Abstract: Rheumatoid arthritis (RA) is a chronic, systemic autoimmune pathology characterized by symmetric synovitis, pannus formation, and the potential for severe extra-articular manifestations. Despite historical associations with high morbidity, the 'treat-to-target' strategy has revolutionized patient outcomes. This review analyzes the pharmacological evolution of RA management over the last decade. We examine the foundational role of Methotrexate (MTX)—specifically its adenosine-mediated mechanism—and the stratification of biologic disease-modifying antirheumatic drugs (b-DMARDs), including TNF inhibitors, IL-6 receptor antagonists, and B-cell depleting agents. Crucially, we discuss the recent paradigm shift in the use of Janus Kinase (JAK) inhibitors following the 2021 ACR Guidelines and emerging safety data regarding cardiovascular and malignancy risks (the ORAL Surveillance trial). Finally, we explore the horizon of RA treatment, including GM-CSF inhibition, the complex management of difficult-to-treat (D2T) phenotypes, and the increasing integration of biosimilars to improve global treatment access.

Abstract: Background: Massive pulmonary embolism (PE) is a well-recognized cause of cardiac arrest and refractory shock. Optimal management requires timely diagnosis, physiologic monitoring, and, in selected cases, mechanical circulatory support (MCS).Case Summary: We present the case of a 45-year-old woman who suffered cardiac arrest from presumed massive pulmonary embolism. She underwent prolonged and complex resuscitation that integrated transesophageal echocardiography (TEE), aortic occlusion catheter placement, and transcranial Doppler (TCD) monitoring. Despite return of spontaneous circulation (ROSC) following aortic balloon inflation, she ultimately succumbed to refractory right-ventricular failure. The case highlights both the physiologic potential of multimodal resuscitation monitoring and the systemic inequities in timely access to extracorporeal support.Discussion: The use of resuscitative TEE, TCD, and near-infrared spectroscopy (NIRS) provides real-time, patient-specific data to individualize resuscitation. These tools may help identify reversible physiology and refine CPR quality. Simultaneously, this case emphasizes the urgent need for equitable MCS access for community hospitals to reduce preventable mortality.

Abstract:

OBJECTIVES: To evaluate the diagnostic performance of Spectralis optical coherence tomography (OCT) parameters for mild cognitive impairment (MCI) and mild dementia in an Asian population from Taiwan. METHODS: This retrospective cross-sectional study evaluated 43 patients with MCI (mean deviation [MD]: −5.05 ± 4.25 dB), 13 patients with mild dementia (MD: −9.03 ± 6.66 dB), and 32 healthy controls (MD: −2.50 ± 2.12 dB). The diagnostic sensitivity in identifying individuals with cognitive impairment of the Spectralis OCT parameters—such as those of the optic nerve head and macula—was compared across these groups. The area under the receiver operating characteristic curve (AUC) for each parameter was calculated to assess its sensitivity in differentiating between healthy eyes and those of individuals with MCI or mild dementia. RESULTS: Among the parameters evaluated, the Bruch’s membrane opening minimum rim width (BMO-MRW) nasal inferior region (ACU = 0.720) was the optimal parameter for distinguishing individuals with MCI from healthy controls. However, the highest AUC of 0.861 was achieved through a combination of five parameters. In distinguishing individuals with mild dementia from healthy controls, the BMO-MRW temporal superior region (ACU = 0.764) was the optimal parameter, with an AUC of 0.940 after adjusting for age and MD. Moreover, the condition of the macular nerve fiber layer outer inferior parameter moderately predicted disease progression (AUC = 0.713). CONCLUSIONS: Our real-world data demonstrate that Spectralis OCT measurements can detect MCI and mild dementia and predict disease progression.

Abstract: Modern geroscience and demographic data suggest that humans possess a biological lifespan potential of approximately 120 years, supported by evolutionary biology, longevity demographics, and cellular aging models. Yet global life expectancy in developed nations remains only 78–80 years—roughly a 20–30% shortfall. This gap is driven not by “inevitable aging” but by preventable chronic diseases rooted in metabolic, toxic, endocrine, inflammatory, and micronutrient dysregulation. This article proposes a Two-Tier Anti-Aging Model. (1) Restorative medicine—the foundation—focuses on restoring existing cells, organs, and systems to youthful physiological function by removing biological stressors and replenishing deficiencies. This includes detoxification, orthomolecular repletion (vitamin C, D₃/K₂, B₃, Mg, minerals), metabolic repair via the insulin–cortisol–vitamin C (ICV) axis, mitochondrial support, NAD⁺ restoration, senolytics, hormonal optimization, and epigenetic stabilization. These interventions repair the internal terrain and can enable recovery of roughly the first 15–20 lost healthy years. (2) Regenerative (specific anti-aging) medicine—built only after restoration—applies targeted biological interventions such as stem cells, exosomes, platelet-rich plasma (PRP), regenerative peptides, gene and epigenetic reprogramming, and tissue/organ engineering to further extend human longevity toward the 100–120-year upper limit. A central flaw in today’s market-driven “anti-aging industry” is the obsession with isolated “magic anti-aging pills,” peptides, or gadgets that ignore underlying terrain dysfunction. Attempting regeneration in a milieu burdened by micronutrient deficiencies, metabolic chaos, mitochondrial decay, chronic inflammation, and toxic load yields short-lived or misleading outcomes, as repeatedly observed in commercial longevity products and failed rejuvenation trials. Integrative Orthomolecular Medicine (IOM) directly addresses this systemic gap by identifying ten root drivers of chronic disease and aging and systematically repairing the internal terrain through detoxification, targeted nutrient repletion, mitochondrial and metabolic optimization, and hormonal rhythm restoration. This systems-biology framework supports realistic goals of healthy, independent longevity into the 90s and beyond, aligning modern biogerontology with practical clinical outcomes.

Abstract: Background: This review examines the relationship between gratitude and flourishing in adults from the perspective of Positive Psychology. It departs from the traditional empha-sis of psychology on mental illness, highlighting instead a comprehensive understanding of mental health that includes well-being and personal strengths. Methods: This study provides a narrative review of empirical studies published in the last decade, integrating the principal theoretical and methodological contributions in this field. Relevant studies were identified through searches in PubMed, Scopus, and Web of Science. Results: The available evidence suggests that gratitude functions as a psychological resource that sup-ports human flourishing by promoting greater life satisfaction, positive affect, and health-ier physical and mental functioning. Its association with better outcomes in groups facing significant stressors (e.g., emerging adults, older adults, people with chronic pain, depres-sion, or disabilities, forced migrants, etc.) and the promising results of gratitude-based in-terventions indicate that it is not only a dispositional trait but also a modifiable target for clinical and preventive programs. In addition, the findings underscore that empirical lit-erature on the relationship between gratitude and flourishing remains scarce and frag-mented. Conclusions: Gratitude is intimately connected to flourishing, as it operates as a positive emotion-focused coping strategy that supports and enhances overall well-being. Further research is required to clarify the mechanisms involved, to examine its long-term effects on flourishing, and to determine how best to integrate gratitude and flourishing in-to culturally and gender-sensitive, scientific evidence-based clinical practices.

Abstract:

Background/Objectives: Biomarker-based prevention is rapidly expanding, driven by advances in molecular diagnostics, genetic profiling, and commercial direct-to-consumer (DTC) testing. General practitioners (GPs) increasingly encounter biomarker results of uncertain relevance, often introduced outside the guideline frameworks. This creates new challenges in interpretation, communication, and equitable resource use in primary care. Methods: This narrative review synthesizes evidence from population-based studies, guideline frameworks, consensus statements, and communication research to evaluate the predictive value, limitations, and real-world implications of biomarkers in asymptomatic adults. Attention is given to polygenic risk scores, DTC genetic tests, neurodegenerative and cardiovascular biomarkers, and emerging multi-omics and aging markers. Results: Several biomarkers, including high-sensitivity cardiac troponins, N-terminal pro–B-type natriuretic peptide, lipoprotein(a), coronary artery calcium scoring, and plasma p-tau species, showed robust predictive validity. However, many widely marketed biomarkers lack evidence of clinical utility, offer limited actionable benefits, or perform poorly in primary care populations. Unintended consequences, such as overdiagnosis, false positives, psychological distress, diagnostic cascades, and widening inequities, are well documented. Patients often misinterpret unvalidated biomarker results, whereas DTC testing amplifies demand without providing adequate counseling or follow-up. Conclusions: Only a minority of biomarkers currently meet the thresholds of analytical validity, clinical validity, and clinical utility required for preventive use in general practices. GPs play a critical role in contextualizing biomarker results, guiding shared decision-making, and mitigating potential harm. The responsible integration of biomarkers into preventive medicine requires clear communication, strong ethical safeguards, robust evidence, and system-level support for equitable, patient-centered care.

Abstract: Background: Preeclampsia (PE) is a leading cause of maternal and perinatal morbidity worldwide, yet its mechanisms remain poorly understood. Dysregulated innate im-munity, specifically aberrant complement activation and excessive neutrophil extracel-lular traps (NETs) formation, contributes to endothelial dysfunction and inflammation in preeclampsia. However, the interaction between complement activation and NETs, as well as the differences between these immune pathways in early-onset and late-onset preeclampsia, remain unclear. To address this gap, we assessed complement components and NET markers across various preeclampsia phenotypes and examined their rela-tionships. Methods: Plasma samples were collected from 56 women with early-onset preeclampsia (EO-PE) before 34 weeks, 32 with late-onset preeclampsia (LO-PE) after 34 weeks, and 32 healthy pregnant women in the control group. Complement components (C1q, C3, C3a, C4, and the terminal complement complex, TCC) and NETs markers (MPO-DNA, cit-rullinated histone H3, and cathepsin G) were measured using ELISA. Group differences were assessed with non-parametric tests, and associations between markers and clinical variables were analyzed using Spearman correlations. Results: We observed higher levels of C1q, C3, C3a, and TCC in pregnant women with severe preeclampsia compared with healthy pregnancies (p < 0.001), while C4 levels remained unchanged. Among neutrophil trap biomarkers, MPO-DNA levels were el-evated in EO-PE (p = 0.019), while CitH3 and cathepsin G levels did not differ significantly between groups. Strong correlations were observed between MPO-DNA and TCC (ρ = 0.30, p = 0.013), as well as between cathepsin G and C3a (ρ = 0.40, p = 0.0007), indicating NETs–complement interactions. Patterns of complement and NETs activation were similar in early and late preeclampsia, despite differences in gestational age. Conclusions: The observed associations between MPO-DNA and TCC, and between cathepsin G and C3a, indicate meaningful crosstalk between NETs and complement ac-tivation. These findings support the role of innate immune dysregulation in preeclampsia and highlight NETs–complement interactions as potential targets for diagnostic and therapeutic approaches.

Abstract: Diabetes mellitus is characterized by elevated blood sugar due to absolute or relative insulin deficiency. Diabetes is broadly classified into 2 major forms: type 1 diabetes mellitus (T1D) and type 2 diabetes mellitus (T2D). It is known also that other categories of diabetes exist, and this includes gestational diabetes, monogenic causes, rare syndromes, and iatrogenic causes. Most cases of T1D and T2D are polygenic with environmental triggers. T1D often results from autoimmune destruction of pancreatic beta cells leading to absolute insulin deficiency. T2D is associated with obesity, insulin resistance with relative insulin deficiency. Genetic studies have focused on the identification of loci associated with increased susceptibility to diabetes. Early studies showed linkage between T1D and several HLA susceptibility loci on chromosome 6. The HLA haplotypes DR3 (DQb1*201) and/or DR4 (DQb1*302) are susceptibility alleles and the DR2 (DQb1*602) is considered a protective allele for development of T1D. Genome-wide association studies (GWAS) have identified more than 100 HLA- and non-HLA loci that increase susceptibility to T1D; many of these loci have small effects to the phenotype and are relevant to autoimmunity. Some of the notable genes for T1D are INS, PTPN22, CTLA4. Regarding T2D risk, thousands of gene variants that are common and contribute small effects have also been identified through GWAS, but the rarer variants may confer significant risk to an individual’s risk. The usefulness of individual variants for genetic counseling in diabetes has been limited in the clinical setting in the past until the development of polygenic risk scores (PRS) and partitioned polygenic risk scores (PPRS) statistics derived from GWAS. PRS and PPRS are statistical methods that combine multiple disease-modifying variants obtained from GWAS to predict and classify diabetes. These scores use the cumulative effect of hundreds to millions of variants generated from GWAS to compute an individual’s relative risk. Currently more than 100 variants for T1D and over 1000 variants for T2D are utilized in risk analysis of diabetes. Continued investment in global consortia such as the Type 1 Diabetic Genetics Consortium (T1DGC), National Institute of Diabetes and Kidney Diseases (NIDDK), and the Wellcome Trust Case-Control Consortium (WTCCC) in genetic variant mapping will help identify genes involved in pathophysiologic pathways involved in insulin secretion and signaling, and provide insight into new targets for prediction, prevention and treatment of diabetes. Monogenic diabetes comprises several clinical dysglycemic disorders that include neonatal diabetes, maturity-onset diabetes of the young (MODY), and several genetic syndromes that have diabetes either as an associated finding and/or complication. Some of the monogenic diabetes gene variants have incomplete penetrance and variable expressivity leading to different ages of onset and variable presentation even within the same family. Hence some patients with these conditions have been previously diagnosed as having T1D or T2D. Monogenic disorders follow Mendelian inheritance patterns so genetic counseling is relatively straightforward. Counseling for forms of diabetes due to maternally inherited mitochondrial cytopathies such MELAS and Kearne-Sayres syndrome are not straight-forward due to heteroplasmy. Clearer definition of diabetes phenotypes, development of powerful statistical methodologies, use of next-generation sequencing applications to interrogate the genome, incorporation of epigenetic mechanisms and accurate curation of gene variants, will help us realize application of genomic medicine and inform diabetes care.

Abstract: Sepsis initiates two primary metabolic responses: insulin resistance in insulin-responsive tissues and suppression of mitochondrial adenosine triphosphate (ATP) production. These mechanisms underpin the hypermetabolic and hypometabolic phases of sepsis. The hypermetabolic phase features a heightened metabolic rate, rapid immune activation, and increased glucose supply and consumption. In contrast, the hypometabolic phase involves a reduction in metabolic rate and physiological activity across multiple organs, mirroring hibernation-like states.During sepsis, the immune system receives priority access to available glucose, prompting insulin resistance that minimises glucose utilisation by less essential tissues. Concurrently, mitochondrial ATP production via oxidative phosphorylation (OXPHOS) is deprioritised, with the immune system relying on anaerobic glycolysis for ATP generation. This suppression of OXPHOS is only a temporary measure; mitochondrial ATP production must resume for complete recovery. Persistent suppression of mitochondrial ATP production can culminate in critical ATP deficits and cell death.This review examines glucose and insulin metabolism in sepsis, concluding that administering high-dose insulin alongside mild hyperglycaemia and intravenous thiamine—a pyruvate dehydrogenase kinase (PDK) inhibitor—may help restore physiological mitochondrial ATP production during a crucial window in the sepsis process, potentially improving survival outcomes.

Abstract: Background/Objectives: Besides the clinical gold-standard tympanometry, several alternatives for middle ear diagnostics have evolved over the last decades. With the so-called pressureless acoustic impedance test, the Neuranix Medwave, another device came into play. Methods: Using a retrospective anonymous study approach, descriptive data reporting and the correlation between Medwave’s results and the types of tympanometry results were evaluated. Also, the correlation between the patients’ age and Medwave resulting parameters was evaluated. We were able to show changes in measurement results over time in the case of paracentesis and tube insertion. Results: The analyzed data show that it is possible to differentiate between tympanometry result type A and type B using the Medwave resulting parameter resonance frequency (fR) but not when using peak admittance (P). Between all other types, it was not possible to differentiate using the Medwave resulting parameters, nor fR not P. Regarding age, only for the tympanometry result type A, a correlation was found. The case over time showed a clear difference in the affected ear between the time before and after the ear surgeries, as well as the contralateral healthy ear. Conclusions: The Medwave device allows differentiation between a healthy ear (type A) and an immobile tympanic membrane (type B) using the resulting parameter fR. As parameters fR and P depend on age in type A, the manufacturer’s age-grouping with individual reference values makes sense. The case with countless measurements of time and paracentesis plus tube insertion showed the possibility of observing the tympanic status.

Abstract: Backgrounds: Recent advances in artificial intelligence (AI) have produced ChatGPT-4o, a multimodal large language model (LLM) capable of processing both text and image inputs. Although ChatGPT has demonstrated usefulness in medical examinations, few studies have evaluated its image analysis performance. Methods: This study compared GPT-4o and GPT-4 using public questions from the 116th–118th Japan National Medical Licensing Examinations (JNMLE), each consisting of 400 questions. Both models answered in Japanese using simple prompts, including screenshots for image-based questions. Accuracy was analyzed across essential, general, and clinical questions, with statistical comparisons by chi-square tests. Results: GPT-4o consistently outperformed GPT-4, achieving passing scores in all three examinations. In the 118th JNMLE, GPT-4o scored 457 points versus 425 for GPT-4. GPT-4o demonstrated higher accuracy for image-based questions in the 117th and 116th exams, though the difference in the 118th was not significant. For text-based questions, GPT-4o showed superior medical knowledge, clinical reasoning, and ethical response behavior, notably avoiding prohibited options. Conclusion: Overall, GPT-4o exceeded GPT-4 in both text and image domains, suggesting strong potential as a diagnostic aid and educational resource. Its balanced performance across modalities highlights its promise for integration into future medical education and clinical decision support.

Abstract: Fraser Syndrome (FS) is an extremely rare genetic disorder with a strong pattern of inheritability that follows the autosomal recessive fashion; the fundamental clinical features include congenital anomalies such as cryptophthalmos, syndactyly, as well as, renal damage. The FRAS1 gene is one of the principal genes implicated in FS. The role of genetic mutations in the development of FS has not been comprehensively elucidated for the present, and novel mutations are still being identified. Hence, the current article addresses two patients who were clinically diagnosed with Fraser Syndrome and included two unique mutations (c.7777C˃T; (p. Q2593X) and c.9821G˃C; (p. R3274P) that are found in the FRAS1 gene. Both patients had clinical features concerning Fraser Syndrome including renal abnormalities and cryptophthalmos, which addresses the severe phenotype associated with FRAS1 mutations. These two novel mutations discovered have expanded the genetic heterogeneity of Fraser Syndrome and have extended the mutational list of the FRAS1 gene. These outcomes might have a profound impact on the further approaches to the therapy of FS and methods of genetic counseling and diagnosis.

Abstract: Background/Objectives: Sepsis detection remains challenging due to clinical heterogene-ity and limitations of traditional scoring systems. This study developed and validated a hospital-wide machine learning model for sepsis detection using retrospectively devel-oped data from prospectively expert-validated cases, aiming to improve diagnostic accu-racy beyond conventional approaches. Methods: This retrospective cohort study analyzed 218,715 hospital episodes (2014-2018) at a tertiary care center. Sepsis cases (n=11,864, 5.42%) were prospectively validated in real-time by a Multidisciplinary Sepsis Unit using modified Sepsis-2 criteria with organ dysfunction. The model integrated structured data (26.95%) and unstructured clinical notes (73.04%) extracted via natural language pro-cessing from 2,829 variables, selecting 230 relevant predictors. Thirty models including random forests, support vector machines, neural networks, and gradient boosting were developed and evaluated. The dataset was randomly split (5/7 training, 2/7 testing) with preserved patient-level independence. Results: The BiAlert Sepsis model (random forest + Sepsis-2 ensemble) achieved AUC-ROC 0.95, sensitivity 0.93, and specificity 0.84, signifi-cantly outperforming traditional approaches. Compared to the best rule-based method (Sepsis-2 + qSOFA, AUC-ROC 0.90), BiAlert reduced false positives by 39.6% (13.10% vs 21.70%, p< 0.01). Novel predictors included eosinopenia and hypoalbuminemia, while traditional variables (MAP, GCS, platelets) showed minimal univariate association. The model received European Medicines Agency approval as a medical device in June 2024. Conclusions: This hospital-wide machine learning model, trained on prospectively ex-pert-validated cases and integrating extensive NLP-derived features, demonstrates supe-rior sepsis detection performance compared to conventional scoring systems. External validation and prospective clinical impact studies are needed before widespread imple-mentation.

Abstract: Objective: To provide the first nationwide description of biologic and targeted synthetic DMARD (b/tsDMARD) use among Estonian patients with rheumatoid arthritis (RA), focusing on treatment effectiveness, persistence, and reasons for discontinuation across sequential lines of therapy. Methods: Data were obtained from the Estonian Biologic Therapy Registry covering years 2006–2022. All adult RA patients (ICD-10 M05.8, M06.0) who had received at least one dose of a b/tsDMARD were included. Effectiveness at 6 months was evaluated using DAS28-CRP as a continuous measure (ΔDAS28) and categorical response definitions: remission (DAS28 ≤2.6), low disease activity (LDA ≤3.2), and EULAR response criteria. Treatment persistence was analyzed using Kaplan–Meier estimates, and reasons for discontinuation were categorized systematically. Results: A total of 1,074 patients were analysed (78% female, mean age 53.7 years, 86% sero-positive). Mean baseline DAS28-CRP was 5.3. The mean 6-month reduction in DAS28-CRP during first-line therapy was ~2.3 points. Remission was achieved in ~20% of patients in lines 1–3 and ~15% in later lines, while LDA occurred in 7–10% across lines 1–4. Drug survival was comparable between treatment lines: 60% of patients remained on therapy at 2 years, and the median time to discontinuation for first-line therapy was 1.66 years. Most patients initiated therapy with a TNF inhibitor and many continued within the same class before switching to IL-6 inhibitors, rituximab, or JAK inhibitors. The main reasons for discontinuation were loss or lack of efficacy (~50%) and adverse events (27.5%), predominantly allergic reactions and infections. Conclusions: In real-world Estonian RA practice, biologic and targeted therapies were effective across multiple treatment lines, with the greatest improvement observed during first-line therapy and sustained clinical benefit in later lines. Treatment persistence remained stable despite multiple switches, and the distribution of discontinuation causes mirrored other European registries. These findings support the continued value of sequential b/tsDMARD therapy in achieving disease control among patients with difficult-to-treat RA.

Abstract: Vaccine safety concerns place informed parents into a dilemma: Take the risk of preventable illnesses by refusing vaccines or risk autism by complying with the vaccine schedule. This query sought a resolution by identifying susceptibility factors to intoxication by aluminium, a suspect component used in some vaccines as adjuvants. A systematic review reconciles that although aluminium decreases parathyroid hormone (PTH) secretion, hyperparathyroidism (hPTH) causes susceptibility to aluminium intoxication. The review results incidentally supported a hypothesis explaining the male-biased gender ratio. Thus, a narrative review seemed appropriate on proceeding. Susceptibility extends beyond chronic kidney disease (CKD) to conditions where hypophosphatemia is mediated by hPTH and efficient aluminium excretion is impaired by renal tubular reabsorption. Aluminium intoxication is marked by hypophosphatemia. Thus, individuals with underlying hypophosphatemic tendencies are less able to tolerate aluminium burden. PTH drives aluminium to tissues such as bone and brain as if it were calcium. The male gender bias is explained by a more limited supply of PHEX enzyme (expressed on the X chromosome) that limits phosphate wasting. These findings might imply that aluminium toxicity is sufficient to cause autism. Research is indicated to develop standards for pre-vaccination screening and intervention of conditions that impair aluminium excretion.

Abstract: AI and ML in spine surgery has both transformative possibilities and notable challenges related to regulatory oversight, algorithmic bias, and clinical responsibility. We propose a governance model to tackle these important issues, ensuring the responsible use of AI tools. This framework introduces the SAIGE-R Index, a tool designed to measure AI system risks based on Clinical Volatility, System Integration Risk, and Data Integrity Confidence. This index supports a tiered oversight system, ranging from minimal checks for low-risk systems to thorough FDA reviews for high-risk applications. In addition, SAIGE sets specific validation standards focused on spine surgery outcomes. These include important differences in patient-reported measures and accuracy in pedicle screw placement, along with quarterly fairness checks to reduce demographic bias. The framework also describes a strong governance structure that focuses on ongoing clinician training, involvement from multiple stakeholders, and strict data security measures. It suggests a liability model that matches responsibility with the evaluated risk level of AI tools. By addressing validation, ethics, and accountability, the SAIGE Framework provides a foundation for safely and effectively incorporating AI into complex surgical settings. This approach encourages innovation while maintaining patient safety and clinical integrity.

Abstract: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) has emerged as a rapidly expanding global clinical challenge, closely intertwined with obesity, type 2 diabetes mellitus, chronic kidney disease, and cardiovascular complications. Given the convergence of metabolic, hepatic and cardiac pathways, an integrated clinical strategy is increasingly essential. This review highlights how coordinated management across various specialties can refine risk stratification, improve diagnostic accuracy, and enhance long-term outcomes for patients with MASLD. The growing epidemiological burden is paralleled by escalating risks of heart failure, arrhythmias and progressive liver injury. Shared mechanisms including insulin resistance, systemic inflammation and lipotoxicity reinforce the need for comprehensive evaluations using non-invasive fibrosis scores, cardiometabolic biomarkers and structured surveillance protocols. Evidence supports the incorporation of lifestyle interventions, GLP-1 receptor agonists, SGLT2 inhibitors and tailored cardiometabolic monitoring within multidisciplinary clinics. Despite barriers such as heterogeneous referral patterns and limited cross-specialty coordination, interdisciplinary models consistently demonstrate superior early detection and more precise therapeutic planning. Moving forward, standardized follow-up pathways, longitudinal risk-based surveillance, and AI-assisted prediction tools may substantially improve personalized care and reduce morbidity in this high-risk population.

Abstract: As a three-dimensional in vitro model, organoid technology represents a revolutionary breakthrough in precision medicine. By harnessing the self-organizing capabilities of stem cells within biomimetic extracellular matrices, it enables the generation of miniature tissues that recapitulate key structural and functional characteristics of their source organs[1]. Conventional two-dimensional cell cultures lack tissue architecture and microenvironmental cues, whereas animal models are hindered by interspecies differences and inadequate representation of human pathological heterogeneity[2]. By effectively addressing these limitations, organoids have emerged as powerful platforms that are highly representative of human physiology and disease processes in oncology, genetic disorders, and infectious diseases. They demonstrate significant potential for use in drug screening, toxicity assessment, and the development of personalized treatment strategies[3, 4]. Although challenges such as limited vascularization, lack of standardized culture protocols, and ethical considerations remain, the integration of multidisciplinary approaches such as AI-assisted analysis, organ-on-a-chip systems, and 3D bioprinting, together with increasing policy support and industrial advancement, is accelerating the clinical translation of organoid technology[5]. In this review, the construction strategies for and applications of organoid models are systematically summarized, and their value and limitations in disease modeling, precision medicine, and preclinical research is highlighted. Finally, future development pathways driven by multidisciplinary collaboration and standardization are outlined.

Abstract:

Background: Hyperuricemia, marked by elevated uric acid levels, is associated with renal disorders like acute kidney injury and chronic kidney disease, through both crystal-dependent and crystal-independent mechanisms. Objective: This review aims to evaluate the crystal-dependent and crystal-independent mechanisms by which hyperuricemia induces renal injury. Design: A systematic review of the literature. Participants: Human and animal studies. Measurements: A total of 1549 articles were initially identified from PubMed, Web of Science, Scopus, and Google Scholar. After removing 659 duplicates and screening titles and abstracts, 572 articles were excluded, and 16 could not be retrieved, leaving 302 for full-text review. Of these, 17 studies met the eligibility criteria and were included. Risk of bias was assessed using SYRCLE for animal studies, ROB2 for human studies, and NOS for observational studies. Results: From seventeen studies: nine animal experiments, one human experiment, and seven observational studies. Animal studies showed hyperuricemia causes preglomerular arteriolopathy, glomerular hypertension, and worsens nephrotoxicity. Human studies demonstrated elevated uric acid, even without crystals, activates intrarenal RAS, increases oxidative stress, and reduces nitric oxide. Clinical studies confirmed high uric acid is linked to CKD progression, with very low levels also risky (“J-shaped” relationship). Endothelial dysfunction is a unifying mechanism, promoting inflammation and fibrosis in crystal-dependent injury and vasoconstriction and renal damage in crystal-independent injury. Conclusions: This review confirmed that hyperuricemia damages the kidney through both crystal-dependent and crystal-independent pathways, with endothelial dysfunction as a key mediator. Further human studies are needed to confirm these findings and explore new treatments.

Abstract: Background Chronic post-stroke spasticity often limits gait despite best-practice botulinum-toxin intramuscular injections (BTI), whose benefit is constrained by short duration, dose ceilings and tachyphylaxis. Cryoneurolysis (CNL) induces a reversible axonotmesis with preserved endoneurium, potentially providing longer tone reduction with fewer adverse effects, but its impact on whole-gait quality and its compatibility with implanted functional electrical stimulation (FES) remain poorly documented. Case presentation A 43-year-old man, 12 years after right middle cerebral artery stroke, walked independently with an implanted common peroneal FES system but complained of effortful gait with left-knee “locking” and drop foot without FES. Multiple BTI series to triceps surae and quadriceps yielded only transient benefit. Two ultrasound-guided CNL sessions targeted tibial (soleus, medial gastrocnemius) and femoral (rectus femoris, vastus intermedius) motor branches. Quantitative gait analysis and fine-wire electromyography (EMG) were performed at baseline, 6 weeks after each CNL, and 6 months, with and without FES. CNL produced immediate and sustained reductions in triceps surae and quadriceps overactivity, resolution of genu recurvatum, normalization of stiff-knee gait, improved ankle dorsiflexion, and increased swing-phase knee flexion (>50°). Gait Deviation Index rose from 69 to 80 and Gillette Gait Index decreased by more than 50%, with preserved strength and no adverse events. Conclusions Targeted, sequential CNL of tibial and femoral motor branches can safely deliver durable, clinically meaningful gait improvements when BTI has reached its ceiling and can act synergistically with implanted FES. Quantitative gait analysis and EMG sharpen clinical decision-making in spasticity management.