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Background: In aortic stenosis, the left ventricle exerts additional force to pump blood through the narrowed aortic valve into the downstream arterial vasculature. Adaptive hypertrophy helps to maintain wall stress homeostasis but at the expense of impaired compliance. Advanced ventricular deformation impacts the extent of functional recovery benefits achieved through transcatheter aortic valve implantation. Methods and Results: Subgroups were stratified based on output, with low-flow severe aortic stenosis defined as stroke volume index <35 mL· m-2. Before intervention, the low-flow subgroup exhibited worse effective orifice area index and arterial and global impedance, along with thinner wall thickness and larger chamber volume marginally. LV performance, including stroke volume index, ventricular elastance, and ventricular-arterial coupling, were notably inferior, consistent with worse adverse remodeling. Although the effective orifice area index was similarly augmented after TAVI, inferior recovery benefits were noted. Persistently higher wall stress and energy consumption were observed, along with poorer ventricular-arterial coupling. These changes in wall stress showed an inverse relationship with alterations in wall thickness and were proportional to changes in dimension and volume. Additionally, they were proportional to changes in left ventricular end-systolic pressure, pressure-volume area, and ventricular-arterial coupling but inversely related to ventricular end-systolic elastance. Conclusions: The study revealed that aortic valve enlargement through transcatheter aortic valve implantation reduces left ventricular wall stress in severe aortic stenosis. The reduced recovery benefits in the low-flow subgroup were evident. Wall stress could serve as a marker of mechanical benefit after the intervention.
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BACKGROUND: This cross-sectional study examines associations between the race-migration nexus, cumulative exposure to intersectional discrimination (2 years before and during the COVID-19 pandemic), and long-term conditions. METHODS: A nationwide self-selected sample (n = 32,605) was obtained from a Statistics Canada's Crowdsourcing online survey from August 4 to 24, 2020. Binary and multinomial logistic regression models were used to examine disparities by the race-migration nexus in accumulative experiences of multiple situations- and identity-based discrimination and their relations with long-term conditions, after controlling for sociodemographic covariates. RESULTS: During the pandemic, discrimination stemming from racialization - such as race/skin color (24.4% vs 20.1%) and ethnicity/culture (18.5% vs 16.5%) - and cyberspace (34.1% vs 29.8%) exaggerated relative to pre-pandemic period; compared to Canadian-born (CB) whites, the likelihood of experiencing multiple discrimination increased alongside the domains of discrimination being additively intersected (e.g., identity-based, all p's < 0.001) among CB racialized minorities (ORs 2.08 to 11.78), foreign-born (FB) racialized minorities (ORs 1.99 to 12.72), and Indigenous populations (ORs 1.62 to 8.17), except for FB whites (p > 0.01); dose-response relationships were found between cumulative exposure to multiple discrimination and odds of reporting long-term conditions (p's < 0.001), including seeing (ORs 1.63 to 2.99), hearing (ORs 1.83 to 4.45), physical (ORs 1.66 to 3.87), cognitive (ORs 1.81 to 3.79), and mental health-related impairments (ORs 1.82 to 3.41). CONCLUSIONS: Despite a universal health system, Canadians who are CB/FB racialized and Indigenous populations, have a higher prevalence of cumulative exposure to different aspects of discrimination that are associated with multiple long-term conditions during the COVID-19 pandemic. Equity-driven solutions are needed to tackle upstream determinants of health inequalities through uprooting intersectional discrimination faced by racialized and immigrant communities.
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Aims: Cardiovascular disease (CVD) may not be detected in time with conventional clinical approaches. Abnormal gait patterns have been associated with pathological conditions and can be monitored continuously by gait video. We aim to test the association between non-contact, video-based gait information and general CVD status. Methods and results: Individuals undergoing confirmatory CVD evaluation were included in a prospective, cross-sectional study. Gait videos were recorded with a Kinect camera. Gait features were extracted from gait videos to correlate with the composite and individual components of CVD, including coronary artery disease, peripheral artery disease, heart failure, and cerebrovascular events. The incremental value of incorporating gait information with traditional CVD clinical variables was also evaluated. Three hundred fifty-two participants were included in the final analysis [mean (standard deviation) age, 59.4 (9.8) years; 25.3% were female]. Compared with the baseline clinical variable model [area under the receiver operating curve (AUC) 0.717, (0.690-0.743)], the gait feature model demonstrated statistically better performance [AUC 0.753, (0.726-0.780)] in predicting the composite CVD, with further incremental value when incorporated with the clinical variables [AUC 0.764, (0.741-0.786)]. Notably, gait features exhibited varied association with different CVD component conditions, especially for peripheral artery disease [AUC 0.752, (0.728-0.775)] and heart failure [0.733, (0.707-0.758)]. Additional analyses also revealed association of gait information with CVD risk factors and the established CVD risk score. Conclusion: We demonstrated the association and predictive value of non-contact, video-based gait information for general CVD status. Further studies for gait video-based daily living CVD monitoring are promising.
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Fibroblast A20 suppresses advanced glycation end products (AGEs)-induced melanogenesis by inhibiting NLRP3 inflammasome activation. AGEs repress A20 expression and significantly m6A-methylate A20 mRNA in fibroblasts. YTHDF2 is the most studied m6A reader protein and can accelerate degradation of m6A-modified mRNA. Whether YTHDF2 regulates AGEs-induced A20 expression and pigmentation is unknown. In this study, we confirmed that YTHDF2 inversely regulated AGEs-BSA-inhibited A20 expression but facilitated AGEs-BSA-activated NF-κB signaling and NLRP3 inflammasome in fibroblasts via YTHDF2 knockdown and overexpression experiments. Mechanistically, YTHDF2 bound to m6A-modified A20 mRNA induced by AGEs-BSA and increased its degradation. Moreover, fibroblast YTHDF2 robustly promoted AGEs-BSA-induced IL-18 level in coculture supernatants and melanin content, tyrosinase activity, and expression of microphthalmia-associated transcription factor and tyrosinase in melanocytes, which were significantly blocked by IL-18 binding protein. Further, fibroblast YTHDF2 markedly increased AGEs-BSA-induced epidermal melanin level in cocultured ex vivo skin and MAPKs activation in melanocytes. Importantly, upregulated dermal YTHDF2 expression was negatively correlated with dermal A20 level and positively associated with both epidermal melanin and dermal AGEs content in sun-exposed skin and lesions of melasma and solar lentigo. These findings suggest that fibroblast YTHDF2 positively regulates AGEs-induced melanogenesis mainly via A20/ NF-κB /NLRP3 inflammasome/ IL-18 /MAPKs axis in an m6A-dependent manner and functions in photoaging-induced hyperpigmentation skin disorders.
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BACKGROUND: Bevacizumab shows superior efficacy in cerebral radiation necrosis (CRN) therapy, but its economic burden remains heavy due to the high drug price. This study aims to evaluate the cost-effectiveness of bevacizumab for CRN treatment from the Chinese payers' perspective. METHODS: A decision tree model was developed to compare the costs and health outcomes of bevacizumab and corticosteroids for CRN therapy. Efficacy and safety data were derived from the NCT01621880 trial, which compared the effectiveness and safety of bevacizumab monotherapy with corticosteroids for CRN in nasopharyngeal cancer patients, and demonstrated that bevacizumab invoked a significantly higher response than corticosteroids (65.5% vs. 31.5%, Pâ¯< 0.001) with no significant differences in adverse events between two groups. The utility value of the "non-recurrence" status was derived from real-world data. Costs and other utility values were collected from an authoritative Chinese network database and published literature. The primary outcomes were total costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). The uncertainty of the model was evaluated via one-way and probabilistic sensitivity analyses. RESULTS: Bevacizumab treatment added 0.12 (0.48 vs. 0.36) QALYs compared to corticosteroid therapy, along with incremental costs of $ 2010 ($ 4260 vs. $ 2160). The resultant ICER was $ 16,866/QALY, which was lower than the willingness-to-pay threshold of $ 38,223/QALY in China. The price of bevacizumab, body weight, and the utility value of recurrence status were the key influential parameters for ICER. Probabilistic sensitivity analysis revealed that the probability of bevacizumab being cost-effectiveness was 84.9%. CONCLUSION: Compared with corticosteroids, bevacizumab is an economical option for CRN treatment in China.
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BACKGROUND: Current approaches for initial coronary artery disease (CAD) assessment rely on pretest probability (PTP) based on risk factors and presentations, with limited performance. Infrared thermography (IRT), a non-contact technology that detects surface temperature, has shown potential in assessing atherosclerosis-related conditions, particularly when measured from body regions such as faces. We aim to assess the feasibility of using facial IRT temperature information with machine learning for the prediction of CAD. METHODS: Individuals referred for invasive coronary angiography or coronary CT angiography (CCTA) were enrolled. Facial IRT images captured before confirmatory CAD examinations were used to develop and validate a deep-learning IRT image model for detecting CAD. We compared the performance of the IRT image model with the guideline-recommended PTP model on the area under the curve (AUC). In addition, interpretable IRT tabular features were extracted from IRT images to further validate the predictive value of IRT information. RESULTS: A total of 460 eligible participants (mean (SD) age, 58.4 (10.4) years; 126 (27.4%) female) were included. The IRT image model demonstrated outstanding performance (AUC 0.804, 95% CI 0.785 to 0.823) compared with the PTP models (AUC 0.713, 95% CI 0.691 to 0.734). A consistent level of superior performance (AUC 0.796, 95% CI 0.782 to 0.811), achieved with comprehensive interpretable IRT features, further validated the predictive value of IRT information. Notably, even with only traditional temperature features, a satisfactory performance (AUC 0.786, 95% CI 0.769 to 0.803) was still upheld. CONCLUSION: In this prospective study, we demonstrated the feasibility of using non-contact facial IRT information for CAD prediction.
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Enfermedad de la Arteria Coronaria , Cara , Termografía , Humanos , Termografía/métodos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Masculino , Femenino , Persona de Mediana Edad , Cara/diagnóstico por imagen , Anciano , Valor Predictivo de las Pruebas , Estudios de Factibilidad , Temperatura Corporal , Aprendizaje Automático , Angiografía Coronaria , Angiografía por Tomografía Computarizada , Estudios Prospectivos , Rayos InfrarrojosRESUMEN
Aim: To estimate the cost-effectiveness of zolbetuximab plus capecitabine/oxaliplatin (CAPOX) in CLDN18.2-positive, HER2-negative, mG/GEJ adenocarcinoma from the perspective of Chinese payers. Materials & methods: A partitioned survival model was developed to assess the costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICER) of zolbetuximab plus CAPOX versus placebo plus CAPOX. Sensitivity analyses were performed to test the robustness of model. Results: Zolbetuximab plus CAPOX gained an additional cost of $91,551 and an extra health benefit of 0.24 QALY over placebo plus CAPOX, producing an ICER of $388,186/QALY, which exceeded the willingness-to-pay threshold of $38,223/QALY. Sensitivity analysis shows that the model was generally robust. Conclusion: Zolbetuximab plus CAPOX would not be a cost-effective first-line treatment regimen in CLDN18.2-positive, HER2-negative, mG/GEJ adenocarcinoma in China.
[Box: see text].
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BACKGROUND: Multi-parametric magnetic resonance imaging (mpMRI) is a diagnostic tool used for screening, localizing, and staging prostate cancer. Patients with Prostate Imaging Reporting and Data System (PI-RADS) score of 1 and 2 are considered negative mpMRI, with a lower likelihood of detecting clinically significant prostate cancer (csPCa). However, relying solely on mpMRI is insufficient to completely exclude csPCa, necessitating further stratification of csPCa patients using biomarkers. METHODS: A retrospective study was conducted on mpMRI-negative patients who underwent prostate biopsy at the First Affiliated Hospital of Zhejiang University from January 2022 to June 2023. A total of 607 patients were included based on inclusion and exclusion criteria. Univariate and multivariate logistic regression analysis were performed to identify risk factors for diagnosing csPCa in patients with negative mpMRI. Receiver Operating Characteristic (ROC) curves were plotted to compare the discriminatory ability of different Prostate-Specific Antigen Density (PSAD) cutoff values for csPCa. RESULTS: Among the 607 patients with negative mpMRI, 73 patients were diagnosed with csPCa. In univariate logistic regression analysis, age, PSA, f/tPSA, prostate volume, and PSAD were all associated with diagnosing csPCa in patients with negative mpMRI (P < 0.05), with PSAD being the most accurate predictor. In multivariate logistic regression analysis, f/tPSA, age, and PSAD were independent predictors of csPCa (P < 0.05). PSAD cutoff value of 0.20 ng/ml/ml has better discriminatory ability for predicting csPCa and is a significant risk factor for csPCa in multivariate analysis. CONCLUSION: Age, f/tPSA, and PSAD are independent predictors of diagnosing csPCa in patients with negative mpMRI. It is suggested that patients with negative mpMRI and PSAD less than 0.20 ng/ml/ml could avoid prostate biopsy, as a PSAD cutoff value of 0.20 ng/ml/ml has better diagnostic performance than the traditional cutoff value of 0.15 ng/ml/ml.
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Imágenes de Resonancia Magnética Multiparamétrica , Antígeno Prostático Específico , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/patología , Estudios Retrospectivos , Anciano , Persona de Mediana Edad , China/epidemiología , Antígeno Prostático Específico/sangre , Factores de Riesgo , Imágenes de Resonancia Magnética Multiparamétrica/métodos , Pronóstico , Estudios de Seguimiento , Hospitales de Alto Volumen/estadística & datos numéricos , Curva ROCRESUMEN
OBJECTIVES: To determine the alteration of peripheral T and B cell subsets in patients with systemic sclerosis (SSc) and to evaluate their correlation with the progression of SSc. METHODS: We recruited 47 SSc patients and 45 healthy controls (HCs) in this study. Demographic and clinical data were then collected. Flow cytometry was used to detect the proportions of 44 different T and B cell subsets in circulating blood. RESULTS: The proportion of total B cells (p = .043) decreased in SSc patients, together with similar frequencies of total T cells, CD4+ T cells, and CD8+ T cells in both groups. Several subsets of T and B cells differed significantly between these two groups. Follicular helper T cells-1 (Tfh1) (p < .001), helper T cells-1 (Th1) (p = .001), regulatory T cells (Treg) (p = .004), effector memory CD8+ T cells (p = .041), and cytotoxic T cells-17 (Tc17) (p = .01) were decreased in SSc patients. Follicular helper T cells-2 (Tfh2) (p = .001) and, helper T cells-2 (Th2) (p = .001) levels increased in the SSc group. Regulatory B cells (Breg) (p = .015) were lower in the SSc group, together with marginal zone (MZ) B cells (p < .001), memory B cells (p = .001), and non-switched B cells (p = .005). The modified Rodnan skin score (mRSS) correlated with helper T cells-17 (Th17) (r = -.410, p = .004), Tfh1 (r = -.321, p = .028), peripheral helper T cells (Tph) (r = -.364, p = .012) and plasma cells (r = -.312, p = .033). CONCLUSIONS: The alterations in T and B cells implied immune dysfunction, which may play an essential role in systemic sclerosis.
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Subgrupos de Linfocitos B , Esclerodermia Sistémica , Humanos , Femenino , Masculino , Persona de Mediana Edad , Adulto , Estudios de Casos y Controles , Subgrupos de Linfocitos B/inmunología , Esclerodermia Sistémica/inmunología , Esclerodermia Sistémica/sangre , Esclerodermia Sistémica/diagnóstico , Subgrupos de Linfocitos T/inmunología , Citometría de Flujo , Fenotipo , Progresión de la Enfermedad , Inmunofenotipificación , AncianoRESUMEN
Cognitive and behavioral rigidity are observed in various psychiatric diseases, including in autism spectrum disorder (ASD). However, the underlying mechanism remains to be elucidated. In this study, we found that neuroligin-3 (NL3) R451C knockin mouse model of autism (KI mice) exhibited deficits in behavioral flexibility in choice selection tasks. Single-unit recording of medium spiny neuron (MSN) activity in the nucleus accumbens (NAc) revealed altered encoding of decision-related cue and impaired updating of choice anticipation in KI mice. Additionally, fiber photometry demonstrated significant disruption in dynamic mesolimbic dopamine (DA) signaling for reward prediction errors (RPEs), along with reduced activity in medial prefrontal cortex (mPFC) neurons projecting to the NAc in KI mice. Interestingly, NL3 re-expression in the mPFC, but not in the NAc, rescued the deficit of flexible behaviors and simultaneously restored NAc-MSN encoding, DA dynamics, and mPFC-NAc output in KI mice. Taken together, this study reveals the frontostriatal circuit dysfunction underlying cognitive inflexibility and establishes a critical role of the mPFC NL3 deficiency in this deficit in KI mice. Therefore, these findings provide new insights into the mechanisms of cognitive and behavioral inflexibility and potential intervention strategies.
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PURPOSE: To investigate the cost-effectiveness of lenvatinib plus pembrolizumab (LP) compared to chemotherapy as a second-line treatment for advanced endometrial cancer (EC) from the United States and Chinese payers' perspective. METHODS: In this economic evaluation, a partitioned survival model was constructed from the perspective of the United States and Chinese payers. The survival data were derived from the clinical trial (309-KEYNOTE-775), while costs and utility values were sourced from databases and published literature. Total costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER) were estimated. The robustness of the model was evaluated through sensitivity analyses, and price adjustment scenario analyses was also performed. RESULTS: Base-case analysis indicated that LP wouldn't be cost-effective in the United States at the WTP threshold of $200 000, with improved effectiveness of 0.75 QALYs and an additional cost of $398596.81 (ICER $531392.20). While LP was cost-effective in China, with improved effectiveness of 0.75 QALYs and an increased overall cost of $62270.44 (ICER $83016.29). Sensitivity analyses revealed that the above results were stable. The scenario analyses results indicated that LP was cost-effective in the United States when the prices of lenvatinib and pembrolizumab were simultaneously reduced by 61.95% ($26.5361/mg for lenvatinib and $19.1532/mg for pembrolizumab). CONCLUSION: LP isn't cost-effective in the patients with advanced previously treated endometrial cancer in the United States, whereas it is cost-effective in China. The evidence-based pricing strategy provided by this study could benefit decision-makers in making optimal decisions and clinicians in general clinical practice. More evidence about budget impact and affordability for patients is needed.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Endometriales , Compuestos de Fenilurea , Quinolinas , Femenino , Humanos , Anticuerpos Monoclonales Humanizados/economía , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , China , Análisis de Costo-Efectividad , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/economía , Compuestos de Fenilurea/economía , Compuestos de Fenilurea/uso terapéutico , Compuestos de Fenilurea/administración & dosificación , Años de Vida Ajustados por Calidad de Vida , Quinolinas/economía , Quinolinas/uso terapéutico , Quinolinas/administración & dosificación , Estados UnidosRESUMEN
Background: This study aimed to evaluate the immediate effect of transcatheter aortic valve implantation (TAVI) on mechanical efficiency. Methods: A total of 46 patients (25 females) with an average age of 83 ± 6.4 years underwent TAVI using the CoreValve system. During the same hospitalization, we conducted a comprehensive comparison of the patients before and after TAVI without inotropic support using echocardiography. The parameters encompassed left ventricular (LV) geometry, valvular load, global LV afterload and ventricular hemodynamics. The analysis using pressure-volume loops enabled the determination of load-independent contractility (Ees) and afterload, in addition to assessing potential energy, stroke work, and mechanical efficiency. Results: The immediate effect was an augmented aortic valve area accompanied by a reduction in the transvalvular pressure gradient. We observed reductions in left ventricular end-systolic volume and end-diastolic volume, and also reductions in global afterload and end-systolic meridional wall stress. The Ea index decreased, while the Ees index remained relatively stable. We noted increases in stroke volume and systemic arterial compliance, indicating more efficient blood transfer from the ventricle to aorta. These changes contributed to the normalization of ventricular-arterial coupling. In terms of mechanical work of the chamber, we observed significant decreases in potential energy, stroke work, and pressure-volume area. There was an increase in the mechanical efficiency of the chamber. Conclusions: The TAVI procedure immediately reduced global afterload and improved diastolic compliance of the chamber, resulting in enhanced ventricular function and mechanical efficiency.
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BACKGROUND: Lipoprotein(a) is a possible causal risk factor for atherosclerosis and related complications. The distribution and prognostic implication of lipoprotein(a) in patients undergoing coronary artery bypass grafting remain unknown. This study aimed to assess the impact of high lipoprotein(a) on the long-term prognosis of patients undergoing coronary artery bypass grafting. METHODS AND RESULTS: Consecutive patients with stable coronary artery disease who underwent isolated coronary artery bypass grafting from January 2013 to December 2018 from a single-center cohort were included. The primary outcome was all-cause death. The secondary outcome was a composite of major adverse cardiovascular and cerebrovascular events. Of the 18 544 patients, 4072 (22.0%) were identified as the high-lipoprotein(a) group (≥50 mg/dL). During a median follow-up of 3.2 years, primary outcomes occurred in 587 patients. High lipoprotein(a) was associated with increased risk of all-cause death (high lipoprotein(a) versus low lipoprotein(a): adjusted hazard ratio [aHR], 1.31 [95% CI, 1.09-1.59]; P=0.005; lipoprotein(a) per 1-mg/dL increase: aHR, 1.003 [95% CI, 1.001-1.006]; P=0.011) and major adverse cardiovascular and cerebrovascular events (high lipoprotein(a) versus low lipoprotein(a): aHR, 1.18 [95% CI, 1.06-1.33]; P=0.004; lipoprotein(a) per 1-mg/dL increase: aHR, 1.002 [95% CI, 1.001-1.004]; P=0.002). The lipoprotein(a)-related risk was greater in patients with European System for Cardiac Operative Risk Evaluation <3, and tended to attenuate in patients receiving arterial grafts. CONCLUSIONS: More than 1 in 5 patients with stable coronary artery disease who underwent coronary artery bypass grafting were exposed to high lipoprotein(a), which is associated with higher risks of death and major adverse cardiovascular and cerebrovascular events. The adverse effects of lipoprotein(a) were more pronounced in patients with clinically low-risk profiles or not receiving arterial grafts.
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Aterosclerosis , Enfermedad de la Arteria Coronaria , Humanos , Lipoproteína(a) , Resultado del Tratamiento , Puente de Arteria Coronaria , Aterosclerosis/complicaciones , Factores de Riesgo , Estudios RetrospectivosRESUMEN
AIMS: Preoperative risk assessment is crucial for cardiac surgery. Although previous studies suggested machine learning (ML) may improve in-hospital mortality predictions after cardiac surgery compared to traditional modeling approaches, the validity is doubted due to lacking external validation, limited sample sizes, and inadequate modeling considerations. We aimed to assess predictive performance between ML and traditional modelling approaches, while addressing these major limitations. METHODS AND RESULTS: Adult cardiac surgery cases (n = 168 565) between 2013 and 2018 in the Chinese Cardiac Surgery Registry were used to develop, validate, and compare various ML vs. logistic regression (LR) models. The dataset was split for temporal (2013-2017 for training, 2018 for testing) and spatial (geographically-stratified random selection of 83 centers for training, 22 for testing) experiments, respectively. Model performances were evaluated in testing sets for discrimination and calibration. The overall in-hospital mortality was 1.9%. In the temporal testing set (n = 32 184), the best-performing ML model demonstrated a similar area under the receiver operating characteristic curve (AUC) of 0.797 (95% CI 0.779-0.815) to the LR model (AUC 0.791 [95% CI 0.775-0.808]; P = 0.12). In the spatial experiment (n = 28 323), the best ML model showed a statistically better but modest performance improvement (AUC 0.732 [95% CI 0.710-0.754]) than LR (AUC 0.713 [95% CI 0.691-0.737]; P = 0.002). Varying feature selection methods had relatively smaller effects on ML models. Most ML and LR models were significantly miscalibrated. CONCLUSION: ML provided only marginal improvements over traditional modelling approaches in predicting cardiac surgery mortality with routine preoperative variables, which calls for more judicious use of ML in practice.
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Procedimientos Quirúrgicos Cardíacos , Propanolaminas , Adulto , Humanos , Mortalidad Hospitalaria , Aprendizaje Automático , Sistema de RegistrosRESUMEN
PURPOSE: Our purpose was to report the clinical and dosimetric attributes of patients with large unresectable hepatocellular carcinoma (HCC) undergoing proton or photon radiation therapy. METHODS AND MATERIALS: We retrospectively analyzed the outcomes and dosimetric indices of 159 patients with >5 cm nonmetastatic HCC who underwent definitive radiation therapy using either protons (N = 105) or photons (N = 54) between 2014 and 2018. Additional photon plans were performed in the 105 proton-treated patients using the same dose prescription criteria for intragroup dosimetric comparison. RESULTS: After a median follow-up of 47 months, patients with biologically effective dose (BED10) ≥ 75 Gy exhibited significantly better local control (LC; 2-year: 85.6% vs 20.5%; P < .001), progression-free survival (PFS; median, 7.4 vs 3.2 months; P < .001), and overall survival (OS; median, 18.1 vs 7.3 months; P < .001) compared with those with BED10 < 75 Gy. Notably, proton-treated patients had a significantly higher BED10 (96 vs 67 Gy; P < .001) and improved LC (2-year: 88.5% vs 33.8%; P < .001), PFS (median, 7.4 vs 3.3 months; P = .001), and OS (median, 18.9 vs 8.3 months; P < .001) than those undergoing photon radiation therapy. Furthermore, patients treated with protons had significantly lower V1 of the liver (P < .001), mean upper gastrointestinal tract dose (P < .001), and mean splenic dose (P < .001), with significantly decreased incidences of radiation-induced liver disease (P = .007), grade ≥3 upper gastrointestinal bleeding (P = .001), and grade ≥3 lymphopenia (P = .003). On multivariate analysis, proton radiation therapy consistently correlated with superior LC (P < .001), PFS (P < .001), and OS (P < .001). In intragroup dosimetric comparison, photon plans demonstrated significantly higher mean liver dose (P < .001) compared with actually delivered proton treatments, and 72 (69%) of them had mean liver dose exceeding 28 Gy, which necessitated target dose de-escalation. CONCLUSIONS: In the context of large HCC radiation therapy, a higher target BED10 was associated with improved outcomes. Notably, proton therapy has demonstrated the capability to deliver ablative doses while also being accompanied by fewer instances of severe toxicity.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Terapia de Protones , Traumatismos por Radiación , Humanos , Carcinoma Hepatocelular/patología , Protones , Estudios Retrospectivos , Neoplasias Hepáticas/patología , Traumatismos por Radiación/etiología , Terapia de Protones/efectos adversos , Terapia de Protones/métodos , Dosificación RadioterapéuticaRESUMEN
OBJECTIVES: Immigrants to Canada tend to have a lower incidence of diagnosed depression than nonimmigrants. One theory suggests that this "healthy immigrant effect (HIE)" is due to positive selection. Another school of thought argues that the medical underuse of immigrants may be the underlying reason. This unclear "immigrant paradox" is further confounded by the intersecting race-migration nexus. METHODS: This population-based study analyzed data of participants (nâ =â 28,951, age ≥45) from the Canadian Community Health Survey (2015-2018). Multivariable logistic regression was employed to examine associations between race-migration nexus and mental health outcomes, including depressive symptoms (Patient Health Questionnaire [PHQ-9] score ≥10). RESULTS: Compared to Canadian-born (CB) Whites, immigrants, regardless of race, were less likely to receive a mood/anxiety disorder diagnosis (M/A-Dx) by health providers in their lifetime. Racialized immigrants were mentally disadvantaged with increased odds of undiagnosed depression (Adjusted odds ratio [AOR]â =â 1.76, 99% Confidence interval [CI]:1.30-2.37), whereas White immigrants were mentally healthier with decreased odds of PHQ depression (AOR=0.75, 99%CI: 0.58, 0.96) and poor self-rated mental health (AOR=0.56, 99% CI=0.33, 0.95). Among the subpopulation without a previous M/A-Dx (Nâ =â 25,203), racialized immigrants had increased odds of PHQ depression (AORâ =â 1.45, 99% CI: 1.15-1.82) and unrecognized depression (AORâ =â 1.47, 99% CI: 1.08-2.00) than CB Whites. Other risk factors for undiagnosed depression include the lack of regular care providers, emergency room as the usual source of care, and being home renters. DISCUSSION: Despite Canadian universal health coverage, the burden of undiagnosed depression disproportionately affects racialized (but not White) immigrants in mid to late life. Contingent on race-migration nexus, the HIE in mental health may be mainly driven by the healthier profile of White immigrants and partly attributable to the under-detection (by health professionals) and under-recognition of mental health conditions among racialized immigrants. A paradigm shift is needed to estimate late-life depression for medically underserved populations.
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Depresión , Emigrantes e Inmigrantes , Humanos , Depresión/diagnóstico , Depresión/epidemiología , Canadá/epidemiología , Estado de Salud , Salud MentalRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Cisplatin (CP) results in acute kidney injury (AKI) and negatively affects patients' therapy and survival. The dried rhizome of Gastrodia elata Blume has been used to treat clinical kidney diseases. Gastrodin (GAS) is an active ingredient of the G. elata tuber. It is unknown whether GAS can alleviate CP-induced AKI. AIM OF THE STUDY: This study aimed to investigate whether GAS, an active ingredient of G. elata Blume, can alleviate CP-induced AKI and to explore its underlying mechanisms. MATERIALS AND METHODS: Experiments were conducted with a CP-induced AKI mouse model and an immortalized human renal tubular epithelial cell line (HK-2). Serum creatinine, Periodic acid-Schiff staining, tissue iron, glutathione, malondialdehyde, and 4-Hydroxynonenal were detected in serum and kidney samples to observe whether GAS inhibits CP-induced tubule ferroptosis. The drug target was verified by detecting the effects of GAS on sirtuin-1 (SIRT1) activity in vitro. Transcriptional regulation of glutathione peroxidase 4 (GPX4) by forkhead box O3A (FOXO3A) was verified by siRNA knockdown, overexpression, and chromatin immunoprecipitation. The effects of FOXO3A, SIRT1, and GAS on CP-induced ferroptosis were measured with propidium iodide, dihydroethidium, monobromobimane, and dipyrromethene boron difluoride staining in HK-2 cells. The relationship between GAS and the SIRT1/FOXO3A/GPX4 pathway was studied using Western blotting. RESULTS: GAS treatment inhibited CP-induced reactive oxygen species, lipid peroxidation, and tubule death in the cell and animal models. GAS activated SIRT1 in vitro. The SIRT1 inhibitor blocked the protective role of GAS in reducing lipid peroxidation in HK-2 cells. FOXO3A transcriptionally regulated GPX4 expression and inhibited CP-induced cell ferroptosis. Compared to CP-damaged mouse kidneys, GAS-treated mice demonstrated significantly increased SIRT1 and GPX4 expression levels, decreased CP-induced acetylation of FOXO3A, and inhibited lipid peroxidation and cell death. CONCLUSIONS: GAS alleviated CP-induced AKI by inhibiting ferroptosis via the SIRT1/FOXO3A/GPX4 signaling pathway. The results offer new insights into the development of new anti-AKI drugs from traditional Chinese medicine.
Asunto(s)
Lesión Renal Aguda , Ferroptosis , Sirtuinas , Humanos , Ratones , Animales , Cisplatino/toxicidad , Sirtuina 1/metabolismo , Sirtuinas/metabolismo , Línea Celular , Transducción de Señal , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/metabolismoRESUMEN
OBJECTIVE: The aim of this study was to estimate the effect of dietary consumption on cancer burden and formulate an effective solution. METHODS: Dietary consumption, number of cancer deaths, disability-adjusted life years, and corresponding age-standardized rates were extracted from the Global Burden of Disease Study 2019. The annual percentage change was used to quantify the temporal trends in cancer burden and dietary consumption. Age, sex, location, and sociodemographic index were stratified to further analyze the discrepancy in cancer burden attributable to dietary intake. RESULTS: Five cancers (breast, colon and rectal, tracheal, bronchus and lung, esophageal, and stomach) were documented to be associated with dietary consumption in the Global Burden of Disease database. The age-standardized death rate and age-standardized disability-adjusted life years rate in 2019 were 7.56 and 1168.77 per 100 000 population, respectively. For most cancers, the age-standardized death rate and age-standardized disability-adjusted life years rate displayed a decreasing tendency, with annual percentage change varying from -3.60 to -0.29 and from -3.64 to -0.03 from 1990 to 2019, respectively. The age-standardized death rate and age-standardized standardized disability-adjusted life years rate were higher in men than in women (9.68 vs 5.79 and 213.16 vs 129.18, respectively). In addition, the diet-related cancer burden in higher sociodemographic index regions exceeded that in lower sociodemographic index regions. CONCLUSION: Dietary consumption has a considerable influence on cancer burden, among which colon and rectal cancer burden account for the largest proportion. Increasing the intake of whole grains, milk, fiber, calcium, vegetables, and fruits and reducing the consumption of processed meat and sodium are instrumental in lowering the disease burden of cancer. The quantitative analysis of dietary consumption would provide a more detailed reference for diet-related decision makers and raise awareness of healthy dietary habits in diet management departments, food production enterprises, and the general public.