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Morphogenesis is one of the most marvelous natural phenomena. The morphological characteristics of biological organs develop through growth, which is often triggered by mechanical force. In this study, we propose a bioinspired strategy for hydrogel morphogenesis through force-controlled chemical reaction and growth under isothermal conditions. We adopted a double network (DN) hydrogel with sacrificial bonds. Applying mechanical force to the gel caused deformation and sacrificial bond rupture. By supplying monomers to the gel, the radicals generated by the bond rupture triggered the formation of a new network inside the deformed gel. This new network conferred plasticity to the elastic gel, allowing it to maintain its deformed shape, along with increased volume and strength. We demonstrated that sheet-shaped DN hydrogels rapidly adopted various three-dimensional shapes at ambient temperature when subjected to forces such as drawing and blowing. This mechanism enables morphogenesis of elastic hydrogels and will promote the application of these materials in biomedical fields and soft machines.
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We numerically establish the controllable conversion between Laguerre-Gaussian and Hermite-Gaussian solitons in nonlinear media featuring parabolic and cross-phase potential wells. The parabolic potential maintains the stability of Laguerre-Gaussian and Hermite-Gaussian beams, while the actual conversion between the two modes is facilitated by the cross-phase potential, which induces an additional phase shift. By flexibly engineering the range of the cross-phase potential well, various higher-mode solitons can be generated at desired distances. Beams carrying orbital angular momentum can also be efficiently controlled by this method. In addition, other types of beams, such as sine complex-various-function Gaussian and hypergeometric-Gaussian vortex beams, can be periodically transformed and manipulated in a similar manner. Our approach allows the intricate internal relationships between different modes of beams to be conveniently revealed.
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In oncology anti-PD1 / PDL1 therapy development for solid tumors, objective response rate (ORR) is commonly used clinical endpoint for early phase study decision making, while progression free survival (PFS) and overall survival (OS) are widely used for late phase study decision making. Developing predictive models to late phase outcomes such as median PFS (mPFS) and median OS (mOS) based on early phase clinical outcome ORR could inform late phase study design optimization and probability of success (POS) evaluation. In existing literature, there are ORR / mPFS / mOS association and surrogacy investigations with limited number of included clinical trials. In this paper, without establishing surrogacy, we attempt to predict late phase survival (mPFS and mOS) based on early efficacy ORR and optimize late phase trial design for anti-PD1 / PDL1 therapy development. In order to include adequate number of eligible clinical trials, we built a comprehensive quantitative clinical trial landscape database (QLD) by combining information from different sources such as clinicaltrial.gov, publications, company press releases for relevant indications and therapies. We developed a generalizable algorithm to systematically extract structured data for scientific accuracy and completeness. Finally, more than 150 late phase clinical trials were identified for ORR / mPFS (ORR / mOS) predictive model development while existing literature included at most 50 trials. A tree-based machine learning regression model has been derived to account for ORR / mPFS (ORR / mOS) relationship heterogeneity across tumor type, stage, line of therapy, treatment class and borrow strength simultaneously when homogeneity persists. The proposed method ensures that the predictive model is robust and have explicit structure for clinical interpretation. Through cross validation, the average predictive mean square error of the proposed model is competitive to random forest and extreme gradient boosting methods and outperforms commonly used additive or interaction linear regression models. An example application of the proposed ORR / mPFS (ORR / mOS) predictive model on late phase trial POS evaluation for anti-PD1 / PDL1 combination therapy was illustrated.
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Antígeno B7-H1 , Neoplasias , Receptor de Morte Celular Programada 1 , Intervalo Livre de Progressão , Humanos , Antígeno B7-H1/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Ensaios Clínicos como AssuntoRESUMO
The US FDA's Project Optimus initiative that emphasizes dose optimization prior to marketing approval represents a pivotal shift in oncology drug development. It has a ripple effect for rethinking what changes may be made to conventional pivotal trial designs to incorporate a dose optimization component. Aligned with this initiative, we propose a novel seamless phase II/III design with dose optimization (SDDO framework). The proposed design starts with dose optimization in a randomized setting, leading to an interim analysis focused on optimal dose selection, trial continuation decisions, and sample size re-estimation (SSR). Based on the decision at interim analysis, patient enrollment continues for both the selected dose arm and control arm, and the significance of treatment effects will be determined at final analysis. The SDDO framework offers increased flexibility and cost-efficiency through sample size adjustment, while stringently controlling the Type I error. This proposed design also facilitates both accelerated approval (AA) and regular approval in a "one-trial" approach. Extensive simulation studies confirm that our design reliably identifies the optimal dosage and makes preferable decisions with a reduced sample size while retaining statistical power.
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Antineoplásicos , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Desenvolvimento de Medicamentos , Humanos , Ensaios Clínicos Fase II como Assunto/métodos , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Desenvolvimento de Medicamentos/métodos , Tamanho da Amostra , Simulação por Computador , Relação Dose-Resposta a Droga , Projetos de Pesquisa , Estados Unidos , United States Food and Drug Administration , Aprovação de Drogas , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias/tratamento farmacológicoRESUMO
OBJECTIVE: To evaluate the early and mid-term outcomes of open repair in patients with thoracoabdominal aortic aneurysm (TAAA) after thoracic endovascular aortic repair (TEVAR). METHODS: This was a retrospective single center study. Data were retrospectively collected and analyzed for consecutive patients undergoing open TAAA repair (TAAAR) after TEVAR from November 2016 to June 2021. Indications for TAAAR included aneurysm progression due to endoleak, persisted false lumen perfusion, proximal/distal disease progression, and aorta rupture. The risk factor of operative mortality was analyzed by multivariable logistic regression model and the survival was evaluated by Kaplan-Meier. RESULTS: Sixty-three patients who met the inclusion criteria for the study were identified. The mean age at TAAAR was 41 ± 12 years and 43 (68.3%) were male. Marfan syndrome (MFS) was presented in 39 patients (61.9%). 60 (95.2%) patients presented with post-dissection aneurysm and 3 (4.8%) patients with degenerative aneurysm. The extent of TAAA was Crawford I in 9 (14.3%), II in 22 (34.9%), III in 23 (36.5%), and IV in 9 (14.3%). Emergent TAAAR was done in 10 (15.9%) patients, and deep hypothermic circulatory arrest was used in 22 (34.6%). Endograft was explanted in 31 (49.2%). Operative mortality was 11 (17.5%). Stroke, paraplegia, and acute kidney failure occurred in 5 (7.9%), 7 (11.1%), and 6 (9.5%) patients, respectively. Pulmonary complications occurred in 19 (30.2%) patients. The estimated survival was 74.8 ± 4.9% at 5 years. Late reoperations were performed in 2 patients at 2.5 years and 1.3 years, respectively. CONCLUSIONS: In this series of TAAA after TEVAR, TAAAR was related with a high risk of operative mortality and morbidity and the midterm outcomes represented a durable treatment and were respectable.
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Aneurisma da Aorta Torácica , Aneurisma da Aorta Toracoabdominal , Implante de Prótese Vascular , Procedimentos Endovasculares , Humanos , Masculino , Feminino , Correção Endovascular de Aneurisma , Prótese Vascular/efeitos adversos , Estudos Retrospectivos , Implante de Prótese Vascular/efeitos adversos , Resultado do Tratamento , Aneurisma da Aorta Torácica/cirurgia , Fatores de Risco , Procedimentos Endovasculares/efeitos adversos , Complicações Pós-OperatóriasRESUMO
OBJECTIVE: To determine if diagnostic ultrasound can reliably distinguish between synovial patterns of prosthetic joint infection and polymeric wear in total knee replacements. METHODS AND METHODS: This retrospective study was approved by our hospital IRB. Using the radiology report database, MR examinations performed within a week of diagnostic ultrasound and/or ultrasound-guided aspiration were identified. This yielded (1) 24 cases with MR and ultrasound comparisons; (2) 44 cases with MR, ultrasound, and aspiration comparisons; and (3) 92 cases with ultrasound and aspiration comparisons. The MR studies were reviewed by a musculoskeletal radiologist. The ultrasound studies were each reviewed by 2 other musculoskeletal radiologists. Each study was graded for synovial pattern indicating infection, polymeric wear, or normal/nonspecific. Agreement between the MR grader and the ultrasound graders as well as ultrasound inter-rater agreement were assessed using k statistics. Sensitivity, specificity, positive predictive value, and negative predictive value of ultrasound were calculated. RESULTS: Agreement between ultrasound and MR imaging was fair to moderate: k of 0.27 (95% CI: 0.04, 0.50) and 0.44 (95% CI: 0.23, 0.65) for ultrasound raters 1 and 2, respectively. Inter-rater agreement between ultrasound graders 1 and 2 was moderate, with k of 0.56 (95% CI: 0.42, 0.70). Ultrasound sensitivities for infection were 0.13 and 0.09, while specificities were 0.94 and 0.98. Ultrasound sensitivities for polymeric wear were 0.38 and 0.62 with specificities of 0.90 and 0.76. CONCLUSION: Ultrasound does not perform well in distinguishing patterns of synovitis either compared to MRI or a reference standard of aspiration/clinical follow-up.
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Articulação do Joelho , Sinovite , Humanos , Estudos Retrospectivos , Articulação do Joelho/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Ultrassonografia , Sensibilidade e EspecificidadeRESUMO
OBJECTIVES: Hybrid coronary revascularization (HCR) involves the use of minimally invasive direct coronary artery bypass grafting (CABG) to treat the left anterior descending artery (LAD), and percutaneous coronary intervention to treat non-LAD vessels. We reported the results of a comparative analysis between HCR and off-pump CABG via sternotomy (OPCABG). METHODS: Data were retrospectively collated from patients who underwent HCR or OPCABG for multivessel coronary artery disease between 2011 and 2022. Propensity score-based matching was performed to reduce the selection bias. The Comparisons of cardiac-related death, major adverse cardiac and cerebrovascular events (MACCE), and repeat revascularization were performed by Kaplan-Meier analysis or the Fine-Gray test. RESULTS: After matching, the baseline characteristics were well-balanced between the two groups with 91 patients per group. There was no significant difference in operative mortality rate (1.1% for HCR vs2.2% for OPCABG, p = 1.000). However, patients undergoing HCR required a significantly lower rate of blood product transfusions (p < .001) and experienced significantly fewer pulmonary complications than OPCABG patients (p < .001). At 10 years, the incidences of cardiac-related death, MACCE and repeat revascularization did not differ significantly between the two groups (9.5% vs11.5%, p = .277; 4.7% vs12.3%, p = .361; 1.2% vs2.5%, p = .914, respectively). CONCLUSIONS: For patients with multi-vessel lesions, HCR was comparable to OPCABG in long-term outcomes such as cardiac-related death, MACCE, and the durability of grafts. Additionally, HCR was better than OPCABG in perioperative outcomes. HCR may be an alternative therapy for OPCABG in patients with multi-vessel coronary artery disease.
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OBJECTIVES: To explore the risk factors of social isolation in older adults by meta-analysis. METHODS: We examined articles that had been published on the China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service platform, VIP Periodical Chinese Journal Service platform, Medical Literature database, PubMed, Embase database, Chinese BioMedical Literature database (CBM), and the Cochrane Library. RevMan 5.3 software was used for meta-analysis. RESULTS: A total of 13 pieces of literature comprising 47,288 patients were included, including five in Chinese and eight in English. According to our review, the common risk factors reported were age, sex, education level, marital status, self-rated health status, depression, social support, cognitive function, and basic diseases. Gender (female), education level (lower education level), marital status (divorced), self-rated health status (poor), depression, lack of social support, inadequate cognitive function, and underlying disorders were the key risk factors for social isolation in older adults. CONCLUSIONS: To reduce social isolation in older adults, paying more attention to the aging population with poor marital statuses, low education levels, poor health statuses, depression, poor cognitive function, and other underlying diseases is necessary. It is essential to encourage patients and their family members to participate in social activities and build a multi-social support system to reduce social isolation in older adults.
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Nível de Saúde , Isolamento Social , Idoso , Humanos , China/epidemiologia , Fatores de RiscoRESUMO
This paper presents a novel, to the best of our knowledge, method for realizing soliton transformation between different potential wells by gradually manipulating their depths in the propagation direction. The only requirements for such a transformation are that the gradient of the manipulated depth is smooth enough and the solitons in different potential wells are both in the regions of stability. The comparison of transformed solitons with the iterative ones obtained by the accelerated imaginary-time evolution method proves that our method is efficient and reliable. An interesting consequence is that in some complex potential wells in which it is difficult to find solitons by iterative numerical methods, stable solitons can be obtained by the transformation method. The controllable soliton transformation provides an excellent opportunity for all-optical switching, optical information processing, and other applications.
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Controllable trajectories of beams are one of the main themes in optical science. Here, we investigate the propagation dynamics of Laguerre-Gaussian (LG) solitons in parabolic potential wells and introduce off-axis and chirp parameters (which represent the displacement and the initial angle of beams) to make solitons sinusoidally oscillate in the x and y directions and undergo elliptically or circularly spiraling trajectories during propagation. Additionally, LG solitons with different orders and powers can be combined into soliton arrays of various shapes, depending on the off-axis parameter. Moreover, the soliton arrays can exhibit periodic converging, rotating, and other evolution behaviors, by the proper choice of the chirp parameter. A series of interesting examples demonstrate typical propagation scenarios. Our results may provide a new perspective on and stimulate further investigations of multisoliton interactions in potential wells and may find applications in optical communication and particle control.
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BACKGROUND: Relatively few studies have explored the differential contributions of the accumulative dosage of psychotropic medications on mortality in patients with schizophrenia. METHODS: We aimed to explore the effects of the exposure dosage of psychotropic medications on mortality during a follow-up period of 5 years with a national cohort of individuals with schizophrenia in 2010. Causes of death were linked through Taiwan's National Mortality Registry. The mean defined daily dose of antipsychotics, antidepressants, mood stabilizers, and sedative-hypnotics, were calculated and survival analyses were conducted. RESULTS: A total of 102 964 individuals (54 151 men, 52.59%) with schizophrenia were included. Compared to patients with no exposure to antipsychotics, those with antipsychotic exposure had better survival outcomes, regardless of antipsychotic dosage. Antidepressant exposure, in low and moderate dosage, was associated with decreased all-cause mortality; exposure to mood stabilizers appeared to be associated with an increase in all-cause mortality. Although 89.7% of the patients had been prescribed sedative-hypnotics, exposure to sedative-hypnotics was associated with dose-related increased mortality risk [hazard ratio (HR) in low dose group: 1.16, 95% confidence interval (CI) 1.07-1.27; HR in moderate dose: 1.32, 95% CI 1.21-1.44; HR in high dose: 1.83, 95% CI 1.67-2.01)]. CONCLUSIONS: The results indicate that in the treatment of schizophrenia, antipsychotics and antidepressants are associated with lower mortality when using adequate dosages and mood stabilizers and sedative-hypnotics with higher mortality compared with no use. Furthermore, exposure to sedative-hypnotics is associated with a dose-related increased mortality risk which warrants clinical attention and further study.
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Antipsicóticos , Esquizofrenia , Masculino , Humanos , Esquizofrenia/tratamento farmacológico , Esquizofrenia/induzido quimicamente , Antipsicóticos/efeitos adversos , Estudos de Coortes , Psicotrópicos/uso terapêutico , Antidepressivos , Hipnóticos e Sedativos/uso terapêutico , Antimaníacos/uso terapêuticoRESUMO
OBJECTIVES: Clinical laboratory results are required for critical medical decisions, underscoring the importance of quality results. As part of total quality management, external quality assessment (EQA) is a vital component to ensure laboratory accuracy. The goal of this survey was to evaluate the current status of global laboratory quality systems and assess the need for implementation, expansion, or harmonization of EQA programs (EQAP) for Clinical Chemistry and Laboratory Medicine. METHODS: The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on Global Laboratory Quality (TF-GLQ) conducted a survey of IFCC full and affiliate members (n=110) on laboratory quality practice. A total of 41 (37.3%) countries representing all IFCC regions except North America provided responses about EQA availability and practices. RESULTS: All 41 countries perform EQA, 38 reported that their laboratories had EQA policies and procedures, and 39 further act/evaluate unacceptable EQA results. 39 countries indicated they have international and/or national EQAP and 30 use alternative performance assessments. EQA frequency varied among countries. Generally, an EQAP provided the EQA materials (40/41) with four countries indicating that they did not have an EQAP in their country. CONCLUSIONS: Globally, most laboratories participate in an EQAP and have defined quality procedures for EQA. There remain gaps in EQA material availability and implementation of EQA as a part of a total laboratory quality system. This survey highlights the need for education, training, and harmonization and will guide efforts of the IFCC TF-GLQ in identifying areas for enhancing global laboratory quality practices.
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Química Clínica , Laboratórios , Humanos , Inquéritos e Questionários , Gestão da Qualidade Total , Garantia da Qualidade dos Cuidados de SaúdeRESUMO
OBJECTIVES: The trueness and precision of clinical laboratory results are ensured through total quality management systems (TQM), which primarily include internal quality control (IQC) practices. However, quality practices vary globally. To understand the current global state of IQC practice and IQC management in relation to TQM the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on Global Laboratory Quality (TF-GLQ) conducted a survey of IFCC member countries on IQC practices and management. METHODS: The survey included 16 questions regarding IQC and laboratory TQM practices and was distributed to IFCC full and affiliate member countries (n=110). A total of 46 (41.8â¯%) responses were received from all regions except North America. RESULTS: Of the responding countries, 78.3â¯% (n=36) had legislative regulations or accreditation requirements governing medical laboratory quality standards. However, implementation was not mandatory in 46.7â¯% (n=21) of responding countries. IQC practices varied considerably with 57.1â¯% (n=28) of respondents indicating that they run 2 levels of IQC, 66.7â¯% (n=24) indicating they run IQC every 24â¯h and 66.7â¯% (n=28) using assay manufacturer IQC material sources. Only 29.3â¯% (n=12) of respondents indicated that every medical laboratory in their country has written IQC policies and procedures. By contrast, 97.6â¯% (n=40) of responding countries indicated they take corrective action and result remediation in the event of IQC failure. CONCLUSIONS: The variability in TQM and IQC practices highlights the need for more formal programs and education to standardize and improve TQM in medical laboratories.
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Laboratórios , Gestão da Qualidade Total , Humanos , Controle de Qualidade , Inquéritos e QuestionáriosRESUMO
BACKGROUND: There is currently a lack of a precise, concise, and practical clinical prediction model for predicting coronary artery disease (CAD) in patients with essential hypertension (EH). This study aimed to construct a nomogram to predict CAD in patients with EH based on flow-mediated dilation (FMD) of brachial artery and traditional risk factors. METHODS: Clinical data of 1752 patients with EH were retrospectively collected. High-resolution vascular ultrasound was used to detect FMD in all patients at the Fujian Hypertension Research Institute, China. Patients were divided into two groups, i.e. training group (n = 1204, from August 2000 to December 2013) and validation group (n = 548, from January 2014 to May 2016) according to the time of enrollment. Independent predictors of CAD were analyzed by multivariable logistic regression in the training group, and a nomogram was constructed accordingly. Finally, we evaluated the discrimination, calibration, and clinical applicability of the model using the area under curve (AUC) of receiver operating characteristic analysis, calibration curve combined with Hosmer-Lemeshow test, and decision curve, respectively. RESULTS: There were 263 (21.8%) cases of EH combined with CAD in the training group. Multivariate logistic regression showed that FMD, age, duration of EH, waist circumference, and diabetes mellitus were independent influencing factors for CAD in EH patients. Smoking which was close to statistical significance (P = 0.062) was also included in the regression model to increase the accuracy. Ultimately, the nomogram for predicting CAD in EH patients was constructed according to above predictors after proper transformation. The AUC values of the training group and the validation group were 0.799 (95%CI 0.770-0.829) and 0.836 (95%CI 0.787-0.886), respectively. Calibration curve and Hosmer-Lemeshow test showed that the model had good calibration (training group: χ2 = 0.55, P = 0.759; validation group: χ2 = 1.62, P = 0.446). The decision curve also verified the clinical applicability of the nomogram. CONCLUSION: The nomogram based on FMD and traditional risk factors (age, duration of EH disease, smoking, waist circumference and diabetes mellitus) can predict CAD high-risk group among patients with EH.
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Doença da Artéria Coronariana , Hipertensão , Humanos , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Modelos Estatísticos , Nomogramas , Estudos Retrospectivos , Prognóstico , Hipertensão/complicações , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Hipertensão Essencial , Fatores de RiscoRESUMO
BACKGROUND: The effects of minimally invasive total mesoesophageal excision (MITME) on the long-term prognosis of locally advanced esophageal squamous cell carcinoma (ESCC) remain unknown. The objective of this study was to compare the static and dynamic failure patterns of MITME and minimally invasive esophagectomy (MIE) for locally advanced ESCC. METHODS: We use propensity score matching (PSM) method to analyze the postoperative failure patterns of the two groups. Cumulative event curves were analyzed for cumulative incidence of failure between different groups, and independent prognostic factors were assessed using time-dependent multivariate analyses. The risk of dynamic failure calculated at 12-month intervals was compared between the two groups using the lifetime table. RESULTS: A total of 366 ESCC patients were studied by 1:1 PSM for T stage and TNM stage (MITME group, n = 183; MIE group, n = 183). In the matched cohort, there was significant differences between the MITME and MIE groups in the failure pattern of regional lymph node recurrence (0.5 vs 3.8%, P = 0.032) and non-tumor death (10.9 vs 31.7%, P < 0.001). The cumulative event curve found that the 5-year cumulative failure rate was lower in the MITME group than in the MIE group (3.3 vs 17.1%, P = 0.026) after 5 years of survival. In addition, multivariate Cox regression analysis showed that MIE was an independent poor prognostic factor for a high cumulative failure rate in locally advanced ESCC patients at 5 years after surgery (HR:4.110; 95% CI 1.047-16.135; P = 0.043). The dynamic risk curve showed that the MITME group had a lower risk of failure within 5 years after surgery than the MIE group. CONCLUSION: Considering that MITME can significantly improve the postoperative failure pattern and the benefit lasts for at least 5 years, it is feasible to use MITME as a treatment for locally advanced ESCC.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/cirurgia , Neoplasias Esofágicas/patologia , Seguimentos , Estudos de Coortes , Esofagectomia/métodos , Resultado do Tratamento , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Procedimentos Cirúrgicos Minimamente Invasivos/métodosRESUMO
O'nyong-nyong fever is a mosquito-borne tropical viral disease while few molecular diagnostic tools have been established for its surveillance until now. In the current study, a single-step, dual-color real-time reverse transcription polymerase chain reaction (RT-PCR) assay which contained both external quality control (EQC) and internal quality control (IQC) prepared by armored RNA technique was developed and evaluated for the detection of o'nyong-nyong virus (ONNV). Results showed that the assay was established successfully without cross-reaction with genetically related or symptom-alike diseases, which showed high specificity of the assay. The coefficient of variation of the assay was 0.97%, far less than 5%, indicating good repeatability of the assay. The lower limit of detection of the assay could reach as low as 100 copies of genome equivalent. During evaluation, the assay could correctly detect ONNV from spiked human serum samples and Anopheles species mosquito samples, while no ONNV positive was observed either from serum samples of patients with acute febrile illness or from local Anopheles species mosquitoes, suggesting no ONNV had been transmitted locally. In conclusion, the assay could potentially provide a valuable platform for ONNV molecular detection, which may improve the preparedness for future o'nyong-nyong fever outbreaks.
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Anopheles , Vírus O'nyong-nyong , Animais , Humanos , Vírus O'nyong-nyong/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Anopheles/genética , Reação em Cadeia da Polimerase em Tempo Real , Reações CruzadasRESUMO
The aim of this study was to explore the role and mechanism of long non-coding RNA (lncRNA) HIF1A antisense RNA 2 (HIF1A-AS2) in regulating imatinib (IM) resistance in gastrointestinal stromal tumor (GIST) cells under hypoxia. The expression of HIF1A-AS2 was silenced by siRNA in GIST cells. Cytotoxicity, apoptosis, and autophagy were evaluated under normoxic and hypoxic conditions. The expression levels of HIF1A-AS2, HIF1A, apoptosis-associated genes, and autophagy-associated genes were determined by qRT-PCR analysis and western blot. We found that lncRNA HIF1A-AS2 was highly expressed in GIST tissues and cells. Knockdown of HIF1A-AS2 increased the sensitivity of GIST cells to IM and increased apoptosis. Moreover, a hypoxic environment decreased the sensitivity of GIST cells to IM, and the knockdown of HIF1A-AS2 reversed this effect. Mechanistically, the knockdown of HIF1A-AS2 inhibited IM-mediated autophagy. Finally, HIF1A was found to positively regulate HIF1A-AS2 under hypoxic conditions. Collectively, these data demonstrate that hypoxia-induced HIF1A-AS2 promotes IM resistance in GIST cells by regulating autophagy.
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Tumores do Estroma Gastrointestinal , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Mesilato de Imatinib/farmacologia , Linhagem Celular Tumoral , Autofagia/genética , Hipóxia/genética , Proliferação de Células/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genéticaRESUMO
Recent studies have shown that global metabolic reprogramming is a common event in plant innate immunity; however, the relevant molecular mechanisms remain largely unknown. Here, we identified a pathogen-induced glycosyltransferase, UGT73C7, that plays a critical role in Arabidopsis disease resistance through mediating redirection of the phenylpropanoid pathway. Loss of UGT73C7 function resulted in significantly decreased resistance to Pseudomonas syringae pv. tomato DC3000, whereas constitutive overexpression of UGT73C7 led to an enhanced defense response. UGT73C7-activated immunity was demonstrated to be dependent on the upregulated expression of SNC1, a Toll/interleukin 1 receptor-type NLR gene. Furthermore, in vitro and in vivo assays indicated that UGT73C7 could glycosylate p-coumaric acid and ferulic acid, the upstream metabolites in the phenylpropanoid pathway. Mutations that lead to the loss of UGT73C7 enzyme activities resulted in the failure to induce SNC1 expression. Moreover, glycosylation activity of UGT73C7 resulted in the redirection of phenylpropanoid metabolic flux to biosynthesis of hydroxycinnamic acids and coumarins. The disruption of the phenylpropanoid pathway suppressed UGT73C7-promoted SNC1 expression and the immune response. This study not only identified UGT73C7 as an important regulator that adjusts phenylpropanoid metabolism upon pathogen challenge, but also provided a link between phenylpropanoid metabolism and an NLR gene.
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Proteínas de Arabidopsis/imunologia , Arabidopsis/fisiologia , Glicosiltransferases/metabolismo , Imunidade Vegetal/fisiologia , Arabidopsis/efeitos dos fármacos , Proteínas de Arabidopsis/genética , Ácidos Cumáricos/metabolismo , Resistência à Doença/imunologia , Regulação da Expressão Gênica de Plantas , Glicosilação , Glicosiltransferases/genética , Glicosiltransferases/imunologia , Interações Hospedeiro-Patógeno/fisiologia , Ácidos Isonicotínicos/farmacologia , Doenças das Plantas/imunologia , Plantas Geneticamente Modificadas , Pseudomonas syringae/patogenicidadeRESUMO
The present study aimed to explore the association between dietary patterns in abdominal obesity obtained by reduced-rank regression (RRR) with visceral fat index (VFI) as a dependent variable and dyslipidemia in rural adults in Henan, China. A total of 29538 people aged 18-79 were selected from the Henan Rural Cohort Study. RRR analysis was used to identify dietary patterns; logistic regression analysis and restricted cubic spline regression models were applied to analyze the association between dietary patterns in abdominal obesity and dyslipidemia. VFI was used as a mediator to estimate the mediation effect. The dietary pattern in abdominal obesity was characterized by high carbohydrate and red meat intake and low consumption of fresh fruits, vegetables, milk, etc. After full adjustment, the highest quartile of dietary pattern scores was significantly associated with an increased risk of dyslipidemia (OR: 1·33, 95 % CI 1·23-1·44, Ptrend < 0·001), there was a non-linear dose-response relationship between them (Poverall-association < 0·001, Pnon-lin-association = 0·022). The result was similar in dose-response between the dietary pattern scores and VFI. The indirect effect partially mediated by VFI was significant (OR: 1·07, 95 % CI 1·06-1·08). VIF explained approximately 53·3 % of odds of dyslipidemia related to the dietary pattern. Abdominal obesity dietary pattern scores positively affected VFI and dyslipidemia; there was a dose-response in both relationships. Dyslipidemia progression increased with higher abdominal obesity dietary pattern scores. In addition, VFI played a partial mediating role in relationship between abdominal obesity dietary pattern and dyslipidemia.
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Dislipidemias , Obesidade Abdominal , Adulto , Humanos , Estudos de Coortes , Gordura Intra-Abdominal , Dieta/efeitos adversos , Obesidade , China , Fatores de RiscoRESUMO
BACKGROUND: Our aim was to evaluate the effect of setting up a full-time infection control nursing service on reducing the prevalence of multidrug-resistant organism (MDRO) in the orthopedic ward. METHODS: From January 2015 to March 2019, routine prevention and control measures were taken for patients infected/colonized with MDRO in this ward, which was set as the pre-intervention period. The intervention period was from April 2019 to June 2021. The study was designed to evaluate whether the establishment of a full-time infection control nursing service could reduce the positive density of MDRO in the hospital by using an interrupted time-series model of a quasi experimental study. RESULTS: There were 11,759 patients during pre-intervention period and 8142 patients during intervention period. The total number of MDRO isolated before intervention was 177, of which 145 were obtained in hospital and 32 were brought in from outside hospital. The total number of MDRO isolated after intervention was 47, of which 29 were obtained in hospital and 18 were brought in from outside hospital. Before intervention, the positive density of MDRO in the orthopedic ward showed an increasing trend (ß1 = 0.02, P = 0.003). After intervention, the positive density of MDRO showed a downward trend (ß3 = - 0.05, P = 0.018). CONCLUSIONS: The establishment of the full-time infection control nursing service in the orthopedic ward can effectively reduce the nosocomial prevalence of MDRO.