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Randomized Trial of Ciclosporin with 2-h Monitoring *** with Trough Monitoring in Liver Transplantation:DELTA Study

journal of Clinical and Translational Hepatology 2023年第4期11卷 839-849页

作者： Bastian N.Ruijter Akin Inderson Aad Pvan den Berg herold j.metselaar jeroen Dubbeld Maarten E.Tushuizen Robert j.Porte Wojciech Polak Danny van der Helm Marjolein van Reeven Mar Rodriguez-Girondo Bart van Hoek Department of Gastroenterology and Hepatology LUMC Transplantation CenterLeiden University Medical CenterLeidenThe Netherlands Department of Gastroenterology and Hepatology University Medical Center GroningenGroningenThe Netherlands Department of Gastroenterology and Hepatology Erasmus MC Transplant InstituteErasmus Medical CenterRotterdamThe Netherlands Department of Surgery LUMC Transplantation CenterLeiden University Medical CenterLeidenThe Netherlands Department of Surgery Section HPB Surgery and Liver TransplantationUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands Department of Surgery Division of HPB and Transplant SurgeryErasmus MC Transplant InstituteErasmus Medical CenterRotterdamThe Netherlands Department of Biomedical Data Sciences Leiden University Medical CenterLeidenThe Netherlands.

Background and Aims:Previous trials comparing cyclosporine and tacrolimus after liver transplantation(LT)showed conflicting *** used trough monitoring for cyclosporine(C0),leading to less accurate dosing than with 2-h monitoring(C2).Only one larger trial compared C2 with tacrolimus based on trough level(T0)after LT,with similar treated biopsy-proven acute rejection(tBPAR)and graft loss,while a smaller trial had less tBPAR with C2 compared to ***,it is still unclear which calcineurin inhibitor is preferred after *** aimed to demonstrate superior efficacy(tBPAR),tolerability,and safety of C2 or T0 after first ***:Patients after first LT were randomized to C2 or ***,patient-and graft survival,safety and tolerability were the main endpoints,with analysis by Fisher test,Kaplan-Meier survival analysis and log-rank ***:In intention-totreat analysis 84 patients on C2 and 85 on T0 were *** incidence of tBPAR C2 vs.T0 was 17.7%vs.8.4%at 3 months(p=0.104),and 21.9%vs.9.7%at 6 and 12 months(p=0.049).One-year cumulative mortality C2 vs.T0 was 15.5%vs.5.9%(p=0.049)and graft loss 23.8%vs.9.4%(p=0.015).Serum triglyceride and LDL-cholesterol was lower with T0 than with *** of diarrhea in T0 vs,C2 was 64%vs.31%(p≤0.001),with no other differences in safety and ***:In the first year after LT immunosuppression with T0 leads to less tBPAR and better patient-/re-transplant-free survival as compared to C2.

关键词： Adverse effects Ciclosporin Liver transplantation Outcome Randomized controlled trial Rejection Survival Renal function Tacrolimus

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Interaction of immunosuppressants with HCV antivirals daclatasvir and asunaprevir: combined effects with mycophenolic acid

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World journal of Transplantation 2018年第5期8卷 156-166页

作者： Petra E de Ruiter Yashna Gadjradj Robert j de Knegt herold j metselaar jan NM Ijzermans Luc jW van der Laan Department of Surgery Erasmus MC-University Medical Center Department of Gastroenterology and Hepatology Erasmus MC-University Medical Center

AIM To investigate the specific effects of immunosuppressants on the antiviral action of daclatasvir and *** The antiviral activity of daclatasvir(DCV) and asunaprevir(ASV) combined with immunosuppressants was tested using two in vitro models for hepatitis C virus(HCV) *** Tacrolimus, rapamycin and cyclosporine did not negatively affect the antiviral action of DCV or ASV. Mycophenolic acid(MPA) showed additive antiviral effects combined with these direct acting antivirals(DAAs). MPA induces interferon-stimulated genes(ISGs) and is a potent GTP synthesis inhibitor. DCV or ASV did not induce ISGs expression nor affected ISG induction by MPA. Rather, the combined antiviral effect of MPA with DCV and ASV was partly mediated via inhibition of GTP *** Immunosuppressants do not negatively affect the antiviral activity of DAAs. MPA has additive effect on the antiviral action of DCV and ASV. This combined benefit needs to be confirmed in prospective clinical trials.

关键词： Immunosuppressant Hepatitis C Daclatasvir Asunaprevir Liver Transplantation

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m TOR signaling in liver regeneration: Rapamycin combined with growth factor treatment

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World journal of Transplantation 2013年第3期3卷 36-47页

作者： Suomi MG Fouraschen Petra E de Ruiter jaap Kwekkeboom Ron WF de Bruin Geert Kazemier herold j metselaar Hugo W Tilanus Luc jW van der Laan jeroen de jonge Department of Surgery and Laboratory of Experimental Transplantation and Intestinal Surgery Erasmus MC-University Medical Center 3015 CE Rotterdam The Netherlands Department of Gas-troenterology and Hepatology Erasmus MC-University Medical Center 3015 CE Rotterdam The Netherlands

AIM: To investigate the effects of mammalian target of rapamycin(mT OR) inhibition on liver regeneration and autophagy in a surgical resection ***: C57BL/6 mice were subjected to a 70% partial hepatectomy(PH) and treated intraperitoneally every 24 h with a combination of the m TOR inhibitor rapamycin(2.5 mg/kg per day) and the steroid dexamethasone(2.0 mg/kg per day) in phosphate bufferedsaline(PBS) or with PBS alone as vehicle control. In the immunosuppressant group, part of the group was treated subcutaneously 4 h prior to and 24 h after PH with a combination of human recombinant interleukin 6(IL-6; 500 μg/kg per day) and hepatocyte growth factor(HGF; 100 μg/kg per day) in PBS. Animals were sacrificed 2, 3 or 5 d after PH and liver tissue and blood were collected for further analysis. Immunohistochemical staining for 5-Bromo-2'-deoxyuridine(Brd U) was used to quantify hepatocyte proliferation. Western blotting was used to detect hepatic microtubule-associated protein 1 light chain 3(LC3)-Ⅱ protein expression as a marker for autophagy. Hepatic gene expression levels of proliferation-, inflammation- and angiogenesisrelated genes were examined by real-time reverse transcription-polymerase chain reaction and serum bilirubin and transaminase levels were analyzed at the clinical chemical core facility of the Erasmus MC-University Medical ***: m TOR inhibition significantly suppressed regeneration, shown by decreased hepatocyte proliferation(2% vs 12% Brd U positive hepatocyte nuclei at day 2, P < 0.01; 0.8% vs 1.4% at day 5, P = 0.02) and liver weight reconstitution(63% vs 76% of initial total liver weight at day 3, P = 0.04), and furthermore increased serum transaminase levels(aspartate aminotransferase 641 U/L vs 185 U/L at day 2, P = 0.02). Expression of the autophagy marker LC3-Ⅱ, which was reduced during normal liver regeneration, increased after mT OR inhibition(46% increase at day 2, P = 0.04). Hepatic gene expression showed an increased infl

关键词： Hepatocyte proliferation Autophagy Microtubule-associated protein 1 light chain 3 Partial hepatectomy Rapamycin

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Alexa,let's train now!——A systematic review and classification approach to digital and home-based physical training interventions aiming to support healthy cognitive aging

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journal of Sport and Health Science 2024年第1期13卷 30-46页

作者： Fabian herold Paula Theobald Thomas Gronwald Navin Kaushal Liye Zou Eling D.de Bruin Louis Bherer Notger GMüller Research Group Degenerative and Chronic Diseases MovementFaculty of Health Sciences BrandenburgUniversity of PotsdamPotsdam 14476Germany Body-Brain-Mind Laboratory Shenzhen UniversityShenzhen 518060China Institute of Interdisciplinary Exercise Science and Sports Medicine MSH Medical School HamburgHamburg 20457Germany Department of Health Sciences School of Health&Human SciencesIndiana UniversityIndianapolisIN 46202USA Department of Health Sciences and Technology Institute of Human Movement Sciences and SportETH ZurichZurich 8093Switzerland Department of Neurobiology Care Sciencesand SocietyKarolinska InstituteStockholm 17177Sweden Department of Health OST-Eastern Swiss University of Applied SciencesSt.Gallen 9001Switzerland Montreal Heart Institute MontrealQC H1T 1C8Canada Department of Medicine Universite de MontrealMontrealQC H3T 1J4Canada Centre de Recherche de l'Institut Universitaire de Geriatrie de Montreal MontrealQC H3W 1W5Canada

Background:There is mounting evidence that regular physical activity is an important prerequisite for healthy cognitive ***,the finding that almost one-third of the adult population does not reach the recommended level of regular physical activity calls for further public health *** this context,digital and home-based physical training interventions might be a promising alternative to center-based intervention ***,this systematic review aimed to summarize the current state of the literature on the effects of digital and home-based physical training interventions on adult cognitive ***:In this pre-registered systematic review(PROSPERO;ID:CRD42022320031),5 electronic databases(PubMed,Web of Science,Psyclnfo,SPORTDiscus,and Cochrane Library)were searched by 2 independent researchers(FH and PT)to identify eligible studies investigating the effects of digital and home-based physical training interventions on cognitive performance in *** systematic literature search yielded 8258 records(extra17 records from other sources),of which 27 controlled trials were considered *** reviewers(FH and PT)independently extracted data and assessed the risk of bias using a modified version of the Tool for the assEssment of Study qualiTy and reporting in EXercise(TESTEX scale).Results:Of the 27 reviewed studies,15 reported positive effects on cognitive and motor-cognitive outcomes(i.e.,performance improvements in measures of executive functions,working memory,and choice stepping reaction test),and a considerable heterogeneity concerning study-related,population-related,and intervention-related characteristics was noticed.A more detailed analysis suggests that,in particular,interventions using online classes and technology-based exercise devices(i.e.,step-based exergames)can improve cognitive performance in healthy older *** one-half of the reviewed studies were rated as having a high risk of bias with respect

关键词： Brain Cognition Digital health Exercise-cognition Physical activity

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Combined antiviral activity of interferon-α and RNA interference directed against hepatitis C without affecting vector delivery and gene silencing

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世界最新医学信息文摘 2016年第11期 8-8页

作者： Qiuwei Pan Scot D.Henry herold j.metselaar Bob Scholte jaap Kwekkeboom Hugo W.Tilanus Harry L.A.janssen Auc j.W.van der Laan

The current standard interferon-alpha(IFN-α)-based therapy for chronic hepatitis C virus(HCV) infection is only effective in approximately half of the patients, prompting the need for alternative treatments. RNA interference(RNAi) represents novel approach to combat HCV by sequence-specific targeting of viral or host factors involved in infection. Monotherapy of RNAi, however, may lead to therapeutic resistance by mutational escape of the virus. Here, we proposed that combining lentiviral vector-mediated RNAi and IFN-α could be more effective and avoid therapeutic resistance. In this study, we found that IFN-α treatment did not interfere with RNAi-mediated gene silencing. RNAi and IFN-α act independently on HCV replication showing combined antiviral activity when used simultaneously or sequentially. Transduction ofmouse hepatocytes in vivo and in vitro was not effected by IFN-α treatment. In conclusion, RNAi and IFN-α can be effectively combined without crossinterference and may represent a promising combinational strategy for the treatment of hepatitis c.

关键词： RNAi IFN-α Gene therapy Lentiviral vector HCV

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Combined antiviral activity of interferon-α and RNA interference directed against hepatitis C without affecting vector delivery and gene silencing

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世界最新医学信息文摘 2017年第30期 281-281页

作者： Qiuwei Pan Scot D.Henry herold j.metselaar Bob Scholte jaap Kwekkeboom Hugo W.Tilanus Harry L.A.janssen Luc j.W.van der Laan

The current standard interferon-alpha(IFN-α)-based therapy for chronic hepatitis C virus(HCV) infection is only effective in approximately half of the patients,prompting the need for alternative *** interference(RNAi)represents novel approach to combat HCV by sequence-specific targeting of viral or host factors involved in *** of RNAi,however,may lead to therapeutic resistance by mutational escape of the ***,we proposed that combining lentiviral vector-mediated RNAi and IFN-a could be more effective and avoid therapeutic *** this study,we found that IFN-α treatment did not interfere with RNAi-mediated gene *** and IFN-α act independently on HCV replication showing combined antiviral activity when used simultaneously or *** ofmouse hepatocytes in vivo and in vitro was not effected by IFN-α *** conclusion,RNAi and IFN-a can be effectively combined without crossinterference and may represent a promising combinational strategy for the treatment of hepatitis C.

关键词： RNAi IFN-α Gene therapy Lentiviral vector HCV

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Linking 24-h Movement Behavior Guidelines to Cognitive Difficulties,Internalizing and Externalizing Problems in Preterm Youth

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International journal of Mental Health Promotion 2024年第8期26卷 651-662页

作者： Zhihui Cheng Ailikute Aikeremu Yanping Gao Zhihao Zhang Anthony G.Delli Paoli Paolo Marcello Cunha Alyx Taylor Fabian herold Liye Zou Body-Brain-Mind Laboratory School of PsychologyShenzhen UniversityShenzhen518060China Department of Kinesiology and Health Rutgers UniversityNew BrunswickNJ 08901USA Metropolitan University Center of Maringá Maringá87020Brazil School of Health and Rehabilitation Sciences AECC University CollegeBournemouthBH52DFUK Research Group Degenerative and Chronic Diseases MovementFaculty of Health Sciences BrandenburgUniversity of PotsdamPotsdam14476Germany

Background:Given the heightened risk of developmental challenges associated with preterm birth,it is crucial to explore interventions that may ameliorate potential adverse *** study aimed to examine whether meeting the 24-h movement behavior(24-HMB)guidelines,which include recommendations on physical activity(PA),screen time(ST),and sleep(SL),is related to indicators of cognitive difficulties,internalizing problems(e.g.,depression and anxiety),and externalizing problems(e.g.,difficulties in making friends and arguing)in a sample of preterm youth(children and adolescents born preterm).Methods:In this cross-sectional study,data from 3410 preterm youth(aged 6 to 17 years)were included for data *** logistic regression was used to investigate associations between meeting the 24-HMB guidelines and the above-mentioned health outcomes,while controlling for sociodemographic and health-related ***:The prevalence of meeting 24-HMB guidelines varied across independent and integrated components of the 24-HMB *** the ST guideline alone(p<0.05)and integrated guidelines(i.e.,ST+SL and ST+SL+PA)were associated with fewer cognitive difficulties and reduced internalizing and externalizing problems(p<0.05).Specifically,meeting the SL guideline alone and integrated guidelines(i.e.,SL+ST)were associated with lower odds of depression and anxiety(p<0.01).Additionally,meeting independent,and integrated(PA and/or ST)guidelines were associated with less pronounced difficulties in making friends and arguing(p<0.05).Meeting 24-HMB guidelines in an isolated and integrated manner are linked to better cognitive performance and fewer internalizing and externalizing problems in preterm ***:Results suggest that advocating for the implementation of the 24-HMB guidelines may reduce cognitive challenges and behavioral issues,which is of high relevance for improving public *** longitudinal studies in preterm youth should inves

关键词： Cognitive difficulties externalizing problems internalizing problems physical activity preterm youth

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Storing Freshwater Versus Storing Electricity in Power Systems with High Freshwater Electric Demand

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journal of Modern Power Systems and Clean Energy 2024年第2期12卷 323-333页

作者： Mubarak j.Al-Mubarak Antonio j.Conejo Department of Electrical and Computer Engineering The Ohio State UniversityColumbusOHUSA Department of Electrical Engineering Kuwait UniversityP.O.Box 5969Safat 13060Kuwait Department of Integrated Systems Engineering and the Department of Electrical and Computer Engineering The Ohio State UniversityColumbusOH 43210USA IEEE

We consider a power system whose electric demand pertaining to freshwater production is high(high freshwater electric demand),as in the Middle East,and investigate the tradeoff of storing freshwater in tanks versus storing electricity in batteries at the day-ahead operation *** storing freshwater and storing electricity increase the actual electric demand at valley hours and decrease it at peak hours,which is generally beneficial in term of cost and ***,to what extent?We analyze this question considering three power systems with different generation-mix configurations,i.e.,a thermal-dominated mix,a renewable-dominated one,and a fully renewable *** generation-mix configurations are inspired by how power systems may evolve in different countries in the Middle *** production uncertainty is compactly modeled using chance *** draw conclusions on how both storage facilities(freshwater and electricity)complement each other to render an optimal operation of the power system.

关键词： Power system operation freshwater production and transportation coordination day-ahead scheduling

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Analysis of ancient mass extinction recoveries in marine environments: generating strategies for managing outcomes of the current mass extinction

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National Science Review 2024年第1期11卷 8-10页

作者： David j.Bottjer Department of Earth Sciences University of Southern California

The defining feature of a mass extinction and its associated recovery is the global amount of extinction that occurred[1]. However, there is finer-scale detail to the story, as seen in the ongoing modern mass extinction(the sixth mass extinction), which exhibits variable effects among marine ecosystems and environments, and hence geographic areas [1].

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Global weirding at mass extinction horizons

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National Science Review 2024年第1期11卷 10-12页

作者： Gregory j.Retallack Department of Earth Sciences University of Oregon

A strong motivation for studying mass extinctions is understanding how current climatic and biodiversity crises will affect creatures living on land such as ourselves. Perhaps the question is: how bad can it get? In that case, terrestrial Permian-Triassic mass extinctions are an irresistible worst-case scenario [1].

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