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Clinical Outcome Event Adjudication in a 10-Year Prospective Study of Nucleos(t)ide Analogue Therapy for Chronic Hepatitis B

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Journal of Clinical and Translational Hepatology 2020年第4期8卷 377-384页

作者： Joseph K Lim Alex Y Chang Atif Zaman Paul Martin conrado M fernandez-Rodriguez Mete Korkmaz Simona Rossi James M Ford Tamara Noonan Elizabeth Cooney Victor Navarro Luis Colombato Yale University School of Medicine New HavenCTUSA Johns Hopkins School of Medicine BaltimoreMDUSA and Johns Hopkins SingaporeSingapore Oregon Health&Science University PortlandORUSA University of Miami Miller School of Medicine MiamiFLUSA Hospital Universitario Fundación Alcorcón MadridSpain OSF Saint Anthony Center for Cancer Care RockfordILUSA Einstein Healthcare Network PhiladelphiaPAUSA Stanford University School of Medicine StanfordCAUSA Bristol-Myers Squibb WallingfordCTUSA Hospital Británico UCA School of MedicineBuenos AiresArgentina

Background and Aims:In the REALM (Randomized, Obser-vational Study of Entecavir to Assess Long-Term Outcomes Associated with Nucleoside/Nucleotide Monotherapy for Pa-tients with Chronic HBV Infection) study, 12,378 patients with chronic hepatitis B virus (HBV) infection received up to 10 years of randomized therapy with entecavir or another HBV nucleos(t)ide analogue. Monitored clinical outcome events (COEs) included malignant neoplasms, HBV disease progres-sion events, and deaths. An external event adjudication com-mittee (EAC) was convened to provide real-time review of reported COEs to optimize data quality, and minimize poten-tial adverse effects of the large cohort, interdisciplinary out-come assessments, geographic scope, and long duration. Methods:The EAC comprised an international group of hep-atologists and oncologists with expertise in diagnosis of tar-geted COEs. The EAC reviewed and adjudicated COEs according to prospectively defined diagnostic criteria cap-tured in the EAC charter. Operational processes, including da-ta collection and query procedures, were implemented to optimize efficiency of data recovery to maximize capture of adjudicated COEs, the primary study outcome measure. Results: A total of 1724 COEs were reported and 1465 of these events were adjudicated by the EAC as reported by the investigators (85.0% overall concordance). Concordance by COE type varied: deaths, 99.6%;hepatocellular carcino-ma (HCC), 83.3%;non-HCC malignancies, 88.0%;non-HCC HBV disease progression, 68.2%. Reasons for lack of con-cordance were most commonly lack of adequate supporting data to support an adjudicated diagnosis or evidence that the event pre-dated the study. Conclusions: The REALM EAC performed a critical role in ensuring data quality and consis-tency;EAC performance was facilitated by well-defined diag-nostic criteria, effective data capture, and efficient operational processes. Trial registration: *** NCT00388674.

关键词： Hepatitis B Antiviral therapy Clinical outcomes Event adjudication Liver cirrhosis

Prevalence of occult hepatitis B virus infection

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World Journal of Gastroenterology 2011年第12期17卷 1538-1542页

作者： Maria Luisa Gutiérrez-García conrado M fernandez-Rodriguez Jose Luis Lledo-Navarro Ingrid Buhigas-Garcia Service of Gastroenterology Hospital Universitario Fundación AlcorcónAv Budapest-128922 AlcorcónMadridSpain

Occult hepatitis B virus(HBV) infection(OBI) is characterized by the persistence of HBV DNA in the liver tissue in individuals negative for the HBV surface *** prevalence of OBI is quite variable depending on the level of endemic disease in different parts of the world,the different assays utilized in the studies,and the different populations *** studies have been carried out on OBI prevalence in different areas of the world and categories of *** studies show that OBI prevalence seems to be higher among subjects at high risk for HBV infection and with liver disease than among individuals at low risk of infection and without liver disease.

关键词： Occult hepatitis B virus infection Hepatitis B virus DNA Anti-HBc Hepatitis B virus seronegative Hepatitis C Crytogenetic hepatitis Dialysis Human immunodeficiency virus Blood donors

Effectiveness and safety of first-generation protease inhibitors in clinical practice:Hepatitis C virus patients with advanced fibrosis

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World Journal of Gastroenterology 2015年第30期21卷 9163-9174页

作者： Javier Salmeron Carmen Vinaixa Ruben Berenguer Juan Manuel Pascasio Juan Jose Sanchez Ruano Miguel angel Serra Ana Gila Moises Diago Manuel Romero-Gomez Jose Maria Navarro Milagros Testillano conrado fernandez Dolores Espinosa Isabel Carmona Jose Antonio Pons Francisco Jorquera Francisco Javier Rodriguez Ramon Perez Jose Luis Montero Rafael Granados Miguel fernandez Ana Belen Martin Paloma Munoz de Rueda Rosa Quiles CIBERehd Instituto de Salud Carlos Ⅲ28029 MadridSpain Unit for Clinical Management of Digestive Diseases Complejo Hospitalario Universitario de Granada Instituto de Investigacion Biosanitaria de Granada University Hospital Politecnico La Fe Unit for Clinical Management of Digestive Diseases University Hospital Virgen Del Rocio Hospital Toledo University Clinic Hospital of Valencia University General Hospital of Valencia Unit for Clinical Management of Digestive Diseases University Hospital Nuestra Senora de Valme Department of Gastroenterology and Hepatology Agencia Sanitaria Costa del Sol University Hospital Cruces Gastroenterology Unit University Hospital Fundacion Alcorcon University Hospital Virgen Macarena University Hospital Virgen de la Arrixaca Hospital of Leon University General Hospital Reina Sofia Department Gastroenterology and Hepatology University Hospital Central de Asturias University Hospital Reina Sofia University Hospital De Gran Canaria Dr. Negrin Hospital San Pedro de Alcantara

AIM:To evaluates the effectiveness and safety of the first generation,NS3/4A protease inhibitors(PIs) in clinical practice against chronic C virus,especially in patients with advanced fibrosis. METHODS:Prospective study and non-experimental analysis of a multicentre cohort of 38 Spanish hospitals that includes patients with chronic hepatitis C genotype 1,treatment-na?ve(TN) or treatment-experienced(TE),who underwent triple therapy with the first generation NS3/4A protease inhibitors,boceprevir(BOC) and telaprevir(TVR),in combination with pegylated interferon and ribavirin. The patients were treatment in routine practice settings. Data on the study population and on adverse clinical and virologic effects were compiled during the treatment period and during follow ***:One thousand and fifty seven patients were included,405(38%) were treated with BOC and 652(62%) with TVR. Of this total,30%(n = 319) were TN and the remaining were TE:28%(n = 298) relapsers,12%(n = 123) partial responders(PR),25%(n = 260) null-responders(NR) and for 5%(n = 57) with prior response unknown. The rate of sustained virologic response(SVR) by intention-to-treatment(ITT) was greater in those treated with TVR(65%) than in those treated with BOC(52%)(P < 0.0001),whereas by modified intention-to-treatment(m ITT) no were found significant differences. By degree of fibrosis,56% of patients were F4 and the highest SVR rates were recorded in the non-F4 patients,both TN and TE. In the analysis by groups,the TN patients treated with TVR by ITT showed a higher SVR(P = 0.005). However,by m ITT there were no significant differences between BOC and TVR. In the multivariate analysis by m ITT,the significant SVR factors were relapsers,IL28 B CC and non-F4; the type of treatment(BOC or TVR) was not significant. The lowest SVR values were presented by the F4-NR patients,treated with BOC(46%) or with TVR(45%). 28% of the patients interrupted the treatment,mainly by non-viral response(51%):this outcome was

关键词： Hepatitis C Boceprevir Telaprevir First-generation protease inhibitors Advanced fibrosis

Junctional epithelium and hemidesmosomes:Tape and rivets for solving the“percutaneous device dilemma”in dental and other permanent implants

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Bioactive Materials 2022年第12期7卷 178-198页

作者： Nicholas G.Fischer conrado Aparicio MDRCBB-Minnesota Dental Research Center for Biomaterials and Biomechanics University of Minnesota16-212 Moos Tower515 Delaware St.SEMinneapolisMN55455USA Division of Basic Research Faculty of OdontologyUIC Barcelona-Universitat Internacional de CatalunyaC/.Josep Trueta s/n08195Sant Cugat del VallesBarcelonaSpain Institute for Bioengineering of Catalonia(IBEC) The Barcelona Institute of Science and Technology(BIST)C/.Baldiri Reixac 10-1208028BarcelonaSpain

The percutaneous device dilemma describes etiological factors, centered around the disrupted epithelial tissue surrounding non-remodelable devices, that contribute to rampant percutaneous device infection. Natural percutaneous organs, in particular their extracellular matrix mediating the “device”/epithelium interface, serve as exquisite examples to inspire longer lasting long-term percutaneous device design. For example, the tooth’s imperviousness to infection is mediated by the epithelium directly surrounding it, the junctional epithelium (JE). The hallmark feature of JE is formation of hemidesmosomes, cell/matrix adhesive structures that attach surrounding oral gingiva to the tooth’s enamel through a basement membrane. Here, the authors survey the multifaceted functions of the JE, emphasizing the role of the matrix, with a particular focus on hemidesmosomes and their five main components. The authors highlight the known (and unknown) effects dental implant - as a model percutaneous device - placement has on JE regeneration and synthesize this information for application to other percutaneous devices. The authors conclude with a summary of bioengineering strategies aimed at solving the percutaneous device dilemma and invigorating greater collaboration between clinicians, bioengineers, and matrix biologists.

关键词： Percutaneous device Percutaneous implant Hemidesmosome Junctional epithelium Bioinspired surfaces

Development of a 3D matrix for modeling mammalian spinal cord injury in vitro

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Neural Regeneration Research 2016年第11期11卷 1810-1815页

作者： Juan Felipe Diaz Quiroz Yuping Li conrado Aparicio Karen Echeverri Department of Genetics Cell Biology and Development University of Minnesota Minneapolis MN USA Center for Biotechnology and Interdisciplinary Studies Rensselaer Polytechnic Institute Troy NY USA Minnesota Dental Research Center for Biomaterials and Biomechanics Department of Restorative Sciences School of Dentistry University of Minnesota Minneapolis MN USA

Spinal cord injury affects millions of people around the world, however, limited therapies are available to improve the quality of life of these patients. Spinal cord injury is usually modeled in rats and mice using contusion or complete transection models and this has led to a deeper understanding of the molecular and cellular complexities of the injury. However, it has not to date led to development of successful novel therapies, this is in part due to the complexity of the injury and the difficulty of deciphering the exact roles and interactions of different cells within this complex environment. Here we developed a collagen matrix that can be molded into the 3D tubular shape with a lumen and can hence support cell interactions in a similar architecture to a spinal cord. We show that astrocytes can be successfully grown on this matrix in vitro and when injured, the cells respond as they do in vivo and undergo reactive gliosis, one of the steps that lead to formation of a glial scar, the main barrier to spinal cord regeneration. In the future, this system can be used to quickly assess the effect of drugs on glial scar protein activity or to perform live imaging of labeled cells after exposure to drugs.

关键词： nerve regeneration spinal cord injury 3D scaffold in vitro models astrocytes reactive gliosis neural regeneration

Heterostructure engineering in electrode materials for sodium-ion batteries:Recent progress and perspectives

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eScience 2023年第5期3卷 1-11页

作者： Eric Gabriel Chunrong Ma Kincaid Graff Angel conrado Dewen Hou Hui Xiong Micron School of Materials Science and Engineering Boise State UniversityBoiseID83725USA X-ray Sciences Division Argonne National LaboratoryLemontIL60439USA College of Textiles&Clothing Qingdao UniversityQingdao266071China Key Laboratory of Bio-Fibers and Eco-Textiles Qingdao UniversityQingdao266071China Center for Nanoscale Materials Argonne National LaboratoryLemontIL60439USA Center for Advanced Energy Studies Idaho FallsID83401USA

Sodium-ion batteries(SIBs)have stepped into the spotlight as a promising alternative to lithium-ion batteries for large-scale energy storage ***,SIB electrode materials,in general,have inferior performance than their lithium counterparts because Nat is larger and heavier than *** engineering is a promising strategy to overcome this intrinsic limitation and achieve practical *** provide a brief review of recent progress in heterostructure engineering of electrode materials and research on how the phase interface influences Nat storage and transport *** strategies for the design and fabrication of heterostructures(in situ methods)are discussed,with a focus on the heterostructure formation *** heterostructure's influence on Nat storage and transport properties arises primarily from local distortions of the structure and chemomechanical coupling at the phase interface,which may accelerate ion/electron diffusion,create additional active sites,and bolster structural ***,we offer our perspectives on the existing challenges,knowledge gaps,and opportunities for the advancement of heterostructure engineering as a means to develop practical,highperformance sodium-ion batteries.

关键词： Heterostructure Sodium-ion batteries Electrode materials Heterogeneous materials Interface engineering Intergrowth

Injection of bone marrow mesenchymal stem cells by intravenous or intraperitoneal routes is a viable alternative to spinal cord injury treatment in mice

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Neural Regeneration Research 2018年第6期13卷 1046-1053页

作者： Bruna dos Santos Ramalho FernANDa Martins de Almeida conrado Mendonca Sales Silmara de Lima Ana Maria Blanco Martinez Laboratorio de Neurodegeneracao e Reparo Departamento de Patologia - Faculdade de Medicina HUCFF Universidade Federal do Rio de Janeiro Rio de laneiro Brazil

In spite of advances in surgical care and rehabilitation, the consequences of spinal cord injury （SCI） are still challenging. Several experimental therapeutic strategies have been studied in the SCI field, and recent advances have led to the development of therapies that may act on the inhibitory microenvironment. Assorted lineages of stem cells are considered a good treatment for SCI. This study investigated the effect of systemic transplantation of mesenchymal stem cells （MSCs） in a compressive SCI model. Here we present results of the intraperitoneal route, which has not been used previously for MSC administration after compressive SCI. We used adult female C57BL/6 mice that underwent laminectomy at the T9 level, followed by spinal cord compression for 1 minute with a 30-g vascular clip. The animals were divided into five groups： sham （anesthesia and laminectomy but without compression injury induction）, MSC i.p. （intraperitoneal injection of 8×10^5 MSCs in 500 μL of DMEM at 7 days after SCI）, MSC i.v. （intravenous injection of 8 × 10^5 MSCs in 500μL of DMEM at 7 days after SCI）, DMEM i.p. （intraperitoneal injection of 500μL of DMEM at 7 days after SCI）, DMEM i.v. （intravenous injection of 500 μL of DMEM at 7 days after SCI）. The effects of MSCs transplantation in white matter sparing were analyzed by luxol fast blue staining. The number of preserved fibers was counted in semithin sections stained with toluidine blue and the presence of trophic factors was analyzed by immunohistochemistry. In addition, we analyzed the locomotor performance with Basso Mouse Scale and Global Mobility Test. Our results showed white matter preservation and a larger number of preserved fibers in the MSC groups than in the DMEM groups. Furthermore, the MSC groups had higher levels of trophic factors （brain-derived neurotrophic factor, nerve growth factor, neurotrophin-3 and neurotrophin-4） in the spinal cord and improved locomotor performance. Our results indicate that injection of MSC

关键词： spinal cord injury mesenchymal stem cells intravenous route intraperitoneal route functional recovery systemic transplantation neural regeneration

Fatigue strength and microstructure evaluation of Al 7050 alloy wires recycled by spray forming,extrusion and rotary swaging

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Transactions of Nonferrous Metals Society of China 2020年第12期30卷 3195-3209页

作者： João G.J.de SALVO conrado RMAFONSO Programa de Pós-graduação em Ciência e Engenharia de Materiais(PPG-CEM) Universidade Federal de São Carlos(UFSCar)Rod.Washington LuizKm 23513565-905 São Carlos-SPBrazil Divisão de Materiais Instituto de Aeronáutica e EspaçoCTAPraça Marechal Eduardo Gomes5012228-904 São Josédos Campos-SPBrazil Departamento de Engenharia de Materiais(DEMa) Universidade Federal de São Carlos(USFCar)Rod.Washington LuizKm 23513565-905 São Carlos-SPBrazil

Recycled high-strength aluminum alloys have limited use as structural materials due to poor mechanical properties. Spray forming remelting followed by hot extrusion is a promising route for reprocessing 7 xxx alloys. The 7050 alloy machining chips were spray formed, hot extruded, rotary swaged and heat-treated in order to improve mechanical properties. Microstructures, tensile properties and fatigue strength results for a 2.7 mm-diameter recycled wire are presented. Secondary phases and precipitates were investigated by XRD, SEM, EBSD, TEM and DSC. As-swaged and heat-treated(solution and aging) conditions were evaluated. Mechanical properties of both conditions outperformed AA7050 aerospace specification. Substantial grain refinement resulted from the extensive plastic deformation imposed by rotary swaging. Refined micrometric and sub-micrometric Al grains, as well as coarse and fine intermetallic precipitates were observed. Subsequent solution treatment resulted in a homogeneous, recrystallized and equiaxed microstructure with grain size of 9 μm. Nanoscale GP(I) zones and η′ phase precipitates formed after aging at 120 ℃, imparting higher tensile(586 MPa) and fatigue(198 MPa) strengths.

关键词： Al−Zn−Mg−Cu alloy spray forming thermomechanical processing microstructure fatigue

Buzz-pollination in Neotropical bees:genus-dependent frequencies and lack of optimal frequency for pollen release

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Insect Science 2020年第1期27卷 133-142页

作者： conrado Augusto Rosi-Denadai Priscila Cassia Souza Araujo Lucio Antonio de Oliveira Campos Lirio Cosme Jr. Raul Narciso Carvalho Guedes Departamento de Entomologia Universidade Federal de VigosaVigosaMinas GeraisBrazil Departamento de Biologia Geral Universidade Federal de VigosaVigosaMinas GeraisBrazil

Over 50 genera of bees release pollen from flower anthers using thoracic vibrations,a phenomenon known as *** efficiency of this process is directly affected by the mechanical properties of the buzzes,namely the duration,amplitude,and ***,although the effects of the former two properties are well described,the role of buzz frequency on pollen release remains ***,nearly all of the existing studies describing vibrational properties of natural buzz-pollination are limited to bumblebees(Bombus)and carpenter bees(Xvlocopa)constraining our current understanding of this behavior and its ***,we attempted to minimize this shortcoming by testing whether flower anthers exhibit optimal frequency for pollen release and whether bees tune their buzzes to match these(optimal)*** true,certain frequencies will trigger more pollen release and lighter bees will reach buzz frequencies closer to this optimum to compensate their smaller buzz *** strategies were used to test these hypotheses:(i)the use of(artificial)vibrational playbacks in a broad range of buzz frequencies and amplitudes to assess pollen release by tomato plants(Solarium Ivcopersicum L.)and(ii)the recording of natural buzzes of Neotropical bees visiting tomato plants during *** playback experiment indicates that although buzz frequency does affect pollen release,no optimal frequency exists for *** addition,the recorded results of natural buzz-pollination reveal that buzz frequencies vary with bee genera and are not correlated with body ***,neither bees nor plants are tuned to optimal pollen release *** frequency of buzz-pollination is a likely consequence of the insect flight machinery adapted to reach higher accelerations,while flower plant response to buzz-pollination is the likely result of its pollen granular properties.

关键词： buzz amplitude buzz frequency floral sonication pollination stingless bees vibration