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AIMS: Dopamine agonists (DA) are the first-line treatment for patients with prolactin-secreting pituitary adenoma (PRL adenoma). However, a subset of individuals exhibits poor responses, known as DA resistance. Previous studies have reported that DA resistance is more prevalent in male patients. This study aims to investigate the relationship between androgen receptor (AR) expression and DA resistance, as well as to explore underlying mechanisms of AR-mediated DA resistance. RESULTS: Our results demonstrated that patients with higher AR expression exhibit greater resistance to DA in our cohort of DA-resistant PRL adenoma. Furthermore, AR was found to be involved in cell proliferation, PRL secretion, and resistance to BRC both in vitro and in vivo. Mechanistically, we demonstrated that intracellular ROS function as upstream mediators of apoptosis and ferroptosis following BRC treatment. As a ligand-dependent transcription factor, AR could translocate to the nucleus and transcriptionally promote NRF2 expression, which regulates intracellular ROS levels, thereby enhancing cell viability, and conferring DA resistance to PA cells. Finally, AR targeting agents were used to inhibit AR signaling, downregulate NRF2 transcription, and sensitize PA cells to BRC treatment. Conclusion and innovation: We demonstrated that AR plays a crucial role in mediating DA resistance in PRL-adenoma. Mechanistically, AR promotes cell proliferation and PRL secretion and confers drug resistance by transcriptionally regulating NRF2 expression to maintain redox homeostasis in PA cells. Finally, combining AR targeting agents with BRC shows promise as a therapeutic strategy for treating PRL adenomas.
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BACKGROUND: Lipid management based on cardiovascular risk level is the cornerstone of primary prevention of coronary artery disease (CAD), while the accuracy and adherence of traditional cardiovascular risk stratification have been questioned. Prevention strategies based on imaging screening for atherosclerotic plaques are found to be more objective and adherent in recent studies. This trial aims to investigate the role of coronary computed tomography angiography (CCTA) in guiding the primary prevention of CAD in a randomized controlled design. METHODS: Approximately 3400 middle-aged asymptomatic community participants will be recruited and randomized in a 1:1 ratio to a traditional cardiovascular risk score-guided (usual care group) or CCTA-guided (CCTA group) strategy. Participants with cardiovascular disease, prior lipid-lowering therapy, CCTA contraindication, or serious diseases that affect life span will be excluded. The intervention strategy includes blood pressure, blood glucose, and lipid management and lifestyle modifications. Blood pressure and glucose targets and lifestyle modification recommendations keep the same in both strategies, while lipid management is personalized based on traditional risk level or CCTA results, respectively. The primary outcome is the proportion of participants taking lipid-lowering medication regularly at both 6 and 12 months. The secondary outcomes include the proportion of participants achieving low-density lipoprotein cholesterol lowering targets at 12 months, mean changes in lipid levels from baseline to 12 months, barriers to adherence, adverse reactions related to CCTA examination, and cardiovascular events. DISCUSSION: The study is the first randomized clinical trial to examine the effectiveness of a CCTA-guided versus a traditional risk score-guided primary prevention strategy in an asymptomatic community-based population. TRIAL REGISTRATION: ClinicalTrials.gov NCT05725096. Registered on 2 February 2023.
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Angiografia por Tomografia Computadorizada , Angiografia Coronária , Doença da Artéria Coronariana , Humanos , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/prevenção & controle , Angiografia Coronária/efeitos adversos , Angiografia Coronária/métodos , Pessoa de Meia-Idade , China , Ensaios Clínicos Controlados Aleatórios como Assunto , Doenças Assintomáticas , Feminino , Prevenção Primária/métodos , Masculino , Fatores de Risco de Doenças Cardíacas , Hipolipemiantes/uso terapêutico , Lipídeos/sangue , Fatores de Risco , Medição de Risco , População do Leste AsiáticoRESUMO
PURPOSE: Screening for nasopharyngeal carcinoma (NPC) has shown an improvement in early detection and survival rates of NPC in endemic regions. It is critical to evaluate whether NPC screening can reduce NPC-specific mortality in the population. METHODS: Sixteen towns in Sihui and Zhongshan cities, China, were selected; eight were randomly allocated to the screening group and eight to the control group. Residents age 30-69 years with no history of NPC were included from January 1, 2008, to December 31, 2015. Residents in the screening towns were invited to undergo serum Epstein-Barr virus (EBV) viral capsid antigen/nuclear antigen 1-immunoglobulin A antibody tests; others received no intervention. The population was followed until December 31, 2019. Nonparametric tests and Poisson regression models were used to estimate the screening effect on NPC mortality, accounting for the cluster-randomized design. The trial is registered with ClinicalTrials.gov (identifier: NCT00941538). RESULTS: A total of 174,943 residents in the screening group and 186,263 residents in the control group were included. NPC incidence and overall mortality were similar between the two groups. A total of 52,498 (30.0% of 174,943) residents participated in the serum EBV antibody test. The overall compliance rate for endoscopic examination and/or biopsies among baseline and ever-classified high-risk participants was 65.9% (1,110 of 1,685) and 67.6% (1,703 of 2,518), respectively. A significant 30% reduction in NPC mortality was observed in the screening group compared with the control group (standardized NPC-specific mortality rate of 8.2 NPC deaths per 1,000 person-years versus 12.5; adjusted rate ratio [RR], 0.70 [95% CI, 0.49 to 0.997]; P = .048). This benefit was most evident among individuals age 50 years and older (RR, 0.56 [95% CI, 0.37 to 0.85]; P = .007) compared with those younger than 50 years (RR, 0.96 [95% CI, 0.64 to 1.46]; P = .856). CONCLUSION: In this 12-year trial, EBV antibody testing resulted in a significant reduction in NPC mortality.
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CDT1, a gene that shows excessive expression in various malignancies, functions as a pivotal regulator of replication licensing. In this study, we observed a positive correlation in expression between CDT1 and E2F2 among patients with lung adenocarcinoma (LUAD). Our findings substantiated that E2F2 directly interacted with the promoter region of CDT1, as confirmed by ChIP-qPCR assays, and depletion of E2F2 resulted in a downregulation of CDT1 expression in LUAD cell lines by gene interference technology. Furthermore, we identified an upregulation of CDT1 mRNA level in Chinese LUAD samples. Notably, in the loss-of-function assays, depletion of CDT1 in LUAD cell lines inhibited cell proliferation, migration, and invasion. Concurrently, it promoted cell apoptosis and induced G0/G1 phase arrest using MTT, flow cytometry, and Transwell assays, reinforcing its role as an oncogene.Furthermore, enhanced tumor ablation was determined in a CDT1-downregulated LUAD tumor-bearing nude mouse model. Collectively, our results strongly suggest that E2F2 positively regulates CDT1 expression and actively participates in the progression of lung adenocarcinoma, thereby providing valuable insights into identifying novel therapeutic targets for LUAD treatment.
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The exposure of protein molecules to interfaces may cause protein aggregation and particle formation in protein formulations, especially hydrophobic interfaces, which may promote protein aggregation in solution. In this study, we found that modification of the surface properties by application of a hydrophobic Octadecyltrichlorosilane (OTS) could reduce the generation of protein aggregates and particles in protein solution induced by fluid shear. A stable protein adsorption layer was formed at the hydrophobic interface through the strong hydrophobic interaction between the protein and hydrophobic surface, which could prevent the aggregated protein from falling off into the bulk solution to form subvisible particles and insoluble protein aggregates. In addition, human complement enzyme linked immunosorbent assay results showed that the particles that were generated in the OTS-coated container did not activate human complement which indicated the OTS-coated container could be used as primary containers for certain types of monoclonal antibody formulation.
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Janus TiPX (X = F, Cl, and Br) monolayers were systematically investigated through first-principles calculations. The Janus TiPX monolayers exhibit mechanical and dynamic stability. Two monolayers are indirect bandgap semiconductors, except the TiPBr monolayer, which has the features of a quasi-direct bandgap semiconductor. Biaxial strain can modify the band gap of single layers. The Janus TiPX monolayers have remarkable flexibility and piezoelectric properties. In particular, the TiPF monolayer shows high horizontal (44.18 pm V-1) and vertical piezoelectric coefficients (-3.59 pm V-1). These values exceed those of conventional bulk materials, like GaN (3.1 pm V-1) and α-quartz (2.3 pm V-1). All of the monolayers have absorption coefficients of 105 cm-1 for visible and ultraviolet (UV) light, which are one order of magnitude greater than that of MoSSe. Furthermore, TiPX monolayers have high carrier mobility. Janus TiPX monolayers represent a class of two-dimensional (2D) materials with exceptional properties and multifunctionality, holding significant promise for various applications in piezoelectric sensors, solar cells, and nano-electronic devices.
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Dengue, an acute febrile disease transmitted by Aedes mosquitoes, is caused by the dengue virus (DENV), presenting a formidable challenge to global public health. By examining clues from ancient Chinese books and conducting a comprehensive review, this study elucidates the characteristics of potential dengue epidemics in China prior to 1978. This evidence indicates that China may not have experience dengue epidemics before 1840. During 1840-1949, however, it experienced a noticeable dengue occurrence and prevalence in the 1870s, 1920s, and 1940s. Then from 1949 to 1978, only sporadic reports were accounted. The disparity in the frequency of dengue occurrences across three time periods suggests that the persistent characteristic of dengue epidemics in China primarily arises from imported cases resulting from international exchanges, subsequently leading to local outbreaks influenced by global epidemic trend. This research offers a novel perspective on retrospectively examining the historical trajectory of dengue epidemics and provides valuable insights into exploration of DENV epidemic patterns.
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Dengue , Epidemias , Dengue/epidemiologia , Dengue/história , China/epidemiologia , Humanos , História do Século XX , Epidemias/história , História do Século XIX , Vírus da Dengue , Animais , Aedes/virologiaRESUMO
The present study introduces a novel fungus, Cystoderma yongpingense, which was identified in the southwestern region of China. The new species is characterized by a pileus that ranges in color from light orange-red to orange-red; the pileus has a wrinkled surface and is accompanied by a persistent annulus that is membranous and floccose-scaly. Above the annulus, the color transitions from white to yellowish brown. This proposal is substantiated through analyses encompassing both morphological characteristics and phylogenetic relationships. The phylogenetic position of the newly discovered species has been further corroborated through comprehensive maximum likelihood and Bayesian sequence analyses of the ITS + nrLSU DNA regions. Additionally, the technical description of C. yongpingense is enhanced by detailed illustrations and comparative studies with species that are closely related.
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Pathological thrombus can cause serious acute diseases that present a significant threat to human health, such as myocardial infarction and stroke. Challenges remain in achieving effective thrombolysis and real-time monitoring of therapeutic effects while minimizing side effects. Herein,a multifunctional nanoplatform (TG-OPDEA@UK/MnO2-H1080) with enhanced thrombus-permeability was developed to monitor the therapeutic effect of antioxidant-thrombolysis by hydroxyl radical-responsive NIR-II fluorescence imaging. The polyzwitterion poly (oxidized N,N-Diethylaminoethyl methacrylate-co-n-butyl methacrylate) (OPDEA) was prepared as the matrix of nanoparticles to simultaneously loading urokinase (UK) and MnO2 QDs, as well as NIR-II fluorescent molecule, H-1080. Subsequently, the fibrin targeted peptide CREKA was modified on the surface of the nanoparticles. OPDEA exhibits efficient loading capacity while endowing nanoparticles with the ability to effectively increased penetration depth of UK by 94.1â¯% into the thrombus, for extensive thrombolysis and fluorescence monitoring. The loaded UK exhibited good thrombolytic effect and greatly reduced the risk of bleeding by 82.6â¯%. TG-OPDEA@UK/MnO2-H1080 showed good thrombolytic efficacy and specific thrombus monitoring in the mouse carotid artery thrombosis model induced by ferric chloride (FeCl3). This work prepares a nanoplatform for thrombolytic therapy and real-time efficacy assessment based on an independent externally forced thrombus penetration delivery strategy.
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OBJECTIVES: The optimal dosing regimen of caspofungin in adolescents undergoing allogeneic haematopoietic stem cell transplantation against Candida spp. is unknown. The study aimed to compare body surface area (BSA)-based and fixed dosing regimens through population pharmacokinetic (PPK) analysis and to optimize dosing regimens likely to achieve therapeutic exposures. METHODS: Opportunistic sampling was used to collect plasma concentrations through a prospective observational pharmacokinetic study. PPK analysis and Monte Carlo simulations (nâ=â1000) were performed using NONMEM. RESULTS: A total of 86 samples of 30 adolescents (12-17â years old) were best described by a two-compartment pharmacokinetic model. BSA is the only covariate on clearance and central volume of distribution. For Candida glabrata and Candida albicans, a standard dosing regimen could achieve at least a 90% probability of target attainment for the indicator of AUC0-24/MIC90. Dosing regimen simulations identified a BSA cut-off value of 1.3â m2, where a fixed loading dose (LD) is preferred when BSAâ≥â1.3â m2 and a BSA-based LD is preferred when BSAâ<â1.3â m2. For maintenance dose (MD), however, the BSA-based dose was proposed, regardless of BSA. The current maximum dosing regimen of LD 70â mg/day and MD 70â mg/day could not result in sufficient antifungal exposure for Candida parapsilosis with MIC90 of 1â mg/L. Furthermore, an LD of 70â mg/day and MD of 60â mg/m2/day rendered 90.4% steady-state trough concentration (Ctrough) over 1â mg/L in the virtual population. CONCLUSIONS: Our study proposed optimized dosing regimens of caspofungin based on AUC0-24/MIC90 or Ctrough, which may support further individualized treatment.
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Antifúngicos , Candidíase , Caspofungina , Transplante de Células-Tronco Hematopoéticas , Método de Monte Carlo , Humanos , Caspofungina/administração & dosagem , Caspofungina/farmacocinética , Adolescente , Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Masculino , Feminino , Criança , Estudos Prospectivos , Candidíase/tratamento farmacológico , Testes de Sensibilidade Microbiana , Candida/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Equinocandinas/farmacocinética , Equinocandinas/administração & dosagem , Transplante Homólogo , Candida glabrata/efeitos dos fármacos , Superfície CorporalRESUMO
Although our understanding of herpes simplex virus type 1 (HSV-1) biology has been considerably enhanced, developing therapeutic strategies to eliminate HSV-1 in latently infected individuals remains a public health concern. Current antiviral drugs used for the treatment of HSV-1 complications are not specific and do not address latent infection. We recently developed a CRISPR-Cas9-based gene editing platform to specifically target the HSV-1 genome. In this study, we further used 2D Vero cell culture and 3D human induced pluripotent stem cell-derived cerebral organoid (CO) models to assess the effectiveness of our editing constructs targeting viral ICP0 or ICP27 genes. We found that targeting the ICP0 or ICP27 genes with AAV2-CRISPR-Cas9 vectors in Vero cells drastically suppressed HSV-1 replication. In addition, we productively infected COs with HSV-1, characterized the viral replication kinetics, and established a viral latency model. Finally, we discovered that ICP0- or ICP27-targeting AAV2-CRISPR-Cas9 vector significantly reduced viral rebound in the COs that were latently infected with HSV-1. In summary, our results suggest that CRISPR-Cas9 gene editing of HSV-1 is an efficient therapeutic approach to eliminate the latent viral reservoir and treat HSV-1-associated complications.
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The saline wastewater produced in industrial activities and seawater use would flow into wastewater treatment plants and affect the characteristic of extracellular polymeric substance (EPS) of activated sludge, which could potentially impact the removal of antibiotics via adsorption. Nonetheless, the effect of salinity on trimethoprim adsorption by activated sludge extracellular polymeric substances at trace concentration and the underlying mechanism remain largely unknown. In this study, the effect of salinity on the adsorption removal of a typical antibiotic, i.e., trimethoprim (TMP) at trace concentration (25.0 µg/L) was evaluated. The results showed the content of EPS was decreased significantly from 56.36 to 21.70 mg/g VSS when the salinity was increased from 0 to 10 g/L. Protein fractions occupied the predominant component of EPS, whose concentration was decreased from 38.17 to 12.83 mg/g VSS. The equilibrium adsorption capacity of activated sludge for TMP was decreased by 49.70% (from 4.97 to 2.50 µg/g VSS). The fluorescence quenching results indicated the fluorescence intensity of tryptophan-like substances was decreased by 30% and the adsorption sites of EPS were decreased from 0.51 to 0.21 when the salinity was increased. The infrared spectrum and XPS results showed that the nitrogen-containing groups from protein were decreased significantly. The circular dichroic analysis showed α helix structure of protein in EPS was decreased with the increase of salinity, which was responsible for the decrease of adsorption capacity for TMP.
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Matriz Extracelular de Substâncias Poliméricas , Salinidade , Esgotos , Trimetoprima , Esgotos/química , Adsorção , Trimetoprima/química , Matriz Extracelular de Substâncias Poliméricas/química , Matriz Extracelular de Substâncias Poliméricas/metabolismo , Águas Residuárias/química , Poluentes Químicos da Água/químicaRESUMO
Silicon (Si), as an ideal anode component for lithium-ion batteries, is susceptible to substantial volume changes, leading to pulverization and excessive electrolyte consumption, ultimately resulting in a rapid decline in the cycle stability. Herein, a new sodium carboxymethyl cellulose-epichlorohydrin (CMC-ECH) binder featuring a three-dimensional (3D) network cross-linked structure is synthesized by a simple ring-opening reaction, which can effectively bond the Si anode through abundant covalent and hydrogen bonds to mitigate its pulverization. Benefitting from the merits of the CMC-ECH binder, the electrochemical performance is significantly enhanced compared to the CMC binder. The CMC-ECH binder is applied to Si anodes, a specific capacity of 1054.2 mAh g-1 can be maintained at 0.2 C following 200 cycles under an elevated Si mass loading of around 1.0 mg cm-2, and the corresponding capacity retention is 65.6%. In the case of the LiFePO4//Si@CMC-ECH full battery, the cycle stability exhibits a substantial enhancement compared with the LiFePO4//Si@CMC full battery. Furthermore, the CMC-ECH binder demonstrates compatibility with micron-Si anode materials. Based on the above, we have successfully developed a facilely prepared water-based CMC-ECH binder that is suitable for Si and micron-Si anodes in lithium-ion batteries.
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Hepatic metachronous oligometastatic nasopharyngeal carcinoma (hmoNPC) exhibits distinct clinical characteristics compared to other types of metastatic NPC. We investigated the optimal therapy for hmoNPC. 160 patients with hmoNPC treated in Sun Yat-sen University Cancer Center between 2010 and 2021 were retrospectively recruited. A total of 56 patients were classified into the local therapy (LT) cohort, 23 into the systemic therapy (ST) cohort and 81 into the combination therapy (LT + ST) cohort. The median PFS was 7.9 months (95% confidence interval [CI]: 4.1-11.9 months) in the LT cohort, 15.5 months (95% CI: 10.5-32.3 months) in the ST cohort, and 31.3 months (95% CI: 20.3 to NA months) in the LT + ST cohort. The median OS was 41.1 months (95% CI: 30.0-54.0 months) in the LT cohort, 50.4 months (95% CI: 41.5 to NA months) in the ST cohort and not reached (NR) (95% CI: 77.3 to NA months) in the LT + ST cohort. Cox analysis was used to construct nomograms to predict patient outcomes. Among patients with no evidence of disease status after LT, the prognosis was significantly better in the LT + ST cohort than LT cohort (median PFS: NR [95% CI: 29.0 to NA months] vs. 20.0 months [95% CI: 10.4 to NA months]). More survival benefits were achieved with platinum-based chemotherapy than oral monotherapy (median PFS: NR [95% CI: 21.7 to NA months] vs. 17.2 months [95% CI: 10.2 to NA months]). Fewer postoperative early progression events were observed in neoadjuvant chemotherapy cohort than in adjuvant chemotherapy cohort (2.78% vs. 18.81%, P = .013). In conclusion, combining neoadjuvant platinum-based chemotherapy and local therapy was the best strategy for patients with hmoNPC.
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BACKGROUND: Effectiveness and safety of advanced therapies for ulcerative colitis (UC) warrant assessment in the real world. OBJECTIVE: To perform a systematic review and summarize real-world evidence of advanced therapies approved for moderate-to-severe UC. METHODS: A systematic literature review was conducted using real-world studies of biologics or small molecules in UC using Embase, MEDLINE, and MEDLINE-In Process databases. Only products approved in any jurisdiction during the search were included. English-language full-papers (January 2005 to February 2022) and congress abstracts (January 2019 to February 2022) were included. Studies with less than 30 patients or only biologic-naive patients were excluded. RESULTS: A total of 139 studies were included out of 3,930 identified articles (75%, published between 2019 and 2022; 64%, retrospective observational; 53%, from 5 countries [Italy, United States, Spain, United Kingdom, and Belgium]). Most studies were single agent (highest: vedolizumab = 50, tofacitinib = 24, and adalimumab = 18), and rates of clinical remission (CR) and adverse events varied widely. From the published comparative effectiveness studies (16), the rates of CR were numerically higher with vedolizumab vs anti-tumor necrosis factor (TNF)-α agents. Compared with vedolizumab, the effectiveness of tofacitinib was numerically greater in CR (occasionally significant). Rates of steroid-free CR were comparable between ustekinumab and tofacitinib. Infliximab was the most effective anti-TNFα agent, as reported by 2 studies. Remarkably, adverse events were similar across therapies in comparative studies. CONCLUSIONS: Vedolizumab and tofacitinib were the most assessed therapies. In comparative studies, remission rates were numerically higher with tofacitinib vs vedolizumab and for vedolizumab vs anti-TNFα. Tofacitinib was comparable with ustekinumab for steroid-free CR. Safety was comparable across therapies. Future studies should explore the literature gaps identified, including limited comparative studies with small sample sizes, variations in study designs and patient characteristics, varied definitions of CR, and limited use of patient-reported outcome measures in real-world settings.
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Colite Ulcerativa , Humanos , Colite Ulcerativa/tratamento farmacológico , Índice de Gravidade de Doença , Fármacos Gastrointestinais/uso terapêutico , Fármacos Gastrointestinais/efeitos adversos , Resultado do Tratamento , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Piperidinas/uso terapêutico , Piperidinas/efeitos adversos , Pirimidinas/uso terapêutico , Pirimidinas/efeitos adversosRESUMO
OBJECTIVES: To screen biomarkers for forensic identification of acute myocardial infarction (AMI) by non-targeted metabolomic studies on changes of urine metabolites in rats with AMI. METHODS: The rat models of the sham surgery group, AMI group and hyperlipidemia + acute myocardial infarction (HAMI) group were established. Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was used to analyze the changes of urine metabolic spectrometry in AMI rats. Principal component analysis, partial least squares-discriminant analysis, and orthogonal partial least squares-discriminant analysis were used to screen differential metabolites. The MetaboAnalyst database was used to analyze the metabolic pathway enrichment and access the predictive ability of differential metabolites. RESULTS: A total of 40 and 61 differential metabolites associated with AMI and HAMI were screened, respectively. Among them, 22 metabolites were common in both rat models. These small metabolites were mainly concentrated in the niacin and nicotinamide metabolic pathways. Within the 95% confidence interval, the area under the curve (AUC) values of receiver operator characteristic curve for N8-acetylspermidine, 3-methylhistamine, and thymine were greater than 0.95. CONCLUSIONS: N8-acetylspermidine, 3-methylhistamine, and thymine can be used as potential biomarkers for AMI diagnosis, and abnormal metabolism in niacin and nicotinamide may be the main causes of AMI. This study can provide reference for the mechanism and causes of AMI identification.
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Biomarcadores , Modelos Animais de Doenças , Metabolômica , Infarto do Miocárdio , Animais , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/urina , Ratos , Metabolômica/métodos , Masculino , Biomarcadores/urina , Biomarcadores/metabolismo , Cromatografia Líquida de Alta Pressão , Ratos Sprague-Dawley , Análise de Componente Principal , Análise Discriminante , Espectrometria de Massas/métodos , Niacina/metabolismo , Niacina/urina , Hiperlipidemias/metabolismo , Niacinamida/urina , Niacinamida/metabolismo , Niacinamida/análogos & derivados , Redes e Vias Metabólicas , Curva ROC , Análise dos Mínimos Quadrados , Medicina Legal/métodos , MetabolomaRESUMO
INTRODUCTION: Varicella has not yet been included in the National Immunization Program (NIP) in China, and varicella vaccination strategies vary by region. To determine the optimal varicella vaccination strategy in Shanghai, China, the cost-effectiveness and 5-year costs of 5 immunization scenarios were analyzed. METHODS: A static decision tree-Markov model was developed in 2022 to assess the cost-effectiveness and 5-year costs of voluntary and routine varicella vaccination programs in the 2019 birth cohort in Shanghai from a societal perspective. Parameters were collected in 2022 from the varicella surveillance system, a questionnaire survey of 414 guardians of patients with childhood varicella, and semi-structured interviews with 20 experts on varicella outbreaks from different institutions in Shanghai. The outcomes included varicella cases avoided, quality-adjusted life year (QALY) loss, and incremental costs per QALY (ICER). The 5-year costs were compared with local medical expenditures. RESULTS: Among the 5 scenarios, one dose of routine varicella vaccination was the most cost-saving (USD 70.2) and cost-effective (Dominant) with a 5-year immunization expenditure of USD 9.9 million. Two doses of routine varicella vaccination had the highest QALY (29.9), and its ICER (USD 791.9/QALY) was below the willingness-to-pay threshold (USD 5,203-23,767/QALY). The 5-year immunization expenditure was USD 19.8 million. The effectiveness and price of vaccines, vaccination coverage, and per capita income are the 4 main factors that affect ICERs. CONCLUSIONS: In Shanghai, the 2 doses of routine varicella vaccination strategy for 1- and 4-year-olds with a 95% coverage rate was found to be the optimal varicella immunization strategy.
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Infarto do Miocárdio , Humanos , Fatores de Risco , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/complicações , Masculino , Ruptura Cardíaca Pós-Infarto/etiologia , Ruptura Cardíaca Pós-Infarto/diagnóstico por imagem , Feminino , Pessoa de Meia-Idade , Idoso , Ruptura Cardíaca/etiologiaRESUMO
This study elucidates the molecular mechanisms by which FABP3 regulates neuronal apoptosis via mitochondrial autophagy in the context of cerebral ischemia-reperfusion (I/R). Employing a transient mouse model of middle cerebral artery occlusion (MCAO) established using the filament method, brain tissue samples were procured from I/R mice. High-throughput transcriptome sequencing on the Illumina CN500 platform was performed to identify differentially expressed mRNAs. Critical genes were selected by intersecting I/R-related genes from the GeneCards database with the differentially expressed mRNAs. The in vivo mechanism was explored by infecting I/R mice with lentivirus. Brain tissue injury, infarct volume ratio in the ischemic penumbra, neurologic deficits, behavioral abilities, neuronal apoptosis, apoptotic factors, inflammatory factors, and lipid peroxidation markers were assessed using H&E staining, TTC staining, Longa scoring, rotation experiments, immunofluorescence staining, and Western blot. For in vitro validation, an OGD/R model was established using primary neuron cells. Cell viability, apoptosis rate, mitochondrial oxidative stress, morphology, autophagosome formation, membrane potential, LC3 protein levels, and colocalization of autophagosomes and mitochondria were evaluated using MTT assay, LDH release assay, flow cytometry, ROS/MDA/GSH-Px measurement, transmission electron microscopy, MitoTracker staining, JC-1 method, Western blot, and immunofluorescence staining. FABP3 was identified as a critical gene in I/R through integrated transcriptome sequencing and bioinformatics analysis. In vivo experiments revealed that FABP3 silencing mitigated brain tissue damage, reduced infarct volume ratio, improved neurologic deficits, restored behavioral abilities, and attenuated neuronal apoptosis, inflammation, and mitochondrial oxidative stress in I/R mice. In vitro experiments demonstrated that FABP3 silencing restored OGD/R cell viability, reduced neuronal apoptosis, and decreased mitochondrial oxidative stress. Moreover, FABP3 induced mitochondrial autophagy through ROS, which was inhibited by the free radical scavenger NAC. Blocking mitochondrial autophagy with sh-ATG5 lentivirus confirmed that FABP3 induces mitochondrial dysfunction and neuronal apoptosis by activating mitochondrial autophagy. In conclusion, FABP3 activates mitochondrial autophagy through ROS, leading to mitochondrial dysfunction and neuronal apoptosis, thereby promoting cerebral ischemia-reperfusion injury.
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Apoptose , Autofagia , Proteína 3 Ligante de Ácido Graxo , Mitocôndrias , Neurônios , Traumatismo por Reperfusão , Animais , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Apoptose/fisiologia , Autofagia/fisiologia , Neurônios/metabolismo , Neurônios/patologia , Camundongos , Mitocôndrias/metabolismo , Masculino , Proteína 3 Ligante de Ácido Graxo/metabolismo , Proteína 3 Ligante de Ácido Graxo/genética , Camundongos Endogâmicos C57BL , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Estresse Oxidativo/fisiologiaRESUMO
INTRODUCTION: Isoniazid is a first-line antituberculosis agent with high variability, which would profit from individualized dosing. Concentrations of isoniazid at 2 h (C2h), as an indicator of safety and efficacy, are important for optimizing therapy. OBJECTIVE: The objective of this study was to establish machine learning (ML) models to predict the C2h, that can be used for establishing an individualized dosing regimen in clinical practice. METHODS: Published population pharmacokinetic (PopPK) models for adults were searched based on PubMed and ultimately four reliable models were selected for simulating individual C2h datasets under different conditions (demographics, genotype, ethnicity, etc.). Machine learning models were trained on simulated C2h obtained from the four PopPK models. Five different algorithms were used for ML model building to predict C2h. Real-world data were used for predictive performance evaluations. Virtual trials were used to compare ML-optimized doses with PopPK model-optimized doses. RESULTS: Categorical boosting (CatBoost) exhibited the highest prediction ability. Target C2h can be predicted using the ML model combined with the dosing regimen and three covariates (N-acetyltransferase 2 [NAT2] genotypes, weight and race [Asians and Africans]). Real-world data validation results showed that the ML model can achieve an overall prediction accuracy of 93.4%. Using the final ML model, the mean absolute prediction error value decreased by 45.7% relative to the average of PopPK models. Using the ML-optimized dosing regimen, the probability of target attainment increased by 43.7% relative to the PopPK model-optimized dosing regimens. CONCLUSION: Machine learning models were developed with great predictive performance, which can be used to determine the individualized initial dose of isoniazid in adult patients.