To predict how movement strategies shape fitness in a changing world, we must build mechanistic models of species’ ranges and range shifts that align environmental data with the scales of individual perception and decision-making and jointly model biological processes from the individual to the population scale.

Background Rett syndrome (RTT) is a neurodevelopmental disorder that almost exclusively affects females and is associated with high clinical burden. However, literature characterizing the real-world journey of patients with RTT is limited. This study provided an overview of the epidemiology, patient characteristics, clinical manifestations, healthcare resource utilization (HRU), costs, and treatment patterns of patients with RTT in the US. Methods IQVIA™ Medical Claims Data and Longitudinal Prescription Data (11/01/2016–10/31/2019) were used to identify female patients with RTT, with the first observed diagnosis defined as the index date. Annual incidence and prevalence of RTT were assessed over the entire study period; clinical manifestations, all-cause and RTT-related HRU and costs, and treatment patterns were evaluated during the observation period—from the index date to end of clinical activity or end of data availability, whichever occurred first. Results were further stratified into pediatric (< 18 years) and adult (≥ 18 years) subgroups. Results In 2019, prevalence and incidence of RTT was 0.32 and 0.23 per 10,000 enrollees, respectively. Among 5,940 female patients (pediatric: 3,078; adult: 2,862) with mean observation period of 2.04 years, the most prevalent clinical manifestations were neurological disorders (72.8%), gastrointestinal/nutritional disorders (41.9%), and orthopedic disorders (34.6%). The incidence rate of all-cause HRU was 44.43 visits per-patient-per-year and RTT-related HRU comprised 47% of all-cause HRU. Mean all-cause healthcare costs were $40,326 per-patient-per-year, with medical costs driven by home/hospice care visits, therapeutic services, outpatient visits, and inpatient visits. RTT-related healthcare costs comprised 45% of all-cause healthcare costs. The most prevalent supportive therapy and pharmacologic agent were feeding assistance (37.9%) and antiepileptic drugs (54.8%), respectively. Trends were similar by subgroup; although, rates of HRU were generally higher among pediatric patients relative to adult patients (all-cause: 52.43 and 35.86, respectively), which translated into higher mean healthcare costs (all-cause: $45,718 and $34,548, respectively). Conclusions Patients with RTT have substantial disease burden, including prevalent clinical manifestations, high rates of HRU and annual healthcare costs, and reliance on pharmacologic and supportive therapies. These findings underscore the unmet need for effective therapies to target the multifactorial manifestations of RTT.

Background Cardiometabolic risk (CMR) is a monotonic if not linear continuum where, over time, incremental rises in biological risk can herald large increases in absolute disease risk and thus incident cardiometabolic disease (CMD). The built environment (BE)—green/open space, walkability, and food environment—may influence biological risk. Assessing the biological plausibility and temporal direction of such associations by linking BE features to the progression of biological indicators of CMR is essential for stronger causal inference. This review summarised longitudinal studies assessing BE factors and continuously expressed biological indicators of CMR. Methods Six databases were searched for longitudinal studies examining associations between BE features and continuous CMR factors, including fasting plasma glucose (FPG), triglycerides, lipoproteins, total cholesterol, glycated haemoglobin (HbA1c), systolic blood pressure (SBP), and diastolic blood pressure (DBP). Four authors screened the titles and abstracts, assessed the full text for inclusion, extracted data, and conducted quality appraisals. Associations were synthesised qualitatively, and a weighted z-score meta-analysis, incorporating study quality and sample size scores, was used to estimate the strength of the pooled evidence. Results Sixteen longitudinal studies met inclusion criteria, with four studies examining multiple BE features. Green/open space was the most frequently examined feature (n = 9), followed by walkability (n = 8), and food environments (n = 3). Pooled weighted z-score meta-analyses showed that greater availability of green/open space environment was associated with lesser increases over time in SBP (n = 4/5, weighted z = 3.43, p < 0.001) and DBP (n = 3/3, weighted z = 2.89, p < 0.01), but findings were inconsistent for triglycerides (n = 1/2), HDL-C (n = 1/2), and FPG (n = 0/2). There was strong evidence for an association between greater walkability and lesser increases over time in SBP (n = 3/5, weighted z = 2.95, p < 0.01) and HbA1c (n = 2/2), but associations with DBP and FPG were inconsistent. Healthful food sources were associated with lesser increases over time in blood pressure, FPG and HbA1c levels (n = 1/1 for each outcome). Conclusions This review provides evidence for the role of the built environment in shaping CMR over time, particularly blood pressure and HbA1c, dependent on BE feature. Greater availability of green/open space environment and healthful food environment were reliably associated with a lesser progression of CMR. Evidence for walkability was inconsistent.

Background Hospital and health system initiatives addressing Social Determinants of Health (SDOH) are essential for achieving whole-person care and advancing health equity. Building on prior research characterizing these efforts (Part 1), this scoping review (Part 2) evaluates the effectiveness of these initiatives, with a focus on SDOH data integration, EHR utilization, and the broader scope of hospital efforts in addressing individual- and system-level determinants of health. Using an integrated conceptual framework combining the DeVoe & Cottrell framework for operational assessment and the National Academy of Medicine (NAM) 5A framework for systemic evaluation, this study provides a multidimensional assessment of hospital-based SDOH interventions. Methods Guided by PRISMA-ScR criteria, this review analyzed 41 U.S.-based studies published between 2018 and 2023, identified through three academic databases. Eligible studies examined hospital initiatives addressing SDOH with measurable outcomes. Analyses assessed SDOH data collection, integration into care practices, EHR use, and overall initiative effectiveness. Results Most studies (66%) were randomized controlled trials in urban settings (68%), targeting patients with chronic or mental health conditions (39%) or high-risk healthcare users (20%). Nearly half of initiatives (49%) addressed multiple SDOH domains, focusing on Social & Community Context, Economic Stability, and Neighborhood & Built Environment. Only 24% of initiatives utilized EHRs for SDOH data collection. EHR-based initiatives demonstrated significantly higher adherence to evidence-based practices, including use of community resource guides for referrals (90% vs. 45%, p = 0.013). Across all outcome measures, 79% demonstrated improvement, with no instances of worsening outcomes. However, 85% of initiatives lacked community-level SDOH data integration, and few employed upstream, universal strategies. Process, clinical, and social outcomes were unevenly prioritized, with only 10% of studies addressing all three outcome types. Conclusions While these initiatives reflect progress in integrating SDOH into care workflows and improving whole-person care at the individual level, progress toward health equity remains insufficient. Persistent gaps in EHR use, community-level data integration, and upstream strategies hinder systemic impact, potentially perpetuating disparities. Strengthening SDOH-EHR integration, fostering community partnerships, and supporting policy advocacy are critical to bridging individual and community needs. Future research should emphasize long-term, sustainable, and community-level impacts of hospital-led SDOH interventions.

The Red Sea hosts highly diverse marine ecosystems that face increasing natural stressors and anthropogenic stresses. Despite its ecological significance, the seasonal dynamics of benthic macrofauna along the Egyptian coast remain weakly understood. This study aimed to assess the influence of seasonal variation and environmental factors on marine benthic macrofaunal biodiversity at three distinct sites along the Red Sea Coast: the front of the National Institute of Oceanography and Fisheries (NIOF), the front of Magawish Village, and El-Hamrawin. Benthic macrofauna were surveyed seasonally (spring, summer, autumn 2021 and winter 2022) using line transects, with simultaneous measurements of environmental factors. A total of 2,942 individuals, representing 60 species from seven phyla, were identified. Cnidaria and Mollusca were the dominant groups, exhibiting marked seasonal and spatial variation in abundance. Two-way ANOVA indicated highly significant differences among seasons and sites for most taxa. Canonical correspondence analysis (CCA) showed strong associations between environmental factors (temperature, salinity, dissolved oxygen) and benthic community composition. These results reveal the sensitivity of benthic assemblages to environmental fluctuations and emphasize the combined effects of seasonal changes and site-specific conditions as key drivers of biodiversity patterns along the Red Sea Coast.

Background One of the major challenges in late-stage cancer research is studying the direct interactions between cancer cells and the metastatic tissue. Metastasis is an inefficient multistep process in which only a small subset of cancer cells successfully colonizes the new microenvironment. Bone is the most common tissue for breast and prostate cancer metastasis and the third most common site across all cancer types. We present an ex vivo co-culture protocol for modeling bone metastasis that enables direct investigation of cancer cell interactions with the native bone and marrow microenvironment. Methods The procedure involves the extraction and preparation of mouse long bones (femurs and tibiae), injection of cancer cells into the bone marrow cavity, maintenance of the co-culture, and sample processing for downstream analysis. The protocol supports functional readouts, including bioluminescence imaging of tumor cell viability, conditioned media sampling, and downstream tissue analysis, such as immunohistochemistry or micro-computed tomography (µCT). The culture setup procedure can be completed in a single day, and daily media maintenance thereafter requires minimal time. Final sample processing times vary, depending on the analysis completed. Discussion The system maintains viable and metabolically active bone, marrow, and cancer cells for up to four weeks and preserves the heterogeneity of the bone microenvironment. It is highly adaptable for various cancer types and bone genotypes and enables high-throughput functional interrogation of cancer colonization in a complex microenvironment. The protocol requires basic expertise in mammalian cell culture and mouse dissection and is suitable for researchers studying metastasis, tumor–stroma interactions, or preclinical therapeutic screening in the bone microenvironment. Clinical trial number Not applicable.

Background Secondary prevention of coronary heart disease (CHD) remains suboptimal due to fragmented care and therapeutic inertia. While digital health interventions offer a promising strategy, few existing tools provide comprehensive, closed-loop management of multidimensional risk factors without increasing clinician workload. This study aimed to evaluate the efficacy of an artificial intelligence (AI)–enhanced management system (AIM-CHD) in improving multidimensional risk factor control among patients with CHD. Methods This single-center, open-label, parallel-group, randomized clinical trial was conducted from November 2024 to June 2025 in China. A total of 1100 adults with confirmed CHD were randomized 1:1 to receive either the AIM-CHD intervention (n = 549) or usual care (n = 551) for 3 months. The AIM-CHD system featured automated multi-source data capture, guideline-directed risk stratification, and closed-loop feedback via smartphone. The primary outcome was the low-density lipoprotein cholesterol (LDL-C) level at 3 months. Secondary outcomes included goal attainment rates for LDL-C (< 70 mg/dL) and blood pressure (BP, < 130/80 mm Hg), glycated hemoglobin, smoking cessation, body mass index (BMI), medication adherence, and a composite cardiovascular endpoint at 3 months. Analysis was performed on an intention-to-treat (ITT) basis. Results Of 1100 randomized participants (mean age 61 years; 75.3% male), 943 (85.7%) completed the 3-month follow-up. The intervention group achieved a significantly lower mean LDL-C level compared with the control group (60.4 ± 23.4 vs. 63.7 ± 26.0 mg/dL), with an adjusted mean difference of − 3.2 mg/dL (95% CI, − 6.2 to − 0.3; p = 0.03). Furthermore, participants in the intervention group were more likely to achieve the LDL-C target (71% vs. 64%; RR, 1.10; 95% CI, 1.01–1.20; p = 0.03) and the BP target (45% vs. 35%; RR, 1.27; 95% CI, 1.09–1.48; p = 0.002). No significant differences were observed for HbA1c, BMI, or medication adherence. Conclusions The AIM-CHD system significantly improved short-term lipid and BP control compared with usual care. These findings support interoperable, low-burden digital management systems as a scalable strategy in routine secondary prevention. Trial registration https://bit.ly/4gtTL58 Identifier: NCT06686056. Registered on 11 November 2024.

Background In laboratory-based injury risk assessments, there is always a small and not entirely avoidable risk of injury to participants. This case report describes an anterior cruciate ligament (ACL) re-rupture of a female participant during the approach run of a stimulus-response change-of-direction (COD) task. Methods Marker-based kinematic data from the injury trial were compared with 14 successful trials of the same participant. These trials included unanticipated CODs in response to an opponent’s kicking action with varying cognitive demands, including one trial under identical high-demand conditions involving a feint. The participant approached at a speed of 4.08 m/s and the feint was initiated 475 ms before the injury step. Results The injury trial differed from the non-injury trials in terms of a markedly prolonged flight phase preceding initial contact in combination with deviations in lower-limb and trunk kinematics during the flight phase and the step before. These deviations exceeded the participant’s typical movement range observed during the non-injury trials and included temporally pre-shifted flexion-extension patterns at the knee and hip, a more extended trunk at initial contact, an altered pelvic drop, and reduced ankle inversion. During the injury stance phase, pronounced hip adduction, knee abduction and ankle eversion were observed. Conclusions The findings substantiate previously theorized mechanisms of non-contact ACL injury and show in a within-subject comparison that critical proximal and distal kinematic deviations at the trunk and lower limbs arise already during the preparatory phase. The occurrence after an opponent’s feint further suggests and highlights the importance of a neurocognitive contribution for ACL injuries. Trial registration The study protocol was preregistered on Open Science Framework ( https://bit.ly/4zPesA6 ).