Search Results (6,804)

Background: Parenteral nutrition (PN) is a life-sustaining therapy essential for patients who are unable to meet their nutritional needs enterally. However, individualized PN formulations impose substantial economic burdens on healthcare systems. This study aims to quantify the cost of individualized PN bags across different patient populations and identify key cost drivers to inform cost-effective clinical practice and policy development. Methods: A retrospective cohort study was conducted at King Fahad Medical City, Riyadh, Saudi Arabia, analyzing 900 unique patient-specific PN orders between February 2023 and August 2023. Patients were stratified into three groups: adults (≥18 years), pediatrics (1 month to 17 years), and neonates (<1 month), with 300 unique patients per group. The cost assessment included macronutrients, micronutrients, consumables, equipment, and personnel time, all measured using a standardized work sampling methodology. Descriptive statistics characterized demographic and clinical profiles. One-way ANOVA was used to compare costs across groups, and multivariate linear regression identified significant cost predictors, with log-transformation applied to address the skewness in the cost data. Results: Mean cost per PN bag varied significantly among patient groups (ANOVA, p < 0.001): adults 517.1 ± 274 SAR, pediatrics 383.2 ± 86.75 SAR, and neonates 243.14 ± 98 SAR. We found that PN volume, lipid dose, and the number of additives were the primary modifiable drivers of PN cost. Multivariate regression analysis identified PN volume (β = 0.182, p < 0.001), lipid dose (β = 0.145, p = 0.002), and number of additives (β = 0.098, p = 0.028) as significant predictors of cost, explaining 91.2% of the cost variance (R² = 0.912). Consumables contributed 18–22% of total costs across groups. Pediatric patients demonstrated markedly longer therapy duration (median 98 days, IQR 65–142) compared to adults (median 18 days, IQR 8–35) and neonates (median 24 days, IQR 12–42). Conclusions: This study provides the first stratified, real-world cost benchmarks for individualized PN in a Saudi tertiary-care setting and quantifies actionable cost drivers. Actionable implications include standardizing stable-patient procedures, implementing pharmacist-led appropriateness screening, and earlier transition to enteral nutrition to reduce costs while maintaining quality of care. Future research should evaluate the cost-effectiveness of standardized versus individualized formulations and investigate the relationship between cost variations and clinical outcomes. Full article

Cervical small-cell neuroendocrine carcinoma (SCNEC) is a rare cervical cancer with high metastatic potential and is frequently associated with high-risk human papillomavirus (HPV) infection. Because of its low incidence, SCNEC remains understudied and treatment options are limited, posing major therapeutic challenges. This study aimed to characterize SCNEC at the molecular and functional levels to support more informed therapeutic strategies. Organoids and spheroids were generated from a cervical SCNEC biopsy, and a matched organoid-derived xenograft was established in immunodeficient mice. Model fidelity was evaluated by histopathology and immunohistochemistry. HPV status was assessed by p16 immunostaining and HPV18 PCR, and viral–host integration sites were inferred using whole-exome sequencing (WES) junction reads. WES was also used to compare shared somatic variants and copy-number alterations across the patient tumor, organoid, and xenograft. Drug responses were assessed in organoids and spheroids following exposure to a panel of chemotherapeutic agents and a targeted inhibitor. Organoids exhibited robust growth, morphologic maturation, and efficient recovery after cryopreservation. The organoids and matched xenografts faithfully recapitulated SCNEC, with preserved neuroendocrine differentiation (CD56, synaptophysin, and NSE positivity), a high Ki-67 proliferative index (>80%), and strong p16 expression. HPV18 status was conserved across the primary tumor, organoids, and xenografts, with an integration site at chr8 (8q24.21) associated with increased MYC expression. Whole exome sequencing (WES) revealed strong cross-model concordance, including 26 shared somatic variants with a canonical PIK3CA hotspot mutation (p.E542K) and conserved oncogenic copy-number gains of PIK3CA, TERT, and MYC, as well as copy number loss of TP53. Functional assays showed dose-dependent loss of viability following exposure to conventional cytotoxic agents or an mTOR pathway inhibitor. This study presents the first integrated molecular and functional analyses of patient tumors and matched organoid and xenograft models in cervical SCNEC. These models offer robust resources for mechanistic studies and may enable precision therapeutic strategies for this rare malignancy. Full article

Human papillomavirus (HPV) is the most common sexually transmitted infection worldwide and is responsible for the majority of cervical, anal, and vaginal cancers. The first prophylactic HPV vaccine was introduced in the United States in 2006. Extensive evidence demonstrates the HPV vaccine is highly efficacious and effective, particularly when administered prior to HPV exposure. Despite strong safety data and proven cost-effectiveness, HPV vaccine uptake in the United States and globally remains suboptimal. Barriers to vaccination include limited knowledge, safety concerns, and logistical challenges. Current advancements focus on single-dose vaccine regimens, development of therapeutic vaccines, and higher-valent formulations. Expanding HPV vaccine coverage is essential to reduce HPV-related diseases, strengthen herd immunity, and advance cancer prevention efforts. Full article

Background: Perianal fistulizing Crohn’s disease (CD) is associated with significant morbidity and remains difficult to treat. Although advanced medical therapies are widely used, much of the available evidence derives from heterogeneous fistula populations or luminal CD trials, with limited perianal-specific synthesis and inconsistent outcome definitions. We conducted a systematic review focusing exclusively on perianal-specific clinical, radiologic, and composite outcomes in adults with perianal fistula (PAF) CD. Methods: We performed a systematic review in accordance with PRISMA 2020. Electronic databases were searched from inception through November 2025. We included randomized controlled trials and cohort studies enrolling adults with CD reporting outcomes specific to PAF. Interventions included biologics and small-molecule therapies, compared with placebo or other therapies. Due to substantial heterogeneity in outcome definitions and study designs, a meta-analysis was not performed. Risk of bias was assessed using Risk of Bias 2 (RoB 2) for randomized trials and the Newcastle–Ottawa Scale for observational studies. Results: Seven studies including >1200 participants with PAF-CD met inclusion criteria. Follow-up ranged from 24 weeks to 5 years. Across studies, outcome definitions and assessment modalities varied. Upadacitinib demonstrated significantly higher clinical fistula closure compared with placebo across multiple dose regimens at 52 weeks. In observational comparisons, ustekinumab and vedolizumab were associated with higher clinical closure rates than anti-TNF therapies. However, infliximab demonstrated higher closure rates than adalimumab as a first-line treatment. The definition for radiologic remission was less consistent across studies and often did not parallel clinical outcomes. Composite clinical–radiologic remission and response were reported in a limited number of studies, with filgotinib showing higher composite outcomes in comparison to placebo in a phase 2 trial. Surgical interventions, relapse outcomes, biomarkers [C-reactive protein (CRP)/fecal calprotectin (FCP)], and patient-reported outcomes were variably reported and not consistently significant across comparisons. Conclusions: Evidence for advanced therapies in PAF CD remains limited by heterogeneity in endpoint definitions, subjectivity in clinical observation, inconsistent radiologic reporting, and reliance on subgroup or observational comparisons. While anti-TNF therapy remains the most established option in guidelines, emerging data suggest significant benefits with ustekinumab, vedolizumab, and JAK inhibitors in selected patients. There is a need for PAF-specific, adequately powered randomized trials using standardized composite clinical and radiologic endpoints. Full article

Photobiomodulation (PBM) has shown promising potential to enhance bone regeneration; however, its optimal delivery parameters and interactions with osteoconductive scaffolds remain insufficiently defined. This preclinical study is the first to incorporate a pilot dosimetry evaluation to standardize 980-nm PBM delivery and ensure that effective irradiance reached the target surface of critical-size calvarial defects in mice. The primary aim was to evaluate the effectiveness of this novel 980-nm PBM protocol delivered using either flat-top (FT) or standard Gaussian (ST) handpieces in enhancing bone regeneration in critical-size defects (CSDs), both with and without Bio-Oss^® grafting. A total of 120 adult mice were allocated into twelve experimental groups (n = 10 per group): untreated (control), Bio-Oss^® alone, PBM alone, and PBM combined with Bio-Oss^®, using either FT or ST handpieces, and evaluated at 30 and 60 days. Animals received 980 nm irradiation at 0.6 W (nominal power output–set on laser interface) in continuous-wave mode for 60 s, three times per week, for two consecutive weeks. Pilot dosimetry included power meter measurements to determine the therapeutic power reaching the defect surface area and temperature monitoring to ensure safe energy delivery. The dosimetry study demonstrated that, after accounting for the optical properties of mouse shaved skin and the Bio-Oss^® graft covered with Bio-Gide^® membrane, the effective irradiance reaching the base of the defect surface area was 1.131 W/cm² for the FT handpiece and 0.413 W/cm² for the ST handpiece. This dose was sufficient to induce significant regenerative effects. Histological, Masson’s trichrome, and immunohistochemical analyses for Runx2, OCN, GLI1, CD34, and CTSK were performed to characterize early and late osteogenic events. The combination of PBM and Bio-Oss^® significantly accelerated bone regeneration compared with PBM alone, with the FT handpiece producing the most uniform and advanced osteogenesis. PBM enhanced progenitor activation, osteoblast differentiation, angiogenesis, matrix deposition, and late-stage remodeling, demonstrating a synergistic effect with the scaffold, whereas Bio-Oss^® alone or defect alone showed limited early regenerative potential. These findings highlight the effectiveness of this novel standardized PBM dosimetry and uniform beam profile (FT), supporting their use as a foundation for future randomized controlled trials in craniofacial bone repair. Full article

This study reports the first successful isolation and characterization of exosome-like nanoparticles from walnut kernels (WELNs). The isolated WELNs exhibited a typical cup-shaped morphology with an average diameter of 139.7 ± 67.5 nm, a concentration of 7.4 × 10¹¹ particles/mL, and a zeta potential of −17.47 ± 4.06 mV. Proteomic and small RNA sequencing analyses confirmed the presence of diverse proteins and microRNAs within WELNs. In vitro assays demonstrated their potent antioxidant capacity, with radical scavenging rates of 67.54% against ABTS⁺ and 48.59% against DPPH⁺ at 102 μg/mL and IC₅₀ values of 89.7 μg/mL and >102 μg/mL for scavenging of ABTS⁺ and DPPH⁺ radicals, respectively. Cytotoxicity assays indicated no adverse effects on RAW264.7 macrophage viability at concentrations up to 60 μg/mL. In LPS-stimulated RAW264.7 macrophages, WELN treatment (20–60 μg/mL) dose-dependently mitigated oxidative stress by reducing intracellular ROS levels (down to 81.22% of the control at 60 μg/mL) and malondialdehyde (MDA) content while restoring the activities of antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD). Furthermore, WELNs significantly suppressed the production of nitric oxide (NO) and pro-inflammatory cytokines TNF-α, IL-6, and IL-1β (reduced to approximately 30.8%, 22.7%, and 23.6% of LPS-induced levels, respectively, at 60 μg/mL). Mechanistic investigation revealed that the anti-inflammatory effect was mediated through the inhibition of the MAPK signaling pathway, as evidenced by decreased phosphorylation of p38, ERK, and JNK. In conclusion, WELNs exhibit dual anti-inflammatory and antioxidant properties. This study provides the first evidence of bioactivity for walnut-derived exosome-like nanoparticles, advancing the mechanistic understanding of walnuts’ health benefits and highlighting their potential as a natural component for functional food applications. Full article

Hyperlipidemia is a metabolic disease of significant current concern. Research has demonstrated that hyperlipidemia is a primary risk factor for cardiovascular disease (CVD). Furthermore, hyperlipidemia significantly increases the risk of intracellular lipid peroxidation, which further contributes to the development of CVD. Dietary bioactive interventions, including polysaccharides, polyphenols, and organic acids, have demonstrated significant potential in regulating lipid metabolism and preventing chronic diseases. This study investigated the hypoglycemic effects of Yongchun aged vinegar powder (YAVP) using an in vitro model. Considering that the bioactivity of dietary components is influenced by gastrointestinal transit, YAVP was first underwent simulated gastric and intestinal digestion in vitro. The resulting digests were applied to a sodium oleate-induced high-fat HepG2 cell model. The results demonstrated that digested YAVP significantly inhibited intracellular lipid accumulation in a dose-dependent manner. Specifically, YAVP intervention substantially lowered concentrations of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C), while simultaneously elevating high-density lipoprotein cholesterol (HDL-C) levels relative to the model group. These findings suggest that YAVP retains its bioactivity after simulated digestion and exerts potent hypoglycemic effects by regulating lipid profiles in HepG2 cells, supporting its potential as a functional dietary supplement for lipid management. Full article

Vasodilatory shock, primarily driven by sepsis, remains a leading cause of mortality in intensive care units (ICU), with mortality rates exceeding 90% in refractory cases. While norepinephrine is the first-line vasopressor, prolonged exposure to high doses of catecholamines is linked to severe adverse effects, including myocardial toxicity, arrhythmias, and immunodepression. Consequently, the concept of decatecholaminization, utilizing non-adrenergic vasopressors to reduce catecholamine burden, has emerged as a critical therapeutic strategy. This comprehensive review aims to define the current role of vasopressin and its analogues, terlipressin and selepressin, in managing patients with circulatory shock, evaluating their physiological rationale, clinical benefits, and adverse event profiles. The vasopressin system provides a multimodal approach to hemodynamic stability independent of α-adrenergic stimulation. Arginine vasopressin (AVP) acts on V1a receptors to induce vasoconstriction and improve glomerular filtration, and on V2 receptors for water reabsorption. Clinical trials indicate that while AVP may not reduce overall mortality, it significantly reduces the need for renal replacement therapy (RRT) and offers survival benefits in the less severe shock subgroup. Synthetic analogues like terlipressin offer a longer half-life but carry an increased risk of peripheral ischemia. Conversely, selepressin, a pure V1a agonist, was designed to mitigate fluid retention and edema, though recent trials have not yet demonstrated superior clinical outcomes over placebo. Modulation of the vasopressin system is a cornerstone of decatecholaminization in distributive and cardiogenic shock. Although a universal mortality benefit has not been established, these agents are crucial for protecting renal function, reducing catecholamine toxicity, and lowering the incidence of arrhythmias. Future strategies should focus on precision medicine, utilizing biomarkers like copeptin and artificial intelligence to optimize the timing and selection of multimodal vasopressor therapy. Full article

Background/Objectives: DNA polymerase ε (Pol ε), encoded by POLE1, plays a pivotal role in high-fidelity DNA replication and in coordinating DNA repair. While pathogenic exonuclease-domain variants are well established in cancer, biallelic POLE1 variants remain largely unexplored in non-malignant human cells. Methods: Here, we analyzed primary fibroblasts derived from a skin biopsy of a compound-heterozygous patient carrying two POLE1 variants. Western blot analysis confirmed detectable Pol ε protein levels, indicating preserved protein expression despite the underlying variants. Results: Nevertheless, functional alterations were observed across multiple independent assays. Compared with healthy control fibroblasts, this patient-derived Pol ε fibroblast line exhibited reduced clonogenic survival following ionizing radiation. Surviving fractions were consistently lower across radiation doses from 2 to 4 Gy, with an approximately twofold reduction at 2 Gy and progressively greater differences at higher doses. The isoeffect dose corresponding to 10% survival was reduced relative to pooled control fibroblasts. In addition, chromosomal breakage was increased, supporting altered processing of radiation-induced DNA damage in this cellular model. Live-cell imaging and senescence assays revealed delayed proliferation and an increased proportion of senescent or senescence-like cells under baseline and genotoxic stress conditions, including enhanced senescence-associated β-galactosidase activity. Flow-cytometric analysis demonstrated S phase accumulation and G2/M arrest, consistent with replication stress and cell-cycle perturbation. Immunofluorescence staining revealed increased γH2AX foci, consistent with persistent DNA double strand breaks. RAD51 foci formation was not reduced; instead, increased RAD51 recruitment was observed under combined cisplatin and irradiation treatment, arguing against a primary defect in RAD51-mediated homologous recombination. POLE1-variant fibroblasts also showed impaired proliferative recovery, reduced wound closure, increased γH2AX accumulation following cisplatin exposure, suggesting heightened susceptibility to DNA crosslinking stress. Conclusions: Collectively, these findings provide the first functional characterization of a patient-derived POLE1-variant fibroblast cell line and indicate that altered Pol ε function may influence cellular responses to genotoxic stress. While based on primary fibroblasts from a single compound-heterozygous patient, validation in additional patient-derived or isogenic models will be required to determine the broader relevance of these findings. Full article

Central nervous system disorders drive disability, yet many neuroactive candidates fail because the brain is a hard compartment to dose. Plant-derived molecules spanning polyphenols, alkaloids, terpenoids, and cannabinoids are attractive because their pleiotropic actions can engage oxidative stress, neuroinflammation, and circuit dysfunction. In practice, the blood–brain barrier (BBB) restricts most native phytochemicals through tight-junction selectivity, rapid metabolism, low solubility, and transporter-mediated efflux. Key gaps include poor standardization of exposure metrics, limited human-relevant BBB models, and few head-to-head studies that compare delivery platforms on the same payload and outcome. This review tackles the mismatch between mechanistic promise and reliable brain exposure that stalls translation. The objectives are to link phytochemical liabilities to enabling strategies in nanomedicine, alternative routes, and transporter-targeted prodrugs, and to propose decision-grade endpoints for translation. We synthesize evidence on BBB transport logic, nanocarrier families, targeting ligands, intranasal delivery, focused ultrasound-mediated opening, and prodrug approaches that hijack influx transporters, while foregrounding safety and chemistry, manufacturing, and controls (CMC) constraints. Here we highlight that effective neurotherapeutics emerge when chemistry, carrier, route, and measurement are co-designed rather than optimized in isolation. This framework can guide platform selection, de-risk first in-human studies, and sharpen trial endpoints. More broadly, it offers a transferable playbook for barrier-limited drug development across neurology, psychiatry, and oncology. Full article

Background/Objectives: Hypoparathyroidism (HPT) is a disorder caused by the insufficient production of parathyroid hormone (PTH). Its main features include decreased serum calcium, increased serum phosphorus, and abnormal bone modeling. In children, HPT is most commonly due to genetic disorders. Among rare genetic syndromes that can include HPT in their clinical spectrum is Kenny–Caffey syndrome (KCS) type 2. Conventional therapy for HPT primarily consists of oral calcium and active vitamin D metabolites. The major limitation of conventional therapy is hypercalciuria with an increased risk of nephrocalcinosis. However, a subset of patients fails to achieve the desired therapeutic response to conventional treatment; the reasons for this remain incompletely understood in some cases. The failure to achieve therapeutic targets and persistent hypercalciuria are the main indications for considering therapy with recombinant human parathyroid hormone (rhPTH). Methods: In addition to the review of the literature on rhPTH use in pediatric hypoparathyroidism, the first application of rhPTH in the treatment of genetically caused HPT in a child with Kenny–Caffey syndrome type 2 (KCS2) was described. Results: In this paper, we present a two-month-old infant who received rhPTH for 14 months. A heterozygous de novo p.Ser541Pro variant in the FAM111A gene was identified through whole-genome sequencing, indicating a diagnosis of KCS2. A biological mechanism linking FAM111A protein function with a more profound disruption of parathyroid development or function was proposed, suggesting that rhPTH therapy may be particularly beneficial in KCS2 cases. Conclusions: This is the first reported use of rhPTH in a child in Serbia and the first reported use in KCS type 2. By reviewing the literature, we analyzed the conditions in which rhPTH has been used, dosing approaches and durations, requirements for concomitant conventional therapy during rhPTH treatment, and the effects of rhPTH on calciuria. We provide an overview of rhPTH use in children. Additionally, based on the pathogenic genetic variant responsible for KCS2 in our patient, we propose possible etiologic explanations. This work aims to encourage a consideration of rhPTH use in children following its official approval. Full article

Background: Obstructive sleep apnea (OSA) is a highly prevalent and heterogeneous disorder associated with substantial cardiometabolic morbidity. Although continuous positive airway pressure (CPAP) remains first-line therapy, long-term effectiveness is frequently limited by suboptimal adherence. Advances in airway devices, surgical techniques, neuromodulation, and pharmacologic therapies have expanded the therapeutic landscape and created opportunities for individualized, mechanism-based treatment. Methods: We conducted a selective, narrative review with structured quantitative synthesis of randomized controlled trials, comparative cohorts, long-term follow-up studies, registries, and mechanistic investigations addressing OSA therapies beyond CPAP. Evidence spanning oral appliances, upper-airway and skeletal surgery, hypoglossal nerve stimulation, neuromuscular electrical stimulation, positional therapy, and pharmacologic interventions targeting metabolic and non-anatomical endotypes was integrated. Outcomes of interest included apnea–hypopnea index (AHI), oxygenation, blood pressure, patient-reported symptoms, durability, safety, and real-world adherence. Results: Mandibular advancement devices (MADs) consistently reduced AHI relative to placebo and produced symptom relief comparable to CPAP in mild-to-moderate OSA, largely due to superior adherence. Palatal surgery yielded meaningful short-term improvement in selected patients but demonstrated limited long-term durability. In contrast, maxillomandibular advancement (MMA) achieved the largest and most durable reductions in OSA severity, with efficacy comparable to CPAP and superior to other surgical modalities in appropriate skeletal phenotypes. Hypoglossal nerve stimulation (HNS) produced substantial, durable improvements in AHI and symptoms with high adherence, supported by randomized trials, long-term follow-up, and real-world registry data; newer bilateral and proximal stimulation systems may further broaden candidacy. Neuromuscular electrical stimulation and positional therapy provided modest, phenotype-dependent benefits, primarily as adjunctive or early-stage interventions. A major advance is the emergence of metabolic and endotype-targeted pharmacotherapy: longitudinal data demonstrate a dose-dependent relationship between weight change and OSA progression or regression, while randomized trials show that GLP-1-based therapies—particularly dual GLP-1/GIP agonism with tirzepatide—produce large, clinically meaningful reductions in AHI and cardiometabolic risk in obesity-associated OSA. Additional pharmacologic strategies targeting ventilatory loop gain and arousal threshold further support an endotype-driven treatment paradigm. Conclusions: Contemporary OSA management is shifting from a CPAP-centric model toward a precision-guided, multimodal framework that aligns therapy with dominant anatomic and physiological contributors to airway collapse. Integrating metabolic, neuromodulatory, and structural interventions—often in combination—offers the potential for durable disease control and improved patient-centered outcomes. Future priorities include head-to-head and combination trials, long-term cardiovascular outcomes, cost-effectiveness analyses, and pragmatic tools to operationalize personalized OSA therapy in routine clinical practice. Full article

Ensuring product integrity across Malaysia’s East Malaysian states (Sabah and Sarawak) requires a cold chain that is resilient to tropical heat, long multimodal routes, intermittent power, and dispersed rural populations. This paper proposes a sustainability-first architecture for vaccine and blood component logistics that combines World Health Organization and the United Nations International Children’s Emergency Fund Effective Vaccine Management (EVM 2.0) criteria with energy-aware transport planning, solar-hybrid edge refrigeration, phase-change materials, and digital temperature monitoring compliant with ISO 23412 for temperature-controlled delivery services. In this study, a mixed-methods methodology was employed, including (1) route and mode optimization under temperature risk and carbon intensity constraints; (2) equipment right-sizing using duty-cycle energy models and IEC 60068 environmental tests as design baselines; (3) governance with real-time earned value management (EVM) and key performance indicators (KPIs); and (4) scenario analysis for riverine, road, air, and drone last-mile segments relevant to remote East Malaysian communities. Results from realistic logistic scenarios indicate a 45–65% reduction in dose-weighted temperature-excursion minutes, 28–41% reduction in CO₂e per successful dose delivered, and 35–52% reduction in product loss compared with status quo planning. For blood components, solar-hybrid storage and mixed-mode routing reduced breach risk by 37% while maintaining red cells (2–6 °C), platelets (20–24 °C, continuous agitation surrogate), and fresh frozen plasma (≤−18 °C) requirements aligned with WHO guidance and Malaysia’s national transfusion policies. We provide a reference architecture, implementation bill of materials, and an EVM-aligned KPI dashboard to guide scale-up. Full article

Emodin, a trihydroxy-methyl anthraquinone abundant in rhubarb, Polygonum species, and other medicinal plants, exemplifies the therapeutic potential and translational complexity of the broader anthraquinone scaffold. Anthraquinone derivatives have demonstrated antiproliferative, anti-inflammatory, metabolic, cardiovascular, antifibrotic, and immunomodulatory effects, consistently reported across diverse preclinical models, targeting pathways such as NF-κB, PI3K/AKT, MAPKs, AMPK, PPARs, NLRP3, and ferroptosis-related axes. Despite strong preclinical efficacy, clinical development has been limited by unfavorable absorption, distribution, metabolism, and excretion (ADME) characteristics, including poor aqueous solubility, extensive first-pass glucuronidation, and active efflux via intestinal and hepatic transporters. These features result in low and variable systemic exposure, while high local concentrations, particularly in the gastrointestinal tract, contribute to context-dependent toxicity signals that complicate risk assessment. The present review integrates pharmacological, toxicological, and formulation-focused evidence to provide a unified assessment of emodin and the anthraquinone scaffold. Particular emphasis is placed on bidirectional, dose- and context-dependent effects on the liver and kidney; the modulation of cytochrome P450 enzymes, UGTs, and transporters; and emerging preclinical formulation strategies that aim to decouple intrinsic bioactivity from pharmacokinetic limitations. Full article

Objectives: The evidence for treating rheumatoid arthritis (RA) with a treat-to-target (T2T) approach was examined for clinical outcomes. Methods: Since August 2010, RA treatment has implemented the T2T strategy, aiming to achieve a simplified disease activity index (SDAI). The SDAI, Health Assessment Questionnaire Disability Index (HAQ), and pain score (PS-VAS) were monitored. The relationships between these clinical outcomes and variables, including changes in medication, were investigated. Results: Over a 15-year follow-up of 764 RA patients, the total duration was divided into two periods for each outcome. In the First period, the average dose of methotrexate (MTX) increased (p < 0.001). At the same time, glucocorticoids use (GCs) decreased (p < 0.001), and biologic and targeted synthetic disease-modifying anti-rheumatic drugs (bDMARDs and tsDMARDs) use increased (p < 0.01). Consequently, the mean SDAI score declined (p < 0.001), which was attributed to an increase in MTX dose and a decrease in GCs use, However, HAQ scores increased (p < 0.01), and PS-VAS remain stable. In the Second period, the average MTX dose decreased despite stable SDAI and decreasing HAQ scores and PS-VAS (p < 0.01), which was attributed to an increase in the use of tsDMARDs, particularly baricitinib, upadacitinib, and filgotinib (p < 0.01). Overall, the average age increased (p < 0.001), while SDAI scores dropped (p < 0.001), and HAQ scores and PS-VAS decreased (p < 0.01). Conclusions: Clinical outcomes stayed stable with changes in medication use under the T2T approach. Full article