This review aims to compare peri-implant tissue changes in terms of clinical and radiographic aspects of implant restoration protocol using one-time abutment to repeated abutment connection in platform switched implant.A structured search strategy was applied to three electronic databases, namely, Pubmed, Embase and Web of Science. Eight eligible studies, including seven randomised controlled studies and one controlled clinical study, were identified in accordance with inclusion/exclusion criteria. Outcome measures included peri-implant bone changes (mm), peri-implant soft tissue changes (mm), probing depth (mm) and postsurgical complications.Six studies were pooled for meta-analysis on bone tissue, three for soft tissue, two for probing depth and four for postsurgical complications. A total of 197 implants were placed in one-time abutment group, whereas 214 implants were included in repeated abutment group. The implant systems included Global implants, Ankylos, JDEvolution , Straumann Bone level and Conelog-Screwline. One-time abutment group showed significantly better outcomes than repeated abutment group, as measured in the standardised differences in mean values (fixed- and random-effect model): vertical bone change  in 6 months,  in 12 months and  in 3 years and soft tissue change . No significant difference was observed in terms of probing depth and complications.Our meta-analysis revealed that implant restoration protocol using one-time abutment is superior to repeated abutment for platform switched implant because of less bone resorption and soft tissue shifts in former. However, future randomised clinical trials should be conducted to further confirm these findings because of the small samples and the limited quality of the original research. The focus of dental implant therapy has shifted from functional therapy in the 1980s and prosthetic-driven therapy in the 1990s to biological-driven therapy since the 2000s. Biological-driven implant therapy does not only recover the function of soft and hard peri-implant tissues but also maintains their aesthetics and long-term stability[Biologic width (BW) of dental implant is critical to the quality and stability of peri-implant structure. BW arouThe microgap and micromotion between the implant body and the abutment, position of the inflammatory response of the soft tissue seal to oral environment and the distribution of stress from loading through the implant are considered to be main mechanisms of such bone resorption–10. The In standard clinical implant restoration protocol, healing abutment /provisional crown is connected to the implant body once implant is exposed to oral cavity. Before final prosthesis fabrication, provisional abutments must be disconnected and reconnected several times for impression making, metal framework try-in, delivery of definitive pre-fabricated standard or customized abutments, and final prosthesis. In the repeated abutment protocol, the dis/re-connected manipulation of abutment may mechanically injure the soft tissue barrier, and may introduce bacteria and other contaminants into the implant–mucosal barrier to induce inflammation. Therefore, dis/re-connected abutment manipulation may disturb the implant–mucosal barrier, that is, disturbance of the zone of ‘junctional epithelium and connective tissue integration’, and further affect the marginal peri-implant tissues, including the peri-implant bone, and finally affect the stability of the peri-implant tissue. On the In literature, confusing is used to describe the process of implant restoration involving abutment dis/reconnection. It is often described as ‘repeated abutment’, ‘removable abutment’, ‘abutment dis/reconnections’ or ‘provisional/healing abutment’. In this review, this method is referred to as ‘repeated abutment’. By contrast, the process of implant restoration involving the use of definitive abutment to connect implant body without dis/reconnection manipulation is often referred to ‘one-time abutment’, ‘one-abutment at one time’, ‘one abutment-one time’, ‘one-time abutment placement’, ‘non-removal of an abutment’ and ‘definitive/final/standard abutment connected without removing during implant placement surgery or at stage two surgery’. In this review, ‘one-time abutment’ was used to denote the above confusing names.Implant design is also one of the facts associated with the bone resorption. Implant with platform switching is widely used in clinics today. Platform switching is based on the use of abutments with smaller diameter compared with the platform diameter of the implant, thereby creating a mismatch between both components at the level of the implant–abutment interface, 14. ThuGiven that repeated abutment dis/reconnections may jeopardise the advantages of platform switching, the use of a definitive abutment connected to implant body without removal during the restoration process should be an additional strategy for using platform-switching implant system. However, conflicting findings regarding its superiority to repeated abutment have been reported in animal study and clinic study–32. WhetSome case reports and randomised controlled clinical trials have been conducted since 2010–32. AlthThe population, intervention, comparison, and outcome of this systematic review are as following:Population or participants: Patients that need implant restorationsIntervention: One-time abutment during implant restorationsComparison: Repeated abutment during implant restorationsOutcome: Peri-implant tissue changes Randomised controlled trials (RCTs) and clinical controlled trials (CCTs) with a minimum of six-month duration of follow-up after abutment connection to implant bodyStudies that compared peri-implant tissue changes in subjects with one-time abutment and subjects with repeated abutmentImplant systems with the characteristics of internal connection and platform switchingParticipants are ≥ 18 years of age and without chronic periodontitis and history of systemic diseasein vitro studyCase report, conference proceedings, reviews, animal studies and Implant systems with the characteristics of external connectionDuplicate publicationA comprehensive electronic search was conducted in the following electronic databases: Web of Science, Pubmed and Embase . The following search terms were used in Pubmed and change depending on the rules of each database: OR  OR  OR  OR  OR ) OR  OR  OR  OR  OR  OR )#1 AND #2in vitro studies. Discrepancies were resolved by discussion between the reviewers. Only RCTs and CCTs that compared one-time abutment with repeated abutment and reported data on peri-implant tissue changes with a follow-up period of at least six months were selected and formed the base of this systematic review. The flow diagram was made using Review Manager Software according to the process of study selection : year of publication, study design, implant surface, single- or multicentre study, number of implants, patient age, follow-up, antibiotic prophylaxis, use of mouth rinse, time from implant surgery to final restorations, implants sites, the relationship between the implant platform and the crest bone, stage of implant surgery, implant system, implant design, abutment manipulation, type of final prosthodontic retention, primary and secondary outcome, and main conclusions.The outcomes in the meta-analyses are as follows:Vertical peri-implant bone changes: Difference in vertical distance between implant platform level and the most coronal bone contacting with implant surface (mm). Vertical peri-implant bone level was recorded as average value in medial and distal site and measured using periapical radiographs with parallelization system and under standard calibration.Peri-implant soft tissue changes: Difference in vertical distance between peri-implant highest buccal mucosa margin in maxillary or lowest buccal mucosa margin in mandible to the most coronal part of the prosthesis  (mm).Probing depth: Difference in probing depth (mm)Postsurgical complications: Difference in occurrence of pain, swelling, mucositis after surgery, or sensory disturbance2) and the pooled data of outcome (as rhomboid). Summary effects were calculated in both random- and fixed-effect models using Review Manager 5.3. The time points of bone changes and complications were from implant surgery, whereas the peri-implant soft tissue shifts and probing depth changes were from loading after mucosal detumescence. The plus sign represents bone growth or coronal soft tissue shifts, whereas the minus sign indicates bone resorption or apical soft tissue shifts. The outcomes of vertical bone changes were divided into subgroups according to their respective follow-up periods. Meta-analyses were performed when the included studies reported the same outcome measurements with the similar follow-up periods.Dichotomous data were expressed as risk ratios (RRs) with 95% confidence interval (CI). Continuous data were expressed as standardised mean difference (SMD) with 95% CI. Forest plots for each meta-analysis presented the original data of outcomes (displayed as blocks) with their respective CIs (displayed as lines), heterogeneity statistic  selection bias refers to sequence generation and allocation concealment; 2) performance and detection bias refer to blinding of participants and outcome assessors; 3) attrition bias refers to incomplete outcome data; 4) reporting bias refers to selective report of outcome.The main outcomes were presented in tables and figures. Supporting information including consort checklist, PRISMA checklist and data availability checklist was presented from vitro studies[The study selection process is summarised in o studies, 40, oneo studies and 11 wo studies, 41–50. o studies reportedo studies did not o studies–28 were The detailed information of the eight eligible clinical trials is listed in A total of 197 implants were placed in the one-time abutment group, whereas 214 implants were included in the repeated abutment group. Among eight eligible studies, seven studies were RCTs, 24–28anStraumann Bone Level ; Camlog, Conelog Screw-Line ; JDEvolution, JdentalCare ; Global Implants  and Ankylos . All implants are with an internal implant–abutment connection and platform switching. Information regarding the length, diameter and shape of the implants were also provided. One study[The implant systems included One study evaluateOne study, 26, 28,One study, 27. FouOne study, 26, 28,One study, 22, 25,One study, 25, 27 One study, 26, 28.One study, 25, 28,One study, 26, thrOne study, 22, 27.Each trial was assessed for risks of bias, and the results are summarised in Six out of eight papers selected in this review can be pooled for meta-analysis. One study reported vertical bone change that was measured from implant platform level to the crest of peri-implant bone, rather than to the most coronal bone contacting with implant surface. AnotherThe results of fixed- and random-effect models are presented in Figs The meta-analysis of peri-implant soft tissue shift was demonstrated in The meta-analysis of probing depth is illustrated in The meta-analysis of postsurgical complications is demonstrated in vs non-platform-switched implants with internal connection. The implants with a platform-switched design show less peri-implant bone resorption during the healing process than non-platform-switched implants[An experimental study in a dog model demonstrated that the disconnection and reconnection of healing/provisional abutments can compromise the mucosal barrier and induce an apical migration of the connective attachment and remodelling of the underlying bone. Abutment manipulation resulted in a mechanical injury to the soft tissue barrier that had to re-establish more apically, causing a marginal bone resorption. However, the implant used was Brӓnemark system with an external implant–abutment connection and non-platform switching. This im implants. However implants. Another implants. However implants. TherefoOur meta-analysis revealed that one-time abutment resulted in less vertical peri-implant bone resorption and soft tissue changes compared with repeated abutment. The microgap between implant and abutment interface is the main negative outcome for crestal bone resorption. The microgap between implant and abutment may lead to micromotion and bacterial leakage, resulting in tissue inflammatory infiltration. This phenomenon can result in increased peri-implant bone resorption and the disruption of peri-implant soft tissue attachments, 36. In For vertical bone resorption, our meta-analysis revealed that one-time abutment resulted in significantly less vertical bone and soft tissue changes, but the difference is of slight clinical significance. The reason for the slight difference may be that the tissue change around the implant is a very complex process, and the abutment manipulation is not the only factor to affect the change. Similarly, platform switched implant shows less bone resorption compared to non-platform switched implant, but the difference is also not obvious, and two type of implant system are both proved successful in clinics, 52. In For probing depth, no significant difference between one-time and repeated abutment was observed. The reasons for similar probing depth may be due to absence of peri-implantitis occurring in follow-up time, and in all the included studies, the implant systems were similar with a platform-switching; thus, they may have similar BW. The BW remains stable for both one-time and repeated abutment protocols. Although our analysis revealed that one-time abutment resulted in less bone resorption than repeated abutment, the difference of resorption may be insignificant to cause significant difference in probing depth.For postsurgical complications, no significant difference between one-time and repeated abutment was observed. The occurrence of pain, swelling and mucositis was associated with surgical procedures and postsurgical care rather than disconnection and reconnection of abutment. All the included studies reported similar implant surgery procedures and postsurgical care.Significant heterogeneity was detected among individual studies in meta-analyses on peri-implant vertical bone resorption and soft tissue shifts. The presence of statistical heterogeneity may be due to the low power of statistical test because only few studies were included in the aforementioned meta-analyses. Therefore, selecting to use either fixed- or random-effect model should not be based on the tests of heterogeneity, and results from both fixed- and random-effect model analyses are presented. Of note, both fixed- and random-effect models were consistent in their statistical inferences.via cements or screws. Some studies reported that the retention type had no influence on peri-implant tissue[Given the limited number of eligible studies, meta-regression analyses were not conducted to address some important confounding factors, including implant level, implant sites and prosthodontics retention type, associated with outcomes. Implant levels can be under crestal bone or at bone level. Some studies reported that implant levels at crestal bone may lead to marginal bone loss, 54, whent tissue, 61, whent tissue.Our meta-analysis revealed that the implant restoration protocol using one-time abutment is superior to repeated abutment for platform-switched implant in terms of less bone resorption and soft tissue shifts. However, the clinical use must be prudent. Future randomised clinical trials should be conducted to compare the outcomes of one-time abutment and repeated abutment to further confirm these findings.S1 Table(DOCX)Click here for additional data file.S2 Table(DOC)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.


Objective: Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders in children and affects 3 to 5% of school-aged children. This study is to demonstrate whether functional near-infrared spectroscopy (fNIRS) can detect the changes in the concentration of oxygenated hemoglobin (oxy-HB) in children with ADHD and typically developing children (TD children).Method: In this study, 14 children with ADHD and 15 TD children were studied. Metabolic signals of functional blood oxygen were recorded by using fNIRS during go/no-go task. A statistic method is used to compare the fNIRS between the ADHD children and controls.Results: A significant oxy-HB increase in the left frontopolar cortex (FPC) in control subjects but not in children with ADHD during inhibitory tasks. Moreover, ADHD children showed reduced activation in left FPC relative to TD children.Conclusion: Functional brain imaging using fNIRS showed reduced activation in the left prefrontal cortex (PFC) of children with ADHD during the inhibition task. The fNIRS could be a promising tool for differentiating children with ADHD and TD children. Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders in children and affects 3 to 5%of school-aged children. The ADHD is mainly characterized by age-inappropriate symptoms of hyperactivity, inattentiveness, and impulsivity  inhibition of an initial pre-potent response, (2) stopping of an ongoing response or delayed responding, and (3) limiting interference or distractibility during delay periods Barkley, . Go/no-gFunctional near-infrared spectroscopy (fNIRS) can measures changes in concentrations of oxygenated, deoxygenated, and total hemoglobin  in brain hemodynamics by measuring the absorption of near-infrared light  projected through the scalp  between children with ADHD and matched typically developing children (TD children). Children with ADHD showed diminished PFC activation compared with TD children. However, the localization of inhibitory-associated activation within the frontal cortex is inconsistent among previous studies that employed fNIRS and go/no-go task. Monden  was recorded in the PFC by using a continuous multichannel fNIRS instrument  that worked with two different wavelengths of near-infrared light (695 and 830 nm). We utilized a probe set containing 17 sources and 16 detectors to obtain 52 fNIRS measurement channels Figure . The fNITo analyze fNIRS data, we focused on the oxy-HB signal because of its higher sensitivity to changes in cerebral blood flow than that of deoxy-HB and total-HB , 48, 49  in control subjects. These channels were located in the left frontopolar cortex (FPC). But we didn't find any channels exhibited a significant oxy-HB increase in ADHD subjects.We screened for any fNIRS channels involved in the go/no-go task for control and ADHD contrasts. We found a significant oxy-HB increase in the left CH 37. We obtained the following findings: First, activation foci (left FPC) were activated in TD children who performed a go/no-go task only. Second, relative to control subjects, children with ADHD exhibited reduced brain activation in the left FPC during go/no-go task blocks. Hence, left PFC activation could be an objective neuro-functional biomarker to distinguish children with ADHD and TD children. fNIRS-based examination on ADHD assisted diagnosis is applicable to children at elementary school ages, including those as young as 6 years old. Therefore, fNIRS-based examination is a promising clinical tool for early diagnosis of patients with ADHD.This study was carried out in accordance with the recommendations of the Ethics Committee of Capital Institute of Pediatrics with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the Ethics Committee of Capital Institute of Pediatrics.SM: Experimental design, data collection, paper writing. JH and YG: Test task writing, data processing. XW, WS, DL and ZL: Data collection. JY and XL: Experimental design, Project implementation management.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Two of these genes, cryptochrome (cry) and Pigment-dispersing-factor (Pdf) are integral to the function of biological clocks. Pdf plays a crucial role in maintaining free-running circadian periods. The cry gene alters blue-light (<420 nm) phototransduction which affects biological clocks, spatial orientation and taxis relative to gravity, magnetic fields, solar, lunar, and celestial radiation in several species. The cry gene is involved in phase resetting (entrainment) of the circadian clock by blue light (<420 nm).Several genes have been shown to alter geotaxis in Geotaxis involves spatial orientation, so it might be expected that geotaxis is linked genetically with other forms of spatial orientation. The association between geotaxis and biological clocks is less intuitive. The data and the literature presented here show that genes, physiology and behavioural aspects of geotaxis, biological clocks, magnetosensitivity and other types of spatial orientation, are complex, intriguing and interrelated. Drosophila melanogaster used in this study have been selected for positive and negative geotaxis since 1958 .For comparison, the geotaxis scores Hirsch obtained from his wild-type, parent population , before selection of the www.trikenetics.com), was used to record motor activity. Individual activity chambers were 5mm x 65mm glass tubes clipped between infrared emitter-detector pairs. A fly passing the detector at the mid-point of the tube broke the infrared beam and the time of activity was recorded in a computer file.Flies were collected as late-stage pupae from stock vials following lights-on of a 12L:12D cycle. A Drosophila Activity Monitoring System (DAMS), obtained from Trikenetics Inc.  at the first scheduled lights-out of the 12L:12D cycle following their collection.Activity counts were collected in six minute data bins (240 bins or data points/day) and stored in computer files for analysis. Records of the two days following the first activity record, which signalled eclosion of each fly, were discarded and the following ten days  were used to determine each fly’s tau. Individual tau lengths and confidence levels were determined by Chi-square Periodogram Analysis 17. The tLo and Hi5 strains. Chi Square Periodogram confidence levels were used only to validate individual tau reliability for inclusion in data sets. One-way ANOVA for unequal sample size was used to test the hypothesis of difference between Lo and Hi5 tau distributions.Statistical tau determinations with p >0.01 were considered marginally unreliable and excluded from the data sets used to test for geotaxis strain difference. Chi Square Periodogram confidence levels were not used to test the hypothesis of difference between tau scores of the tau distributions of the Lo and Hi5 strains in constant dark conditions. The Lo strain exhibited significantly longer tau  than the Hi5 strain , . Standard deviations of Lo and Hi5 tau were not significantly different .Figure Ore-R) geotaxis response to that of flies selected for positive and negative geotropism. The wild-type Ore-R flies have little up-down preference in the maze. The difference in free-running, circadian, activity-periods of Lo and Hi5 geotaxis strains , flies do not. The circadian clock of wild-type D. melanogaster is slowed (longer tau) in constant magnetic fields, in a dose dependent manner, but only in blue light and with a functional cry gene. Mutants with a hypomorphic cryptochrome allele (bcry) do not show this response to magnetic fields, whereas the clocks of mutants that over-express CRY, exhibit a greater than wild-type geotaxis response [cry-dependent magnetosensitivity does not require a functioning circadian clock, but it does require a functional cry gene [Wild-type response . Interescry gene .cry’s functional requirement for blue light (<420nm) in phase shifting circadian clocks and in altering spatial orientation and taxis in several species relative to gravity, magnetic fields, solar, lunar, and celestial radiation [22adiation 2223 makeRitz et al. 22 and WiThe literature and the data presented here suggest that genes, physiology and behavioural aspects of geotaxis, circadian clocks, magnetosensitivity and spatial orientation are complex, intriguing and interrelated. Thiessen refers to behavior as a pleiotropic reflection of physiological processes. ‘Gene influence on behavior is always indirect’ , p.87. DThe author declares that they have no competing interests.


Epigenetic drugs are chemical compounds that target disordered post-translational modification of histone proteins and DNA through enzymes, and the recognition of these changes by adaptor proteins. Epigenetic drug-related experimental data such as gene expression probed by high-throughput sequencing, co-crystal structure probed by X-RAY diffraction and binding constants probed by bio-assay have become widely available. The mining and integration of multiple kinds of data can be beneficial to drug discovery and drug repurposing. HEMD and other epigenetic databases store comprehensively epigenetic data where users can acquire segmental information of epigenetic drugs. However, some data types such as high-throughput datasets are not provide by these databases and they do not support flexible queries for epigenetic drug-related experimental data. Therefore, in reference to HEMD and other epigenetic databases, we developed a relatively comprehensive database for human epigenetic drugs. The human epigenetic drug database (HEDD) focuses on the storage and integration of epigenetic drug datasets obtained from laboratory experiments and manually curated information. The latest release of HEDD incorporates five kinds of datasets: (i) drug, (ii) target, (iii) disease, (vi) high-throughput and (v) complex. In order to facilitate data extraction, flexible search options were built in HEDD, which allowed an unlimited condition query for specific kinds of datasets using drug names, diseases and experiment types.Database URL:http://hedds.org/ Eukaryotic DNA is packaged into chromatin, which incorporate repeating nucleosomes by wrapping 1.67 turns around a histone octamer that comprise of two molecules each of the common histones H2A, H2B, H3 and H4 . EpigeneIn the past decades, epigenetics has emerged as a novel and important research area in drug discovery, which includes most of the human pathology in which deregulation in gene expression is observed . HistoriWith the advancement of epigenetic drug researches, laboratories and researchers around the world have profiled a mass of epigenetic drug data . As shown in It is useful to have a repository of these data. This would boost calls for the comprehensive collection and systemization of epigenetic drug-related experimental data in in-depth data mining. There have been few resources for drugs or chemical compounds such as ChEMBL , PubChemhttp://www.hedds.org. HEDD focuses on the storage and integration of epigenetic drug information obtained from experimental data. The latest release of HEDD provides five kinds of datasets: (i) drug, (ii) target, (iii) disease, (vi) high-throughput and (v) complex. HEDD incorporates a set of tools for querying and browsing different datasets. Furthermore, schematism was adopted to interpret the structure of drug, drug-target complex and the interaction within the binding pocket. By integrating the Jmol Project (https://sourceforge.net/projects/jmol), HEDD provids a visual function to display the 3D structure of epigenetic drugs and the drug-target complex. HEDD may be a useful resource for a variety of biologists, primarily bench scientists, who look for new convenient resources of epigenetic drugs. Moreover, information relating to HEDD is also meritorious for computational biologists for in silico approaches, in order to advance epigenetic drugs, mine the epigenetic-relevant chemical space, uncover the structure activity relationship (SAR), and assist computer-aided drug design (CADD).In reference to HEMD and other epigenetic databases, we developed the human epigenetic drug database (HEDD), which is available at HEDD was designed to store epigenetic drugs information for Homo species, which was created at 9/2016. The current version of HEDD consists of 64 epigenetic drugs collected from public drug resources: PubChem Compound, DrugBank and ZINC . RelatedBefore being finally stored, epigenetic drugs and related annotation information and experimental data were converted into five kinds of datasets in HEDD: (i) drug, (ii) target, (iii) disease, (vi) high-throughput and (v) complex. These 64 durg datasets provide the basic information and structure of epigentic drugs. Furthermore, the 1606 target datasets quantitatively describe the inhibitor action of epigenetic drugs to a specific target with four kinds of binding constants . In addition, the 571 disease datasets describe the application of epigenetic drugs for treating diseases. According to the period of research state, disease datasets are classified as follows: approved, in clinical trials, and preclinical. The 276 high-throughput datasets were probed from arrays, sequencing and RT-PCR to measure gene expression, SNP, genome binding/occupancy profiling and DNA melatyation profiles with the single or combination treatment of epigenetic drugs for Homo species. Furthermore, 57 complex datasets describe the co-crystal structure of the drug-target complex for epigenetic drugs using X-RAY diffraction or NMR.https://chemapps.stolaf.edu/jmol/jmol.php); and structure and high-throughput data can be downloaded for further locally analysis.Flexible query options and dataset list browsers are provided for the acquisition and investigation of epigenetic drugs and related datasets of interest . Users can specify the query options such as drug name and disease to acquire the specific dataset according to their own needs. They can also fast browse the dataset list according to dataset categories. The dataset pages provides information and experimental data of an epigenetic drug. Moreover, the structure of the drug and drug–target complex can be viewed through visualization modules based on the Jmol.php , status (completed or terminated), NCT number  and phases. Links to the clinical trials database, ClinicalTrials.gov , are avaHEDD supports flexible queries for various epigenetic drugs and related datasets by providing the five search options , as shown in DISEASE search is a module to display the application of epigenetic drugs in clinic. The user can separately or jointly use the drug name pull-down menu and the disease textbox to execute the disease search process. Using ‘suberoylanilide hydroxamic acid’ and ‘breast cancer’ as inputs, a report of five dataset summaries will be returned. TARGET search and COMPLEX search are two modules to study mechanistic details on the inhibitor action of epigenetic drugs. TARGET search focuses on quantitative descriptions and COMPLEX search focuses on explaining the interaction of spatial structures. Users can separately or jointly use the drug name pull-down menu and target textbox to execute the target search and complex search processes. Using ‘suberoylanilide hydroxamic acid’ and ‘histone deacetylase 8’ as inputs, results of the TARGET search and COMPLEX search would contain 62 and 4 datasets, respectively. HIGH-THROUGHPUT search is a specific module dedicated to study application of high-throughput experiments in epigenetic drugs researches. Users who are interested in gene expression, DNA methylation and histone modification pattern variations with treatment of epigenetic drugs for Homo species may find this module helpful. For instance, users interested in DNA methylation can select ‘5-Azacytidine’ or other options from the pull-down menu ‘Methylation profiling by array’, with others as default. In this case, a report of three high-throughput datasets annotated with 5-Azacytidine and DNA methylation summaries will be returned.et al.  was used for the 3D visual function. HEDD allows users to access all of the key features of the web application through their mobile device. FireFox explorer is recommended for using HEDD.HEDD was developed using J2EE. Browser-based interfaces were built using JSP and Eclipse (Mars). HEDD is running on an Apache Tomcat web server (version 8.0) and a MySQL relational database (version 5.0). The server operating system is windows 2008 server R2 enterprise. in silico approaches would be recorded into HEDD, such as molecular docking, virtual screening, pharmacophore modeling, molecular dynamics and similarity searching. As a resource to study the potential roles of epigenetic drugs in remodeling epigenetic modification, HEDD could be extended with utilities for the identification and confirmation of targets (genes and pathways) related to epigenetic drugs from large-scale high-throughput data (such as gene expression)  , 43. Sin


This study aims to provide an overview of different treatment for advanced gastric cancer. In the present study, we systematically reviewed the major findings from relevant meta-analyses. A total of 54 relevant papers were searched via the PubMed, Web of Science, and Google scholar databases. They were classified according to the mainstay treatment modalities such as surgery, chemotherapy and others. Primary outcomes including overall survival, response rate, disease-free survival, recurrence-free survival, progression-free survival, time-to-progression, time-to failure, recurrence and safety were summarized. The recommendations and uncertainties regarding the treatment of advanced gastric cancer were also proposed. It was suggested that laparoscopic gastrectomy was a safe and technical alternative to open gastrectomy. Besides, neoadjuvant chemotherapy and adjuvant chemotherapy were thought to benefit the survival over surgery alone. And it was demonstrated in the study that targeted therapy like anti-angiogenic and anti-HER2 agents but anti-EGFR agent might have a significant survival benefit. In global, about 952,000 cases of gastric cancer (GC) are newly diagnosed every year. As the third-leading cause of cancer related mortality, GC accounts for 841 000 deaths in 2013 globally . Thus, mOverall, 239 papers were identified. Among them, 54 meta-analysis papers were finally included -60 Figu. The chaversus OG . Three of them came to the conclusion that the combination therapy was superior to single or doublet therapy in terms of OS [There were four meta-analyses to compare the outcomes of combination therapy, which included doublet and triplet therapy Only RCT studies, rather than non-RCTs were included in the four meta-analyses.n = 13) followed by the meta-analyses by Liu (n = 12), Wagner 2006 (n = 11) and Zhang (n = 10)  . NotablyGiven its superiority in the quantity of RCT studies, the results of the meta-analysis by Wagner 2010 might be more reliable. In details, combination chemotherapy improved survival compared to single-agent therapy. However, toxicity was higher in combination chemotherapy. In addition, the meta-analysis of Zhang indicated that no significant survival benefits were observed in doublet cytotoxic chemotherapy regimens while the addition of targeted agent to mono-chemotherapy as salvage treatment for pretreated AGC patients had substantial survival benefits.versus without cisplatin. Both of them favored three-drug combination therapy. Other outcomes were not evaluated between the two groups [Two meta-analyses compared the outcomes of FU/anthracycline-containing therapy with o groups , 59.Only RCTs studies, rather than non-RCTs were included in the two meta-analyses.n = 7)  . Thus thvs. without anthracyclines. Both of them favor three-drug combination therapy. Other outcomes were not evaluated between the two groups [Two meta-analyses evaluated the outcomes of FU/cisplatin-containing regimens with o groups , 59.Only RCT studies, rather than non-RCTs were included in the two meta-analyses.n = 3)  . The incOne meta-analysis focused on the efficacy of docetaxel-containing regimens. According to the study, Docetaxel containing therapy seemed not to be associated with significant better OS, objective RR and TTP compared to non-docetaxel based therapy. Besides, there were also no significant differences in treatment related death or treatment discontinuation due to toxicity between two groups .Lentinan containing chemotherapy was evaluated in one meta-analysis. OS was enhanced by the use of the lentinan combination therapy . Other oOne meta-analysis compared EPIPC with early postoperative intravenous chemotherapy. EPIPC was associated with better 1-, 2-, 3-, and 5-year survival rate compared to early postoperative intravenous chemotherapy. Besides, 2- and 3-year intra-abdominal recurrence was significantly reduced by the use of early postoperative intravenous chemotherapy. Significant lower incidence of nausea and vomiting were observed in EPIPC group. Additionally, EPIPC was superior to intravenous chemotherapy in terms of liver and renal protection .versus chemotherapy alone [Two meta-analyses compared the outcomes of SQFZ injection combined with chemotherapy py alone , 25. Onlpy alone . The othOnly RCT studies, rather than non-RCTs were included in the meta-analysis by Li while the information regarding RCT studies was not available in the meta-analysis by Yao.n = 15) followed by the meta-analysis by Li (n = 13)  . NotablyGiven its superiority in the quantity of RCT studies, the results of the meta-analysis by Li might be more reliable. In details, SQFZ injection combined with chemotherapy could improve the clinical efficacy and performance status in patients with AGC.versus chemotherapy alone. There was no significant difference in 1-year OS between two groups. Besides, Huachasu plus chemotherapy was favorable over chemotherapy alone in term of total RR, KPS, gastrointestinal side effects, and leucocytopenia [Only one meta-analysis evaluated the efficacy of Huachasu plus chemotherapy ytopenia .versus cisplatin regimen alone. Quality of life and clinical efficacy were favorable for compound matrine injection combined with cisplatin therapy over cisplatin therapy alone. Additionally, compound matrine injection plus cisplatin therapy was associated with significantly lower incidence of leukopenia, thrombocytopenia, and gaastrointestinal AEs compared to cisplatin therapy alone [One meta-anaysis compared the outcomes between compound matrine injection plus cisplatin regimen py alone .One meta-analysis evaluated the efficacy of KLT combined with chemotherapy regimen. KLT significantly improved 1-year OS compared to chemotherapy alone. KLT plus chemotherapy was associated with better quality of life and clinical efficacy compared with chemotherapy alone according to the results. Besides, KLT combined with chemotherapy regimen was superior to chemotherapy alone in terms of liver protection, incidence of cachexia and AEs .The treatment for AGC include surgery gasterectomy, perioperative chemotherapy with or without chemoradiation, palliative chemotherapy, targeted therapy BSC and other.Surgery remains the most important component of curative therapy . AccordiWe recognize that the present review has some limitations. First, not all the related survival and clinical data were evaluated in every meta-analysis. As a result, made it difficult to compare directly between meta-analyses. Second, the accuracy of the findings in every meta-analysis could not be guaranteed since it was not possible for us to repeat every meta-analysis and the heterogeneity among included studies in every meta-analysis were not considered. Third, there was overlap of the original studies in each meta-analysis; and we arbitrarily evaluated the reliability of meta-analysis according to the quality and quantity of the included meta-analysis. Fourth, conversion therapy, immune therapy and radiation therapy were not discussed in the present study.grade of recommendation: moderate).LG is a safe and technical alternative to OG for AGC patients with a lower complication rate and enhanced postoperative recovery (grade of recommendation: high).NAC can improve the tumor resection rate and the survival rate in AGC patients without increasing the operative risk and perioperative mortality (grade of recommendation: high).Postoperative chemotherapy can improve OS after radical surgery for gastric cancer (grade of recommendation: high).IPC has positive effect on overall and peritoneal recurrence and distant metastasis. Besides, loco-regional lymph-nodes invasion in patients affected by AGC is not a contraindication to IPC (grade of recommendation: low).Palliative gastrectomy for patients with incurable AGC was associated with longer OS, especially for patients with stage M1 gastric cancer (grade of recommendation: low).Palliative gastrectomy combined with hepatectomy might provide better OS than palliative gastrectomy only (grade of recommendation: high).Avoiding the use of abdominal drains might reduce drain-related complications and shortened hospital stay after gastrectomy (grade of recommendation: high).Chemotherapy significantly improved survival in comparison to BSC (grade of recommendation: high).S-1-based regimens are effective and tolerable as first-line treatment of AGC in both Asian and Western countries though the toxicity profile of S-1 was clearly more advantageous in Western patients (grade of recommendation: high).S-1 and capecitabine could be used interchangeably for AGC, at least in Asia (grade of recommendation: high).S-1 combination therapy was more efficacious than S-1 monotherapy though AEs was higher and safety profile was poorer in S-1 combination therapy (grade of recommendation: moderate).Oxaliplatin-based therapy was associated with a small but significant survival benefit with less toxicity and better tolerability (grade of recommendation: high).CPT-11-containing regimen had survival benefit as first-line treatment for AGC patients (grade of recommendation: high).New-generation agent such as S-1, taxanes and irinotecan seemed to be valid options for patients with inoperable AGC as first-line chemotherapy (grade of recommendation: high).Replacing cisplatin with oxaliplatin, CPT-11, or taxane significantly enhanced OS, RR and PFS compared with cisplatin-based combination chemotherapy (grade of recommendation: high).Targeted therapy may have a significant survival benefit, which could be ascribed to anti-angiogenic and anti-HER2 agents (grade of recommendation: high).Combination chemotherapy may improve survival compared to single-agent therapy at a price of higher toxicity (rade of recommendation: high).Better survival results should be achieved in FU, anthracycline and cisplatin combination therapy no matter comparing to FU/anthracycline doublet regimens FU/or FU/cisplatin doublet regimens (grade of recommendation: high).The addition of lentinan to standard chemotherapy may offer a significant advantage over chemotherapy alone in terms of survival (grade of recommendation: high).EPIPC may improve survival rate and reduce both recurrence rate and side effects (grade of recommendation: high).SQFZ injection combined with chemotherapy could improve the clinical efficacy and performance status in patients with AGC (grade of recommendation: high).Huchansu combined with chemotherapy provides benefits for AGC on improving the response rate, increasing Karnofsky score, reducing leucocytopenia and major side effects (grade of recommendation: high).Compound matrine injection combined with cisplatin chemotherapy can improve the quality of life with lower AEs  All meta-analyses regarding the treatment of AGC. 2) Duplicate publications. 3) Only abstract available. 4) Meeting abstracts. 5) Only systematic reviews without meta-analyses. 6) Patients without AGC. 7) Other topics, but not treatment modalities.Primary outcomes were OS, RR, DFS, RFS, PFS TTP, TTF and other endpoints.As the results were different among the meta-analyses, the reliability was evaluated according to the quality and quantity of original studies included in every meta-analysis. First, the results of a meta-analysis would be more reliable if a larger number of RCTs were included. And if the larger number of patients were included in the RCTs, the results of a meta-analysis would be more reliable. Second, the number of non-RCT studies was further evaluated if the number of RCTs and patients were similar. Third, if the number of RCTs and non-RCT studies included was similar but the results were not consistent among meta-analyses, the total number of the included patients and statistical methods would be further evaluated. If the hazard ratio was calculated, the results of a meta-analysis would be more reliable.Grade of recommendation was determined in the way that was suggested by a previous study . High gr


Subjective dental fear improved clinically significantly in about one fourth (25.6%) of therapy completers. All post-treatment effects remained stable over time. Concerning the behavioral fear dimension, we observed a strong ceiling effect. Already at pre-assessment, participants accomplished more than six out of seven BAT-steps. Thus, behavioral approach did not increase significantly following treatment. Overall, the LG-OST protocol proved feasible and efficient. Compared to other one-session individual and multi-session group treatments the observed LG-OST effects were smaller. However, if LG-OST could match the efficacy of highly intensive short treatments delivered in an individual setting in the future, for example, by applying a wider array of exposure exercises, it could be a very useful treatment option as an intermediate step within a stepped care approach.A large-group one session treatment (LG-OST) combining exposure and diaphragmatic breathing as a bodily coping element was carried out to investigate its feasibility and effectiveness in a sample of 43 highly dental fearful individuals treated simultaneously. We assessed subjective dental fear, dysfunctional dental-related beliefs, and perceived control pre- and post-intervention and at four-month follow-up. Participants additionally performed a behavioural approach test (BAT) pre- and post-intervention. During the applied exposure exercises, four participants (9.3%) discontinued the program all reporting too high levels of distress. Regarding subjective dental fear and dysfunctional dental related beliefs post treatment effects, LG-OST showed medium to large effect sizes, ranging from Cohen’s  Specific Phobias (SP) are proven to be of high health-economic relevance, although they are widely considered to be less restrictive than other mental disorders. With a 12-month prevalence rate between seven and nine percent in Western countries , about 2Dental Phobia (DP) is among the most critical SPs in terms of both prevalence and impairment . About 2Considering the sheer number of afflicted individuals and limited number of clinical professionals, the existing health care system cannot provide sufficient treatment options for all. Therefore, more efficient treatment approaches that are short in time and minimize the patient to therapist ratio would represent a very useful treatment option; especially in those mental disorders that are comparably moderate and for which well-established treatment forms already exist, as both is the case in SP.in vivo and elements of participant modeling. However, cognitive and motivational aspects have been added through psychoeducative elements, skills training, reinforcement, and cognitive challenges  have been demonstrated to reduce SP-symptoms very effectively  did not significantly differ from effects in larger group conditions (n = 7–8). With the aim to significantly increase treatment efficiency, a recent study  in a sample of highly dental-fearful individuals.The present study aimed to investigate whether a LG-OST containing well evaluated exposure and coping strategies is feasible and effective in a sample of highly dental-fearful individuals. LG-OST evaluation contained subjective, cognitive and behavioral fear dimensions as well as dental-related control in order to investigate treatment efficacy on all levels afflicted by clinical dental fear as well as subjective therapy success. Following the concept of evidence-based psychotherapy , the des1 were recruited via ‘Dental Clinic Bochum’; a dental clinic specialized in treating dental fearful individuals. There, during initial anamneses, dental fear is routinely screened using the ‘Hierarchischer Angstfragebogen’ . Associated univariate tests showed highly significant treatment effects in regard to both measures assessing subjective dental fear . The same was true for dysfunctional beliefs . Furthermore they showed that participants’ predictions in regard to control (IDCI-R p) during dental surgery . However, some participants did not complete the DCQ correctly at pre assessment, which is why we only could apply data of 35 participants in the MANOVA. Therefore, in Table 1 we report the results of single ANOVAs with repeated measures conducted for each measure separately. In terms of p-levels there was only one difference between the MANOVA’s and the single ANOVAs’ results: the BAT changes following treatment did no longer reach the level of significance. In this context, it is worth noting that already at pre-assessment, participants accomplished more than six out of seven BAT-steps (see Table 1).MANOVA showed a highly significant main effect of time  and the associated univariate tests did not yield significant results. Single post hoc ANOVAs regarding the DAS,  and dysfunctional dental related thoughts , did not show significant changes from post to FU. The same was the case for predicted control (IDCI-R p) during dental surgery . However, the desire for control during dental surgery (IDCI-R d), which did not change significantly from pre to post, decreased significantly from post to FU . The ratings of therapy success from post to FU did not decrease significantly .To analyze the course of dental related symptoms within the post-FU interval, we conducted a MANOVA with repeated measures within LG-OST as also applied for the pre to post analyses . Dental-related dysfunctional beliefs decreased by 27.78% from pre to FU. Regarding control (R-IDCI), we found only a small increase of 8.68% in the predicted control and decrease of 4.50% in the desired control dimension.In this Phase I study, we investigated whether a OST approach combining coping with exposure is feasible and efficacious in a large group setting (LG-OST). To the best of our knowledge, dental fear treatment has not been delivered in an OST-group format so far. In terms of mere feasibility, the results were promising: participant inflow was good and the participants did not address us with concerns regarding the effectiveness of the treatment. Furthermore, we did not notice any signs of individual or even mass panic symptoms amongst participants during the large-group exposure exercises.In fact, we observed a marked reduction in subjective dental fear, dysfunctional beliefs and loss of dental-related control from pre to post in our LG-OST group. In about one third of the participants, subjective dental fear improved clinically significantly. Four participants discontinued the treatment abruptly during video exposure. However, the total number of patients, who received the intended dose of treatment, was considerably high compared to dropout rates of up to 45% reported for other exposure based dental fear treatments  group treatments of dental fear as conducted by In sum, our results corroborate to the suggestion that an LG-OST protocol might sufficiently address the needs for fear treatment of some but not all participants. Therefore, due to its high efficiency, lower costs and threshold of access compared to individual treatment, the LG-OST protocol might be useful as an intermediate step within a future framework of stepped care for phobic fears. So far, there have been some promising efforts to implement stepped care in the field of anxiety disorders, for example, in the treatment of panic or generalized anxiety (GAS); it has been proven that for some patients minimal CBT interventions can be as effective as standard interventions , was relatively small. As mentioned, we attempted to minimize participants’ doubts to participate in a large group training by guaranteeing anonymity. Therefore, in turn, participants were required to actively waive anonymity to be contacted and scheduled for a follow up appointment. However, we presented data suggesting that dropout was random or non-systematic and that the reported FU-effects can be considered suitable indicators of long-term effects of LG-OST. Finally, we did not measure subjective distress during the BAT, which prevented the depiction of subjective changes in fear perception during the behavioral assessment.Due to the very high efficiency and general effectiveness of our large-group treatment combining coping with exposure, it is worthwhile to think about how to maximize the potential benefits. We applied a breathing technique as the sole coping strategy, thereby only focusing on bodily fear responses. However, it might have been useful to offer some positive self-verbalizations such as used by A large-group OST, combining coping with exposure elements proved feasible in highly dental-fearful participants. However, studies investigating the effects of small-group multiple-session treatments or one-session single-treatments on subjective dental reported larger effects than we found in LG-OST.However, if LG-OST could match the efficacy of highly intensive short treatments delivered in a single setting, for example, by applying a wider array of coping strategies or exposure exercises, LG-OST could be a very useful treatment option due to its exceptional efficiency.This study was approved by Local Ethics Committee of the psychology faculty of the Ruhr-University Bochum. We used informed consent.Conceived and designed the study: AW, JM, H-PJ, AB, JB, MM, and MV; Analyzed the data: AW; Wrote the paper: AW and SS.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


To see the early post-operative outcomes of off-pump versus on-pump coronary artery bypass graft surgery.This retrospective analytical study was conducted at Ch. Pervaiz Elahi Institute of Cardiology Multan, Pakistan. Our Primary outcome variables were; necessity of inotropic support, nonfatal myocardial infarction, ICU stay, nonfatal stroke, new renal failure requiring dialysis and death within 30 days after operation. There were two groups of patients; Group-I (On-pump group) and Group-II (Off-pump Group). SPSS V17 was used for data analysis. Independent sample t-test and Mann Whitney U test were used to compare quantitative Variables. Chi-square test and Fisher’s exact test were used to analyze qualitative variables. P-value ≤ 0.05 was considered significant.Three hundred patients were included in this study. There were no significant difference regarding risk factors except hyper-cholestrolemia which was high in off pump group . Angiographic and Echocardiographic characteristics e.g. preoperative ejection fraction, LV function grade and severity of CAD was same between the groups. Mortality risk scores and Priority status for surgery were also same. Regarding post-operative outcomes; Post-op CKMB Levels, need and duration of inotropic support, mechanical ventilation time and ICU stay was significantly less in Off-Pump group . Peri-operative chest drainage was significantly high in On-pump CABG group . Incidence of post-op complications was not statistically different between the groups.At 30 days follow-up, Incidence of myocardial infarction, necessity and duration of inotropic support, ICU stay period and peri-operative bleeding were significantly less in off-pump group. The incidence of neurologic, pulmonary and renal complications was same between the off-pump and on-pump groups. Coronary-artery bypass graft (CABG) surgery reduces mortality in patients with severe coronary artery disease.4In the mid-1990s, interest developed in performing Off-Pump CABG without the use of cardiopulmonary bypass, in order to reduce postoperative complications associated with the use of cardiopulmonary bypass,10Several previous trials have compared off-pump CABG with on-pump CABG.14So we conducted this study to compare the early outcomes of off pump versus on pump coronary artery bypass graft surgery to see whether off pump or on pump surgery is better in our center.It was a retrospective analytical study conducted at Ch. Pervaiz Elahi Institute of Cardiology Multan, Pakistan. The data of patients operated from January 2012 to December 2014 was retrieved from cardiac surgery database of the hospital. Patients having similar pre-operative characteristics were selected for study to minimize the effect of these on post-operative outcomes. Patients who were scheduled to undergo CABG were eligible to participate in this study if they required isolated CABG with median sternotomy.Patients having any clinically significant valvular disease , requiring immediate surgery, with small target vessels  or diffuse coronary artery disease were excluded from the study.Our primary outcomes were; necessity of inotropic support, nonfatal myocardial infarction, ICU stay, nonfatal stroke, new renal failure requiring dialysis and death within 30 days after operation. All deaths in these 30 days were considered to be the result of cardiovascular causes.All procedures were carried out through median sternotomy. For On-pump CABG surgeries, in all patients standard cardiopulmonary bypass (CPB) was established with an ascending aortic straight tip arterial cannula and a two stage single venous cannula in the right atrium. For on-pump procedures, aortic-cross clamp and cardioplegic arrest was applied in every patient. Cold blood cardioplegia was used to arrest the heart. The body temperature during surgery was maintained to about 28-32°C. For off-pump surgery, various stabilization devices were used to provide a motionless surgical field. Conversion from the assigned procedure to the other procedure was performed when clinically necessary.The necessity of inotropic support on weaning from cardiopulmonary bypass (CPB), and in Intensive Care Unit (ICU) was noted. Peak post-op CK-MB levels were noted twice after 6 & 24 hours of arrival of patient in ICU. Inotropic support was defined as mild if dobutamine was administrated at a rate <5 µg/kg/min, moderate (dobutamine 5-10 µg/kg/min) and high dose  and Pulmonary Embolism was recorded as pulmonary complication.SPSS Version 17 was used for data analysis. Independent sample t-test and Mann Whitney U test was used to compare quantitative Variables. Chi-square test and Fisher’s exact test (if appropriate) was used to analyzed qualitative variables. P-value ≤ 0.05 was considered significant.There was no significant difference regarding demographic characteristics of patients except BMI that was significantly high in patients of group I. Risk factors of Ischemic Heart Disease were same between the two groups. Similarly Angio-graphic, Echocardiographic, mortality risk scores and Priority status for surgery all were same between groups . No of gTrend of Off-pump CABG has been increasingly in use in Western countries since the early 1990s, when BenettiOff pump CABG has demonstrated decreased blood loss and need for transfusion, decreased length of stay, less myocardial enzyme leak, less inflammation, and less renal and neurologic impairment in addition to decreased cost.Our study supports the results of these studies as in our study, peri-operative chest drainage was significantly low in Off-Pump Group. We found significant difference regarding post-op CK-MB levels, need and duration of inotropic support, mechanical ventilation time and ICU stay time, all were high in on-pump CABG group. However we do not find any significant difference in immediate post-operative complications in both groups pulmonary and neurologic complications were a bit high in on-pump CABG group but this difference was not statistically significant. In our study, operative mortality was high in on-pump CABG group, there were two deaths in this group in a one month follow up in this group but there was no mortality in Off-pump CABG group.The results of our study revealed that off pump CABG is a safe and better option as regards to early extubation, respiratory complications and early recovery and a lower risk of short term mortality.At 30 days follow-up, Incidence of myocardial infarction, necessity and duration of inotropic support, ICU stay period and peri-operative bleeding were significantly less in off-pump group. And the incidence of neurologic, pulmonary and renal complications was same between the off-pump and on-pump groups.


Sleep plays important roles in sensory and motor memory consolidation. Sleep oscillations, reflecting neural population activity, involve the reactivation of learning-related neurons and regulate synaptic strength and, thereby affect memory consolidation. Among sleep oscillations, slow waves (0.5–4 Hz) are closely associated with memory consolidation. For example, slow-wave power is regulated in an experience-dependent manner and correlates with acquired memory. Furthermore, manipulating slow waves can enhance or impair memory consolidation. During slow wave sleep, inter-areal interactions between the cortex and hippocampus (HC) have been proposed to consolidate declarative memory; however, interactions for non-declarative (HC-independent) memory remain largely uninvestigated. We recently showed that the directional influence in a slow-wave range through a top-down cortical long-range circuit is involved in the consolidation of non-declarative memory. At the synaptic level, the average cortical synaptic strength is known to be potentiated during wakefulness and depressed during sleep. Moreover, learning causes plasticity in a subset of synapses, allocating memory to them. Sleep may help to differentiate synaptic strength between allocated and non-allocated synapses . Herein, we offer perspectives on inter-areal interactions and synaptic plasticity for memory consolidation during sleep. Neural oscillations during sleep support memory consolidation, which refers to post-learning processes whereby new memory transitions from a fragile to a stable form. The existence of the memory consolidation process has been verified by the transient susceptibility of memory to amnesic interventions including sleep-deprivation and drugs inactivating neural activity or preventing synaptic plasticity  frequency-dependent curve  in experience-related brain areas. In humans, tactile stimulation for 6 h in the right hand causes a local increase in slow-wave power in the left hemisphere , a leading hypothesis of synaptic plasticity through the sleep/wake cycle, states that the net synaptic strength increases during wakefulness and decreases during sleep , which is conventionally used for assessing baseline synaptic strength in many LTP/LTD studies  are causally linked to memory consolidation. In humans, visually acquired declarative memory is slow wave-dependent, while non-declarative motor memory is spindle-dependent  remain unclear. First, the activities of individual neurons or neural ensembles during slow waves that cause synaptic plasticity and memory consolidation remain unclear. Recent advances in all-optical imaging and manipulation of neural activity with cellular resolution (Rickgauer et al., This study was carried out in accordance with the recommendations of “the guidelines of RIKEN”. The protocol was approved by “the Animal Investigation Committee of the RIKEN BSI”.DM wrote the manuscript. DH performed experiments and analyzed data. MM supervised the project.The authors declare that this study received funding from the KAO corporation. The funder was not involved in the study design or collection, analysis, or interpretation of the data.


Health care-associated infections (HAI) have been shown to increase length of stay, the cost of care, and rates of hospital deaths :306–11, 2014; Roberts and Scott, Med Care 48(11):1026–35, 2010; Warren and Quadir, Crit Care Med 34(8):2084–9, 2006; Zimlichman and Henderson, JAMA Intern Med 173(22):2039–46, 2013). Importantly, infections acquired during a hospital stay have been shown to be preventable . In particular, due to more invasive procedures, mechanical ventilation, and critical illness, patients cared for in the intensive care unit (ICU) are at greater risk of HAI and associated poor outcomes. This meta-analysis aims to summarise the effectiveness of chlorhexidine (CHG) bathing, in adult intensive care patients, to reduce infection.Staphylococcus aureus (MRSA); vancomycin-resistant Enterococcus; and Clostridium difficile. Summary estimates were calculated as incidence rate ratios (IRRs) and 95% confidence/credible intervals. Variation in study designs was addressed using hierarchical Bayesian random-effects models.A systematic literature search was undertaken to identify trials assessing the effectiveness of CHG bathing to reduce risk of infection, among adult intensive care patients. Infections included were: bloodstream infections; central line-associated bloodstream infections (CLABSI); catheter-associated urinary tract infections; ventilator-associated pneumonia; methicillin-resistant Seventeen trials were included in our final analysis: seven of the studies were cluster-randomised crossover trials, and the remaining studies were before-and-after trials. CHG bathing was estimated to reduce the risk of CLABSI by 56% , 0.26, 0.75)), and MRSA colonisation and bacteraemia in the ICU by 41% and 36%, respectively ; and IRR = 0.64 ). The numbers needed to treat for these specific ICU infections ranged from 360 (CLABSI) to 2780 (MRSA bacteraemia).This meta-analysis of the effectiveness of CHG bathing to reduce infections among adults in the ICU has found evidence for the benefit of daily bathing with CHG to reduce CLABSI and MRSA infections. However, the effectiveness may be dependent on the underlying baseline risk of these events among the given ICU population. Therefore, CHG bathing appears to be of the most clinical benefit when infection rates are high for a given ICU population.The online version of this article (doi:10.1186/s13054-016-1553-5) contains supplementary material, which is available to authorized users. Health care-associated infections (HAI) have been shown to increase length of hospital stay, the cost of care, and rates of hospital deaths –4. ImporStaphylococcus aureus (MRSA); vancomycin-resistant Enterococcus (VRE); and Clostridium difficile (C-diff).The skin of patients is considered a major reservoir for pathogens associated with hospital-acquired infections , and hasThis meta-analysis was planned, undertaken, and reported using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines .A systematic literature search was undertaken of medical literature databases including MEDLINE, EMBASE, and Cochrane Library published up until March 2016. Keywords and title searches included a combination of: “Chlorhexidine”, “bath$”, “intensive care”, “prevention”, “infection$”, and “effectiveness”. Hand searching of the references of research papers was also undertaken until no new studies were identified.The eligibility for inclusion of research papers into in this meta-analysis was considered independently by two authors (SAF and M-CA). Only trials of the effectiveness to reduce infections in adult ICU patients were included. Review papers, non-adult populations, non-ICUs, and papers that did not report the rates per ICU-days at risk were excluded.Data extracted from each paper included: first authors’ names and publication year, country of study, duration of study, study site, study design  type of ICU setting , infection of interest, and number of events and ICU-days at risk.I2 statistic and p < 0.1 was chosen as evidence of statistical heterogeneity. Initial analysis identified the presence of statistical heterogeneity, and therefore summary estimates for fixed effects and random effects (RE) models are presented [Individual study and combined estimates of the effectiveness of CHG bathing to prevent infections (incidence rate ratios (IRRs)) are presented as forest plots . Heterogresented .p values to assess statistical significance; in a similar manner to the use of confidence intervals (CIs), credible intervals (CrIs) are used to identify the significance of results. For instance, an estimate of effect as a ratio (i.e. a relative risk) with a 95% CrI that does not include the null (1.0) is considered statistically significant. To assess the potential role of baseline risk for the observed heterogeneity between individual studies, a Bayesian meta-regression approach was also used [Because of the inclusion of both before-and-after and randomised-cluster crossover trials, summary estimates are also presented using the method suggested by Sutton and Abrams . This aplso used .In this approach, any regression estimates exhibiting a negative relationship between baseline risk and treatment effect are showing that treatment benefit increased when baseline risk of infection was higher among the given ICU population. Traditional meta-analysis models were developed using the R metafor and meta packages . BayesiaThe electronic search resulted in 114 potential papers to be included. Following review of the abstract, or the complete paper when required, 17 before-and-after or randomised-cluster crossover trials were included in our analysis. Reasons why papers were excluded from our final analysis were due to being them being review papers, not among adult ICU patients, and trials that included multiple interventions. Characteristics of the 17 studies are presented in Additional file Summary estimates of the effectiveness CHG bathing to reduce infections among adult ICU patients are presented in Table Daily bathing with CHG was estimated to reduce BSI in the ICU by approximately 20% . Summary estimates for specific study designs were IRR = 0.86  and IRR = 0.79  for before-and-after and RCT studies respectively. Meta-regression of the relationship between risk among the control group and effectiveness of CHG bathing . Summary estimates for specific study designs were IRR = 0.47  and IRR = 0.50  for before-and-after and RCT studies respectively. From meta-regression of the relationship between risk among control group and effectiveness of CHG bathing . Summary estimates for specific study designs were IRR = 0.77  and IRR = 1.19  for before-and-after and RCT studies respectively. From meta-regression of the relationship between risk among control group and effectiveness of CHG bathing . Summary estimates for specific study designs were IRR = 0.98  and IRR = 0.89  for before-and-after and RCT studies respectively. From meta-regression of the relationship between risk among control group and effectiveness of CHG bathing Table , slope =Daily bathing with CHG was estimated to reduce MRSA colonisation and bacteraemia in the ICU by approximately 41% and 36%, respectively . For MRSA colonisation, summary estimates for specific study designs were IRR = 0.52  and IRR = 0.68  for before-and-after and RCT studies respectively. From meta-regression of the relationship between risk among control group and effectiveness of CHG bathing to prevent MRSA colonisation . From meta-regression of the relationship between risk among control group and effectiveness of CHG bathing to prevent VRE colonisation . Summary estimates for specific study designs were IRR = 0.0.98  and IRR = 0.89  for before-and-after and RCT studies respectively. From meta-regression of the relationship between risk among control group and effectiveness of CHG bathing .Relative risk, median baseline risk during control periods, risk with treatment, absolute risk reduction, and number needed to treat (NNT) to prevent a single event are presented in Table This meta-analysis presents a summary of the estimated benefit of CHG bathing to prevent infection in the ICU. CHG bathing was most effective for the prevention of CLABSI among ICU patients, demonstrating a 56% reduction. However, the magnitude of benefit is affected by the underlying risk of CLABSI among ICU populations. Even among an average risk group of five CLABSI per 1000 central-line-days, 360 patients will need to be bathed with CHG to prevent a single event. If the underlying risk of CLABSI is only 1 per 1000 central-line-days than the NNT increases to 1780. Effectiveness was also shown for reducing MRSA colonisation and MRSA bacteraemia. However, even among average baseline-risk populations, the NNT is approximately 600 and 2800, respectively. Because of varying study designs , there remains uncertainty in the effectiveness of CHG-B to prevent other infections among adults in the ICU.Previous reviews of daily CHG bathing to reduce infections in the ICU have been undertaken –24, and A potential strength of our meta-analysis is the inclusion of a wide range of infections associated with an ICU stay. In particular, we have attempted to account for the uncertainty of average estimates by using a Bayesian approach to account for variation due to study design. We have also presented the potential clinical effectiveness of CHG bathing for various ICU infections by estimating the absolute rates of infection with treatment and therefore the absolute risk reduction and NNT.Any systematic review and meta-analysis has a potential weakness of missing unpublished trials, and potential individual trial heterogeneity that is difficult to account for in analysis. It is obvious from the published trials that before-and-after trials tend to overestimate effectiveness, and even variation in the length of a randomised trial may affect the ability to detect underlying benefit. The study by Huang et al.  reports The length of the study intervention and the control period have been proposed to suggest the difference between the results obtained by Climo et al.  and NotoAnother potential limitation of our meta-analysis is inclusion of the study by Huang et al. , in whicC-diff, UTIs and VAP, many studies included these as secondary outcomes, and may have lacked adequate sample sizes to assess a lesser effectiveness of CHG bathing.The results of our meta-analysis have some important clinical implications. Each ICU must assess the potential benefit of instituting daily CHG bathing to reduce infections in the ICU such as CLABSI and MRSA. For instance, in an ICU with specific bundles to prevent CLABSI, such as those developed by Pronovost , 27, basThere are concerns regarding the use of daily bathing of ICU patients with CHG. Although CHG bathing aims to reduce HAI, it may promote the emergence of CHG resistance, and increase Gram-negative organism bacteraemia . HoweverOur meta-analysis of the effectiveness of CHG bathing to reduce infections among adults in the ICU has found evidence for the benefit of daily bathing with CHG to reduce CLABSI and MRSA infections in the ICU. However, the effectiveness was dependent on the underlying risk of these events in the given ICU.