Search Results (437)

Background: The use of plasma rich in growth factors (PRGF) is a promising regenerative treatment for knee osteoarthritis (OA), but clinical response is heterogeneous. This study aimed to identify molecular features and explore clinical factors associated with PRGF non-response and explore potential biomarkers for patient stratification. Methods: One hundred patients with knee OA (Kellgren–Lawrence II–III) treated with two intra-articular PRGF injections were evaluated at baseline and 6 months. Clinical response was defined by a ≥8-point improvement in overall knee injury and osteoarthritis outcome score (KOOS). Exploratory proteomic profiling was performed in a subgroup of 33 patients (13 responders and 20 non-responders) using platelet-rich plasma-derived platelet lysate (PRP-PL) generated from the same blood-derived preparation used for treatment. Samples were analyzed by data-independent acquisition mass spectrometry, followed by a bioinformatic analysis of differential proteins and enriched pathways. To further investigate selected proteomic findings, IgA levels were quantified in PRP-PL from the entire cohort. Results: Responders showed significant improvements in pain, overall KOOS, and functional outcomes. Proteomic analysis identified a non-responder signature characterized by increased immunoglobulin chains, complement-related proteins, acute-phase molecules, extracellular matrix remodeling proteins, and metabolic stress markers. Functional enrichment revealed the activation of immune, inflammatory, and tissue remodeling pathways. IgA levels in PRP-PL were significantly higher in non-responders, consistent with the immunoglobulin-related proteomic findings. Conclusions: PRGF non-response is associated with an inflammatory and immune-related phenotype. Higher IgA levels in PRP-PL were associated with reduced treatment responsiveness and may help identify a biological phenotype less likely to benefit from PRGF treatment. Full article

Background/Objectives: Licochalcone A (LA), a bioactive chalcone derived from Glycyrrhiza species, exhibits anticancer activity in several tumor models; however, its effects on endometrial cancer remain poorly understood. This study investigated the antiproliferative, cytotoxic, and antimigratory effects of LA in Ishikawa endometrial cancer cells and characterized associated changes in Akt/mTOR- and LC3-related molecular responses. Methods: Metabolic activity, colony formation, cell cycle distribution, migration, and invasion were evaluated following LA treatment. Ki-67 and LC3-II immunoreactivity, PI3K, Akt, mTOR, and MAP1LC3B transcript levels, and Akt phosphorylation were also assessed. Results: LA reduced metabolic activity and clonogenic capacity, decreased Ki-67 expression after prolonged exposure, increased apoptosis, and induced S-phase accumulation at higher concentrations. LA markedly reduced cell migration after 48 h, whereas no statistically significant change in invasion was detected. RT-qPCR revealed concentration- and time-dependent changes in PI3K, Akt1, mTOR, and MAP1LC3B transcript levels, with mTOR significantly reduced at all tested concentrations after 48 h. Akt phosphorylation was markedly reduced across all tested concentrations after 48 h, while MAP1LC3B transcript levels and LC3-II immunoreactivity showed concentration- and time-dependent changes. Conclusions: These findings demonstrate antiproliferative, cytotoxic, and antimigratory effects of LA in Ishikawa endometrial cancer cells and identify associated changes in Akt/mTOR- and LC3-related molecular responses. Full article

Osteoarthritis (OA) is a common, disabling joint disease characterized by complex inflammatory, oxidative, and catabolic cascades that culminate in progressive cartilage degradation, subchondral bone remodeling, and synovitis. Standard pharmacological treatments such as nonsteroidal anti-inflammatory drugs (NSAIDs) provide symptomatic relief of pain but do not prevent the progression of the disease and are often associated with serious gastrointestinal, renal and cardiovascular side effects following long-term use. Epigallocatechin-3-gallate (EGCG), resveratrol, curcumin, quercetin, luteolin and genistein are naturally occurring polyphenols which have been identified as promising disease-modifying osteoarthritis drugs (DMOADs). Mechanistically, these phytochemicals suppress key pro-inflammatory signaling pathways (NF-κB, MAPK), downregulate matrix-degrading enzymes (MMP-13, ADAMTS-5), mitigate reactive oxygen species (ROS), and attenuate chondrocyte apoptosis and senescence. Polyphenols have been shown in pre-clinical and clinical trials to reduce joint pain and preserve cartilage integrity. They also have a synergistic effect with conventional drugs, resulting in lower doses and reduced toxicity. However, their clinical translation has been hampered by poor oral bioavailability, rapid Phase II metabolism, and short intra-articular retention. Advanced drug-delivery systems, such as nanoparticles, liposomes, and sustained-release hydrogels, are essential to overcome these pharmacokinetic bottlenecks and realize their full therapeutic potential in OA management. Full article

Reliable storage and distribution are important for developing ready-to-use encapsulated cell products for transplantation and bioartificial liver applications. This study evaluated the cryopreservation of alginate-encapsulated HepaRG cells using a programmable controlled-rate freezing (CRF) protocol at −0.3 °C/min or conventional passive cooling at approximately −1 °C/min. Five media were tested: four commercial xeno-free formulations, including two DMSO-containing and two DMSO-free media, and a conventional formulation containing 90% fetal bovine serum and 10% DMSO. Following thawing and a 3-day recovery period, metabolic activity, albumin secretion, ammonia and lactate clearance, and phase I and phase II biotransformation activities were assessed. Cryopreservation reduced metabolic activity relative to non-frozen controls, but key hepatic functions remained detectable. The tested CRF protocol generally yielded equal or higher functional values than conventional freezing. Medium performance varied according to the endpoint assessed. Within CRF, CryoStor CS10 produced relatively high mean PrestoBlue and albumin secretion values, whereas Cellvation produced the highest mean CYP1A1/1A2 activity. These product-specific observations do not establish a general effect of DMSO. The findings support the short-term feasibility of the tested CRF protocol for this encapsulated HepaRG model but not broader clinical or drug-testing applications. Full article

This study evaluated the performance of a non-aerated 22 L column photobioreactor treating synthetic wastewater (SWW) under increasing organic loading rates (SWW x1, x2, and x3) at a hydraulic retention time of 2 days to investigate how purple phototrophic bacteria (PPB) inoculation timing affects operational stability and nutrient removal. Two strategies were compared: supplementing a microalgae–bacteria consortium with PPB after 15 days (Phase I) versus co-inoculation from startup (Phase II). Phase I maintained active photosynthesis, reaching dissolved oxygen (DO) levels of 14.7 ± 3.8 mg L⁻¹ in SWW x2. Conversely, Phase II sustained persistently low DO (<1.5 mg L⁻¹), which correlated with reduced inorganic carbon fixation and raised effluent inorganic carbon to 205.2 mg L⁻¹ under SWW x3. The highest load (SWW x3) also induced orthophosphate accumulation and elevated ammonium levels up to 150 mg L⁻¹ due to nitrogenase suppression. Phase II also exhibited a higher nitrite accumulation (approx. 10 mg L⁻¹) with minimal nitrate (<3 mg L⁻¹), suggesting impaired nitrifying activity. In conclusion, the early PPB co-inoculation strategy established a distinct microbial community trajectory that favored a sub-optimized, dissipative metabolic regime that impaired carbon fixation and resource recovery under high loading rates. Full article

Ulcerative colitis remains a major clinical challenge due to limited availability of safe, orally active anti-inflammatory drugs. Although phase II metabolism is traditionally viewed as a detoxification process, certain metabolites retain or exhibit enhanced pharmacological activity, offering an underexplored drug discovery opportunity. Here, we investigated phase II metabolite-inspired tripeptide editing using M13, a glutathione-conjugated metabolite of the anti-inflammatory natural product 6-shogaol, as a lead scaffold. A focused library of 38 analogs was generated by systematic tripeptide editing while preserving the central cysteine-containing 6-shogaol-derived scaffold. Phenotypic nuclear factor-κB (NF-κB) reporter screening identified 29 of 38 analogs with greater inhibitory activity than M13 at the screening concentration. Two selected leads, MLY2 and MLY8, demonstrated enhanced anti-inflammatory activity in Dextran Sulfate Sodium-induced experimental colitis, including restoration of colon length and reductions in fecal lipocalin-2 and pro-inflammatory cytokines. Both compounds also suppressed inflammatory cytokine production more effectively than M13 in ex vivo colonic biopsies from patients with treatment-refractory ulcerative colitis. In parallel, MLY2 and MLY8 showed no detectable mutagenicity under the Ames assay conditions and were well tolerated in a preliminary single-dose maximum tolerated dose study. Collectively, these findings establish phase II metabolite-inspired tripeptide editing as a productive lead-discovery strategy and identify MLY2 and MLY8 as anti-inflammatory leads warranting further preclinical characterization. Full article

Background: Concurrent chemoradiotherapy (cCRT) followed by 1 year of consolidation durvalumab remains the standard of care for unresectable stage III non-small cell lung cancer (NSCLC), yet long-term survival is still limited and around 20% of patients present locoregional relapse. Hypofractionation may improve the therapeutic ratio by increasing the biologically effective dose (BED), shortening overall treatment time (OTT) and potentially mitigating radiation-induced lymphopenia. Objective: To identify which patients with unresectable stage II–III NSCLC may benefit most from radical-intent hypofractionated radiotherapy (HypoRT), with or without systemic therapy, and to define the technical aspects, contouring margins, and dosimetric requirements necessary for the safe use of hypofractionated schedule. Methods: A systematic search of PubMed, EMBASE, CENTRAL and Web of Science (January 2010–January 2024, English language) was performed following PRISMA principles. Eligible studies included unresectable NSCLC treated with a BED10 > 40 Gy, allowing induction systemic or targeted therapy; reviews were included for context. Records were screened by six independent reviewers. Studies were classified as non-photon vs. photon, and photon studies were further divided into non-concurrent and concurrent strategies. Clinical outcomes (dose, fractionation, biologically effective Dose for alpha/beta:10 (BED10), equivalent dose of 2 Gy/fraction (EQD2), overall treatment time (OTT), follow-up (FU), median progression-free survival (mPFS), median Overall Survival (mOS), local control (LC), grade ≥ 3 toxicity (G3) and technical variables (immobilization, simulation, GTV imaging, CTV/PTV margins, delivery, image-guided radiotherapy (IGRT), organ at risk (OAR) constraints) were extracted. Results: Of 340 records (170 duplicates), 26 studies including stage II–III disease were analyzed (1155 patients): 1 prospective cohort, 5 phase I, 12 phase II, 1 phase III and 2 phase I/II dose-escalation trials, 2 carbon-ion and 3 proton series. Of these, 13 were photon-based studies with contemporary simulation techniques. Two clinically distinct scenarios emerged. Group A (non-concurrent platinum-based strategies; 166 patients with modern 4DCT simulation) showed wide variability, ranging from a simultaneous-integrated-boost regimen to 75 Gy with 0% grade ≥ 3 toxicity and mPFS 40 months to a chemotherapy-driven schedule with 70% grade 4 chemo-related toxicity. Only one phase III trial was identified, reporting a 2-year local control of 85.8%. Group B (concurrent strategies; nine of the 14 platinum-based studies retrieved, namely those using modern simulation techniques) achieved a median BED of 89.7 Gy to the highest dose-volume, median of OS 20 months and toxicity GIII ≥ ranging 10–20%, with a median study-level grade 5 toxicity of 5.5% (range 0–17.8%; 34 fatal events among 431 evaluable patients, 7.9%), rising to 20.8% (11/53) in the most escalated randomized arm and 22.2% (2/9) in the highest dose-escalation cohort; adaptive SABR boost to 70 Gy/15 fr delivered high local control but clinically meaningful fatal toxicity. Fatal toxicity was confined to schedules exceeding BED10 100 Gy delivered to the whole tumor volume with concurrent platinum, whereas an equivalent BED restricted to a metabolically defined subvolume without concurrent chemotherapy produced no grade ≥3 events. Conclusions: Radical-intent hypofractionation is feasible across both unfit and fit unresectable stage II–III NSCLC populations, but the randomized evidence remains scarce and heterogeneous. Benefit appears most consistent when high BED is delivered with strict normal-tissue sparing in carefully selected patients using modern 4DCT-based simulation, IGRT and intensity-modulated delivery. The pattern of fatal toxicity with aggressive concurrent systemic treatments and dose escalation schedules argues for caution and for prospective trials with harmonized minimum technical standards. Full article

Gastrointestinal (GI) malignancies account for approximately one-quarter of new cancer diagnoses and more than one-third of cancer-related deaths worldwide, yet as of August 2026, only one CAR-T therapy has received regulatory approval for a solid tumor indication anywhere in the world. The recent CT041-ST-01 phase II trial of satricabtagene autoleucel, the first randomized CAR-T trial conducted in a solid tumor, demonstrated a significant improvement in progression-free survival for patients with advanced gastric cancer (median 3.25 vs. 1.77 months; hazard ratio (HR) 0.37, p < 0.001). While this landmark study established the clinical feasibility of CAR-T therapy in solid tumors, it also underscored the biological barriers that continue to limit durable responses. GI tumors are characterized by heterogeneous antigen expression, dense desmoplastic stroma, inefficient immune-cell trafficking, profoundly immunosuppressive tumor microenvironments, and progressive T-cell dysfunction, all of which are further compounded by the logistical and economic challenges of autologous cell manufacturing. In this narrative review, we organize these obstacles within a unified four-barrier engineering framework and critically examine the strategies being developed to overcome each of them. We discuss advances in multi-antigen and logic-gated CAR architectures, stromal remodeling through fibroblast activation protein (FAP)-targeted approaches and extracellular matrix-degrading enzymes, chemokine receptor engineering, regional delivery, hypoxia-responsive CARs, cytokine-armored and persistence-enhanced constructs, dominant-negative and switch receptors, metabolic reprogramming, and intrinsic checkpoint disruption. We also review emerging manufacturing platforms, including allogeneic CAR-T and CAR-natural killer (CAR-NK) cells, induced pluripotent stem cell-derived products, CAR-macrophages, and in vivo CAR generation, together with engineering strategies designed to improve safety and scalability. Rather than relying on a single technological advance, the future of CAR-based therapy for GI malignancies will likely depend on integrating multiple engineering approaches to address the diverse biological barriers within the tumor microenvironment. By synthesizing current preclinical and early clinical evidence, this review provides a translational framework for the next generation of CAR-based cellular therapies in gastrointestinal oncology. Full article

Resveratrol remains one of the most extensively studied plant-derived polyphenols because of its broad antioxidant, anti-inflammatory, cardioprotective, neuroprotective, and anticancer activities. However, its clinical translation has been substantially limited by its poor aqueous solubility, rapid phase II metabolism, and low systemic bioavailability, despite decades of intensive investigation. Structural modification through methoxylation has emerged as a promising strategy to overcome these pharmacokinetic limitations by enhancing metabolic stability, lipophilicity, membrane permeability, and biological activity. While considerable attention has focused on resveratrol and a limited number of established analogs, emerging methoxylated derivatives remain comparatively underexplored. This review highlights the structural characteristics, biological activities, and molecular mechanisms of two such derivatives, 4,4-(ethane-1,2-diyl)bis(2-methoxyphenol) (EG) and (Z)-3,5,4′-trimethoxystilbene (Z-TMS), and discusses evidence from structurally similar, better-characterized compounds that may aid in understanding their activities. Despite promising experimental findings, the therapeutic relevance of EG and Z-TMS remains insufficiently characterized because the available evidence is predominantly derived from in vitro studies, while data on toxicity, therapeutic index, long-term safety, pharmacodynamics, and clinically relevant systemic exposure remain limited. This review emphasizes the anticancer potential of these emerging methoxylated derivatives, identifies current knowledge gaps, and provides a basis for considering them as lead compounds for anticancer drug development. Full article

Background and Objectives: The main neurodegenerative diseases (NDs)—Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS)—represent a growing global health burden with no available disease-modifying therapies. Curcumin, a polyphenol from Curcuma longa, is a promising candidate owing to its pleiotropic antioxidant, anti-inflammatory, and neuroprotective profile observed mainly in preclinical models, but the poor oral bioavailability (<1%) and negligible BBB penetration (<0.1%) have substantially limited curcumin’s clinical translation. The objective of this work was to critically examine the therapeutic potential of curcumin in NDs, focusing on advanced drug delivery systems (DDSs) designed to overcome its pharmacokinetic barriers. Methods: This is a narrative, non-systematic review of PubMed/MEDLINE, Scopus, and Web of Science. The review is organized around five complementary thematic areas selected to span the full translational pipeline of curcumin in neurodegeneration, from mechanistic rationale to clinical applicability: (1) molecular mechanisms, addressing the pleiotropic activities that justify therapeutic interest; (2) pharmacokinetic barriers, the principal obstacle to clinical translation; (3) the evolution of drug delivery systems (DDSs), documenting the technological strategies developed to overcome these barriers; (4) disease-specific applications, evaluating the available evidence across the four main NDs; and (5) translational limitations, identifying the methodological and regulatory gaps that must be closed to enable clinical implementation. Results: Curcumin exhibits neuroprotective activity in preclinical models of the four NDs analysed, acting on six interconnected mechanisms and the gut–brain axis. Four generations of DDSs have been developed, from phytosomes and clinically used lipid dispersions (Meriva^®, BCM-95^®, Longvida^®, and Theracurmin^®) to fourth-generation systems (biomimetic nanoparticles, MOFs, microneedles, 3D scaffolds, hydrogels, and carbon dots) that substantially increase the bioavailability in preclinical studies. Combination strategies, such as curcumin with resveratrol and dutasteride, show preliminary clinical signals in ALS. However, clinical translation remains limited: over 80% of positive animal findings have not been replicated in humans, formulation characterization is frequently incomplete, and most trials lack CNS-exposure biomarkers. Importantly, most of the reported bioavailability claims are based on total curcumin measurements (parent aglycone plus its inactive Phase II conjugates) rather than the active aglycone alone, a methodological limitation that should be considered when interpreting the magnitude of the bioavailability improvements reported for novel formulations. Conclusions: Curcumin exhibits pleiotropic neuroprotective activity in preclinical models of AD, PD, MS, and ALS, mediated by interconnected antioxidant, anti-inflammatory, anti-amyloidogenic, mitochondrial, and gut–brain axis mechanisms. However, its poor systemic bioavailability (<1%), minimal blood–brain barrier penetration, and extensive first-pass metabolism have limited clinical translation. Advanced drug delivery systems (including lipid-based carriers (liposomes, solid lipid nanoparticles, and nanostructured lipid carriers), polymeric nanoparticles (PLGA and chitosan), and bioinspired vesicles (exosomes)) are essential in order to overcome these barriers. Nevertheless, the formulation heterogeneity, limited long-term safety data, and reliance on preclinical models remain major obstacles; a definitive clinical translation will therefore require well-characterized formulations validated in phase II/III trials with cerebrospinal fluid exposure biomarkers, the pharmacokinetic monitoring of active aglycone (rather than total curcumin including inactive conjugates), and adaptive trial designs in neurological populations. Full article

Gut microbiota regulate the intestinal expression of drug-metabolizing enzymes, transporters, and barrier properties that determine oral drug absorption and disposition. This study compares germ-free Swiss Webster mice to mice colonized with fecal microbiota from a single human donor, evaluating microbiota-driven differences in colonic gene expression and P-gp protein expression, as well as small intestinal mucosal permeability. Transcriptomic analysis of colonic tissue revealed microbiota-induced upregulation of genes encoding P-gp and other drug transporters, including MCT1 and OCTN2. Immunofluorescence also indicated greater P-gp expression and apical localization in colonized mice. Gene expression of drug-metabolizing enzymes was also higher in colonized mice, including phase I enzymes (carboxylesterase 2 paralogs), phase II enzymes (UDP-glucuronosyltransferases and glutathione S-transferases), and enzymes responsible for synthesizing their co-substrates, UDP-glucuronic acid and glutathione. Small intestinal mucosal explants demonstrated lower permeability to ¹⁴C-labeled polyethylene glycol 4000 in colonized mice compared to germ-free mice. In the colon, transcriptomic analysis identified microbiota-dependent changes in genes regulating paracellular tight junctions and actomyosin contractility. These results show that human-derived gut microbiota alter gene expression in the mouse colon, identifying candidate microbiota-responsive genes relevant to oral drug absorption and disposition. Full article

We review a theoretical and experimental programme with the aim of understanding two intimately related fundamental phenomena in biophysics: (i) the classical analogue of Fröhlich phonon condensation in macromolecules driven out of thermal equilibrium and (ii) the consequent activation of long-range resonant electrodynamic intermolecular forces. Both phenomena are underpinned by explicit Hamiltonian models. The first is derived by applying the time-dependent variational principle (TDVP) to the quantum Wu–Austin model, producing a fully classical Hamiltonian in action-angle variables whose nonlinear rate equations exhibit a nonequilibrium phase transition: the channelling of supplied energy into the lowest-frequency collective mode. The second is grounded in a classical electrodynamic Hamiltonian for two coupled oscillating dipoles whose normal-mode structure predicts long-range (∼$1/r^3$) resonant interactions, absent at thermal equilibrium but activated by out-of-equilibrium collective oscillations. We also discuss a complementary Hamiltonian approach that connects Fröhlich’s rate equations directly to Hamilton’s equations of motion, clarifying the role of bath-mediated nonlinear coupling and the conditions for strong condensation at room temperature. In addition, the TDVP is applied to a Davydov–Holstein–Fröhlich Hamiltonian describing electron–phonon motion along the backbone of a specific DNA sequence and its cognate restriction enzyme, EcoRI: the time-domain Fourier cross-spectrum of the resulting electron currents exhibits a sharp co-resonance peak for the canonical recognition sequence that disappears upon randomisation, providing a sequence-specific electrodynamic signature of DNA–protein recognition. Experimental evidence from THz near-field spectroscopy, fluorescence correlation spectroscopy, and direct observation of protein clustering is reviewed in relation to these theoretical predictions. The results establish a coherent physical picture suggesting that metabolic energy supply can play a role in driving macromolecules into coherently oscillating states that activate selective, distance-reaching electrodynamic forces capable of contributing to the organisation of biochemical reactions in living matter. Full article

Replication and transcription share the DNA template and must be coordinated to preserve genome integrity. Although temporally organized across the cell cycle, essential transcriptional programs—encoding replication machinery, canonical histones, and DNA repair factors—operate concurrently with DNA synthesis during S phase. Transcription–replication conflicts (TRCs) therefore constitute a recurrent endogenous source of replication stress (RS), particularly under hypertranscriptional or chromatin-constrained conditions. A frequent outcome of TRCs is the formation of R-loops–RNA:DNA hybrids that can stall or collapse replication forks, leading to DNA damage. This review summarizes current evidence supporting a broader involvement of ERCC6/CSB at the transcription–replication interface beyond its established role in transcription-coupled repair. We discuss how ERCC6 participates in RNA polymerase II processing, chromatin remodeling, R-loop metabolism, replication fork protection, and repair pathway engagement following RS, operating through both its ATPase domain and intrinsically disordered regions. Conversely, in homologous recombination-deficient contexts, ERCC6 may favor mutagenic restart mechanisms, including break-induced replication; and recent evidence indicates that ERCC6 status influences cellular fate and the genomic distribution of stress-induced mutations, linking transcription-coupled repair with transcription-dependent mutagenesis. These observations support a model in which ERCC6 coordinates transcription-associated repair with RS responses, shaping genome maintenance and mutational outcomes, with implications for cancer and therapeutic strategies. Full article

Background and Objectives: Critically ill surgical patients frequently fail to achieve prescribed enteral nutrition targets because of feeding interruptions and variability in conventional physician-directed feeding practices. Although volume-based feeding (VBF) has been proposed to improve nutritional delivery, concerns remain regarding refeeding syndrome and gastrointestinal intolerance. The aim of this study was to evaluate whether a Volume-Based Plus (VBF+) protocol integrating volume-targeted feeding with mandatory refeeding risk stratification and a standardized semi-elemental enteral formula improves nutritional delivery without increasing gastrointestinal or metabolic complications. Materials and Methods: We conducted an ambispective before-and-after implementation study (retrospective control phase, prospective intervention phase) in the surgical intensive care unit of a tertiary care center between January 2023 and March 2026. Ninety-six patients requiring enteral nutrition for ≥3 days were enrolled (48 control and 48 intervention). Both groups underwent the same refeeding risk stratification to guide feeding strategy, while the intervention group additionally received the standardized VBF+ protocol with risk-stratified caloric advancement and volume-based compensation for feeding interruptions, and a standardized semi-elemental enteral formula. The primary outcomes were median daily caloric delivery (% of target) and mean daily protein delivery (g/kg/day). Multivariable regression analyses adjusted for Nutritional Assessment Form (NAF), APACHE II score, and Charlson Comorbidity Index (CCI) were performed. Results: The VBF+ protocol was independently associated with higher caloric delivery (β = 31.2 percentage points, 95% CI 17.6 to 44.8; p < 0.001) and higher protein delivery (β = 0.168 g/kg/day, 95% CI 0.040–0.297; p = 0.011). Longitudinal analysis showed a significantly faster increase in protein delivery in the intervention group (p < 0.001), while the group-by-time interaction for caloric delivery did not reach statistical significance (p = 0.073). Rates of gastrointestinal intolerance and metabolic complications were comparable between groups; as VBF+ bundled the compensatory algorithm with a semi-elemental formula, this gastrointestinal benefit is hypothesis-generating. Conclusions: In this before-and-after study, the VBF+ bundle protocol was associated with improved caloric and protein delivery and reduced gastrointestinal intolerance; because the algorithm and formula were not evaluated independently, the gastrointestinal benefit remains hypothesis-generating and requires confirmation in randomized trials. Full article

Population aging and the rising prevalence of motor disorders are driving demand for assistive lower-limb robotic systems capable of decoding user intention rather than merely providing mechanical support. We present CM-FuseNet, an attention-augmented hybrid Brain–Computer–Muscle Interface (BCMI) that simultaneously fuses cortical concentration indices extracted from electroencephalography (EEG) and lower-limb intention patterns derived from electromyography (EMG) to adaptively control a 4-DOF assistive lower-limb exoskeleton. To eliminate the burden of human-subject ethics review and to ensure reproducibility of the proposed methodology, all validation is performed exclusively on (i) permissively licensed open-access biomedical datasets, (ii) high-fidelity OpenSim 4.5 and MuJoCo 3.1 musculoskeletal–exoskeleton co-simulation, and (iii) limited self-experimentation by the corresponding author with non-invasive consumer-grade devices. Three components are introduced: (i) a log-tanh normalized concentration index CI in (0, 1) derived from the $(P_{SMR}+P_{Mid-Beta})/P_{Theta}$ ratio; (ii) a bidirectional Cross-Modal Transformer (CMT) with eight-head self- and cross-attention; and (iii) a Soft Actor-Critic (SAC) reinforcement-learning controller that adaptively tunes four servo PID gains using a concentration-weighted state. Experiments on the PhysioNet EEGMMIDB, Ninapro DB2/DB7, HuMoD and WAY-EEG-GAL datasets (combining N = 162 trial sessions, 47,520 windows, and five-fold cross-validation) yield a gait-phase classification accuracy of 96.84 ± 1.18%, torque-tracking RMSE of 0.072 ± 0.008 N·m, information transfer rate of 38.6 bits/min, end-to-end latency of 9.4 ms, and a 27.4% reduction in simulated metabolic cost over an EMG-only PID baseline (one-way ANOVA: F(4, 75) = 47.83, p < 0.001; Tukey HSD: p < 0.01 against all baselines). Under high cognitive load, CM-FuseNet preserves accuracy with only a 4.63 percentage-point degradation versus 13.22 percentage points for the EMG-only baseline. Full article