Search Results (808)

Background: Despite stable fixation, aseptic tibial shaft nonunion represents a severe orthopedic complication. Teriparatide and adipose-derived stem-cell augmentation have been proposed as biological supports, but comparative clinical evidence remains limited. This study explored whether adding adjuvant therapies to reamed intramedullary nailing was associated with faster healing than nailing alone. Methods: We retrospectively reviewed 43 adults with aseptic tibial shaft nonunion treated at three level I trauma centers between 2017 and 2020. Patients underwent reamed intramedullary nailing alone (n = 15), nailing plus teriparatide (n = 15), or nailing plus adipose-derived stem-cell augmentation (n = 13). Group allocation was nonrandom and based on contraindications and patient acceptance; results were therefore interpreted as exploratory. Outcomes included time to tricortical radiographic healing, pain, radiographic healing scores over time, complications, ASAMI classification, and SF-12. Results: Baseline demographic and fracture characteristics were comparable across groups. Time to tricortical radiographic healing was shorter in the teriparatide group (87.46 ± 6.34 days) and the adipose-derived stem-cell group (86.41 ± 5.67 days) than in the nailing-alone group (99.71 ± 4.29 days; p = 0.034). Pain, complication rates, ASAMI outcomes, and quality-of-life recovery did not differ significantly among groups at final follow-up. Conclusions: In this exploratory multicenter retrospective cohort, teriparatide and adipose-derived stem-cell augmentation were associated with shorter radiographic healing time after reamed intramedullary nailing for aseptic tibial shaft nonunion, but not with superior long-term functional outcomes. Because no comparator group treated with standard graft-based biological augmentation was included, the findings should be interpreted cautiously. Larger prospective studies or randomized controlled trials comparing these strategies with established graft-based approaches are needed to validate the present data. Full article

Lipedema is a chronic adipose tissue disorder characterized by disproportionate and often painful enlargement of the extremities, occurring predominantly in women. Despite increasing clinical recognition, the underlying pathophysiology remains incompletely understood and is likely multifactorial. Existing evidence suggests contributions from vascular alterations, adipose tissue remodeling, inflammatory activation, hormonal influences, and lymphatic dysfunction. This review proposes a hypothesis-generating integrative framework in which lipedema may reflect a regenerative imbalance of subcutaneous adipose tissue. Within this model, genetically and hormonally modulated endothelial permeability could promote activation of perivascular adipose-derived stromal/stem-cell niches and stromal vascular fraction signaling pathways, thereby facilitating coupled angiogenesis and adipogenesis. Progressive adipocyte hyperplasia and hypertrophy may subsequently contribute to inflammatory remodeling, pain generation, and secondary impairment of dermal and subdermal lymphatic drainage. The proposed framework attempts to integrate clinical, histological, imaging, molecular, and endocrine observations into a biologically coherent conceptual model. At the same time, the review emphasizes the current limitations of the available evidence, the heterogeneity of lipedema phenotypes, and the ongoing controversies regarding disease progression, obesity overlap, and the relative role of lymphatic dysfunction. Finally, the potential mechanistic rationale of lymphatic-sparing liposuction is discussed in the context of tissue decompression, restoration of lymphatic transport, and interruption of persistent adipose remodeling. The model presented here should be interpreted as a hypothesis-generating conceptual scaffold requiring prospective validation. Importantly, the present framework should be interpreted as a biologically plausible and hypothesis-generating conceptual model rather than a definitive mechanistic doctrine. Several proposed interactions remain associative and require prospective biological validation. Full article

Background: Migraine (MIG) management guidelines support a comprehensive approach combining medication, therapeutic patient education (TPE), behavioral strategies, lifestyle changes, diet, and physical activity (PA). Objective: To present an innovative interdisciplinary outpatient model for individuals with MIG, focusing on PA, sedentary behavior, eating habits (EH), metabolic health, temporomandibular disorders, and postural dysfunctions. Design: A randomized controlled trial will enroll 200 adults with MIG over two years. Inclusion criteria are chronic MIG (≥15 attacks/month for ≥3 months) or high-frequency episodic MIG (8–14 attacks/month), physical inactivity, and independent walking ability. Exclusion criteria include contraindications to PA and lack of informed consent. Participants will be randomized to standard care (SC) or an intervention group receiving TPE plus three months of supervised exercise (EXE). All participants will receive an informational brochure with nutritional tips (included in SC) and undergo: (1) neurological examination, (2) validated questionnaires, (3) kinesiological and postural assessment, and (4) gnathological evaluation. The primary outcome is change in monthly MIG frequency at 6 and 12 months; additional outcomes include disability, quality of life, and intensity of MIG, PA levels, sedentary behavior, medication use, EH, functional capabilities, postural parameters, and temporomandibular disorder-related variables. Results: Hypothetically, the intervention may reduce monthly MIG frequency by approximately 15–20% relative to baseline. Improvements may also occur in disability, quality of life, medication use, lifestyle behaviors, and psychological and cardiometabolic parameters. Conclusions: This trial will evaluate whether adding supervised EXE and TPE to SC may improve MIG outcomes compared with SC alone, supporting a comprehensive management strategy. Full article

Integrated care is increasingly shaped by digital infrastructures, data governance, and AI-enabled analytics, yet the relevant literature remains fragmented across health-services research, digital health, and machine learning. This article reports a scoping review, conducted in line with PRISMA-ScR guidance, that maps how integrated care models have evolved conceptually, what digital and AI-enabled infrastructures support them, how their clinical, economic, and equity impacts can be evaluated, and what current implementations imply for sustainable scaling. We searched PubMed, Scopus, Semantic Scholar, and Crossref (retrieval date 31 October 2025; forward screening to 31 March 2026) and added grey literature from named policy bodies. The searches identified 15,189 records, reducing to 11,789 after intra- and cross-source deduplication and grey-literature integration; 620 full texts were assessed and 192 were included in the synthesis. Four domains were synthesised: conceptual foundations of integrated care, AI and multimodal analytics, implementation barriers, and digital-governance foundations. We chart the field using a Type I–V maturity scheme (disease, cohort, whole-system, digital-integrated, learning), benchmarked against the Rainbow, MacColl, EMRAM/AMAM, and NHS ICS models. Most deployments cluster at digitally integrated but only weakly adaptive Type IV; recurrent failure modes—temporal blind spots, maintenance debt, semantic drift, and governance gaps—block progression to Type V, and high-profile clinical-AI failures illustrate the cost of attempting Type V analytics on Type IV-or-worse infrastructure. A walk through nine world regions maps each to its current Type I–V position and shows that organisational and payment integration—not digital sophistication alone—is currently the dominant driver of progress. The COMFORTage Integrated Care Model Library is positioned as a workflow of AI agents orchestrating predictive, preventive, and personalised care across the integrated-care lifecycle rather than as a single federated-learning programme. The review positions AI-enabled integrated care less as a finished model than as an emerging design space requiring longitudinal data assets, stewarded model lifecycles, accountable governance, and outcome-based contracting for clinically useful, equitable, and trustworthy learning systems. Full article

Background: Oral health is increasingly recognized as a potentially modifiable factor in Alzheimer’s disease (AD), although its influence on cognitive outcomes remains uncertain. Methods: This scoping review followed the Arksey and O’Malley framework and was reported in accordance with PRISMA-ScR guidelines. Searches were conducted in PubMed, Scopus, and Web of Science through August 2025. Eleven studies met the inclusion criteria: one randomized controlled trial, one nonrandomized trial, and nine observational studies. Results: Poor oral health, including tooth loss, periodontal disease, and impaired mastication, was consistently associated with worse cognitive and dementia-related outcomes. Interventions improved oral and functional measures but yielded limited and inconsistent evidence of cognitive benefit. Proposed mechanisms, including systemic inflammation and microbiome alterations, were infrequently evaluated directly. Conclusions: Overall, oral health correlates with cognitive status in AD, but the causal impact of interventions remains uncertain, highlighting the need for rigorous trials with standardized cognitive and mechanistic outcomes. Full article

The link between neutrophil extracellular traps (NETs) and hepatocyte ferroptosis in liver ischemia–reperfusion injury (LIRI) is unclear. Adipose-derived mesenchymal stem cell exosomes (ADSCs-Exo) hold therapeutic potential for LIRI. This study employed miniature pigs to investigate the NETs’ role and ADSCs-Exo’s protection in LIRI. In vitro, established hepatocyte oxygen-glucose deprivation/reoxygenation (OGD/R) model and Transwell co-culture system with polymorphonuclear neutrophils (PMNs). In vivo, a laparoscopic minimally invasive LIRI model was constructed in miniature pigs, followed by ADSCs-Exo intervention. Results demonstrated that NETs exacerbate OGD/R-induced hepatocyte ferroptosis via myeloperoxidase. ADSCs-Exo inhibited NET formation via the NADPH/MAPK pathway, thereby mitigating ferroptosis, and ultimately improved liver histopathology and function. This study is the first to demonstrate in a large animal model that ADSCs-Exo alleviate LIRI by inhibiting NET formation via the NADPH/MAPK pathway, consequently attenuating hepatocyte ferroptosis. These findings provide novel insights into LIRI pathogenesis, support the translational potential of ADSCs-Exo as a cell-free therapeutic strategy, and highlight the value of the miniature pig model in liver research. Full article

Adipose tissue (AT) browning is an inducible cellular phenomenon that promotes lipid oxidation to increase energy expenditure, reducing adiposity. Various transcription regulators involved in the AT browning process have been reported, but their complex molecular mechanisms remain poorly understood. Here, we explore the effects of SIRT7, one of seven mammalian sirtuins, on AT browning and elucidate the underlying mechanisms. SIRT7 deficiency increased the expression of browning genes in beige adipocytes differentiated from subcutaneous white AT (scWAT) stromal vascular fraction (SVF) cells isolated from adipocyte-specific Sirt7 knockout (Sirt7 AdKO) mice. The effect of SIRT7 on beige adipocyte differentiation was confirmed in Sirt7 knockdown (KD) mouse scWAT and human supraclavicular brown AT (scBAT) SVF cell lines. Mechanistically, SIRT7 deacetylated PPARγ2 (peroxisome proliferator-activated receptor γ2) at lysine (K) 382, thereby attenuating interaction with the transcriptional coactivator PRDM16 (PR domain-containing 16). In differentiated beige adipocytes, the acetylation-mimicking mutant PPARγ2^K382Q had higher transcriptional activity compared with the deacetylation-mimicking mutant PPARγ2^K382R. Furthermore, the interaction between endogenous SIRT7 and PPARγ2 decreased at the onset of beige adipocyte differentiation. Our findings reveal that SIRT7 is an important thermogenic regulator that puts the brake on AT browning by deacetylating PPARγ2. Full article

Babassu (Attalea speciosa) is one of the most abundant palm species in the Brazilian Amazon and an important unconventional crop, playing a key socioeconomic role due to the commercial exploitation of its oil-rich almonds. However, approximately 90–93% of the fruit biomass—mainly mesocarp, epicarp, and endocarp—is generated as underutilized residue. This systematic review aims to analyze extraction methods, phytochemical composition, and antioxidant capacity of bioactive compounds derived from different babassu fractions. Following PRISMA guidelines, searches of five databases (Embase, ScienceDirect, Scopus, PubMed, and Web of Science) retrieved 410 records, of which 23 met the inclusion criteria. The results show that, although research has predominantly focused on the almond fraction, non-edible parts contain significant levels of phenolic compounds, flavonoids, phytosterols, and other bioactive metabolites with antioxidant properties. Green and non-thermal extraction technologies, such as ultrasound-assisted extraction (UAE), supercritical CO₂ extraction (SC-CO₂), and pressurized liquid extraction (PLE), demonstrated advantages in improving extraction efficiency while reducing solvent consumption and thermal degradation. Overall, the available evidence indicates that babassu residues represent a promising and still underexplored source of bioactive compounds. Their valorization may contribute to sustainable extraction strategies, waste reduction, and the development of value-added products within agricultural and bioeconomic systems. Full article

Background: Short-term mortality stratification in sepsis remains clinically challenging, particularly because outcome is influenced by acute inflammation, coagulation abnormalities, organ dysfunction, and baseline comorbidity burden. This study evaluated the clinical performance of the BIO-S and BIO-SC composite bioscores for 28-day mortality stratification in adults with sepsis and septic shock. Methods: We conducted a prospective observational monocentric cohort study including 572 adult patients admitted between January 2022 and December 2024. BIO-S integrated procalcitonin (PCT), neutrophil-to-lymphocyte ratio (NLR), International Normalized Ratio (INR), and Sequential Organ Failure Assessment (SOFA) score, while BIO-SC extended this model by adding the Charlson Comorbidity Index (CCI). Prognostic performance was assessed using receiver operating characteristic (ROC) curve analysis, DeLong comparisons, bootstrap validation, calibration analysis, Kaplan–Meier survival curves, and Cox proportional hazards models. Results: The cohort included 418 patients with sepsis and 154 patients with septic shock. Overall 28-day mortality was 31.5% and was significantly higher in septic shock than in sepsis, 77.9% versus 14.4%, p < 0.001. BIO-S and BIO-SC showed strong discriminatory ability for 28-day mortality, with areas under the curve (AUCs) of 0.889 and 0.897, respectively. BIO-SC had the highest AUC, although the difference between BIO-SC and BIO-S was not statistically significant by the DeLong test, p = 0.328. At the optimal thresholds, BIO-S showed 97.8% sensitivity and 69.4% specificity, while BIO-SC showed 89.4% sensitivity and 77.8% specificity. Both bioscores stratified observed mortality across predefined risk categories and remained significantly associated with 28-day mortality in adjusted Cox models. Conclusions: BIO-S and BIO-SC showed clinically relevant performance for 28-day mortality stratification in adults with sepsis and septic shock. BIO-SC provided a numerically higher AUC and slightly better calibration, suggesting that comorbidity burden may improve prognostic characterization, although further independent multicenter validation is needed before broader clinical implementation. Full article

Alzheimer’s Disease (AD), the most common form of dementia, is pathologically defined by extracellular beta-amyloid (Aβ) plaques and intraneuronal neurofibrillary tangles (NFTs), accompanied by chronic neuroinflammation. Recent advances in single-cell RNA sequencing (scRNA-seq/snRNA-seq) and spatial transcriptomics have provided unprecedented resolution for unraveling the cellular and molecular landscape of neuroinflammation in AD. While scRNA-seq enables high-throughput profiling of cellular heterogeneity across brain regions, spatial transcriptomics preserves tissue architecture to map cell-type-specific gene expression within its anatomical context. This review synthesizes the neuroinflammatory mechanisms of AD, outlines the technical evolution and comparative capabilities of single-cell and spatial omics platforms, including resolution, throughput, and compatibility with multiple sample types, and critically evaluates findings from studies in both animal models and human brain tissues. These approaches have revealed state-specific transitions in microglia and astrocytes, including shifts in transcriptional programs, metabolic reprogramming, and pro-inflammatory polarization across disease stages. Notably, spatial transcriptomic analyses demonstrate pronounced regional heterogeneity: periplaque microenvironments exhibit distinct immune-cell compositions and gene expression signatures. Collectively, these omics technologies are redefining the cellular basis of AD progression and hold the potential to impact the discovery of early diagnostic biomarkers and precision therapeutic targets. Full article

Oligodendrocytes (OLs) are specialized glial cells essential for the formation and maintenance of the myelin sheath within the central nervous system (CNS). Historically, OLs were considered a functionally homogeneous population. However, the advent and widespread application of single-cell and single-nucleus RNA sequencing (scRNA-seq/snRNA-seq) technologies since 2015 have revealed substantial transcriptional heterogeneity, varying according to developmental stage, anatomical region, and disease state. In this review, we synthesized current advances in the understanding of OL heterogeneity. Nine OL cell classes have been identified in the mouse somatosensory cortex and hippocampal CA1 region, later expanding to 13 distinct subpopulations across ten CNS regions. Furthermore, we characterized disease-associated oligodendrocytes (DAOs)/disease-associated oligodendrocyte lineages (DOLs), identified in various neurological diseases, including multiple sclerosis (MS), Alzheimer’s disease (AD), and spinal cord injury, focusing on their molecular markers, spatial distribution, and pathophysiological roles. We summarized key transcriptional regulatory networks underlying DAO induction, including the signal transducer and activator of transcription (STAT)/interferon regulatory factor (IRF) family, the Yin Yang 1 (YY1)/nuclear factor kappa B (NF-κB) axis, and the SOX9/SOX10 regulatory system. The utility of region-specific brain analyses using spatial transcriptomics (ST) in conjunction with these approaches was also discussed. Finally, we compiled the implications of patient stratification according to white matter glial response patterns derived from large-scale snRNA-seq analyses of patients with progressive MS. Our synthesis shows that oligodendrocytes consist of multiple distinct subtypes that vary across development, brain regions, and disease conditions. In pathological states, they adopt specific disease-associated programs that reflect context-dependent responses and may influence disease progression and repair. This work provides a framework for understanding how oligodendrocyte diversity contributes to neurological disease and may support the development of targeted remyelination therapies. Full article

Nervous system and corneal disorders are major causes of permanent disability worldwide, largely due to the limited regenerative capacity of ectoderm-derived tissues. Therefore, the development of accessible and ethically acceptable cell-based therapies promoting the repair and regeneration of these tissues is of considerable translational importance. In this study, we aimed to comparatively evaluate the ectodermal differentiation potential of human adipose-derived stem cells (ADSCs) and human amniotic epithelial cells (hAECs) in vitro, with hAECs serving as a reference cell population with established ectodermal plasticity. Primary ADSCs and hAECs were characterized phenotypically using flow cytometry and functional differentiation assays. Cells were subjected to a directed ectodermal differentiation protocol and assessed via morphological analysis, immunostaining for ectoderm-associated proteins, and RT-qPCR analysis of lineage-specific genes. ADSCs exhibited morphological changes following differentiation, including a more epithelial-like phenotype and an increased nucleus-to-cytoplasm ratio. Immunostaining revealed the induction of nestin and OTX2 expression after differentiation, which was particularly pronounced in ADSCs. Gene expression analysis demonstrated statistically significant upregulation of the ectoderm-related genes EN2, SOX1, and PAX6 exclusively in hAECs. Results suggest that in ADSCs the differentiation process was only partially activated. In conclusion, our findings further support the suitability of hAECs as a reference cell line for studies investigating ectodermal differentiation protocols, while also demonstrating that ADSCs exhibit a limited but detectable capacity for acquiring ectoderm-specific characteristics under defined in vitro culture conditions. Full article

Background/Objectives: Alzheimer’s disease (AD) remains a significant global health challenge, characterised by a persistent resistance to traditional pharmacological interventions. While non-invasive brain stimulation (NIBS) techniques like transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) show therapeutic promise, their limited depth of penetration restricts their efficacy in targeting deep-brain AD pathology. Transcranial focused ultrasound stimulation (tFUS) has emerged as a novel, non-invasive neuromodulatory tool capable of precise deep-brain targeting. This scoping review aims to systematically map the current evidence base regarding the neuromodulatory application of tFUS in AD. Methods: Following PRISMA-ScR guidelines, a scoping search was conducted across four major databases (Ovid MEDLINE, Embase, Web of Science, and CENTRAL). Studies were included if they investigated focused ultrasound stimulation (FUS) as a neuromodulatory intervention for AD, excluding applications involving blood–brain-barrier disruption via microbubbles. Two independent reviewers performed screening and data extraction, with inter-rater reliability assessed via Cohen’s kappa. Results: Our analysis indicates that tFUS represents a safe and potent multi-modal intervention for AD that addresses both pathological protein aggregation and electrophysiological network failure. Its ability to modulate neuroplasticity and metabolic recovery suggests a promising therapeutic trajectory. Conclusions: Future research should prioritise the standardisation of acoustic protocols and the pursuit of longitudinal clinical cohorts to establish the long-term efficacy of this non-invasive technology. Full article

Background: We investigated whether combining a sural nerve sensory conduction study (s-SCS) and tibial nerve SEPs (t-SEPs) improves diagnostic accuracy for peripheral sensory neuropathy. Methods: We retrospectively reviewed 74 consecutive cases (114 lower limbs) of patients suspected of having neuropathy or radiculopathy who underwent s-SCSs and t-SEPs between July 2021 and December 2024. Abnormal S-SCSs were defined as a reduction in amplitude or a slowing of conduction velocity. Abnormal t-SEPs were defined as failure to evoke N20 or P37, or prolonged latency of either. Results: No cases showed s-SCS abnormalities with normal t-SEPs. Then, we classified the groups based on the combination of abnormality of s-SCSs and t-SEPs. Group 1 (G1) had normal s-SCSs and normal t-SEPs, which were observed in 31 limbs (27.2%). Group 2 (G2) had normal s-SCSs and abnormal t-SEPs, which were found in 45 limbs (39.5%). Subgroups of G2 included normal N20 with abnormal P37, abnormal N20 with normal P37, and N20/P37 abnormalities. Group 3 (G3) had abnormal s-SCSs with abnormal t-SEPs, which were seen in 38 limbs (33.3%). Conclusions: Electrophysiological testing reveals normal distal and proximal sensory nerves in G1, suggesting preserved sensory nerve function. The distal sensory nerves are normal in G2. However, abnormal N20/P37 and abnormal N20 with normal P37 indicate proximal sensory nerve involvement. Normal N20 with abnormal P37 indicates posterior column dysfunction. In G3, both the distal and proximal sensory nerve segments are abnormal. Therefore, adding t-SEPs to s-SCSs allows us to evaluate the full length of the peripheral nerves, which is useful for diagnosis and assessing treatment efficacy. Full article

Adipose-derived stem cells (ADSCs) are widely used in regenerative medicine and are considered key effectors underlying the therapeutic efficacy of autologous fat grafting for scarring and skin fibrosis, yet clinical outcomes remain variable. This review examines how obesity alters the adipose microenvironment through chronic inflammation and metabolic dysfunction, resulting in epigenetic changes, mitochondrial impairment, oxidative stress, and premature cellular senescence in ADSCs. ADSCs from obese individuals exhibit reduced stemness, impaired differentiation, and a pro-inflammatory secretome with diminished regenerative capacity. While weight loss may partially reverse these effects, persistent epigenetic and functional memory limits full recovery. This review argues that donor metabolic status is a determinant of ADSC therapeutic potency and discusses key challenges and opportunities for improving regenerative outcomes. Full article