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Background: Active Charcot neuro-osteoarthropathy (CNO) requires prolonged offloading, yet no reliable markers exist to predict time to remission at diagnosis. This study examined whether plantar pressure and radiographic deformity at diagnosis are associated with time to remission, and whether these measures provided independent and complementary prognostic value. Methods: This retrospective cohort study included 20 adults with active CNO. Barefoot peak plantar pressure and five radiographic angles from weight-bearing lateral radiographs were assessed at diagnosis. Associations with time to remission were examined using Spearman correlation and receiver operating characteristic (ROC) analysis. Results: Median time to remission was 132 days (interquartile range [IQR] 102 to 155). Medial midfoot plantar pressure showed a moderate non-significant association with time to remission (&#x3c1; 0.42, p = 0.064, area under the curve (AUC) 0.71). Of three radiographic angles with significant associations after false discovery rate correction, talar declination showed the strongest association with time to remission (&#x3c1; 0.76, p < 0.001) and demonstrated good discriminative performance for delayed remission (AUC: 0.89, 95% CI: 0.74 to 1.00). Meary's angle performed comparably (AUC 0.86, 95% CI 0.69 to 1.00), consistent with high collinearity between measures (&#x3c1; = -0.94). Adding plantar pressure to talar declination did not improve discriminative performance (combined AUC 0.89, DeLong p = 1.00). Conclusions: In this exploratory cohort, talar declination and Meary's angle demonstrated good discriminative performance for delayed remission. Plantar pressure showed a positive association with time to remission that did not reach statistical significance and did not improve discriminative performance when combined with radiographic assessment. Radiographic measurement at diagnosis, specifically talar declination or Meary's angle, may support prognostic discussions with patients and inform decisions around offloading duration, pending prospective validation.

Constraint-based modeling is a well-established modeling methodology used to study biological networks at both the medium-scale and genome-scale. Due to their large size and complexity, such steady-state flux models are typically analyzed using constraint-based optimization techniques, such as Flux Balance Analysis (FBA). The Flux Balance Constraints (FBC) Package extends SBML Level 3 to provide a standardized format for encoding, exchanging, and annotating constraint-based models. It includes support for modeling concepts such as objective functions, flux bounds, and annotation of model components that facilitate reaction balancing. Version two extended the original release by adding support for encoding gene-protein associations. Version three builds upon and maintains backwards compatibility with Version two by introducing new elements and attributes that include: user-defined constraints, a new quadratic variable type and key-value pair annotation that can be used to store additional information relevant to constraint-based modeling. The only changes to existing attributes are that a Species charge is no longer restricted to an integer value and chemicalFormula can now include generic components. In addition to providing the elements necessary to uniquely encode constraint-based models, the FBC package provides an open platform that facilitates the continued, cross-community development of an interoperable, constraint-based model encoding format.

Background/Objectives: To examine adherence to the specific goals of the nutrition component of a healthy lifestyle intervention program during pregnancy (the Nutrition and Exercise Lifestyle Intervention Program; NELIP) from baseline at 12-18 weeks gestation to trial midpoint (24-25 weeks gestation) and endpoint (34-36 weeks gestation). Methods: A convenience sample of 90 individuals were included in the secondary analysis. Participants completed the pregnancy intervention in one of three groups: NE, nutrition and exercise introduced simultaneously; N+E, nutrition introduced first followed by exercise introduced at midpoint; or E+N, exercise introduced first followed by nutrition introduced at midpoint. A meal plan with guidelines for carbohydrate and protein consumption was included in the nutrition component, and adherence to the specific meal plan goals was tracked using a novel rubric developed especially for the meal plan in the NELIP intervention. Results: All groups had improvements in nutrition adherence from baseline to midpoint, with the NE group scoring highest in adherence (12.9 &#xb1; 2.0 points) at midpoint compared to the N+E (11.2 &#xb1; 1.8 points) and E+N (11.8 &#xb1; 2.0 points) groups (F(2, 85) = 6.08, p = 0.00, &#x3b7;2 = 0.13). From midpoint to endpoint, N+E was the only group with no decline in adherence. Conclusions: The N+E group had the most stable improvements in adherence over the course of the intervention, despite better improvements in adherence from baseline to midpoint in groups NE and E+N. Time of intervention component introduction may have a differential impact on adherence score fluctuation, with baseline nutrition scores potentially influencing nutrition habits over time.

Background/Objectives: Accurate data subcategorising is vital for reliability and traceability in the training and validation of all artificial intelligence (AI) models. Methods: In this paper we show the complexity of clinical and technical features likely to affect the appearance and interpretation of mammography images and in turn affect the output of AI software used to aid clinical decisions. Results: Using mammography as a case study, the equitability covers screened population characteristics (e.g., women's age and ethnicity) and image acquisition key factors (e.g., brand of system, exposure factors, image processing). We examine some studies and available datasets of mammography images, summarising the metadata available. Conclusions: We recommend that, where possible, AI models are trained and evaluated using data that includes subcategories based on these features, ensuring increased equitability in the data and coverage of image heterogeneities; or, where not possible, that the subcategories for which the AI model is valid are clearly defined. Such practices can easily be implemented in a wide range of AI applications but are illustrated here with mammography. Clinical Relevance: Reliable AI holds invaluable potential for both clinical efficiency and accuracy in diagnosis. With appropriately categorised training data, a reduction in subjective assessment can be achieved, leading to trustworthy and rapid assessment.

Ruthenium oxide (RuO2) is the most promising alternative to iridium oxide (IrO2) catalyst in proton-exchange-membrane water electrolysis (PEMWE). However, its practical application has been hindered by poor stability. Here, we developed an interface-growth-assisted molten salt synthesis (MSS) strategy for the preparation of stable cobalt (Co)-embedded RuO2 (Co-RuO2) nanorods using a lanthanum cobaltate (LaCoO3) template. The MSS environment is beneficial for anisotropic growth and the exposure of highly active RuO2 crystal planes. Moreover, the in situ topological transformation arising from the interface growth of RuO2 on LaCoO3 can further enhance these effects and incorporate Co into the RuO2 lattice. The PEMWE electrolyzer with Co-RuO2 as the anode catalyst can operate steadily for over 300 h at 500 mA cm-2. Theoretical simulations indicate that Co substitutions would stabilize oxygen vacancies and increase metal-oxygen covalency, thereby lowering cell voltage and improving the stability of the PEMWE electrolyzer. This work pioneers template-directed interface growth in an MSS environment to prepare anisotropic RuO2 catalysts for practical PEMWE applications.

The Sick, Control, One, Fat, Food (SCOFF) is a questionnaire that screens for risk of eating disorders. Some symptoms and psychological factors associated with disorders of gut-brain interaction (DGBI) may resemble the features of eating disorders, potentially overestimating the risk of eating disorders in populations with high DGBI prevalence such as those with Hypermobile Ehlers-Danlos syndrome/hypermobility spectrum disorder (hEDS/HSD). This study aimed to identify factors associated with screening positive on SCOFF among adult with hEDS/HSD to explore the questionnaire's suitability for this population. A secondary analysis of data from 670 adults with hEDS/HSD recruited from Ehlers-Danlos Support UK and tertiary Neurogastroenterology. &#x3c7;2 tests and logistic regression were used to examine factors associated with positive SCOFF screening result and positive responses to individual SCOFF questions. DGBI presence did not predict a positive SCOFF screen. However, high gastrointestinal symptom-specific anxiety (GSA) (AOR: 3.19, p&#x2009;<&#x2009;0.001), fear of aversive consequences from eating (AOR: 1.97, p&#x2009;=&#x2009;0.013), and anxiety (AOR&#x2009;=&#x2009;2.53, p&#x2009;<&#x2009;0.001) were significant predictors. Notably, high GSA strongly predicted a positive response to questions two (Do you worry you have lost Control over how much you eat?) and five (Would you say that Food dominates your life?) (Q2 AOR&#x2009;=&#x2009;2.58, p&#x2009;=&#x2009;0.006, Q5 AOR&#x2009;=&#x2009;5.98, p&#x2009;<&#x2009;0.001). In hEDS/HSD, high GSA strongly predicted a positive SCOFF screening outcome, suggesting that SCOFF's questions might detect behaviors associated with worries around GI symptoms rather than an eating disorder. Positive screens in this population should be interpreted with caution and accompanied by GSA-focused assessments to enhance biopsychosocial management. People with hypermobile Ehlers&#x2013;Danlos syndrome/hypermobility spectrum disorder (hEDS/HSD) often experience gastrointestinal symptoms. The SCOFF is a short questionnaire commonly used to screen for eating disorders, however, it may not work perfectly in this group because gastrointestinal symptoms can affect how people answer its questions. In this study, we looked at factors that predicts SCOFF screening results and found that people with high anxiety about gastrointestinal symptoms and fears about the negative consequences of eating were more likely to have a positive SCOFF screen. This suggests that a positive SCOFF screen may reflect concerns about gastrointestinal symptoms rather than an eating disorder. Therefore, clinicians should interpret positive SCOFF results carefully in individuals with hEDS/HSD and gastrointestinal disorders.

Clinical guidelines suggest body mass index (BMI) thresholds of &#x2265;25&#x2009;kg/m&#xb2; to identify individuals at elevated risk of type 2 diabetes and (T2D) hypertension, however, growing evidence suggests that higher BMI values within the normal weight range may also be associated with increased risks. A systematic search was conducted in PubMed and Scopus, with an updated PubMed search through October 2025, to identify cohort studies from the US and Europe that reported risk estimates of T2D or hypertension for higher normal weight BMI values (e.g., 22.5-24.9&#x2009;kg/m&#xb2;) compared with lower normal weight BMI values. Asian studies were excluded because of lower BMI thresholds in Asian populations. Random-effects meta-analysis was performed to estimate summary relative risks (RRs) and 95%CIs. Eleven cohort studies were included, with 23% of participants and 17% of cases being classified as having high normal weight BMI values (22.5-24.9&#x2009;kg/m&#xb2;). Compared with lower BMI values within the normal weight range, high normal weight BMI values were associated with a greater risk of T2D (RR&#x2009;=&#x2009;1.78, 95% CI: 1.30-2.45, I&#xb2;&#x2009;=&#x2009;98%; n&#x2009;=&#x2009;10 studies with 1,818,036 participants and 84,414 cases; moderate certainty evidence). Evidence for hypertension was limited, based on three US cohort studies (RR&#x2009;=&#x2009;1.42, 95% CI: 1.33-1.51, I2&#x2009;=&#x2009;0; n&#x2009;=&#x2009;3 studies with 129,046 participants and 22,254 cases; low certainty evidence). Compared with lower normal weight BMI values, higher BMI within the normal range was associated with a higher risk of T2D and hypertension, suggesting that current BMI classifications may not fully capture the increased risk among individuals at the upper end of the normal weight spectrum. If replicated, the findings may justify reconsideration of BMI thresholds to better reflect the higher cardiometabolic risk observed among individuals with high normal weight BMI.

The SARS-CoV-2 JN.1 subvariant has attracted attention due to the accumulation of mutations in the Spike (S) glycoprotein, particularly within the receptor-binding domain (RBD), contributing to the structural heterogeneity of the Spike protein. However, the extent to which conformational dynamics influence ligand-recognition patterns across functional Spike states remains insufficiently characterized. In this study, we applied a hierarchical computational framework combining homology modeling, molecular dynamics simulations, and molecular docking to determine whether conformational sampling modifies the location, accessibility, and recurrence of ligand-interaction regions in the JN.1 Spike protein. Closed, semi-closed, and open conformations were modeled and subjected to triplicate simulations, including an initial 100 ns phase followed by extended 200 ns simulations. Representative conformations were obtained by trajectory clustering and used for docking analyses. Two flavonoids, hesperitin-7-O-rutinoside (H7R) and flavanone-7-O-glucoside (F7G), were employed as structural probes to assess how ligand interaction patterns vary across conformational states. Comparative analyses revealed that conformational sampling modifies the location, accessibility and spatial distribution of ligand-interaction regions while generating distinct docking poses and recurrent interaction patterns not fully captured by static structural models. These findings highlight the importance of dynamics-informed structural ensembles for docking analyses in flexible viral proteins. Rather than predicting absolute binding affinities, this study provides an exploratory computational framework for evaluating ligand-recognition behavior in structurally dynamic viral systems.

Contemporary food systems are increasingly shaped by financialization, corporate concentration, and unequal distributions of power that influence food production, food environments, dietary exposures, and population health. However, the relationships among food-system financialization, food sovereignty, and oral health remain insufficiently integrated within food-security, sustainability, and One Health research. This structured narrative review critically synthesized interdisciplinary evidence from Scopus, Web of Science, PubMed/MEDLINE, Google Scholar, citation searching, and authoritative institutional sources to examine these relationships and develop an integrative conceptual framework. The synthesis indicates that financialization may influence health through market concentration, commodity dependence, corporate control of food environments, and the expansion of ultra-processed foods, whereas food sovereignty may modify these pathways by strengthening agency, equitable resource distribution, local governance, and ecological resilience. Dietary exposures and related biological mechanisms provide plausible pathways through which these structural processes may contribute to oral-health outcomes and inequalities. The proposed framework integrates food-system structures, governance, food environments, dietary exposures, biological pathways, oral health, and One Health implications within a common analytical model. Oral health is therefore proposed as a potential biological interface through which food-system transformations and inequalities may become measurable. Empirical research is required to test these pathways and evaluate the framework's applicability across populations and food-system contexts.

Rett syndrome (RTT, OMIM 312750) is a complex multisystem neurodevelopmental disorder. Evidence suggests that RTT may have an autoimmune component and inflammatory activation. However, the autoimmune manifestations remain poorly described. Pemphigus foliaceus is a debilitating autoimmune blistering condition caused by IgG autoantibodies that target desmoglein-1 (Dsg1), resulting in widespread skin blistering and lesions. We report a case of pemphigus foliaceus in a 20-year-old female with RTT and discuss its clinical implications. Clinical data obtained from electronic health records were extracted and reviewed. Genetic testing was performed to identify the specific methyl-CpG-binding protein 2 (MECP2) mutation and on an expanded panel of 55 genes associated with pemphigus foliaceus and related blistering disorders. The individual had pemphigus foliaceus, which required immunosuppression, intravenous immunoglobulin (IVIg) therapy, and Rituximab. The disease trajectory was complicated by infections, aspiration pneumonia, and hypoxic cardiac arrest. There was progressive functional decline, and disease control was difficult to achieve, with frequent flares. Genetic testing confirmed a heterozygous pathogenic MECP2 variant (NM_001110792.1:c.952C>T; p.(Arg318Cys)). HLA genotyping identified alleles consistent with the HLA-DRB1*04:02-HLA-DQA1*03:01-HLA-DQB1*03:02 (DR4/DQ8) haplotype. Furthermore, genetic analysis identified a heterozygous DSG1 variant rs12967407. This study reports the first case of pemphigus foliaceus in RTT, expanding the clinical spectrum of RTT beyond its neurodevelopmental phenotype. The DR4/DQ8 haplotype, previously associated with pemphigus susceptibility, supports a background of genetic susceptibility in this individual. No causal association between RTT and pemphigus foliaceus can be inferred from this single case. Rather, this case demonstrates that a rare autoimmune disorder such as pemphigus foliaceus can co-occur with a pathogenic MECP2 mutation. The coexistence of a genetic and autoimmune disease can result in a more complex clinical presentation and treatment course. The case further emphasises the need for increased vigilance in identifying new and emerging systemic pathology alongside RTT.

Emilia sonchifolia (L.) DC is a medicinal and edible herb of Asteraceae with Lingnan characteristics. Flavonoids are its core pharmacodynamic substances, but the molecular regulation mechanism of differential accumulation of flavonoids in different organs of this species is still unclear. In this study, the molecular basis of tissue-specific synthesis of flavonoids was analyzed by integrating UPLC-MS broad-target metabolome and Illumina high-throughput transcriptome with four tissues of Emilia sonchifolia: root, stem, leaf, and flower. The results showed that a total of 73 flavonoid metabolites were identified in the metabolome, including naringenin chalcone, luteolin, quercitrin, and other pharmacologically active substances. Multi-omics joint analysis showed that the floral organ was the core tissue for the synthesis and enrichment of flavonoids, and there were specific characteristic flavonoid subtypes in different tissues. A total of 211 differentially expressed genes related to the flavonoid synthesis pathway were screened by transcriptome analysis, including 16 flavonol synthases, five cinnamic acid 4-hydroxylases, and five chalcone synthases. The WGCNA and gene-metabolite association network showed that the transcription levels of key enzyme genes such as CHS, C4H, F3'H, and F3H were highly positively correlated with the accumulation of downstream flavonols. The qRT-PCR quantitative verification showed that the expression patterns of CHS1, CHI4, F3'H5, F3H, FLS4, and GT in the four tissues were highly consistent with the transcriptome sequencing results, which confirmed that the transcriptome data were reliable. For the first time, this study revealed the molecular regulatory network of tissue-specific accumulation of flavonoids in Emilia sonchifolia, and clarified that the flower organ was the optimal medicinal harvesting site of flavonoids. It provided key theoretical support for the breeding of high-efficacy Emilia sonchifolia germplasm, the development of flavonoid active ingredients, and the study of secondary metabolic evolution of Compositae plants.

Background/Objectives: The levonorgestrel-releasing intrauterine device (LNG-IUD) is widely used as a long-acting reversible contraceptive and as a therapeutic option for heavy menstrual bleeding, endometriosis, adenomyosis, and endometrial hyperplasia. Although its predominant effect is local, systemic levonorgestrel exposure has raised questions regarding its potential influence on cancer risk. This review aims to summarise and critically appraise the available evidence on the association between LNG-IUD use and gynaecologic, breast, and selected non-gynaecologic malignancies (including colorectal, lung, pancreatic, gastric, thyroid, skin [melanoma], and haematological cancers). Methods: A structured narrative review was developed by a multidisciplinary expert group affiliated with the European Society of Gynaecological Oncology (ESGO) and the European Society for Gynaecological Endoscopy (ESGE). PubMed/MEDLINE, Embase, and Scopus were searched in December 2024 without publication-date restrictions. We critically appraised epidemiological and clinical evidence on LNG-IUD use and breast, endometrial, ovarian, cervical, and selected non-gynaecologic cancer risks, prioritising population-based cohorts, registry-based studies, case-control studies, systematic reviews, and meta-analyses. Results: The strongest and most consistent evidence supports a substantial reduction in endometrial cancer risk among LNG-IUD users, with a possible protective association also suggested for ovarian cancer. Available data do not indicate a clear increase in cervical cancer, CIN3+, or invasive cervical disease. In contrast, evidence for breast cancer remains heterogeneous, with some registry-based studies suggesting a modest relative increase and other cohort or case-control studies showing no significant association. Evidence regarding non-gynaecologic cancers remains limited and inconclusive. Conclusions: Overall, current evidence suggests that the LNG-IUD has a favourable oncological safety profile, with the strongest evidence supporting a significant reduction in endometrial cancer risk and a potential protective effect against ovarian cancer. There is no evidence pointing to increased risk of cervical cancer. However, results related to breast cancer are mixed, and a slight risk increase cannot be ruled out; thus, counselling should be personalised based on the indication, menopausal status, duration of use, and individual breast cancer risk.

Background: Epiretinal membrane (ERM) is a fibrocellular preretinal proliferation composed of fibroblasts, glial cells, and hyalocytes overlying the internal limiting membrane. Pars plana vitrectomy (PPV) with membrane peeling is the standard surgical treatment, but postoperative cystoid macular edema (CME) can limit visual recovery. Inflammation plays a key role in CME pathogenesis, and corticosteroids may help reduce the inflammatory response associated with both ERM-related traction and surgical trauma. Therefore, sustained-release dexamethasone (DEX) intravitreal implants have been investigated as an adjunct to surgery. Methods: This SANRA-guided narrative review evaluated studies investigating DEX implantation during PPV for ERM surgery or as treatment for persistent postoperative CME. Eligible studies included human clinical studies reporting functional, anatomical, biomarker, or safety outcomes following DEX use in the ERM surgical setting. Results: DEX implantation appears to promote faster resolution of postoperative inflammation and CME, with consistent improvements in anatomical parameters such as central macular thickness. However, the impact on visual acuity remains variable, with some studies reporting earlier functional recovery and others showing no significant long-term benefit. Reported adverse events mainly include intraocular pressure elevation manageable with medical therapy and cataract progression. Available evidence suggests that intraoperative DEX implantation is associated with more consistent anatomical benefit than superior long-term functional improvement, while delayed DEX administration may benefit selected eyes with persistent postoperative cystoid macular edema. Conclusions: Current evidence suggests that DEX implantation may represent a potentially useful adjunctive strategy in selected patients undergoing ERM surgery, particularly in eyes at higher risk of postoperative inflammation or cystoid macular edema. While available studies suggest potential anatomical benefits, evidence regarding superior long-term functional outcomes remains inconsistent. Moreover, while current evidence suggests that DEX implantation may accelerate anatomical recovery and improve postoperative inflammatory control in selected patients, long-term functional superiority over PPV alone, including sustained BCVA improvement and patient-reported visual outcomes such as metamorphopsia, remains unproven. Larger prospective randomized studies are needed to better define optimal patient selection and treatment timing.

Nickel-based cathodes are widely used in alkaline water electrolysis, yet the nature and stability of the active surface under operating conditions remains unclear. In particular, the role of metal/oxo-hydroxo interfacial structures in governing hydrogen evolution activity is not well understood. Here, we employ a multimodal, depth-sensitive approach combining operando Ni L-edge X-ray absorption spectroscopy, depth-sensitive X-ray absorption measurements in total electron yield and Auger electron yield modes, X-ray photoelectron spectroscopy, isotopically labeled nano secondary ion mass spectrometry, and online electrochemical mass spectrometry to directly track the evolution of Ni/NiOxHy interfaces during the hydrogen evolution reaction. Using well-defined sputtered Ni thin films as a model system, we show that progressive reduction of near-surface oxide/hydroxide species is accompanied by a gradual loss of hydrogen evolution activity. Depth-resolved measurements reveal a predominantly metallic outermost surface under cathodic bias, while NiOxHy forms on the surface upon relaxation to open-circuit conditions. Importantly, mild anodic pre-conditioning regenerates subsurface NiOxHy species, resulting in a sustained increase in hydrogen evolution activity upon subsequent cathodic polarization. These results establish the crucial role of metal/oxo-hydroxo interfaces as active phases for hydrogen evolution and provide a framework for engineering robust, Earth-abundant HER cathodes capable of operating under dynamic, real-world electrolysis conditions.

Opioid-related adverse effects have prompted interest in opioid-sparing strategies in joint arthroplasty. This systematic review evaluates the safety and efficacy of perioperative nefopam, a non-opioid, non-NSAID analgesic, in patients undergoing hip and knee arthroplasty. Medline, Cochrane, Embase, and Scopus were searched from database inception to September 2025. For meta-analysis, continuous outcomes were pooled as mean differences (MD) with 95% confidence intervals (CI), and dichotomous outcomes as risk ratios (RR). Certainty of evidence was assessed using GRADE. Four unique randomised control trials (n&#x2009;=&#x2009;425) were included. Nefopam was not associated with significant reductions in opioid consumption at 24&#xa0;h (4 studies, 425 patients, MD&#x2009;-&#x2009;6.73&#xa0;mg; 95% CI&#x2009;-&#x2009;18.56 to 5.09&#xa0;mg; GRADE: +). However, nefopam significantly reduced pain during movement at 24&#xa0;h (3 studies, 225 patients, MD&#x2009;-&#x2009;8.24; 95% CI&#x2009;-&#x2009;13.52 to -&#x2009;2.96; GRADE: +++) but not 24-hour pain score at rest (4 studies, 425 patients; MD -4.96; 95% CI -12.78 to 2.87; GRADE: +). Nefopam was also associated with improved knee range of motion at 24&#xa0;h postoperatively (2 studies, 177 patients, MD 7.78&#xb0;; 95% CI 7.33&#xb0; to 8.24&#xb0;; GRADE: +++). No significant differences were observed for length of hospital stay, patient satisfaction, or adverse-event outcomes. Nefopam reduced pain during movement and improved early knee range of motion at 24&#xa0;h but did not reduce acute opioid consumption or drug-related adverse effects after hip or knee arthroplasty.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the buildup of aggregated amyloid-beta (A&#x3b2;) peptides. We previously demonstrated that A&#x3b2; is produced from APP following its lysosomal internalization via macropinocytosis. However, the regulation of APP macropinocytosis in neuronal cells remained uncharacterized. Arf6 and the Rho GTPases Rac1, Cdc42 and RhoA are known to regulate macropinocytosis in response to signaling at the cell surface. Fe65, an adaptor protein known to interact with APP, may link APP to these regulatory elements. We hypothesized that APP binding/crosslinking recruits Fe65, which recruits/activates Arf6 and then Rac1, Cdc42, and RhoA, driving APP macropinocytosis. We found that antibody-mediated binding/crosslinking APP resulted in the transient recruitment of Fe65 and Arf6 to APP within 30 s of APP binding/crosslinking. Rac1, Cdc42, and RhoA were also recruited at 30 s, but remained recruited through 2 min. The mutation of the APP 'YENPTY' sequence and Arf6 inhibition by NAV-2729 prevented the recruitment of Rac1, Cdc42, and RhoA. Together, these observations are the first to demonstrate that a network of regulatory proteins is recruited to bound/crosslinked APP and regulates its macropinocytosis. Targeting these regulatory proteins to modulate APP trafficking to the lysosome could be a therapeutic strategy to reduce A&#x3b2; production in AD.

Background: Robotic-assisted spinal instrumentation is increasingly used to support implant placement, reduce radiation exposure, and improve operative workflow. However, UK NHS data describing early programme experience across elective and emergency practice remain limited. This study aimed to evaluate the feasibility, safety profile, and early learning curve of robotic-assisted spinal instrumentation in an unselected UK NHS cohort. Methods: A retrospective, single-centre, single-arm observational cohort study was conducted, including the first 50 consecutive patients treated from programme inception between June 2024 and January 2026. No exclusion criteria were applied, and each record represented one patient and one operation. Missing data were not imputed, and denominators were reported per variable. Learning curve effects were assessed using Spearman correlation and cumulative sum analysis. Wilson 95% confidence intervals were reported for complication rates. Results: The mean age was 61.9 years; 50% were male; mean body mass index was 29.0; and median Charlson Comorbidity Index was 3. Indications were degenerative disease in 74%, trauma in 24%, and deformity in 2%. Emergency admissions accounted for 18/50 cases. Robot-specific adverse events included abandonment or conversion in 2/50 cases and system malfunction in 1/50. Surgical complications occurred in 7/50 patients. On surgeon-reviewed routine post-operative imaging, no screw malpositions required revision and no durotomies or vascular injuries were recorded; this represents a clinical revision rate rather than a formal radiological measure of screw accuracy, for which blinded Gertzbein-Robbins grading was not performed. Cumulative sum analysis suggested a potential fluoroscopy change point around case 30, with the median fluoroscopy events falling from 151 to 16 thereafter. Emergency cases involved more instrumented levels, longer operative times, and more open surgery than elective cases. Conclusions: Robotic-assisted spinal instrumentation was feasible across a diverse UK NHS caseload from C1 to S2, with a low observed complication rate. The findings suggest a fluoroscopy learning curve threshold around case 30. Larger comparative studies with formal radiological accuracy assessment are required.

Background/Objectives: Alzheimer's disease (AD) is a progressive neurodegenerative disorder necessitating accurate and timely diagnosis for effective clinical intervention. While deep learning methods have shown promise in AD classification, many rely on computationally intensive architectures and high-dimensional feature representations. This study introduces a lightweight hybrid framework combining deep feature extraction, dimensionality reduction, and adaptive classification for MRI-based Alzheimer's disease stage classification. Methods: Utilizing MRI images from a publicly available Alzheimer's disease dataset encompassing four clinical stages (Non-Demented, Very Mild Demented, Mild Demented, and Moderate Demented), deep features were extracted using a pre-trained SqueezeNet model as a fixed feature extractor, generating 1000-dimensional feature vectors. Due to the computational complexity and for the improvement of the model efficiency, the dimensionality reduction technique, Principal Component Analysis (PCA) was then applied. This resulted in an optimum representation of 100 principal components, retaining about 96% of the variance. Then, the performances of various machine learning classifiers such as k-Nearest Neighbors (kNN), Support Vector Machine (SVM), Decision Tree (DT), Neural Network (NN), Na&#xef;ve Bayes (NB), Logistic Regression (LR) and Enhanced Fuzzy Min-Max Neural Network (EFMM) were tested. The accuracy, precision, recall, F1-score, area under the receiver operating characteristic curve (AUC), and confusion matrices were used to evaluate the performance. Stratified 5-fold cross validation was used to ensure the strength of our results. Results: The findings show that PCA has a significant improvement in classification accuracy for most of the models. In particular, the EFMM classifier outperformed the other classifiers, with an accuracy of 97.19% on the independent test set. After PCA, the AUC values for classes such as Mild Demented, Moderate Demented, Non-Demented and Very Mild Demented were obtained as 97.12%, 99.97%, 93.79% and 95.26% respectively. We further validated our proposed framework using stratified 5-fold cross validation which further corroborated the robustness of our proposed framework. The EFMM achieved a mean accuracy of 98.38% &#xb1; 0.36 and a mean macro-F1 score of 98.48% &#xb1; 0.43. Friedman statistical testing demonstrated that there were significant differences between the performance of the classifiers evaluated (p < 0.001), which further validated the performance of the EFMM. Conclusions: To sum up, the proposed SqueezeNet-PCA-EFMM is an effective and efficient method for Alzheimer's disease stage classification under MRI images. The combination of SqueezeNet, PCA, and EFMM-led not only to high classification performance, but also to good cross validation results. Furthermore, this property of incremental learning is the intrinsic one of the EFMM and renders this framework interesting for its incorporation in the next-generation intelligent clinical decision supports in particular, as medical care evolves.

Background: Advancing age is incorporated as a strong risk variable in EuroSCORE II and is consistently associated with adverse outcomes after conventional coronary artery bypass grafting (CABG). Whether minimally invasive direct coronary artery bypass (MIDCAB)-which avoids both sternotomy and cardiopulmonary bypass-modifies this age-related risk in patients with single-vessel or LAD-predominant coronary artery disease remains insufficiently characterised. Methods: We retrospectively analysed 350 consecutive patients who underwent MIDCAB at Hannover Medical School between July 1999 and April 2025 (follow-up to April 2025). Elderly patients (age &#x2265;70 years; n = 117) were compared with younger patients (age <70 years; n = 233) before and after 1:1 propensity score matching using greedy nearest-neighbour matching with a caliper of 0.2 &#xd7; SD of the logit propensity score; age was excluded from the propensity model as it represented the exposure variable. A pre-specified sensitivity propensity model that additionally excluded EuroSCORE II (because EuroSCORE II contains an age component) was also evaluated. The primary endpoint was all-cause long-term mortality; secondary endpoints included perioperative complications and in-hospital outcomes. Long-term survival was assessed by Kaplan-Meier analysis and multivariable Cox proportional hazards regression, with a pre-specified parsimonious Cox model (age, LVEF, renal impairment) and cluster-robust standard errors on matched-pair identifiers. Results: Matching produced 109 pairs with excellent covariate balance (all standardized mean differences < 0.20). MIDCAB was completed without intraoperative conversion in all patients. No 30-day mortality, perioperative stroke, or new postoperative dialysis was observed in either age stratum (Clopper-Pearson 95% CI 0.00-3.33% for each zero-event outcome). Perioperative complications-including new-onset atrial fibrillation, re-exploration for bleeding, and intensive care unit and hospital length of stay-did not differ significantly between elderly and younger patients in the matched cohort (Newcombe 95% CI for risk differences all crossing zero; McNemar's exact tests non-significant for all matched-pair binary endpoints; Hodges-Lehmann median difference for hospital length of stay +1.0 day, bootstrap 95% CI 0.0-1.0 days). At a median follow-up of 19.0 years (IQR 11.5-24.3; reverse Kaplan-Meier potential median 19.7 years), all-cause mortality was higher in the elderly (20.2% vs. 5.5%, p = 0.002; log-rank p = 0.001; exact McNemar's p = 0.0025 for the matched-pair mortality endpoint). After multivariable adjustment, elderly age (&#x2265;70 years) was independently associated with long-term mortality (adjusted hazard ratio 4.48, 95% CI 1.79-11.20, p = 0.001), as was EuroSCORE II (HR 2.40 per unit, p = 0.034); a pre-specified parsimonious model (age, LVEF, renal impairment) with pair-cluster robust standard errors yielded an essentially identical adjusted HR for elderly age of 4.08 (95% CI 1.65-10.04, p = 0.002), and a sensitivity propensity model without EuroSCORE II yielded HR 3.95 (95% CI 1.68-9.29, p = 0.002). Conclusions: In this propensity-matched analysis with a median follow-up of ~19 years, MIDCAB was associated with excellent observed perioperative outcomes in appropriately selected elderly patients (no 30-day mortality, stroke, or new dialysis observed; upper 95% CI 3.3%) and no evidence of an excess of major in-hospital complications compared with younger patients within the statistical resolution of the cohort. The long-term mortality excess in the elderly is consistent with age-related life-expectancy curves in the source population; cause-specific mortality was not available in this cohort. External benchmarks from large MIDCAB cohorts in which long-term survival approximates that of the age-matched general population support this interpretation indirectly. These findings support MIDCAB as a feasible revascularization strategy associated with favourable observed early outcomes and long-term survival consistent with published MIDCAB literature, in appropriately selected elderly patients with single-vessel or LAD-predominant coronary artery disease treated at experienced centres.