In this study, we aimed to evaluate the proportion of nonobstructive azoospermia (NOA) cases exhibiting features resembling the obstructive azoospermia (OA) phenotype and assess the applicability of the Schoor criteria in an East Asian cohort. We retrospectively reviewed azoospermic patients who presented with low follicle-stimulating hormone level (≤9.2 IU/L) and large testicular volume (≥15 mL), consistent with the "phenotypical OA (phOA)" criteria proposed by Huang et al. All patients underwent a testicular biopsy to confirm the pathological diagnosis. Complete spermatogenesis was considered the key feature of "pathological OA (pOA)." A total of 271 patients with azoospermia were included in the analysis. Among them, 222 (81.9%) exhibited complete spermatogenesis consistent with pOA, whereas 49 (18.1%) were diagnosed with pathological NOA (pNOA). According to the Schoor criteria, 17 patients were classified as phOA; however, two (11.8%) were subsequently confirmed to have pNOA. Conversely, 31 patients were classified as having phNOA, of whom 23 (74.2%) demonstrated pOA on testicular biopsy. Under the Schoor criteria, the positive predictive value (PPV) for pOA was 88.2%, and the negative predictive value (NPV) for pOA was 25.8%. Using the Huang criteria, 49 of 271 patients (18.1%) met the definition of phOA but were diagnosed as pNOA on biopsy (ie, false positives), yielding a PPV of 81.9% for pOA. The Schoor criteria, derived from a Caucasian cohort, may be unsuitable for East Asian patients, given the much lower NPVs for pOA in our cohort (25.8%) than that in the Schoor study (92.3%). These findings highlight the limitations of relying solely on clinical criteria, either Schoor or Huang, to guide sperm retrieval strategies, including the choice of retrieval method and microsurgical approach. Therefore, a testicular biopsy is essential to confirm complete spermatogenesis in patients with clinically phOA.
Geroscience - the interdisciplinary field investigating the causal relationship between the biology of aging and age-related chronic disease - has undergone a remarkable evolution since its formalization within the United States National Institutes of Health in the early 2010s. Grounded in the recognition that aging is the paramount modifiable risk factor for most noncommunicable diseases, geroscience has produced a coherent molecular taxonomy of aging processes (twelve hallmarks), delineated pro-aging and anti-aging molecular pathways (gerogenes, gerosuppressors, and gerozymes), and catalyzed a new clinical vocabulary - geroprotection, gerodiagnostics, and gerotherapeutics. Two institutional milestones anchor the field's translational ambitions: the WHO's codification of Ageing-Associated Decline in Intrinsic Capacity as ICD-11 code MG2A; and the FDA's acceptance of the Targeting Aging with Metformin (TAME) trial - the first prospective clinical trial designed to delay aging as a composite multi-disease outcome, currently underway. The biomarker science of aging has advanced in parallel, from first-generation DNA methylation clocks to organ-specific plasma proteomic signatures capable of predicting various age-related diseases with clinical-grade precision. The gerotherapeutic landscape has expanded substantially. Metformin, which engages more aging hallmarks than any other candidate gerotherapeutic, provided the regulatory impetus for TAME; in a rigorous 40-month multi-omics study in cynomolgus monkeys, it decelerated plasma proteomic biological age by 6.41 years - the strongest pharmacological evidence to date for systemic biological age modification in a primate model. Senolytics and senomorphics target senescent cell burden; SGLT-2 inhibitors represent the first approved class with direct senotherapeutic properties; GLP-1 receptor agonists attenuate inflammaging; NAD⁺ precursors restore mitochondrial and sirtuin function; and the gerozyme (15-PGDH) inhibitor offers a mechanistically distinct pro-regenerative approach with emerging relevance as an adjunct to GLP-1 receptor agonist therapy. Multidomain lifestyle programs address multiple aging hallmarks simultaneously and have demonstrated measurable intrinsic capacity improvement in randomized trials. Building on these foundations, this review proposes the Geroscience-Responsive Aging Care Ecosystem (GRACE) - a three-element service model operationalizing geroscience and gerotherapeutic evidence within the WHO Integrated Care for Older People (ICOPE) framework.
The associations of prenatal maternal depression and exposure to antidepressants and benzodiazepines/Z-drugs with the risks of offspring asthma and atopic dermatitis are unclear. The data of 1,369 child-mother dyads with maternal depression and 13,690 birth year- and sex-matched child-mother dyads without maternal depression for the period from 2002 and 2009 were selected. Prenatal exposure to antidepressants and benzodiazepines/Z-drugs was also considered. All children were followed from their birth date to the end of 2011 to identify the development of asthma and atopic dermatitis. The offspring of mothers with depression were more likely to develop atopic dermatitis (hazard ratio [HR], 1.16) and asthma (HR, 1.12) during the follow-up period relative to the control group. Prenatal exposure to benzodiazepines/Z-drugs was strongly associated with an increased risk (HR, 1.27) of offspring asthma. However, prenatal exposure to antidepressants was not associated with the risks of offspring asthma and atopic dermatitis. The mechanisms underlying the complex relationship between maternal depression, exposure to benzodiazepines/Z-drugs, and the risk of offspring atopy warrant further investigation.
Anaplastic thyroid cancer (ATC) is a highly aggressive malignancy with few effective treatments. Although the KRAS gene has been implicated in the progression of thyroid cancer, its specific mechanism in ATC remains unclear. This study aims to reveal the impact of cancer-associated fibroblasts (CAFs) with KRAS overexpression on the malignant biological behavior of ATC. The single-cell RNA sequencing (scRNA-seq) was used to analyze the KRAS expression profile of fibroblasts (Fibs) in ATC progression, including cell subpopulation identification, KRAS distribution across different cell types, and functional pathway enrichment. Paracancerous tissue fibroblasts (PTFs) and CAFs were co-cultivated with ATC cells, respectively, and were treated with KRAS inhibitor BI-2865. Western blot, colony formation assay, 5-ethynyl-2'-deoxyuridine (EdU) staining, Transwell, and Annexin V-fluorescein isothiocyanate/propidium iodide (FITC/PI) staining were used to analyze the effects of KRAS on the proliferation, migration, and invasion abilities of ATC cells, as well as its influence on downstream signaling pathways. In contrast to papillary thyroid cancer (PTC), the proportion of Fibs significantly increased in ATC, with KRAS observed to be highly expressed in Fibs. Further analysis revealed that Fib_KRAS+, which was highly expressed in ATC samples, did not show expression in PTC samples. In vitro cell experiments confirmed that CAFs with KRAS overexpression enhanced the proliferation, migration, and invasion of ATC cells and activated the downstream signaling pathway rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase (MAPK). In summary, CAFs with KRAS overexpression play a crucial role in the malignant biological characteristics of ATC. Targeting KRAS may be a potential strategy to effectively curb the malignant progression of ATC.
Recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) generally carries a poor prognosis. Although immunotherapies have improved outcomes for patients with high programmed death-ligand 1 (PD-L1) expression, treatment options remain poorly defined for those with low PD-L1 expression or those refractory to the EXTREME regimen (platinum-based chemotherapy plus cetuximab). To address this gap, we retrospectively evaluated the efficacy of the MEMOCLUB regimen (methotrexate, epirubicin, mitomycin-C, Oncovin, cisplatin, leucovorin, 5-fluorouracil, and bleomycin) for the treatment of platinum-refractory R/M HNSCC. This retrospective cohort study, conducted at Taipei Veterans General Hospital, Taiwan, assessed the efficacy and safety of the MEMOCLUB chemotherapy regimen, administered with or without cetuximab, for platinum-refractory R/M HNSCC between 2015 and 2022. The study measured objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) according to the Response Evaluation Criteria in Solid Tumors 1.1 criteria. Statistical analyses were performed using Kaplan-Meier survival curves, log-rank tests, and the Cox proportional hazards model for identifying prognostic factors. A total of 124 patients were enrolled. The median PFS was 2.9 months and OS was 5.3 months. The ORR was 10.5%, with a corresponding disease control rate of 27.4%. In both univariate and multivariate analyses, cetuximab coadministration emerged as a significant prognostic factor for improved OS. Subgroup analysis revealed that cetuximab-naive patients derived the greatest survival benefit from the addition of cetuximab to the MEMOCLUB regimen. Hematological effects were the most common adverse events, with anemia being the most frequent. No cases of grade 3 or higher mucositis were reported. The MEMOCLUB regimen is a feasible salvage therapy in refractory HNSCC, which demonstrates reasonable efficacy and tolerability. The addition of cetuximab significantly prolonged survival in cetuximab-naive patients, suggesting that its coadministration is an advantageous strategy for this specific subgroup of platinum-refractory R/M HNSCC patients.
Although evidence suggests that levator ani muscle (LAM) entheseal pain is a novel etiology of chronic pelvic pain (CPP), its association with lower urinary tract symptoms (LUTS) remains underexplored. This study examined the urodynamic manifestations of LUTS in patients with LAM entheseal pain. In this retrospective cohort, women with chronic pelvic pain (CPP) and LUTS underwent standardized palpation and were divided into three groups: an isolated LAM muscular pain, an isolated LAM entheseal pain, and a combined muscle and entheseal pain group. Between-group differences in symptom prevalence and urodynamic parameters were analyzed. A total of 307 female patients were enrolled. Enthesis-related pain groups exhibited significantly higher prevalences of urinary symptoms, including urinary frequency (muscle pain, n = 81 vs entheseal pain, n = 32 vs combined pain, n = 194: 82.7% vs 87.5% vs 85.1%, p = 0.011), residual urinary sensation (46.9% vs 65.6% vs 63.4%, p < 0.001), and painful bladder symptoms (45.7% vs 59.4% vs 61.9%, p < 0.001). Additionally, these groups demonstrated significantly higher rates of pain-related comorbidities, including bearing-down sensation (33.3% vs 37.5% vs 49.0%, p < 0.001), dysmenorrhea (22.2% vs 25.0% vs 35.1%, p < 0.001), irritable bowel syndrome (29.6% vs 32.4% vs 44.3%, p < 0.001), and systemic myofascial pain (28.4% vs 40.6% vs 52.6%, p < 0.001). However, direct comparison between isolated muscular and entheseal pain groups revealed no significant differences in LUTS or pain comorbidities, whereas combined pain group demonstrated the highest symptom prevalence. Notably, no significant intergroup differences were observed in urodynamic parameters. LAM entheseal pain represents a distinct, clinically palpable entity in CPP. Its urodynamic similarity to myofascial pain suggests that LUTS reflect a shared final pathway of central sensitization rather than peripheral structural dysfunction. Moreover, its unique association with morning stiffness supports a divergent pathophysiology.
Zolpidem is a widely prescribed hypnotic agent; however, its potential cardiovascular safety remains clinically uncertain. This study aimed to investigate the association between zolpidem use and the risk of various cardiac arrhythmias, specifically identifying which subtypes are most prevalent, using a nationwide population-based cohort in Taiwan. This population-based, matched-cohort study utilized the Longitudinal Generation Tracking Database (2000-2015) in Taiwan, comprising two million randomly sampled individuals. To establish a robust new-user design and minimize confounding, we included only those with zolpidem use for at least 7 days and strictly excluded individuals with any history of arrhythmia or heart failure. Users were matched 1:2 with controls by age, sex, and index year. The primary outcome was the incidence of cardiac arrhythmia, defined using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes. Data were analyzed using Cox regression and Kaplan-Meier methods, adjusting for multiple comorbidities including hypertension and diabetes. A total of 457 956 participants (152 652 zolpidem users and 305 304 matched controls) were analyzed. The groups were well-balanced with a mean age of 55.4 years and 49.2% being male. Zolpidem use was associated with a significantly increased risk of cardiac arrhythmia (adjusted hazard ratio [aHR], 1.983; 95% CI, 1.149-2.760; p < 0.001). Subgroup analyses revealed that zolpidem use notably increased the risk of paroxysmal tachycardia (aHR, 2.574; 95% CI, 1.514-3.998; p < 0.001) and atrial flutter (aHR, 2.491; 95% CI, 1.457-4.212, p < 0.001). Zolpidem use is independently associated with an increased risk of incident arrhythmia, particularly tachyarrhythmias such as paroxysmal tachycardia and atrial flutter. Clinicians should incorporate cardiac risk assessment into their prescribing decisions and consider periodic monitoring for high-risk patients. Study limitations include the observational design and the unavailability of granular dosage data.
Extracellular vesicles (EVs) are membrane-bound vesicles released by various cell types and contain biologically active molecules that participate in key physiological and pathological processes. EVs play crucial roles in intercellular communication, immune regulation, tissue repair, and disease progression, particularly in cancer, neurodegenerative disorders, and cardiovascular conditions. Because of their structural stability and ability to evade immune detection, EVs are potential noninvasive biomarkers and therapeutic delivery vehicles. Advances in isolation and purification techniques have further supported their application in precision medicine, with research indicating EVs provide insight into disease mechanisms and therapeutic responses. EVs also facilitate the transfer of nucleic acids, proteins, and lipids between cells, thereby modulating gene expression and cellular activities. Their emerging role as biomarkers for diagnosis and outcome prediction, especially in cancer and neurodegenerative diseases, are areas of active investigation. Despite these promising applications, several challenges hinder clinical translation, including difficulties in distinguishing disease-derived EVs from normal EVs, the absence of standardized therapeutic protocols, the possibility of oncogenic cargo, high production costs, and variability in immune responses. Addressing these challenges by developing improved isolation techniques, standardized evaluation protocols, and cost-effective production strategies and continuing to conduct research is essential to fully realizing the diagnostic and therapeutic potential of EVs in precision medicine.
Benign prostatic hyperplasia (BPH) is a common urological condition affecting middle-aged and elderly men, and it significantly impairs their quality of life. Although metabolic disorders are suspected to contribute to BPH, the causal relationship between metabolic markers and BPH remains unclear due to the limitations of traditional observational studies. In this study, Mendelian randomization (MR) analysis was performed by integrating genome-wide association study (GWAS) data from European populations, integrating metabolites from the GWAS Catalog, BPH-related GWAS data from OpenGWAS, and gene expression data from GEO. Five regression models were employed for two-sample MR analysis, with reverse MR analysis also performed. Sensitivity analysis was carried out through stringent instrumental variable selection criteria, including heterogeneity tests, horizontal pleiotropy tests, and leave-one-out analysis. Additionally, differential gene expression analysis, consensus clustering of BPH subtypes, characteristic gene screening, diagnostic model construction, immune infiltration analysis, and single-gene Gene Set Enrichment Analysis (GSEA) were performed. MR analysis identified several metabolic markers, including total cholesterol, valine, and alanine in HDL, that were significantly associated with BPH, all acting as risk factors. Reverse MR analysis revealed no evidence of reverse causal effects of BPH on most metabolic markers. Additionally, distinct BPH subtypes were identified, along with three key genes (GRAMD2B, HEBP2, and STRADB). A highly accurate diagnostic model was constructed based on these genes. This study elucidates the causal relationship between metabolic markers and BPH, offering new insights into the etiology, diagnosis, and treatment of the disease. However, limitations include the lack of in vitro experimental validation. Future research should address these limitations, further explore the pathogenesis of BPH, and facilitate the development of more effective prevention and treatment strategies.
The role of adjuvant concurrent chemoradiotherapy (CCRT) in stage III gastric cancer remains unclear, particularly after D2 lymphadenectomy. While CCRT may benefit patients with residual disease, its value for patients with R0 resection remains uncertain. Accordingly, this study evaluated the survival effect of adjuvant CCRT in R0 and non-R0 resection groups. We retrospectively reviewed the medical records of patients with stage III gastric adenocarcinoma who underwent gastrectomy with D2 lymphadenectomy between January 2011 and June 2024. Patients were stratified by resection margin (R0 vs non-R0) and receipt of adjuvant therapy. Propensity score matching (PSM) was performed to adjust for baseline imbalances. Overall survival (OS) was analyzed using Kaplan-Meier and Cox regression analyses. A total of 559 patients were included, of whom 483 (86.4%) underwent R0 resection and 76 (13.6%) underwent non-R0 resection. Overall, 78.9% received adjuvant therapy, with CCRT more frequently used in the non-R0 group (28.9% vs 4.6%; p < 0.001). In the non-R0 resection group, both adjuvant chemotherapy and CCRT were associated with significantly improved OS, with CCRT demonstrating additional benefits over chemotherapy ( p = 0.039). After PSM, CCRT was associated with a nonsignificant trend toward improved OS (34.2 vs 28.4 months, hazard ratio: 0.55, 95% confidence interval: 0.26-1.15; p = 0.096) compared with chemotherapy. In matched patients with R0 resection, no survival benefit was observed with CCRT (24.1 vs 36.0 months, hazard ratio: 1.29, 95% confidence interval: 0.56-2.98; p = 0.550). Adjuvant CCRT was associated with a trend toward improved survival in patients with non-R0 resection. However, it was not associated with additional survival benefits compared with chemotherapy in patients undergoing R0 resection after D2 lymphadenectomy, indicating that systemic therapy alone may be sufficient. These findings support the selective use of CCRT and underscore the need for prospective studies to optimize adjuvant strategies.
Intracerebral hemorrhage (ICH) is the second most common stroke worldwide and is associated with high mortality rates. Despite established guidelines for ICH treatment, the prognosis of ICH remains poor. Traditional Chinese Medicine (TCM), including Chinese herbal medicine (CHM) and acupuncture, has been used as complementary therapy; however, its long-term survival benefits remain uncertain. This study aimed to evaluate the effectiveness of TCM, including CHM and acupuncture, in reducing mortality among patients with ICH, using data from Taiwan's National Health Insurance Research Database (NHIRD). This retrospective cohort study analyzed patients with ICH (ICD-9-CM, 430-432; ICD-10-CM, I60-I62) between 2000 and 2018. Patients who received TCM or acupuncture (≥2 outpatient or ≥1 inpatient visits) were matched 1:1 with non-TCM patients based on age, sex, urbanization, and income. Mortality was the primary outcome; analyzed using Cox proportional hazards models. Among 6,450 patients (3,225 TCM; 3,225 control), TCM, including CHM and acupuncture, was significantly associated with reduced all-cause mortality in patients with ICH (adjusted hazard ratio [aHR]=0.42; 95% confidence interval [CI]: 0.39-0.46; p<0.001), with CHM alone showing aHR=0.40 (95%CI: 0.35-0.45; p<0.001) and CHM combined with acupuncture showing aHR=0.43 (95%CI: 0.39-0.47; p<0.001) compared with non-TCM users. Among the top 10 single herbs used, Di-Long (Lumbricus rubellus) exhibited the greatest reduction in mortality risk, with an aHR of 0.36 (95%CI: 0.28-0.47; p<0.001), followed closely by Dan-Shan (Salvia miltiorrhiza), Tian-Ma (Gastrodia elata), Ji-Xue-Teng (Millettia dielsiana), and Gou-Teng (Uncaria rhynchophylla), each with an aHR of 0.37. For formula, Xue‑Fu‑Zhu‑Yu‑Tang and Chai‑Hu‑Jia‑Long‑Gu‑Mu‑Li‑Tang demonstrated the strongest protective associations with mortality (aHR: 0.35; p<0.001), followed by Huang‑Qi‑Wu‑Wu‑Tang and Shao‑Yao‑Gan‑Cao‑Tang (both aHR: 0.35), suggesting consistent survival benefits associated with these core herbal formulas in the management of ICH. Network core pattern analysis identified the key components of treatment, including Bu-Yang-Huan-Wu-Tang, Yuan-Zhi (Polygala tenuifolia), Shi-Chang-Pu (Acorus tatarinowii), Tian-Ma (Gastrodia elata), and Gou-Teng (Uncaria rhynchophylla). Acupuncture exhibited a similar dose-response effect, with mortality risk decreasing progressively with more sessions (aHR: for ≥18 sessions: 0.45; 95%CI: 0.40-0.49; p<0.001). TCM, particularly with longer treatment and more acupuncture sessions, is associated with lower mortality in patients with ICH. Further research is needed to confirm these findings and explore the underlying mechanisms.
Chemoradiotherapy (CRT) remains the standard practice for patients with non-surgical esophageal squamous cell carcinoma (ESCC). However, the impact of radiation duration is poorly understood. We aimed to determine the effect of CRT duration on the prognosis of patients with ESCC. We retrospectively analyzed patients with ESCC treated with CRT at the Ditmanson Medical Foundation Chia-Yi Christian Hospital between January 1, 2010 and December 31, 2021. Patients were either treated with continuous CRT or protracted CRT, which was interrupted due to reassessment of disease status. Differences in survival according to the treatment strategy were examined using propensity score matching (PSM). The risk factors for survival and recurrence were analyzed using Cox regression models. A total of 238 patients who underwent CRT were included in our cohort. After 2:1 PSM, the continuous and protracted CRT groups comprised 41 and 82 patients, respectively. Median survival was 12.2 [interquartile range (IQR), 10.0-19.1] months for the protracted CRT group and 11.4 (IQR, 9.9-17.1) months for the continuous CRT group (p=0.395). The multivariable analysis revealed that duration of radiation > 90 days was an independent risk factor for survival [adjusted hazard ratio (HR), 2.14; 95% confidence interval (CI), 1.23-3.70, p=0.006] and progression-free survival (adjusted HR, 1.74; 95% CI, 1.08-2.80, p=0.022). In addition, a neutrophil-to-lymphocyte ratio > 3 was associated with poor prognosis (adjusted HR, 1.83; 95% CI, 1.09-3.05, p=0.02). This study demonstrated that continuous CRT and protracted CRT resulted in similar prognoses; however, a radiotherapy duration exceeding 90 days was associated with inferior survival. These findings have implications for treatment planning in patients with ESCC.
Anesthesia induction involves rapid autonomic shifts that may compromise hemodynamic stability. Propofol administered via target-controlled infusion (TCI) produces a more gradual onset, whereas rapid manual bolus (MB) administration often triggers abrupt autonomic disturbances. Thus, the propofol delivery method is critical to autonomic stability; however, conventional monitoring lacks sufficient temporal resolution to capture transient fluctuations during early induction. To address this gap, we compared TCI and MB using high-temporal-resolution wavelet-based spectral analysis (WBSA) of heart rate variability (HRV) and pulse photoplethysmography amplitude (PPGA) to characterize real-time autonomic dynamics. This prospective, single-center observational study included adult patients undergoing elective surgery who received propofol induction via TCI or MB administered over 10 seconds. HRV and PPGA were continuously recorded and analyzed using WBSA. High-frequency power and low-to-high frequency ratio assessed parasympathetic tone and sympathovagal balance, while PPGA served as a surrogate for peripheral sympathetic tone. Simulated effect-site concentrations (CeP) were calculated to examine relationships between concentration dynamics and autonomic responses. Forty-four patients were analyzed. Compared with MB, TCI produced significantly more gradual and attenuated changes in high-frequency, low-frequency, and low-to-high frequency ratio (all p < 0.05), along with slower and smaller increases in PPGA, indicating better preservation of autonomic balance and milder peripheral sympatholysis. Simulated CeP reached 5.5 μg·mL - 1 at 117 seconds with TCI vs 36 seconds with MB. Greater transient autonomic disturbance was associated with a faster rise in CeP, rather than absolute CeP values, indicating that delivery mode and rate were primary determinants of autonomic modulation. TCI provided smoother autonomic modulation than did MB during the physiologically unstable induction phase. By enabling real-time detection of short-lived fluctuations, WBSA revealed mechanistic differences not captured by conventional analyses, supporting TCI as a potentially more stable and physiologically balanced induction strategy, particularly for patients at risk of peri-induction instability.
Tinnitus is defined as the perception of sound without an external stimulus. It is classified as a subjective phenomenon described as ringing, buzzing, or hissing in the ears. Tinnitus often co-occurs with migraine, as both conditions originate from disturbances of the central nervous system, specifically the auditory and trigeminal nerve pathways. The overlap in populations and pathophysiological similarities between tinnitus and migraine provide strong evidence for overlap between the conditions and a shared potential for therapy. Calcitonin gene-related peptide (CGRP) medications are a recent development in migraine treatment that have proven to be effective prophylactic agents. CGRP medications work by blocking CGRP's inflammatory role in migraine formation, a physiological process that may also be involved in the loudness of tinnitus. This narrative review aims to provide an overview of the role of CGRP in migraine and tinnitus and discuss managing CGRP and central sensitization as a potential therapeutic role in tinnitus.
Dysembryoplastic neuroepithelial tumor (DNET) and low-grade astrocytoma (LGA) could present very similar magnetic resonance imaging (MRI) findings. DNET has good seizure control after surgical removal and low malignant potential, while LGA may recur or progress. This study was designed to obtain a more accurate pretreatment diagnosis of DNET and LGA based on MRI findings. We retrospectively enrolled patients with pathologically proven DNET and LGA from 2000 to 2024. Individual qualitative and quantitative MRI features were evaluated in both tumors, especially the T2-weighted signal intensity ratio (T2SR), which compared tumor T2-weighted signal with that of normal cerebral white matter. The diagnostic performance of conventional qualitative models, including meaningful qualitative MRI features and combined quantitative model, including T2SR and apparent diffusion coefficient (ADC) values, was evaluated using area under the curve (AUC). In total, 70 patients (30 DNET, 40 LGA) were included, with a mean age of 23.2 ± 11.3 (15-57) years, including 36 men (51.4%), 34 women (48.6%). For individual MRI features, DNET had more FLAIR (fluid attenuated inversion recovery) ring sign (16 [53.3%] vs 12 [30.0%], p = 0.049), higher ADC value (2076.2 [53.4] vs 1660.1 [71.9], p < 0.001), and higher T2SR (3.56 ± 0.12 vs 2.68 ± 0.63, p < 0.001). The AUC of the T2SR and ADC value was 0.886 (0.811-0.962) and 0.824 (0.724-0.924), respectively. The combined quantitative model had higher discriminative performance than the conventional qualitative model (AUC: 0.905 vs 0.727, p = 0.011). Our study suggested that quantitative MRI features, including T2SR and ADC values, enhanced the discrimination between DNET and LGA and could potentially serve as a complementary imaging marker for improving preoperative diagnostic accuracy.
Data on the risk of morbidity and mortality following conversion arthroplasty for fixation failure of femoral neck fractures (FNFs) or intertrochanteric fractures (ITFs) remains limited. This study compares medical outcomes between: (1) initial fixation and conversion arthroplasty for failed FNFs and ITFs, and (2) conversion arthroplasty for failed FNFs vs failed ITFs. A retrospective review of an institutional database at Taipei Veterans General Hospital identified patients who underwent conversion arthroplasty for failed internal fixation of FNFs or ITFs from January 2010 to December 2022. Primary outcomes included frequencies of in-hospital complications, 90-day readmissions following initial fixation and conversion arthroplasty, and 90-day and 1-year mortality after conversion arthroplasty. To compare outcomes for conversion arthroplasty between failed FNFs and ITFs, cohorts were matched by age, body mass index, and age-adjusted Charlson Comorbidity Index. A total of 70 patients with failed FNFs and 66 patients with failed ITFs were included. The in-hospital complication frequency was higher following conversion arthroplasty (FNF: 44.3% vs 17.1%, p < 0.001; ITF: 54.5% vs 31.8%, p = 0.008) compared with initial fixation. Although conversion arthroplasty for failed ITFs involved a longer procedure time (125.5 ± 46.2 vs 86.8 ± 31.1 minutes, p < 0.001), greater estimated blood loss (1088.1 ± 603.8 vs 513.1 ± 287.7 mL, p < 0.001), and higher transfusion rate (81.0% vs 31.7%, p < 0.001) and volume (2.6 ± 2.0 vs 0.8 ± 1.2 units, p < 0.001) compared with failed FNFs, the in-hospital complication, readmission, and mortality rates were similar between the two groups. Conversion arthroplasty for failed FNFs and ITFs was associated with worse medical outcomes, including a higher rate of in-hospital complications, compared with initial fixation. Despite greater surgical complexity associated with conversion arthroplasty for failed ITFs compared with failed FNFs, the in-hospital complication, readmission, and mortality rates were similar.
Anemia is a common complication in patients with chronic kidney disease (CKD), for which recombinant human erythropoietin (rhEPO) is the standard treatment. UB-851 is a biosimilar rhEPO developed as an alternative to epoetin alfa (Eprex ® ). This study evaluated the clinical equivalence, safety, and immunogenicity of UB-851 compared with epoetin alfa in patients with anemia due to CKD receiving hemodialysis. In this 52-week, multicenter, randomized, parallel-group, phase III trial, patients with anemic CKD undergoing maintenance hemodialysis were assigned to receive either UB-851 or epoetin alfa. Part I (weeks 1-24) included dose titration and hemoglobin (Hb) maintenance. Part II (weeks 25-52) focused on long-term safety and immunogenicity. The primary endpoint was the change in Hb levels from baseline to the efficacy evaluation period (weeks 21-24). The secondary endpoints included epoetin dose, adverse events (AEs), and anti-drug antibody formation. A total of 201 participants were randomized, and the mean change in Hb levels during the efficacy period was within the predefined equivalence margin (±0.6 g/dL) in both the intention-to-treat and per-protocol populations. Differences in weekly epoetin dose changes between the groups also fell within the predefined equivalence range (±45 IU/kg/wk). No significant differences were observed in the laboratory parameters, electrocardiograms, or vital signs. No anti-epoetin antibodies were detected in the UB-851 group. Regarding AEs, the UB-851 appears to be biosimilar to epoetin alfa. UB-851 demonstrated clinical equivalence with epoetin alfa in maintaining Hb levels in patients with anemic CKD undergoing hemodialysis. The safety and immunogenicity profiles were comparable, supporting UB-851 as a biosimilar to epoetin alfa.
Infertility constitutes a dyadic stressor, as it inherently involves both members of a couple; nevertheless, its psychological impact is frequently evaluated from an individual perspective. We tested whether etiologic diagnosis (male and female factors) is associated with both partners' quality of life (QoL) during assisted reproductive technology (ART). We conducted a retrospective cross-sectional study at the assisted reproduction center of a tertiary university hospital in southern Taiwan, enrolling married heterosexual couples undergoing ART who completed the Fertility Quality of Life questionnaire during treatment. Using a distinguishable-dyads actor-partner interdependence model (APIM), we estimated actor effects (one's diagnosis on one's QoL) and partner effects (one's diagnosis on the partner's QoL) in all domains. Sensitivity analyses of the APIM adjusted for age, body mass index, infertility duration, and prior embryo-transfer attempts. A total of 105 couples were eligible to be enrolled. Men reported higher QoL than women across domains (p < 0.01). The APIM showed a significant, asymmetric partner effect: female-factor infertility was associated with lower Mind-Body (β = -17.54, p = 0.017) and Core (β = -10.15, p = 0.045) scores in male partners. No partner effect of male-factor infertility on women's QoL was detected, and actor effects were not significant for either partner. Adjusted models yielded directionally consistent results. Infertility etiology relates to the couple's well-being in an asymmetric pattern. Female-factor infertility is linked to poorer QoL in male partners, consistent with distress from witnessing treatment and sociocultural expectations, underscoring the need for dyadic, couple-centered support during ART. Limitations include the cross-sectional design and potential selection bias arising from a high exclusion rate of incomplete dyads, which restricts generalizability.
Endometriosis is a chronic estrogen-dependent inflammatory disorder associated with pelvic pain, infertility, and an increased risk of endometriosis-associated ovarian cancer. Despite extensive research, its molecular mechanisms remain incompletely understood. This study aimed to identify dysregulated biological functions and potential molecular signatures in the eutopic endometrium of women with endometriosis using an integrative functionome-based approach. An integrative gene ontology-driven functionome analysis was conducted using publicly available transcriptomic datasets. A modified Differential Rank Conservation algorithm was applied to reconstruct sample-specific Gene Set Regularity (GSR) indices across 10,192 Gene Ontology (GO)-defined gene sets. Statistical analyses, exploratory factor analysis, and support vector machine (SVM)-based machine learning were used to identify dysregulated functionomes, dysfunctional pathways, and key differentially expressed genes (DEGs). The analysis included 196 patients with endometriosis and 246 healthy controls. Functionome profiling revealed widespread dysregulation of immune, metabolic, angiogenic, and extracellular matrix-related pathways. Among the top 50 dysregulated functionomes, eight were related to copper ion transport and homeostasis. Integrative analysis identified a recurrent four-gene copper-regulatory signature consisting of ATP7A, ATP7B, ATOX1, and SLC31A1 (p <0.05), suggesting coordinated disruption of copper homeostasis in endometriosis. Dysregulation of copper ion homeostasis and cuproptosis-related pathways may represent a previously underappreciated molecular feature of endometriosis. Although causal relationships cannot be established from this comparative analysis, the identified copper-regulatory signature provides a reproducible transcriptomic framework for future mechanistic and translational studies.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by pathogenic NOTCH3 variants, most commonly heterozygous cysteine-altering variants. Disease severity varies widely, and the impact of reduced NOTCH3 dosage on CADASIL severity remains unclear. We describe a family of four individuals carrying a cysteine-altering NOTCH3 variant and/or a frameshift loss-of-function (LoF) variant, demonstrating marked intrafamilial phenotypic heterogeneity. Four related individuals underwent standardized clinical assessment, brain MRI, genetic analysis, skin biopsy, and NOTCH3 complementary DNA (cDNA) sequencing. The proband, carrying p.Cys1146Ser and p.Cys1024Valfs248 in trans, developed progressive gait disturbance, dysphagia, and slurred speech beginning in his mid-thirties. Brain MRI demonstrated extensive white matter hyperintensities, multiple lacunar infarcts, and numerous cerebral microbleeds. In contrast, the father (carrying p.Cys1146Ser alone) and the mother and brother (carrying p.Cys1024Valfs248 alone) exhibited milder clinical and imaging phenotypes. Only the carriers of the cysteine-altering variant demonstrated NOTCH3 extracellular domain (NOTCH3 ECD) immunoreactivity in skin vessels. NOTCH3 cDNA sequencing from the skin tissue demonstrated reduced LoF allele expression. Reduced NOTCH3 dosage may modify the disease severity of CADASIL.