The Brain Imaging Data Structure (BIDS) is a community-driven specification for organizing neuroscience data and metadata with the aim to make datasets more transparent, reusable, and reproducible. Intracranial electroencephalography (iEEG) data offer a unique combination of high spatial and temporal resolution measurements of the living human brain. To improve internal (re)use and external sharing of these unique data, we present a specification for storing and sharing iEEG data: iEEG-BIDS. Electrodes can be placed during epilepsy monitoring, tumor surgery, or for deep brain stimulation (DBS). During these times, patients can voluntarily participate in scientific experiments9. Due to the specialized clinical setting in which iEEG data are recorded, iEEG is relatively rare compared to EEG or MRI, and researchers sometimes have to wait several years before completing a study. This makes it important to have a consistent way of archiving and documenting iEEG data within a lab. In addition, because of its unique spatiotemporal properties9 and the high cost of acquisition, it is important that these unique data, contributed by rare patients, are made maximally useful and reusable to the scientific community.Human intracranial electroencephalographyCurrently, iEEG datasets are stored in many different structures, with each lab adopting their own methods for data and metadata organization, which imposes a substantial barrier to collaboration, reproducibility, and scientific progress. In addition, there are many electrophysiology file formats, which do not generally include all information needed to understand, analyze, and reproduce scientific results. This includes the electrode position, referencing method prior to digitization, simultaneously recorded physiology data, the timing of task events, details on the presented stimuli, or anatomical imaging data from the same subjects. There is a clear need for a community standard to better describe all aspects of iEEG data and its experimental context.2, and the EEG community has recently finished preparing their extension10.BIDS comprises a standardized specification for folder and file naming, the choice of data formats, and the representation of metadata. It is a modality-agnostic specification, relying on community-driven processes to extend the original specification (written for MRI) to new modalities. For example, the MEG community has extended BIDS for this type of dataThis paper announces the extension of the BIDS specification to raw, unprocessed human iEEG data, spanning stereo EEG (sEEG), electrocorticography (ECoG), and deep brain stimulation (DBS). It describes the global BIDS structure and some highlights of the current iEEG-BIDS specification. Adoption of iEEG-BIDS will minimize the burden of data curation, facilitate multimodal data integration, and make iEEG data more valuable to future researchers working in the specific lab and to the wider scientific community.The general BIDS specification is designed to modularize data such that it can gracefully handle multiple modalities and recording devices that belong to a single dataset. Metadata are stored either as a Tab Separated Value (TSV) file for tabular data (.tsv) or as JavaScript Object Notation (JSON) file for “key-value” data (.json) Fig. . These felectrodes , and channels (a part of an acquisition system) can potentially overlap, and several definitions were discussed and added as a part of the iEEG-BIDS and EEG-BIDS specifications. Input from members of these communities (as well as those from others such as MEG) resulted in the following definitions for “electrode” and “channel”:Channel: a single analog-digital converter in the recording system that regularly samples the value of a transducer, which results in a signal being represented as a time series in the data. This can be connected to two electrodes , a magnetic field or magnetic gradient sensor, temperature sensor, accelerometer, etc.Electrode: a single point of contact between the acquisition system and the recording site . Multiple electrodes can be organized as caps (for EEG), arrays, grids, leads, strips, probes, shafts, etc.Terms for https://bids-specification.readthedocs.io/en/latest/99-appendices/05-units.html).As the original BIDS specification dealt primarily with data from an MRI machine, it was also necessary to create standards around the units to be used for electrophysiology data. This was done in partnership with the EEG-BIDS and MEG-BIDS communities. Physical units of any data in a BIDS structure are presented according to their SI unit symbol and possibly prefix symbol , now specified in the BIDS specification , cortical surfaces, or 2-D images of the patient’s brain. To accommodate localization of iEEG electrodes, iEEG-BIDS added several new options for localization metadata in “_electrodes.tsv” and “_coordsystem.json” files. Electrodes can be localized in multiple spaces by specifying multiple JSON files, and the IntendedFor field makes it straightforward to pair electrode position data with its corresponding image. Finally, iEEG-BIDS explicitly allows for electrode positions to be given in 2-dimensional space in the event that anatomical data are only provided in the form of either operative photos or cortical surface photos.https://bids.berkeley.edu/news/bids-megeegieeg-data-format-survey).A challenge in extending the BIDS format to iEEG data was handling the diversity of data formats. Contrary to the MRI community, there is no single accepted format used across iEEG groups. In choosing the data formats considered to be compliant with iEEG-BIDS, the community attempted to cover as many possible iEEG data use-cases with as few unique formats as possible, and an informal survey was sent to the electrophysiology communities to help determine which formats were most suitable as “first class citizens” in the iEEG-BIDS specification. A description of this process and the results was originally published in a blog post for the Berkeley Institute for Data Science .After reviewing community feedback and discussing with the MEG-BIDS and EEG communitieshttps://en.wikipedia.org/wiki/European_Data_Format, .edf files, and BrainVision Core Data Format  (https://www.brainproducts.com/productdetails.php?id=21&tab=5). They have been chosen because they jointly cover the majority of use-cases in iEEG while also providing a solution for most major technical challenges in iEEG data. EDF is a prolific format in the iEEG community and offers variable sampling rates per channel. BrainVision is supported by EEG-BIDS, and makes up for some technical shortcomings of EDF . Compliant formats in iEEG-BIDS will continue to be supported in the future, and will have the majority of community effort and development in creating tooling.There are two compliant data formats for the iEEG-BIDS extensions: European Data Format  due to its shared goals in facilitating sharable and reproducible neurophysiology datasets, EEGLab (.set) due to its prevalent use in the iEEG community, and Multiscale Electrophysiology Format version 3 (MEF3) due to its suitability and future potential for clinical iEEG recordings and device-related applications (such as HIPAA-compliant multi-layer encryption of sensitive data). Unofficially-supported formats will pass the validator, but are not guaranteed to become supported in the future, and unofficial support may be dropped.There is no hard rule about the number of compliant data formats allowed, though the number will be kept as low as possible. Unofficially supported formats may be dropped , or promoted to compliant format status (if they fill a specific niche and meet the guidelines for compliant format status). This process will be carried out by the iEEG-BIDS community in future extension proposals.BIDS is a community project with two primary products: a specification for organizing neuroscience data, and a collection of software and tooling that facilitates the use of BIDS data structures. Creating the iEEG-BIDS specification involved the development of several new community tools. Below we list those that required the most new development for iEEG-BIDS.A validator (written in javascript) determines whether a given dataset adheres to the BIDS specification . It parses a folder, checks whether its hierarchy and naming structure conform to BIDS, and checks text files for the proper metadata and file types needed for the BIDS specification. The BIDS validator was modified in order to validate the new metadata fields and folder structures introduced by the iEEG-BIDS extension.As a part of creating the iEEG-BIDS specification, five datasets were converted to BIDS format and added to the BIDS-examples github repository (github.com/bids-standard/bids-examples). These examples are meant to demonstrate how the BIDS specification maps onto different scientific use-cases. The neural data of each dataset is removed in order to make it easier to download, though instructions are provided for accessing the full datasets. The datasets available include: an auditory filtered speech experiment, a motor-movement dataset, a visual stimulus dataset, seizure sEEG recordings from a focal epilepsy of the left temporo-occipital junction, and a multimodal dataset with fMRI and ECoG per subject.http://github.com/bids-standard/bids-starter-kit/wiki/Creating-a-BIDS-compatible-iEEG-dataset) and Matlab and Python scripts are also available to produce iEEG sidecar .json and .tsv files.The BIDS starter kit is a collection of community-driven guides, tutorials, helper scripts, and wiki resources to help researchers get started with the BIDS data structure (github.com/bids-standard/bids-starter-kit). These resources cover the two main languages supported by iEEG-BIDS (Matlab and Python). A tutorial that describes how to create a BIDS-compatible iEEG dataset has been provided on the starter-kit wiki  and European Data Format (github.com/bids-standard/pyedf) files. These will be maintained by the BIDS community.11.The MNE-Python package is an open-source tool for electrophysiology analysis, visualization, and data representation in Python, and has recently been extended to include functionality for iEEG. Alongside the creation of the iEEG-BIDS specification, the community worked alongside those in the EEG and MEG communities to create a new package for moving between MNE-Python and the BIDS specifications in electrophysiology: MNE-BIDS (github.com/mne-tools/mne-bids). MNE-BIDS facilitates converting electrophysiology workflows in MNE-Python into the BIDS dataset framework13. It supports importing data from a large number of iEEG formats and can export data to BIDS recommended formats. Furthermore, FieldTrip includes the data2bids.m function to help users to organize their iEEG and MRI data and to provide proper metadata annotation (www.fieldtriptoolbox.org/example/bids).FieldTrip is an open toolbox for electrophysiology analytics in the Matlab language14. It can read and write iEEG electrode coordinates and associated neuroimaging files using BIDS-iEEG conventions. See the BIDS-iEEG compatibility page for more information (http://ielvis.pbworks.com/w/page/130759893/BIDS-iEEG%20Compatibility).iELVis (github.com/iELVis/iELVis) is an open source Matlab package for localizing iEEG electrodes and visualizing their data overlaid on neuroimaging15. It provides user interfaces for positioning electrode contacts in post-implantation CT or T1 scans as well as reviewing/annotating long data records such as clinical iEEG signals . It supports most file formats commonly used in iEEG and can convert them into BrainVision or EDF files. Studies in Brainstorm’s database can be imported and exported automatically as BIDS-formatted datasets.Brainstorm is an open-source Matlab application for the analysis of multimodal neurophysiology dataOpen Neuro is a repository for public neuroimaging data, currently supporting MRI and MEG (OpenNeuro.org). It heavily capitalizes on the BIDS standard - each dataset is validated prior to upload using the bids-validator. OpenNeuro now supports, validates, and accepts iEEG-BIDS data. This allows researchers that adopted BIDS in their labs to easily archive and share their iEEG datasets online.The BIDS specification is an ongoing process with a growing community. It uses the BIDS Extension Proposals (BEP) process to discuss and integrate improvements in the BIDS specification. Several outstanding questions will require further community input and discussion, such as formally describing coordinate systems, merging metadata across modalities, and handling derivatives of raw iEEG data. In particular, further discussion is warranted to adapt iEEG-BIDS for non-human subjects and clinical iEEG recordings. As projects such as BIDS make datasets easier to discover and use, it is particularly important to protect the privacy of subjects. BIDS does not directly address privacy concerns - it only provides a structure for how the data should be stored. It is possible for data to be stored with BIDS in a manner that does not divulge subject identity , but this is up to the researcher. Future extensions to the BIDS specification, and documentation from the BIDS community, could help guide researchers in ensuring the privacy of the individuals that have provided their data in a BIDS dataset.16. Within the HBP, iEEG-BIDS has been adopted in the Medical Informatics Platform  (http://humanbrainproject.eu/en/medicine/) as well as the Neuroinformatics Platform (where it is supported in the HBP data sharing platform as well as the HBP interactive atlas viewers) (https://www.humanbrainproject.eu/en/explore-the-brain/neuroinformatics-platform/). These institutional stakeholders will be critical in spreading the adoption of BIDS, and encouraging more voices to guide the evolution of the specification moving forward.This process will be further improved as the BIDS community continues to grow. Data sharing, reproducibility, and quality control are priority areas of large research consortia, such as the US Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative as well as the Human Brain Project (HBP). Within these efforts it has become clear that community-wide accepted data standards are essentialiEEG-BIDS specifies a structured way of storing iEEG data and metadata. BIDS is a community-driven project, and the iEEG-BIDS specification was created after many months of open discussion with the broader iEEG community. One of the core benefits of adopting community standards such as iEEG-BIDS is that it provides a common point that can be the basis for future collaborations. It facilitates reproducibility and cross-modal integration across datasets, experiments, and recording sites.


Statin has been more and more widely used in chronic liver disease, however, existed studies have attained contradictory results. According to the present study, we aimed to test the efficacy and safety of statin via a meta-analysis.I2) test. All results of analysis were illustrated as forest plots. Publication bias was assessed using the Begg’s adjusted rank correlation test. Standard mean difference (SMD) was calculated in continuous variables. Pooled hazard ratio or odds ratio was calculated in catergorical variables.Different databases were searched for full-text publication based on inclusion and exclusion criteria. For data-pooling, fixed-effect model was applied if heterogeneity wasn’t detected. Otherwise, random-effect model was adopted. Heterogeneity was detected by I squire (I2 > 50%) and lower the occurrence of hepatocellular carcinoma  in liver cirrhosis. Statin seemed not to decrease the risk of esophageal variceal bleeding and spontaneous bacterial peritonitis. However, statin was proved to decrease the risk of hepatic encephalopathy and ascites. Incidence of drug related adverse events didn’t increase in statin users. Dose-dependent effects of statin on hepatocellular carcinoma development, decompensated cirrhosis events occurrence, and liver cirrhosis progression.Seventeen clinical studies were finally included. Hepatic portal hemodynamic parameters were improved in statin users for a short-term response. For a long-term follow-up, statin treatment surprisingly decreased mortality rate (HR = 0.782, 95% CI: 0.718–0.846, Statin influenced parameters of hepatic portal vessel pressure in short-term treatment. Prognosis of liver cirrhosis benefited from statin treatment in long term follow-up. The efficacy and safety of statin in liver cirrhosis treatment is confirmed. To date, similar study is hardly seen before. The major causes of liver cirrhosis are: alcoholic liver disease (ALD), chronic viral hepatitis , non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), and others such as primary biliary cholangitis , primary sclerosing cholangitis (PSC), autoimmune hepatitis, hemochromatosis, Wilson’s disease, alpha-metabolic diseases such as: 1-antitrypsin deficiency, galactosemia and glycogen storage disorders, and heart failure with liver congestion . NowadayStatins is a set of lipid-lowering agents by targeting at inhibiting the activity of 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase, resulting in inhibition of cholesterol generation and serum cholesterol levels downregulation , 7. ExceThis study design was stringently conformed to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement . Five daTwo investigators who were not informed with the protocol of the present study checked the quality and eligibility of all retrieved studies and collected the data independently. The finally included literature met criteria as follows: English language; comparison between statin treatment group and non-statin treatment group; with full-text instead of abstract only; clear definition of decompensation events of liver cirrhosis and statin related complications, e.g. variceal haemorrhage, ascites, hepatic encephalopathy, diarrhea, and myalgia, etc. Exclusion criteria included: animal studies (basic research); case-reports, case-series, and reviews articles; acute hemodynamic study. In cases of different publications from the same study, the one with the most complete data was chosen. Interested data such as the number of total patients and the number of patients with clearly defined events were carefully collected. Besides, basic demographic data and follow-up duration were collected as well –42.I2) test. Heterogeneity was defined as I2 < 50%, and the value of I2 was shown in the forest plot. Results were presented as pooled hazard ratio (HR) or pooled odds ratio (OR). All results of analysis were illustrated as forest plots to make them visualizable. Additionally, publication bias was assessed using the Begg’s adjusted rank correlation test and shown as funnel plot [If non-heterogeneity was detected, fixed-effects models were introduced to integrate data to compare statin treatment or not in the difference of short term follow-up and long term follow-up. Other than, the random-effects models were adopted. Heterogeneity was detected by I squire .Statistical heterogeneity was measured using the Inverse Variance (I-V) statistics. Statistical analyses were performed using Stata software 12.0 . Standard mean difference (SMD) was calculated in continuous variables, and pooled HR value or pooled OR value was calculated in catergorical variables. All Literature search, data extraction, and general description of included studies were carried out by two independent researchers. Total of 1776 articles was searched after excluding 176 duplications. Six hundred sixteen articles were excluded afterwards for not meeting the inclusion/exclusion criteria. Based on the aim of the present study, 17 clinical studies were finally included –37. The HVPG = − 1.146, 95% confidence interval (CI): − 1.3120-0.981, I2 > 50%). However, compared to patients without statin treating, patients receiving statin intervention was proved to fail to lower value of FHVP and WHVP , respectively. Consequently, HVPG was verified under condition of statin taking , and the decreased risk of mortality as a hard clinical end-point persuasively verified the beneficial effects of statin  after long-term follow up. Although decompensation events of liver cirrhosis were decreased . Logically, statin could decrease the case need for liver transplantation .Influence of statin in survival rate, decompensation events of liver cirrhosis, and HCC were investigated for long term follow-up as long as 14 years, and related data was extracted and analyzed to interpret the effect of statin. Statin treatment surprisingly improved survival rate in liver cirrhosis , in comparison with control group. Myalgia events were evenly distributed between different groups , and the frequency of myalgia was comparable no matter stain was treated or not . Therefore, statin might not increase risk of diarrhea in liver cirrhosis patients  was performed when the number of included literatures was enough for this purpose. End-point events involved in this part contained mortality, decompensation events, SBP, ascites, esophageal variceal bleeding. And it indicated the results of pooled data from RCT study was not consistent with results from non-RCT study, except for decompensation events and esophageal variceal bleeding . Low dose of statin didn’t influence decompensation of liver cirrhosis . However, both medium dose and high dose of statin could decrease incidence of decompensation events of liver cirrhosis . Liver puncture biopsy to evaluate liver cirrhosis pathological progression indicated that all doses of statin could mitigate liver fibrosis and sclerosis . It seemed that higher dose of statin tended to have better effect on relieving pathological progression of liver cirrhosis  in a funnel plot  was performed. It indicated the results of pooled data from RCT study was not consistent with results from non-RCT study, except for decompensation events and esophageal variceal bleeding. To our knowledge, similar systematic study was hardly seen before.As one of the mostly prescribed medication, statin is widely used in the primary prevention of coronary ischemic heart disease by outstandingly inhibiting the activity of HMG-CoA. However, laboratory studies showed that statin could further attain endothelial functional improvement independently from down-of cholesterol level , 47. PreA systematic review has already been done to quantitatively summarize effects of statin and accentuate the important role of statin in treating chronic liver disease. Based on this study, statin use is probably associated with lower risk of hepatic decompensation and mortality, and might reduce portal hypertension, in patients with chronic liver diseases . NonetheThis study included 17 studies, parts of which were of characterized with observational and case-control design. The included articles had defects such as no randomization, retrospective design, and small scale, and these flaws could somehow devaluate the quality of our study. However, studies with high quality were involved with high weighting ratio, which meant that study with higher quality contributed more on the present meta-analysis. The included studies investigated liver disease with different aetiology, such as alcoholic liver disease, NAFLD, HBV, HCV, and so on. As a result, the heterogeneity of liver cirrhosis aetiology at baseline might lead to bias of treatment response to statin. In addition, the present regarded different kinds of statin, such as simvastatin, artovastatin, fluvastatin, and so on, as a whole, however, the head-to-head comparison of effects of different kinds of statin on liver cirrhosis should be discussed in future. Perhaps, a network meta-analysis could solve this problem. Furthermore, the limited number of articles eligible for different research target made sensitivity analysis not applicable. Additionally, patients with β-blocker administration or comorbidities of chronic kidney disease were also susceptible to exacerbated hepatic function, and these confounding factors were not presented in the included studies. Therefore, risk-stratified analysis couldn’t be carried out. Consequently, large scale, prospective, multi-center, and randomized clinical trials are still highly needed with clearly reported confounding factors.In the present study, statin was proved to be effectively lowering the risk of the occurrence of decompensated liver cirrhosis such as encephalopathy and ascites, which was treated as life-threatening event in chronic liver cirrhosis in a long-term follow-up. Unfortunately, statin might have no effect on variceal haemorrhage and spontaneous bacterial peritonitis. Besides, statin could decrease the incidence of HCC which was a serious complication of liver cirrhosis. In addition, the dose-dependent effect of statin in liver cirrhosis was testified base on pooled data, and it indicated that higher dose of statin tended to have better effect on relieving pathological progression of liver cirrhosis. Even in short-term therapeutic of statin, the hemodynamics of portal vessel was significantly improved. Drugs related adverse events between statin treated group and non-statin treated group show no difference. This study was characterized with the largest sample size to comprehensively evaluate the efficacy and safety of statin on liver cirrhosis and its development.Additional file 1: Figure S1. Typical diagram of publication bias analysis.Additional file 2: Figure S2. Subgroup analysis by the study design of RCT versus non-RCT. A: mortality in RCT study; B: mortality in non-RCT study; C: decompensation events in RCT study; D: decompensation events in non-RCT study; E: spontaneous bacterial peritonitis (SBP) in RCT study; F: spontaneous bacterial peritonitis (SBP) in non-RCT study; G: ascites in RCT study; H: ascites in non-RCT study; I: esophageal variceal bleeding in RCT study; J: esophageal variceal bleeding in non-RCT study.


The European Hematology Association Theme of the year 2017–2018 has rather chosen itself. Any other topic risked being swamped by the flood of excitement emanating from the field of immunotherapy. This is reflected in the recent explosion of related publications in scientific journals and eye-catching articles in the mainstream media. Not one of my outpatient clinics now passes without hopeful questions about immunotherapy from my patients and their relatives. As clinicians, we share our patients’ desperation for better outcomes. There is a widespread appetite to engage with the field, provide clarity for our patients, and contribute to progress through clinical trials.https://ehaweb.org/education/learning-center/).EHA is working to satisfy this appetite through a variety of focused activities in the coming year aimed at facilitating education and empowerment of our community, as well as driving forward this exciting field at what feels like a pivotal time in blood cancer therapeutics. At the core of these activities is the recently convened Scientific Working Group (SWG) on Immune Therapies for Hematologic Disorders, chaired by Professor Hermann Einsele of the University of Würzburg, Germany, a global opinion leader in this field. The SWG will help drive cooperation on studies, and will contribute to scientific exchange at the EHA meetings as well as provide input for the EHA Learning Center , and chimeric antigen receptor T cells (CAR-T) Fig. .Haematologica of Dr Santosha Vardhana and Professor Anas Younes.)1Checkpoint inhibition, by releasing cancer cell-suppressed T cells in waves of systemic immune activation, has shown great promise, particularly in Hodgkin lymphoma. Mixed responses in other blood cancers and excess deaths halting certain trials in myeloma have highlighted the need for further optimization of this strategy.  with blinatumomab gaining United States Food and Drug Administration (FDA) and European Medicines Agency approval.The most excitement in recent years has been generated by CAR-T, T cells re-programmed ex vivo to recognize specific tumor-associated antigens (TAA), leading to activation and tumor killing. The remainder of this article will focus on the biology and clinical application of CAR-T technologies, directing readers to notable review articles.New England Journal of Medicine, Dr Lisa Rosenbaum reminds us that the vision, ambition, and stubborn persistence of scientists, investors, patients, and their relatives, can drive successful translational research.3 Referencing a connectedness between parties with shared goals, this is a genuinely inspirational story with a much broader message than simply documenting the rise of CAR-T.The promise of CAR-T is considerable. The most successful application has been through targeting CD19 on B-cell malignancies. This follows proof of principle with bare antibody therapies that this approach can be effective and safe. Dramatic responses in chemorefractory individuals, combined with the vast potential to refine this approach through genetic engineering of the product, have captured the imagination of cancer patients and physicians alike. CAR-T technology has also attracted vast sums of financial investment. Such is the belief that CAR-T herald a new era in cancer therapeutics, the story of their successful development is already being told. In a beautifully written commentary article in the Nature Reviews Clinical Oncology.4 Dr Kochenderfer writes with particular authority as one of the first to publish successful responses of B-cell malignancies to CAR-T infusion.5 In this review, the fundamentals of CAR-T technology are outlined, with a subsequent focus on their application to treating patients with B-cell malignancies.A balanced review of this field must also recognize the relative immaturity and limitations of the clinical data, and the significant adverse effects related to CAR-T infusions. Dr Jennifer Brudno and Dr James Kochenderfer have composed a state-of-the-art appraisal of this technology in The CAR comprises a fusion of an extracellular antigen recognition domain with transmembrane and intracellular T-cell signaling domains. The genetic code for the CAR construct is transferred into harvested T cells using a vector. This vector is usually a replication-incompetent retrovirus, but lentiviral or transposon systems have also been used. The antigen recognition domain is usually a single-chain variable fragment derived from a monoclonal antibody targeting a TAA.Developments in the composition of the T-cell signaling construct impact CAR-T function and efficacy. First-generation CAR-T products use an intracellular portion of the T-cell receptor alone, with second- and third-generation products incorporating co-stimulatory domains and T-cell activation domains leading to improvements in tumor killing and CAR-T persistence.The majority of CAR-T technologies under development use patient-derived autologous T cells harvested by leucapheresis. The optimal cell product in terms of cell dose and T-cell subset composition (unselected versus chosen ratios of CD4 and CD8 cells) remains to be elucidated. The production of autologous CAR-T products poses logistical challenges. Leucapheresis, transport to a CAR-T production unit then back to a clinical department is time-consuming, expensive, and demanding of fail-safe governance systems for this individualized cellular product. The typical current turnaround time from harvest to re-infusion is about 3 weeks, during which time the patient may progress. Universal donor or matched “off-the-shelf” allogeneic CAR-T products offer the potential advantages of reduced costs and swifter delivery from the time of request. Allogeneic CAR-T products are being used in early phase clinical trials.Lympho-depleting conditioning regimens given before re-infusion of CAR-T, such as fludarabine with cyclophosphamide, appear necessary for optimal CAR-T survival and function. Further optimization of conditioning may improve CAR-T persistence and durability of antitumor responses. Moreover, interesting questions are being explored regarding postinfusional modification of CAR-T responses with other immunotherapies. The prospect of combining CAR-T with checkpoint inhibition might be attractive from a tumoricidal perspective, but may prove “too much of a good thing” as regards systemic immune activation.6Although autologous CAR-T products avoid the risks of graft-versus-host disease (GvHD), they are not without considerable toxicity. Infusion can precipitate a florid systemic inflammatory response, termed the cytokine release syndrome, and a range of neurologic toxicities termed CAR-T-cell-related encephalopathy syndrome. Deaths have resulted from these toxicities. Anti-interleukin 6 therapies and steroids can be effective antidotes. This may be at the cost of CAR-T persistence and efficacy. The incorporation of suicide genes encoding druggable “off-switches” also holds promise. Optimal surveillance and management of CAR-T toxicities is highly challenging and currently limits safe administration of these products to centers experienced in stem cell transplant. Dr Sattva Neelapu and colleagues address these issues in a recent expert review.Once acute toxicities have passed, disease relapse is the greatest risk. As such, the durability of responses is of great interest. Relapse is observed not only when CAR-T are no longer detectable in blood samples, but also when they persist. Antigen escape, with the survival and clinical relapse through therapeutic selection pressure of target antigen-negative clones is well described. Administering CAR-T against multiple TAA, or constructing bi-specific CAR, may mitigate this risk.Refinement of the technology and its clinical application seem very likely to herald a new age of immunotherapy in hematology, with more patients living longer and better. There is rapid ongoing innovation in gene transfer technology and design of CAR-T constructs. Investigation and optimization of cell source and dose, conditioning, patient selection, combination with other immunotherapies, and management of toxicities, will surely herald further improvements and hopefully extension of benefit to more disease groups Fig. .In August 2017, tisagenlecleucel , a CD19-engaging construct, became the first CAR-T product to gain FDA approval. Dr Scott Gottlieb, Commissioner of the FDA, declared this an “inflection point” in science, with advances in CAR-T therapy marking a milestone in the approach to harness immunotherapy in personalized cancer therapy.The listed cost of Kymriah, at a headline-grabbing $475,000 for a single infusion, is itself unprecedented. This sum appears vast even when compared to the costs of competing cellular therapies such as allogeneic stem cell transplantation, even accounting for added costs of GvHD or relapse. A negotiated cost reimbursement program for a lack of response after 30 days will do little to soften the financial blow to US healthcare systems, particularly as most relapses seem to occur beyond 30 days. It must be hoped that economies of scale as regards harvest, manufacture, and distribution, allied with the impact of competition, will lead to a fall in price. Without this, CAR-T will be available outside clinical trials only to the extremely wealthy or well insured.Kymriah has been approved for relapsed/refractory ALL in pediatric and young adult populations, in which response rates of about 80% have been observed in early phase clinical trials. Such unprecedented response rates appear to have forced changes in the approval process, with regulators seeming to deem it unethical to wait for survival data to mature. Perhaps, this poses a dilemma for our clinical community? Innovative rapid approval processes for promising new therapies in areas of urgent unmet need are very welcome. However, surely we are beholden to our patients to ensure that rigorous post-marketing studies are completed to confirm meaningful benefit and refine practice. We must recognize that current clinical outcome data from early phase studies is affected by selection bias, with corresponding “real-world” denominator numbers not yet known. High initial response rates in relapsed/refractory patients are truly exciting. We must also remain mindful that for our patients, a durable response with long-term disease-free survival is largely what constitutes true benefit. Long-term follow-up of appropriately randomized phase 3 studies is needed to establish durability of responses and long-term survival benefit.Through promoting balanced and evidence-based discussions on CAR-T and other immunotherapy for hematologic disorders, we hope EHA can contribute not only to scientific and clinical progress in this highly promising field, but also to promote realistic and ethically sound dialogue between clinicians and patients. This promises to be a truly intriguing year.


In diabetics, cardiac microvascular circulation disorder increases the risk of arrhythmia and sudden cardiac death. Tpeak-Tend (Tp-e) interval, Tp-e dispersion, and Tp-e/QT and Tp-e/QTc ratios measured by surface electrocardiogram (ECG) are new parameters used to evaluate ventricular arrhythmogenity. We aimed to compare QT dispersion (QTd), corrected QT dispersion (QTcd), P dispersion (Pd), Tp-e interval, Tp-e dispersion, and Tp-e/QT and Tp-e/QTc ratios in patients with type- 2 diabetes (T2D) with healthy population.Electrocardiographic parameters of a total of 100 patients diagnosed with T2D were retrospectively analyzed and compared with the ECG results of 100 healthy age-, sex-, and body weight and height-matched controls.the values of low-density lipoprotein, systolic blood pressure, and Tp-e dispersion.The Pd, QT interval, QTc interval, QTd, QTcd, Tp-e/QT, Tp-e/QT ratios were higher in the patients. A statistically significant correlation was found only between hemoglobin A1c and Tp-e dispersion, QTd, QTcd, Pd, Tp-e/QT and Tp-e/QTc parameters, in linear regression analysis. There was also a statistically significant positive correlation between The risk of arrhythmia can be predicted by evaluating Tp-e interval, Tp-e dispersion, Tp-e/QT, and Tp-e/QTc ratio, suggesting heterogeneity of ventricular repolarization and P wave and Pd showing heterogeneity of atrial repolarization in diabetic patients. Along with glycosylation, LDL particles become more atherogenic. Dyslipidemia also contributes to the endothelial dysfunction. In addition, the expression of proinflammatory cytokines, such as serum interleukin-6, C-reactive protein and tumor necrosis factor-α is increased in T2D, leading to a proinflammatory condition. Coronary artery disease and arrhythmias caused by rapid developing atherosclerosis are major complications in this patients.3Patients with diabetes mellitus have a high risk of cardiovascular disease and the cardiovascular complications are the leading cause of morbidity and mortality associated with diabetes.In diabetic patients, the blood circulation in cardiac microvascular bed was disturbed by depending on autonomic neuropathy, prothrombotic, and proinflammatory state. This process increases the risk of arrhythmia, silent infarction and sudden cardiac death.4The surface electrocardiogram (ECG) is often used in the evaluation of an increased arrhythmia risk. The measurements such as corrected QT interval (QTc), QTc dispersion (QTcd) and QT dispersion (QTd) in the surface ECG reveal the heterogeneity of cardiac repolarization. Also, these parameters are used to identify the risky patients which are associated with the increased risk of ventricular arrhythmia.10In this study, we aimed to compare QTd, QTcd and Pd with Tp-e, Tp-e dispersion, Tp-e/QT and Tp-e/QTc as new markers in surface ECGs of T2D patients with those of healthy individuals.Between June 2015 and June 2017, ECG results of 100 patients with T2D  who were followed in the endocrinology and metabolism diseases outpatient clinic of our hospital for T2D were retrospectively analyzed and compared with the ECG results of 100 healthy age-, sex-, and body weight and height-matched controls . Patients with the history of coronary artery disease, cerebrovascular disease and peripheral artery disease, valvular heart disease, atrial and ventricular arrhythmia, and those with cardiomyopathy, hypertension, chronic pulmonary disease, chronic liver disease, malignancies, acute or chronic renal insufficiency, thyroid dysfunction, electrolyte disturbance, anemia or other major disease were excluded from the study. Only the patients who underwent cardiac check-up during follow-up and those whose echocardiographic (ECHO) evaluations did not indicate valvular heart pathology and those with normal ejection fractions were included in the study. A written informed consent was obtained from each participant. The study was approved by the Ethics Committee for Clinical Researches of Dumlupinar University, Faculty of Medicine and conducted in accordance with the principles of the Declaration of Helsinki.All patients had sinus rhythm in ECG. The patients with findings suggesting ischemia on ECG, or branch block and atrioventricular conduction abnormalities, and those with the history of drug use which might affect ECG were excluded. In the study, 12-lead ECGs with the rate of 25 mm/s and voltage of 10 mm/mV were performed in the supine position of the cases. The P wave duration (PW) was determined as the intersection spot of the point where the P deflection separated from the isoelectric line and the isoelectric line of the last part of the P wave. Pd was calculated as the difference of the longest and shortest P-wave (Pd=Pmax-Pmin). The QT interval was determined the distance from the beginning of the QRS complex to the descending part of the T wave and the junction point of the isoelectric line. The QTc value was calculated according to the Bazett formula as QTc (milliseconds) = measured QT/√RR(seconds). QTd was calculated as the difference between the longest and shortest QT intervals (QTd=QTmax - QTmin), while QTcd was calculated as the difference between the longest QTc and the shortest QTc (QTcd=QTc max-QTc min). The Tp-e interval was determined as the distance from the peak of T wave to the descending part of the T wave and the junction of the isoelectric line. The Tp-e dispersion was calculated as the difference between the maximum and minimum Tp-e intervals. Tp-e/QT and Tp-e/QTc ratios were calculated by using these measurements.The fasting blood sugar following the 10-12 hour night starvation, glycosylated hemoglobin (HbA1c), thyroid-stimulating hormones (TSH), free T4, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride, calcium, sodium, potassium and complete blood count were measured. Total cholesterol (TC), HDL cholesterol, LDL cholesterol and triglycerides (TG) were measured by an automatic analyzer (Beckman Coulter AU 2700). Fasting glucose level was determined by using the glucose hexokinase method (Beckman Coulter AU 2700). HbA1c values were determined by the method of high-performance liquid chromatography (TOSOH G7 device). TSH and free T4 were determined by immunoenzymatic method based on the principle of measuring chemiluminescence (Beckman Coulter DXI 600). Sodium, potassium and calcium were detected by ion selective electrode (Beckman Coulter AU 2700).p-value of less than 0.05.Statistical analysis was performed using the SPSS version 18.0 program . Descriptive data were expressed in mean ± standard deviation. The Kolmogorov-Smirnov test was used for normality analysis of the distribution of the numerical data. The Student’s t-test was used for normally distributed data, while the Mann-Whitney U test was used for the abnormally distributed data. In addition, the chi-square test was used to compare the categorical data. Stepwise multivariate linear regression model, including significant variables in univariate analyses was then used to determine which determinants independently explained a significant (p<0.05) fraction of the variance of the dependent variables. The data were analyzed at a 95% confidence level and considered significant at a In our study, a total of 100 patients with T2D were compared with 100 healthy controls. The overall characteristics of the participants are summarized in The electrocardiographic parameters of both groups are shown in A statistically significant correlation was observed between HbA1c and Tp-e dispersion, QTd, QTcd, Pd, Tp-e/QT and Tp-e/QTc parameters in multivariate linear regression analysis . There wIn many cardiovascular and non-cardiovascular diseases, QT interval, QTc, and QTd were shown to be increased than those in healthy subjects.13In recent years, a number of studies have been conducted on reliability of aforementioned parameters in signaling ventricular arrhythmogenesis. Moreover, Tp-e interval, Tp-e dispersion, Tp-e/QT and Tp-e/QTc ratios as new parameters for transmyocardial repolarization have been shown to be superior to QT interval and QTd in predicting arrhythmia. However, they were also found to be more reliable in terms of being affected by heart rate and body weight.17The formation of ventricular arrhythmias is explained by the presence of reentry circuits, triggered activity, and increased autonomy. Myocardial fibrosis, the cell loss in the living myocardial tissue and myocardial conduction pathways can create a favorable environment for the formation of micro-reentry circuits. Ventricular arrhythmias from simple ventricular extrasystole to fatal ventricular tachycardia may be triggered by the contribution of impaired electrical balance of the heart and the increased sympathetic system.In the study including fewer diabetic patients (n=43), Tokatli et al. showed that Tp-e interval, Tp-e/QT, Tp-e/QTc was higher in the patient group than those in the control group.21Diabetes mellitus has been shown to be an independent and potent risk factor for the development of atrial fibrillation.First, the parameters used in our study were measured manually. Although manual measurement has been accepted scientifically and many studies have been conducted by this method, it has been recognized that the measurement performed by a high resolution monitor with digital ECG recording gives much more accurate and standardized results in recent years. Another limitation is that normotensive patients with normal ECHO and ECG results were included in the study. As coronary angiography was not possible to perform for all patients in practice, subclinical ischemic heart disease might have been overlooked in the study group.Tp-e interval, Tp-e dispersion, Tp-e/QT and Tp-e/QTc ratio showing heterogeneity of ventricular repolarization with PW and Pd indicating heterogeneity of atrial repolarization are important electrocardiographic markers that should be evaluated in diabetic patients. These markers can be used to predict the risk of arrhythmia in diabetic patients. In addition, since these markers have significant correlation with HbA1c, the patients with high HbA1c values during the follow-up should be closely monitored in terms of important life-threatening cardiac events. Cardiologists should evaluate these patients in the early period and the detailed evaluation for antithrombotic, antihypertensive and antilipemic treatment should be started. In each control of outpatient clinic, ECG parameters showing the heterogeneity of cardiac repolarization should be evaluated until the HbA1c levels reach the target values.


Estimates of self-neglect among older and/or disabled adults are much higher than the estimated 10% of older adults in the U.S. who experience physical or emotional abuse, neglect, and exploitation by others. It is not clear how the social environment affects these vulnerable adults who become self-neglecting. This study uses network analysis and a GIS approach to explore patterns of needs and environmental risks for adult healthcare patients who had risk factors for self-neglect. Sources of data included face-to-face interviews, self-neglect risk factors  from electronic medical records, and neighborhood information from census block data. More than two-thirds of the 480 study participants reported an average income of less than $1,360 monthly, and 89% self-identified as Hispanic or Latino. Using ArcGIS Pro, respondents’ geocoded addresses were matched to mapped neighborhood census information. The maps showed that most respondents live in Hispanic-dominated communities, in neighborhoods with crime rates above average and median household income of less than $49,066/year. These neighborhoods were probably resource-poor and had spatial inequalities. Using network analysis, the study found that the at-risk patients’ most frequently reported needs  appear clustered together, demonstrating that people had multiple needs. The study findings suggest that practitioners and policymakers must not only provide a range of services to help disadvantaged groups, but also focus specifically on offering services in neighborhoods where low-income minority groups reside and there is a lack of community resources.


The increasing understanding of the immune system and the critical role of antigenic epitopes in eliciting robust immune responses has led to the development of peptide vaccines. Peptide-based vaccines or—more technical—epitope ensemble vaccines represent an alternative approach to the discovery of disease-specific prophylactic and therapeutic vaccines, distinct from other vaccine moieties, such as attenuated or killed whole pathogen vaccines, subunit or toxoid vaccines, and carbohydrate-based vaccines. Epitopes represent the relevant part of the antigen recognized by T and/or B cells, mediating adaptive immunity. Consequently, the major potential of epitope vaccine ensembles is that of inducing desirable T and B cell-mediated immune responses. The risk of causing pathogenic or off-target responses with epitope vaccines is thus much lower than with convectional vaccines and can, on that basis, be regarded as safer. Epitope ensemble vaccines are also very versatile and can be formulated as synthetic peptides or encoded as DNA and RNA formulations. Currently, there are many epitope vaccines under development, spanning a wide range of diseases, including chronic viral infections and therapeutic anticancer vaccines, but as yet none are available. The case for epitope ensemble vaccines is nonetheless compelling, and the research community remains certain it is only time that separates us from a viable and deployable vaccine.Developing a successful peptide-based vaccine involves identifying disease-specific epitopes inducing protective immunity and tackling a number of steps, such as determining appropriate means of epitope delivery and overcoming the intrinsically low immunogenicity of isolated epitopes. Following the success of previous special issues on peptide-based vaccines and immunotherapeutics, we present a new edition of the special issue in which we have incorporated seven original articles and two reviews, addressing various aspects of peptide-based vaccine design.The reviews in the issue deal with epitope databases and epitope prediction. Peptide databases with information on T and B cell epitopes and peptide binding to MHC molecules are important tools for analyzing immune responses, benchmarking predictive methods, generating new ones, and developing peptide-based immunotherapeutics . CurrentShigella species and provide wide population coverage. In addition, the authors identified that MHC II molecules could also present two of the CTL epitopes and thus stimulate T helper responses. In the other, J. Alonso-Padilla et al. have expanded on an emerging strategy that relies on the use of experimentally defined T-cell epitopes [The original articles in this special issue include two papers focusing on computational vaccine design. In one, A. R. Oany et al. proposed a peptide vaccine candidate for shigellosis consisting of four predicted cytotoxic T cell (CTL) epitopes from the SigA antigen, which is known to be highly immunogenic. These four candidates are conserved among epitopes  and formThe experimental articles in the issue range widely. We have a work by M. Niki et al. which aims to identify appropriate antigens for tuberculosis (TB) vaccines. The study is an extension of a previous work in which the authors did a cross-sectional assay in TB patients . Here, tDendritic cell- (DC) and peptide-based immunotherapies often go hand in hand. In this issue, J. Lo et al. investigate on whether DCs unpulsed or pulsed with antigenic dominant determinants (DD), subdominant determinants (SD), and ignored determinants (ID) could prevent type 1 diabetes (T1D) in a mouse model. The authors found that diabetes was significantly delayed by DCs pulsed with SD or ID peptides. Moreover, they also found that Tregs from DC-treated mice proliferated more actively and showed enhanced immunosuppressive activities. Overall, this study demonstrates that DC therapy leads to long-lasting immunomodulatory effects in an antigen-dependent manner, providing support for DC-guided peptide-based interventions for autoimmune diabetes.Toxicity is a handicap for vaccine design and, here, A. Latanova et al. present a work addressing this issue. In the study, the authors fused a flaviviral leader peptide to reverse transcriptase (RT), a crucial target of immunotherapy against drug-resistant HIV-1. This fusion allowed RT secretion and reduced its toxicity and ability to induce oxidative stress, with no major effects on its immunogenicity. Subsequently, the authors proposed the use of leader peptides to increase safety of RT-based DNA vaccines. Genetic diversity of pathogens remain also a substantial obstacle for vaccine design. V. S. Kichatova et al. addressed this subject for human hepatitis C virus (HCV). These authors characterized the occurrence of IFN resistance-conferring mutations in HCV isolates circulating in the Russian Federation, identifying that the spread of viral variants was linked to mutations on HCV-specific CTL epitopes in association with the immunogenetic background of HCV-infected individuals. These results are useful in identifying those individuals in need of IFN-free treatments and for developing epitope-based vaccines that circumvent viral immune escape.Finally, we include a work by I. Soria et al. showing that combining viral-specific B and T cell epitopes onto appropriated structures can increase immunogenicity and enhance protection. These authors work with foot-and-mouth disease virus (FMDV), which has a high morbidity in cloven-hoofed animals, like cattle and swine. In cattle, there are known FMDV-specific B and T cell epitopes that could be used for safer and more effective vaccines. However, immunization with linear synthetic peptides encompassing the epitopes has failed to induce protection in cattle. In contrast, in the study, the authors immunized cattle with a dendrimeric peptide structures consisting of 4 copies of a peptide encompassing a B cell epitope linked through thioether bonds to a single copy of a CD4 T cell epitope. As a result, I. Soria et al. obtained that these dendrimeric peptides elicited humoral and cellular immune responses that conferred partial protection against heterologous virus challenge.In conclusion, the articles included in this special issue examined relevant aspects of peptide-based vaccines, and we trust that readers shall find them both interesting and motivating.Pedro RecheDarren R. FlowerMasha Fridkis-HareliYoshihiko Hoshino


Knee osteoarthritis (KOA) is a progressive joint disease involving intraarticular and periarticular structures. In recent years, there has been increasing interest in the use of autologous growth factors, such as intraarticular injections of platelet-rich plasma (PRP), to treat KOA. It is necessary to update the research and reevaluate the efficacy and safety of PRP to provide up-to-date evidence for KOA management. Therefore, we provide a protocol for a systematic review of PRP for KOA.The aim of this study was to retrieve papers on the topic of PRP treatment for KOA in electronic databases including PubMed, Embase, and the Cochrane Library. The search will include studies that were published from the time the databases were established until April 2018. The entire process will include study selection, data extraction, risk of bias assessment, and meta-analyses.The literature will provide a high-quality analysis of the current evidence supporting PRP for KOA based on various comprehensive assessments including the Western Ontario and McMaster Universities Osteoarthritis Index, visual analog scale scores, International Knee Documentation Committee scores, Lequesne index scores, and adverse events.This proposed systematic review will provide up-to-date evidence to assess the effect of PRP treatment for patients with KOA.CRD42018108825. Despite advances in medical technology, to date there are no medications or surgical interventions proven to alter the course of KOA development. The current standard of care for patients with symptomatic KOA includes oral anti-inflammatory drugs, physical therapy, topical anti-inflammatory gels, and intra-articular injections.,3 Nonsurgical treatments including exercise and weight loss are recommended due to poor symptomatic and functional outcomes with surgical management. However, compliance with nonsurgical treatments is poor, and medications, such as simple analgesics and nonsteroidal anti-inflammatory drugs, are associated with adverse events.,6 As reported in many studies and meta-analyses, intra-articular hyaluronic acid (HA) injections are widely used to treat KOA; HA injections are efficacious because the visco-induction properties of HA increase joint lubrication. However, while intra-articular injections of drugs are usually associated with pain relief and increased joint function, they are not effective in patients with severe KOA.Knee osteoarthritis (KOA) is a progressive joint disease involving intra-articular and periarticular structures. Recent research suggests that growth factors and other cytokines released by platelets in response to injury or pathology may modulate inflammatory processes and contribute to the maintenance or regeneration of tissue structures.,11 PRP is an autologous blood product that contains an increased concentration of platelets, and it has become an emerging treatment used in orthopedic and sports medicine practices for ligament, tendon, cartilage, and bone injuries.–14 As a minimally invasive treatment option, intra-articular injection of PRP has been widely used in clinical therapy. A new technique for the delivery of PRP reported by Sanchez et al is intraosseous infiltration combined with intra-articular injection to treat severe KOA; moreover, no adverse events were reported. A number of randomized controlled trials (RCTs) reported favorable outcomes of PRP injections–18; several systematic reviews and meta-analyses have been published that concluded that PRP was an effective and safe orthobiologic to use in the treatment of KOA when compared with other intra-articular injections.–21 However, these reviewers did not reach consensus in terms of the effects of PRP on pain relief and functional recovery; they also concluded that more RCTs, in particular high-quality studies, were still needed. Prior reviews either included non-RCTs or only synthesized a small number of RCTs (<10) for analysis, and additional randomized trials have since been published. Therefore, it is necessary to perform an updated systematic review and meta-analysis to fully investigate the temporal effect of PRP on knee pain and physical function. We aimed to identify all prospective, randomized trials published to date to provide the latest insights into the efficacy of the use of PRP for treating KOA.During the past decade, there has been increasing interest in the use of autologous growth factors, such as intra-articular injections of platelet-rich plasma (PRP) to treat KOA.22.1The study was approved by the ethics committee of Guangdong Provincial Hospital of Chinese Medicine. We will adhere to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statements for reporting systematic reviews. A comprehensive of the PubMed (1966–April 2018), Embase (1980–April 2018), and Cochrane Library (1966–April 2018) databases will be performed. The search terms will include “platelet-rich plasma,” “PRP,” “knee,” “osteoarthritis,” “arthritis,” and “arthritic.” No language exclusions will be applied. The references of the identified studies will be manually searched.2.22.2.1Only published articles enrolling adult participants with a diagnosis of KOA will be included. All participants will be diagnosed with KOA. The patient's gender, age, and grades of KOA will not be limited.2.2.2The intervention group will have received intraarticular PRP, and there will be no restriction on the dosages of PRP or the time interval between injections.2.2.3The control group will have received HA alone.2.2.4The primary outcome will be the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index. The secondary outcomes will be visual analog scale (VAS) scores, International Knee Documentation Committee (IDKC) scores, Lequesne index scores, and adverse events.2.2.5Clinical RCTs will be considered eligible for our study. Articles will be excluded from the current meta-analysis if they are duplicate articles, cohort studies, retrospective studies, case reports, letters, editorials, conference abstracts, or animal experimental studies. The flow diagram of the study selection is shown in Figure 2.3Two reviewers will independently extract the key data from the included studies: first authors’ names, date of publication, sample size, patients’ age and gender, grades of KOA, injection dose, times, intervals of PRP and HA, and follow-up periods. The primary outcome will be the WOMAC osteoarthritis index. The secondary outcomes will be VAS scores, IDKC scores, Lequesne scores, and adverse events. In the event of missing data, we will attempt to contact the corresponding authors for details.2.4The methodologic quality of the included studies will be independently evaluated by 2 reviewers using the Cochrane Collaboration tool for assessing the risk of bias (ROB). Each study will be reviewed and scored as having a high, low, or unclear ROB according to the following domains: selection bias , performance bias (blinding of participants and personnel), detection bias (blinding of outcome assessments), attrition bias (incomplete outcome data), reporting bias (selective reporting), and other bias (other sources of bias). Any discrepancies between the findings of the reviewers will be arbitrated by the corresponding author.2.5I2 statistic. We will use an I2 value of <25% to represent low heterogeneity and an I2 value of <75% to indicate high heterogeneity. When high heterogeneity exists, random-effects models will be used. The results will be presented as MDs with 95% confidence intervals. A P-value of <.05 will be considered statistically significant.All statistical analyses will be performed using Manager 5.3.5  software. Continuous outcomes will be calculated and expressed as the mean difference (MD), and dichotomous outcomes will be expressed as risk ratios (RRs). Heterogeneity between studies will be quantified using the 3 and it imposes a heavy economic and social burden. The etiology and pathogenesis of KOA are still not clear; the main pathologic change is articular cartilage degeneration with changes in synovial fluid components.As a chronic progressive joint disease, KOA is the second leading cause of loss of function, PRP can promote tissue repair and is increasingly being used in the treatment of KOA. Some reports suggest that PRP may induce the migration, proliferation, and differentiation of precursor cells in the synovial fat pad or cartilage. Therefore, PRP can promote repair of damaged cartilage while reducing pain and the effects of the inflammatory response.As a vector for large growth factors,; thus, the temporal effects of PRP injections on knee pain and physical function have not been fully investigated. Chang et al found that patients receiving PRP exhibited better and more prolonged improvement than those receiving HA; however, half of the 16 studies they included in their analysis were case series, and 5 were RCTs. Laudy et al pooled 10 trials, including 6 RCTs and found that PRP injections reduced pain and improved function more effectively than placebo or HA injections in patients with KOA. Nonetheless, most comparisons included only 1 or 2 studies due to the small number of RCTs that were pooled for analysis.Most of the previous systematic reviews and meta-analysis have shown that PRP is an effective and safe alternative treatment for long-term pain relief and functional improvement in patients with KOA. However, the previous conclusions were reached on the basis of the small number of RCTshttps://www.crd.york.ac.uk/PROSPERO/).It cannot be denied that a high-quality trial is still lacking; however, clinical studies on this topic have also been published recently. We have reported a protocol for performing a systematic review to provide up-to-date data regarding the effectiveness and safety of PRP for KOA. Therefore, we will begin to conduct the review when the necessary trials are met, and all operating procedures will be performed in accordance of Cochrane Handbook to ensure that the provided information is helpful for clinicians and KOA patients. This review is registered in PROSPERO Registry: CRD42018108825 (The authors thank American Journal Experts for their linguistic assistance during the preparation of this manuscript.Conceived and designed the experiments: JL and YHH. Performed the experiments: YHH, JKP, and HTH. Analyzed the data: JTL, LFZ, and GHL. Contributed reagents/materials/analysis tools: YHH, LFZ, HTH, and WYY. Wrote the paper: YHH, JKP, and HTH.Conceptualization: Yan-hong Han, Jun Liu.Data curation: Yan-hong Han, He-tao Huang, Jian-ke Pan.Formal analysis: Yan-hong Han, Jian-ke Pan, Wei-yi Yang.Funding acquisition: Jiong-tong Lin, Ling-feng Zeng, Jun Liu.Investigation: He-tao Huang, Jiong-tong Lin, Gui-hong Liang, Jun Liu.Methodology: Jian-ke Pan, Ling-feng Zeng, Gui-hong Liang, Jun Liu.Project administration: He-tao Huang, Ling-feng Zeng, Gui-hong Liang, Jun Liu.Resources: Jian-ke Pan, Wei-yi Yang.Software: Yan-hong Han, He-tao Huang, Jian-ke Pan, Jiong-tong Lin.Supervision: Gui-hong Liang, Wei-yi Yang.Validation: Wei-yi Yang, Jun Liu.Visualization: Jiong-tong Lin.Writing – original draft: Yan-hong Han, Jian-ke Pan.Writing – review & editing: Jun Liu.


Among preventable conditions, the greatest decrease was observed in uncontrolled diabetes ; ptrend < 0.001), followed by short-term complications ; ptrend < 0.001), long-term complications ; ptrend < 0.001), and lower-extremity amputations ; ptrend < 0.001). These reductions were observed in all age strata for overall DM-related PPH and by preventable condition but lower-extremity amputations for those <65 years old. There was a greater reduction in overall DM-related PPH, uncontrolled DM, long-term-complications, and lower extremity amputations in females than in males . No significant difference was shown for short-term complications (p = 0.101). Our study shows a significant reduction in national trends for diabetes-related potentially preventable hospitalizations in Spain. These findings could suggest a sustained improvement in diabetes care in Spain, despite the burden of these diabetes-related complications and the increase in the diabetes mellitus prevalence.We aimed to assess national trends in the rates of diabetes-related potentially preventable hospitalizations  in the total adult population of Spain. We performed a population-based study of all adult patients with diabetes who were hospitalized from 1997 to 2015. Overall potentially preventable hospitalizations and hospitalizations by diabetes-related preventable conditions  were examined. Annual rates adjusted for age and sex were analyzed and trends were calculated. Over 19-years-period, 424,874 diabetes-related potentially preventable hospitalizations were recorded. Overall diabetes-related potentially preventable hospitalizations decreased significantly, with an average annual percentage change of 5.1 (95%CI: −5.6–(−4.7%);  Patients with diabetes mellitus (DM) are at greater risk to be hospitalized. Admission rates for these patients have been reported as being up to 6 times higher than those of patients without DM ,2. A higA substantial proportion of hospitalizations for acute or chronic conditions in relationship with DM may be potentially avoided with an adequate and effective ambulatory care. Early diagnosis, effective treatment, and appropriate education could improve the management of DM, prevent the development and worsening of DM-related complications, and reduce hospitalizations . These DThis issue has been controversially described in United States and European countries, with declining and increasing rates of DM-related PPH in the last two decades ,12,13,14Using the Spanish National Hospital Discharge Database  from the Spanish National Health System, we performed a nation-wide, retrospective, population-based study of all adult patients with DM who were hospitalized in Spain between 1997 and 2015. Overall DM-related PPH and DM-related PPH conditions were analyzed.The CMBD compiles patient data  for all public and private hospitals in Spain, covering more than 98% of hospitalizations. Admissions in emergency departments lasting less than 24 h are not included in the database. This national database is coordinated by the Spanish Ministry of Health, Social Services and Equality, which sets standards for record keeping and performs routine audits of the data .Disease classifications were established according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), which is used in the Spanish CMBD. We selected all patients aged 18 or older who were discharged from January 1997 to December 2015 with the diagnosis of DM (ICD-9-CM codes: 250.0–250.9).DM-related PPH conditions were defined according to AHRQ report for Prevention Quality Indicators 1, 3, 14 and 16 (ICD-9-CM codes) [Data confidentiality and patient anonymity were maintained at all times, in accordance with Spanish regulations on observational studies . PatientAll data analysis were performed using SPSS Statistics for Windows, version 15.0 , Joinpoint Regression Program, version 4.2.0.2  and Epidat: programa para análisis epidemiológico de datos, version 4.2 .The comparative analysis was assessed by carrying out repeated measures analysis of variance (ANOVA).p-value was <0.05.Annual rates for overall DM-related PPH and each DM-related preventable condition were calculated per 1000 hospitalized patients with DM, adjusting for age and sex using the direct method. The total Spanish population as of 2015 was used as the standard population. Also, data was stratified by age  and sex . The average annual percent change (AAPC) and 95% confidence interval (CI) was computed for overall DM-related PPH and by preventable DM-related condition and adjusted by age and sex. The trends were considered significant when the slope of the trend was not equal to zero and a n = 424,874) were DM-related PPH.Among the 7,393,341 admissions in patient with DM in Spain during the 19-years study period in Spain, 5.7% . Hospitalizations for short-term complications showed non-significant difference (p = 0.101).The AAPC for overall DM-related PHH and according to preventable condition for both the overall diabetic population hospitalized and stratified by age and sex are summarized in p < 0.01). No significant difference was shown for short-term complications (p = 0.101).The AAPC for overall DM-related PHH and according to preventable condition for both the overall diabetic population hospitalized and stratified by age and sex are summarized in This Spanish population-based retrospective study of all patients with DM who were hospitalized, found that adjusted overall DM-related PPH and according to preventable condition decreased from 1997 to 2015. Short-term and long-term complications remained as the most frequent conditions of PPH during the period of study, followed by uncontrolled DM and lower-extremity amputations. The greatest average annual decrease was observed in uncontrolled DM, followed by short-term complications, long-term complications, and lower-extremity amputations. The decrease in hospitalizations for lower extremity amputations was non-significant among patients <65 years old. Females experienced a greater reduction overall in uncontrolled diabetes, long-term complications, and lower extremity amputation hospitalizations.These results are important because they show decreasing DM-related PPH rates in a large sample over a wide period of time. Furthermore, they provide valuable information such as the adjusted AAPC and stratification by age and sex. Also, although there is a considerable interest in health care aspects of DM, epidemiological data of hospitalizations in patients with DM have been insufficiently described in many regions worldwide.Prior studies from different countries have reported similar DM-related PPH trends. In the United States of America, a nationwide study published by Wang et al. , using tDecline in hospitalization rates for uncontrolled DM was also reported by AHRQ from 1994 to 2000 . HoweverRecently, a study found that DM-related PPH rates did not change significantly during the years 2005–2014 in the United States, unlike the results in a previous reports. A slight increase in hospitalization rates due to short-term complications balanced by a slight decrease in hospitalization rates due to uncontrolled diabetes has been suggested as the main reason of these trends .In Europe, several studies have reported data in this line. A retrospective review of medical records of patients hospitalized for acute diabetic complications carried out in Italy between 2001 and 2010 showed a decreasing temporal trend . ConsistThe different methodologies used to estimate the hospitalization rates in each study and different periods analyzed could be the main reasons for these differences. In our study, we used the total number of adults who were hospitalized with DM, adjusting concomitantly by age and sex with the direct method, and the total Spanish population of 2015 as the standard population, being probably the most sensible method to determine changes in the rates of DM-related complications.p = 0.101) over the study period. These trends have also been observed in other studies [Although both males and females showed a significant reduction in the overall and specific conditions of DM-related PPH, there was a higher reduction among females for all conditions except for short-term complications ( studies ,11,13, bReasons for the reductions in rates of DM-related PPH are not fully understood. Improvements in primary care, the availability of safer and more effective antidiabetic drugs and efforts of clinicians and health organizations in prevention or earlier detection strategies in DM could be the main reasons for these declines ,12,19,20The persistent high rates of smoking among patients with DM in Spain and the funding of new services for diabetic foot disease have increased the patients who are diagnosed with peripheral artery disease and subsequently, the identification of need for vascular procedures ,22. ThesDM-related PPH are an emerging health care outcome to health systems worldwide ,24. The We acknowledge the following limitations in this study. Firstly, using ICD-9-CM codes to describe trends may lead to bias and inaccuracy, depending on the validity of the coding. In this regard, we could not distinguish between type-1 and type-2 DM, as diagnosis codes are not reliable. Secondly, we did not study geographical variations in the rate of DM-related PPH within the same country and it could be important. Studies from Italy , FinlandThis population-based study of all patients with DM who were hospitalized, found that adjusted overall DM-related PPH according to preventable condition decreased from 1997 to 2015. Short-term and long-term complications remained as the most frequent conditions of PPH during the period of study and the greatest average annual decrease was observed in uncontrolled DM. These results could reflect as a good indicator of the improvement in DM care in Spain, despite the burden of these complications due to the increase in the prevalence of DM. However, further research is needed to implement interventions for reducing lower-extremity amputation procedures in the younger strata and to fully identify the reasons for these hospitalization declines, evaluating geographical, gender, social, and individual determinants for the differences in the occurrence of DM-related PPH.


Here we present a comprehensive review of the literature concerning the utility of convex probe endobronchial ultrasound (CP-EBUS) in the diagnosis and treatment of nonmalignant conditions and discuss the associated complications. CP-EBUS has been conventionally used for the staging of lung cancer and sampling of mediastinal and hilar nodes. However, its application is not limited to malignant conditions, and it is gaining acceptance as a diagnostic modality of choice for nonmalignant conditions such as tuberculosis, sarcoidosis, pulmonary embolism, thyroid lesions, and cysts. Moreover, its therapeutic value allows for extended applications such as mediastinal and thyroid cyst drainage, fiducial marker placement for radiation therapy, and transbronchial needle injection. The noninvasiveness, low complication rate, high diagnostic yield, and satisfactory sensitivity and specificity values are the main attributes that lend credence to the use of CP-EBUS as a standalone primary diagnostic and therapeutic tool in pulmonary medicine in the foreseeable future. In 1897, a metal tube with an electric light served as the first rigid bronchoscope for the removal of pork bone from the airway . ContinuBecause of its noninvasiveness, CP-EBUS-guided real-time TBNA has largely replaced invasive sampling and diagnostic modalities such as mediastinoscopy. The value of CP-EBUS for the diagnosis and staging of lung cancer is well known. CP-EBUS can also aid in the diagnosis of nonmalignant conditions such as tuberculosis, sarcoidosis, and pulmonary embolism and facilitate treatments such as bronchogenic cyst drainage and transbronchial injection .Here we present a comprehensive review of the literature regarding the utility of CP-EBUS for nonmalignant conditions, with focus on its expanded prospects in terms of diagnosis and treatment. Complications associated with CP-EBUS are also discussed. et al. and Garwood et al. first reported the use of CP-EBUS-guided TBNA for the diagnosis of sarcoidosis, with diagnostic sensitivities of 91.8% and 85%, respectively [Sarcoidosis is a multisystemic inflammatory disorder with an unknown etiology that is characterized by the accumulation of macrophages and the formation of epithelioid cell nonnecrotizing benign granulomas. The lungs and hilar or mediastinal nodes are affected in 90% patients with sarcoidosis; therefore, pulmonary sarcoidosis is the most common form of the disease. Diagnostic modalities include computed tomography (CT), transbronchial lung biopsy (TBLB), endobronchial biopsy (EBB), TBNA, and mediastinoscopy. Pneumothorax and haemoptysis are major side effects of TBLB, which also exhibits moderate diagnostic sensitivity. Although mediastinoscopy is highly effective in the diagnosis of sarcoidosis, the associated costs and invasiveness limit its routine use. CP-EBUS-guided TBNA is an effective, noninvasive approach for sampling on an outpatient basis. Wongectively , 5. In aectively . A meta-ectively . CP-EBUSectively . et al. presented a positive pathological diagnosis rate of 93% for EBUS-TBNA or TBNA alone and 100% for EBUS-TBNA combined with TBNA [Several studies have compared sensitivity and accuracy values among various diagnostic modalities for sarcoidosis. Okiith TBNA . In anotith TBNA . Compariith TBNA , whereasith TBNA . In anotith TBNA . Howeverith TBNA . Finallyith TBNA .Multiple factors influencing the sensitivity of EBUS-TBNA have been studied; these include the gauge size, lymph node size, disease stage, number of sampled lymph node stations, and number of needle passes per lymph node. A prospective, randomized, double-blind trial found no significant difference between 21G and 22G needles in terms of the diagnostic yield of EBUS-TBNA in patients with sarcoidosis . HoweverIn summary, direct comparisons between conventional diagnostic modalities and EBUS-TBNA have favored the use of EBUS-TBNA as a primary diagnostic tool for sarcoidosis . Mycobacterium tuberculosis is a global public health concern for clinicians and researchers. Sputum or smear culture remains the gold standard for the diagnosis of pulmonary tuberculosis (TB). However, these methods are not efficient for the diagnosis of mediastinal tuberculous lymphadenopathy (TBLA). Moreover, 25% and 60% patients have negative sputum smears and no spontaneous sputum production, respectively [ et al. first used EBUS-TBNA for the diagnosis of mediastinal intrathoracic lymphadenopathy in patients infected with the human immunodeficiency virus (HIV) [ et al. demonstrated the use of EBUS-TBNA for the diagnosis of multidrug-resistant TB [Infectious manifestation ofectively . EBUS-TBus (HIV) . Subsequstant TB , anotherstant TB . Similarstant TB . A meta-stant TB . EBUS-TBstant TB . et al. confirmed the utility of EBUS-TBNA for the diagnosis of histoplasmosis in 452 patients, with a diagnostic yield of 78% [Conventionally, diagnosis of fungal infection-related lymphadenopathy requires tissue biopsy for obtaining adequate material for fungal culture. However, Sodhid of 78% . In anotd of 78% . EBUS wad of 78% . The used of 78% . et al. confirmed the accuracy of CP-EBUS in diagnosing reactive hyperplasia in a cohort of patients suspected to have lymphoma or other nonneoplastic lesions [Reactive hyperplasia involving the mediastinal and hilar lymph nodes is a nonspecific diagnosis. The condition is potentially caused by benign etiologies such as fungal infection . CP-EBUS lesions . Nocardia spp. Fujikura et al. successfully used CP-EBUS to sample purulent exudates containing N. asteroids [ Nocardia strains from a lung mass in a patient who had undergone kidney–pancreas transplantation [Nocardiosis is an infectious disease caused bysteroids . CP-EBUSantation . These fPulmonary embolism (PE) occurs when a blood clot gets lodged in blood vessels anywhere in the lungs, consequently blocking blood flow to the relevant parts of the lungs. It is a common disease and can be life-threatening depending on the presence of comorbid conditions, anatomical site, and size of the clot. Thus, prompt diagnosis is essential. Contrast-enhanced CT, ventilation perfusion scanning, and, less commonly, pulmonary arteriography are the preferred diagnostic methods. However, these techniques cannot be used for individuals with contraindications for the use of contrast agents, such as allergy or renal failure, pregnancy, and hemodynamic instability. In such cases, CP- EBUS serves as an effective alternative diagnostic modality. et al. initially reported the use of EBUS-CP for the diagnosis of PE in a 26-year-old patient [ et al. conducted a multicenter pilot study involving the use of CP-EBUS for the diagnosis of PE after angio-CT in 32 patients. Angio-CT detected 101 PEs while CP-EBUS detected only 97. However, CP-EBUS diagnosed at least one thrombus per patient, which was sufficient to establish the diagnosis. Three thrombi in the left upper lobe and one in the middle lobe could not be detected by CP-EBUS. The duration of CP-EBUS was 5 min/patient for the first 16 patients and 3 min/patient thereafter [The pulmonary arteries are located in close proximity to the bronchial and tracheal airways and can be easily visualized by CP-EBUS. CP-EBUS equipped with color Doppler imaging enables the pulmonologist to characterize the size of the thrombus and the extent of the blockage in real time. Casoni patient . Subsequereafter . In 2010ereafter . Subsequereafter –46. The ereafter . Anotherereafter . In yet ereafter .  FigureCP-EBUS can easily visualize and monitor the aortic arch, left and right pulmonary artery trunks, azygos vein, hilum, and lobar arteries; however, the image quality is generally suboptimal because of the low frequency (5–10MHz). Consequently, confirmation by angio-CT is required. Furthermore, the probe diameter of 6.3–6.9 mm facilitates the visualization of clots only in adjacent vascular structures. Nevertheless, CP-EBUS is a safe and sensitive method for real-time evaluation of PE, enabling not only diagnosis but also real-time evaluation of thrombolytic therapies in clinical studies [t al. initially reported the use of EBUS-TBNA for the diagnosis of substernal solitary thyroid nodules [ et al. reported 12 cases of thyroid biopsy performed using EBUS-TBNA [ et al. reported three cases of mediastinal ectopic thyroid diagnosed by EBUS-TBNA [EBUS-TBNA has been infrequently used for thyroid aspiration. Chalhoub e nodules . In anot nodules . Casal eBUS-TBNA . More reBUS-TBNA . et al. systematically reviewed 12 cases where EBUS-TBNA was used for the diagnosis of NELs in the pulmonary artery and lungs. The diagnoses included sarcoma (n = 6), lung cancer (n = 2), thyroid cancer (n = 1), renal cell cancer (n = 1), melanoma (n = 1), and PE (n = 1) [Al-Saffar (n = 1) . The fin et al. successfully used CP-EBUS for the placement of 2–5 fiducial markers around tumor masses in 43 patients scheduled for radiosurgery [CP-EBUS is reportedly used for the placement of fiducial markers for tracking purposes in patients requiring stereotactic radiation therapy and CyberKnife therapy for mediastinal and lung cancers , 54. Harosurgery . et al. used EBUS-TBNI of liposomal amphotericin B for the treatment of symptomatic aspergilloma [EBUS-TBNI in patients with mediastinal diseases is another therapeutic application of CP-EBUS. Two independent case studies have documented EBUS-TBNI of cisplatin for the treatment of lung cancer , 57. In rgilloma . et al. initially reported the therapeutic use of EBUS-TBNA for aspiration during the treatment of central airway stenosis caused by a mediastinal cyst. The Doppler mode in CP-EBUS helps in the differentiation of cysts from vascular structures [Nakajimaructures . Drainagructures , 61. As ructures .n = 50), followed by infectious complications (n = 14), breakage of the ultrasound bronchoscope (n = 98), and needle puncture (n = 15) [CP-EBUS is a noninvasive procedure with an excellent safety profile. Although it has several applications beyond the diagnosis of malignancies, it cannot cover the entire mediastinum and allows visualization of only the anterosuperior portion. Moreover, some anatomical locations such as the upper lobes cannot be accessed by CP-EBUS . A natio(n = 15) .In summary, CP-EBUS is a minimally invasive procedure that plays a pivotal role in the diagnosis and treatment of malignant and nonmalignant mediastinal diseases. CP-EBUS-guided TBNA provides the highest diagnostic yield in cases involving nonmalignant mediastinal diseases such as tuberculosis and sarcoidosis. However, combination with TBLB and EBB increases the yield to 100%, with minimal complications. Furthermore, CP-EBUS can provide adequate information for the diagnosis of most benign diseases without the need for other invasive procedures such as mediastinoscopy. There is overwhelming evidence on the efficacy and safety of CP-EBUS for benign conditions, with the noninvasiveness, low complication rate, high diagnostic yield, and satisfactory sensitivity and specificity values comprising the main attributes that lend credence to its use as a standalone primary diagnostic and therapeutic tool in pulmonary medicine. Therefore, the acquisition of this technology is highly recommended for most institutions to enable pulmonologists to safely and effectively diagnose benign and malignant diseases of the mediastinum.


Dens invaginatus (DI) represents an endodontic challenge because of its complex root canal morphology. This case report presents the clinical management of a 22-year-old woman with type II DI in right maxillary lateral incisor with a painful swelling. Pulp testing revealed no response with the tooth. Type II DI with open apex and large periradicular lesion was seen on radiograph. The treatment was planned by using cone-beam computed tomography (CBCT) imaging. Canal treatment was completed in two appointments with the aid of a dental operating microscope. In the first appointment, the internal anatomy was modified using an ultrasonic tip, and chemo-mechanical preparation was performed using the XP-endo Finisher instrument and NaOCl; calcium hydroxide intracanal dressing was used for one month. In the second appointment, an apical plug of mineral trioxide aggregate (MTA) Repair HP was performed and the remaining pulp space was then filled with gutta-percha and AH Plus sealer using the continuous wave of condensation technique. At the fourteen-month reevaluation, the patient was asymptomatic, the tooth had remained functional, and radiographic and CBCT assessment showed significant osseous healing of the lesion. Successful non-surgical management of the present type II DI was achieved in the present case. The association of CBCT, dental operating microscope, XP-endo Finisher, NaOCl and MTA Repair HP were important for ensuring a predictable outcome. Key words:Cone beam computed tomography, dens invaginatus, MTA apexification, XP-endo Finisher. Dens invaginatus (DI) is a developmental abnormality resulting from the invagination of enamel organ into the dental papilla, which begins at the crown and sometimes extends into the root before the occurrence of calcification . The preDifferent clinical approaches have been described to treat DI, including restorative procedures, nonsurgical endodontic treatment, endodontic surgery, intentional replantation or even teeth extraction ,5. CasesRecently, a new concept-finishing instrument  was developed with the purpose of improving root canal cleaning. It consists in a tip size 25 and non-tapered rotary nickel-titanium instrument made of a special proprietary alloy . Because of this new alloy, the instrument changes its shape according to the temperature: in room temperature, in its martensitic phase (M-phase), the instrument stands straight; however, when submitted to body temperatures, the file changes to its austenitic phase (A-phase) assuming a spoon-shape of 1.5 mm depth in the final 10 mm of its length. According to the manufacturer, the A-phase shape allows the instrument to access and clean areas that other instruments might not have reached, without damaging dentin or altering the original canal shape . This coA 22-year-old woman with no general health problems was referred by her dentist to the Endodontic Department, School of Dentistry, Feira de Santana State University. The patient complained of painful swelling on the mucosa over the maxillary right lateral incisor. Clinical examination revealed a sinus tract Fig. A, and thRadiographic examination revealed a large periradicular radiolucency, an open apex and a complex canal anatomy with type II DI Fig. B. Cone-bRoot canal treatment was performed under local anesthesia using 2% lidocaine with 1:100,000 epinephrine . A rubber dam was placed, and the access cavity was performed using diamond burs in high-speed rotation. The invaginated tissue was carefully removed using an ultrasonic tip   Repair HP  with approximately 3 mm was performed. The remaining pulp space was then carefully filled with gutta-percha (VDW) and AH Plus sealer  using the continuous wave of condensation technique. The continuous wave of condensation technique was performed using a fine tip plugger of the System B, which was heated to 200°C and taken to a depth 6-mm short of the apical plug. The tip was allowed to cool for 15 s, and a single burst of heat was applied for 1 s and the tip was removed. The canal was completely backfilled with Obtura II gutta-percha  with the unit set at 200°C.The access was sealed with a temporary filling material (Cavit), a final radiographic was performed , the XP-endo Finisher instrument assumes a spoon-shape at body temperature, performing debridement on hard-to-reach areas of the canal system. This specific feature of the instrument could be visualized in trans-operative radiographs Fig. B,C. In aEndodontic management of a permanent tooth with open apex, pulp necrosis, and periapical lesion consists on apexification or revascularization. Some studies have compared these procedures and have shown that revascularization was not superior to other apexification techniques in either clinical or radiographic outcomes . MTA apeIn conclusion, a successful non-surgical management of type II DI with wide canal, open apex, and large periradicular lesion was achieved. The association of CBCT, dental operating microscope, XP-endo Finisher, NaOCl and MTA Repair HP were important for ensuring a predictable outcome with a successful 14 months’ follow-up showing periapical healing.