Large language model (LLM)-powered Virtual Standardized Patients (VSPs) offer scalable practice opportunities for clinical interviewing, but their added value within established human Standardized Patient (SP) curricula remains unclear. This study examined how self-directed VSP engagement relates to interview performance on traditional SP assessments through the lens of self-regulated learning theory. We analyzed VSP usage logs and SP assessment data from fourth-year medical students (n = 92) enrolled in a 7-week diagnostics course with weekly human SP sessions and optional VSP access. Engagement was measured by valid sessions and total question-answer (QA) pairs. The primary outcome was the composite SP interview score (0-100). Associations were evaluated using correlation and regression analyses. Students generated 359 valid dialogues comprising 19,380 QA pairs (hallucination rate 0.34%). Median engagement was 2 sessions (IQR 1-7) and 132 QA pairs (IQR 38-323). Session frequency correlated modestly with SP scores (ρ = 0.25, p=.016); each additional session predicted a 0.15-point increase (R2=0.070). Students with ≥7 sessions outperformed those with fewer (94.1 ± 2.0 vs 92.5 ± 2.4, p=.013). QA volume showed a stronger association (ρ = 0.28, p=.006), explaining 10.6% of variance. The high-QA group (≥132) scored higher than the low-QA group (93.3 ± 2.3 vs 92.3 ± 2.3, p=.030). Voluntary VSP use within a human SP curriculum was associated with small but measurable differences in interview performance. Findings align with self-regulated learning and deliberate practice frameworks-students who independently sought repeated, feedback-rich practice tended to achieve higher scores. These observational data do not establish causality. VSPs may serve as scalable cognitive scaffolds for self-directed skill refinement, though their benefits likely vary with learner motivation and baseline ability.
The lack of healthcare trust is strongly associated with low rates of access and utilization of care, adherence to medical advice, and adverse health outcomes, especially among vulnerable populations. We used a descriptive qualitative design and employed thematic analysis to examine the contributing factors to the lack of trust in healthcare among African immigrants in Florida, US. We conducted in-depth interviews with 19 participants selected through purposive and snowball sampling. The interviews were audio-recorded, transcribed verbatim, and thematically analysed using Nvivo14 software. The findings revealed two overarching themes: (a) personal and (b) institutional factors of lack of healthcare trust. Personal factors included language and communication challenges, lack of knowledge, past negative healthcare experiences, fear of losing legal status, and the use of traditional medicine and prayer as a substitute for modern medicine. Institutional factors included providers' lack of knowledge, wrong assumptions and ignorance, lack of diversity in healthcare, repeated tests and burdensome documentation, malpractice, lack of financial transparency and unfair cost, over-medicalisation, racial divide and discrimination, and unfavourable policy conditions. The findings suggest a holistic approach that involves improving healthcare navigation skills among African immigrants; adopting a patient-centred approach; enhancing health literacy; strengthening cultural competency training and education on tropical medicine for healthcare providers; promoting diversity within the healthcare workforce; and engaging in anti-racism practices that ensure provider accountability. It is also critical to promote policies that ensure financial transparency and coordinated care, reduce unnecessary testing and documentation, and promote safe and equitable access to healthcare for African immigrants.
To systematically evaluate the accuracy, reliability, and clinical applicability of artificial intelligence and large language models (LLMs) in pediatric orthopedics, comparing their performance against established clinical guidelines and assessing their utility for patient education and clinical decision support. A search of PubMed and ScienceDirect (2020-2025) identified 2624 articles using the keywords 'ChatGPT', 'Gemini', 'Claude' and 'orthopedic pediatrics'. After screening and refinement using Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, 15 studies met inclusion criteria. Studies evaluated ChatGPT, Google Gemini, Meta AI, Microsoft Copilot, and Claude across multiple pediatric orthopedic conditions across conditions like developmental dysplasia of the hip, slipped capital femoral epiphysis, and scoliosis. Heterogeneity was assessed using Cochran's Q and I2 statistics, and publication bias was evaluated using funnel plots and Egger's test. LLM accuracy ranged from 44.3 to 93% (pooled: 74.1%), with pooled accuracy of 74.1%. Reproducibility was moderate, with ChatGPT demonstrating a Spearman coefficient of 0.55 for complex queries. Regional expert consensus scores varied significantly (Europe: 80, North America: 65; P = 0.034; Fleiss\kappa = 0.113). Up to 33% of responses to guideline-based questions were rated neutral or inaccurate. Reading complexity was elevated (Flesch-Kincaid grade: 12.7), exceeding the recommended sixth-grade level. Parent surveys indicated 82% trust in artificial intelligence as supplementary tools with professional oversight. Minimal statistical heterogeneity was observed (I2 = 0.00%), though publication bias was detected (Egger's test P = 0.0001). LLMs show potential for education and triage but lack consistency in complex scenarios, elevated reading complexity, and significant regional variability in expert assessments. These tools should be used as educational supplements under professional medical supervision rather than for independent clinical decision-making. Broader clinical application requires domain-specific tuning, standardized evaluation, and readability optimization. Level V- systematic review.
Chronic skin ulcers remain a significant therapeutic challenge, particularly in patients with underlying medical conditions, and often prove difficult to treat with conventional methods. Platelet-rich plasma (PRP), an autologous preparation rich in growth factors, has garnered attention as a promising treatment option; however, its clinical efficacy remains inconsistent. In this study, we retrospectively evaluated 12 patients with refractory skin ulcers who received PRP therapy between 2018 and 2023. PRP was prepared from the patients' own blood and administered once weekly for 4 weeks; treatment efficacy was assessed based on the rate of reduction in ulcer area. Clinical outcomes varied depending on the etiology of the ulcer. Marked improvement was observed in patients with livedoid vasculopathy and burn-related ulcers, whereas moderate to marked improvement was seen in diabetic ulcers only when peripheral blood flow was preserved. In contrast, the response was minimal or absent in ulcers associated with pressure ulcers or peripheral arterial disease. Importantly, no adverse events were observed during treatment. These findings suggest that PRP therapy is a safe and potentially effective option for refractory skin ulcers, particularly in non-ischemic conditions. However, its efficacy appears to be limited in wounds involving ischemia or mechanical injury, highlighting the importance of appropriate patient selection and wound condition optimization. Further studies using standardized protocols are necessary to clarify its clinical indications.
Pretibial injuries manifest as lacerations or haematomas. Despite differences in pathogenesis and treatment, these entities have been mixed together in previous classifications. No classification for pretibial haematomas exists, and the Modified Dunkin Classification includes a Type V category that conflates lacerations with haematomas. To present the Sinuhe Classification-a comprehensive system categorising pretibial lacerations and haematomas with evidence-based treatment recommendations-and propose the umbrella term 'dermatoporotic wounds' to encompass the full spectrum of cutaneous injuries arising from chronic skin fragility. A narrative literature review of PubMed, MEDLINE and EMBASE was conducted. Treatment recommendations and clinical findings were synthesised from the available literature, including a doctoral thesis on pretibial injuries. The Sinuhe Classification categorises pretibial lacerations into linear lacerations; flap lacerations (vital, i.e., with adequate perfusion and non-vital, i.e., with flap necrosis); and total skin loss. Pretibial haematomas are classified into open (ruptured), closed and necrotic haematomas. Each subtype is paired with specific treatment guidance. The classification eliminates the Modified Dunkin Type V category and provides a classification framework for pretibial haematomas. The Sinuhe Classification offers a unified yet distinct framework for diagnosing and treating pretibial injuries. Adoption into clinical practice and medical education is recommended.
Orthostatic myoclonus is characterized by irregular, lower limb myoclonic bursts during stance and is a major cause of postural instability and falls. However, studies are limited, and little is known about its pathophysiology. We sought to define the clinical and electrophysiological features of orthostatic myoclonus in a large, single-center cohort. We included 42 participants (24 males, 18 females) with a mean age of 74 years (range, 46-93) from Westmead Hospital presenting with orthostatic myoclonus from 2007 to 2023. Medical records were retrospectively reviewed for demographic details, symptoms, co-morbidities, and treatment. Lower limb surface electromyography (EMG) was analyzed using a custom-designed algorithm to automatically identify myoclonic bursts and measure their duration, synchronicity, and rhythmicity. Differences in burst parameters between muscles and associations between burst parameters and clinical characteristics were statistically evaluated. Mean burst durations during standing were 77 to 90 ms across lower limb muscles. Maximum burst activity and bilateral synchronicity occurred in tibialis anterior. Only 12% of participants exhibited any rhythmicity. A total of 79% of participants had a coexistent neurological disorder including 26% with parkinsonism. There was no significant association between parkinsonism and burst parameters. However, there was a significant, inverse correlation between the presence of neuropathy or radiculopathy and synchronous activity (P = 0.02). We provide a computationally robust clinical and electrophysiological analysis of orthostatic myoclonus in a large cohort. Our findings support the theory of a subcortical generator arising from protean secondary causes and subject to peripheral modulation. Further work is needed to clarify treatment outcomes.
To evaluate the efficacy and safety of adjunctive perampanel (PER) in young children with drug-resistant epilepsy (DRE) aged 7-46 months, and to identify predictors of treatment response in real-world clinical practice. We conducted a nonrandomized, open-label, single-arm, self-controlled real-world study at the Children's Hospital of Chongqing Medical University between December 2020 and August 2024. Eighty-seven children with DRE received PER as adjunctive therapy to existing antiseizure medications (ASMs). The primary endpoint was the responder rate (≥ 50% reduction in seizure frequency) at 3, 6, 9, and 12 months. Secondary endpoints included seizure freedom, treatment retention, and treatment-emergent adverse events (TEAEs). Responder rates were 39.5%, 46.9%, 43.2%, and 44.4% at 3, 6, 9, and 12 months, respectively. Responder rates were 50.0% in Dravet syndrome, 50.0% in Lennox-Gastaut syndrome, and 34.8% in infantile epileptic spasms syndrome. Children with genetic etiologies had a 51.7% responder rate, including 60.0% in those with SCN1A variants. Multivariable logistic regression identified perinatal brain injury as an independent predictor of favorable response, while concomitant use of three ASMs predicted poorer outcomes. Treatment retention rates were 87.4%, 69.0%, 59.8%, and 55.2% at 3, 6, 9, and 12 months. TEAEs occurred in 23.0% of patients, most commonly somnolence (11.5%) and irritability/aggressive behavior (9.2%); 4.6% discontinued due to TEAEs. Adjunctive PER demonstrated clinically meaningful efficacy and a favorable safety profile in young children with DRE, supporting its potential role as a broad-spectrum ASM in this age group.
The amyloid cascade hypothesis provided a compelling rationale for Alzheimer's disease (AD) drug development, but many amyloid-β (Aβ)-targeted agents failed to show benefit. The present review article evaluated emerging Aβ-directed therapies, focusing on mechanisms, clinical efficacy, safety, and regulatory progress. The recent approvals of lecanemab and donanemab offered the first convincing evidence that reducing Aβ burden can modestly slow cognitive decline in early AD. Beyond these first-generation monoclonal antibodies, the pipeline includes next-generation antibodies with enhanced brain penetration (trontinemab), therapies designed also for presymptomatic intervention (remternetug tested for secondary prevention), and novel approaches targeting galectin-3 to disrupt Aβ aggregation and neuroinflammation. Active immunotherapies like UB-311 and small molecules such as ALZ-801, avoiding amyloid-related imaging abnormalities (ARIA), broaden the therapeutic horizon with potentially safer and more accessible options, but with no proven efficacy. Clinical benefits for Aβ-centric therapies are modest, ARIA pose ongoing safety concerns, and high costs coupled with intensive monitoring limit accessibility. Regulators have begun to restrict approval to genetically defined subgroups according to apolipoprotein E genotype, underscoring the need for precision medicine. Therefore, while Aβ-centric therapies are incremental, they represent essential steps toward combination and precision strategies in the treatment of AD. Alzheimer’s disease (AD) is a growing global health problem, with no cure currently available. Most existing treatments only relieve symptoms and do not slow the underlying disease process. One of the earliest and most important biological changes in AD is the buildup of amyloid-β (Aβ), a protein that forms plaques in the brain. For this reason, many new drugs have been designed to remove Aβ or prevent it from accumulating. In recent years, several Aβ–targeting therapies have shown that they can successfully reduce amyloid plaques in the brain. These include monoclonal antibodies given by infusion or injection, vaccines that stimulate the immune system, and oral drugs designed to block the formation of toxic Aβ species. Some of these treatments have reached late-stage clinical trials, and a few have received regulatory approval in certain regions. However, while these drugs clearly reduce amyloid levels, their effects on memory and daily functioning are modest, especially when used after symptoms have already appeared. In addition, treatment can be associated with side effects such as brain swelling or small brain bleeds, requiring frequent medical monitoring, costly for healthcare systems. Most evidence so far comes from carefully controlled randomized clinical trials, and real-world experience remains limited. Current research is therefore shifting toward earlier treatment, including prevention in people at high risk, improved drug delivery methods, and combination approaches that also target other disease processes such as tau pathology, inflammation, and vascular or metabolic changes. New blood-based biomarkers are also making it easier to diagnose AD earlier and to select patients more precisely. Overall, Aβ–centered therapies represent an important scientific advance, but they are unlikely to be sufficient on their own. Future progress in AD treatment will depend on better understanding how amyloid may interact with other brain changes, identifying the right patients at the right time, and developing safer, more affordable, and more comprehensive therapeutic strategies.
The psychological impact of stillbirth on parents is profound, increasing the need for respectful care. Despite the existence of international guidelines, there has been no clinical confirmation of their efficacy in improving parental mental health outcomes. This study is a web-based cross-sectional study and part of the OPALE (Observatory on PerinatAL hEalth) project. Participants were selected if they suffered a pregnancy loss after 20 weeks (including termination of pregnancy for medical reasons) in the last 10 years. The survey includes: the CiaoLapo Stillbirth Support (CLASS) checklist, the Perinatal Grief Scale (PGS), the National Stressful Events Survey PTSD Short Scale (NSESSS), and questions on satisfaction with care. 261 participants completed the survey. In a multivariate analysis, higher CLASS scores were correlated with lower PGS and NSESSS scores, suggesting a direct relationship between guideline adherence and better psychological outcomes. Specifically, satisfying over 40 of the 60 checklist items independently predicted greater care satisfaction (OR 2.0, CI 1.1-3.8), higher experiences of respectful care (OR 3.6, CI 1.9-7.0), lower grief (OR 0.08, CI 0.1-0.2), and reduced PTSD symptoms (OR 0.21, CI 0.1-0.5). This is the first study which identifies a correlation between adherence to stillbirth care guidelines and better psychological outcomes, indicating their importance in enhancing parents' mental health.
Apelin-13 and Galectin-3 (Gal-3) are bioactive mediators linked to inflammation and cardiometabolic pathways. Their clinical utility in COVID-19 alongside routine laboratory tests remains unclear. In this case-control study, 89 adults were enrolled (COVID-19 negative controls, n = 44; COVID-19 positive patients confirmed by PCR and/or CT, n = 45). Serum Apelin-13 and Gal-3 were measured by ELISA, and routine biochemical parameters were obtained using automated analyzers. Group comparisons and correlation analyses were performed, and receiver operating characteristic (ROC) analysis assessed discriminatory performance. Compared with controls, the COVID-19 group showed higher ALT (p = 0.046), GGT (p = 0.004), ALP (p = 0.001), total bilirubin (p = 0.008), direct bilirubin (p = 0.001), urea (p = 0.001), creatinine (p = 0.001), glucose (p = 0.001), and CRP (p = 0.001), and lower eGFR (p = 0.001), albumin (p = 0.010), and total cholesterol (p = 0.021). In controls, Apelin-13 correlated negatively with urea (r = -0.333, p = 0.027) and Gal-3 correlated negatively with cholesterol (r = -0.342, p = 0.023). In COVID-19 patients, Apelin-13 correlated positively with glucose (r = 0.320, p = 0.032) and negatively with sodium (r = -0.323, p = 0.030). ROC analysis showed limited diagnostic value for Gal-3 (AUC = 0.549; p = 0.426) and Apelin-13 (AUC = 0.533; p = 0.594). Apelin-13 and Gal-3 showed limited associations with selected biochemical alterations in COVID-19, but neither biomarker demonstrated adequate standalone discriminatory performance.
Osteoporosis is characterized by excessive bone resorption driven by aberrant osteoclast activation. Solasodine (SOL), a natural steroidal alkaloid, has undefined roles in bone metabolism. This study investigated SOL's effects on RANKL-induced osteoclastogenesis and its underlying mechanisms. Pharmacological targets predicted via network pharmacology and validated by molecular docking identified 81 overlapping targets, which were primarily enriched in MAPK, NF-κB, and JAK-STAT pathways, confirming robust affinity between SOL and core targets including NFκB1, JAK1/2, and STAT3. In vitro, bone marrow-derived macrophages (BMMs) were stimulated with M-CSF and RANKL. Evaluation via TRAcP staining, F-actin immunofluorescence, and hydroxyapatite assays showed that SOL dose-dependently inhibited RANKL-induced osteoclast formation, fusion, and resorptive activity without cytotoxicity. Mechanistic investigations through RT-qPCR, Western blotting, luciferase assays, ROS detection, and live-cell calcium monitoring revealed that SOL suppressed key markers, including NFATc1, c-Fos, CTSK, Atp6v0d2, and Integrin β3. Specifically, SOL attenuated MAPK (p38, JNK, ERK) and STAT3 phosphorylation, inhibited NF-κB activity, and prevented IκB-α degradation. Furthermore, SOL curtailed RANKL-induced ROS generation, intracellular calcium oscillations, and subsequent CaMKIV activation. Ultimately, SOL inhibits RANKL-induced osteoclastogenesis and bone resorption by suppressing the NFATc1/c-Fos axis through coordinated modulation of the MAPK, NF-κB, and JAK-STAT pathways, alongside mitigation of ROS production and calcium signalling, representing a promising natural candidate for treating osteolytic bone diseases.
1. Radix Bupleuri (RB)-induced hepatotoxicity and herb-drug interactions have raised clinical concerns, yet the role of its intestinal metabolites, saikogenins (SGs), in modulating human UDP-glucuronosyltransferase (UGT) activity remains poorly understood.2. Using 11 recombinant human UGT isoforms and 4-methylumbelliferone as the probe substrate, we demonstrate that the parent saikosaponins (SSA, SSC, SSD) produced no potent, isoform-selective inhibition of any of the tested UGT isoforms at 100 μM, whereas the deglycosylated aglycones SGA and SGD selectively and potently inhibited UGT2B7 and UGT2B15 (IC50: 0.24-1.88 μM; Ki: 0.14-1.34 μM) through competitive mechanisms.3. Molecular docking revealed that deglycosylation removes steric hindrance from the sugar moiety, enabling the aglycone backbone to penetrate the catalytic pocket, where the most potent metabolite SGD anchored the conserved catalytic histidine of UGT2B7 (HIS481); inhibition of UGT2B15 instead arose from deep occupancy of the hydrophobic pocket.4. In vitro-in vivo extrapolation yielded an R-value of 1.36 for SGD-UGT2B7, exceeding the regulatory threshold (R ≥ 1.1), indicating a clinically significant risk when RB preparations are co-administered with narrow-therapeutic-index UGT2B7 substrates such as morphine or zidovudine.
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may affect cognition, but its association with incident dementia remains inconsistent. We explored the association of SARS-CoV-2 infection and its vaccination with dementia risk in a nationwide sample of middle-aged and older adults. This nested case-control study used electronic healthcare data from Israel's largest health provider. Participants were dementia-free individuals aged ≥ 50 years at baseline (March 2020), followed up until May 2022. Incident dementia cases were matched to dementia-free controls using density sampling by age, sex, and date of entry to the study, with a ratio of 1:10. SARS-CoV-2 was defined by positive polymerase chain reaction (PCR) or institutional antigen tests. Multivariable conditional logistic regression models evaluated the association of SARS-CoV-2, its severity and vaccination, and pneumonia as a comparator, with dementia risk. Among the 1,145,322 eligible participants, 27,280 dementia cases were matched to 272,800 controls. SARS-CoV-2 infection was associated with increased dementia risk (OR = 1.18; 95% CI 1.12-1.24; p < 0.001). This association was confined to hospitalized individuals with mild (OR = 2.39; 95% CI 2.07-2.76) and moderate-to-severe disease (OR = 1.93; 95% CI 1.70-2.20), was comparable to pneumonia (OR = 1.89; 95% CI 1.80-1.99), and was no longer evident after 6 months (OR = 1.04; 95% CI 0.96-1.12). COVID-19 vaccination was associated with 7%, 15%, and 31% lower dementia risk after two, three, and four doses, respectively. Unvaccinated individuals with prior COVID-19 had the highest dementia risk. Dementia diagnoses are increased after COVID-19, especially in hospitalized patients. Risk is comparable to other respiratory infections.
Tumour budding (TB) has been recognized as an additional prognostic factor in the TNM (2017) and WHO (2019) classification systems. However, its prognostic impact in stages II and III colorectal cancer (CRC) remains inconsistently defined. This study aims to systematically evaluate the prognostic value of high-grade TB in stage II-III CRC. A systematic search of PubMed, Embase and Cochrane Library was conducted to identify studies reporting the association between high-grade TB and survival outcomes in stage II-III CRC. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free survival (DFS), overall survival (OS) and cancer-specific survival (CSS) were calculated using random-effects models. A total of 43 studies involving 17,831 patients were included. Univariable analysis showed that high-grade TB was significantly associated with worse DFS (HR 2.53, 95% CI 2.14-3.00), OS (HR 2.40, 95% CI 1.69-3.42) and CSS (HR 3.37, 95% CI 2.19-5.19). Multivariable analysis confirmed the independent prognostic value of high-grade TB for all three outcomes. Subgroup analysis stratified by TNM stage revealed that high-grade TB consistently predicted adverse outcomes in both stage II and stage III disease. This study confirms that high-grade TB is an independent prognostic factor in stage II-III CRC, consistently associated with worse DFS, OS and CSS. Incorporating TB into routine histopathological assessment may improve risk stratification and help identify high-risk patients, although its role in guiding therapeutic decisions requires further prospective validation.
Social determinants of health influence maternal and perinatal outcomes, yet tools to operationalize these risks in clinical care remain scarce. We aimed to study social determinants in Brazilian pregnant women and develop a social vulnerability index (SVI) that could correlate with pregnancy and perinatal outcomes. The present study was a secondary analysis of 1565 low-risk nulliparous women enrolled in two Brazilian cohort studies. We selected vulnerability indicators from sociodemographic data and tested the performance and risk association of multiple SVI models with any adverse outcome (preterm birth, gestational diabetes mellitus, pre-eclampsia, small or large for gestational age, low 5-min Apgar score, neonatal intubation, neonatal intensive care unit admission, fetal or neonatal death) using chi-square tests, logistic regression, and receiver operating characteristic analysis. Advanced maternal age, non-white ethnicity, and exclusive publicly funded antenatal care were the most consistent vulnerability predictors of adverse outcomes. The final three-variable SVI demonstrated a significant dose-response gradient, with maternal adverse outcomes increasing from 16.4% (no vulnerabilities) to 43.8% (3 vulnerabilities) and perinatal adverse outcomes rising from 22.1% to 35.6%. The model presented a sensitivity of 64.71%, a specificity of 42.56%, a positive predictive value of 47.46% and a negative predictive value of 60.07% for any adverse outcome. The three-variable SVI offers a simple, reproducible, and context-adapted screening tool for primary care. Either for individual or population screening, it can be easily combined with clinical risk assessment, targeting those who may benefit from equity-oriented maternal health strategies.
Liver metastasis is a key adverse prognostic factor in breast cancer patients. This research was aimed to assess the development, risk factors, and prognostic determinants of breast cancer liver metastasis (BCLM). We retrospectively analyzed the data of breast cancer from the Surveillance, Epidemiology, and End Results (SEER) (N = 560,908) and Jiangsu Province Hospital (JSPH) database (N = 294). The risk factors for BCLM were identified via multivariate logistic regression, and overall survival (OS) was assessed with Kaplan-Meier (KM) survival curves and Cox regression models. In the SEER cohort, liver metastasis attacked 1.3% of patients, and the highest incidence was found in the HR-/HER2+ subtype (4.4%). The risk factors for BCLM include young age, high pathological grade, concurrent bone, lung or brain metastasis, and HER2-positive or triple-negative subtype. The median OS of BCLM patients was short (SEER: 22 months; JSPH: 33.5 months). OS was shorter in patients with concomitant metastasis to other organs or with HER2-negative subtype. Hepatic resection remarkably prolonged survival (SEER: 90 vs. 35 months; JSPH: not reached vs. 31.3 months). In the JSPH cohort, molecular subtype changed in 27.5% of patients during metastasis. The occurrence of BCLM is affected by age, tumor grade, other organ involvement, and molecular subtype. Survival was improved in BCLM patients with liver-only metastasis, HER2-positive subtype, or those who underwent hepatic resection. The number and molecular characteristics of liver metastasis are important prognostic predictors, and receptor conversion highlights the need for reassessment of therapeutic strategies during metastatic progression.
To determine the trajectories of benzodiazepine (BZD) and Z-drug use among older adults (n = 3590) followed in a network of geriatric outpatient clinics in Brazil. This longitudinal study evaluated BZD and Z-drug use over a 24-month follow-up period. The proportion of use at baseline and at the end of the study period was compared using the McNemar test. Two trajectories were considered: started using and stopped using. Comparisons between trajectories and independent variables were performed using Pearson's chi-square test. Variables with p < 0.20 were eligible for multivariate analysis. Multivariate models were also used to identify factors associated with BZD or Z-drug use at baseline and with trajectories of initiation and discontinuation. Odds ratios (OR) with 95% confidence intervals were estimated. A small but significant reduction in overall BZD or Z-drug use was observed (17.4% to 16.0%; p = 0.007), with a marked decrease in isolated Z-drug use (6.1% to 4.0%; p < 0.001). At baseline, use was associated with female sex (OR = 1.48; 95% CI 1.19-1.84), age 60-74 years (OR = 1.64; 95% CI 1.29-2.10), having ≥ 2 fall-related conditions (OR = 2.53; 95% CI 1.94-3.31), higher frailty scores, and cognitive dysfunction (OR = 1.32; 95% CI 1.00-1.74). Initiation was associated with pharmacist consultations during follow-up (OR = 5.01; 95% CI 2.88-8.71), depression (OR = 2.59; 95% CI 1.80-3.73), insomnia (OR = 1.97; 95% CI 1.19-3.25), and panic syndrome. Pharmacist consultation was also associated with discontinuation (OR = 0.34; 95% CI 0.15-0.76). Clinical vulnerability and psychiatric conditions were associated with BZD or Z-drug use and initiation, while pharmacist consultations were associated with both initiation and discontinuation trajectories. Benzodiazepines and Z‐drugs are commonly used to treat anxiety and sleep problems, but their use in older adults is associated with risks such as falls, cognitive impairment, and dependence. Understanding how the use of these medications changes over time can help to improve the care of older patients. This study followed 3590 older adults treated in a network of geriatric outpatient clinics in Brazil for 24 months. We analyzed two patterns of medication use: individuals who started using benzodiazepines or Z‐drugs and those who stopped using them during the follow‐up. We also examined clinical and care‐related factors associated with these changes. Overall, the use of these medications decreased slightly during the study period, with a more pronounced reduction in Z‐drug use. At the beginning of the study, the use was more common among women, aged 60–74 years, with two or more conditions related to falls, higher frailty scores, and cognitive dysfunction. Starting use during follow‐up was associated with depression, insomnia, panic syndrome, and pharmacist consultations. Pharmacist consultations were also associated with stopping these medications, suggesting that contact with healthcare professionals may influence medication use among older adults.
Aquaporin-1 (AQP1) is a well-characterized transmembrane water channel widely expressed in the peripheral nervous system (PNS), where it contributes to water balance and regulation of the local neural microenvironment. Beyond its classical role in water transport, AQP1 has been implicated in edema formation, Schwann cell activity, nociceptive signaling, and inflammatory responses. However, these findings derive largely from experimental settings and vary in consistency across different models. Direct evidence supporting a role for AQP1 in uremic peripheral neuropathy (UPN) is currently lacking. This review re-examines the relevance of AQP1 in the PNS by integrating structural, cellular, and functional evidence, and evaluating how far current observations can be extended to the UPN context. We synthesized available literature on AQP1 in peripheral nerve biology, with particular attention to non-uremic models including nerve injury, hypoxia, osmotic stress, and inflammation. The applicability of these mechanistic clues to the complex metabolic, toxic, and inflammatory environment of uremia was critically assessed. Alterations in AQP1 expression or function may plausibly contribute to peripheral nerve dysfunction under uremic conditions, potentially involving disrupted water homeostasis, Schwann cell instability, and altered neuroimmune interactions. However, these assumptions remain speculative. Existing models do not fully reproduce the uremic milieu, and no direct experimental validation in UPN is currently available. Current knowledge on AQP1 in UPN remains fragmented, necessitating a clearer distinction between established findings and hypothesis-driven interpretations. Further studies in uremia-specific animal models and clinical cohorts will be essential to clarify the pathophysiological and therapeutic significance of AQP1 in this condition.
Nuclear magnetic resonance (NMR) metabolomics offers a robust platform for the analysis of complex biological samples, but its application is often constrained by signal overlap and limited sensitivity. In this study, we developed an optimized two-dimensional NMR approach (probe-induced sensitivity enhancement with nonuniform sampling and band-selective 1H-13C HSQC [PRISE-NUS-bs-HSQC]) to enable high-throughput, high-resolution semiquantitative profiling of 22 amino acids in plasma from a rat model of heart failure (HF). When combined with spatially resolved metabolomics of cardiac tissue using AFADESI-MSI, plasma levels of valine, leucine, isoleucine, phenylalanine, methionine, and glutamine showed positive correlations with metabolic disturbances in the infarct (I) area of the heart. A composite biomarker panel derived from these amino acids distinguished HF rats from controls with an area under the curve (AUC) of 0.926. Using multiple therapeutic strategies, including traditional Chinese medicine (TCM), Western medicine, combined therapy with TCM and Western medicine, and active ingredients from Chinese medicine, we observed that all interventions reversed HF-associated amino acid metabolic dysregulation to varying extents. Notably, combined treatment with Qishen Yiqi dropping pills and sacubitril/valsartan produced broader metabolic normalization and more pronounced synergistic effects than either monotherapy. Collectively, this study establishes a noninvasive and efficient 2D NMR-based framework for exploring the association between systemic amino acid metabolism and regional cardiac injury in HF. The integrated analytical strategy provides mechanistic insight into amino acid metabolic remodeling during HF progression and underscores its translational potential for noninvasive diagnosis and therapeutic evaluation.
This multicenter study aimed to analytically compare the performance of automated quantitative assays-chemiluminescence immunoassay (CLIA) and multiplexed bead immunoassay (MBI)-for detecting anti-Ro/La antibodies in Chinese patients with primary Sjögren's syndrome (pSS), compared to line immunoassay (LIA) that is most commonly used in China. Based on the Chinese Sjögren's Syndrome Collaborative Research Group, serum samples from 434 patients with pSS and 100 healthy controls were analyzed using LIA, CLIA, and MBI. Sensitivity, specificity, and qualitative agreement were assessed. Receiver operating characteristic (ROC) analysis was carried out to compare the analytical accuracy among assays in detecting anti-Ro/La antibodies, and the DeLong test was used to compare areas under curves (AUCs). High specificity (95% to 100%) was observed in these assays, and LIA demonstrated the highest sensitivity for anti-Ro60 (92.6%) and anti-Ro52 (89.2%). CLIA and MBI exhibited comparable sensitivity to LIA for anti-La (50.9% vs. 50.2% vs. 48.2%). Qualitative agreement among assays was good for anti-Ro60 (κ: 0.84-0.93) and moderate for anti-La (κ: 0.74-0.86). MBI achieved the highest AUC values for anti-Ro60 (0.980), anti-Ro52 (0.970), and anti-La (0.935), outperforming CLIA and LIA (p  < 0.05). Automated assays (CLIA and MBI) demonstrate high specificity and analytical accuracy for anti-Ro/La antibody detection in pSS. MBI achieved the highest accuracy, whereas LIA showed superior sensitivity for anti-Ro60/52 detection. CLIA provided reliable specificity but failed to detect anti-Ro52 in this study. Collectively, these findings indicate that CLIA and MBI may represent reliable alternatives to LIA, although validation in disease-controlled cohorts is required before clinical implementation.