Identification of B-cell epitopes is a fundamental step for development of epitope-based vaccines, therapeutic antibodies, and diagnostic tools. Epitope-based antibodies are currently the most promising class of biopharmaceuticals. In the last decade, in-depth in silico analysis and categorization of the experimentally identified epitopes stimulated development of algorithms for epitope prediction. Recently, various in silico tools are employed in attempts to predict B-cell epitopes based on sequence and/or structural data. The main objective of epitope identification is to replace an antigen in the immunization, antibody production, and serodiagnosis. The accurate identification of B-cell epitopes still presents major challenges for immunologists. Advances in B-cell epitope mapping and computational prediction have yielded molecular insights into the process of biorecognition and formation of antigen-antibody complex, which may help to localize B-cell epitopes more precisely. In this paper, we have comprehensively reviewed state-of-the-art experimental methods for B-cell epitope identification, existing databases for epitopes, and novel in silico resources and prediction tools available online. We have also elaborated new trends in the antibody-based epitope prediction. The aim of this review is to assist researchers in identification of B-cell epitopes. Antigen-antibody interaction is a key event in humoral immune response to invading pathogen. A specific antibody (Ab) recognizes antigen (Ag) at discrete regions known as antigenic determinants or B-cell epitopes. B-cell epitopes can be defined as a surface accessible clusters of amino acids, which are recognized by secreted antibodies or B-cell receptors and are able to elicit cellular or humoral immune response .Most of the Ag surface may become part of epitopes after recognition with antibodies and the exact selection mechanism why certain antigen regions become B-cell epitopes is not fully understood . The claBased on the spatial structure B-cell epitopes can be categorized as a continuous  and discontinuous  epitopes; in the latter case amino acid residues are in close contact due to the three-dimensional conformation . The minThe experimental methods developed to identify the epitopes can roughly be divided into structural and functional studies. The X-ray crystallography can exactly locate the position of epitope within the protein structure but is laborious, time consuming, costly, technically difficult, and not applicable for all antigens . Some of2 organized in loops. The epitope surface accessibility is common feature. Sequence of the epitopes is enriched with Y, W, charged, and polar amino acids (amino acids with exposed side chains) and with specific amino acid pairs. The Ag-Ab interaction occurs without preference for a specific CDR loop and involves epitope compression [Rubinstein and colleagues proposed a null hypothesis that the surface of the antigen is homogeneously antigenic. With the large-scale statistical analysis of Ag-Ab cocrystals derived from the protein databases, they were able to define physicochemical, structural, and geometrical aspects of epitopes and concluded that epitopes are clearly distinguishable from the remaining antigen surface . In anotpression . In receAdvancement in the epitope mapping technologies hand in hand with bioinformatics has greatly contributed to developing immunoinformatics, which involves application of computational methods in immunology to unveil structures of antibody, B-cell, T-cell, and allergen, prediction of MHC binding, modelling of epitopes, and analysis of immune networks. Several algorithms have been developed to predict B-cell epitopes from their sequence or structure –18. The Identification B-cell epitopes is extensively employed in the development of diagnostic tests, therapeutics and vaccines –26. Use The main purpose of this review is to provide researcher with the general knowledge about existing methods of B-cell epitope mapping and short overview of epitope databases, recently used prediction methods, and publicly available tools.Most of the existing methods for epitope mapping  are expensive, laborious, time consuming, and often fail to identify all epitopes. Structural epitope mapping methods interpret the protein structure comprising residues in direct contact with an antibody but often fail to reveal contribution of amino acids in binding strength. The identification and characterization of residues important for binding within structurally defined antigenic determinant are the aim of functional epitope mapping tools.The most accurate method for structural epitope mapping is X-ray crystallography of Ag-Ab complexes and is often regarded as the only method to define a structural epitope . Among “The methods for functional epitope mapping can be divided into four main groups: competition methods, antigen fragmentation methods, modification methods, and methods using synthetic peptides or peptide libraries . CompetiMutagenesis is a rapid epitope mapping method that relies on the fact that substitution of individual residue/s (hot-spot/s) that constitutes a functional epitope causes loss of antibody binding. Hot-spots  are energetically important residues and comprise only a fraction of the complete protein-protein interface area . The proβ-carbon without additional flexibility of protein backbone) for each nonalanine residue one at a time. Although this mapping strategy may not identify every residue in contact with an antibody, the critical residues identified using this approach represent amino acids whose side chains make the highest energetic contributions to the paratope-epitope interaction [http://robetta.bakerlab.org/alaninescan) [The majority of epitope contacts in Ag-Ab complex occur through amino acid side chains . Alanineeraction . The geninescan) .The combinatorial mutagenesis enables identifying residues, which are not critical for binding but contribute to the formation of epitope or establish multiple individually weak interactions with paratope. This strategy is based on combinatorial randomization of a discrete antigenic region and grouping of mutated residues (primary sequence proximity) to maximize the chances of underscoring combined effects mediated by neighboring residues .Another technique in mutagenesis, a shotgun mutagenesis, enables identification of both linear and conformational epitopes with mapping rates of over 20 epitopes/month. This high-throughput strategy is based on large-scale mutagenesis, where each clone bears a defined amino acid mutation  and direct cellular testing for mAb reactivity of natively folded proteins . Shotgun mutagenesis has been used to map over 250 mAbs targeting dengue, chikungunya, and hepatitis C viruses, with additional mAb epitopes mapped on hepatitis B virus, respiratory syncytial virus, and HIV  represents popular way of generation of antigenic fragments which are screened for antibody binding [One of the most frequent and popular display methods for epitope mapping is phage display. Construction of phage display peptide libraries (displaying >10 binding . This po binding ).Thanks to the technological advances in genomics, proteomics, and epitope mapping techniques, huge amounts of data are being generated and are necessary to organize in a searchable form. B-cell epitope databases provide a training set for evaluation of existing epitope prediction methods and constitute platform for development of novel and better algorithms for prediction. The B-cell epitope databases can be classified as multifaceted database such as IEDB and AntiJen, B-cell oriented database such as BciPep, Epitome, and SDAP, and single pathogenic organism oriented database such as the HIV Molecular Immunology Database, FLAVIdB, and Influenza Sequence and Epitope Database. It has to be mentioned that most of the available databases include peptide/s recognized by the receptors of the adaptive immune system and/or amino acid residues of antigen that are in close contact with antibody  and lack important epitope information such as a detailed molecular characterization of epitopes and the mention of contact residues that make energetic contributions to binding. The databases that collect B-cell epitope are listed in The Immune Epitope Database (IEDB) is a comprehensive resource aimed to catalogue experimentally determined B-cell and T-cell epitopes from human, nonhuman primates, and other animal species along with the experimental contexts. It captures epitopes related to category A-C pathogens, emerging and reemerging pathogens, allergens, and autoantigens. IEDB contains epitopes derived from the peer-reviewed literature, patent applications, direct submission, and other publicly available databases, for example, FIMM , HLA LigAntiJen v2.0 (developed from JenPep) contains quantitative binding data for peptides binding to MHC ligand, TCR-MHC complexes, T-cell epitopes, TAP (a transporter associated with the MHC class I restricted antigen processing), and B-cell epitopes. It also contains immunological protein-protein interactions and biophysical data such as diffusion coefficient and cellular data , 57. AntConformational Epitope Database (CED) provides a manually curated dataset of conformational epitopes that can be used to evaluate existing epitope prediction methods and develop new and better algorithms for prediction . This daThe comprehensive database BciPep provides dataset of experimentally validated linear B-cell epitopes derived from literature and other publicly available databases .In BciPep, B-cell epitopes are categorized into three classes: immunodominant , immunogenic , and null-immunogenic . The database provides information (isotype and name/number) about anti-peptide antibodies produced against an epitope and their neutralization potential. The database is linked with Swiss-Prot, PDB, MHCBN, and PubMed .Structural Epitope Database (SEDB) contains 3D complexes of B-cell, T-cell, and MHC bound molecules and shows Ag-Ab interaction plot. SEDB collects related information of epitopes, like gene-ontology information, Ag-Ab interaction graph, and epitopes location in protein with interaction data, which are missing in currently available epitope databases .Structural Database of Allergenic Proteins (SDAP) contains sequences, structures, and IgE epitopes of allergenic proteins and offers additional computational tools for structural studies. SDAP enables allergen-peptide matching for the detection of novel allergens and the cross-reactivity between known allergens . Flavivirus spp. derived from external databases  and corresponding literature. It contains flavivirus antigen sequences, T-cell epitopes, B-cell epitopes, and molecular structures of the dengue virus envelope protein. Database is equipped with tools for block entropy analysis and flavivirus species classification [Databases oriented on single pathogenic organism have been developed to target vaccine design. The HIV Molecular Immunology Database collects cytotoxic, helper T-cell epitopes and B-cell epitopes in annotated and searchable form and offers several generic data analysis tools. FLAVIdB is a comprehensive database of antigens fromfication .Correlation between B-cell epitope localization and physicochemical properties , has been demonstrated in several studies (reviewed in ). Earlie Echinococcus multilocularis (the causative agent of zoonotic helminthosis) were predicted using BCPred and ABCPred [The first prediction method using recurrent neural network, ABCPred, has been trained on B-cell epitopes obtained from BciPep database and nonepitopes obtained randomly from Swiss-Prot database. The ABCPred is a neural network based method for prediction of continuous B-cell epitopes using fixed length pattern . The ABC ABCPred .APCPred combines amino acid anchoring pair composition (APC) and support vector machine (SVM) methods, which significantly improved the prediction accuracy. APCPred achieved an improved area under curve (AUC) of 0.794 . BCPred BCPred method employs subsequence kernel-based SVM classifier and was trained on homology-reduced dataset of linear B-cell epitopes (with <80% sequence identity) derived from dataset previously used to test ABCPred. The performance of BCPred (AUC 0.758) outperforms implementation of AAP (AUC 0.7).FBCPred is a novel method developed for prediction of B-cell epitopes with flexible length. Homology-reduced dataset is publicly available for comparing existing linear B-cell epitope prediction methods and testing of new prediction software.BepiPred predicts continuous epitopes by combining two residues properties with Hidden Markov Model. BepiPred was evaluated on dataset of epitopes extracted from the literature, AntiJen, and HIV databases. This method has a quite low sensitivity .The server BcePred is used for prediction of continuous B-cell epitopes based on physicochemical properties and allows user to select any residue property or combination of two or more properties employed in prediction. The performance of BcePred was evaluated on dataset containing epitopes obtained from BciPep database and dataset of randomly chosen nonepitopes from Swiss-Prot. The accuracy of BcePred combining four amino acid properties  is 58.70% .A novel continuous B-cell epitope prediction method EPMRL was developed using multiple linear regression. EPMLR was tested on BEOD dataset containing only experimentally verified epitopes and nonepitopes and achieves overall sensitivity of 81.8% and precision of 64.1% and area under the receiver operating characteristic curve (AUC) of 0.728 .B-cell epitope prediction using support vector machine tool (BEST) is sequence-based tool designed for prediction of both linear and conformational epitopes from full antigen sequence. Prediction is based on averaging of selected scores  generated from 20-mers. BEST achieves AUC at 0.81 and 0.85 for the fragment-based prediction and 0.57 and 0.6 for full antigen. BEST outperforms several modern sequence-based B-cell epitope predictors including ABCPred, BCPred, COBEpro, and CBTOPE .SVMTriP employs support vector machine to combine the tripeptide similarity and propensity scores to predict linear epitopes. SVMTriP achieves a sensitivity of 80.1% and a precision of 55.2% and the AUC value 0.702, when tested on nonredundant epitopes extracted from IEDB . A compaAlthough the majority (~90%) of the B-cell epitopes are discontinuous , to date much effort was concentrated on identification of continuous epitopes . HoweverThe first attempts at epitope prediction based on 3D structure began with development of CEP server, which is based on accessibility of amino acid residues and requires the 3D data in PDB format . HithertBEpro server (formerly known as PEPITO) uses a combination of amino acid propensity scores along with side chain orientation and solvent accessibility information using half sphere exposure values at multiple distances to predict discontinuous B-cell epitopes. It achieves AUC of 75.4 on the DiscoTope dataset . BEpro aPEPOP is structure-based method, which identifies clusters of accessible surface residues and segments that might form putative discontinuous epitopes and can be used to design immunogenic peptides. The anti-peptides antibodies showed reactivity with the cognate antigens in 80% of the cases (four cases from five) and were used in sandwich capture assay. Compared to CEP and DiscoTope, PEPOP showed comparable specificity and slightly better sensitivity [Improved Spatial Epitope Prediction of Protein Antigens server (SEPPA) focusing on single residue propensity scales and continual segment clustering was developed in 2009 by Sun and colleagues . SEPPA eServer ElliPro (derived from Ellipsoid and Protrusion) implements modified method for identifying continuous epitopes in the protein regions protruding from the globular surface of antigen  in combiComputational prediction tool EPITOPIA employs Naïve Bayes classifier to predict epitopes in linear sequence or 3D structure. It distinguishes the nonepitope and epitope regions by computing an immunogenicity score  for each solvent accessible residue or a score for every amino acid. EPITOPIA yields higher success rate of 89.4%  when compared to ElliPro and DiscoTope .CBTOPE was proposed for the prediction of discontinuous epitopes from antigen primary structure. This SVM-based predictor combines traditional features of physicochemical profiles and sequence-derived inputs including composition and collocation of amino acids. It outperformed other structure methods using binary profile of pattern and physicochemical profile of patterns with better sensitivity and AUC on the same benchmark dataset .Epitope prediction method, which uses Consensus Scoring (EPCES) combines scores from residue epitope propensity, residue conservation, side-chain energy, contact number, surface planarity, and secondary structure composition. EPCES predicts discontinuous epitopes with 47.8% sensitivity, 69.5% specificity, and an AUC value of 0.632, which is statistically similar to other published methods.The Antigenic Epitopes Prediction with Support Vector Regression server (EPSVR) employs vector regression to integrate same scores as are combined in EPCES and achieves AUC value of 0.597. EPSVR is integrated in metaserver EPMeta together with five existing prediction servers  and provides consensus prediction results. The performance of EPMeta is AUC value of 0.6, which is higher than performance of any other existing single server. Unfortunately, this server met unsolvable technical difficulties and is no more available.Evaluation of performance of prediction tools is often difficult, especially when each of them has their own testing dataset. To solve this problem and help users to choose the tool, the recent web servers, CEP , DiscoToThe traditional antibody-ignored epitope prediction methods do not take into account the reconfiguration of epitope residues when an antigen is in complex with a specific antibody . ReconfiA method using Antibody-Specific Epitope Prediction (ASEP) index developed by Soga and coworkers, represents the first benchmark in epitope prediction for individual antibody and has been used to narrow down candidate epitopes previously predicted by the conventional methods .The EpiPred combines conformational matching of the Ab-Ag structures and knowledge based asymmetric Ab-Ag scoring to annotate the likely epitope regions specific to the given antibody . This glPredicting Epitopes Using Antibody Sequences (PEASE) evaluates a pair score for all combinations of one residue from the complementarity determining regions (CDR) of antibody and one residue from the surface exposed region of antigen. A residue score of antigen surface residue is its highest pair score. A higher residue score means that contact between antibody and antigen residue is more strongly predicted and that this residue constitutes a part of B-cell epitope. PEASE also identifies surface patches on the antigen, which contain multiple residues with high residue scores . PEASE wB-cell epitope prediction through association rules (Bepar) is predicting epitopes based on antibody-antigen (paratope-epitope) association patterns which can be applied to any antibody-antigen sequence pair. Residue cooperativity and relative composition have been used to enhance the performance of this method. Bepar shows competitive performance on epitope prediction and outperforms CEP even without antigen 3D structure information .In recent years, the epitope prediction methods employing mimotopes derived from phage display experiments were developed. In general, these methods can be classified as methods that map mimotopes to the overlapping location patches on the antigen surface using statistical features of mimotopes and methods using mimotope mapping back to the antigen sequence through alignment. Mimotope has similar physicochemical properties and spatial organization but however rarely shows sequence similarity to the native antigen. In some cases, mimotope mapping back to the antigen can indicate B-cell epitope location . B-cell Antibodies are currently the most promising class of biopharmaceuticals. The main objective of epitope identification is to replace an antigen in the immunization, antibody production, and serodiagnosis. The accurate identification of B-cell epitopes and large-scale data integration still presents major challenges for immunologists. Advances in B-cell epitope mapping and computational prediction have yielded molecular insights into the process of biorecognition and formation of Ag-Ab complex, which may help to formulate even more precise algorithms to predict their localization in the antigen. However, based on statistics it is not possible to precisely determine the epitope characteristics, which allow biorecognition. One has to keep in mind that the epitopes are not intrinsic feature of proteins and antibody-ignored prediction methods predict only putative epitope to which an undefined Ab might bind. The real epitopes cannot be predicted ignoring the structural effect upon Ag-Ab complex formation. This fact opens new space for all algorithms to improve further.


Dear Colleagues,We have always been working hard to keep the Brazilian Journal of Cardiovascular Surgery(BJCVS) active and up-to-date, despite the uncertainties that pervade the political,economic, social and scientific activities in our country.Those who did not imagine the evil influence that would be exerted by the instabilitythat has taken place in the public or private Universities, were wrong. The negativeimpact on teaching and research, caused by a lack of resources, was enormous.Much more serious was the impact on hospitals, medical clinics, primary healthcarecenters, Intensive Care Units (ICUs), as well as on health equipment, dependent onfederal, state, municipal or private funding, due to the widespread undercapitalizationof governments and the population, seriously damaging the patient care, and the datageneration, essential to the research.The question that won't go away is: What does the BJCVS have to do with all thisbackground?Unfortunately, we have a lot to do with it, because the manuscripts that come to us arebasically from "Stricto or Lato Sensu" postgraduate programs, related to patient care,and to a lesser extent regarding the basic research.In the Editorial Issue 31-1 of the BJCVS, I pointed out that we were facing a greatchallenge in 2016, due to the many changes and adjustments implemented during thisperiod. I was concerned about the flow of manuscripts and their quality, could be enoughto celebrate the journal's 30th anniversary with dignity, getting a better Impact Factor(IF).In this issue we have the intelligent answer to my apprehension.In the section BJCVS 30 YEARS, the brilliant Professor Paulo Evora gives us a lessonon the Impact Factor (IF) and its ills.I ask you to carefully, read the article: Brazilian Journal of Cardiovascular Surgery30 years: Does, the Impact Factor, matter? (Page 266).By reading this article, we can appreciate not only the author's opinion, as well asother subject-matter experts cited by him, showing how flawed the valuationprocesses are, performed by Thompson Reuters and Scimago exclusively in order toguide the booksellers. However, it was adopted in Brazil to generate the Qualis,which is maintained by CAPES, a methodological excrescence that harms thepublications of countries like Brazil, and also the specialties, which are unlikelyto have as many citations as a generalist journal who has a huge field of authorsand readers.At the beginning of the article, Professor Evora expresses my hope, in the paragraphthat should always be repeated:"Brazil is much greater than the crises it faces. It is essential to show what we arecapable of in order to stand amidst other nations". .I hope this optimism becomes a reality.In the same section, there are also two excellent articles; one of them, by theProfessor Walter J. Gomes: Thirtieth anniversary of the Brazilian Journal ofCardiovascular Surgery. And devising the next decades (page 265)The author presents us with a futuristic vision of hope, only seen in patrioticleaders.Another article that is also worth reading is: 30 Years of BJCVS (page 267)Written by Professor João de Deus e Brito, who besides doing a very wellprepared historical review, shows his deep knowledge of the BJCVS, whose he hasalways been a dedicated reviewer.I thank the collaboration of these professors on my own behalf and in the name of thewhole Editorial Board and Technical Clerks, who continue the saga and the traditionof our journal.As I mentioned at the beginning of this Editorial, we have been working with a focuson modifications that were suggested to improve the performance of our journal.For now, were indicated seven Associate Editors, in the areas of coronary diseases,valve diseases, congenital diseases, aorta diseases, advances in cardiovascularsurgery and basic research.The choice criteria were absolutely based on meritocracy, dependent on theperformance of the Associate Editors and Reviewers over the years.The task was made easier by the ongoing assessment performed by the journal's stafffor many years.The selection of the Area Editors, and the areas themselves, is not finished yet, andshould be perfected throughout the time.As almost everyone knows, we are migrating to the: submission, review, approval, orrejection of the manuscript to ScholarOne platform, developed by Thomson Reuters andadopted by SciELO, with FAPESP's economic support.This platform is internationally considered ideal for the globalized journals.The deadline for the definite migration to the new platform is scheduled to August15th.I hope the implantation time can be fulfilled, since all the work is being developedwith great professionalism.Among the good news about the events, I emphasize some very important factors:The participation of the SBCCV with a special session during the 71st Congress of theSBC in Fortaleza, on September 23, 2016.In the 44th Congress of SBCCV the main theme will be: High Technology: (acquiringknowledge to employ it better), to be held in Rio de Janeiro, on April 20-22, 2017with special participation of international speakers such as Prof. Eric J. Velazquez; Prof. Hartzell V. Schaff ; Prof. John Puskas ; Prof. Michael M. Madani  and Prof. Manuel Antunes.As you will see, we have good national and international articles in this issue, withnotable articles from China - Mild Hypothermia May Offer Some Improvement toPatients with MODS after CPB Surgery (page 246); Fungal Endocarditis (page 252); Onefrom Romania - Primary Aortoduodenal Fistula: First you Should Suspect it (page261).With great satisfaction, we received the first article from Portugal, EndovascularAbdominal Aneurysm Repair in Women: What are the Differences Between the Genders?(Page 232).I wish you all a very nice and instructive read.I thank, as always, the essential support of the Board of Directors, AssociateEditors, Technical Staff and especially the Authors and Readers who keep the BJCVSalive.Warmest regards, Editor-in-Chief - BJCVSDomingo M. Braile


The aims of this study were to (i) assess the expectations of general practice departments regarding health sciences libraries’ subscriptions to journals and (ii) describe the current general practice journal collections of health sciences libraries.A cross-sectional survey was distributed electronically to the thirty-five university general practice departments in France. General practice departments were asked to list ten journals to which they expected access via the subscriptions of their health sciences libraries. A ranked reference list of journals was then developed. Access to these journals was assessed through a survey sent to all health sciences libraries in France. Adequacy ratios (access/need) were calculated for each journal.La Revue Prescrire (96.6%), La Revue du Praticien–Médecine Générale (90.9%), the British Medical Journal (85.0%), Pédagogie Médicale (70.0%), Exercer (69.7%), and the Cochrane Database of Systematic Reviews (62.5%) had the highest adequacy ratios, whereas Family Practice (4.2%), the British Journal of General Practice (16.7%), Médecine (29.4%), and the European Journal of General Practice (33.3%) had the lowest adequacy ratios.All general practice departments completed the survey. The total reference list included 44 journals. This list was heterogeneous in terms of indexation/impact factor, language of publication, and scope . Among the first 10 journals listed, General practice departments have heterogeneous expectations in terms of health sciences libraries’ subscriptions to journals. It is important for librarians to understand the heterogeneity of these expectations, as well as local priorities, so that journal access meets users’ needs. Health sciences libraries’ missions include subscribing to journals (print or electronic) and databases, purchasing books, and providing access to these resources through their websites . One curGeneral practice  is defined as “an academic and scientific discipline, with its own educational content, research, evidence base and clinical activity, and a clinical specialty orientated to primary care” . In FranThe needs of academic general practitioners for journal access and the degree to which their affiliated health sciences libraries meet these needs are unknown. Also, it is uncertain whether previous literature can fit to the context of French university general practice. The authors, therefore, conducted a cross-sectional descriptive study aiming to: (i) assess the expectations of faculty in general practice departments in France regarding health sciences libraries’ subscriptions to journals and (ii) describe the current journal collections of French health sciences libraries.The first phase of the study was conducted between September 17, 2015, and January 15, 2016. We contacted all of chairs and heads of scientific programs of the thirty-five university general practice departments in France via email . Three rAn illustrative list of fifty-seven journals was attached to the email to assist the respondents . This liThe second phase of the study was conducted between January 20, 2016, and March 21, 2016, among the thirty-six existing health sciences libraries . Based on the reference list of journals developed through the questionnaire, we asked the head librarian of each health sciences library to indicate whether a subscription for their library was available in print or electronically in 2015. The first contact with the health sciences libraries was made by phone before sending an email. Two reminders were sent. If a health sciences library did not participate despite the reminders, we collected the data using Périscope , which iWe counted the number of general practice departments that expected to have access to each journal on the reference list  and that had access to a subscription through their health sciences library or had the journal listed in their catalog if it was an OA journal. An adequacy ratio (access/demand) was then calculated.All data were analyzed using Microsoft Excel (version 14.0.0). Quantitative variables are represented as absolute number (percentage) unless otherwise stated. This study was conducted in agreement with the Collège National des Généralistes Enseignants (CNGE)–Collège Académique . No ethics committee approval was necessary according to French law, given the observational nature of the collected data .Exercer, La Revue Prescrire, Family Practice, the British Medical Journal (BMJ), Pédagogie Médicale, British Journal of General Practice, Médecine, the European Journal of General Practice, La Revue du Praticien–Médecine Générale, and the Cochrane Database of Systematic Reviews  were in French, 3 (6.8%) were bilingual , and the others (56.8%) were in English. Twenty-eight journals (63.6%) had an impact factor (IF) in JCR.Six journals that were mentioned did not appear in the representative list, and each was mentioned fewer than 2 times: Of the 36 health sciences libraries contacted, 35 returned the list of their collections (97.2%). We used Périscope data for 1 health sciences library. The complete health sciences library offerings for each of the 44 journals are presented in La Revue Prescrire, La Revue du Praticien-Médecine Générale, and BMJ, and the 3 journals with the lowest adequacy ratios were Family Practice, the British Journal of General Practice, and Médecine. An adequacy ratio greater than 50% was obtained for 6 of these 10 journals (60%).La Revue Prescrire, La Revue du Praticien–Médecine Générale, BMJ, Pédagogie Médicale, Exercer, and the Cochrane Database of Systematic Reviews had the best adequacy, whereas Family Practice, the British Journal of General Practice, Médecine, and the European Journal of General Practice had the least adequacy.We identified and prioritized forty-four journals, based on expectations of library subscriptions of the thirty-five French general practice departments. The journal subscription offerings of the thirty-six French health sciences libraries were heterogeneous, and adequacy in meeting demand was imperfect. Among the first ten journals listed, Great heterogeneity was noted among lists of journals mentioned by different departments in terms of scores, number of mentions, language of publication, IF, and scope. Cross-checking this list to previously developed lists  illuminaSimilar observations were made with the 2003 Brandon/Hill list , the McKExercer. This journal provides consensus in the French general practice community [The journal mentioned most frequently in our reference list was ommunity , althougLa Revue Prescrire was in second place on the list. Like Exercer, it is not indexed in MEDLINE and has no IF. This journal is more oriented toward therapeutics than the general practice discipline. Its high ranking might be related to its independence from industrial interests. It is the second journal (after Exercer) in terms of numbers of individual subscriptions among French teaching general practitioners (85.2%) [ (85.2%) .Family Practice. This is the first journal on the reference list that is indexed in MEDLINE. Nevertheless, it has a low IF (2.0 in 2015), compared to other journals with lower scores.In third place was the international journal BMJ (IF of 19.7 in 2015), or a lower, IF such as the British Journal of General Practice (IF of 2.7 in 2015) and the European Journal of General Practice (IF of 1.4 in 2015), had the same degree of expectation as French non-indexed journals such as Pédagogie Médicale, Médecine, and La Revue du Praticien–Médecine Générale.Journals in the fourth through tenth positions had similar scores, and almost one-third of general practice departments expected to have access to them. International journals with a high IF, such as New England Journal of Medicine (IF of 59.6 in 2015), The Lancet (IF at 44.0 in 2015), and JAMA (IF at 37.7 in 2015), which had IFs far superior to those of the first journals listed. Overall, therefore, IF does not appear to be a major factor influencing expectations of general practice departments.From the eleventh position onward, expectations were lower but still heterogeneous. These journals included some internationally highly reputed journals, such as the La Revue du Praticien–Médecine Générale) and others were only oriented toward medical education , most addressed all three themes and, thus, are important to both teachers and researchers in general practice.A recent survey identified the multiple expectations of teaching general practitioners with regard to what a general practice journal should address . The mosLa Revue Prescrire, La Revue du Praticien–Médecine Générale, and BMJ . Pédagogie Médicale and Exercer had acceptable scores of around 70.0%. Conversely, Family Practice, the British Journal of General Practice, and Médecine had low adequacy scores , although their subscription costs were similar to those of the other journals  is a nonprofit organization financed by the contributions of its members and government grants (Ministry of Higher Education and Research) . This coOn a local level, sharing electronic collections between institutions avoids the uncoordinated dispersion of purchases. For example, agreements between university hospital centers and health sciences libraries have avoided duplicate subscriptions , 22. FurAppendix AClick here for additional data file.Appendix BClick here for additional data file.Appendix CClick here for additional data file.Table 3Click here for additional data file.Table 4Click here for additional data file.Table 5Click here for additional data file.


Staying current with the literature is of paramount importance to the pharmacist engaged in an evidence-based clinical practice. Given the expanding roles and responsibilities of today’s pharmacists combined with exponential growth in new medical and health sciences literature, staying current has become an extremely daunting task. Traditional journal clubs have focused upon their role as a training vehicle for teaching critical reading skills to residents. However, schools of pharmacy are now required to provide instruction in biostatistics, research design, and interpretation. We present a paradigm shift in the traditional journal club model whereby a collection of periodicals is screened and a short synopsis of the pertinent articles is provided. The associated tasks for screening and presenting of the primary literature are shared among a group of clinicians and trainees with similar practice interests resulting in a more reasonable workload for the individual. This journal club method was effective in identifying a significant majority of articles judged to be pertinent by independent groups of clinicians in the same practice arenas. Details regarding the shared core practice and knowledge base elements, journal club format, identification of journals, and evaluation of the success of the journal club technique are provided. Journal clubs are commonplace in academic medical centers and hospitals in various fields of clinical practice including pharmacy. The first record of a medical journal club was attributed to Sir William Osler at McGill University in 1875 . The purStaying current with the literature is an essential requirement for the pharmacist engaged in an evidence-based clinical practice. It has been suggested that the gap between implementation of new knowledge into clinical practice is a primary reason for the suboptimal provision of quality health care for some institutions . HoweverFive clinical faculty members with direct patient care responsibilities and three second post-graduate year (PGY2) pharmacy residents comprise the core of the journal club group. All faculty are within the same department at the University of Tennessee College of Pharmacy and are based at the same university-affiliated hospital . Advanced clinical pharmacist activities are required via a contractual agreement between the College of Pharmacy and the hospital. Two faculty members have clinical responsibilities and coordinator duties for the Nutrition Support Service (NSS), another two faculty members provide critical care pharmacy services, and one faculty member shares responsibilities for both services. The NSS faculty members provide clinical services to adult patients throughout the entire hospital that require parenteral nutrition and to select complicated patients who require enteral nutrition. The critical care faculty members provide pharmacotherapy services to a Level 1 Trauma Intensive Care Unit (TICU) and its associated step-down unit. Most of the patients managed by the NSS are also trauma and surgical intensive care unit patients that frequently coincide with the population followed by the TICU faculty. The PGY2 pharmacy residents are required to complete four months of NSS experience and four months of TICU clinical pharmacy services with the remaining months dedicated to elective experiences, research, and miscellaneous activities. Thus, all clinical faculty and PGY2 trainees share a common thread of required knowledge and reading sources necessary for optimal performance of their respective duties. It would be intuitive that both NSS and TICU clinical pharmacy services could streamline their ability to stay current with the literature by sharing reading sources and communicating findings from pertinent articles with each other.The primary intent of our journal club is to stay current with new literature that may confirm, alter, or augment conventional practice in pharmacy nutrition support or pharmacy trauma intensive care. A second objective is to accomplish the task of screening and compiling pertinent studies on a consistent basis without burdening a sole person with the excessive workload. Third, this journal club methodology provides a forum for training pharmacy resident mentees via dialogic teaching of emerging innovative therapies, where perspective on the paper’s application to clinical practice and what is currently known in the field can be provided. This model exemplifies one method on how to facilitate continued growth in knowledge of current literature for trainees to potentially emulate upon completion of their training.The journal club process and organization are overseen by five clinical pharmacy faculty mentors. In addition to the faculty mentors, other active participants are also expected to screen journals, prepare materials for the journal club, and present papers at each session. These other participants include our three PGY2 critical care pharmacy residents and PGY1 pharmacy residents  enrolled in an elective NSS or TICU rotation. Students on Advanced Pharmacy Practice Experience (APPE) rotations for the month with the clinical faculty are also required to attend as non-presenting participants. Most journal club sessions are comprised of 12–15 attendees.Journal club meetings are scheduled twice monthly on the second and fourth Tuesday of every month at 3 P.M. and is to last no longer than 1 h. This time was found to be conducive for attendance as the NSS and TICU pharmacy services tend to complete most of their clinical activities for the day by that time as clinical service responsibilities usually begin at 6 or 7 a.m. for each service. In addition, a consistent time and day facilitates the development of a routine, whereby the session is unlikely to be inadvertently forgotten and missed. The location of journal club meetings is also kept consistent and held in a conference room at the College of Pharmacy building, which is located adjacent to the hospital. The tables and chairs are arranged in a rectangular format to facilitate interactive communication among the participants. The presenter may be located within any location in the rectangle.It has been suggested that journal clubs can encourage residents to regularly and critically read the medical literature but will not succeed if the journal club suffers from poor attendance or periodic abandonment . AttendaTwenty-nine journals are screened monthly . The jouThe scheduled presenter must screen the assigned journals and develop a packet of materials consisting of a face sheet, the table of contents for all assigned periodicals for the month, the first page of selected articles containing the abstract of the paper, and sometimes an entire article if the presenter considers the paper of pivotal importance. A truncated example of the journal club packet is provided in Reviews, guidelines, and position papers are not reviewed but may be provided on the face sheet and mentioned during the presentation to alert journal club attendees of its presence. The following month’s presenters use the current month’s face sheet to ascertain what issues of the assigned journals have already been evaluated so that a lapse in coverage in evaluating journal content can be avoided.Our journal club’s current periodicals identified for screening and presentation are listed in To evaluate the success of our journal club in identifying articles pertinent to our practice, we examined a series of publications which was intended to identify the most significant articles for pharmacy nutrition support and critical care pharmacy practice published from 2013 to 2017 ,16,17,18Eighty-seven papers significant to pharmacy nutrition support practice were identified by the author group over the four-year observation period. Seventy-five articles were from periodicals included in our journal club. An additional three articles were from a journal that was not included in the screening list of periodicals but all faculty and PGY2 residents receive as part of their membership of the journal’s sponsoring organization . SeventyStaying current with the literature is a daunting but essential task for the pharmacist who is engaged in an evidenced-based clinical practice. Presented in this review is a method for redesigning journal clubs from the traditional technique of an in-depth analysis of one or two articles to a screening tool that effectively keeps pharmacists informed of current literature. This technique reduces workload of the individual by sharing duties among multiple pharmacists and provides a forum for faculty and senior clinicians to mentor their trainees. This methodological redesign of the traditional journal club is offered to others for consideration.


On behalf of everyone at PR&P, I convey the passing of our Editor‐in‐Chief, Dr Darrell Abernethy. Darrell has been part of PR&P since its inception, initially as Deputy EiC and since 2016 as EiC. He was a stalwart of the journal and assisted in the recruitment of a strong editorial board and the communication with editors of its supporter journals. From a professional perspective, Darrell had a distinguished career as a clinical pharmacologist and geriatrician. Darrell completed MD / PhD degrees at the University of Kansas, followed by training in Internal Medicine at the University of Miami (Florida) and in Clinical Pharmacology at Harvard Medical School / Massachusetts General Hospital. He had a number of academic positions and also directed an NIH program regarding the effects of drugs in the elderly. His last appointment was with the FDA where he investigated ways to predict adverse effects of therapeutic drugs. Darrell's excellence was recognized by his peers with numerous awards, including the Nathaniel T. Kwit Memorial Distinguished Service Award from the American College of Clinical Pharmacology and the William B. Abrams Award in Geriatric Clinical Pharmacology and the Rawls‐Palmer Progress in Medicine Award from the American Society for Clinical Pharmacology and Therapeutics.Darrell contributed back to the discipline at a high level. He was EiC of Pharmacological Reviews and Associate Editor of the Journal of Pharmacology & Experimental Therapeutics as well as Clinical Pharmacology and Therapeutics. This experience was brought to bear during his tenure with PR&P. In addition to his editorial responsibilities and leadership, Darrell was also a leader within the broader pharmacology community being a key contributor to the Clinical Division of the International Union of Basic and Clinical Pharmacology (IUPHAR).Darrell's major pastimes included sailing and music. He was an affable person and a great encourager of his juniors. He will be sorely missed.Professor Andrew J Lawrence BSc(Hons), PhD, FBPhSCurrent EiC of PR&P


It remains inconclusive whether hyperuricemia is a true risk factor for kidney graft failure. In the current study, we investigated the association of hyperuricemia and graft outcome. We performed a multi-center cohort study that included 2620 kidney transplant recipients. The patients were classified as either normouricemic or hyperuricemic at 3 months after transplantation. Hyperuricemia was defined as a serum uric acid level ≥ 7.0 mg/dL in males or ≥ 6.0 mg/dL in females or based on the use of urate-lowering medications. The two groups were compared before and after propensity score matching. A total of 657 (25.1%) patients were classified as hyperuricemic. The proportion of hyperuricemic patients increased over time, reaching 44.2% of the total cohort at 5 years after transplantation. Estimated glomerular filtration rate and donor type were independently associated with hyperuricemia. Hyperuricemia was associated with graft loss according to multiple Cox regression analysis before propensity score matching  as well as after matching . Cox regression models using time-varying hyperuricemia or marginal structural models adjusted with time-varying eGFR also demonstrated significant hazards of hyperuricemia for graft loss. Cardiovascular events and recipient survival were not associated with hyperuricemia. Overall, hyperuricemia, especially early onset after transplantation, showed an increased risk for graft failure. Further studies are warranted to determine whether lowering serum uric acid levels would be beneficial to graft survival. Hyperuricemia is common in kidney transplant recipients (KTRs). The prevalence of hyperuricemia in KTRs has been documented to range from 15% to 52% . Male geConvincing evidence indicates that hyperuricemia is associated with the prevalence of chronic kidney disease (CKD) , 6 or prHyperuricemia is closely related to kidney dysfunction due to decreased urate excretion and is used as a marker of kidney damage. However, hyperuricemia with normal kidney function could also be a contributor to adverse renal outcome such as ESRD. We hypothesized that early onset hyperuricemia after kidney transplantation is distinct from the hyperuricemia that is generated from graft dysfunction. Therefore, we investigated the clinical impact of early onset hyperuricemia on graft dysfunction, cardiovascular events and recipient mortality using propensity score matching (PSM) analysis with a multicenter cohort. Then we evaluated the association of time-varying hyperuricemia and graft dysfunction using time-varying Cox proportional hazards model and marginal structural model.A total of 3374 adult KTRs who underwent kidney transplantation between January 1999 and August 2012 at Seoul National University Hospital and Asan Medical Center were screened. The patients with following criteria were excluded: (1) retransplant (n = 127), (2) simultaneous liver kidney transplant, simultaneous pancreas kidney transplant or simultaneous heart kidney transplant (n = 130), (3) early graft loss or mortality within 3 months (n = 38), (4) prescription of uric acid-lowering agents consistently from pre-transplant to post-transplant (n = 104), (5) no data of serum uric acid or serum creatinine at 3 months after transplantation (n = 355). The remaining 2620 participants were followed from 3 months after transplant until death or March 31, 2015. .Hyperuricemia was defined as a serum uric acid (SUA) level over 7.0 mg/dL for males or over 6.0 mg/dL for females or based on the use of urate-lowering agents such as allopurinol, febuxostat or benzbromarone. The study population was classified into two groups: a hyperuricemic group and a normouricemic group.The study was approved by our Institutional Review Board (H-1507-027-686), and the need for informed consent was waived due to the retrospective design. The study was conducted in accordance with the 2008 Declaration of Helsinki.The demographics and laboratory results of the KTRs were retrospectively obtained from medical records. Age; gender; body weight; transplant date and donor type; donor age; donor gender; comorbid disease; post-transplant medications including immunosuppressants and urate-lowering agents; and laboratory data were collected. Steroids, calcineurin inhibitors, and inhibitors of purine synthesis were used as the basic immuonosuppressive agents. We reviewed serum levels of creatinine (SCr), SUA, hemoglobin, albumin, and total cholesterol. Data for SUA and SCr were collected at 1, 3, 6, 9, 12, 18, 24, 36, 48 and 60 months after transplantation. SCr was measured using the kinetic alkaline picrate (Jaffe) reaction and was standardized using an isotope dilution mass spectrometry method. Body mass index (BMI) and prescription of allopurinol, febuxostat, and benzbromarone were also reviewed. Estimated glomerular filtration rate (eGFR) was calculated using the CKD Epidemiology Collaboration equation . IschemiThe primary objective was to evaluate whether hyperuricemia affected graft survival. Graft failure was defined as the need for dialysis, the need for subsequent renal transplantation, or death with a functioning graft. The secondary objective was to evaluate the associations of hyperuricemia with IHD and patient survival.Categorical variables were presented as frequencies, and proportions were compared using the chi-square test. Continuous variables were compared using Student’s t-test. Most continuous values were expressed as the mean ± standard deviation. A logistic regression model was used to investigate independent associated factors of hyperuricemia. Kaplan-Meier survival curves were compared with log-rank tests.In Cox proportional hazard regression analyses with time-fixed hyperuricemia, hyperuricemia at 3 months after transplantation was considered as a categoric variable. Significant factors in univariate analysis were included in the final model in multivariate analyses to determine the associations between hyperuricemia and graft failure, ischemic heart disease, and mortality. PSM was used to adjust for cases of hyperuricemia associated with decreased eGFR. Propensity scores were estimated using multiple logistic regression analysis adjusted for recipient age, gender, eGFR, and donor type. We then matched the patients in the normouricemic and hyperuricemic groups with similar propensity scores at a 1:1 ratio using the nearest neighbor method, no replacements and no caliper. The characteristics of both groups were compared before and after the PSM.Time-varying Cox model was fitted to estimate the independent association with longitudinal change in hyperuricemia. Estimated GFR was considered as time-varying covariates. A marginal structural model estimated the independent association between a time-varying exposure of hyperuricemia and graft failure, with eGFR as a time-varying confounder. A P-value of <0.05 was considered statistically significant. All statistical analyses were conducted using SPSS version 22.0  and STATA 13 . R software (version 2.15.0) was used for the PSM.The trends in SUA levels and the proportion of hyperuricemic patients after transplantation are depicted in The clinical characteristics of the 2620 included KTRs are summarized in 2. The mean SUA level in the normouricemic group was 5.1 ± 1.1 mg/dL, and it was 7.4 ± 1.4 mg/dL in the hyperuricemic group. The hyperuricemic group showed lower levels of hemoglobin and total cholesterol and higher SCr compared to the normouricemic group , episodes of acute rejection within 3 months after transplantation, eGFR, hemoglobin level, and cholesterol level according to univariate analysis. Any variables deemed statistically significant by univariate analysis were subjected to multivariate analysis. Only DDKT  and eGFR  were independently associated with hyperuricemia at 3 months after transplantation according to multivariate analysis .The patients were followed up for 85.9 ± 53.3 months (median 72.0) post-transplant . Graft loss occurred in 201(7.7%) of the patients. A total of 122(6.2%) cases in the normouricemic group and 79 (12.0%) cases in the hyperuricemic group lost their grafts p<0.001, . After PTo examine the independent association between SUA level and graft survival at 3 months post-transplant, we used multiple Cox regression analysis with the number of HLA mismatches, episodes of acute rejection, donor type, eGFR, and hyperuricemia before performing PSM . HyperurDuring the study period, 83(3.2%) patients died, 56(2.9%) of whom were in the normouricemic group and 27(4.1%) of whom were in the hyperuricemic group. There was no difference in patient survival  cases, and there was no post-transplant difference between the two groups before , however, not in time-varying cox model   and marginal structural model  in the subjects with eGFR over 60ml/min/1.73m= 0.053) .In the current study, we examined the predictive value of hyperuricemia at 3 months post-transplantation for long-term graft outcomes. Almost half of the KTRs included in the study developed hyperuricemia within 5 years after transplantation. There was a significant correlation between SUA level and corresponding eGFR; however, even after adjustment for eGFR and PSM, hyperuricemia was significantly associated with worse graft outcome.Improving the long-term outcome of kidney transplantation depends on identifying novel risk factors that lead to poor outcomes. Many clinicians consider uric acid as a risk factor for graft loss; however, whether SUA has a causative role in graft dysfunction is inconclusive. Most previous studies regarding hyperuricemia in KTRs were performed using a retrospective design and a small sample size . AdditioVarious time points and statistical techniques have been used to investigate the causal relationship between uric acid and graft outcomes; the time points previously used include one month , 18, 3 mAlthough previous study by Kim et al  suggesteIn this study, type of donor (DDKT) and eGFR were independently associated with gender-specific hyperuricemia. Kidney dysfunction is a widely known risk factor of hyperuricemia, while association with DDKT is not well recognized. Acute tubular necrosis is a common complication associated with allograft transplants from deceased donors with prolonged ischemia time, causing delayed graft function or primary nonfunction . As the A consensus on whether to treat asymptomatic hyperuricemia in CKD has not been established, and current international guidelines do not recommend the treatment of asymptomatic hyperuricemia in patients with CKD  or KTRs In animal studies, the use of the xanthine oxidase inhibitors allopurinol , 35 or fHyperuricemia was related to graft failure, but not to patient mortality or cardiovascular outcome. However, the total numbers of patient deaths and adverse cardiovascular outcomes in the current study were too small to form robust conclusions. Cardiovascular events are relatively rare in Korea in both the general population  and in KThere are several limitations in the current study. First, the study was performed using a retrospective cohort design, so several factors influencing SUA and dosage of immunosuppressants were not fully collected. Second, the effects of urate-lowering agents could not be investigated. Despite these limitations, the current multi-center, retrospective cohort study still provided useful information on how hyperuricemia affects graft outcome based on PSM or time varying covariate.In summary, post-transplant hyperuricemia, especially early onset hyperuricemia, strongly correlates with poor graft outcome. Further studies are warranted to determine whether lowering serum uric acid levels would be beneficial to graft survival.S1 Fig(A) The standardized mean difference and (B) the distribution in propensity scores before and after propensity score matching. The propensity scores of matched patients were almost the same between groups.(TIF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S1 Data(XLSX)Click here for additional data file.


Liver transplantation (LT) has been established as the most effective treatment modality for end-stage liver disease over the last few decades. Currently, patient and graft survival after LT are excellent, with 1- and 5-year survival of 90% and 80%, respectively. However, the timing of referral to LT is crucial for improving survival benefit and outcome. The current shortage of donors and the increasing demand for LT currently lengthen the waiting time. Thus, waiting list mortality is about 10–15%, according to the geographical area. For this reason, over the last several years, alternatives to deceased donor LT and new options for prioritizing patients on the waiting list have been proposed. The continuous improvement of surgical techniques, organ conservation, and immunosuppression management as well as optimization of intensive care have improved the results of liver transplantation (LT), and today this surgical procedure is a viable treatment option for patients with end-stage liver disease or acute liver failure (ALF).1. Now, LT is the standard treatment for ALF and chronic liver failure of all etiologies, and over 80,000 procedures have been carried out since its inception. Survival rates are significantly better now than they were a quarter of a century ago: 96% at 1 year and 71% at 10 years post-LT2. This review focuses on hot topics in the field of transplant hepatology and includes indications for LT, timing for LT, use of extended criteria donors, management of early and long-term complications after LT, and transplant benefit.Between 1963 and 1968, Thomas Starzl and Roy Calne performed the first LT in Denver (USA) and Cambridge (Europe), respectively3. For this reason, previous and strict criteria for accepting organs for liver donation have slowly become more liberal4.Since indications for LT are increasing, transplant teams are searching for new ways to increase the donor pool. In the United States, less than 40% of patients on the waiting list eventually receive a graft, and almost 10% die while waiting owing to a paucity of organs compared to the need for organs for transplantation5. In the first group, a special mention needs to be made for DCD, whereas amongst the latter we will address the SLT procedure and LDLT.Although the definition of an extended donor has not been thoroughly established, most agree that it conveys a higher risk of either physiologic dysfunction or infectious/metabolic disease transmission. Extended criteria can be separated into two groups: donor-related risk factors and surgical technique-related issues. Donor-related issues include donation after cardiac death (DCD), advanced age, increased cold ischemia time, ABO incompatibility, steatosis, previous malignancies in the donor, hepatitis C virus (HCV) or hepatitis B virus (HBV) infection, human T-cell lymphotrophic virus type I/II infection, or other active infections. These extended criteria donors can generally be accepted or declined by the transplant team during evaluation of the allograft. Surgical technique-related issues of extended donors include split LT (SLT) and partial grafts used in living donor LT (LDLT). Both of these methods can provide a graft when a whole cadaveric organ is unavailableDonation after cardiac death. DCD organs are expected to expand the donor pool. Indeed, in the past 10 years in the US, 2,710 liver donors have been DCD organ donors, with the largest numbers used in the last 2 years6. Although previous experiences with DCD have been associated with greater risk of graft failure7, more recent reports did not confirm this finding, showing similar outcomes between DCD and donation after brain death (DBD)8. Still, some limitations need to be considered by the transplant team. In order to ensure a similar outcome to those associated with DBD, several variables need to be taken into account, such as donor age, warm and cold ischemia times, and duration of donor hypotension or hypoxemia11. Hopefully, in the next few years, improving our ability to perform ante mortem interventions will improve the likelihood of successful donation and graft outcomes. On the other hand,post mortem intervention such as the use of machine perfusion (MP) systems to improve graft function during the preservation period will be an additional challenging issue to improve DCD utilization. MP indicates several dynamic strategies appliedex vivo of organs for transplantation that aimed to improve the static cold storage preservation12. Recently, De Carliset al.13 reported their experience in using the MP in the setting of DCD. Even if the relatively small sample size (7 cases) limits the general applicability of the results, patient and graft survival were both 100% after a mean follow up of 6.1 months (range 3 – 9) and no cases of ischemic cholangiopathy occurred during the follow-up. Hopefully, the extensive use of MP will lead to a significant increase of the availability of transplant livers as well as a significant reduction in several types of graft dysfunction and biliary complications.Split liver transplantation. Over the 25 years since the first LTs were performed14, in light of continuing organ shortages and growing numbers of patients dying whilst waiting for transplants, SLT enlarges the donor pool and is one of the few surgical options to do so. LT performed with split grafts in Europe and in the US accounted for about 6% in the past decade15. Although the outcomes of LTs performed using partial grafts are good, there are specific complications associated with this technique. For example, small for size syndrome, related to a reduced ratio between graft and recipient body weight, is characterized by prolonged jaundice, graft dysfunction, and sometimes graft failure. Favorable results with SLT depend on not only the technical factors but also scrupulous recipient and donor selection.Living donor liver transplantation. LDLT has emerged as a promising alternative to overcome donor shortage16. The improvements in LDLT have led to the expansion of the recipient criteria to include patients previously considered not suitable for LT because of older age or co-morbidities. Living donors older than 45 years are often discarded, since the risks of these LDLTs remain controversial. Goldaracenaet al.17 compared patients receiving a LDLT from 91 donors aged ≥50 years with 378 younger than 50 years. The incidence of biliary complications as well as graft and patient survival at 1, 5, and 10 years were similar between both groups. Similarly, Oezceliket al.18 evaluated the use of LDLT in recipients older than 70 years. No significant differences in complications, hospital stay, perioperative mortality, or median survival compared to the younger group were found. Although LDLT is not a “100%” safe procedure and donor death rate has been reported around 0.1–0.3% (possibly reaching 0.5% when using the right hemiliver for adult-to-adult transplantation)19, the understanding of the biochemical mechanisms of graft injury and the possibility of promoting liver regeneration will be the key issues for the improvement of the use of partial liver grafts.20. Several factors play a role in this scenario, and four different categories should be considered at least: the donor’s age, gender, ethnicity, and viral serology; the graft’s size and quality; the recipient’s age, size, and gender; and the transplant’s major or minor blood group compatibility as well as immunological factors21. A detailed analysis of all these factors goes much further than the scope of this review. However, in the last few years, it has become clear that suitable matching together with adjusting surgical practise and developing novel peri-transplant approaches enables the utilization of grafts that would normally be rejected, thereby widening the donor pool. It is our opinion that they should include not only “simple mathematical variables” but also, at the same time, the global probability of death whilst waiting for transplant, survival after transplantation, cost-effectiveness, and survival benefit. We can achieve transparency, justice, utility, and equity when we consider all factors in one method20.Understanding the interactions among donor, graft, and recipient factors will ensure the best outcomes are attained after LT. Donor-recipient (D-R) matching can be defined as “the technique to check D-R pairs adequately associated by the presence of the constituents of some patterns from donor and patient variables”23.Candidates for LT must have irreversible ALF, progressive end-stage liver disease, or rarer diseases characterized by a normal liver producing toxic products . LT should be considered for any patient in whom survival after LT will exceed life expectancy of the underlying disease or where a significant increase in quality of life can be achieved. In more detail, intractable pruritus in cholestatic liver disease recipients, abdominal pain due to polycystic liver disease, and persistent/refractory hepatic encephalopathy are clinical conditions that severely affect patients' and relatives' quality of life; thus, they are considered to be accepted indications for LT24, in 2012 non-alcoholic steatohepatitis (NASH) was the etiology with the most rapid rise in frequency, increasing 4-fold from 2002 to 201225. Other main indications for LT are alcoholic liver disease, HBV-related cirrhosis, primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), and autoimmune hepatitis (AIH). Liver malignancies, like intra-hepatic hepatocellular carcinoma (HCC) or other rarer benign and malignant tumors, are considered to be a common indication for LT. Biliary atresia, Alagille syndrome, and metabolic liver diseases are the most common indications in the pediatric population23.Although HCV is currently the leading etiology among adult LT recipients26. Steroids are accepted treatment for severe AAH although their use is still a matter of debate. A meta-analysis by Rambaldiet al.27, including 721 patients, showed that steroids did not reduce mortality compared with placebo or no intervention. In a very select group of patients with AAH not responding to steroids, LT has been experimentally proposed after a selection process based on a multidisciplinary approach that involves transplant hepatologist, anesthetist, surgeon, ethicist, psychiatric and nurse28. The 6 and 24 months survival were significantly higher than not transplanted matched controls (77% vs 23%). Furthermore, the risk of recidivism was about 11.5% up to more than 3 years after LT, not significantly higher than the risk of patients who were transplanted after 6 month of abstinence.Acute alcoholic hepatitis (AAH) is associated with 1, 3 and 6 months mortality of 16%, 27%, and 40% respectivelyThere are also absolute and relative contraindications for LT, such as active alcohol and illicit drug abuse, extrahepatic malignancies , sepsis, severe pulmonary hypertension, coexistent medical disorders , and poor familial/social support. Relative contraindications include recipient age over 70 years, severe malnutrition or morbid obesity , severe osteoporosis with spontaneous fracture, cholangiocarcinoma, and previous extensive abdominal surgery.29.During the assessment of a patient with liver disease, signs of decompensation , suggest the need for a referral for evaluation for LT30. This decision must take into account both quality of life and prognosis related to natural history of liver disease as well as post-surgical mortality and morbidity. For these reasons, patients should be strictly selected and prioritized using prognostic scores. Currently, severity and mortality with liver disease is best highlighted by the MELD (model for end-stage liver disease) score, which predicts a recipient’s survival within 6 months through a logarithmic scale that includes as the variables a patients total bilirubin, INR, and creatinine.The ideal timing for performing LT should be balanced between mortality rate while on the waiting list and perioperative and postoperative mortality (10–15% at 1 year and 15–25% at 3 years)31 is now the most used formula to predict survival among candidates for LT, especially for those with significant portal hypertension.However, the MELD score without modification was shown not to adequately reflect all of the complications of portal hypertension . Thus, some efforts to update the prognostic value of the MELD score have been made over time. The MELD-Na formula 32.The MELD-based model applied a "sickest-first policy" and was adopted for use for graft allocation in US by UNOS in 2002 and in Europe by Eurotransplant in 2007. In a large study, LT candidates with a MELD score ≥18 demonstrated considerable transplant benefit, while those transplanted with a MELD score <15 showed a higher mortality rate when compared to those still waiting for transplant33. This survival matches the post-transplant survival of most other indications for LT; therefore, the MC still represent the globally accepted score system to consider patients with HCC suitable for LT. However, modest expansion of the MC could increase the number of selected candidates for LT without negative impact on survival35. Other authors recently proposed the evaluation of tumor behavior as a criterion for listing36. Even though the MC remain the preferred model to allocate organs to patients with HCC, because of the excellent post-LT survival, a modest expansion of these criteria could be one of the future challenges for transplant hepatologists in the next decade37.HCC is one of the common indications for LT worldwide. About 20 years ago, the Milan criteria  were proposed to select patients with HCC achieving the best survival after LT. Patients within the MC had a 5-year survival of about 70% with a tumor recurrence of <10%38, being caused by a massive necrosis of liver parenchyma exceeding the so-called minimum "critical mass" of hepatocytes capable of preserving organ function39. The most important etiological factors of ALF are viral infection (mainly HBV), drugs . Other less common causes are severe AIH, Wilson’s disease, mushroom poisoning, and toxic substance consumption . In a significant percentage of patients, no etiological factor can be found, especially in the pediatric population40. The timing of encephalopathy onset is crucial to establishing the type of ALF  and to providing an adequate short-term prognosis. Different selection criteria for emergency LT are used worldwide. Commonly used criteria evaluate multiorgan impairment , etiology, and severity of coagulopathy as the most important factors for listing ALF patients. King's College criteria41 are the most commonly applied; however, other algorithms have been proposed over time43. Nevertheless, several factors, such as recipient age, severity of pre-transplant illness, comorbidities, and the nature of graft used, could affect the outcome of emergency LT38.ALF is a clinical manifestation of sudden and severe hepatic injury, mainly characterized by the onset of hepatic encephalopathy and severe coagulopathy45.It is important to determine, in every aspect of medicine, whether or not an administered therapy will provide benefit to the patient. When dealing with organ failure, not all patients can be given the ideal treatment (organ transplantation) because of low availability. In some situations, even in the event of there being enough donor organs, for some patients the benefit of LT is not enough if compared to the waiting list mortality and the high postoperative and perioperative mortality, according to the literature. In LT programs, organ allocation reflects the policy of the “sickest first”: the organ is assigned to the recipient with the highest MELD score. In addition, the organ allocation policy can also be based on the transplant benefit, which is the benefit that best balances the recipient’s urgent need for transplantation with the need to optimize resource donation, producing good postoperative results in terms of patient and graft survival46. Conversely, post-LT long-term morbidity and mortality is caused mainly by the adverse effects of the immunosuppressive drugs. Acute rejection occurs with higher incidence within 2 weeks after transplantation, with a prevalence of 25–60% within 12 months after LT; acute rejection is treatable with steroid therapy or with more potent immunosuppressive drugs.Of the life-threatening complications related to LT, most occur perioperatively. These include primary graft dysfunction, acute rejection episodes, severe infections, and technical complications such as hepatic artery thrombosis or biliary leaks47.Chronic rejection occurs in about 5% of cases, usually after 6 months, and may evolve irreversibly with end-stage liver disease. Even if the rate of graft loss due to chronic rejection has significantly decreased to less than 2%, re-LT is indicated in those non-responders to medical therapy48.Finally, the cornerstone of LT recipients’ long-term management comprises not only the preservation of graft function but also the prevention and treatment of metabolic complications and cardiovascular disease, as well as regular screening for malignanciesLT is the treatment of choice for selected patients with end-stage liver disease, with HCC within restricted criteria, or with ALF. Graft and patient survival are markedly improving compared to the early period of LT owing to greater expertise in the surgical procedure and management of immunosuppressive therapy.An important limitation to LT is donor shortage. Split liver and the use of organs from living donors, extended criteria donors, or DCD are techniques used to increase the number of transplants. Optimizing the donor pool while offering equal access to LT have become the main challenges today. Patient survival is now >90% and 70–80% at 1 and 5 years, respectively. However, there is a need to identify which patients achieve significant survival benefit from transplantation and which do not so that resources are better directed to achieve greater good for all patients with liver disease.AIH, autoimmune hepatitis; ALF, acute liver failure; DBD, donation after brain death; DCD, donation after cardiac death; D-R, donor-recipient; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LDLT, living donor liver transplantation; LT, liver transplantation; MC, Milan criteria; MELD, model for end-stage liver disease; SLT, split liver transplantation.


Microarrays released its first volume in 2012. Since then, the journal has published 129 articles on the topic of microarrays, including their applications, analysis and new developments.MDPI’s journal The array technology saw its infancy in the mid–late 1970s, when the work of Grunstein and Hogness  allowed The advent of next-generation sequencing (NGS) added a new powerful tool to the technological resources available for genome-wide investigations, thus widening the potential of high-throughput investigations in biology and medicine ,12,13,14Microarrays will be renamed High-Throughput.To keep pace with these constant technological changes, the journal has chosen to change its name: Not only the name of the journal is being updated but also its scope, covering any high-dimensional approaches and the accompanying computational developments that enable the analysis and interpretation of large volumes of data generated in the Omics era.Microarrays during these years, and welcome them to join us in developing High-Throughput to its full potential.On behalf of the Editorial Board and the Editorial Office, I wish to thank all authors, reviewers and external editors for their support to


DWI was obtained by using of an axial EPI sequence. Minimal ADC values (ADCmin), mean ADC values (ADCmean), and maximal ADC values (ADCmax) were estimated. DCE MRI was performed by using dynamic T1w DCE sequence. The following parameters were estimated: Ktrans, Ve, and Kep. Spearman's correlation coefficient was used to analyze associations between investigated parameters. In overall sample, ADCmean correlated significantly with Ve and Ktrans, ADCmin correlated with Ve, and ADCmax correlated with Ktrans and Ve. SUVmean tended to correlate slightly with Ktrans. In G1/2 tumors, only Ktrans correlated well with ADCmax and SUVmean. In G3 tumors, Ktrans correlated well with Kep and Ve. Ve showed significant correlations with ADCmean and ADCmax. Ktrans correlated with ADCmax. Kep was higher in cancers with N2/3 stages. Tumor metabolism, water diffusion, and tumor perfusion have complex relationships in HNSCC. Furthermore, these associations depend on tumor grading. Kep may predict lymphonodal metastasizing.Our purpose was to analyze associations between positron emission tomography (PET), diffusion weighted imaging (DWI), and dynamic contrast-enhanced (DCE) imaging in patients with head and neck squamous cell carcinoma (HNSCC). The study involved 34 patients . In all patients a simultaneous  Head and neck squamous cell carcinoma (HNSCC) is the most frequent malignancy of the upper aerodigestive tract in humans .Contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) provide the mainstay of imaging for diagnosis, staging, and treatment response assessment in HNSCC . FunctioIt has been shown that HNSCC lesions had high standardized uptake values (SUV) and low apparent diffusion coefficient (ADC) values , 5. Furt18F fluorodeoxyglucose PET (18F-FDG-PET), DWI, and DCE and attempted to characterize complexity of imaging findings reflecting tumor biology [Some authors performed multiparametric investigation of HNSCC including  biology , 7, 8. T biology . Thereby biology . For exa biology .However, in other studies, no significant correlations between these parameters were identified –13. TherThis discrepancy of reported data questions the possibility of using multiparametric imaging findings as surrogate markers of tumor consistency in HNSCC.The analysis of possible relationships between microcirculation, cellularity, and glucose metabolism has not only scientific importance but also clinical significance. As mentioned previously, an understanding of such complexities could expand the knowledge of tumor characteristics and have clinical implications such as in guidance for treatment planning, early prediction of treatment responses, and evaluation of treatment outcome .18F-FDG-PET/MR including DWI and DCE in patients with HNSCC.The purpose of this study was to analyze possible associations between multiparametric imaging findings of simultaneous This prospective study was approved by the institutional review board of the University of Leipzig and all patients gave their written informed consent. All methods were performed in accordance with the relevant guidelines and regulations.Overall, 34 patients with primary HNSCC of different localizations were involved in the study . There w18F-FDG-PET/MR  was performed from the upper thigh to the skull after a fasting period of at least 6 hours. Application of 18F-FDG was performed intravenously with a body weight-adapted dose . PET/MR image acquisition started on average 170 minutes (range 60–300 minutes) after 18F-FDG application. In 28/34 patients a PET/CT scan was performed prior to PET/MRI, which explains the later PET/MRI image acquisition time in these patients. For attenuation correction of the PET data a coronal 3D-encoded gradient-echo sequence (Dixon-VIBE) was used. For each tumor, maximum and mean SUV  were determined.In all patients a simultaneous PET images were analyzed by one nuclear medicine physician (S. P.) with 7 years of experience.PET/MR datasets were evaluated by a board certified nuclear medicine and a board certified radiologist with substantial PET/MR experience in oncological image interpretation. PET/MR image analysis was performed on the dedicated workstation of Hermes Medical Solutions, Sweden.max threshold 40%) (Tumor margins of the HNSCC were identified on MR images (T1-sequence) and a polygonal volume of interest (VOI) was placed in the fused PET/MR dataset (SUVold 40%) .b-values of 0 and 800 s/mm2 . ADC maps were automatically generated by the implemented software. DWI images were analyzed by one radiologist . Polygonal regions of interest (ROI) were manually drawn on the ADC maps along the contours of the tumor on each slice (min), mean ADC values (ADCmean), and maximal ADC values (ADCmax) were estimated  sequence with ch slice . In all stimated .Ktrans: volume transfer constant, which estimates the diffusion of contrast medium from the plasma through the vessel wall into the interstitial space, representing vessel permeabilityVe: volume of the extravascular extracellular leakage space (EES)Kep: parameter for diffusion of contrast medium from the EES back to the plasma. It is in close relation with Ktrans and Ve and is calculated by the formula kep = Ktrans × Ve−1.DCE images were analyzed by one radiologist .In 31 patients, DCE MRI was performed by using dynamic T1w DCE sequence  after intravenous application of contrast medium (0.1 mmol Gadobutrol per kg of body weight)  as reported previously . The acqp) was used to analyze associations between investigated parameters. P values < 0.05 were taken to indicate statistical significance.Statistical analysis and graphics creation were performed using SPSS 20 . Collected data were evaluated by means of descriptive statistics (absolute and relative frequencies). Spearman's correlation coefficient  and slightly with Ktrans (0.04), ADCmin correlated with Ve (P = 0.0007), and ADCmax correlated with Ktrans (0.0032) and Ve (0.045) (Ktrans correlated well with Kep (P = 0.0017) and Ve (P = 0.0002).Сorrelation analysis identified the following: in overall sample, ADC (0.045) . Ktrans max tended to correlate slightly inversely with ADCmin (P = 0.08) and SUVmean had a tendency to correlate with Ktrans (P = 0.08).In addition, SUVKtrans correlated well with ADCmax and SUVmean (max tended to correlate inversely with ADCmin (P = 0.09). Ve had a tendency to correlate with ADCmean and ADCmin . In addition, DCE parameters did not correlate together.On the next step, the estimated parameters were correlated in different tumor subgroups. In G1/2 tumors,  SUVmean . No otheKtrans correlated well with Kep (P = 0.015) and Ve (P = 0.003) (Ve showed significant strong correlations with ADCmean (P = 0.0014) and ADCmin (P = 0.01). Ktrans correlated moderately with ADCmax (P = 0.04). Finally, SUV values did not correlate with ADC and perfusion parameters.However, in G3 tumors, = 0.003) . Ve showNo significant differences were identified in the analyzed parameters between poorly and moderately/well differentiated tumors .Kep was higher in cancers with N2/3 stages versus N0/1 stages  [Ktrans, Ve, and Kep) also correlated well together [max and ADCmean  was found [mean correlated inversely with Ktrans  [According to previous reports, several parameters of tumor perfusion, diffusion, and glucose metabolism were associated together –10. So B = 0.03) . Furthertogether . In the  = 0.04) .However, other authors did not identify significant correlations between analyzed parameters –13. For It is still unclear why some authors found significant correlations between water diffusion, glucose metabolism, and perfusion parameters in HNSCC while others did not. Presumably, tumor heterogeneity may play a role here. For example, well, moderately, and poorly differentiated tumors might show also different associations of imaging parameters. In fact, our results confirmed this hypothesis.max tended to correlate slightly with Ktrans and ADCmin. All ADC parameters showed significant associations with Ve. In addition, Ktrans correlated slightly with ADCmean and moderately with ADCmax and Kep and well with Ve.In the present study, no significant correlations between different ADC parameters and SUV values were identified in overall sample. Furthermore, SUVKtrans, Ve, and Kep did not significantly correlate together in well and moderately differentiated tumors. However, they correlated well in high grade carcinomas. Additionally, Ktrans correlated well with SUVmean in G1/2 lesions but not in G3 tumors. Finally, Ve correlated well with ADCmean and ADCmin in G3 tumors, but not in G1/2 lesions.Separate correlation analyses in the G1/2 and G3 tumors showed, however, other associations between the investigated parameters. As seen, perfusion parameters Our data suggest that tumor metabolism, cellularity, and perfusion show complex relationships in HNSCC. Furthermore, these associations depend on tumor grading. Previously, it has been shown that SUV and ADC values as well as perfusion parameters correlated with different histopathological features in HNSCC , 15. We Kep may predict lymphonodal metastasizing.In conclusion, multiparameter imaging provides information regarding tumor composition. Our study shows that tumor metabolism, water diffusion, and tumor perfusion have complex relationships in HNSCC. Furthermore, these associations depend on tumor grading. Perfusion parameter