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BACKGROUND: The successful treatment and improvement of acute kidney injury (AKI) depend on early-stage diagnosis. However, no study has differentiated between the three stages of AKI and non-AKI patients following heart surgery. This study will fill this gap in the literature and help to improve kidney disease management in the future. METHODS: In this study, we applied Raman spectroscopy (RS) to uncover unique urine biomarkers distinguishing heart surgery patients with and without AKI. Given the amplified risk of renal complications post-cardiac surgery, this approach is of paramount importance. Further, we employed the partial least squares-support vector machine (PLS-SVM) model to distinguish between all three stages of AKI and non-AKI patients. RESULTS: We noted significant metabolic disparities among the groups. Each AKI stage presented a distinct metabolic profile: stage 1 had elevated uric acid and reduced creatinine levels; stage 2 demonstrated increased tryptophan and nitrogenous compounds with diminished uric acid; stage 3 displayed the highest neopterin and the lowest creatinine levels. We utilized the PLS-SVM model for discriminant analysis, achieving over 90% identification rate in distinguishing AKI patients, encompassing all stages, from non-AKI subjects. CONCLUSIONS: This study characterizes the incidence and risk factors for AKI after cardiac surgery. The unique spectral information garnered from this study can also pave the way for developing an in vivo RS method to detect and monitor AKI effectively.
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Lesión Renal Aguda , Biomarcadores , Procedimientos Quirúrgicos Cardíacos , Espectrometría Raman , Urinálisis , Humanos , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/orina , Lesión Renal Aguda/etiología , Espectrometría Raman/métodos , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Biomarcadores/orina , Urinálisis/métodos , Creatinina/orina , Máquina de Vectores de Soporte , Ácido Úrico/orina , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/orina , Complicaciones Posoperatorias/etiología , Factores de Riesgo , Análisis de los Mínimos CuadradosRESUMEN
Objectives This study aimed to identify the association between lactate dehydrogenase (LDH) levels and 30-day mortality in patients with intracranial hemorrhage (ICH) with acute leukemia during the induction phase. Methods This cohort study included patients with acute leukemia with ICH during induction. We evaluated serum LDH levels upon admission. Multivariable Cox regression analyzed the LDH 30-day mortality association. Interaction and stratified analyses based on factors like age, sex, albumin, white blood cell count, hemoglobin level, and platelet count were conducted. Results We selected 91 patients diagnosed with acute leukemia and ICH. The overall 30-day mortality rate was 61.5%, with 56 of the 91 patients succumbing. Among those with LDH levels ≥ 570 U/L, the mortality rate was 74.4% (32 out of 43), which was higher than the 50% mortality rate of the LDH < 570 U/L group (24 out of 48) ( p = 0.017). In our multivariate regression models, the hazard ratios and their corresponding 95% confidence intervals for Log2 and twice the upper limit of normal LDH were 1.27 (1.01, 1.58) and 2.2 (1.05, 4.58), respectively. Interaction analysis revealed no significant interactive effect on the relationship between LDH levels and 30-day mortality. Conclusions Serum LDH level was associated with 30-day mortality, especially in patients with LDH ≥ 570 U/L.
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BACKGROUND: Hypertension and hypercholesterolemia are important risk factors for cardiovascular disease, and treatment with fixed-dose combination (FDC) regimens is recommended by current guidelines. However, the clinical outcomes of different FDC dosages remain unknown. This study aimed to examine the clinical outcomes of FDC regimens and the free combination of amlodipine and atorvastatin at different dosages. METHODS AND RESULTS: Patients with concurrent hypertension and hypercholesterolemia treated daily with an FDC of 5 mg amlodipine and 10 mg atorvastatin (5/10 fixed group), and FDC of 5 mg amlodipine and 20 mg atorvastatin (5/20 fixed group), or free combination of 5 mg amlodipine and 20 mg atorvastatin (5/20 free group) were identified from the National Health Insurance Research Database of Taiwan. The primary outcome was the composite cardiovascular outcomes, including cardiovascular death, acute myocardial infarction, stroke, and coronary intervention. A total of 9095 patients were eligible for inclusion. The incidence of primary outcome per 1000 person-years was 16.6 in the 5/10 fixed group, 12.6 in the 5/20 fixed group, and 16.5 in the 5/20 free group (5/20 fixed versus 5/20 free: hazard ratio [HR], 0.76 [95% CI, 0.64-0.91]; 5/20 fixed versus 5/10 fixed: HR, 0.76 [95% CI, 0.63-0.90]). CONCLUSIONS: Among patients with concomitant hypertension and hypercholesterolemia, treatment with an FDC of amlodipine and high-dose atorvastatin led to a lower risk of a composite of cardiovascular outcomes than treatment with the free combination or a similar FDC with a lower dose of atorvastatin.
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Amlodipino , Atorvastatina , Combinación de Medicamentos , Ácidos Heptanoicos , Hipercolesterolemia , Hipertensión , Pirroles , Humanos , Amlodipino/administración & dosificación , Amlodipino/efectos adversos , Masculino , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/complicaciones , Hipercolesterolemia/epidemiología , Hipertensión/tratamiento farmacológico , Hipertensión/complicaciones , Hipertensión/epidemiología , Femenino , Persona de Mediana Edad , Atorvastatina/administración & dosificación , Anciano , Taiwán/epidemiología , Resultado del Tratamiento , Antihipertensivos/administración & dosificación , Antihipertensivos/uso terapéutico , Antihipertensivos/efectos adversos , Estudios Retrospectivos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/efectos adversos , Anticolesterolemiantes/uso terapéutico , Bloqueadores de los Canales de Calcio/administración & dosificación , Bloqueadores de los Canales de Calcio/efectos adversos , Bloqueadores de los Canales de Calcio/uso terapéutico , Presión Sanguínea/efectos de los fármacosRESUMEN
OBJECTIVES: Manual compression (MC) or vascular closure devices (VCDs) are used to achieve hemostasis after percutaneous transluminal angioplasty (PTA). However, limited data on the comparative safety and effectiveness of VCDs vs MC in patients with end-stage renal disease (ESRD) undergoing PTA are available. Accordingly, this study compared the safety and effectiveness of VCD and MC in patients with ESRD undergoing PTA. METHODS: This single-center retrospective cohort study included the data of patients with ESRD undergoing peripheral intervention at Chang Gung Memorial Hospital, Taiwan, from January 1, 2019, to June 30, 2022. The patients were divided into VCD and MC groups. The primary endpoint was a composite of puncture site complications, including acute limb ischemia, marked hematoma, pseudoaneurysm, and puncture site bleeding requiring blood transfusion. RESULTS: We included 264 patients with ESRD undergoing PTA, of whom 60 received a VCD and 204 received MC. The incidence of puncture site complications was 3.3% in the VCD group and 4.4% in the MC group (hazard ratio: .75; 95% confidence interval: .16-3.56 L P = 1.000), indicating no significant between-group difference. CONCLUSION: VCDs and MC had comparable safety and effectiveness for hemostasis in patients with ESRD undergoing peripheral intervention.
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Técnicas Hemostáticas , Fallo Renal Crónico , Enfermedad Arterial Periférica , Punciones , Dispositivos de Cierre Vascular , Humanos , Masculino , Femenino , Estudios Retrospectivos , Anciano , Técnicas Hemostáticas/instrumentación , Técnicas Hemostáticas/efectos adversos , Fallo Renal Crónico/terapia , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/complicaciones , Persona de Mediana Edad , Resultado del Tratamiento , Enfermedad Arterial Periférica/terapia , Enfermedad Arterial Periférica/diagnóstico por imagen , Taiwán , Factores de Riesgo , Factores de Tiempo , Presión , Hemorragia/etiología , Anciano de 80 o más Años , Medición de RiesgoRESUMEN
The loss of semaphorin 3A (Sema3A), which is related to endothelial-to-mesenchymal transition (EndMT) in atrial fibrosis, is implicated in the pathogenesis of atrial fibrillation (AF). To explore the mechanisms by which EndMT affects atrial fibrosis and assess the potential of a Sema3A activator (naringin) to prevent atrial fibrosis by targeting transforming growth factor-beta (TGF-ß)-induced EndMT, we used human atria, isolated human atrial endocardial endothelial cells (AEECs), and used transgenic mice expressing TGF-ß specifically in cardiac tissues (TGF-ß transgenic mice). We evaluated an EndMT marker (Twist), a proliferation marker (proliferating cell nuclear antigen; PCNA), and an endothelial cell (EC) marker (CD31) through triple immunohistochemistry and confirmed that both EndMT and EC proliferation contribute to atrial endocardial fibrosis during AF in TGF-ß transgenic mice and AF patient tissue sections. Additionally, we investigated the impact of naringin on EndMT and EC proliferation in AEECs and atrial fibroblasts. Naringin exhibited an antiproliferative effect, to which AEECs were more responsive. Subsequently, we downregulated Sema3A in AEECs using small interfering RNA to clarify a correlation between the reduction in Sema3A and the elevation of EndMT markers. Naringin treatment induced the expression of Sema3A and a concurrent decrease in EndMT markers. Furthermore, naringin administration ameliorated AF and endocardial fibrosis in TGF-ß transgenic mice by stimulating Sema3A expression, inhibiting EndMT markers, reducing atrial fibrosis, and lowering AF vulnerability. This suggests therapeutic potential for naringin in AF treatment.
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Fibrilación Atrial , Proliferación Celular , Células Endoteliales , Transición Epitelial-Mesenquimal , Flavanonas , Atrios Cardíacos , Semaforina-3A , Factor de Crecimiento Transformador beta , Animales , Humanos , Masculino , Ratones , Fibrilación Atrial/metabolismo , Fibrilación Atrial/patología , Fibrilación Atrial/genética , Fibrilación Atrial/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Fibrosis , Flavanonas/farmacología , Atrios Cardíacos/metabolismo , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/patología , Ratones Transgénicos , Semaforina-3A/metabolismo , Semaforina-3A/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
The pathophysiology of diabetic gastroparesis (DGP), a common complication in diabetic patients, is not fully known. Its development has been linked to several causes, including hyperglycaemia, vagal nerve dysfunction, aberrant Cajal's interstitial cell network (ICC), lack of nerve nitric oxide synthase (nNOS) expression in the intermuscular plexus, and hormonal alterations in the gastrointestinal tract. Glucose management, diet control, gastric stimulants, anti-emetic medications, Helicobacter pylori eradication, stomach electrical stimulation, and surgery are the main current treatments. These methods, however, could have unfavourable consequences. By examining recent studies and literature reviews, we outline the state of the study on diabetic gastroparesis in this paper.
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Complicaciones de la Diabetes , Gastroparesia , Humanos , Gastroparesia/terapia , Gastroparesia/etiología , Gastroparesia/tratamiento farmacológicoRESUMEN
OBJECTIVES: To estimate the association between early surgery and the risk of mortality in patients with left-sided infective endocarditis in the context of stroke. DESIGN: Retrospective cohort study. SETTING: This study was a multiinstitution study based on the Chang Gung Research Database, which contains electronic medical records from 7 hospitals in northern and southern Taiwan; these include 2 medical centers, 2 regional hospitals, and 3 district hospitals. PARTICIPANTS: Patients with active left-sided infective endocarditis who underwent valve surgery between September 2002 and December 2018. INTERVENTIONS: The authors divided patients into 2 groups, with versus without preoperative neurologic complications, had undergone early (within 7 d) or later surgery, and with brain ischemia or hemorrhage. MEASUREMENTS AND MAIN RESULTS: Three hundred ninety-two patients with a median time from diagnosis to surgery of 6 days were included. No significant differences in postoperative stroke, in-hospital mortality, or follow-up outcomes were observed between the patients with and without neurologic complications. Among the patients with preoperative neurologic complications, patients who underwent early surgery had a lower 30-day postoperative mortality rate (13.1% v 25.8%; hazard ratio, 0.21; 95% CI 0.07-0.67). In the subgroup analysis of the comparison between brain ischemia and hemorrhage groups, there was no significant between-group difference in the in-hospital outcomes or outcomes after discharge. CONCLUSIONS: Early cardiac surgery may be associated with more favorable clinical outcomes in patients with preoperative neurologic complications. Thus, preoperative neurologic complications should not delay surgical interventions.
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Isquemia Encefálica , Endocarditis Bacteriana , Endocarditis , Enfermedades del Sistema Nervioso , Accidente Cerebrovascular , Humanos , Estudios Retrospectivos , Endocarditis Bacteriana/complicaciones , Endocarditis Bacteriana/cirugía , Endocarditis/complicaciones , Endocarditis/cirugía , Accidente Cerebrovascular/cirugía , Accidente Cerebrovascular/complicaciones , Isquemia Encefálica/complicaciones , Isquemia Encefálica/cirugía , Enfermedades del Sistema Nervioso/epidemiología , Enfermedades del Sistema Nervioso/etiología , Hemorragia , Resultado del TratamientoRESUMEN
BACKGROUND: Wildfires in the Western United States are a growing and significant source of air pollution that is eroding decades of progress in air pollution reduction. The effects on preterm birth during critical periods of pregnancy are unknown. METHODS: We assessed associations between prenatal exposure to wildland fire smoke and risk of preterm birth (gestational age < 37 weeks). We assigned smoke exposure to geocoded residence at birth for all live singleton births in California conceived 2007-2018, using weekly average concentrations of particulate matter ≤ 2.5 µm (PM2.5) attributable to wildland fires from United States Environmental Protection Agency's Community Multiscale Air Quality Model. Logistic regression yielded odds ratio (OR) for preterm birth in relation to increases in average exposure across the whole pregnancy, each trimester, and each week of pregnancy. Models adjusted for season, age, education, race/ethnicity, medical insurance, and smoking of the birthing parent. RESULTS: For the 5,155,026 births, higher wildland fire PM2.5 exposure averaged across pregnancy, or any trimester, was associated with higher odds of preterm birth. The OR for an increase of 1 µg/m3 of average wildland fire PM2.5 during pregnancy was 1.013 (95 % CI:1.008,1.017). Wildland fire PM2.5 during most weeks of pregnancy was associated with higher odds. Strongest estimates were observed in weeks in the second and third trimesters. A 10 µg/m3 increase in average wildland fire PM2·5 in gestational week 23 was associated with OR = 1.034; 95 % CI: 1.019, 1.049 for preterm birth. CONCLUSIONS: Preterm birth is sensitive to wildland fire PM2.5; therefore, we must reduce exposure during pregnancy.
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Contaminantes Atmosféricos , Exposición Materna , Material Particulado , Nacimiento Prematuro , Humo , Incendios Forestales , Femenino , Embarazo , Humanos , Nacimiento Prematuro/epidemiología , California/epidemiología , Material Particulado/análisis , Adulto , Exposición Materna/estadística & datos numéricos , Humo/análisis , Humo/efectos adversos , Contaminantes Atmosféricos/análisis , Incendios Forestales/estadística & datos numéricos , Adulto Joven , Contaminación del Aire/estadística & datos numéricos , Recién NacidoRESUMEN
The organizational citizenship behavior (OCB) of teachers is crucial for effective school functioning, and accessing valuable resources from principals greatly influences this behavior. Grounded in the conservation of resources (COR) theory, this study explored how a principal's emotional intelligence (EI) and teachers' organizational trust (OT) impact teachers' OCB. A survey was conducted on 521 elementary teachers in Taiwan using established scales to measure the constructs. Perceived principal's EI was assessed across self-awareness, self-management, social awareness, and relationship management dimensions. Similarly, teachers' OCB was examined through interpersonal citizenship performance, organizational citizenship performance, and job/task conscientiousness dimensions. Teachers' OT was explored in terms of personal trust in the individual, trust in the principal, and trust in the school. The mediation effect of OT in the relationship between a principal's EI and teachers' OCB was analyzed using Hayes' PROCESS macro for SPSS. The results yielded valuable evidence supporting the mediating model that teachers' OCB, influenced by the principal's EI, can be seen as secondary gains driven by higher levels of OT cultivated by emotionally intelligent principals. This study emphasizes the pivotal role of a principal's EI in fostering teachers' OT and OCB, underscoring the significance of EI in educational leadership. Investing in the EI development of school principals can nurture a positive school culture, enabling teachers to fully realize their potential and contribute to the overall well-being of the school community. However, the research results face limitations in generalizability due to the restricted sample size exclusive to Taiwan and the reliance on self-report measures in the study.
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Ciudadanía , Instituciones Académicas , Humanos , Taiwán , Inteligencia Emocional , Poder PsicológicoRESUMEN
BACKGROUND: When mitral valve (MV) surgery is indicated, repair is preferred over replacement; however, this preference is not supported by evidence from clinical trials. Furthermore, the benefits of MV repair may not be universal for all etiologies of MV disease. METHODSâANDâRESULTS: This study identified a total of 18,428 patients who underwent MV repair (n=4,817) or MV replacement (n=13,611) during 2001-2018 from Taiwan's National Health Insurance Research Database. These patients were classified into 4 etiologies: infective endocarditis (IE, n=2,678), rheumatic heart disease (RHD, n=4,524), ischemic mitral regurgitation (IMR, n=3,893), and degenerative mitral regurgitation (DMR, n=7,333). After propensity matching, all-cause mortality during follow-up was lower among patients receiving MV repair than among patients receiving MV replacement in the IE, IMR, and DMR groups (hazard ratio [HR]=0.72, 95% confidence interval [CI]: 0.55-0.93; HR=0.82, 95% CI: 0.73-0.92; and HR 0.73, 95% CI: 0.64-0.84, respectively). However, in the RHD group, the MV reoperation rate was higher after MV repair than after MV replacement (subdistribution HR=1.91, 95% CI: 1.02-3.55). CONCLUSIONS: In comparison with MV replacement, MV repair was associated with a lower late mortality in patients with IE, IMR, and DMR, and a higher risk of reoperation in patients with RHD.
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Implantación de Prótesis de Válvulas Cardíacas , Insuficiencia de la Válvula Mitral , Cardiopatía Reumática , Humanos , Insuficiencia de la Válvula Mitral/etiología , Válvula Mitral/cirugía , Estudios de Cohortes , Resultado del TratamientoRESUMEN
BACKGROUND: In Taiwan, infective native aortic aneurysms (INAAs) are relatively common, so the aim of present study was to demonstrate the comparative outcomes of endovascular repair for thoracic and abdominal INAAs.MethodsâandâResults: Patients with naïve thoracic or abdominal INAAs managed with endovascular repair between 2001 and 2018 were included in this multicenter retrospective cohort. The confounding factors were adjusted with propensity score (PS). Of the 39 thoracic and 43 abdominal INAA cases, 41 (50%) presented with aneurysmal rupture, most of which were at the infrarenal abdominal (n=35, 42.7%) or descending thoracic aorta (n=25, 30.5%). Salmonella spp. was the most frequently isolated pathogen. The overall in-hospital mortality rate was 18.3%. The risks of in-hospital death and death due to rupture were significantly lower with thoracic INAAs (12.8% vs. 23.3%; PS-adjusted odds ratio (OR) 0.24, 95% confidence interval (CI) 0.06-0.96; 0.1% vs. 9.3%; PS-adjusted OR 0.11, 95% CI 0.01-0.90). During a mean follow-up of 2.5 years, the risk of all-cause death was significantly higher with thoracic INAAs (35.3% vs. 15.2%; PS-adjusted HR 6.90, 95% CI 1.69-28.19). Chronic kidney disease (CKD) was associated with death. CONCLUSIONS: Compared with thoracic INAAs, endovascular repair of abdominal INAAs was associated with a significantly higher in-hospital mortality rate. However, long-term outcomes were worse for thoracic INAAs, with CKD and infections being the most important predictor and cause of death, respectively.
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Aneurisma Infectado , Aneurisma de la Aorta Abdominal , Aneurisma de la Aorta Torácica , Aneurisma de la Aorta , Implantación de Prótesis Vascular , Procedimientos Endovasculares , Insuficiencia Renal Crónica , Humanos , Estudios Retrospectivos , Mortalidad Hospitalaria , Implantación de Prótesis Vascular/efectos adversos , Resultado del Tratamiento , Aneurisma de la Aorta/complicaciones , Aneurisma de la Aorta Torácica/cirugía , Aneurisma de la Aorta Abdominal/cirugía , Aneurisma de la Aorta Abdominal/complicaciones , Aneurisma Infectado/cirugía , Aneurisma Infectado/complicaciones , Insuficiencia Renal Crónica/complicaciones , Procedimientos Endovasculares/métodos , Factores de Riesgo , Complicaciones PosoperatoriasRESUMEN
Multi-agent reinforcement learning (MARL) algorithms based on trust regions (TR) have achieved significant success in numerous cooperative multi-agent tasks. These algorithms restrain the Kullback-Leibler (KL) divergence (i.e., TR constraint) between the current and new policies to avoid aggressive update steps and improve learning performance. However, the majority of existing TR-based MARL algorithms are on-policy, meaning that they require new data sampled by current policies for training and cannot utilize off-policy (or historical) data, leading to low sample efficiency. This study aims to enhance the data efficiency of TR-based learning methods. To achieve this, an approximation of the original objective function is designed. In addition, it is proven that as long as the update size of the policy (measured by the KL divergence) is restricted, optimizing the designed objective function using historical data can guarantee the monotonic improvement of the original target. Building on the designed objective, a practical off-policy multi-agent stochastic policy gradient algorithm is proposed within the framework of centralized training with decentralized execution (CTDE). Additionally, policy entropy is integrated into the reward to promote exploration, and consequently, improve stability. Comprehensive experiments are conducted on a representative benchmark for multi-agent MuJoCo (MAMuJoCo), which offers a range of challenging tasks in cooperative continuous multi-agent control. The results demonstrate that the proposed algorithm outperforms all other existing algorithms by a significant margin.
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Algoritmos , Aprendizaje , Benchmarking , Entropía , PolíticasRESUMEN
OBJECTIVE:At present,there are a variety of treatment methods for scoliosis using specific exercise therapy,but there is a lack of comparison of efficacy between different specific exercise therapy.This article compared the effectiveness of different specific exercise therapies to treat adolescent idiopathic scoliosis through a network meta-analysis. METHODS:Domestic and foreign electronic databases of relevant studies were searched for randomized controlled trials of specific exercise therapy for adolescent idiopathic scoliosis.Search time was from January 2000 to July 2023.The literature was screened by two reviewers using RevMan 5.4 and Stata 16.0 software to extract data and assess the bias risk of of inclusion studies. RESULTS:(1)This article includes 20 randomized controlled trials with 1 377 patients.Of them,12 studies involved Schroth therapy;2 studies involved BSPTS therapy,and 6 studies involved SEAS therapy.(2)The network meta-analysis indicated that in terms of improving Cobb angle and reducing trunk rotation angle in scoliosis patients,the BSPTS therapy group and Schroth therapy group were better than the conventional control group[WMD=-4.60,95%CI(-8.37,-0.82),P<0.05;WMD=-3.37,95%CI(-4.98,-1.75),P<0.05;WMD=-3.20,95%CI(-5.50,-0.90),P<0.05;WMD=-2.13,95%CI(-3.16,-1.09),P<0.05].The Schroth therapy group performed better than the conventional control group effective in improving the International Society for Scoliosis Research-22 Questionnaire quality of life score[WMD=1.41,95%CI(0.07,2.75),P<0.05]. CONCLUSION:Given the current evidence,BSPTS therapy group and Schroth therapy group were better than the conventional control group in improving Cobb angle and reducing trunk rotation angle.In the comparison of different specific exercise therapies,BSPTS therapy can be preferred to improve Cobb angle and reduce trunk rotation angle in adolescent idiopathic scoliosis patients.In addition,Schroth therapy may be the best treatment to improve the quality of life of adolescent idiopathic scoliosis patients.Limited by the quantity and quality of the included studies,the above conclusions should be interpreted with caution and need more high-quality studies to further validation.
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Variants in the gap junction beta-2 (GJB2) gene are the most common cause of hereditary hearing impairment. However, how GJB2 variants lead to local physicochemical and structural changes in the hexameric ion channels of connexin 26 (Cx26), resulting in hearing impairment, remains elusive. In this study, using molecular dynamics (MD) simulations, we showed that detached inner-wall N-terminal "plugs" aggregated to reduce the channel ion flow in a highly prevalent V37I variant in humans. To examine the predictive ability of the computational platform, an artificial mutant, V37M, of which the effect was previously unknown in hearing loss, was created. Microsecond simulations showed that homo-hexameric V37M Cx26 hemichannels had an abnormal affinity between the inner edge and N-termini to block the narrower side of the cone-shaped Cx26, while the most stable hetero-hexameric channels did not. From the perspective of the conformational energetics of WT and variant Cx26 hexamers, we propose that unaffected carriers could result from a conformational predominance of the WT and pore-shrinkage-incapable hetero-hexamers, while mice with homozygous variants can only harbor an unstable and dysfunctional N-termini-blocking V37M homo-hexamer. Consistent with these predictions, homozygous V37M transgenic mice exhibited apparent hearing loss, but not their heterozygous counterparts, indicating a recessive inheritance mode. Reduced channel conductivity was found in Gjb2V37M/V37M outer sulcus and Claudius cells but not in Gjb2WT/WT cells. We view that the current computational platform could serve as an assessment tool for the pathogenesis and inheritance of GJB2-related hearing impairments and other diseases caused by connexin dysfunction.
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Proteolysis-targeting chimeras (PROTACs) are heterobifunctional small molecules by utilizing the ubiquitin proteasome system (UPS) to degrade proteins of interest. PROTACs have exhibited unprecedented efficacy and specificity in degrading various oncogenic proteins because of their unique mechanism of action, ability to target "undruggable" and mutant proteins. A series of PROTACs have been developed to degrade multiple key protein targets for the treatment of hematologic malignancy. Notably, PROTACs that target BCL-XL, IRAK4, STAT3 and BTK have entered clinical trials. The known PROTACs that have the potential to be used to treat various hematological malignancies are systematically summarized in this review.
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Neoplasias Hematológicas , Quimera Dirigida a la Proteólisis , Humanos , Neoplasias Hematológicas/tratamiento farmacológico , Complejo de la Endopetidasa Proteasomal/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
The incidence of heart failure (HF) is increasing and is associated with a poor prognosis. Moreover, HF often coexists with renal dysfunction and is associated with a worsened outcome. In many experimental studies on cardiac dysfunction, the function of other organs was either not addressed or did not show any decline. Until now, the exact mechanisms for initiating and sustaining this interaction are still unknown. The objective of this study is to use volume overload to induce cardiac hypertrophy and HF in aortocaval fistula (ACF) rat models, and to elucidate how volume overload affects metabolic changes in the kidney, even with normal renal function, in HF. The results showed the metabolic changes between control and ACF rats, including taurine metabolism; purine metabolism; glycine, serine, and threonine metabolism; glycerophospholipid metabolism; and histidine metabolism. Increasing the downstream purine metabolism from inosine to uric acid in the kidneys of ACF rats induced oxidative stress through xanthine oxidase. This result was consistent with HK-2 cells treated with xanthine and xanthine oxidase. Under oxidative stress, taurine accumulation was observed in ACF rats, indicating increased activity of the hypotaurine-taurine pathway as a defense mechanism against oxidative stress in the kidney. Another antioxidant, ascorbic acid 2-sulfate, showed lower levels in ACF rats, indicating that the kidneys experience elevated oxidative stress due to volume overload and HF. In summary, metabolic profiles are more sensitive than clinical parameters in reacting to damage to the kidney in HF.
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Leaves are the primary photosynthetic organs, providing essential substances for tree growth. It is important to obtain an anatomical understanding and regulatory network analysis of leaf development. Here, we studied leaf development in Populus Nanlin895 along a development gradient from the newly emerged leaf from the shoot apex to the sixth leaf (L1 to L6) using anatomical observations and RNA-seq analysis. It indicated that mesophyll cells possess obvious vascular, palisade, and spongy tissue with distinct intercellular spaces after L3. Additionally, vacuoles fuse while epidermal cells expand to form pavement cells. RNA-seq analysis indicated that genes highly expressed in L1 and L2 were related to cell division and differentiation, while those highly expressed in L3 were enriched in photosynthesis. Therefore, we selected L1 and L3 to integrate ATAC-seq and RNA-seq and identified 735 differentially expressed genes (DEGs) with changes in chromatin accessibility regions within their promoters, of which 87 were transcription factors (TFs), such as ABI3VP1, AP-EREBP, MYB, NAC, and GRF. Motif enrichment analysis revealed potential regulatory functions for the DEGs through upstream TFs including TCP, bZIP, HD-ZIP, Dof, BBR-BPC, and MYB. Overall, our research provides a potential molecular foundation for regulatory network exploration in leaf development during photosynthesis establishment.
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Skepticism exists among healthcare workers and patients regarding the efficacy and safety of generic medication, despite its potential to lower healthcare costs. This study aimed to compare the outcomes of a generic clopidogrel and its brand-name counterpart for secondary prevention in patients with acute myocardial infarction (AMI). Using the Taiwan National Health Insurance Research Database, we identified 49,325 patients who were hospitalized for AMI between January 1, 2008 and December 31, 2013 and prescribed either generic or brand-name clopidogrel. Among them, 2419 (4.9%) were prescribed the generic clopidogrel. After propensity score matching, both the generic and brand-name groups consisted of 2382 patients. The primary efficacy outcome was a composite of myocardial infarction, coronary revascularization, ischemic stroke, and all-cause death. The primary safety outcome was major bleeding requiring hospitalization. At a mean follow-up of 2.5 years, the generic and brand-name clopidogrel groups had comparable risks of primary efficacy outcome (41.9% vs. 42%; hazard ratio [HR] 0.96; 95% confidence interval [CI] 0.88-1.04), and the risks of the individual components were also similar. There were no significant differences between the two groups in major bleeding (7.9% vs. 7.9%; HR 0.99; 95% CI 0.81-1.21). Subgroup analyses also revealed no statistically significant interactions between the treatment effect and various subgroups. In this retrospective database analysis, the generic clopidogrel was comparable to its brand-name counterpart regarding cardiovascular and bleeding outcomes for the treatment of patients with AMI.
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Infarto del Miocardio , Humanos , Clopidogrel/efectos adversos , Estudios de Cohortes , Estudios Retrospectivos , Prevención Secundaria , Infarto del Miocardio/prevención & control , Hemorragia/inducido químicamente , Hemorragia/prevención & control , Resultado del Tratamiento , Inhibidores de Agregación Plaquetaria/efectos adversosRESUMEN
Accurate identification of tissue types in surgical margins is essential for ensuring the complete removal of cancerous cells and minimizing the risk of recurrence. The objective of this study was to explore the clinical utility of Raman spectroscopy for the detection of oral squamous cell carcinoma (OSCC) in both tumor and healthy tissues obtained from surgical resection specimens during surgery. This study enrolled a total of 64 patients diagnosed with OSCC. Among the participants, approximately 50% of the cases were classified as the most advanced stage, referred to as T4. Raman experiments were conducted on cryopreserved tissue samples collected from patients diagnosed with OSCC. Prominent spectral regions containing key oral biomarkers were analyzed using the partial least squares-support vector machine (PLS-SVM) method, which is a powerful multivariate analysis technique for discriminant analysis. This approach effectively differentiated OSCC tissue from non-OSCC tissue, achieving a sensitivity of 95.7% and a specificity of 93.3% with 94.7% accuracy. In the current study, Raman analysis of fresh tissue samples showed that OSCC tissues contained significantly higher levels of nucleic acids, proteins, and several amino acids compared to the adjacent healthy tissues. In addition to differentiating between OSCC and non-OSCC tissues, we have also explored the potential of Raman spectroscopy in classifying different stages of OSCC. Specifically, we have investigated the classification of T1, T2, T3, and T4 stages based on their Raman spectra. These findings emphasize the importance of considering both stage and subsite factors in the application of Raman spectroscopy for OSCC analysis. Future work will focus on expanding our tissue sample collection to better comprehend how different subsites influence the Raman spectra of OSCC at various stages, aiming to improve diagnostic accuracy and aid in identifying tumor-free margins during surgical interventions.
RESUMEN
RATIONALE: Ear keloid is one of the more common forms of keloid, which may cause pain and itching, and is aesthetically unappealing. Recurrence is common with any monotherapy which prompted a comprehensive, multidimensional approach. PATIENT CONCERNS: A 24-year-old female was evaluated in our department on April 6, 2021, due to an "8-year recurrence following a left ear keloid resection." In July 2013, a left auricle keloid excision was performed in a local hospital. One year following the operation, the scar at the surgical site had proliferated, gradually spreading beyond the original scar borders. Patients worry about recurrence after surgery affecting the appearance of the ear. DIAGNOSIS: Ear keloid. INTERVENTIONS: The patient underwent a 2-stage re-resection of the keloid, followed by postoperative radiotherapy, and triamcinolone acetonide injection around the incision at the time of the second operation. Finally, silicone gel was applied for antiscar treatment. OUTCOMES: There has been no postoperative recurrence of ear keloid during the 12-month follow-up. LESSONS: For ear keloids, combination therapy offers an improved approach with an excellent aesthetic appearance and less risk of recurrence than traditional monotherapy.