Search Results (16,119)

Background: To evaluate the association of point-of-care ultrasound (PoCUS) performed within one hour of emergency department (ED) arrival with ED length of stay (LOS) and healthcare costs in admitted ED patients with non-traumatic abdominal pain. Methods: This retrospective, inverse probability of treatment weighting (IPTW) cohort study was conducted at a tertiary medical center in Taiwan. This study analyzed data from 2021–2023, focusing on adult patients admitted to an ordinary ward with non-traumatic abdominal pain. Patients discharged from the ED, admitted to the ICU, or receiving PoCUS > 1 h (N = 864) were excluded. The final cohort of 6866 patients comprised those receiving PoCUS within 1 h (N = 1542) and those receiving no PoCUS (N = 5324). Primary and secondary outcomes (ED LOS, costs) were adjusted for age, gender, triage, vital signs, BMI, and comorbidities using generalized linear models with a Gamma distribution. Results: After IPTW adjustment in 6866 admitted abdominal pain patients, PoCUS within one hour was associated with a 14% shorter ED LOS (RM 0.86, 95% CI 0.83–0.89). A notable finding was that PoCUS performed within one hour was associated with 44% higher odds of CT utilization (OR 1.44, 95% CI 1.25–1.65) and 5% lower total healthcare costs (RM 0.95, 95% CI 0.91–0.99). Stratification by CT use revealed distinct patterns underlying these associations: in the non-CT subgroup, PoCUS was associated with 12% lower ED costs (RM 0.88, 95% CI 0.83–0.94), whereas in the CT subgroup, it was associated with 9% lower admission costs (RM 0.91, 95% CI 0.86–0.96). Conclusions: In admitted patients, PoCUS performed within one hour was associated with shorter ED LOS and lower total costs, despite a concurrent association with higher CT utilization. These findings are consistent with a dual, context-dependent role for PoCUS: associated with reduced ED costs in non-CT pathways and lower admission costs in CT pathways. However, as this is an observational study, these results represent associations rather than causal effects and may be influenced by unmeasured confounding. Prospective trials are required to validate these findings. Full article

Parkinson’s disease (PD) is a neurodegenerative disorder due to damage of the nigrostriatal pathway and consequent dopamine (DA) deficiency. The main classic symptoms are those related to motor disturbances, such as postural instability, resting tremor, bradykinesia, and muscle rigidity. Other symptoms, such as non-motor symptoms, do not attract the attention of clinicians and are often overlooked, remaining undiagnosed and untreated, even though they can significantly impair quality of life of PD patients. Dopaminergic therapy is primarily aimed at treating motor symptoms, although it can bring measurable benefits for various non-motor problems. This narrative review analyzes the scientific literature and describes the most recent information on the impact of dopaminergic therapy on non-motor symptoms in PD; both its beneficial and undesirable effects. We discuss evidence that non-motor symptoms such as cardiovascular dysfunction, thermoregulatory issues, dysphagia and drooling, urinary symptoms, pain, neuropsychiatric symptoms, and sleep disorders, including obstructive sleep apnea, can be effectively treated with various dopaminergic strategies, while noting the contraindications and adverse effects of these therapies. Full article

Background: The “weekend effect” describes the concern that patients treated on weekends experience worse outcomes due to differences in staffing, resource availability, and workflow. Evidence for a weekend effect in elective orthopedic surgery is limited and inconsistent, and most prior work does not ensure that surgery itself actually occurs on the weekend. We aimed to evaluate whether weekend admission and surgery are associated with worse in-hospital or 90-day outcomes in a contemporary nationwide cohort of elective primary total knee arthroplasty performed on hospital day 0. Methods: We conducted a retrospective cohort study using the U.S. Nationwide Readmissions Database (NRD) from 2020 to 2022. Adult patients (≥18 years) undergoing elective primary TKA with surgery on hospital day 0 were identified using ICD-10-PCS procedure codes in the primary procedure position. Weekend admissions (Saturday–Sunday) were compared with weekday admissions (Monday–Friday). Baseline demographics, comorbidities, and hospital characteristics were assessed. Outcomes included length of stay, total hospital charges, in-hospital mortality, major postoperative complications, and 90-day all-cause readmissions, time to readmission, readmission length of stay, and procedures during readmission. Continuous variables were compared using t-tests and categorical variables using chi-square or Fisher’s exact tests (two-sided α = 0.05). Results: Among 437,121 elective day-0 TKA admissions, 435,822 (99.7%) occurred on weekdays and 1299 (0.3%) on weekends. Baseline characteristics were highly similar between groups. No clinically meaningful differences were observed in in-hospital complications, mortality, or 90-day readmission outcomes. Small statistical differences in blood transfusion, blood-loss anemia, and postoperative pain did not follow a pattern consistent with a weekend effect. Conclusions: In this large contemporary national cohort of elective primary TKA with surgery on hospital day 0, weekend admission and surgery were not associated with worse in-hospital outcomes or higher 90-day readmission rates. Within standardized perioperative pathways, elective TKA appears safe when performed on weekends, without evidence of a weekend effect. Full article

Background/Objectives: Neovascular age-related macular degeneration (nAMD) poses a serious threat to the eyesight of older adults, representing a leading cause of irreversible vision loss. Anti-vascular endothelial growth factor (anti-VEGF) treatments are effective but require repeated intraocular injections and show poor responses in some patients. CGK012 is a novel derivative of decursin that inhibits the Wnt/β-catenin pathway. This study aimed to elucidate the mode of action of CGK012 and examine its therapeutic effects. Methods: We performed in vitro cellular studies in a retinal pigment epithelial (RPE) cell line (ARPE-19) and human umbilical vein endothelial cells (HUVECs). We examined the in vivo efficacy of CGK012-loaded implants in laser-induced choroidal neovascularization (CNV) rabbit models. We also determined the implants’ in vitro dissolution, intraocular release, and disposition characteristics. Results: CGK012 decreased angiogenic/proinflammatory factor expression and suppressed the epithelial–mesenchymal transition (EMT) in RPE cells by promoting intracellular β-catenin degradation. Additionally, it repressed the expression of cyclin D1 and c-myc, downstream target genes of β-catenin, and inhibited HUVEC capillary tube formation. CGK012-loaded poly (lactic-co-glycolic acid) (PLGA) intravitreal implants significantly reduced vascular leakage in a laser-induced CNV rabbit model. Notably, CGK012 released from the implant was highly permeable to retina/choroid tissue and downregulated β-catenin, angiogenic/inflammatory factors, and vimentin in the rabbit model. The CGK012 concentration reached a plateau at 28–42 days in the vitreous humor and decayed with a half-life of 14 days without systemic exposure. Conclusions: Our findings demonstrate that CGK012 implants prevent choroidal neovascularization through the Wnt/β-catenin pathway suppression and produce high concentrations of CGK012 in the posterior eye segment with prolonged release. Thus, these implants provide more therapeutic choices for nAMD treatment. Full article

The tumor microenvironment (TME) orchestrates tumor growth, immune evasion, and therapeutic response in head and neck squamous cell carcinoma (HNSCC). Current immune checkpoint inhibitors (ICIs) target the programmed death receptor-1/programmed death-ligand 1 (PD-1/PD-L1) axis and improve survival in recurrent, metastatic, and locally advanced HNSCC. Tumor cells produced exosomes directly suppress cytotoxic T-lymphocytes activity by modulating immune checkpoint pathways and disrupting T-cell receptor signaling. Cancer-associated fibroblast-derived exosomes (CAF-Exos) function indirectly by conditioning immune escape and tumor growth. Together, these exosomal populations cooperate to create an immunosuppressive niche that hinders the efficacy of immunotherapies. CAF-Exos induce TME changes that exclude CD8⁺ T-cells, promote regulatory T-cells (Tregs), and upregulate PD-L1 expression in tumor cells. The bidirectional transfer of microRNAs (miRNAs) between tumor cells and CAFs enhances epithelial–mesenchymal transition (EMT), suppresses cytotoxic lymphocytes, and undermines ICI efficacy. This review article summarizes recent publications about plasma-derived exosomes from HNSCC patients. These exosomes carry tumor and immune checkpoint markers, reflect tumor burden and treatment response, and strongly modulate immune cells by suppressing T- and B-cell activity and promoting immunosuppressive macrophages. We encourage functional and biomechanistic future studies in the field of HNSCC that examine how CAF subtypes exosomes achieve an immunoresistant TME. Full article

This study examined the long-term transcriptomic reprogramming in peripheral blood mononuclear cells (PBMCs) of severe COVID-19 patients and its effects for cancer development. RNA sequencing was conducted on PBMCs obtained from healthy controls, COVID-19 patients without pneumonia, and COVID-19 patients exhibiting severe pneumonia one year post-infection. Differential gene expression analysis identified a sustained pro-oncogenic molecular signature, especially among severe COVID-19 patients. Functional enrichment analysis revealed a substantial enrichment of cancer-associated pathways, encompassing apoptosis, viral carcinogenesis, and transcriptional dysregulation. Notably, the autophagy-related gene SQSTM1/P62 was recognized as a distinctive hub gene within the severe COVID-19 patients, interacting with pivotal genes associated with inflammation, apoptosis, and cancer advancement. Survival analysis demonstrated that elevated expression of COVID-19-associated hub genes correlated with unfavorable prognosis in various cancer types, including adrenocortical carcinoma, bladder urothelial carcinoma, and brain lower-grade glioma. These findings indicate that severe COVID-19 infection may establish a systemic milieu favorable to cancer development or recurrence, highlighting the necessity of prolonged oncological monitoring in these patients. Finding specific molecular targets and pathways can help us understand how COVID-19 might be linked to a higher risk of cancer. Full article

Background/Objectives: The Notch signaling pathway regulates cell fate, proliferation, and differentiation, and its dysregulation has been implicated in various cancers, including breast cancer. MicroRNAs (miRNAs) are critical post-transcriptional regulators that can modulate Notch pathway components. The aim of this study was to identify miRNAs that may potentially regulate the expression of Notch pathway-related genes across five molecular subtypes of breast cancer in Polish women. Methods: Tumor and adjacent normal tissue samples were collected from 405 patients with five breast cancer subtypes: luminal A (n = 130), HER2-negative luminal B (n = 100), HER2-positive luminal B (n = 96), non-luminal HER2-positive (n = 36), and triple-negative breast cancer (n = 43). Gene expression was profiled using mRNA microarrays and validated with RT-qPCR and ELISA. Candidate regulatory miRNAs were identified by miRNA microarrays and confirmed using the miRDB database. Results: APH1A, CTBP1, DTX1, HEY1, HEY2, JAG2, NOTCH4, TLE2, and TLE4 were consistently dysregulated across all breast cancer subtypes. Overexpression of HEY1 and JAG2 may be driven by decreased levels of miR-145, miR-98, and miR-381. Conversely, downregulation of TLE4 may be associated with elevated expression of miR-196a and miR-155. No regulatory miRNAs meeting the selection criteria were identified for APH1A, CTBP1, DTX1, HEY2, NOTCH4, or TLE2. Conclusions: The consistent alterations suggest the presence of a shared Notch-driven oncogenic signature in breast cancer, potentially driving cell proliferation, stemness, and resistance to therapy. These findings enhance our understanding of Notch signaling in breast cancer and propose novel miRNA–Notch interactions as candidate targets for therapeutic intervention. Full article

Eosinophilic esophagitis (EoE) has emerged as a major cause of dysphagia and food impaction worldwide. This narrative review traces the evolving therapeutic pipeline for EoE, highlighting agents spanning from late-stage clinical development to final approval. We summarize mechanistic insights that have driven a shift from broad immunosuppression to precise inhibition of type-2 inflammatory pathways, including blockade of key interleukin pathways. Randomized trials have demonstrated histologic and symptomatic gains, yet regulatory approvals and optimal positioning within treatment algorithms are pending. Parallel innovations in drug delivery aim to maximize mucosal exposure while minimizing systemic burden. Key challenges include heterogeneity in disease phenotype, paucity of long-term safety data, and the need for non-invasive biomarkers to guide precision prescribing. Cost considerations and patient preferences will shape adoption. By integrating advances across immunology, formulation science and clinical trial design, the therapeutic pipeline for EoE holds promise to transform care from empirical suppression to mechanism-based disease modification. Full article

Background/Objectives: Secondary stroke prevention is a cornerstone of long-term recovery and healthy aging among older adults, yet adherence to preventive strategies remains suboptimal. This global systematic review aimed to synthesize evidence from randomized controlled trials evaluating interventions that support sustained secondary prevention in older adults after stroke. Methods: A systematic search of PubMed and Scopus databases was conducted up to April 2025, following PRISMA 2020 guidelines and registered in PROSPERO (CRD420251177501). Eligible studies included randomized controlled trials targeting adults aged 60 years or older and assessing pharmacological, behavioral, educational, rehabilitative, or technology-assisted interventions for stroke recurrence prevention. Data were narratively synthesized due to study heterogeneity, and methodological quality was appraised using the Cochrane RoB 2 tool. Results: Seventeen randomized trials involving approximately 17,000 participants met the inclusion criteria. Multicomponent programs integrating medication management, behavioral education, exercise, cognitive rehabilitation, and digital support consistently improved adherence, vascular risk control, and quality of life. Pharmacological strategies alone showed limited or transient benefits, underscoring the importance of patient education and sustained follow-up. Common barriers included low motivation, cognitive decline, and technological challenges, while key facilitators were personalized education, multidisciplinary coordination, and culturally adapted implementation. Conclusions: Effective secondary stroke prevention in older adults depends on integrated, person-centered models that combine education, behavioral reinforcement, and technology-assisted monitoring. Structured, continuous educational programs, embedded within rehabilitation and primary care, emerge as the most promising pathway to improve adherence, reduce recurrence, and promote active, autonomous aging. Full article

Homologous recombination deficiency (HRD) is a clinically relevant biomarker that predicts sensitivity to PARP inhibitors and enables personalized cancer therapy. Validated local HRD testing solutions are essential to ensure timely and equitable access, ultimately improving treatment outcomes. We evaluated a shallow whole-genome sequencing (sWGS) approach for genomic instability (GI) assessment combined with a 52-gene targeted panel in ovarian cancer. Validation used reference materials and 24 archival samples with prior HRD characterization, comparing performance with the Myriad myChoice^® HRD test. A prospective cohort of 124 newly diagnosed ovarian cancer patients was then analyzed. sWGS-derived GI status showed strong concordance with the reference test (95.8% overall agreement; κ = 0.913; NPV 100%, PPV 93.3%). Pathogenic BRCA1/2 variants were detected in 30 patients (24.19%). An additional 22.76% were BRCA1/2-negative but GI-positive, giving an overall HRD prevalence of 47.15%. Platinum sensitivity occurred in 90.0% (18/20) of HRD-positive patients with follow-up. Among 12 patients assessed for PARP-inhibitor response, the overall response rate was 66.7% (95% CI 39.1–86.2) and disease control rate 83.3% (95% CI 55.2–95.3). TP53 alterations were most frequent (62.90%), followed by BRCA1 (19.35%) and BRCA2 (4.83%). Pathogenic variants in other HR-pathway genes (ATM, CHEK2, BRIP1, RAD51C, BARD1) appeared in 9.57% of BRCA-wild-type cases, with heterogeneous GI impact. Two cases showed concurrent BRCA2 variants and microsatellite instability, indicating possible eligibility for anti-PD-1/PD-L1 therapy in addition to PARPi. This first comprehensive analysis of Romanian ovarian cancer patients suggests that integrating sWGS-based genomic instability assessment with BRCA testing can improve HRD detection and reflects the heterogeneity of HR-pathway variants. Preliminary clinical observations were consistent with known HRD-associated treatment responses, although larger studies are needed to confirm these findings. Full article

Neurological disorders and cardiovascular disease (CVD) remain leading causes of global morbidity and mortality and often coexist, in part through shared mechanisms of chronic inflammation and oxidative stress. Neuroinflammatory signaling, including microglial activation, cytokine release, and impaired autonomic regulation, contributes to endothelial dysfunction, atherosclerosis, hypertension, and stroke, while cardiac and metabolic disturbances can reciprocally exacerbate brain pathology. Increasing evidence shows that several antidiabetic agents exert pleiotropic anti-inflammatory and antioxidant effects that extend beyond glycemic control. Metformin, SGLT2 inhibitors, DPP-4 inhibitors, and GLP-1 receptor agonists modulate key pathways such as AMPK, NF-κB, Nrf2 activation, and NLRP3 inflammasome suppression, with demonstrated vascular and neuroprotective actions in preclinical models. Clinically, GLP-1 receptor agonists and SGLT2 inhibitors reduce major cardiovascular events, improve systemic inflammatory markers, and show emerging signals for cognitive benefit, while metformin and DPP-4 inhibitors exhibit supportive but less robust evidence. This review synthesizes molecular, preclinical, and clinical data across drug classes, with particular emphasis on GLP-1 receptor agonists, and highlights outstanding translational questions including blood–brain barrier penetration, biomarker development, optimal patient selection, and timing of intervention. We propose a unified framework to guide future trials aimed at leveraging antidiabetic therapies such as DDP-4 anti-inflammatory and antioxidant interventions for neurological and cardiovascular diseases. Full article

Branched-chain amino acids (BCAAs) are essential amino acids in humans, with reported anti-proliferative effects on HepG2 hepatoma cells and the potential to reduce hepatocellular carcinoma (HCC) development in cirrhotic patients. PDCD4, a tumor suppressor that is downregulated in many cancers, is also suppressed by serum, EGF, or TPA treatment. This study examined the effect BCAA has on PDCD4 expression and related cellular pathways in Huh7 hepatoma cells. Cells were treated with different concentrations of BCAA, and analyzed by Western blotting, qRT-PCR, and immunofluorescence staining. Treatment with BCAA upregulated the protein levels of PDCD4, while downregulating its mRNA levels. BCAA enhanced the phosphorylation of mTORC1 substrate 4E-BP1, p70S6K1, and p70S6K1 substrate S6 ribosomal protein. BCAA also elevated the protein levels of autophagy factors p62 and ATG5 while reducing LC3-II particle formation, thus indicating impaired autophagy. ULK1 knockdown also upregulated the protein levels of PDCD4 and p62. Additionally, BCAA upregulated the phosphorylation of ULK1 at serine 757, which was inhibited by rapamycin. These findings suggest that BCAA inhibits autophagy through the mTORC1-mediated phosphorylation of ULK1 at serine 757, thereby impairing autophagosome formation and upregulating the PDCD4 protein levels by inhibiting its degradation via autophagy. Furthermore, FACS analysis showed that BCAA inhibited the proliferation of Huh7 cells. BCAA may have a preventive effect against tumor development through the modulation of autophagy and the tumor suppressor pathways. Full article

Despite continuing improvement in the standard of care, the clinical outcomes in metastatic colorectal cancer (CRC) remain poor, especially among patients whose tumors carry activating mutations in BRAF or RAS-family oncogenes. These mutations initiate a series of oncogenic signal transduction events, known as the mitogen-activated protein kinase (MAPK) cascade. While therapeutic targeting of this pathway achieved impressive results in other malignancies, the effectiveness of this approach remains low in CRC. In the current study, we observed that inhibitors of GTP production synergize with various inhibitors of the MAPK cascade in suppressing a variety of CRC cell lines. Furthermore, we discovered that an inhibitor of guanylate biosynthesis increases the efficacy of MAPK cascade inhibitors against human CRC grown in mice. Moreover, a combination of MEK and guanylate biosynthesis inhibitors is more potent than the MEK inhibitor alone in increasing the efficacy of immune therapy in an immunocompetent mouse model. Considering that guanylate biosynthesis inhibitors are already used in clinical practice for other applications, their use in synergistic combinations with the inhibitors of the MAPK cascade may present an actionable strategy to increase the efficacy of the latter. Full article

The early differentiation of benign choroidal naevi from malignant melanoma remains one of the most nuanced challenges in ophthalmic oncology, with profound implications for patient survival. Conventional diagnostic pathways rely on multimodal imaging and expert interpretation, but inter-observer variability and the rarity of melanoma limit timely and consistent detection. Recent advances in artificial intelligence (AI) offer a promising adjunct to conventional ophthalmic practice. This review provides a critical comparative synthesis of the studies to-date which have looked at AI’s use in the detection, risk stratification, and longitudinal monitoring of choroidal melanoma. While early results are promising—with some models achieving an accuracy comparable to expert clinicians—significant challenges remain regarding generalisability, dataset bias, interpretability, and real-world deployment. We conclude by outlining practical priorities for future research to ensure that AI becomes a safe, effective, and equitable tool for improving patient outcomes. Full article

Diabetes mellitus and its microvascular complications, including diabetic retinopathy (DR), present significant health challenges. DR is a leading cause of vision impairment and blindness among working-age individuals in developed countries. The prevalence of DR continues to rise, underscoring the need for more precise diagnostic and therapeutic strategies. Due to its multifactorial nature and despite advancements in understanding DR pathophysiology, predicting its onset and progression remains challenging. Traditional screening and treatment methods often fall short of addressing the heterogeneous nature of the disease, underscoring the need for personalised therapeutic strategies. Recent research has highlighted the vital role of genetic biomarkers in the development and progression of DR, paving the way for a precision medicine approach. Personalised eye care in patients with diabetes aims to accurately predict the risk of DR progression and visual loss in real time. A precision medicine approach that utilises genetic biomarkers offers a promising pathway for personalised diagnosis and treatment strategies. Each DR case is distinct in phenotype, genotype, and therapeutic response, making personalised therapy crucial for optimising outcomes. Advancements in genomics, including genome-wide association studies (GWAS) and next-generation sequencing (NGS), have identified numerous genetic markers associated with DR susceptibility and severity. Emerging evidence underscores the critical role of genetic factors, which account for 25–50% of the risk of developing DR. Advances in identifying genetic markers, such as gene polymorphisms and human leukocyte antigen associations, along with the development of targeted drugs, highlight a promising future for personalised medicine in DR. By identifying specific genetic variants associated with DR, we can enhance prevention and early diagnosis, tailor personalised treatment plans, and more accurately predict disease progression. This represents a critical step toward personalised medicine in DR management. Integrating genetic and epigenetic biomarkers into clinical models may transform DR care through earlier diagnosis and precision-guided interventions, gearing it toward precision ophthalmology. Full article