Individuals with autism spectrum disorder (ASD) have been characterized by altered cerebral cortical structures; however, the field has yet to identify consistent markers and prior studies have included mostly adolescents and adults. While there are multiple cortical morphological measures, including cortical thickness, surface area, cortical volume, and cortical gyrification, few single studies have examined all these measures. The current study analyzed all of the four measures and focused on pre-adolescent children with ASD.We employed the FreeSurfer pipeline to examine surface-based morphometry in 60 high-functioning boys with ASD  and 41 gender-, age-, and IQ-matched typically developing (TD) peers (mean age = 8.83 years), while testing for age-by-diagnosis interaction and between-group differences.During childhood and in specific regions, ASD participants exhibited a lack of normative age-related cortical thinning and volumetric reduction and an abnormal age-related increase in gyrification. Regarding surface area, ASD and TD exhibited statistically comparable age-related development during childhood. Across childhood, ASD relative to TD participants tended to have higher mean levels of gyrification in specific regions. Within ASD, those with higher Social Responsiveness Scale total raw scores tended to have greater age-related increase in gyrification in specific regions during childhood.ASD is characterized by cortical neuroanatomical abnormalities that are age-, measure-, statistical model-, and region-dependent. The current study is the first to examine the development of all four cortical measures in one of the largest pre-adolescent samples. Strikingly, Neurosynth-based quantitative reverse inference of the surviving clusters suggests that many of the regions identified above are related to social perception, language, self-referential, and action observation networks—those frequently found to be functionally altered in individuals with ASD. The comprehensive, multilevel analyses across a wide range of cortical measures help fill a knowledge gap and present a complex but rich picture of neuroanatomical developmental differences in children with ASD.The online version of this article (doi:10.1186/s13229-016-0076-x) contains supplementary material, which is available to authorized users. Autism spectrum disorder (ASD) is a highly prevalent , stronglhttp://surfer.nmr.mgh.harvard.edu/), which uses surface-based morphometry (SBM), as opposed to voxel-based morphometry (VBM), that reconstructs and characterizes key information about brain structure. It provides better alignment of cortical landmarks than volume-based registration and does not result in an age-associated bias between older and younger children when registering children’s brains to a common space ),children . Furtherhttp://www.neurosynth.org/). At the time of this research, the Neurosynth dataset v0.5 contains activation data for over 10,900 studies and feature information for over 3300 term-based features. The term-based features were derived from the abstracts of articles in the Neurosynth database. For each feature, the database stores the whole-brain, reverse inference, meta-analysis map, P(Term|Activation), that is, the likelihood that a feature term is used in a study given the presence of reported activation )The current study is the first to examine cortical thickness, surface area, cortical volume, and cortical gyrification in the same study that included pre-adolescent children with ASD. In addition to rigorous characterization in ASD participants, this study includes a TD comparison group that was well-matched on sex, age, and IQ, which help to minimize possible confounds. The four cortical morphological measures describe a complex but rich picture of the neurodevelopmental structural differences in ASD in this age range. Our sample sizes are relatively large, with 60 participants in ASD and 41 participants in TD, which increase the reliability of the results and the statistical power to detect true effects in MRI studies, especially in heterogeneous populations such as ASD . Given t


In diffuse large B-cell lymphoma, first-line treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; salvage with cisplatin-based regimens for relapsing patients; and autologous stem cell therapy are standards of care. Treatment approaches are less clear for patients who are refractory or who are not candidates for autologous stem cell therapy. Options may include palliative regimens or clinical trial enrollment. One therapy under investigation in diffuse large B-cell lymphoma is lenalidomide, an immunomodulatory agent with antiangiogenic activity.We present the case of a 55-year-old Caucasian male patient diagnosed with diffuse large B-cell lymphoma who had an early relapse after treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. He then had a subsequent early relapse after cisplatin-based salvage consolidated with autologous stem cell therapy. The efficacy of gemcitabine-cisplatin-rituximab was limited to five months, followed by systemic and central nervous system progression. Fourth-line treatment with lenalidomide plus rituximab and involved-field radiotherapy followed by lenalidomide monotherapy greatly improved this patient’s quality of life and performance status, allowing over two years of progression-free survival to date (excluding a brief relapse due to treatment interruption).A lenalidomide-based regimen was highly effective in this patient with diffuse large B-cell lymphoma. Although diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma, immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) - widely regarded as the standard of care for first-line patients ,2 - is eLenalidomide  is an immunomodulatory agent that is approved for patients with previously treated multiple myeloma and for patients with myelodysplastic syndrome who have the 5q cytogenetic abnormality. Lenalidomide has both direct tumoricidal and immunomodulatory effects. Direct effects include inhibition of vascular endothelial growth factor-mediated microvessel formation, indicating antiangiogenic and antimetastatic activities ,5, as weP=0.006) [In vitro studies indicate that the differential effects of lenalidomide on non-GCB DLBCL cells are dependent on the expression of interferon regulatory factor 4 and cereblon, an E3 ubiquitin ligase complex co-receptor protein [Numerous studies of lenalidomide in DLBCL as monotherapy or in combination with other agents are ongoing in first-line patients and relapsed or refractory patients, as well as in the maintenance setting. In first-line patients with DLBCL, the combination of lenalidomide with rituximab plus CHOP (R2-CHOP) has yielded promising results in phase 1 and 2 studies -18. In rP=0.006) . The benP=0.006) ,18. An oP=0.006) . In vitr protein .Prognosis is poor for patients with multiply relapsed or refractory DLBCL, and current treatment guidelines suggest either autologous stem cell transplant (ASCT) or treatment within a clinical trial ,2, underOur 55-year-old Caucasian male patient presented with a two-month history of gastrointestinal symptoms, including severe dyspepsia, vomiting, and ‘black stool.’ At that time, it was not clear whether our patient’s weight loss 14kg), high fever (>38.5°C), and drenching night sweats were general symptoms or whether they were the result of an undiagnosed gastrointestinal tract disorder. The first histopathological confirmation of lymphoma came from a gastric biopsy sample , our patient was treated with standard R-CHOP chemotherapy  Table  from MarA second CR was further consolidated by Z-BEAM-conditioned  combined with the carmustine, etoposide, cytarabine, and melphalan regimen (BEAM)) ASCT. An initial dose of rituximab in June of year 3 was followed a week later by a second rituximab dose plus Y90-labeled ibritumomab tiuxetan and BEAM-conditioned ASCT 11 days after initiating therapy. Our patient was released from the hospital in July of year 3, with good hematopoietic reconstitution and no complications.At a three-month follow-up visit in October of year 3, our patient presented with no symptoms or abnormalities on physical examination. However, a small lesion was detected by PET-CT in his sternum . A relapse of his DLBCL with high proliferation fraction was confirmed in material from an urgent partial sternectomy  involvement: headaches and signs of VII cranial nerve paralysis. Although this conclusion could not be definitively diagnosed by lumbar puncture with cerebrospinal fluid (CSF) cytology and repeated imaging studies (CT and magnetic resonance imaging), intrathecal liposomal cytarabine was given as CNS prophylaxis. In April of year 4, our patient presented with diplopia and right-side ptosis. CT scans demonstrated a left orbit tumor that infiltrated his frontal sinus. A neurological examination and CSF cytology were otherwise normal. Our patient received intravenous steroids and liposomal cytarabine, followed by involved-field radiotherapy (IFRT) of the orbit in April of year 4 and prophylactic radiotherapy of the CNS in May of year 4 Table . The dipDuring this period of treatment, our patient’s quality of life remained poor. He was always either home-bound or hospitalized and was constantly undergoing medical procedures, including lumbar puncture. He experienced pain and the loss of some neurological function, and continued to be in great stress with survival fears.2 every four weeks) initiated during third-line treatment. In May of year 4, he started fourth-line treatment with lenalidomide in addition to rituximab  , the lenHematologic adverse events during lenalidomide-based treatment were manageable and comprised transient thrombocytopenia , and leuko- and neutropenia . The cytopenia was exacerbated during the concomitant palliative radiotherapy. Our patient developed two infections: sinusitis in March of year 5, which was treated with amoxicillin, and herpes  from July to October of year 5, which was treated with acyclovir and analgesics.During treatment with lenalidomide plus rituximab and then later on lenalidomide monotherapy, our patient’s quality of life and performance status remained surprisingly high  and much improved compared with his quality of life and performance status during previous therapies. Inpatient hospitalization was not required, all procedures were performed in a day clinic, and he returned to full-time work and engaged in physical activities.DLBCL is the most common aggressive non-Hodgkin’s lymphoma in adults and accounts for 25% to 35% of newly diagnosed cases . Despiteet al. [et al. [et al. [et al. [et al. reported remarkable regression of refractory intraocular DLBCL during monotherapy with lenalidomide [Lenalidomide has an acceptable toxicity profile and is easily manageable and effective in heavily pretreated patients with high-grade lymphoma , based oet al. , Witzig  [et al. , Zinzani [et al. , and Wan [et al. . The fir [et al.  and medi [et al. ,22, with [et al. ,21. In tlidomide . LenalidIn our patient, we observed an early relapse after first-line R-CHOP chemotherapy, indicating a dynamic and aggressive lymphoma with poor prognosis. Although radioimmunotherapy (ibritumomab tiuxetan) was added to a BEAM conditioning regimen supported by ASCT, it did not overcome disease resistance. Considering the rapid progression of lymphoma at each relapse, it is very unlikely that local, palliative radiotherapy would have effectively cured the disease and prevented distant relapses. Treatment with lenalidomide was considered under compassionate use after failure of all other treatments available at our institution. The lenalidomide-rituximab regimen was based on Wiernik and Witzig protocols ,20; howeWe demonstrate that lenalidomide can be efficacious in DLBCL, and we believe that it should be considered in relapsed or refractory DLBCL, particularly for heavily pretreated patients.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.ABC: Activated B-cell; ASCT: Autologous stem cell transplant; BEAM: Carmustine etoposide, cytarabine, and melphalan; CHOP: Cyclophosphamide doxorubicin, vincristine, and prednisone; CNS: Central nervous system; CR: Complete response; CSF: Cerebrospinal fluid; CT: Computed tomography; DLBCL: Diffuse large B-cell lymphoma; GCB: Germinal center B-cell; HE: Hematoxylin and eosin; IFRT: Involved-field radiotherapy; IPI: International Prognostic Index; MBPS: Mediastinal blood pool structures; NK: Natural killer; ORR: Overall response rate; PD: Progressive disease; PET-CT: Positron emission and computed tomography; PR: Partial response; R-CHOP: Rituximab plus cyclophosphamide doxorubicin, vincristine, and prednisone; R-ESHAP: Rituximab plus etoposide methylprednisolone, cisplatin, and cytarabine; SD: Stable disease; SUV: Standard uptake value; SUVmax: Maximum standard uptake value; Z: Zevalin.The authors declare that they have no competing interests.KK, WJ, KG, AG, and ABS wrote the paper. All authors read and approved the final manuscript.


Both of the two types of approaches can benefit from an accurate prediction of theoretical spectrum. A theoretical spectrum consists of m/z and intensity of possibly occurring ions, which are estimated via simulating the spectrum generating process. Extensive researches have been conducted for theoretical spectrum prediction; however, the prediction methods suffer from low prediciton accuracy due to oversimplifications in the spectrum simulation process.Tandem mass spectrometry (MS/MS) acts as a key technique for peptide identification. The MS/MS-based peptide identification approaches can be categorized into two families, namely, y ions, from which the whole theoretical spectrum can be constructed. On a collection of representative spectra datasets with annotated peptide sequences, experimental results suggest that OpenMS-Simulator can predict theoretical spectra with considerable accuracy. The study also presents an application of OpenMS-Simulator: the similarity between theoretical spectra and query spectra can be used to re-rank the peptide sequence reported by SEQUEST/X!Tandem.In the study, we present an open-source software package, called OpenMS-Simulator, to predict theoretical spectrum for a given peptide sequence. Based on the mobile-proton hypothesis for peptide fragmentation, OpenMS-Simulator trained a closed-form model for the intensity ratio of adjacent OpenMS-Simulator implements a novel model to predict theoretical spectrum for a given peptide sequence. Compared with existing theoretical spectrum prediction tools, say MassAnalyzer and MSSimulator, our method not only simplifies the computation process, but also improves the prediction accuracy.Currently, OpenMS-Simulator supports the prediction of CID and HCD spectrum for peptides with double charges. The extension to cover more fragmentation models and support multiple-charged peptides remains as one of the future works.The online version of this article (doi:10.1186/s12859-015-0540-1) contains supplementary material, which is available to authorized users. Tandem mass spectrometry (MS/MS) has been considered as an indispensable technique for high-throughput peptide identification and characterization in the field of proteomics . Extenside novo identification approaches: unlike the database search strategy, the de novo approach does not require a peptide sequence database as input. In essence, de novo approach can be treated as a search process working on a virtual peptide sequence database — the virtual database consists of all possible peptide sequences with the same precursor mass to the query experimental spectrum.The MS/MS-based peptide identification approaches can be categorized into two families: (1) database searching approaches: for each peptide sequence in a database, the corresponding theoretical spectrum is predicted and compared against the query experimental spectrum. The most similar peptide-spectrum match (PSM) is reported as the final identification result. (2) m/z and intensities of possibly occurring ions, is important to both database search and de novo identification approaches. Although theoretically possible, the accurate prediction of theoretical spectrum still remains a challenge due to the lack of deep understanding of the complex physical-chemical peptide fragmentation process during a MS/MS experiment. Therefore, most existing peptide identification tools employ an over-simplified model to simulate the peptide fragmentation process, leading to an inaccurate estimation of the ion intensities. Taking SEQUEST as an example, all y-ions are given a fixed intensity, regardless of the factors with substantial effects on the peptide fragmentation process, such as amino acid type and fragmentation sites, etc.Accurate prediction of theoretical spectrum, including The relationship between peptide sequences and ion intensities has been studied to improve the accuracy of theoretical spectrum prediction -12. A piy-ions. In brief, the intensity of a y-ion is determined by both near neighbouring amino acids and remote amino acids. The remote amino acids, however, were observed to have approximately equal effects on ion intensities yi and yi+1, and thus can be canceled out when calculating intensity ratio Based on the “mobile proton” peptide fragmentation model, we have proposed a novel theoretical spectrum prediction approach called MS-Simulator . Unlike Analyzer ,16, the The study presents an open source package implementation of MS-Simulator called OpenMS-Simulator, which can be freely downloaded through our website.theoretical spectrum prediction, PSM re-ranking, FDR analysis, and spectrum visualization. These functionalities are briefly described as follows:Theoretical spectrum prediction and spectrum visualization.y-ions and the corresponding isotopic derivatives. The current version of OpenMS-Simulator supports predicting theoretical spectra of both HCD  and CID (Collision-induced dissociation) types.OpenMS-Simulator takes peptide sequences as input and reports predicted theoretical spectra as output. A theoretical spectrum consists of CC) is also calculated as a quantitative measure of the similarity  analysis to evaluate the performance of PSMs re-ranking. In particular, two FDR curves are drawn: one curve is calculated based on the original ranks given by SEQUEST/X!Tandem, and another curve is calculated according to the new score calculated by OpenMS-Simulator. This way, the improvement of re-ranking strategy can be intuitively demonstrated. The FDR was estimated using the decoy count method; that is:OpenMS-Simulator package has four functionalities, namely, CC between experimental and theoretical spectrum predicted by OpenMS-Simulator is as high as 0.890. In Figure The theoretical spectrum prediction performance of OpenMS-Simulator is evaluated on the SwedCAD_7 T_LTQ-FT dataset (downloaded from http://www.bmms.uu.se/CAD/download.html). The dataset consists of 15,897 unmodified, doubly charged CID spectra together with highly confident peptide sequence annotations. On the dataset, the average Pearson m/z of m in the corresponding spectra.We also evaluated OpenMS-Simulator by comparing with two other theoretical spectrum prediction models, namely MSSimulator that uses the support vector regression technique, and MassAnalyzer that uses a kinetic model . For each spectrum in PAe000350 or PAe000351, SEQUEST was executed to generate the most likely peptide sequence, and for spectra in PAe003641, X!Tandem was executed to give the peptide identification results. Subsequently the PSMs were re-ranked by running OpenMS-Simulator. FDR analysis suggests that by using the re-ranking strategy, the correctly identified PSM number can be significantly improved  and D, respectively. Thus, the Eq. 1 in MS-Simulator model was improved to be:Compared with the previous version of MS-Simulator, more fragmentation pathways are taken into consideration in OpenMS-Simulator. Specifically, besides the common  pathway ,17 was ayi ion, only 4 neighbouring amino acids are used by OpenMS-Simulator to build prediction model. This way, the number of parameters is reduced with little influence on the prediction accuracy. The model parameters Δ used in OpenMS-Simulator are summarized as follows:d≤1 for x being any amino acid except for LYS or ARG.−2≤d≤5 for x being LYS or ARG.−8≤d≤10 for x being Cterm.0≤Nterm is divided into 5 levels according to d, i.e., Δ≃Δ′, where The effect of Unlike MS-Simulator utilizing 5 consecutive neighbouring amino acids around the concerned Based on the “mobile proton” hypothesis, OpenMS-Simulator employs a statistical model to predict intensity for possible ions, which extends our previous work MS-Simulator with several extensions and modifications. To avoid repetitions, only the extensions and modifications are listed as below:The estimated parameters can be found in Additional file We present an open source package OpenMS-Simulator implemented in Java language. OpenMS-Simulator can be used to accurately predict theoretical spectrum for a given peptide sequence. To show the performance of theoretical spectrum prediction, OpenMS-Simulator provides a functionality to re-rank PSMs reported by SEQUEST or X!Tandem. Experimental results suggest that the predicted theoretical spectrum help improve peptide identification.Project name: OpenMS-Simulator.Project home page:http://www.bioinfo.org.cn/OpenMS-Simulator.Operating system: Platform independent.Programming language: Java.Other requirements: Java 1.6 or higher.License: GNU GPL FreeBSD.Any restrictions to use by non-academics: licence needed.


Databases and biobanks are developed in relation to a research question having its own strategy and specific demands on quality and annotation of the collected samples, resulting in multiple designs according to the different possible goals . TranslaWe used ASP.NET as front-end tool, SQL Server Management Studio as back-end tool, and JavaScript and Ajax control toolkit for client-side purpose.We successfully developed an in-house Clinical Database and Biobank Management System called BioSearch, a disease-oriented general Biobank, with the goals correspond to disease biomarkers and drug target discovery through prospective and/or retrospective collections of samples and their derivates (DNA/RNA/proteins), usually associated with clinical data Figure . BioSearIn conclusion, “BioSearch” is a platform independent highly flexible web-based user friendly system allowing clinician, researchers and biobank staff to submit, store and retrieve samples and their associated clinical information. In future, we plan to extend its capabilities by implementing new plug-in devoted to experimental research data and bioinformatics for data analysis.Authors would like to acknowledge the KACST, Riyadh, Saudi Arabia (Project ID: 10-BIO1258-03 and 10BIO1073-03) for funding the research.


The Adverse Event Reporting System (AERS) is an FDA database providing rich information on voluntary reports of adverse drug events (ADEs). Normalizing data in the AERS would improve the mining capacity of the AERS for drug safety signal detection and promote semantic interoperability between the AERS and other data sources. In this study, we normalize the AERS and build a publicly available normalized ADE data source. The drug information in the AERS is normalized to RxNorm, a standard terminology source for medication, using a natural language processing medication extraction tool, MedEx. Drug class information is then obtained from the National Drug File-Reference Terminology (NDF-RT) using a greedy algorithm. Adverse events are aggregated through mapping with the Preferred Term (PT) and System Organ Class (SOC) codes of Medical Dictionary for Regulatory Activities (MedDRA). The performance of MedEx-based annotation was evaluated and case studies were performed to demonstrate the usefulness of our approaches.Our study yields an aggregated knowledge-enhanced AERS data mining set (AERS-DM). In total, the AERS-DM contains 37,029,228 Drug-ADE records. Seventy-one percent  of normalized drug concepts in the AERS were classified to 9 classes in NDF-RT. The number of unique pairs is 4,639,613 between RxNorm concepts and MedDRA Preferred Term (PT) codes and 205,725 between RxNorm concepts and SOC codes after ADE aggregation.We have built an open-source Drug-ADE knowledge resource with data being normalized and aggregated using standard biomedical ontologies. The data resource has the potential to assist the mining of ADE from AERS for the data mining research community. Since the early 1990s, adverse drug events (ADEs) have received considerable attention from researchers in quality and patient safety . The US In the AERS, drugs can be registered by arbitrary names, including trade names, abbreviations, and even typographical errors since they are directly entered by health care professionals  and consumers  . There iIn terms of ADE names, AERS does provide normalized terms based on Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs), though the use of MedDRA requires a license. In this study, we have demonstrated that MedDRA PT-based normalization actually enables the powerful data aggregation capability when we link the PT terms to their corresponding System Organ Class (SOC) categories.In this study, we aim to produce an open-source AERS data mining set (AERS-DM), which is normalized and aggregated with two standard drug ontologies, including RxNorm and the National Drug File-Reference Terminology (NDF-RT), and one ADE terminology, MedDRA.The FDA AERS database is a public database that includes 7 tables. Its structure is in compliance with the international safety reporting guidance (ICH E2B) . InformaRxNorm, released initially in 2004, is a standardized nomenclature for clinical drugs and drug delivery devices . Since iAcetanilides), Mechanism of Action , Physiological Effect , drug-disease relationship describing the Therapeutic Intent , Pharmacokinetics describing the mechanisms of absorption and distribution of an administered drug within a body , and legacy VA-NDF classes for Pharmaceutical Preparations  [NDF-RT was developed by the Veterans Health Administration, providing clinical information about medications, and has been included in RxNorm. NDF-RT uses a description logic-based, formal reference model that groups drugs and ingredients into the high-level classes for Chemical Structure  . Figure algesic)  togetherWe utilized RxNorm and NDF-RT for normalizing and aggregating drug information in AERS in consideration of three reasons. First, these two ontologies are publicly available medication ontologies that have been intensively developed and used for drug data integration ,24,25. SFinally MedDRA is a controlled terminology developed for reporting adverse events, related to drugs, to regulatory agencies . MedDRA In our study, we used a natural language processing (NLP) tool, MedEx, to normalize AERS drugs. MedEx extracts medication information from clinical notes . BesidesFigure According to the FDA’s recommended method for de-duplication, for reports with the same CASE number, we select the latest (most recent) report date  in the AERS “DEMO” table. For reports with the same CASE and FDA_DT values, we select the one with the highest ISR number. Table After de-duplication, we concatenate the following fields in the DRUG table: “DRUGNAME,” “ROUTE,” and “DOSE_VBM, and the resulting strings are normalized with MedEx. Compared to DRUGNAME alone, the concatenated string gives more comprehensive information about the corresponding drug, since the “ROUTE” field can provide information such as “Oral” and the “DOSE_VBM” field can provide information such as “Tablet.” The results are mapped to the RxNorm code RxCUI. For example, the concatenated string “POTASSIUM CHLORIDE EXTENDED RELEASE TABLET EXTENDED RELEASE TABLET ORAL 20 MEQ BID ORAL” is normalized to RxCUI 198116 . Meanwhile, we map “PT” entries of the REAC table to PT and SOC codes of MedDRA.The algorithm for classifying AERS drugs based on NDF-RT includes two parts; the first part is to identify the corresponding NDF-RT concepts for those normalized AERS drugs and the second is to extract the associated NDF-RT classification information.Specifically, RxNorm contains NDF-RT ingredients and clinical drugs. Meanwhile, NDF-RT ingredients are connected to their mechanisms of action, physiologic effects, and therapeutics (indications and contraindications) and the corresponding clinical drugs inherit those relations. NDF-RT clinical drugs are also connected to their corresponding VA drug classes. Therefore, if a given RxCUI itself is an NDF-RT concept , we use it to find NDF-RT classification information. Otherwise, we traverse the relations provided by RxNorm to greedily identify the related NDF-RT ingredients and clinical drugs, and then extract the associated classification information .For the experiments, we first gathered the AERS data that are publicly available from 2004 to 2011 . We usedWe evaluated the normalization performance of MedEx in two steps. For the first step, we randomly selected 200 unique input drug names before MedEx-based annotations. We recruited three reviewers with medical background who manually reviewed the 200 drug names and annotated them using the RxNorm codes. The version of the RxNorm used in the evaluation was the same as that included in MedEx. A gold standard was generated after the reviewers achieved inter-agreements. Precision (P), Recall (R), and F-measure (F) were calculated for these selected drug names, using P = TP/(TP + FP), R = TP/(TP + FN), and F = 2PR/(P + R), in which TP stands for True Positive, FP stands for False Positive, and FN stands for False Negative. For the second step, we randomly selected 100 drug names that failed to be normalized. Then we confirmed whether or not the drug names are included in RxNorm. In addition, we checked to see if an unmatched drug name is a valid domestic or foreign drug by using two drug resources. The first resource is Drugs@FDA, a drug dictionary providing FDA-approved brand and generic drug information , and theAdditionally, we evaluated the validity of the algorithm used for identifying the mappings between RxNorm codes and NDF-RT concepts. We randomly selected 20 AERS drug names and manually checked the accuracy of the mappings produced by our algorithms.After de-duplicating reports, according to the recommended method in the download files provided by FDA , the numFor drug name normalization, 1,125,045 of 1,517,811 (74%) AERS unique drug names were normalized to 14,489 unique RxNorm concepts, of which 10,221 (71%) were classified in NDF-RT.For the ADE normalization, we mapped 14,740 existing MedDRA PT terms in the AERS to MedDRA codes, accounting for 76% of 19,294 total MedDRA PT terms. These MedDRA PT codes were then mapped to 26 MedDRA SOCs.Figure We classified the RxNorm concepts using the NDF-RT. Table The AERS-DM includes two tables, as discussed above. There are 37,029,228 Drug-ADE records after de-duplication. The number of unique pairs between RxNorm concepts and MedDRA codes is 4,639,613, and between RxNorm concepts and SOC pairs after ADE aggregation, 205,725. Tables The initial inter-annotator agreement on the 200 annotated drug names was 62.8%, a low agreement rate, maybe due to the various understandings in the rules for drug name normalization from the annotation training. It indeed indicated the difficulty of the drug normalization in AERS. Comparing MedEx-based annotations with the gold standard generated from majority votes by three human reviewers, we calculated the performance measures. TP, FP and FN were calculated as 138, 7 and 6 respectively. Recall, Precision and F-measure were then calculated as 95.8%, 95.2% and 95.5% respectively, which is comparable with performance measures in the original evaluation of MedEx . The sliTable Manual evaluation shows the greedy algorithm used to find mapping between RxNorm and NDF-RT is 100% valid.As described in the section above, the study produced an AERS-DM containing normalized and aggregated AERS reporting data. To demonstrate the usefulness of the AERS-DM, we used the AERS-DM to analyze the NDF-RT drug class “Pharmacokinetics” and their corresponding ADE categories represented by the MedDRA SOCs. Specifically, we joined the two tables in the AERS-DM and retrieved the AERS reports under seven existing pharmacokinetics classes. We then analyzed the data, including their corresponding MedDRA SOC-based ADE categories.Figure In addition to the significance described in the Introduction section above, the present study was also partially motivated by our previous work on building a standardized knowledge base of ADEs known as ADEpedia, in which we intended to integrate and normalize known ADE knowledge from disparate ADE datasets  ,36. We cNDF-RT is a major national source of drug classification information, providing multi-axial classifications such as physiological effect, mechanism of action, etc. It has proved to be capable of representing medications in clinical settings. For example, Rosenbloom et al.  investigOn the other hand, the applicability of NDF-RT and RxNorm for clinical drug classification was explored, and the imperfect mappings between RxNorm and NDF-RT and incomplete drug classification were evidenced by several studies ,24,25. PIn the context of standardizing the AERS data in this study, we developed a systematic algorithm in which the rich semantic connections within RxNorm were fully utilized to build the mappings with the related concepts in NDF-RT. The mappings were then used to aggregate the AERS data under multi-axial classifications in NDF-RT. Different from those related studies, the present study focuses on real-world data in the AERS and presents a normalized AERS-DM data set together with all corresponding drug classification information provided by NDF-RT for large-scale data mining purposes. The evaluation results show that the greedy algorithm for maximum mapping to corresponding NDF-RT concepts from RxNorm codes was valid. We believe that the mapping method developed in our study could be useful in other similar context.We found that the MedDRA PT terms coding ADEs in the AERS changed over time. The used AERS data ranged from 2004 to 2011, and during that time period the MedDRA versions had been updated twice annually . Some ADIn addition, other studies have identified a number of issues related to the use of MedDRA. For example, the hierarchy problems and semantic reasoning incapability of MedDRA mitigate its usefulness for querying and analyzing AERS data. SNOMED-CT, as the largest clinical terminology, can complement these disadvantages, with as many levels of hierarchy as are considered appropriate, and the semantic consistency in relationships . In addiWe demonstrated the usefulness of the AERS-DM produced by this study by analyzing the data set using the pharmacokinetics class. There are other class dimensions available for analysis, including physiologic effect, mechanism of action, and VA class, all of which come from the knowledge structure asserted in the NDF-RT. We believe that the knowledge asserted in the standard ontologies will enrich the AERS-DM and enable the meaningful use of AERS data for ADE signal detection and data mining.Based on AERS-DM, more efficient data mining and ADE detection in individual drugs would be achieved and facilitated. The reasons are three-fold as follows. First, having enriched features of drugs and enlarged cohort information, AERS-DM could provide potential explanations for individual differences in ADEs. Second, with the capability of large-scale ADE mining, comparative analysis of different drug classes could be explored, thus accumulating ADE evidence in the field of individual drugs. Third, presenting more meaningful organization of drug and ADE data with standard terminologies, AERS-DM could be a platform for deeper mining by further connecting with clinical notes, scientific literature, gene expression, proteomics and pharmacogenomics data, and various other ontologies. We believe that AERS-DM could be used to explore the complex network among drugs and ADEs, and such research would bear far-reaching significance in terms of the study paradigm of ADEs.We used only two drug ontologies (RxNorm and NDF-RT) and one ADE terminology (MedDRA) to normalize and aggregate AERS data. We believe additional investigations of other standard terminologies, such as SNOMED-CT would be beneficial in exploring the potential of standardized AERS reporting data in data mining.In this study, we leveraged three biomedical ontologies―RxNorm, NDF-RT, and MedDRA―for normalizing and aggregating the AERS data and produced a standardized ADE dataset referred to as AERS-DM. With the normalized codes and aggregated features, the AERS-DM would be useful for the research community in the data mining field. We will continue to refine and optimize the AERS-DM and update it periodically in the future. In addition, we will investigate the integration of the AERS-DM data set with other health data sources, such as EHR data, literature databases  and othDataset name: AERS-DMDataset home page:http://informatics.mayo.edu/adepedia/index.php/DownloadOperating system(s): Platform independentOther requirements: NoneLicense: GPLAny restrictions to use by non-academics: NoneRxNorm Files:http://www.nlm.nih.gov/research/umls/rxnorm/docs/rxnormfiles.htmlRxNorm concept relationships:http://www.nlm.nih.gov/research/umls/rxnorm/docs/2013/appendix1.htmlAERS: The Adverse Event Reporting System; NDF-RT: National Drug File-Reference Terminology; MedDRA: Medical Dictionary for Regulatory Activities; PT: Preferred Term; SOC: System organ class; HGLT: High-Level Group Term; HLT: High-level term; LLT: Lowest-level term; ADEs: Adverse drug events; AERS-DM: AERS data mining set; EHRs: Electronic health records; PRR: Proportional reporting ratio; ROR: Reporting odds ratio; IC: Information component; EBGM: Empirical Bayes geometric mean; RRF: Rich Release Format; NLM: National Library of Medicine; RxCUI: RxNorm concept unique identifier; UMLS: Unified Medical Language System.The authors declare that they have no competing interest.All co-authors are justifiably credited with authorship, according to the authorship criteria. Final approval is given by each co-author. In detail: LW –design, development, analysis of data, interpretation of results, and drafting of the manuscript; GJ – conception, interpretation of results, and critical revision of the manuscript; DL – analysis of data; HL – conception, design, development, interpretation of results, and critical revision of manuscript.


Primary Cutaneous Peripheral T-Cell Lymphoma NOS (PTL-NOS) is a rare, progressive, fatal dermatologic disease that presents with features similar to many common benign plaque-like skin conditions, making recognition of its distinguishing features critical for early diagnosis and treatment . A 78-year-old woman presented to ambulatory care with a single 5 cm nodule on her shoulder that had developed rapidly over 1-2 weeks. Examination was suspicious for malignancy and a biopsy was performed. Biopsy results demonstrated CD4 positivity, consistent with Mycosis Fungoides with coexpression of CD5, CD47, and CD7. Within three months her cancer had progressed into diffuse lesions spanning her entire body. As rapid progression is usually uncharacteristic of Mycosis Fungoides, her diagnosis was amended to PTL-NOS. Cutaneous T-Cell Lymphoma (CTCL) should be suspected in patients with patches, plaques, erythroderma, or papules that persist or multiply despite conservative treatment. Singular biopsies are often nondiagnostic, requiring a high degree of suspicion if there is deviation from the anticipated clinical course. Multiple biopsies are often necessary to make the diagnosis. Physicians caring for patients with rapidly progressive, nonspecific dermatoses with features described above should keep more uncommon forms of CTCL in mind and refer for early biopsy. Primary Cutaneous Peripheral T-Cell Lymphoma not otherwise specified (PTL-NOS) is an aggressive and life threatening dermatologic malignancy that often presents mimicking other less severe plaque-like skin conditions. Due to the nonspecific nature of these lesions, CD4-positive CTCL is often misdiagnosed as either Mycosis Fungoides or Sezary Syndrome. It is not until the disease progresses that further investigation into alternative diagnoses is prompted. Biopsy and immunohistochemical analysis of CTCL are nonspecific and a discrepancy in the clinical picture may require the diagnosis to be amended. The 5-year survival rate for PTL-NOS is less than 20%, which makes timely diagnosis an important measure to improve outcome . We descA 78-year-old female without significant past medical history presented to an outpatient surgery center with a two-week history of a rapidly growing nodule on her right shoulder. The patient noted that the nodule spontaneously bled as it became caught on clothing but otherwise was asymptomatic. She applied Polysporin topically without signs of healing or regression of the lesion. There were no other lesions of concern. She admitted to malaise but denied weight loss, night sweats, fevers, or loss of appetite. Her family history was negative for any malignancies.On examination, the patient had a solitary 5 cm ill-defined, red-violaceous, immobile, irregular nodule on her right posterior shoulder . The lesBiopsy revealed a dense pan-dermal infiltrate of medium- to large-sized atypical lymphocytes with irregular nuclei and perinuclear halos (>25% large cells). The lymphocytes exhibited epidermotropism, blurring the dermal-epidermal junction and epidermis. The infiltrate formed large groups within the epidermis and extensively infiltrated the subcutaneous adipose tissue. Scattered mitotic figures were also identified. Immunohistochemical staining showed CD4-positive T-cell population that coexpressed CD5, CD45, and CD7. EBV, CD30, and CD56 were negative.These results prompted surgical excision with wide margins and referral to a hematology/oncology specialist. The patient was initially diagnosed with Mycosis Fungoides and was started on Methotrexate. Unfortunately, the Methotrexate proved to be ineffective, and over the next three months her disease continued to progress with multiple new nodules and plaques arising over several areas of her body Figures  and 3. SAfter recognizing the aggressive nature of her disease, her diagnosis was amended to Primary Cutaneous Peripheral T-Cell Lymphoma, NOS. She was started on combination Cyclophosphamide, Hydroxydaunomycin (Doxorubicin), Oncovin (Vincristine), and Prednisone. The disease partially responded to chemotherapy with regression of lesions on her lower extremities. Unfortunately the chemotherapy was poorly tolerated by the patient and, after two cycles of chemotherapy, she declined any further treatment. She eventually succumbed to sepsis due to skin barrier breakdown six months after diagnosis.Cutaneous T-Cell Lymphoma (CTCL) is a form of Non-Hodgkin Lymphoma that involves neoplasms of T-cells primarily concentrating within the skin . CTCL caPatients with PTL-NOS may present with a solitary red-violaceous tumor-like nodule on any area of the body; however, most commonly patients present with scattered multifocal or diffuse nodules . Many ofDue to the rarity of cases, PTL-NOS is not well understood and algorithms for treatment are lacking. PTL-NOS falls within the rarest CTCL subtype of Primary Cutaneous Lymphomas (PCLs) and accounts for only about 2% of PCLs , 2. PTL-The WHO-EORTC established a set of criteria to help define PTL-NOS from other, more well-defined rare subtypes of Primary Cutaneous Lymphomas . This crDue to the rarity of PTL-NOS, there are gaps in the knowledge about evidence-based treatments and survival . HoweverDue to the rapidly evolving nature of PTL-NOS, treatment usually includes systemic chemotherapy and/or hematopoietic stem cell transplantation , 4. SystCTCL should be suspected in patients with patches, plaques, erythroderma, or papules that persist or multiply despite conservative treatment. Initial biopsies are often nondiagnostic. Diagnosis requires a high degree of suspicion and multiple rebiopsies are often necessary to make the diagnosis. Although Mycosis Fungoides is the most common form of CD4-positive CTCL, it is prudent to consider PTL-NOS as the initial diagnosis for such a presentation, bearing in mind the rarity of the disease and nonspecific immunohistochemical analysis. One must have a high index of suspicion for alternative diagnoses if clinical progression is inconsistent with usual course of disease.


N = 67, age range 15–65 years at time of injury) 2–5 years after TBI, compared to a healthy matched control group (N = 72). Results revealed significantly more attentional, emotional regulation, and psychological difficulties in the TBI group than controls. Demographic and early clinical variables were associated with poorer cognitive and emotional outcome. Fewer years of education and depressive symptoms predicted greater executive dysfunction. Younger age at injury predicted more aggressive and rule-breaking behaviour. TAI and depressive symptoms predicted Internalizing problems and greater executive dysfunction. In conclusion, age, education, TAI, and depression appear to elevate risk for poor long-term outcome, emphasising the need for long-term follow-up of patients presenting with risk factors.Survivors of moderate-severe Traumatic Brain Injury (TBI) are at risk for long-term cognitive, emotional, and behavioural problems. This prospective cohort study investigated self-reported executive, emotional, and behavioural problems in the late chronic phase of moderate and severe TBI, if demographic characteristics , injury characteristics , or duration of posttraumatic amnesia), symptoms of depression, or neuropsychological variables in the first year after injury predicted long-term self-reported function. Self-reported executive, emotional, and behavioural functioning were assessed among individuals with moderate and severe TBI ( Adolescents and adults surviving moderate and severe Traumatic Brain Injury (TBI) often experience long-lasting cognitive, emotional, and behavioural problems –4. In paExecutive function is a complex, overarching concept that refers to all functions related to goal-directed regulation of thoughts, actions, and emotions, including problem-solving, monitoring ongoing operations, switching between operations, emotion regulation, initiation of behaviour, and inhibition of nonadaptive behaviour , 16. WhiSeveral self-report inventories have been developed aiming to assess not only the goal-directed regulation of thoughts, but also regulation of actions and emotions. Studies have demonstrated significant changes in self-reported executive function after TBI related to the individuals overall ability to regulate thoughts, emotions, and behaviour , 22. HowPrevious research has shown that a broad assessment is necessary to capture the variety of emotional and behavioural problems that persons may experience after TBI, including both Internalizing emotional problems such as depression or anxiety as well as Externalizing problems such as aggressive behaviour , 13, 25.Assessing cognitive, emotional, and behavioural changes after TBI using self-report gives access to unobservable, internal experiences to which only the person with TBI is privileged. A number of adult TBI studies have shown reasonable correspondence between self-report and family report , 29, 30.When considering possible predictors of self-reported executive problems after TBI sustained in late adolescence and adulthood, association has been found with length of education , lesion Associations with self-reported emotional and behavioural change after TBI are equally complex. Development of depression and anxiety after TBI has been observed to be associated with low socioeconomic resources  , 25, whiThis study adresses the gaps in the previous litterature by investigating long-term cognitive, emotional, and behavioural self-reported outcomes after moderate and severe TBI sustained in adolecense and adulthood by utilizing fine-tuned tools assessing a broad range of possible symtoms; providing methodologicaly sound methods such as prospective recruitment, comparisons to a large, matched control group; and providing high quality imaging methods for assessing the impact of TAI. The aims of this study were to (1) investigate long-term self-reported executive, emotional, and behavioural function after moderate-to-severe TBI sustained in late adolescence and adulthood and (2) to explore the association between demographic, injury-related, psychological, global outcome, and neuropsychological factors, as obtained in the postacute phase and later self-reported problems. We hypothesised that persons with TBI would report more overall problems with executive function as well as more symptoms of emotional and behavioural problems than healthy individuals 2–5 years after the injury. Based on previous literature using fine-tuned tools such as the Behaviour Rating Inventory of Executive Function-Adult version (BRIEF-A) , 38, we From October 2004 to July 2008, 236 consecutive patients with moderate and severe TBI according to the Head Injury Severity Scale (HISS) criteria  were admn = 28), being not fluent in the Norwegian language (n = 4), and GOSE scores < 5 (n = 13). This left 95 patients eligible for this study, of which 74 (78%) consented to a single follow-up assessment between 2 and 5 years after injury. Seven were excluded from analysis owing to invalid questionnaire completion. This left 67 TBI survivors for the full analysis. There were no differences in the distribution of age, gender, education, or injury severity between participants and nonparticipants. Description of patient selection and nonparticipants as well as timeline is described in the flowchart in Of the 231 patients in the database, 51 died, and 40 were outside the age range. Forty-five were excluded because of premorbid or ongoing illness endorsed in the unstructured clinical interview during the hospital stay after the injury (p = 0.042). There were no differences between the participants as a whole group compared to the nonparticipants.Forty-nine patients (injured October 2004–October 2007) consented to participate in a study on longitudinal cognitive outcome with neuropsychological assessment and screening for depressive symptoms 3 and 12 months after injury, as well as participating in the follow-up study 2–5 years after injury. Eighteen participants (injured October 2004–October 2008) consented to participate in the 2–5 years after injury follow-up study, but not to participate in the assessments at 3 and 12 months after injury. There were no differences in the distribution of age, gender, education, or injury severity between the persons participating in the neuropsychological assessment + follow-up compared to those participating only in the follow-up, except that a larger proportion of participants in the first group had PTA durations of >1 week  or invalid completion of the forms (n = 3). As a result, 72 control participants were included.Sex-, age-, and education-matched healthy control participants were recruited from the family and friends of the patients with TBI, hospital employees, and through advertisement. Six of 78 recruited controls were excluded because of previously diagnosed psychiatric or neurological conditions . A few participants were unable to complete all questionnaires. While 17 (25%) of the participants were between 15 and 18 years of age at the time of injury (adolescents), all but one participant were ≥18 years of age when completing the questionnaires at follow-up 2–5 years after injury and one was 17 years old. We used a self-report form and an interview to estimate the number of years of education completed at the time of follow-up.T-score ≥65, with higher scores indicative of poorer function. The technical manual classifies a score on the negativity scale of >4 and a score on the inconsistency scale as >7 as an invalid report. Any reports that were classified as invalid according to these criteria were excluded from further analysis.Self-reported executive function was assessed with the BRIEF-A questionnaire, which consists of 75 items that measure behavioural, emotional, and cognitive aspects of executive function. It features sound psychometric properties , 58, gooT-scores as the threshold in research  with higher scores indicative of poorer function. The clinical range is classified as T-score ≥ 70 and the borderline range is classified as T-score ≥ 65 for the syndrome scales; the respective ranges are classified as T-score ≥ 63 and ≥60 for the composite scales [Self-reported emotional and behavioural problems were assessed with the ASEBA: Adult Self-Report (ASR) Form . The ASRe scales . The sub∗-weighted gradient echo sequence, fluid-attenuated inversion recovery (FLAIR) sequences, and diffusion-weighted imaging. MRI parameters and the evaluation procedure have been reported in previous studies [GCS score was recorded at or after admittance if the patient deteriorated or before intubation in cases of prehospital intubation. GCS scores of 9–13 were classified as moderate TBI and scores ≤8 were considered severe TBI , 60. Dur studies , 62.n = 66).Global TBI related outcome was assessed with the Glasgow Outcome Scale Extended (GOSE)  structurT-scores applying normative data provided by the test manufacturers, except for the Symbol Digit Modality test in which a normative sample quoted by Lezak et al. [T-scores were used in the analysis. These tests have demonstrated adequate validity and reliability [n = 47) and 12 months (n = 44) after injury [The subgroup was assessed at 3 months after injury, with performance-based neuropsychological tests grouped into cognitive domains covering processing speed , 65, attk et al.  was usediability . The Vociability . Depressr injury .The Regional Committee for Medical Research Ethics approved the study protocol. Written consent was obtained from patients aged ≥16 years at injury and from both participants and their parents if patients were aged <16 years at injury.p values <0.05 were considered statistically significant. p values between 0.01 and 0.05 should be interpreted with caution owing to multiple hypotheses. Statistical analyses were performed with SPSS 18.0.Demographic characteristics, injury severity characteristics, and the different cognitive domains are presented as mean  for normally distributed data, and otherwise as median with interquartile range . For missing data, we used available case analysis, utilizing all cases for which the variables were present. We reported 95% confidence intervals (CIs) where relevant, and two-sided t-tests based on 2000 bootstrap samples were used. The Kruskal-Wallis test and Mann-Whitney U test were used for nonnormally distributed data. Effect sizes were calculated as Cohen's d based on pooled variance (dpooled) [d of 0.8 as large, 0.5 as medium, and 0.2 as small effect sizes [z-pooled test [To describe differences in function between persons with TBI and controls, independent samples pooled) . Cohen dct sizes . Differeled test , and theled test , 78.r) was used to analyse associations between the main indexes on BRIEF-A and the symptom scales on ASR.To test associations between outcome measures and predictors, linear regression analyses were performed with composite scores from BRIEF-A and ASR as dependent variables; preinjury variables, injury-related variables, and GOSE scores were employed as covariates. In the subgroup analyses, neuropsychological test scores at 3 months after injury and BDI were employed as covariates. These covariates were included separately and then adjusted for age at injury and length of education at follow-up. An additional linear regression analysis was performed with main indexes and composite scores from BRIEF-A and ASR as dependent variables and the presence of TAI employed as a covariate with adjustment for BDI. Pearson's correlation coefficient (p = 0.03).Participant characteristics are presented in p < 0.001), BRI , and MI . On the BRI subscales, participants with TBI also reported more difficulties with inhibition, set-shifting, emotional regulation, and self-monitoring, with effect sizes in the medium range. On the MI subscales, individuals with TBI reported more problems with working memory than healthy controls, with 37% reporting working memory problems in the clinical range .Individuals with TBI reported more problems on all three composite indexes of BRIEF-A  than healthy controls . Effect p = 0.002), Internalizing problems , and Externalizing problems . On the syndrome scales, individuals with TBI also reported more problems with anxiousness/depression, somatic complaints, thought problems, attention problems, and aggressive behaviour than healthy controls. Among the DSM-IV-oriented scales, respondents with TBI reported higher scores for depression, anxiety, somatic problems, and attention problems. They also reported higher scores than controls on critical items (d: 0.84).On the ASR adaptive scales, respondents with TBI reported significantly fewer personal strengths than healthy controls. They did not differ from controls with regard to problems in their family relationships or friendships. On the composite scales Total problems, Internalizing problems, and Externalizing problems, persons with TBI reported significantly more problems compared with controls . Effect β ranging from −0.187 to 0.137, p > 0.05 for all; see Fewer years of education predicted endorsement of greater problems on the GEC and BRI, but not on the MI . TAI on Younger age at injury predicted more emotional and behavioural problems at follow-up, particularly regarding Externalizing problems . Presencβ ranging from −0.086 to 0.588, p > 0.05 for all; see Lower GOSE score at 12 months after injury predicted later high scores on both ASR Total problems and Internalizing problems when adjusted for age and education. Neuropsychological test performance at 3 months after injury was not associated with any of the ASR scales . Patients that reported more problems on the ASR symptom scales also reported more problems on the GEC, with correlation coefficients ranging from 0.327 (thought problems) to 0.823 . This pattern held true also for the indexes BRI  and MI . An exception was ASR intrusive behaviour, which was associated only with BRI , and not with GEC  or MI  and behaviour regulation. This association persisted even after adjusting for early self-reported depressive symptoms. TAI is a microscopic strain injury of axons and blood vessels in different predilection locations of the brain, typically causing widespread damage often localized in frontotemporal and subcortical structures , also afAs hypothesised, we found that self-reported symptoms of depression within the first year after injury predicted later perceived overall problems with goal-directed cognitive and behavioural regulation, in addition to Externalizing and Internalizing problems. These findings support previous studies showing that emotional distress affects the extent of self-reported cognitive problems , 55. HowFurther, younger age at injury predicted more self-reported Externalizing problems in the longer-term post-TBI, which is in accordance with previous studies that employed methods of retrospective assessment  or clustWe hypothesised that both global function and neuropsychological performance within the first year after injury would be associated with outcome 2–5 years after TBI. As expected, reduced global outcome one year after injury was associated with more reported executive and Internalizing problems. Experiencing reduced global function, including less ability to resume social relationships or leisure activities, may lead to a negative self-image and the increased endorsement of problems. However, the reported executive problems may also reflect cognitive impairment caused by the injury. Contrary to what we hypothesised, we observed no association between performance-based measures of cognitive function three months after injury and later self-reported executive, emotional, and behavioural function. This is in contrast to other studies demonstrating associations between performance-based and self-reported measures of task monitoring and switching , 30. TheBy assessing self-reported executive, emotional, and behavioural long-term outcome, our study revealed that the persons with TBI experienced subjective problems that were not detected with, for instance, neuropsychological tests, illustrating the importance of including self-evaluation inventories in addition to tests. Our results indicate that detection of DAI on early MRI and assessment of self-reported symptoms of depression within the first year after injury can aid in identifying persons at risk of experiencing poorer executive, emotional, and behavioural long-term outcome. This can be used for more targeted and cost efficient rehabilitation. Furthermore, psychological and/or pharmaceutical interventions, with a focus on depressive symptomatology, may be helpful in reducing the long-term problems experienced by persons sustaining a TBI and lessen their overall symptom burden. In addition, the results suggest that age is a notable risk factor for development of aggressive behaviour, and initiating interventions targeting this should be part of the rehabilitation of adolescence sustaining TBI.Our main aim was to explore long-term change in self-reported executive, emotional, and behavioural function after moderate and severe TBI sustained in adolescence as well as in adulthood, which also guided the development of the study design. The reliance on self-report forms may limit transferral to studies applying performance-based neuropsychological tests or diagnostic interviews and makes our study less optimal for exploring the validity of the BRIEF-A and ASR as proxies for cognitive function and psychiatric diagnoses. Performance-based measures were available for only the subgroup that consented to participate in both the neuropsychological study and the long-term follow-up study. Due to this design, the findings should be interpreted with caution.Persons with moderate and severe TBI reported significantly more pronounced difficulties in aspects of executive functions related to attentional control, working memory, and emotional regulation, as well as emotional and behavioural problems related to symptoms of depression, anxiety, and aggressive behaviour 2–5 years after injury compared to healthy controls. Both the presence of TAI on early MRI and reported symptoms of depression during the first year after injury were important predictors of later self-reported executive, emotional, and behavioural problems. Our findings indicate that demographic, neuropathological, and psychological factors all influence the development of self-reported executive, emotional, and behavioural problems for years after TBI. Our study highlights that early radiological and broad psychological evaluations may give clues as to which patients may be at risk for poorer long-term outcome. In summary, this study yields new information to guide the clinical management of TBI survivors and provides groundwork for additional clinical research regarding the long-term consequences of TBI.


Depression is a common and distressing mental health problem that is responsible for significant individual disability and cost to society. Medication and psychological therapies are effective for treating depression and maintenance anti-depressants (m-ADM) can prevent relapse. However, individuals with depression often express a wish for psychological help that can help them recover from depression in the long-term. A recently developed treatment, mindfulness-based cognitive therapy (MBCT), shows potential as a brief group program for people with recurring depression.This trial asks the policy research question; is MBCT with support to taper/discontinue antidepressant medication (MBCT-TS) superior to m-ADM in terms of: a primary outcome of preventing depressive relapse/recurrence over 24 months; and secondary outcomes of (a) depression free days, (b) residual depressive symptoms, (c) antidepressant medication (ADM) usage, (d) psychiatric and medical co-morbidity, (e) quality of life, and (f) cost effectiveness? An explanatory research question also asks whether an increase in mindfulness skills is the key mechanism of change.The design is a single-blind, parallel randomized controlled trial examining MBCT-TS versus m-ADM with an embedded process study. To answer the main policy research question the proposed trial compares MBCT-TS with m-ADM for patients with recurrent depression. Four hundred and twenty patients with recurrent major depressive disorder in full or partial remission will be recruited through primary care.Depressive relapse/recurrence over two years is the primary outcome variable. Analyses will be conducted following CONSORT standards and overseen by the trial’s Data Monitoring and Safety Committee. Initial analyses will be conducted on an intention-to-treat basis, with subsequent analyses being per protocol. The explanatory question will be addressed in two mutually informative ways: quantitative measurement of potential mediating variables pre- and post-treatment and a qualitative study of service users’ views and experiences.If the results of our exploratory trial are extended to this definitive trial, MBCT-TS will be established as an alternative approach to maintenance antidepressants for people with a history of recurrent depression. The process studies will provide evidence about the effective components which can be used to improve MBCT and inform theory as well as other therapeutic approaches.ISRCTN26666654.Trial registered 7 May 2009;  This update relates to the study protocol for a randomized controlled trial comparing mindfulness-based cognitive therapy with maintenance anti-depressant treatment in the prevention of depressive relapse/recurrence: the PREVENT trial. This update should be read in conjunction with the original protocol publication .To ensure that readers clearly understand that this trial is not a direct comparison between antidepressant medication (ADM) and Mindfulness-based cognitive therapy (MBCT), but ADM versus MBCT plus tapering support (MBCT-TS), the primary research question has been changed following the recommendation made by the Trial Steering Committee at their meeting on 24 June 2013. The revised primary research question now reads as follows: ‘Is MBCT with support to taper/discontinue antidepressant medication (MBCT-TS) superior to maintenance antidepressant medication (m-ADM) in preventing depression over 24 months?’ In addition, the acronym MBCT-TS will be used to emphasise this aspect of the intervention.et al.  and local research governance approval for all sites . The study personnel, management group, and independent Trial Steering Committee will ensure that the study is conducted within appropriate NHS and professional ethical guidelines, ensuring that Good Clinical Practice guidelines are observed at all times. This trial has been approved by the Medicines and Healthcare products Regulatory Agency (EudraCT number 2009-012428-10). All participants gave full informed consent.ADM: Antidepressant medication; m-ADM: Maintenance antidepressants; MBCT: Mindfulness-based cognitive therapy; MBCT-TS: MBCT with support to taper/discontinue antidepressant medication.The authors declare that they have no competing interests.WK, SB, RB, TD, GL, RT, ERW, PL, DK and NM conceived and designed the study and obtained funding. AE is the lead MBCT therapist responsible for training and supervision. RH is the trial manager. WK drafted the manuscript and all other authors contributed to editing of the final manuscript. All authors contributed to, and approved, the final manuscript.


Dear Editor,We thank you for the opportunity for commenting on the letter by Ascerbi and co-workers. We feel the discussions surrounding fluorescence stimulating and interesting.Our first experience with fluorescein was in 1991 when we used fluorescein for marking perilesional edema in the cortical cold lesion model . We demoSimilarly, when first using fluorescein for brain tumor surgery Moore et al. (1948)  noted thSince then, investigators have taken up this technology on and off, e.g., Kuoriwa and co-workers –13 for bhttps://www.youtube.com/watch?v=mST6oPE69dE and http://abcnews.go.com/Health/making-brain-tumors-glow-saves-lives/story?id=17076243#) and draw their own conclusions.Currently, due to the availability of new filter systems, investigators have again adopted fluorescein for malignant gliomas. Anybody interested in the present use of this technique should appraise footage from fluorescein surgery on the internet  are handled. In addition, publications should strictly adhere to the STARD statement  for studFinally, the argument is frequently put forward , 20 that


Here, we present an easy-to-use command line tool, dCLIP, for quantitative CLIP-seq comparative analysis. The two-stage method implemented in dCLIP, including a modified MA normalization method and a hidden Markov model, is shown to be able to effectively identify differential binding regions of RBPs in four CLIP-seq datasets, generated by HITS-CLIP, iCLIP and PAR-CLIP protocols. dCLIP is freely available at  Eukaryotic genomes encode large numbers of RNA-binding proteins (RBPs), each of which has unique associating properties with RNAs and impacts the structure, localization, generation and function of both coding and non-coding RNAs ,2. Compaad hoc, and does not utilize the spatial dependency among neighboring genomic locations, which is an important characteristic in creating differential binding profiles. A straightforward way to compare RNA-RBP interaction profiles across conditions is to analyze individual CLIP-seq data separately to identify the peaks (or binding sites) for each condition and then use coordinate overlapping or similar approaches to obtain common and differential binding sites. However, this ad hoc approach compares the results qualitatively but not quantitatively. For example, if a region is bound by an RBP under two conditions  with both significant enrichment but different binding intensities, the ad hoc approach will not be able to detect this region as a differential binding site. In addition, this ad hoc approach is over-sensitive to the cutoffs used for analyzing individual data, and has been shown to underestimate the similarity of two samples when applied to the analysis of multiple chromatin immunoprecipitation (ChIP)-seq experiments  and mapped to the mm9 reference genome by Bowtie . Unmappe88 and maZfp652 gene. A bin size of 10 bp was chosen for this analysis and sensitivity profiling across a big range of bin size values showed that the majority of these 1,469 regions were constantly detected regardless of the bin size used  or one bulge  to the perfect 6-mer seed miR-155 motif (GCATTA), and found a total of 58 seed-like motifs with one bulge and 441 seed-like motifs with one mismatch, as well as 150 motifs having perfect matches. Although not all of, and not only, these sites are non-canonical miR-155 target sites, the numbers indicate the prevalence of possible non-canonical binding sites for miR-155.Among the 1,469 genomic regions, 150 regions contained at least one 6-mer seed motif of miR-155 (GCATTA). These represented the putative miR-155 targets, as evidenced by the accumulation of a large number of deletion mutations immediately upstream of the miR-155 seed motif matches in the mapped reads  conservation scores in a 200 bp window covering the seed motif matches of miR-155. Then the conservation scores were averaged for the 57 sites found only by dCLIP and the 51 sites found only by the d Figure . Because matches ,35, our ad hoc-specific target genes did not  . The FMRxpressed . The autSmad4 gene. The blue bar marks the binding region that has reduced binding upon mutation. Both the total tag counts and T → C mutation counts are shown.We downloaded the raw sequencing files from [GEO:GSE39686]. Adapters were trimmed and the sequencing reads were aligned to the hg19 genome using Bowtie . Then weP <2e-16 for ACTT, P = 1.9e-12 for ACTG) than the TGGA motif (P = 1.4e-5). This was expected because the I304N point mutation locates in the KH2 domain responsible for binding to the ACTT/ACTG motif. Because the ACTT/ACTG and TGGA/AGGA motifs always occur in adjacent or nearby regions on the genomic sequence, a loss of binding affinity to the ACTT/ACTG motifs by the I304N mutation should lead to a secondary, weaker effect on the binding of the protein to neighboring TGGA/AGGA motifs. Overall, the analysis of this FMR1 PAR-CLIP dataset shows that dCLIP also performs well on PAR-CLIP datasets.We further calculated the number of T → C mutations that occur on top of all ACTT, ACTG and TGGA motifs found within those 9,859 binding sites in both the wild-type and I304N condition  and those could only be found by Piranha (216) to conduct downstream comparison. First, we searched for motifs matching to any 7-mer from the reverse-complement of the miR-124 mature sequence within the RNA sequences of method-specific target sites. We plotted the motif matches relative to the target site centers in Figure dCLIP identified a total of 419 sites that were more enriched in the miR-124-transfected than the control cells, with an average tag count of at least five in the miR-124 transfected cells. We ranked target sites identified by Piranha by dCLIP is also able to analyze iCLIP datasets. The major difference of processing iCLIP datasets from HITS-CLIP and PAR-CLIP datasets is that cDNA counts, rather than total tag counts, are analyzed by the algorithm and no mutant tag counts are collected. We downloaded the TDP-43 iCLIP datasets from . The TDPThe original publication determined that the FTLD iCLIP samples, compared to healthy samples, had increased binding of TDP-43 to small nucleolar RNAs (snoRNAs), small nuclear RNAs (snRNAs), transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), while binding to miRNAs decreased . Figure The two-stage procedure implemented in dCLIP includes an MA normalization step and a HMM to identify differential and common binding sites. The MA normalization is a critical step to make the CLIP-seq data comparable across conditions. The straightforward rescaling by the total number of reads across samples is not appropriate for comparative CLIP-seq analysis because the signal-to-noise ratio usually varies across different conditions. The modified MA plot normalization method in dCLIP not only addresses the issue of different signal and noise levels effectively, but also works on much smaller units than those used for microarray and ChIP-seq data analysis, allowing dCLIP to detect binding sites of higher resolution required for CLIP-seq data analysis. To reduce potential bias and conduct rigorous comparison across different conditions, we recommend adopting the same experimental and bioinformatics procedures, such as RNase digestion, high-throughput sequencing and alignment, for both conditions.The HMM plays a key role in identifying differential and common binding sites of two CLIP-seq samples in the dCLIP software. HMM can increase signal-to-noise ratios for sequencing data analysis, because it takes into account the correlation between consecutive bins. This is particularly important for CLIP-seq data, because of small bin size and high correlations between consecutive bins. The HMM in dCLIP defined a common binding state and two differential binding states. One thing to note for the three-state HMM is that the identified differential binding sites, for example the ones with inferred state of enriched and non-enriched, may actually only have a small tag enrichment in condition one, and an even smaller tag enrichment in condition two. Therefore, the differential binding sites need to be ranked and screened as such sites may not be of real interest to biologists. The analysis of the miR-155/AGO HITS-CLIP dataset, for example, set a cutoff of average tag intensity of 30 in the wild-type condition.One assumption of the dCLIP algorithm is that most sites will not have changes in their binding between conditions. Our simulation studies (Additional file The dCLIP software was benchmarked against the Piranha software. Piranha incorporates covariates which could represent transcript abundance, count data in the second condition or positional mutation information. However, the covariate is incorporated in the statistical model in the exactly same way no matter which type of data it actually represents. This design enables Piranha to be easily applied to a wide variety of CLIP-seq data analysis scenarios. However, this one-for-all method also harms the detection power of RBP binding regions of interest in each specific scenario, as different data types have their unique properties and should be treated differently. The dCLIP method is specialized in comparing two CLIP-seq experiments and was shown to perform better than Piranha in identifying differential binding sites. Therefore dCLIP should be a better choice when the users are interested in identifying differential or common RBP-binding sites.n states need to be implemented in the HMM. Theoretically, dCLIP can be easily modified to handle as many samples as possible. However, if n exceeds 10, the computation cost will increase dramatically. In addition, the normalization method also needs to be changed to suit the multiple-sample comparison. For example, the trimmed mean of M values method [The pairwise approach to compare CLIP-seq data in dCLIP can be extended to multiple-sample comparison. When there are n samples, a transition matrix of 2s method  or the us method  could bes method ,46 and, s method , do not We present a new computational approach, dCLIP, for the comparative analysis of CLIP-seq data. dCLIP was implemented as an easy-to-use command line tool in the Perl programming language. The dCLIP software is able to handle HITS-CLIP, PAR-CLIP and iCLIP datasets, and can take single-end or paired-end sequencing files as input. The dCLIP software is strand-sensitive and is able to detect differential binding sites at almost single-base resolution. It also correctly keeps all of the characteristic mutation information for later analysis. Real data analysis shows that dCLIP can accurately identify differential binding regions of RBPs and outperforms another CLIP analysis program, Piranha . We antiAGO: argonaute; bp: base pair; ChIP: chromatin immunoprecipitation; CLIP-seq: crosslinking immunoprecipitation coupled with high-throughput sequencing; FTLD: frontotemporal lobar degeneration; HITS-CLIP: high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation; HMM: hidden Markov model; iCLIP: individual-nucleotide resolution crosslinking and immunoprecipitation; miRNA/miR: microRNA; PAR-CLIP: photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation; PCR: polymerase chain reaction; phyloP: phylogenetic p-score; RBP: RNA-binding protein; rRNA: ribosomal RNA; snoRNA: small nucleolar RNA; snRNA: small nuclear RNA; tRNA: transfer RNA; UCSC: University of California Santa Cruz; UTR: untranslated region; RIP-seq: RNP immunoprecipitation followed by high-throughput sequencing.The authors declare that they have no competing interests.TW, YX and GX designed the project and developed the underlying algorithms. TW designed and developed the software, performed all of the testing and analysis and wrote the user guide. All authors wrote, read and approved the final manuscript.Source code of the dCLIP software 1.0.Click here for fileUser guide for the dCLIP software 1.0.Click here for fileExemplary output files of the dCLIP software.Click here for fileSimulation results to test the robustness of the dCLIP software.Click here for file


The substance secreted by mussels, also known as nature’s glue, is a type of liquid protein that hardens rapidly into a solid water-resistant adhesive material. While in seawater or saline conditions, mussels can adhere to all types of surfaces, sustaining its bonds via mussel adhesive proteins (MAPs), a group of proteins containing 3,4-dihydroxyphenylalanine (DOPA) and catecholic amino acid. Several aspects of this adhesion process have inspired the development of various types of synthetic materials for biomedical applications. Further, there is an urgent need to utilize biologically inspired strategies to develop new biocompatible materials for medical applications. Consequently, many researchers have recently reported bio-inspired techniques and materials that show results similar to or better than those shown by MAPs for a range of medical applications. However, the susceptibility to oxidation of 3,4-dihydroxyphenylalanine poses major challenges with regard to the practical translation of mussel adhesion. In this review, various strategies are discussed to provide an option for DOPA/metal ion chelation and to compensate for the limitations imposed by facile 3,4-dihydroxyphenylalanine autoxidation. We discuss the anti-proliferative, anti-inflammatory, anti-microbial activity, and adhesive behaviors of mussel bio-products and mussel-inspired materials (MIMs) that make them attractive for synthetic adaptation. The development of biologically inspired adhesive interfaces, bioactive mussel products, MIMs, and arising areas of research leading to biomedical applications are considered in this review. Th. Thin vipolymers . These b strands . This me strands . The metet al.  and heparin have been studied in relation to mussel-inspired heparin-mimicking coatings. DOPA is grafted onto HepLP or heparin to obtain DOPA-grafted HepLP (DOPA-g-HepLP) or DOPA grafted heparin (DOPA-g-Hep) using carbodiimide. A Polyethersulfone dialysis membrane is chosen as the substrate for the surface coating of the DOPA-g-HepLP and DOPA-g-Hep. The coated surface displays augmented hydrophilicity and electronegativity, decreased plasma protein adsorption, and suppressed platelet adhesion compared to a control. Heparin-coated membranes show anticoagulant bioactivities and superior performance in terms of endothelial cell proliferation and morphology differentiation. This kind of construct can have multi-biomedical applications in hemodialysis, blood purification, organ implantation, and tissue cultures systems . Po. Po36]. The marine microenvironment and the human body have many similarities. Understanding the physics and chemistry of marine bio-products will provide scientists with insight into the design of biomaterials for medical applications.The conversion of tyrosine to DOPA is an important event in the processing of the adhesive protein in mussels as there are multiple roles played by DOPA at the interfaces in the adhesion process. For inorganic surfaces, unoxidized DOPA forms high-strength but reversible coordination bonds; however, on organic surfaces, it is able to adhere to surfaces via the formation of covalent bonds. This remarkable ability to adhere to both organic and inorganic surfaces is related in part to the equilibrium that exists between DOPA and dopaquinone at marine pH levels, allowing the species to interact with surfaces. It is also notable that the strong bonds between DOPA and organic and inorganic surfaces are formed in the presence of sea water, which is likely a fundamental feature of protein-based glues which operate in wet oceanic environments. The use of DOPA and related catecholic molecules has recently been considered as part of a potential means of anchoring macromolecules onto oxide surfaces for medical applications . Researcet al. [Scientists at the Max Planck Institute for Polymer Research in Mainz, Germany, led by Aránzazu del Campo, synthesized an underwater adhesive that bonds strongly to various types of surfaces . In contet al.  create tet al. [®, Histoacryl®, and Tissucol fibrin glues along with three types of in situ formed PEG-based polymer hydrogels in a bonding and acute toxicity study upon direct contact with fetal membranes. They found that biological Tissucol fibrin glue has appealing properties for membrane sealing as compared to other glues. They also developed a new synthetic hydrogel formulation in the form of a mussel-mimetic sealant and the biologic Tissucol fibrin glue with good properties for membrane sealing. Extracts of all adhesives were shown to be non-toxic for cultured cells. Tissucol and one PEG-based hydrogel, which is a type of mussel-mimetic tissue glue, demonstrated efficient, non-disruptive, non-toxic bonding to fetal membranes. Their synthetic hydrogel-type tissue adhesive, which merits further evaluation in vivo, has emerged as a potential sealing modality for iatrogenic membrane defects. These results demonstrated that mussels glue efficiently seals elastomeric membranes under wet or moist conditions with comparable viscoelastic properties [Ex vivo studies also showed that proteolytic degradation does not affect mussels or mussel-inspired glues [Recently, Bilic et al.  investigoperties . Ex vivoed glues . These met al. [et al. [3+ interpolymer cross-linking via changing the pH. The Raman resonance signature of catechol-Fe3+ cross-linked polymer gels at high pH levels is similar to that of natural adhesives secreted by mussels. These gels display elastic moduli (G′) that approach those of covalently cross-linked gels as well as self-healing properties [et al. [in vivo performance of the material was assessed in a mouse extra-hepatic syngeneic islet transplantation model. They designed the adhesive polymer with a branched PEG core whose end groups were derivatized with catechol, a functional group inspired by mussels adhesive proteins. In an oxidizing environment, the adhesive forms within a minute from catechol-derivatized PEG (cPEG) solutions. The cPEG adhesive elicited minimal inflammatory responses in mice and maintained a bond with supporting tissue for up to one year upon implantation. The synthesized cPEG adhesive was shown to immobilize transplanted islets at epididymal fat pads and external liver surfaces efficiently, permitting normoglycemic recovery and graft revascularization. The findings by Messersmith et al. [et al. [in vivo, which can serve as an appropriate property for signaling molecules. Several mechanisms by which protein-bound 3,4-dihydroxyphenylalinine may trigger oxidative defenses via NF-κB and other transcription factors have been suggested  by-products. They tested fractions on four cancerous cell lines: A549 lung adenocarcinoma, BT549 breast tumor, HCT15 human colon tumor and PC3 prostrate cancer. The 50 kDa fraction, enriched in peptides, presented anti-proliferative activity in all cell lines. They claimed that hydrolysates formed due to fractionation from Mytilus edulis after enzymatic hydrolysis. At a protein concentration of 44 µg/mL, the 50 kDa fraction induced mortality rates of 90% for PC3, 89% for A549, 85% for HCT15 and of 81% for the BT549 cell lines. The 50 kDa fraction consists of 56% of proteins, 3% of lipids and 6% of minerals on a dry weight basis and the lowest levels detected of taurine and methionine and the highest levels of threonine, proline and glycine amino acids. Their study suggests that Mytilus edulis by-products should be viewed as high-value products with strong potential as anti-proliferative agents.Wakimoto et al.  demonstr [et al.  also rep [et al. . Beaulie [et al.  reportedPolymeric materials that basically heal at damage sites under wet conditions are urgently needed for biomedical applications. Recent research has demonstrated self-repairing in the metal-free water of synthetic polyacrylate and polymethacrylate materials that are surface-modified with mussel-inspired catechols . This coet al. [in vivo trials. Moreover, Qin and Buehler [A mussel-inspired surface functionalization to immobilize bioactive peptides for the enhanced endothelialization of decellularized vein matrixes (DVMs) was developed by Lee et al. . These a Buehler  reportedThe biological activity of nanoparticles is strongly dependent on the surface properties of the substrate. The present part illustrates the use of mussel-inspired proteins in the fabrication of functionalized bio-inspired nanomaterials leading to the possible realization of important biomedical applications.et al. [Gluconobacter oxydans via a synthetic adhesive biomimetic material inspired by the protein adhesive of mussels [G. oxydans and resulting in cell aggregation. Importantly, the G. oxydan aggregates showed high specific activity and good reusability. This facile approach offers potential advantages of a low cost, easy cell separation, low diffusion resistance, and high efficiency. Moreover, this approach is a convenient platform technique for the magnetization of cells in situ via direct mixing of nanoparticles with a cell suspension. Another study demonstrated that air-plasma-treated electrospun PCL and PLA nanofibers can be used as carriers for the loading and release of charged molecules in a pH-responsive manner [Amstad et al.  developeet al. . Alternaet al. . Researcet al. . The hyd mussels . Their ae manner . It alsoe manner .S. epidermidis and E. coli cells upon exposure to light due to the combined antibacterial effects of plasmonic heating and the release of silver [Recently gold@silver core-shell NRs were prepared using a novel biomimetic method, including deposition of a thin organic PD primer onto gold NRs surfaces, followed by spontaneous electroless silver metallization and the conjugation of antibacterial antibodies and passivating polymers for targeting to Gram-negative and Gram-positive bacteria. These nanorods showed high cytotoxicity on f silver . In anotf silver . The PD-f silver . PD-funcf silver . GO can f silver ,59.Recently, chemically cross-linked fracture-resistant nanocomposite hydrogels were prepared using dopamine methacrylamide consisting of a biomimetic side chain, inorganic nano-silicates, and Laponite . The preA human gelatin nano-coating was developed by conjugating dopamine with carbodiimide, the surface modifier, to form bio-adhesive surfaces . Human uEnhanced cell adhesion and migration were shown by newly construct monomeric catechols on the surfaces of polymeric nanofibers. The nanofiber (NF) of poly(ε-caprolactone)-polyethylene glycol-amine, fabricated with dihydroxyphenyl propionic acid, displayed catechol moieties on the surface . CatechoA three-dimensional (3D), ultralight, mussel-inspired dopamine-fabricated nitrogen-doped graphene aerogel was also developed . DopaminGold nanorods, fabricated with biomimetic PD, have been recently used for exposing antibodies to target tumor cells as a photothermal therapy . PD was 3O4@polydopamine nanoparticles are also used in a pH-sensitive manner for the controlled drug release of anticancer drugs  via reversible bonding between the catechol and boronic acid groups of PD and anticancer drugs [3O4 PD nanoparticles can serve as a platform for responsive drug delivery, a recyclable catalyst support and an adsorbent. These constructs of PD onto magnetic nanoparticles have unique features which allow them to act as a versatile platform for multiple biomedical applications. For drug delivery, polymer capsules are also considered to be desirable transport vehicles. A monodisperse PD capsule is prepared by the one-step interfacial polymerization of dopamine on dimethyldiethoxysilane emulsion droplets [3O4) nanoparticles, fluorescent quantum dots, and anti-cancer hydrophobic drugs can be preloaded in the emulsion droplets, and these advanced functional materials remain encapsulated in the capsules. This strategy provides a new avenue for PD polymer capsule preparation and encapsulation, and can be used in many biomedical applications. Recently for developing highly efficient nanoconjugates, Fe2O3 nanoparticles are functionalized also using an approach involving mussel-inspired dopamine with human serum albumin for the labeling of various types of cell lines, including stem cells [in vivo magnetic resonance imaging with xenograft and focal cerebral ischemia models.Feer drugs . The susdroplets . The sizem cells . These pDOPA-containing proteins are crucial for wet adhesion in mussels in a microenvironment that retards oxidation by shielding the amino acids from the solvent and endowing the protein with the ability to maintain adhesion at neutral to slightly basic pH levels. More importantly, hydrophobic interactions and inter-residue H-bonding combine to result in strong cohesion within Mfp3 layers over a relatively wide range of pH levels. By exploring the adhesive and cohesive mechanisms of bonding by the adhesive proteins of mussels, recent studies reveal that the adhesion of mussels is more complicated than a simple DOPA-mediated procedure, thus providing the motivation for a new generation of bio-inspired synthetic adhesive polymer materials. Some findings also explained the roles of hydrophobic and hydrophilic interactions in both biological and non-biological instances of mussels and mussel-inspired adhesion. The issues of redox and adhesion may be much broader and not limited solely to mussel DOPA chemistry. Understanding the aspects of natural redox control can provide fundamentally important insight for adhesive polymer engineering, surface modification and antifouling strategies.i.e., hernia). Research on mussel-inspired medical adhesives has also focused on tissue-specific medical applications, including wound care for diabetic patients, sutures for corneal tissue, and the surgical repair of nerves. MIMs are also capable of repairing defects in human fetal membranes, and they are biocompatible and effective at sealing small holes. The mussels unstable fatty acid components may have potent anti-inflammatory effects, which will be important for various types of autoimmune and inflammatory diseases. Some fractions of peptides from mussels show significant anti-proliferative activities with high nutritive potential as a source of protein, vitamin C, iron, zinc and omega-3. Mussel-inspired controlled drug delivery systems are also a promising emerging area for research. Some advanced types of novel formulations or conjugations with nanomaterials can also lead to the realization of applications in drug delivery to specific targets that are related to variations in pH levels and other physiochemical factors. Using a biodegradable mussel-inspired polymer surface coating also can regulate the adhesion, proliferation and differentiation of human mesenchymal stem cells. Collectively, we can conclude here that MIMs are important for many types of biomedical applications and that many more without immunogenicity issues will be explored by scientific communities and industries in the future.Mussel-inspired adhesive exhibit attractive properties for use immediately following tissue injuries, for applications in soft tissues including the gut and the vasculature, and for adhesion in an inflamed environment (