Search Results (9,532)

Dysregulation contributes to Alzheimer’s disease (AD) pathophysiology. Zinc therapy promotes enterocyte copper sequestration, potentially reducing systemic copper. Individual biological responses may vary. Methods: ZINCAiD was a 24-week, randomized, double-blind, placebo-controlled phase II trial assessing zinc therapy in individuals with mild cognitive impairment (MCI) due to AD (EudraCT No.: 2019-000604-15; registered on 26 March 2020). Participants were randomized 2:1 to receive elemental zinc (135 mg/day for 12 weeks, then 65 mg/day) or placebo. Ceruloplasmin was measured at predefined intervals for safety monitoring, blinded to the investigators. Post hoc, “Zinc Responders” were defined by ≥20% reduction in ceruloplasmin at week 12. The primary cognitive endpoint was the Cognitive Composite 2 scale (CC2); secondary endpoints included MMSE and CDR-Sob. Findings: Of the 48 participants randomized, 9 discontinued, primarily due to unrelated clinical deterioration; 39 had complete ceruloplasmin data. Two serious adverse events occurred in the Placebo group. Mild gastrointestinal symptoms occurred in eight participants, with only four leading to dropout. In the primary zinc vs. placebo analysis, no significant differences emerged in cognitive outcomes. A post hoc exploratory analysis stratified participants by pharmacodynamic response: 12 individuals with MCI due to AD (31%) met the criteria for “Zinc Responder,” defined by ≥20% reduction in serum ceruloplasmin at week 12. Only Zinc Responders maintained cognitive stability over 24 weeks, whereas the combined group of Zinc Non-Responders and placebo-treated participants showed a significant decline. For the composite cognitive score (CC2), the interaction between visit and response group was significant (p = 0.030), with deterioration observed only in the Non-Responder + Placebo group (Δ = –2.72, p < 0.0001 vs. –0.71, p = 0.35 in Responders). Similar patterns were observed for CDR-Sob (interaction p = 0.017) and MMSE (trend p = 0.09). Interpretation: Zinc therapy stabilized cognition in a pharmacodynamically defined MCI subgroup. These exploratory findings suggest serum ceruloplasmin as a feasible biomarker of target engagement. Larger trials are needed for confirmation. Full article

Background: Chronic illnesses pose a major global health challenge with an estimated 1.56 billion people affected worldwide in 2025, and 85% of these being older adults facing at least one chronic condition. These patients are particularly vulnerable to severe influenza complications and higher mortality rates due to weakened immune responses; in addition, vaccination rates in China remain significantly lower than those in developed nations. Methods: This review examines how chronic conditions exacerbate influenza-related effects through immune dysfunction and metabolic imbalances, and how influenza infection worsens chronic diseases by triggering inflammation, suppressing immunity, and causing secondary infections that lead to respiratory complications, cardiac complications, and blood sugar disturbances. Results: A bidirectional adverse interaction exists in which chronic illnesses increase influenza severity via poor immunity, while influenza accelerates chronic disease progression (e.g., cardiac events and diabetic ketoacidosis). Vaccination reduces hospitalization by 32–52% in patients with lung disease and mortality by 16–46% in diabetic patients, with good safety. Conclusions: The findings emphasize the urgent need for improved vaccination strategies in patients with chronic diseases. Such strategies are crucial to reducing disease burden, enhancing clinical outcomes, and improving quality of life, while also providing critical evidence for the development of public health policies. Full article

On 22 September 2020, China announced an ambitious decarbonization commitment, leading to significant stock market reactions. Using a comprehensive dataset of China’s listed firms and a manually updated political connections index, we employ an event study approach with regression analysis to examine the effects of political connections and industry heterogeneity on firm value following the announcement. Our analysis reveals several key findings: First, there were overall negative market reactions to the announcement. Second, political connections negatively impact firm value by acting as a “grabbing hand” in China’s private sector, as private firms with strong political ties often prioritize political agendas over shareholders’ profit maximization objectives. Third, the adverse effects of political connections are industry-specific, with firms in the environmental protection and decarbonization sectors being more vulnerable to environmental policies. Lastly, we observe a limited moderating effect of the economic development of the firm’s host province. Our results are robust across different estimation techniques, model specifications, and major financial announcements such as quarterly financial statements, M&A, and dividend offering. Full article

Background: Gastrointestinal neuroectodermal tumour (GNET), also known as clear cell sarcoma (CCS) of the gastrointestinal tract, is a rare neural crest-derived malignancy characterized by EWSR1-ATF1 or EWSR1-CREB1 fusions. Due to its rarity, there is limited evidence and no established guidelines for standard management. GNET is aggressive, with high rates of local recurrence, metastasis, and mortality. Case Presentation: We report the case of a 46-year-old woman with a family history of gastrointestinal cancers who was diagnosed in 2020 with an intestinal GNET. She underwent a segmental enterectomy as the first step of multimodal therapy. After three years of follow-up, she developed hepatic and peritoneal metastases. In November 2023, she began combined therapy with the anti-VEGF tyrosine kinase inhibitor cabozantinib and the immune checkpoint inhibitor nivolumab. The patient has maintained stable disease for 18 months with good tolerance and no adverse events. Molecular analysis of the tumour, which showed an EWSR1-CREB1 fusion, supported the selection of targeted therapy and immunotherapy as the preferred treatment approach. Conclusions: Immunotherapy and targeted therapy show promise for GNET/CCS treatment, but clinical standards are lacking, and evidence comes primarily from case reports. Additional data are needed to determine the best sequence and combination of therapies for this very rare disease. Full article

Background/Objectives: The prevalence of obesity continues to rise globally, and with this an increase in the use of herbal weight loss supplements (WLS). At present, there is limited evidence to support the efficacy and safety of WLS, and there have been growing reports of adverse events associated with their use. We aimed to determine those WLS that caused toxicity in vitro and to use ¹H nuclear magnetic spectroscopy (NMR) to examine the metabolomic changes induced by these WLS in human hepatic and intestinal cells. Materials and Methods: This study used in vitro methods and ¹H NMR spectroscopy to analyse the metabolomic changes in vitro of WLS available for purchase in Australia. Ten WLS were selected, nine WLS caused significant toxicity in HepG2 human liver cells, and of these, six met the criteria for ¹H NMR analysis, which was based on a 25–50% reduction in cell viability. Results: All 10 WLS caused a significant reduction in viability of Caco-2 human intestinal cells, with seven selected for metabolic profiling. Orthogonal partial least squares discriminant analysis (O-PLS-DA) of ¹H NMR spectral data was used to characterise the metabolites that differed between the untreated and treated cells and the fold changes of the metabolites were determined. The results showed alterations to key metabolites such as amino acids, glucose, carboxylic acids, and amines in all treatment groups compared to untreated controls across both cell lines. Conclusions: Collectively, these biochemical changes represent disturbances to intracellular proteins, energy metabolism, and membrane lipids suggestive of oxidative stress. This study highlights the need for further investigations into the actions of these WLS in vivo, and, as these products were regulated by the Therapeutic Goods Administration (TGA) at the time of purchase, this study suggests improved pre-market screening to ensure consumer health is protected. Full article

Background: The objective of this study was to assess the efficacy and safety of faricimab in diabetic macular edema (DME) in patients who were treatment-naïve or previously treated in a real-world setting. Methods: This was a retrospective, observational, single-center study that included 105 eyes from 79 patients diagnosed with DME and treated with intravitreal faricimab between January 2024 and January 2025. Patients were categorized into two groups according to their treatment history, namely treatment-naïve eyes and eyes previously treated (switch group). Functional (best-corrected visual acuity, BCVA) and anatomical (central foveal thickness, CFT; macular volume, MV) outcomes were assessed. The safety of faricimab was evaluated from changes in intraocular pressure and the occurrence of adverse events. Results: BCVA improved significantly in both groups, with a mean gain of +0.16 in treatment-naïve eyes and +0.10 in switch eyes. The mean reduction in CFT was −53.7 µm in the naïve group and −37.8 µm in the switch group. MV decreased by −0.4 mm³ overall, with significant reductions in both groups. No adverse events were reported, confirming the safety of faricimab in routine clinical practice. Conclusions: Faricimab showed significant improvements in functional and anatomical outcomes in patients with DME, regardless of the use of previous anti-VEGF therapies. These findings support the effectiveness and safety of faricimab in a real-world clinical setting and reinforce its potential as a valuable treatment option for DME. Full article

Background: This study aimed to evaluate the risk of upper gastrointestinal (UGI) adverse events (AEs) associated with oral anticoagulants (OACs) and identify potential interactions with cardiovascular (CV) drugs. Methods: Individual case safety reports (ICSRs) from the FDA Adverse Event Reporting System from July 2014 to December 2023 were analyzed. Dataset I was constructed to assess the associations between OACs and UGI AEs using disproportionality analysis. Dataset Ⅱ included OAC-related ICSRs to explore potential interactions with CV drugs through logistic regression. Positive signals were defined as potential associations identified by disproportionality analysis metrics, such as reporting odds ratios (RORs) or adjusted RORs (aRORs) accounting for confounders. Results: Dataset I included 12,905,290 ICSRs, and a positive signal for dabigatran was detected with an ROR of 1.19 (95% CI, 1.13–1.25). A total of 364,044 OAC-related ICSRs were included in dataset II. At the pharmacologic drug class level, several positive signals were identified, represented as aRORs with 95% CIs: for warfarin, amiodarone analogs (1.22; 1.04–1.43); for apixaban, angiotensin-converting enzyme inhibitors (1.34; 1.24–1.45), angiotensin receptor blockers (1.23; 1.14–1.33), dihydropyridine calcium channel blockers (1.30; 1.21–1.41), and digitalis glycosides (1.72; 1.49–2.00); and for edoxaban, angiotensin receptor blockers (1.88; 1.48–2.37), amiodarone analogs (1.73; 1.06–2.85), and anti-platelets (1.56; 1.20–2.03). No signals were observed for rivaroxaban or dabigatran. At the individual drug level, 62 OAC-CV pairs were identified as having potential interactions. Conclusions: Drug-specific interaction profiles should be considered to ensure safe and personalized use of OACs in clinical practice. Full article

Objective: Sinonasal squamous cell carcinoma (SNSCC) is a rare and aggressive malignancy, with limited treatment strategies in the recurrent or metastatic cases. Although immune checkpoint inhibitors (ICIs) have shown efficacy in head and neck cancers (HNCs), clinical data specific to SNSCC are scarce. This study aimed to evaluate the therapeutic efficacy and prognosis of ICIs in patients with SNSCC. Methods: We conducted a retrospective review of 18 patients with pathologically confirmed SNSCC treated with nivolumab or pembrolizumab at Gifu University Hospital between May 2017 and December 2024. Treatment response was assessed using RECIST v1.1 criteria. Overall response rate (ORR) and disease control rate (DCR) were evaluated as treatment effects, and overall survival (OS) and progression-free survival (PFS) were evaluated as prognoses. Subgroup analyses were performed according to treatment regimen. Results: The ORR and DCR for all patients were 43.8% and 56.3%, respectively. Pembrolizumab-treated patients showed higher response rates (ORR: 66.7%; DCR: 83.3%) compared to those treated with nivolumab (ORR: 30%; DCR: 40%). Median OS and PFS were 21.5 and 7.9 months, respectively. Long-term durable responses exceeding two years were observed in several cases. Although pembrolizumab tended to result in better outcomes, no statistically significant difference was found between groups. Immune-related adverse events were infrequent and manageable. Conclusions: This study suggests that a subset of patients with SNSCC may benefit from ICI therapy, particularly in combination with chemotherapy. Despite the rarity of SNSCC, accumulating clinical evidence—including prospective studies—is essential to establish standardized treatment strategies for this disease. Full article

Introduction: Craniotomy, a common neurosurgical procedure, is frequently associated with substantial perioperative challenges and delayed recovery. While Enhanced Recovery After Surgery (ERAS) protocols have demonstrated clear benefits in multiple surgical fields, their application in neurosurgery, particularly elective craniotomy, remains emerging. Objective: This systematic review and meta-analysis aimed to evaluate the efficacy and safety of ERAS protocols in adult patients undergoing elective craniotomy, focusing on key outcomes such as length of hospital stay (LOS), postoperative pain, complications, and functional recovery. Methods: Following PRISMA guidelines, a comprehensive search was conducted in PubMed, Embase, Scopus, Web of Science, and the Cochrane Library up to June 2025. Eligible studies included adult patients (≥18 years) undergoing elective craniotomy and compared ERAS protocols to conventional perioperative care. Primary outcomes were LOS, postoperative complications, pain, early oral intake, and early mobilization. Data extraction and risk of bias assessment (RoB 2.0) were independently performed by two reviewers. Results: Nine randomized controlled trials (RCTs), totaling 1453 patients, were included. Meta-analysis showed that ERAS protocols significantly reduced length of hospital stay (mean difference: −2.17 days; 95% CI: −2.92 to −1.42; p < 0.00001) and decreased the incidence of postoperative nausea and vomiting (odds ratio [OR]: 0.29; 95% CI: 0.19 to 0.44; I² = 0%). ERAS protocols were associated with higher odds of early mobilization (OR: 6.88; 95% CI: 3.46 to 13.68) and early oral intake (OR: 14.04; 95% CI: 7.80 to 25.26). Postoperative complications were significantly reduced in the ERAS group (OR: 0.49; 95% CI: 0.24 to 0.99; p = 0.048; I² = 0%). While early urinary catheter removal showed a favorable trend (OR: 13.48), high heterogeneity (I² = 95.7%) limits interpretability. Postoperative pain on day 1 did not differ significantly between groups (mean difference: −0.37; 95% CI: −2.38 to 1.63; p = 0.72). The overall risk of bias was rated low to moderate across studies. Conclusions: ERAS protocols in elective craniotomy are associated with shorter hospital stays, lower complication rates, reduced PONV, and earlier return to function, without increasing adverse events. These findings support broader implementation of ERAS in neurosurgical practice. Further multicenter RCTs are warranted to standardize and refine ERAS components for craniotomy. Full article

Fractional laser (FL) and fractional radiofrequency (FRF) are effective treatments for atrophic acne scars, yet comparative data in Asian populations with darker skin types remain limited. This retrospective cohort study compared the clinical effectiveness and safety of FL and FRF in Thai patients aged 18–60 years with Fitzpatrick skin types III–IV who underwent at least two treatment sessions between 2012 and 2023. Baseline characteristics were balanced using propensity score stratification, and missing data were addressed through multiple imputation with chained equations. The primary endpoint was the proportion of patients achieving ≥25% improvement in scarring at 6 months, with equivalence testing performed using a 20% margin. A total of 397 patients (254 FL, 143 FRF) were included, with balanced baseline characteristics after stratification. At 6 months, 88.1% of FRF-treated and 71.9% of FL-treated patients achieved the primary endpoint. FRF showed numerically greater mean improvement at all time points, though differences were not statistically significant. FL met the non-inferiority criterion but not equivalence. FRF was associated with significantly higher pain scores (p < 0.001), while adverse events, including post-inflammatory hyperpigmentation, were rare and similar between groups. Both modalities demonstrated meaningful clinical benefit and acceptable safety, although statistical equivalence could not be established and FRF was associated with greater procedural discomfort. Full article

Early-stage knee osteoarthritis (knee OA) lacks effective regenerative therapies. This study aimed to compare the cartilage regenerative effects, clinical efficacy, and safety of intra-articular injections of autologous adipose-derived mesenchymal stem cells (ADSCs) versus hyaluronic acid (HA). Forty-eight patients with early knee OA were enrolled in a prospective open-blinded multi-center study at Suranaree University of Technology Hospital and Phramongkutklao Hospital. Participants were randomized into either the ADSC or HA group. Primary outcomes included MRI-based cartilage lesion volume, synovial thickness via ultrasound, and WOMAC scores over 6 months. MRI results revealed significant and progressive cartilage regeneration in the ADSC group. In particular, medial femoral cartilage lesion volume decreased by 50.06 mm³, whereas the HA group showed an increase of 36.44 mm³. Synovial thickness also declined significantly in the ADSC group at 3 and 6 months. Both groups demonstrated reduced symptoms, but the ADSC group achieved superior and sustained improvements in WOMAC pain, stiffness, and function scores throughout the 6-month follow-up. The clinical benefits were consistent and more pronounced compared with HA. No serious adverse events occurred. In conclusion, intra-articular ADSC injections show superior cartilage restoration on MRI and better clinical outcomes than HA injection, making them a promising treatment for early-stage knee OA. Full article

Background/Objectives: This study evaluated a novel PET tracer, ⁶⁸Ga-NOTA-CYT-200, which targets human granzyme B (GZB) as a biomarker for cytotoxic T-cell activation in a clinically relevant model of melanoma-bearing mice with a humanized immune system treated with immune checkpoint inhibitor (ICI) therapy. Methods: The binding affinity of the tracer was determined using an enzymatic colorimetric assay. Tumor-bearing humanized NSG mice underwent PET imaging before and during ICI monotherapy or combination therapy to assess ⁶⁸Ga-NOTA-CYT-200 uptake within tumors and other organs. The tumor growth was carefully monitored. The treatment response was evaluated based on the percentage change in tumor size at days 5 and 15 after the treatment started. A tracer biodistribution study and immunohistochemical staining of the tumors and organs were also performed. Results: The inhibition constant (Ki) of ⁶⁸Ga-NOTA-CYT-200 was estimated at 4.2 nM. PET imaging showed a significantly higher ⁶⁸Ga-NOTA-CYT-200 uptake in mice receiving the combination therapy compared to those receiving monotherapy or a vehicle (p < 0.0001 or p = 0.0005, respectively), which correlated with the greatest reduction in tumor size in the combination ICI group. Regardless of treatment, the responders presented with a significantly higher ⁶⁸Ga-NOTA-CYT-200 uptake at days 4 or 7 after the treatment began (p = 0.0002 and p = 0.0109, respectively). An increased uptake of ⁶⁸Ga-NOTA-CYT-200, especially in the intestines and liver within the combination ICI group, suggested immune-related adverse events (IrAEs). Conclusions: Our study demonstrates that ⁶⁸Ga-NOTA-CYT-200 PET imaging can predict the early treatment response in melanoma models treated with ICI and may also help in detecting IrAEs. Full article

Hepatocellular carcinoma (HCC) is the most common primary liver cancer. At the time of diagnosis, many HCC patients are not candidates for surgical resection and are considered for other locoregional therapies, including transarterial radioembolization (TARE) and stereotactic body radiation therapy (SBRT). To date only a few studies have explored the safety and efficacy of combining TARE and SBRT. Therefore, we aimed to evaluate it. Patients who received both SBRT and TARE from 2016 to 2024 were retrospectively evaluated for treatment-related toxicity based on criteria for adverse events (CTCAE v4.0). Treatment response was evaluated by modified response evaluation criteria for solid tumors (m-RECIST). We identified 12 patients with median age of 66.5 (range: 40, 87) and median follow up of 12 months. The median time between TARE and SBRT was 6.5 months (range: 1.5 to 24). Following the second treatment, ALBI grade remined the same among all patients at 3-month post treatment compared to baseline. Baseline CP was A among all patients and remained unchanged during follow-up and no higher than grade 3 clinical or biochemical toxicity was seen. The objective response rate (ORR) among patients receiving treatment to the same lesion was 100%. The combination treatment was consistent with prior studies in which the combination of TARE and SBRT has been shown to have good local control with few cases of grade 3 toxicity. Our study demonstrates that treatment with TARE and SBRT was safe and effective among our small sample of patients. Full article

Background and Objectives: Ofatumumab (OFA) is the first fully human anti-CD20 monoclonal antibody approved for the treatment of RRMS classified as a high-efficacy treatment agent. Real-world evidence is essential for evaluating the effectiveness and safety of OFA. Materials and Methods: A total of 184 patients (72.3% women, mean age 38 years (±10.9), 51 naïve patients and 133 after switch. Among them, 142 patients were evaluated after first 12-months of treatment according to relapse rate, neurological status expressed by Expanded Disability Status Scale (EDSS), new T2-weighted (T2-w) lesions and gadolinium-enhancing lesions (GELs) in magnetic resonance imaging (MRI), confirmed disability progression, as well as adverse events. Logistic regression identified factors associated with disease activity at ofatumumab initiation, including age, sex, disease duration, prior treatment, and baseline EDSS. Results: After the first 12 months of OFA treatment, relapses occurred in 12.0% of patients; new or enlarging T2-w lesions were observed in 12.7%; GELs in 3.5%; EDSS progression in 12.7%; and EDSS improvement in 14.2%. The No Evidence of Disease Activity-3 (NEDA-3) status was achieved in 76.1% of patients overall—75.8% in those who switched from another disease-modifying therapy (DMT), and 76.6% in treatment-naïve individuals. No significant differences were observed between the naïve and switch groups. Baseline EDSS at ofatumumab initiation was a significant predictor of relapse activity, while age was significantly associated with MRI activity (GELs) at 12 months. Conclusions: Real-world data confirmed high efficacy and safety of ofatumumab in RRMS. NEDA-3 was achieved more often than in registration trials. No efficacy differences between naïve and switch patients were observed. Full article

Background and Objectives: Musculoskeletal pain is a global public health issue. Eight Constitution Medicine (ECM), a type of East Asian Traditional Medicine, offers personalized, minimally invasive treatment through Eight Constitution Acupuncture (ECA) and Eight Constitution Lifestyle Intervention (ECLI). Despite its clinical use, scientific evidence supporting ECM’s effectiveness remains limited. This study aimed to evaluate the effectiveness in treating musculoskeletal pain in primary care settings. Materials and Methods: This retrospective study analyzed medical records from three ECM clinics (Gangnam-Shingwang, Yeson, and Yebon) between January 2018 and August 2023. A total of 163 patients were included, with 44 providing follow-up data. Pain intensity, quality of life, and functional outcomes were assessed using validated instruments including the PainDETECT questionnaire, Korean Cancer Pain Assessment Tool (KCPAT) somatic pain scores, EuroQol 5-Dimension 5-Level (EQ-5D-5L), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Oswestry Disability Index (ODI), Neck Disability Index (NDI), and Shoulder Pain and Disability Index (SPADI). Pre- and post-treatment scores were statistically analyzed. Results: Significant decreases were observed in KCPAT somatic pain scores (11.77 ± 4.77 to 9.77 ± 5.32) and significant improvements in EQ-5D-5L scores (0.74 ± 0.12 to 0.80 ± 0.07). WOMAC and ODI scores also showed significant improvements. However, the changes in the NDI, SPADI, and PainDETECT scores were not statistically significant. No adverse events were reported. Conclusions: ECM, through ECA and ECLI, may offer effective personalized treatment for musculoskeletal pain, improving both pain intensity and quality of life. Despite its small sample size and retrospective design, this study offers valuable preliminary evidence for ECM. Further large-scale prospective studies are needed to confirm these findings. Full article