Functional connectivity studies based on resting-state functional magnetic resonance imaging (rs-fMRI) have shown alterations in brain networks associated with self-referential processing, cognitive control, and somatosensory processing in anorexia nervosa (AN). This study aimed to further investigate the functional connectivity of resting-state networks (RSNs) in homogenous subsamples of individuals with restrictive AN (current and recovered) and the relationship this has with core eating disorder psychopathology. rs-fMRI scans were obtained from 12 female individuals with restrictive AN, 14 females recovered from restrictive AN, and 16 female healthy controls. Independent components analysis revealed a set of functionally relevant RSNs, previously reported in the literature. Dual regression analysis showed decreased temporal coherence within the lateral visual and auditory RSNs in individuals with current AN and those recovered from AN compared to healthy individuals. This decreased connectivity was also found in regions associated with somatosensory processing, and is consistent with reduced interoceptive awareness and body image perception, characteristic of AN. Widespread gray matter (GM) reductions were also found in both the AN groups, and differences in functional connectivity were no longer significant when GM maps were added as a covariate in the dual regression analysis. This raises the possibility that deficits in somatosensory and interoceptive processing observed in AN may be in part underpinned or exacerbated by GM reductions. Anorexia nervosa (AN) is a psychiatric disorder in which the relentless and compulsive pursuit of self-starvation leads to severe malnourishment. Recovery rates are low and around a quarter of those affected go on to develop a chronic course of the disorder . It has This study used resting-state functional magnetic resonance imaging (rs-fMRI), in which the temporal synchronicity of spatially separate brain regions is measured. This cross-brain synchronicity is thought to reflect functional networks integral to information processing . fMRI bla priori regions of interest and looks at the patterns of temporal synchronicity between brain regions which emerge while the brain is at rest , a data-driven approach which does not require  at rest , 17. Alo at rest ].In the first published study of rs-fMRI in individuals recovered from AN, our group found increased connectivity within the default mode network (DMN) between the precuneus and dorsolateral prefrontal cortex (DLPFC) using whole-brain ICA . The DMNDifferences in networks implicated in cognitive control have also been observed, including increased connectivity of the DLPFC and ventromedial PFC, regions associated with cognitive inflexibility . ReducedConsistent with the changes in body image perception characteristic of AN, altered connectivity patterns associated with disturbed body image have also been seen. Favaro and colleagues found decreased connectivity in the ventral-visual network in both acute and recovered AN groups and increased connectivity in the somatosensory network in the acute AN group. These results were correlated with visuospatial abilities and were suggested to reflect the inability to integrate visual and somatosensory perceptual information. This inability might sustain body image disturbance in AN . PhillipThis study is a novel application of the exploratory whole-brain ICA approach in a group which includes a sample of restrictive currently ill individuals and a group who have recovered from AN. Only two previous studies have used whole-brain ICA to study resting-state functional connectivity in AN, and these studies were methodologically different to this study. In our previous study , the resIn this study, we sought to address a number of limitations in our previous study . While oIn this study, we predicted that with this more homogenous sample and in the absence of any bias from a previous symptom-provocation task, RSNs associated with somatosensory and interoceptive processes will show changes in connectivity, particularly in the current AN group, consistent with altered body image perception and interoception reported in the illness .Forty-two participants were recruited for three experimental groups: 12 female individuals with anorexia nervosa , 14 recovered (AN-R) females, and 16 female HCs , one currently suffered from comorbid Generalized Anxiety Disorder (GAD), and five presented with both MDD and GAD. In the AN group, five participants were on SSRI/SNRI antidepressant drugs, and three participants were also taking atypical antipsychotic drugs. In the AN-R group, three participants were taking SSRI/SNRI antidepressant drugs.The Structured Clinical Interview for DSM-V Axis I Disorders  was usedDepressive symptoms were measured using the BDI-II . AnxietyOn the day of the scan, participants were asked not to eat for 4 hrs prior to the fMRI scan and to drink only water or calorie-free drinks. Participants completed Visual Analog Scales for the dimensions “how do you see yourself” (very thin–very fat) and “fear of weight gain”  to assess feelings about body image immediately prior to the scan.Scanning was performed at the University of Oxford, Centre for Clinical Magnetic Resonance Research (OCMR) using a 3-T Siemens Trio scanner with a 32-channel head-coil. The neuroimaging protocol comprised functional and structural sequences as follows.Whole-brain functional imaging was performed using a gradient-echo EPI sequence . For the resting-state scan, subjects were instructed to lie in dimmed light with their eyes open, think of nothing in particular, and not to fall asleep.A functional scan involving a food-pictures task was performed following the resting-state scan, prior to the structural MRI, data are not reported in this paper, see Ref. .Structural MRI was acquired at the end of the two functional MRI sequences. 3D high-resolution T1-weighted MR images were acquired using a magnetization-prepared rapid gradient-echo sequence .http://www.fmrib.ox.ac.uk/fslmelodic/)  . IndividFirst, the pre-processed functional data containing 180 time-points for each subject were temporally concatenated across subjects in order to create a single 4D dataset. Then, the (group-wise) concatenated multiple rs-fMRI datasets were decomposed using a group ICA to identify large-scale patterns of functional connectivity in the population of subjects.Second, dual regression was carried out on the data, which allowed voxel-wise comparisons of resting functional connectivity to be made between subjects . Within p < 0.05 applied to the suprathreshold clusters. This results in spatial maps characterizing the between-subject/group differences. The GLM comparison included the groups of interest comparison . Each of the contrasts of interest was tested for group averages and difference between groups.Third, a voxel-wise general linear model (GLM) based analysis was used to assess group differences in each spatial map using permutation-based non-parametric testing   with cluNon-parametric tests were used to safeguard against the possibility that the between-subjects effects were non-Gaussian, and because such non-parametric inference has greater robustness against spatial non-stationarity than commonly used parametric methods . Becausewww.fmrib.ox.ac.uk/fsl/fslvbm/. In brief, brain extraction and tissue-type segmentation were performed and resulting gray matter (GM) partial volume images were aligned to standard space using first linear (FLIRT) and then non-linear (FNIRT) registration tools. The resulting images were averaged, modulated, and smoothed with an isotropic Gaussian kernel of 5 mm FWHM to create a study-specific template, and the GM images were re-registered to this, including modulation by the warp field Jacobian. In the figures, the result maps are reported in accordance with neurological convention (right is right).Whole-brain analysis was carried out using a voxel-based morphometry-style analysis (FSL-VBM)  using dep < 0.05 applied to the suprathreshold clusters.Voxel-wise GLM analysis was carried out using permutation testing in a similar fashion as described for the rs-fMRI analysis. Permutation-based non-parametric testing   with cluFor each subject, GM, white matter (WM), and cerebrospinal fluid (CSF) volumes were derived and computed as a percentage of total brain volume. This was compared between groups and GM volume in the AN group was correlated with BMI, age, lowest BMI, duration of disease and past YBC-EDS-SRQ scores.p < 0.05.Statistical analyses of non-imaging variables were carried out using SPSS software  version 22.0. Threshold for statistical significance was set to http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/FAST/), registered to standard space, smoothed to match the intrinsic smoothness of the rs-fMRI data, voxel-wise demeaned across all subjects in both groups together and added as a confounding regressor (nuisance) to the GLM design matrix used to analyze rs-fMRI data. Adding GM maps reduces variance in the data due to potentially confounding anatomical differences between subjects (p = 0.092), a subsequent analysis also included age as a covariate. The results did not survive the inclusion of age as a covariate. When examining group differences in SPSS, age was added as a post hoc covariate.Structural images were used as additional covariates on a voxel by-voxel basis to interrogate rs-fMRI data. GM images of each subject were extracted using FMRIB’s Automated Segmentation Tool  = −2.45, p = 0.02. Age of onset was significantly later in the AN than the AN-R group: t = −2.17, p = 0.04. Lowest BMI, past YBC-EDS-SRQ scores, and NART did not differ between groups (p > 0.05). The AN group reported significantly higher state anxiety and depression (BDI) levels than HC group. The AN group also reported higher trait anxiety than the AN-R group. The AN-R group also had higher trait anxiety than HC but state anxiety and depression were not significantly different. There was a significant group effect on the measure “how afraid are you of gaining weight”. Both AN groups were significantly more afraid of gaining weight than HC , the AN group were also more afraid of gaining weight than the AN-R group (p < 0.05).Table Independent component analysis (ICA) defined 33 independent components. Of these, nine components were identified as RSNs (covering the majority of GM) and were evaluated further Figure .t = 4.44, voxel size 819; see Figures t = 4.04, voxel size 176; see Figures The results of the GLM found significant between-group differences in the voxel-wise spatial distribution of the functional connectivity maps in the lateral visual and auditory networks. Significantly decreased temporal correlation (coherence) was observed in the contrast: HC greater than AN and AN-R within the auditory network in clusters in the following regions: the right insula extending into the central opercular cortex, the left opercular cortex, right Heschl’s gyrus, the right precentral gyrus extending into the inferior frontal and postcentral gyri, the left precentral and postcentral gyri  did not significantly correlate with either RSN dual regression output F = 0.8, p = 0.45). There was a significant between-group difference in CSF volume , driven by an increase in CSF volume in the AN group compared with AN-R (p = 0.032) and HC (p = 0.004).The data for global CSF, WM, and GM volumes are reported in Table F = 4.868, p = 0.013) driven by reduction in GM in the AN group compared with HC (p = 0.012). There was no significant difference in global GM between the AN group and the AN-R group (p = 0.093). In the results of the GLM, the contrast HC > AN revealed a widespread reduction in GM in the brains of individuals with AN, with significant clusters in the left precentral gyrus, left middle frontal gyrus, bilateral inferior frontal gyrus, right lateral prefrontal cortex, dorsal anterior cingulate/juxtapostional lobule, left planum polare-insular cortex, bilateral thalamus, bilateral hippocampus, bilateral putamen, left angular gyrus/supramarginal gyrus, and superior parietal lobule p < 0.05 , there was a significant cluster in the right supramarginal gyrus/superior parietal lobule, To determine whether BOLD differences at rest between the groups were influenced by the significant GM reduction in the AN and AN-R groups, GM maps were added as covariates (nuisance variables) in the RSN fMRI analysis model (GLM). The BOLD-related group differences in the lateral visual and auditory networks (reported above) did not survive correction for GM. One possible explanation for this is that GM differences account for a significant part of the group differences in functional RSN data. Another possibility is that as adding GM as a covariate changes the degrees of freedom in the model, such that the results no longer reach significance. No significant correlations were found between the percentage signal change in the functional data and the GM values for the same areas. There was also virtually no overlap between those regions found to be significant in the RSN analysis and those significantly with reduced GM Figure . This suThe results of this study suggest that regions associated with interoceptive and somatosensory functioning, including the processing of body image information, show hypoconnectivity in individuals with a history of AN (both current and past). As the recovered AN group were not currently malnourished, the observed differences cannot be solely explained by starvation-associated brain atrophy. Rather, these results suggest that AN is associated with enduring functional differences in brain organization, which could be either a scar of the illness or a premorbid feature, which represents an illness-related biomarker. In contrast to our previous resting-state study in recovered AN , we did The lateral visual network was described by Beckman and colleagues  as one wThe auditory network includes the primary and secondary auditory cortices, insular cortex, the anterior cingulate cortex, anterior supramarginal gyrus, and thalamus . There hDecreased connectivity of the insula within the auditory network was also observed. Dysfunction of the insula has often been reported in neuroimaging studies of AN –66. The a priori hypotheses about regions of possible differences between groups, and it allows comprehensive measurements throughout the entire brain.We performed a VBM on the structural data, a technique which allows investigation of local concentrations of brain tissue, through voxel-wise comparison of multiple brain images. This approach requires no We found reduced GM in parts of the postcentral gyrus and insula cortex in the AN group. Reductions in these regions were no longer seen in the AN-R group, while a reduction in the supramarginal/angular gyrus region was shown in both AN groups. This raises the possibility that although there may be structural recovery from atrophy caused by malnourishment in regions responsible for interoceptive awareness of the bodily state and body image perception, functional changes may have taken place, which do not recover. Indeed, deficits in interoceptive processes and body image perception are also found in individuals recovered from AN , 77. In This study has several methodological limitations of note, as well as some important strengths. While our participants were asked to fast overnight prior to the resting-state scan to control for levels of hunger, ED research has been criticized for failing to control for the effects of dehydration and starvation, particularly in relation to brain matter volume . The effAs with many studies in this area, the sample size used was fairly small. However, we did isolate a sample of purely restrictive AN. A number of resting-state studies in AN have included both restrictive and binge/purge AN subtypes and, as such, are unable to control for the possibility of within-group variability in brain network activity, which may be related to important differences in psychopathology between subtypes of AN. However, future research may benefit from larger sample sizes enabling the inclusion and comparison of both AN subtypes. In addition, a number of participants had comorbid anxiety or depression diagnoses and, as such, were taking serotonergic antidepressants and/or antipsychotic medications. Antidepressant and antipsychotic medications have been shown to alter resting neural connectivity –86, and Consistent with our predictions and with clinical characteristics of AN we have demonstrated decreased connectivity in regions associated with somatosensory and interoceptive function, as well as body image processing in individuals with current AN and those recovered from AN. These results are consistent with clinical and research findings of deficits in interoceptive awareness in AN, abnormalities in the way the body is experienced, and body image distortion. Despite normal global GM volumes in recovered AN individuals, whose weight is fully restored, functional changes in RSNs remain. These may contribute to more persistent body image issues and potentially represent a vulnerability to relapse. Future research would benefit from larger sample sizes allowing the comparison of AN subtypes, and stricter controls on nutrition and hydration prior to imaging.This study was carried out in accordance with the recommendations of NRES South Central—Oxford A Research Ethics Committee. The protocol was approved by the NRES South Central—Oxford A Research Ethics Committee.JS, LG, CH, and RP designed research; JS, LG, and NF acquired and analyzed the data; JS, LG, CH, NF, and RP wrote the manuscript.CH has received consultancy fees from Lundbeck, P1vital, Astra Zeneca and Servier. She is a company director of Oxford Psychologists Ltd. and holds shares in the same company. CH has received grant funding from UCB, J&J, Astra Zeneca, Lundbeck, and Sunovion. JS, LG, NF, and RP report no biomedical financial interests or potential conflicts of interest.


Background: Treatment of diabetes requires a strict treatment scheme which demands patient self-management. Pharmacists are in a good position to provide self-management support. This review examines whether pharmacist-led interventions to support self-management in diabetes patients improve clinical and patient-reported outcomes.Methods: This review was conducted according to the PRISMA guidelines. An extended literature search was conducted with the keywords “pharmacist,” “diabetes,” and “self-management” using the electronic databases Pubmed, Embase, CINAHL, PsycINFO, Web of Science, and the Cochrane Library from the beginning of the database through September 2017. In addition reference lists of systematic reviews and included studies were searched. Eligibility criteria included; self-management intervention tested with an RCT, performed in an ambulatory care setting, led by a pharmacist and reporting at least one clinical- or patient-reported outcome. Primary outcomes were HbA1c , self-management and components of intervention. Secondary outcomes were blood glucose, blood pressure, BMI, lipids, adherence to medication, quality of life, and diabetes knowledge. For the meta-analysis HbA1c values were pooled with a random-effects model in Revman 5.3. Risk of bias was assessed with the Cochrane Risk of Bias tool.Results: Twenty-four studies representing 3,610 patients were included. Pharmacist-led self-management interventions included education on diabetes complications, medication, lifestyle, and teaching of self-management skills. Some studies focused on patient needs through a tailored intervention. No key components for a successful self-management intervention could be identified. Pharmacist-led self-management interventions improve HbA1c levels with a mean of 0.71%  and had a positive effect on blood pressure , BMI , lipids , self-management skill development, and adherence to medication.Conclusion: Pharmacist-led self-management interventions significantly improve HbA1c values in diabetes patients. These results underline the added value of pharmacists in patient-related care. Pharmacists should offer self-management support to diabetes patients in order to improve diabetes outcomes. Diabetes is a disease which is complex to manage. Treatment consists of lifestyle adaptations often combined with medication to control blood glucose levels  the study population was diagnosed with diabetes excluding gestational diabetes, (2) the intervention targeted patients' self-management Barlow,  in an amSelf-management interventions are not always described as such. Therefore, both direct and indirect self-management interventions were included. By indirect self-management interventions we mean interventions containing components that eventually could lead to improved self-management skills, e.g., diabetes and lifestyle education or concordant goal setting.Two reviewers, LvE and LvD, independently assessed all titles and abstracts identified with the initial searches. For all potentially eligible studies the full text papers were obtained via the University of Groningen catalogs, open sources and by emailing first authors. Full text papers were read by both reviewers (LvE and LvD) independently for final inclusion. Any disagreements between the reviewers were resolved by discussion or consultation with a third party (HdG or KT).The following data were extracted from the included studies: general study characteristics, description of the study population, follow-up time, number and duration of contact moments during intervention, description, and components of the intervention , clinical outcomes , and patient-reported outcomes   and patient-reported outcomes . Results for HbA1c, blood glucose, blood pressure, BMI, lipids, and Summary of Diabetes Self-care Activities Assessment (SDSCA) were pooled in a meta-analysis. Meta-analyses were performed with Review Manager 5.3 by using a random effects model because of clinical heterogeneity across the included studies. Subgroup analyses were performed for the outcome HbA1c, for different intervention elements  in order to explain any heterogeneity (I2) across the studies and to explore key intervention components. Sensitivity analyses were performed to test for robustness of the results regarding including studies with a cluster randomization design and studies with a high risk of bias affecting the outcome HbA1c. Results for adherence, diabetes knowledge and quality of life were described narratively.In total 5,919 hits were identified from the electronic database searches, of which 3,996 were unique. After the title and abstract assessment 3,932 references were excluded because they did not meet the inclusion criteria. The full text of 64 papers was assessed, with 24 papers finally being included in the review. . Several subgroup analyses were performed based on different study characteristics  can be considered as clinically relevant and can be associated with risk reduction in microvascular complications (Stratton et al., This study has several strengths. All of the studies included measured HbA1c values, which made it possible to compare the effect of the described interventions in a meta-analysis. Also the results for blood glucose, blood pressure, BMI, lipids, and self-management skills could be pooled in meta-analyses.Though most studies used proxies to measure the effect of pharmacist-led self-management interventions, a few studies directly measured self-management. The results of these studies reveal a positive direct relation between the self-management intervention and the development of self-management skills in diabetes patients. This is most likely because the interventions in almost all of the included studies addressed medication and medication-related problems that are rather common among diabetes patients (Haugbolle and Westh Sorensen, This study also has some limitations. The reporting of the interventions and study results were very limited in some of the studies (Armour et al., The most frequently used instrument to measure self-management in diabetes patients was the SDSCA questionnaire. However, the SDSCA questionnaire pays limited attention to medication related issues (Toobert et al., The interventions reported in all of the included studies can be considered as complex interventions, because all of them consisted of multiple components. Also the mechanisms of action for implicating practice were complex as this depended on both the pharmacists delivering and implementing the intervention and the patient implementing it into daily life (Kelly et al., The overall results of our study argue that pharmacists take an active role in improving patient diabetes self-management since the effectiveness of pharmacist-led interventions is at least comparable to that of other healthcare providers (Sherifali et al., Future research into self-management support should focus on developing an intervention from a multidisciplinary perspective to combine the knowledge from the different disciplines involved in diabetes care. Most studies only focus on the role of a single healthcare professional. Combining the strengths of different disciplines might increase the effect of the intervention. Particular emphasis should be placed on vulnerable patient groups and using valid measurements of self-management skills in multiple dimensions.This review demonstrates that pharmacists contribute additional value in self-management support interventions for diabetes patients. Pharmacists are involved in a variety of different self-management interventions, which vary in many key aspects such as follow-up time and use of a tailored approach. Overall pharmacist-led self-management interventions have a positive effect on lowering HbA1c values.LvE: Main researcher in this review. Involved in all parts of the review including; research protocol, search strategy, literature search, study selection, risk of bias, data extraction, data analysis, and composing the manuscript. LvD: Study selection, risk of bias, data extraction, and revising manuscript. KT: Search strategy, risk of bias, data extraction, revising manuscript. HdG: Protocol, risk of bias, data extraction, revising manuscript.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.


Furthermore, group differences map of FCS exhibited parts of overlapping areas with that of RS-LA, however, less specificity in detecting PTSD patients. In conclusion, apparent alterations of time latency were observed in DMN and primary sensorimotor areas of PTSD patients. These findings provide us with new evidence to explain the neural pathophysiology contributing to PTSD.The abnormal brain activity is a pivotal condition for the occurrence of posttraumatic stress disorder. However, the dynamic time features of intrinsic brain activities still remain unclearly in PTSD patients. Our study aims to perform the resting-state lag analysis (RS-LA) method to explore potential propagated patterns of intrinsic brain activities in PTSD patients. We recruited 27 drug-naive patients with PTSD, 33 trauma-exposed controls (TEC), and 30 demographically matched healthy controls (HC) in the final data statistics. Both RS-LA and conventional voxel-wise functional connectivity strength (FCS) methods were employed on the same dataset. Then, Spearman correlation analysis was conducted on time latency values of those abnormal brain regions with the clinical assessments. Compared with HC group, the time latency patterns of PTSD patients significantly shifted toward later in posterior cingulate cortex/precuneus, middle prefrontal cortex, right angular, and left pre- and post-central cortex. The TEC group tended to have similar time latency in right angular. Additionally, significant time latency in right STG was found in PTSD group relative to TEC group. Spearman correlation analysis revealed that the time latency value of mPFC negatively correlated to the PTSD checklist-civilian version scores (PCL_C) in PTSD group ( Posttraumatic stress disorder (PTSD) is one of the most prevalent psychiatric disorders after suffering from severe traumatic events. The major recurrent symptoms including intrusion, avoidance, and hyper-vigilance may seriously impair the ability to get involved in social activities . It has The resting-state functional MRI (rs-fMRI) is a straightforward and efficient technique to measure the brain activities. There was adequate evidence across multi-model rs-fMRI studies demonstrating abnormal brain activity in PTSD patients. The variable results have shown the abnormalities in regional areas  , 6, inteThe emerging data-driven resting-state lag analysis (RS-LA) method, developed by Mitra et al. , 19, couA healthy neural system is expected to accommodate the changes of internal or external conditions in real-time, wherefore shows the greater temporal variability compared with unhealthy one . Recent In this study, we introduced RS-LA method to explore the temporal propagation patterns of brain activity in PTSD patients. The conventional rs-fMRI analysis was also applied to the same datasets so that it could provide comparison and supplement to the novel technique. A comprehensive understanding of the neural dynamics would make a difference in revealing the exact neuropathological mechanism of PTSD.n = 3), excessive head movement (n = 3), brain infarction (n = 1), denture-artifacts (n = 2), and pregnancy (n = 1). Thirty demographically matched healthy controls (HC) without trauma-exposure were also enrolled in our study. Every participant provided written informed consent prior to MRI scan and neuropsychological assessments.In June 2014, Typhoon Rammasun struck Hainan Province and caused at least 14 deaths. More than a thousand people were trapped and almost drown in the worst hit area. From November 2014 to January 2015, we ultimately recruited 70 trauma-exposed survivors. This study was conducted according to the declaration of Helsinki and was granted permission by the ethics committee of Jinling Hospital, People's Hospital of Hainan Province and the Second Xiangya Hospital. Before the examination, all the participants did not undergo any anti-depressant or psychotherapy. The inclusion criteria of the current study were as followed: age 18–65 years; right-handedness; no use of psychiatric medication or substances abuse; without MR imaging contraindications. Subjects with any history of head trauma, loss of consciousness, long-term significant physical conditions, neurologic or psychiatric disorders except for depression and anxiety should be excluded. After considering the rigid requirements, we totally excluded 10 trauma-exposed subjects for failing to obtain complete imaging data (All the typhoon survivors were screened with PTSD checklist-civilian version (PCL_C) , a 17-it2, slice thickness = 3.6 mm, 35 axial slices with no intersection gap). Each volume was whole-brain coverage and aligning along the anterior-posterior commissure. Additionally, high-resolution T1-weighted 3-Dimension anatomical images were obtained in the sagittal orientation using a rapid gradient-echo sequence .The resting-state functional MR imaging was acquired with a 3.0 Tesla MR scanner  equipped with the standard head coil. Each subject was instructed to lay supine, rest, and keep his or her eyes closed with the head still during MRI scanning. Firstly, the routine diagnostic T1 weighted image and T2 fluid-attenuated inversion-recovery image acquisitions were conducted to rule out subjects with structural brain lesions. The resting-state fMRI data were then acquired using a single-shot, gradient-recalled echo planar imaging   to reduce low-frequency noise   based oncy noise , 33. Thecy noise  were regcy noise  with a tcy noise . Therefocy noise –40.Cxixj (τ) exhibited an extremum defines the temporal lag between signals xi and xj. T is the interval of integration. BOLD time series are aperiodic (Our method for computing lags between time series was according to previously published literature . Consideperiodic . Accordix1(t), x2(t), …, xn(t)}, extracted from all voxels , finding all τi, j corresponding to the extrema of Cxixj (τ) yields the antisymmetric, time-delay (TD) matrix:http://www.nitrc.org/projects/bnv/).Voxels were defined by dividing the gray matter mask in atlas space into 6-mm isotropic cubic regions. Given the time series {Besides, we evaluate the voxel-wise whole-brain functional connectivity strength (FCS) to offer a reference for comparison with the results of RS-LA. Conventional FCS was defined by computing the average functional connectivity between a given voxel and all other voxels in the brain . The propost-hoc analysis was employed for inter-group comparisons.SPSS 22.0  was used to analyze the demographic and clinical data. The Chi-square test was applied to evaluate gender difference among three groups. Normally distributed material expressed as mean ± standard deviation was assessed by one-way analysis variance (ANOVA) and the homogeneity of variance in these data was examined by the Bartlett test. When the ANOVA analysis revealed significant differences, post-hoc t-test to confirm the between-group differences. Regardless of the trauma effect, we also compared the group differences between PTSD patients and all control subjects with two-sample t test. The above analyses were respectively based on the Statistical non-Parametric Mapping software for RS-LA  and Statistical Parametric Mapping software for FCS . All the maps were multiple compared and corrected with AlphaSim Program, with the threshold set at P < 0.01 and the voxel numbers of the cluster larger than 75, which corresponded to P < 0.05.Due to the group differences in education level, RS-LA and FCS differences among the three groups were analyzed by using ANOVA with educational level as covariates, followed by P < 0.05 .Finally, to investigate the association between latency structures and PTSD symptoms, the average latency values extracted from the clusters with significant lagged differences were correlated with the clinical measurements. Spearman correlation analysis with the significant level of Ultimately, 27 drug-naïve patients with PTSD , 33 TEC , and 30 HC  underwent data analysis. The detailed demographics and clinical characteristics are shown in Table Latency projections results obtained from the PTSD, TEC, and HC group are displayed in Figure The group differences among three groups are showed in Table r = −0.578, P = 0.002 < 0.05, Figure r = 0.030, P = 0.868).The time latency values with significant group differences were extracted and displayed in the form of bar chart at the group level Figure . The resConventional resting-state functional connectivity strength (RS-FCS) differences of the three groups are shown in Figure In the current study, by using RS-LA, we identified the lagging structures of intrinsic brain activities in PTSD patients. The disturbance of brain activities was not only involved in the inter-regional connectivity but the laggingly driven of the specific brain regions, mainly distributing in DMN and the primary sensorimotor areas. Time latency values of the mPFC negatively correlated with the severity of PTSD symptoms. Moreover, comparing with the conventional functional connectivity method, results of LA-RS appeared to be more complementary to describe the brain activity changes in PTSD patients. These observations are significant in shedding the light of potential relations between the structures with apparent time latency and the occurrence of PTSD.The present study revealed predominant temporal postponement of mPFC, PCC/PCu and angular gyrus in PTSD group. These regions have been previously identified as major regions of DMN. The explanation for our results relies on the underlying neural physiological basis of lag structure. It has been speculated that the propagation of spontaneous low-frequency activity in lag structure might be concerned with the regional variation in time latency of either neurovascular coupling or transduction of neuronal activities into BOLD signals , 43. NumAdditionally, in PTSD group, the significant time latency of right STG was found compared with TEC group and that of the Pre/PostCG was also found relative to HC group. The structural abnormities in these regions have been widely reported, which mainly demonstrated increased gray matter density , 50. So In RS-FCS result, we equally observed the abnormal activities in PCC/PCu and left Pre/PostCG gyrus in PTSD patients and TEC group. By contrast, our finding of time latency in these two regions was only observed in PTSD group, thus complementarily expressing that the lagged propagation of brain activities might be pertinent to the patients. Jin el al also found that PTSD patients with abnormal static connectivity would couple with altered temporal variability of connections . EspeciaTo our best knowledge, this is the first study employing RS-LA to investigate the dynamically intrinsic brain activity in PTSD patients. We included the traumatic controls experiencing the same trauma events to reduce the impact of interference factors. However, some limitations need to be acknowledged. Firstly, it should be regarded as a preliminary study because of the relatively small samples. Secondly, there are significant educational level differences among the three groups, and we regressed the educational effect as a covariate to minimize the influences. Thirdly, we only retrieved the clusters with significant group differences in lagged structures to focus on the latency patterns related to PTSD, while further discussion on static results is needed in our future works. Lastly, our exploration of the clinical correlates of altered lag structure is limited to the clinical assessments collected in the current study. More detailed and comprehensive clinical materials are required in the future.In summary, we demonstrated that the time latency patterns related to the occurrence of PTSD. The altered propagation of BOLD signals markedly happened in DMN and primary sensorimotor regions. We also observed that the changes in some DMN regions might be associated with PTSD severity. Compared with conventional methods, these results detected by the novel technology provided evidence that aberrant propagation of brain activities would contribute to PTSD. Notably, further researches, especially with longitudinal designs, are still needed to confirm the potential value for clinical application.This study was in accordance with the declaration of Helsinki, and was approved by the ethics committee of Jinling Hospital, People's Hospital of Hainan Province and the Second Xiangya Hospital of Central South University. All participants provided written informed consent after a detailed description of this study.YW was involved in the literature review, experimental design, data analysis and writing of the manuscript. RQ, FC, ZZ, and GL designed the study. JK, QX, and YZ analyzed the data. LC, JL, and LZ acquired the neuropsychological data, which all authors reviewed and approved for publication.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.


Guam parkinsonism–dementia complex (G-PDC) is an enigmatic neurodegenerative disease that is endemic to the Pacific island of Guam. G-PDC patients are clinically characterized by progressive cognitive impairment and parkinsonism. Neuropathologically, G-PDC is characterized by abundant neurofibrillary tangles, which are composed of hyperphosphorylated tau, marked deposition of 43-kDa TAR DNA-binding protein, and neuronal loss. Although both genetic and environmental factors have been implicated, the etiology and pathogenesis of G-PDC remain unknown. Recent neuropathological studies have provided new clues about the pathomechanisms involved in G-PDC. For example, deposition of abnormal components of the protein quality control system in brains of G-PDC patients indicates a role for proteostasis imbalance in the disease. This opens up promising avenues for new research on G-PDC and could have important implications for the study of other neurodegenerative disorders. Guam parkinsonism–dementia complex (G-PDC) is a mysterious neurodegenerative disorder that afflicts the indigenous Chamorro people of Guam (Mariana Islands). It was first described in clinicopathological studies by Hirano et al. in 1961 . Mental lytico-bodig)  was previously found in the same Western Pacific focus of neurological disease –12. Becao-bodig) , 14. Howo-bodig) –20.Although several causes have been suggested for G-PDC, including genetics, infectious agents, mineral deficiencies, and environmental toxins, the etiology and pathogenesis of this disease remain unknown –26. DeteThe search for the cause of G-PDC has become increasingly challenging due to a notable decline in neurological disease incidence on the island in the last decades –31. The Neuropathologically, G-PDC is characterized by severe neuronal loss and abundant NFTs in different brain regions, including the temporal and frontal cortex, basal ganglia, thalamus, and brainstem , 32, 33.Besides frequent tangles, other pathological protein deposits have been identified in neurons of G-PDC brains. These include cytoplasmic TDP-43-containing aggregates Figure C and focIt is interesting to point out that glial cells, i.e., astrocytes and oligodendroglia, also contain pathological inclusions  in G-PDC and that these cells may play a significant role in G-PDC pathogenesis , 52. ExtImportantly, findings related to multiple proteinopathy have been complemented by the detection of molecular markers that link G-PDC to certain protein homeostasis (proteostasis) pathways. We have recently found some evidence for activation of the unfolded protein response (UPR) in G-PDC brain . The UPR is an adaptive signaling cascade that is triggered by endoplasmic reticulum (ER) stress and is associated with abnormal protein aggregation and neurodegeneration , 56. PhoTogether, some of these pathological characteristics suggest proteostasis network dysfunction in G-PDC. Disruption of the intracellular protein degradation machinery and proteostasis collapse has been associated with many neurodegenerative diseases, and it will be interesting to see if, and to what extent, protein degradation pathways are affected in G-PDC , 60. Fai+1), have been found to accumulate in G-PDC brains , i.e., frameshift mutants of ubiquitin-B  not present in DNA into mRNA, resulting in the generation of aberrant proteins (+1) that is necessary to ubiquitinate other proteins, but can still be ubiquitinated itself. The abnormal C-terminal domain of UBB+1 can be recognized by UBB+1 antibodies  proteins in cells and impairment of the UPP has been reported to occur during neurodegeneration –65. UBB+proteins –68  and polyglutamine (polyQ) diseases  and has been shown to be detrimental to neurons  , by impairing ER-associated degradation  , and thas (DUBs) . UBB+1 eransport . Transge disease , 78. Alsradation . UBB+1 mntingtin .+1 in neurodegeneration is complicated by its dual role as both substrate and inhibitor of the UPP: at low concentrations, UBB+1 is degraded via the ubiquitin-fusion degradation pathway, but at high concentrations it is a potent inhibitor of the UPP  as well, because MAPS enables PQC when conventional proteasomal degradation is impaired   Figure D and the) Figure E 61). A. A+1, se) Figure , 98. Mut) Figure , 100 and) Figure . Strikin) Figure .+1, different UPP components, and PQC mechanisms in G-PDC remain to be determined.Based on these findings, we conclude that the UPP is disturbed in G-PDC. The definite roles of UBBAccumulation of  PQC components in G-PDC brains could be an important clue as to why disease-associated proteins aggregate and neurons degenerate in G-PDC. Impaired PQC and several neurodegenerative diseases have been causally linked through genetic analyses of familial cases , demons+1 in the context of the multiproteinopathy that characterizes G-PDC, in different experimental models , will likely increase our knowledge of the timing (early vs. late) and relative importance of different disease processes. We take the view that mechanistic studies in such experimental model systems, and validating new findings against the reality of human tissues (neuropathology), will be a powerful approach for making discoveries. It is well recognized that abnormal PQC is implicated in AD, ALS(-FTD), PD, and other neurodegenerative disorders. Because this is a quite recent finding for G-PDC, insights derived from studies on other neurodegenerative diseases will be valuable to help understanding G-PDC, including its unique characteristics.Detailed examination of the PQC system and UBBThe cellular mechanisms that control proteostasis are not limited to protein degradation by the UPP, but also involve protein synthesis, folding, trafficking, and other (extracellular) clearance routes . PQC criC. elegans germ lineage, “exopher” formation in C. elegans neurons and during differentiation of mouse embryonic stem cells)  –117. ComNovel neuropathological findings in G-PDC stress the importance of utilizing pathway-specific markers to unravel disease mechanisms. While determining the  cause of G-PDC, perhaps through new genetic and/or exposome  studies in the geographical isolate, remains a major outstanding problem, more studies into the pathomechanisms underlying neurodegeneration in G-PDC are warranted. Applying insights derived from studies on other neurological diseases that share molecular neuropathology, including work on postmortem human brains and various experimental model systems, will help to identify critical disease mechanisms. Investigating the interplay between G-PDC-associated pathological proteins and specific cellular/molecular pathways , using relevant experimental models , will be an exciting and challenging task for the future. Such studies have also been initiated on the Kii peninsula of Japan, another hyperendemic focus of ALS/PDC –120 Ver, 122.Is impairment of the PQC system an important pathogenic mechanism in G-PDC?+1 modify the cytotoxicity of aggregation-prone proteins, like tau and TDP-43?Does UBB+1 on glial cells?What is the role of glia in G-PDC? What are the effects of UBB+1 and PQC proteins also deposited in diseases that are similar to G-PDC, e.g., Kii ALS/PDC?Are UBBWhat are the roles of the UPR and other adaptive stress response pathways in G-PDC?+1 and PQC dysfunction an early or late event in G-PDC? Is it a cause or consequence (or both) of disease?Is accumulation of UBB+1 and particular PQC components be used as therapeutic targets in neurodegenerative disorders?How can new insights into pathogenic mechanisms of G-PDC be used to advance the understanding and treatment of other neurodegenerative diseases? E.g., can UBBAll authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.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.


The exponential growth of publicly available RNA-sequencing (RNA-Seq) data poses an increasing challenge to researchers wishing to discover, analyse and store such data, particularly those based in institutions with limited computational resources. EMBL-EBI is in an ideal position to address these challenges and to allow the scientific community easy access to not just raw, but also processed RNA-Seq data. We present a Web service to access the results of a systematically and continually updated standardized alignment as well as gene and exon expression quantification of all public bulk  RNA-Seq runs in 264 species in European Nucleotide Archive, using Representational State Transfer.The RNASeq-er API (Application Programming Interface) enables ontology-powered search for and retrieval of CRAM, bigwig and bedGraph files, gene and exon expression quantification matrices  as well as sample attributes annotated with ontology terms. To date over 270 00 RNA-Seq runs in nearly 10 000 studies (1PB of raw FASTQ data) in 264 species in ENA have been processed and made available via the API.http://www.ebi.ac.uk/fg/rnaseq/api. The commands used to analyse the data are available in https://github.com/nunofonseca/irap/wiki/iRAP-single-library.The RNASeq-er API can be accessed at Bioinformatics online. The pattern of rapid growth of RNA-sequencing (RNA-Seq) data, observed in recent years, is set to continue as costs of sequencing experiments decrease and novel technologies and analysis methods reach maturity, e.g. single-cell RNA-Seq . The analysis pipeline behind the RNASeq-er API offers an important service to researchers performing RNA-Seq experiments that choose to submit their data to ArrayExpress via https://www.ebi.ac.uk/fg/annotare submission tool: the deposited studies are not only described by rich, ontology-annotated experimental metadata; the associated raw data is also analysed for free, and for qualifying studies, is subsequently visualized in Expression Atlas (via private access if pre-publication). This combined metadata-rich deposition, analysis and visualization service aims to make data depositions not only easily discoverable, but also to facilitate understanding and reproducibility of the underlying research results. The results of our analysis can also inform and feed into the submitters’ own downstream analyses well before the paper is ready for submission to a journal.This sustained growth only exacerbates the challenges facing researchers wishing to discover, analyse and store available RNA-Seq data, particularly those based in institutions with limited computational resources. EMBL-EBI is in an ideal position to address these challenges and to allow the scientific community easy access to not just raw, but also processed RNA-Seq data. We have therefore undertaken the task of on-going standardized alignment and gene and exon expression quantification of all public bulk  RNA-Seq data in ENA (https://genome.ucsc.edu/goldenpath/help/bigWig.html) and bedGraph (https://genome.ucsc.edu/goldenpath/help/bedgraph.html) genome track files are also generated. Where groups of technical replicates corresponding to a single biological sample were identified via manual curation in ArrayExpress, the corresponding CRAM, bigWig and bedGraph files are aggregated for each such biological replicate. The expressions (raw counts) of genes and exons defined in the corresponding GTF file (obtained from the same source as the genome reference) are quantified using HTSeq  and http://www.ebi.ac.uk/fg/rnaseq/api/doc (pdf).The full API documentation is available in the Supplementary DataClick here for additional data file.


Gamma-glutamyltransferase (GGT) is a membrane-bound enzyme involved in the metabolism of glutathione. Studies suggested that GGT played an important role in the tumor development, progression, invasion and drug resistance and prognosis. The association between GGT and prognosis of patients with nasopharyngeal carcinoma (NPC) was unknown. This study was conducted to investigate the association of pretherapeutic serum level of GGT with clinical-pathological parameters and survival in patients with NPC.Two hundred and twenty-two patients with NPC were recruited in this study and were stratified into two GGT risk groups . The association of pretherapeutic serum GGT levels with clinical–pathological parameters was examined. Univariate and multivariate survival analyses were performed.The pretherapeutic serum level of GGT was not associated with gender, age, pathology, T stage, N stage, TNM stage, chemotherapy or radiotherapy in patients with NPC. Patients in the high-risk GGT group had a poorer survival than the low-risk GGT group . Multivariate analysis suggested that patients in the high-risk GGT group had 2.117  times the risk of death, 2.836  times the risk of progression, 2.551  times the risk of relapse, and 3.331  times the risk of metastasis compared with those in the low-risk GGT group.The pretherapeutic serum level of GGT might serve as a novel independent prognostic factor for overall-survival, progression-free survival, loco-regional relapse-free survival and distant metastasis-free survival in patients with NPC. Nasopharyngeal carcinoma (NPC) is endemic in southern China and Southeast Asia, with high incidence rates of 20–30 cases per 100,000 population , C-reactGamma-glutamyltransferase (GGT) is a cell-membrane bound enzyme involved in the metabolism of glutathione (GSH), catalyzing the degradation of extracellular GSH and subsequently promoting amino-acid recovery for intracellular GSH synthesis . As GSH To the best of our knowledge, there have been few report about the prognostic impact of pretherapeutic serum level of GGT on patients with NPC in detail untill now. A recent study aimed to investigate the association of serum LDH and ALP with NPC showed that increased GGT level (> 50 U/L) had no significant impact on survival of patients with NPC. However, it also indicated that patients with higher GGT level had a worse survival when by using the optimal cutoff value of GGT (28.5 U/L) determined by receiver operative characteristic (ROC) curve . It seemA total of 222 patients with primary NPC were consecutively recruited from January 2011 to December 2014 at the Cancer Center of Guangzhou Medical University, China. This study was reviewed and approved by the institutional review board and ethics committee of Cancer Center of Guangzhou Medical University. Written informed consent was obtained from all patients. Patients who presented with pre-existing comorbidities, known to be related with elevation of GGT  were excluded from this study (number = 128).The pre-treatment evaluation included a complete patient history, physical examinations, haematology and biochemistry profiles, fibreoptic nasopharyngoscopy, chest X-ray, abdominal sonography, magnetic resonance imaging (MRI) of the nasopharynx and neck, and whole-body bone scan or whole-body FDG PET/CT. All patients were restaged according to the seventh American Joint Committee on Cancer (AJCC) TNM staging manual. In total, 21 (9.5%) patients were treated with three-dimensional conformal radiotherapy radiotherapy (3DCRT), and 201 (90.5%) patients were treated with intensity-modulated radiotherapy (IMRT). In addition, 209 (94.1%) patients with stage II–IV disease received platinum-based chemotherapy. A stratified multitherapeutic protocol was used. Radiation alone was administered for stage I disease, and radiation alone or with concurrent platinum-based chemotherapy was administered for stage II disease . ConcurrBlood samples for the evaluation of serum GGT levels were obtained by peripheral venous puncture 24–48 h prior to therapy. Gamma-glutamyltransferase was routinely determined to rule out liver damage before treatment starts. Gammaglutamyltransferase concentrations were analysed with an enzyme kinetic assay .U test and chi-square test were performed to analyse the association between pretherapeutic serum level of GGT and clinical-pathological parameters. Receiver operative characteristic (ROC) curve was used to determine the optimal cutoff value of GGT for survival. According to the cutoff value, serum level of GGT was divided into two groups, high-risk group and low-risk group. Survival probabilities were calculated by the Kaplan–Meier method. Differences between groups were measured using the log-rank test. Survival times of patients still alive or dead as a result of other causes than cancer were censored with the last follow-up date. The primary end point of this study was progression-free survival (PFS). PFS was defined as the duration from the date of definite diagnosis to the date of disease progression or censored at the date of last follow-up. The secondary end points include overall survival (OS), locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS). OS was calculated from the time of definite diagnosis to the time of death from any cause or to the time of last follow-up (at which time data were censored). LRRFS and DMFS were also evaluated and calculated from the date of definite diagnosis until the day of first locoregional or distant relapse or until the date of the last follow-up visit. Univariate and multivariate analysis was performed using Cox’s proportional hazards regression model with a forward stepwise procedure . Analyses were performed using the statistical software package SPSS 20.0  and Graph Pad Prism for windows, version 6 . A two-sided P-value less than 0.05 was considered statistically significant.Values were described by mean (standard deviation [SD]) when normally distributed or by median when presented with skewed distribution. The Mann–Whitney A total of 222 patients with primary NPC were included in the final analysis. The clinical–pathological characteristics of the study cohort were presented in The pretherapeutic serum level of GGT was not associated with gender, age, pathology, T stage, N stage, TNM stage, chemotherapy or radiotherapy. No association between GGT and clinical–pathological characteristics was found when analying the categorical variables by chi-square test either .In univariate survival analysis, high-risk level of GGT, advanced T stage, advanced N stage, and advanced TNM stage were associated with poorer OS, PFS, LRRFS and DMFS Tables  and 3. TIn the present study, we investigated the associations of the serum level of pretherapeutic GGT with the clinical–pathological parameters and prognosis of NPC. To the best of our knowledge, there have been few report on the prognostic impact of pretherapeutic serum level of GGT on patients with NPC in detail up to now. We stratified the patients into high-risk group and low-risk group, according to the best cutoff value determined by ROC curve. We demonstrated that high-risk group of GGT was associated with poorer prognosis in patients with NPC. Pretherapeutic serum level of GGT was an independent prognostic factor for patients with NPC. Patients in the high-risk GGT group had significant worse 5-year OS, PFS, LRRFS and DMFS than patients in the low-risk GGT group. Patients in the high-risk GGT group had higher risks of death, progression, relapse and metastasis than those in the low-risk GGT group. Our finding was similar to a recent study which showed that NPC patients with higher GGT level (> 28.5 U/L) had a worse survival except that the cut-off value was different . FurtherAlthough previous studies have indicated that GGT might play a meaningful role in tumor cell biology, the exact functional mechanisms remain unclear. Several potential mechanisms through which GGT impacts cancer biology have been postulated. GGT was demonstrated to participate in the important redox-sensitive processes, such as antioxidant/antitoxic defenses and cellular proliferative/apoptotic balance , 28, theOn the other hand, GGT and GSH were regarded as essential components of the antioxidant defence by quenching free radicals on DNA , 11. TheFurthermore, evidences indicated that GGT mRNA might be induced by several cytokines, such as tumor necrosis factor alpha  , and intAs a retrospective study, our study was limited by biases such as lack of random assignment, and patient’s incomplete data acquisition. Nonetheless, patients with clinically relevant comorbidities known to be associated with elevated GGT, such as hepatobiliary tract, pancreatic and heart disease or alcohol abuse were excluded from the study. Despite the potential limitations, our results were clinically valuable.We conclude that pretherapeutic serum level of GGT might be a novel independent prognostic factor for OS, PFS, LRRFS and DMFS in patients with NPC. Patients with higher level of GGT have poorer prognosis. However, whether GGT itself has a direct etiological role in carcinogenesis or may just be a marker of an underlying etiology needs further research.S1 Dataset(XLSX)Click here for additional data file.


Propionibacterium acnes, a commonly implicated etiologic agent of sarcoidosis, in myocardial tissues obtained from CS patients.Although rare, cardiac sarcoidosis (CS) is potentially fatal. Early diagnosis and intervention are essential, but histopathologic diagnosis is limited. We aimed to detect P. acnes-specific monoclonal antibody. We found granulomas in 16 (62%) CS-group samples. Massive (≥14 inflammatory cells) and minimal (<14 inflammatory cells) inflammatory foci, respectively, were detected in 16 (62%) and 11 (42%) of the CS-group samples, 10 (67%) and 10 (67%) of the M-group samples, and 1 (3%) and 18 (46%) of the CM-group samples. P. acnes-positive reactivity in granulomas, massive inflammatory foci, and minimal inflammatory foci were detected in 10 (63%), 10 (63%), and 8 (73%) of the CS-group samples, respectively, and in none of the M-group and CM-group samples.We examined formalin-fixed paraffin-embedded myocardial tissues obtained by surgery or autopsy and endomyocardial biopsy from patients with CS , myocarditis , or other cardiomyopathies  using immunohistochemistry (IHC) with a P. acnes in sarcoid granulomas of originally aseptic myocardial tissues suggests that this indigenous bacterium causes granuloma in many CS patients. IHC detection of P. acnes in massive or minimal inflammatory foci of myocardial biopsy samples without granulomas may be useful for differentiating sarcoidosis from myocarditis or other cardiomyopathies.Frequent identification of  Sarcoidosis, a systemic disease, is characterized by the presence of noncaseating epithelioid cell granulomas in multiple organs, including the heart, lung, skin, eyes, and central nervous system. Sarcoidosis is generally a benign disease, but cardiac involvement leading to functional abnormalities is an independent predictor for a poor prognosis . CardiacPropionibacterium acnes (P. acnes) is the only microorganism to be isolated from sarcoid lesions [P. acnes (anti-P. acnes antibody) that reacts with cell membrane-bound lipoteichoic acid [P. acnes antibody revealed P. acnes-positive reactivity in sarcoid granuloma tissue samples from 74% of lungs and 88% of lymph nodes from patients with sarcoidosis, whereas no P. acnes-positive reactivity was detected in non-sarcoid granulomas of these organs from patients with tuberculosis or sarcoid reaction.Although the etiology of sarcoidosis remains undetermined, mycobacterial and propionibacterial organisms are the most commonly implicated etiologic agents . To date lesions . This in lesions . Recentloic acid . ImmunohP. acnes-specific monoclonal antibody to detect P. acnes in myocardial tissues from CS patients to evaluate the possible etiologic link of this bacterium with CS, and to estimate the feasibility of IHC analysis of P. acnes in myocardial biopsy samples to distinguish between CS and other cardiomyopathies.In the present study, we performed IHC with the This study was designed as a retrospective multi-centre observational study. We collected 107 samples  from patients clinically diagnosed with CS , myocarditis , or other cardiomyopathies  between January 1994 and April 2015 in seven Japanese Medical hospitals . We collected the EMB samples from the right ventricular septum. For the surgical samples, we punched a hole in the LV myocardial tissue to implant a left ventricular assist device or resected during left ventriculoplasty. The CS-group samples were collected from patients with histologically-proven myocardial sarcoidosis. All CS-group samples included one or more granulomas in the original histologic sections prepared for pathologic diagnosis. A definite diagnosis of CS was based on the presence of both myocardial granulomas and cardiac manifestation with or without extra-cardiac sarcoidosis involvement of at least one organ, according to the 2006 revised version of the Japanese Ministry of Health and Welfare guidelines . CS patiP. acnes antibody [2 in the myocardium, consistent with the criteria that define myocarditis [P. acnes-positive reactivity by IHC in granulomas and massive or minimal inflammatory foci was compared between the CS-, M-, and CM-group samples and between the surgical/autopsy and EMB samples.Formalin-fixed paraffin-embedded myocardial tissues were obtained by EMB, or at cardiac surgery and autopsy. Serial paraffin sections on silane-coated slides  were stained with haematoxylin-eosin (HE) and immunostained with the anti-antibody  and the antibody  as a conantibody . Brieflycarditis . Minimalcarditis . Seven sContinuous variables are expressed as the mean ± standard deviation, and compared with a one-factor repeated-measures analysis of variance. Post-hoc comparisons were performed using Tukey’s Honestly Significant Difference test. Categorical variables are expressed as frequencies with percentages, and were compared using Fisher’s exact test followed by the Holm correction. A P value of less than 0.05 was considered statistically significant. Statistical analyses were performed using JMP 12 .The patient demographics and clinical characteristics are summarized in P. acnes detected by IHC in each corresponding lesion are summarised for the surgical or autopsy samples and the EMB samples from each patient group (The number and frequency (%) of samples with granulomas or inflammatory cells  detected by HE, and the number and frequency (%) of such samples with nt group . NoncaseP. acnes antibody revealed one or a few small round bodies in some of sarcoid granuloma cells, including epithelioid cells and multinucleated giant cells (P. acnes-positive reactivity in granulomas was found in 10 (63%) of 16 CS-group samples with granuloma (P. acnes-positive reactivity in massive inflammatory foci was detected in 10 (63%) of the 16 CS-group samples and in none of the 10 M-group samples or 1 exceptional CM-group sample with massive inflammatory foci. The difference in the detection frequency between the CS-group and M-group samples was statistically significant (P = 0.003). P. acnes-positive reactivity in minimal inflammatory foci was detected in 8 (73%) of the 11 CS-group samples and in none of the 10 M-group and 18 CM-group samples with minimal inflammatory foci. The difference in the detection frequency between the CS-group and M-group or CM-group samples was statistically significant (P = 0.002 and P < 0.001), respectively. The frequency of P. acnes-positive reactivity in granulomas and massive or minimal inflammatory foci was not significantly different between the surgical or autopsy samples and the EMB samples, or between the CS-group patients with and without clinical characteristics, including extra-cardiac manifestations. Granulomas were not detected in the 10 (38%) of 26 CS-group samples. P. acnes-positive reactivity was detected within inflammatory foci even in 3 of 10 CS-group samples without granulomas. No positive reactivity was detected by the control IHC with the anti-mycobacterial antibody in any samples from the CS-group, M-group, and CM-group patients.IHC with the anti-nt cells . Such P.ranuloma . A few oranuloma  and miniranuloma  inflammaP. acnes by IHC, for the first time, in myocardial tissues from CS patients. P. acnes-positive reactivity in granuloma cells was found in 63% of the CS-group samples with granulomas. P. acnes-positive reactivity was also found in massive and minimal inflammatory foci, in 63% and 73% of the CS-group samples, respectively, and in none of the M-group and CM-group samples with each corresponding lesion. The high frequency and specificity of the detection of the indigenous bacterium in sarcoid granuloma and inflammatory cells from originally aseptic myocardial tissues more strongly implicates its involvement in sarcoidosis etiology than earlier similar detection of P. acnes in sarcoid granulomas of the lungs and lymph nodes because the bacterium is thought to be commensal to these organs [P. acnes in massive or minimal inflammatory foci of myocardial biopsy samples without granulomas could be useful for differentiating sarcoidosis from myocarditis or other cardiomyopathies.In this study, we identified e organs . The resA definitive CS diagnosis usually requires a histologic examination of tissue samples obtained by EMB. A previous study demonstrated that a histologic CS diagnosis is limited to less than 30% of small EMB samples obtained from CS patients ; this isP. acnes-positive reactivity in the granulomas was found in 56% of the surgical or autopsy samples and 75% of the EMB samples with no significant difference between the large and small myocardial tissue samples. Negi et al. reported that no P. acnes-positive reactivity is found in non-sarcoid granulomas of lungs and lymph nodes from patients with tuberculosis or sarcoid reaction [P. acnes may be useful for distinguishing sarcoid granulomas from other non-sarcoidosis granulomas with a similar histologic appearance.Granulomas in myocardial tissues, even when detected in surgical or autopsy samples and EMB samples, require a differential diagnosis between CS and other granulomatous diseases . A minimreaction . TherefoP. acnes-positive reactivity was detected in 63% of the CS-group samples with massive inflammatory foci and in 73% of those with minimal inflammatory foci. Three autopsy samples from the CS-group with P. acnes detected in inflammatory foci contained only inflammatory lesions without granuloma in these histologic sections. These findings suggest that IHC with anti-P. acnes antibody may be useful for differentiating sarcoidosis from non-sarcoidosis myocarditis and other cardiomyopathies, especially when no granuloma is found but some inflammatory cells are observed in the myocardial biopsy samples.Additionally, minimal inflammatory cell infiltration in the myocardium is observed in some patients with DCM classified as inflammatory dilated cardiomyopathy (DCMI) , 23. A sP. acnes-positive reactivity was also observed in many samples with sarcoid granulomas and accompanying inflammatory foci . In general, granulomas are formed to sequester and degrade an invading agent. An epithelioid cell granuloma is the pathologic hallmark of sarcoidosis; thus, the sarcoid granuloma must contain, or have contained, an etiologic agent of sarcoidosis. According to these basic principles of granuloma formation, the high frequency and specificity of P. acnes detected in sarcoid granuloma and inflammatory cells in originally aseptic myocardial tissues suggest that this indigenous bacterium causes granuloma formation in many CS patients.P. acnes [P. acnes can cause latent infection primarily in the lungs and lung hilar lymph nodes and the secondarily in other systemic organs, such as the heart, eyes, and skin. The dormant form of P. acnes is activated endogenously under certain environmental conditions and proliferates at the site of latent infection. In patients with P. acnes hypersensitivity, granulomas are formed around macrophages with intracellular P. acnes supported by an active Th1 immune response to the bacterium during the process of granulomatous inflammation, as shown in A hypersensitive Th1 immune response to this commensal bacterium is thought to lead to granuloma formation in the susceptible subjects –26. BaseP. acnes , P. acneP. acnes reactivity was not detected in some patient samples, even within sarcoid granulomas of the CS-group, requires further investigation. One possible explanation is that other bacteria, such as Propionibacterium granulosum and Mycobacterium tuberculosis, cause granuloma formation in some sarcoid samples. The anti-P. acnes antibody used in the present study was specific to P. acnes and did not cross-react with these bacteria. The mycobacterial etiology of sarcoidosis has long been suspected in many Western countries, even though bacterial culture from sarcoid lesions and IHC detection of M. tuberculosis in sarcoid granulomas has been unsuccessful. In this study, we examined all samples with a monoclonal antibody specific to all species of mycobacteria as a control, and found no positive reaction in any samples by IHC with the antibody, which reacts with lipoarabinomannan and detects mycobacteria in tuberculous granulomas of formalin-fixed paraffin-embedded tissue sections [P. granulosum genomes in 3 of 15 Japanese sarcoidosis patients [P. granulosum contained P. acnes-specific sequences. The findings from other studies using real-time PCR also suggested this possibility [P. acnes in the granulomas of some CS samples failed because the granuloma cells, which have a more powerful intracellular digestion ability than macrophages, destroyed the P. acnes antigens [P. acnes antigen could have been totally eradicated from the granuloma cells. According to this possibility, the lack of P. acnes detection in granuloma cells by IHC does not necessarily rule out sarcoidosis as the cause of the granuloma.The fact that sections . Ishige patients , yet nonsibility . It is aantigens . Thus, aP. acnes detection using real-time PCR could not be performed because of the poor quality of the autopsy samples (due to long-term fixation) and the small size of EMB samples. Detection of P. acnes DNA by in situ hybridization, as described in our previous study [There are several limitations to the present study. First, this was a retrospective study, and the sample size was relatively small. Thus, further studies are needed to generalize the present findings. Second, lower frequency of granulomas in the large tissue samples obtained by surgery or autopsy seemed to be due to persistent inflammation with prominent fibrosis in these samples obtained from end-stage heart failure patients. Third, a higher frequency of granulomas in the small EMB tissue samples may be due to selection bias when we collected the EMB samples. Fourth, subjects of the myocarditis group included only lymphocytic cell type excluding eosinophilic and giant cell types in the present study as results of accurately distinguishing three major cell types of myocarditis by H-E staining. Finally, us study , was notP. acnes in tissue sections obtained by myocardial biopsy as a diagnostic or clinical tool. IHC results for each sample were defined as positive when at least one signal was detected within any of the granuloma or inflammatory cells. The P. acnes-positive signals, especially those in inflammatory cells, may not have been detected in the original sections, but only in the deep-cut sections of the biopsy samples. Therefore, we may need to examine both the original and deep-cut sections by IHC as well as HE staining in routine pathologic diagnostic processes. Another limitation was the high percentage of samples excluded from this study due to non-specific background staining. The non-specific staining was mainly caused by strong signals of perinuclear lipofuscin pigments in the myocardial cells in some samples, whereas in other samples these pigments did not produce non-specific reactions. This unfavorable phenomenon seems to have been caused by inappropriate tissue preparation including long-term fixation with formalin and was not observed in recent biopsy samples that were fixed with Carnoy solution.There are also limitations for IHC detection of P. acnes in the pathogenesis and diagnosis of CS. Notably, frequent detection of P. acnes in both granuloma and inflammatory cells in myocardial biopsy samples from CS patients suggests that IHC with the anti-P. acnes monoclonal antibody can be an additional diagnostic method to the present limited use of EMB in the differential diagnosis of CS from non-sarcoidosis myocarditis and other cardiomyopathies.The present study implicated S1 File(XLSX)Click here for additional data file.


The objective of this study was to provide an up-to-date summary of the current evidence that may be useful for updating guidelines. We comprehensively searched the published literatures and conferences for studies that compared curative with palliative treatments in colorectal cancer patients with peritoneal metastasis. The primary outcomes considered in this study were three- and five-year overall survival rates. We pooled data across studies and estimated summary effect sizes. Overall, patients who received curative treatments had improved three-year survival (hazard ratio (HR), 2.19 ) and five-year survival  compared with those who received palliative treatments. Patients who received curative treatments had an increased risk of treatment-related morbidity (odds ratio (OR), 2.90 ), but there was no significant difference in treatment-related mortality between patients who received curative treatments and those who received palliative treatments . Curative treatments improved overall survival in colorectal cancer patients with peritoneal metastasis and did not increase the risk of treatment-related mortality. Curative treatments were associated with a higher risk of treatment-related morbidity. These data highlight the importance for further investigation aimed at prevention of treatment-associated morbidity. Colorectal cancer (CRC) poses an increasing threat to global health. In 2014, more than 1.4 million individuals developed CRC, and CRC-related deaths accounted for nearly 9% of the global cancer mortality burden , 4, 5. EConsidering the poor life expectancy of CRC-PC, identifying an optimal treatment strategy to extend survival has always been a main objective of clinical oncologists. Traditionally, PC has been regarded as a terminal disease that is only amenable to palliation by systemic chemotherapy, palliative surgery or supportive care. However, with increasing knowledge regarding the patterns of CRC metastatic dissemination, experts are beginning to accept the viewpoint that PC may only be a local-regional disease entity that can be addressed in a more aggressive manner –16. In tCRS combined with IPC (CRS/IPC) is aimed at removing all visible peritoneal tumor implants by surgery firstly, followed by IPC to eliminate superficial peritoneal tumor remnants or solitary tumor cells , 22, 23.Figure The risk of bias evaluation of the three included RCTs is displayed in Figure 2 = 36.0%), and 2.22 for five-year survival   of survival data in all included studies were calculated based on the information extracted from Kaplan-Meier survival plots. Overall, patients who received curative treatments (53.8% [1287/2390 participants]) had improved short-term and long-term overall survival compared to those who received palliative treatments (46.2% [1103/2390 participants]) at the end of follow up. The pooled HR was 2.19 for three-year survival  Figure .2 = 68.0%), but there was no evidence indicating that curative treatments were associated with an increased treatment-related mortality .Seven studies provided data on the overall treatment-associated morbidity. Among 305 patients who received curative treatments, 151 49.5%) developed treatment-associated complications compared to 167 out of a total of 477 patients (35.0%) in the palliative treatment group. In eight studies, 31 deaths were recorded, of which 16 deaths  occurred in the curative treatment group and 15 deaths  occurred in the palliative treatments group. As shown in Figure 9.5% deve2 = 84%) and three-year peritoneal-disease-free survival , and had a decreased risk of recurrence . In the group that received curative treatments, the rate of readmission  was higher than in the group who received palliative treatments. No statistically significant differences between groups with respect to the rate of termination of the planned therapy were found . Because of the statistically significant heterogeneity in the method of data analysis or an irregular type of data, some studies could not be combined for meta-analysis. Verwaal et al. [p = 0.020). In addition, Park et al. [Individual and pooled HRs or ORs for other secondary outcomes are displayed in l et al.  reportedk et al.  and Simkk et al.  found a p = 0.80; five-year survival: p = 0.14) showed that there was no publication bias . Funnel plots and Egger's weighted regression  to assess the impact of other factors on clinical treatment endpoints of these curative treatments. We noticed that quite a few factors, such as higher Peritoneal Cancer Index , 34, higOverall survival benefits, although important, are certainly not the only concern in treating patients with CRC-PC. Treatment of CRC-PC requires high patient compliance, consideration of treatment-associated morbidity and mortality, and assessment of the risk for disease progression or recurrence. Our meta-analysis, although underpowered with regard to many of these important secondary outcomes, indicated that curative treatments could prolong disease-free survival and peritoneal-disease-free survival, decreases the risk of recurrence, and did not show any statistically significant difference in treatment-associated mortality or termination of the planned treatment. Curative treatments were associated with increased treatment-related complications, longer duration of hospital stay, and higher risk for short-term readmission. These data highlight the importance of further investigation aimed at prevention of treatment-associated morbidity in high-volume hospitals where CRS and IPC are widely implemented, by improving patient enrollment criteria, optimizing CRS and IPC procedures, and intensifying perioperative management.Our search for systematic reviews and meta-analyses on curative versus palliative treatments in patients with CRC-PC was updated in December 2016 and 2 additional published studies were identified. Cao et al.  concludeStrengths of this review include the detailed search strategy used to identify all potential eligible comparative studies on the treatment of CRC-PC. Furthermore, we assessed the risk of bias rigidly and applied rigorous means to control the bias during the analytic process. There are, however, several limitations of the present study. Based on the information available to us, we considered the majority of the included studies to be high quality. However, most of the included studies were retrospective nonrandomized studies, and thus inevitably subject to potential bias as a result of unmeasured variables that could have affected outcomes, for example an imbalance in baseline characteristics between groups. Another limitation is the issue of heterogeneity. Clinical and methodological diversity can be observed in any meta-analysis. Although we conducted subgroup analysis and utilized a random-effects model to assess and control the impact of heterogeneity, clinical heterogeneity  between studies may still be a potential source of bias in our report. Finally, although we used the endpoint of overall treatment-associated complications as reported from individual studies, we acknowledge the possibility of adjudication of related events due to lack of a uniform morbidity classification system.This systematic review and meta-analysis was conducted according to PRISMA  guidelines, and the background, rationale and basic methods utilized were specified in advance and documented in the PROSPERO database (CRD: 42016036628).We systematically searched the PubMed, Ovid, Embase, Web of Science, International Clinical Trials Registry Platform, and Cochrane Library up until December 31, 2016. We applied a highly sensitive search strategy, using a combination of the search terms “intraperitoneal chemotherapy”, “hyperthermia intraperitoneal chemotherapy”, “cytoreductive surgery”, “colorectal cancer ”, and “peritoneal carcinomatosis” to conduct literature retrieval without language restriction. Furthermore, we searched for abstracts from major cancer conferences from 2016 onward, including the American Society of Clinical Oncology Conference, the American Association for Cancer Research Conference, the European Society for Medical Oncology Conference, the European Cancer Congress, the European Society for Therapeutic Radiology and Oncology Conference, the World Congress on Gastrointestinal Cancer, and the World Cancer Congress. In addition, we identified other potentially eligible studies from the reference lists of studies identified through the search methods described above.Two researchers independently assessed the eligibility of studies obtained from the literature retrieval. Any disagreements were resolved through discussion, and the agreements were reached by consensus. We included studies that provided comparative data for curative treatments (CRS/IPC) versus palliative treatments  in adult patients with synchronous or metachronous CRC-PC. If the study reported comparative outcomes for different cancer subtypes, we only included data for patients with CRC-PC. When multiple articles reported on the same study, only the most recent or most informative publications were included. The primary outcomes considered in this study were three- and five-year overall survival rates. Secondary outcomes included incidence of treatment-related morbidity and mortality, disease-free survival, peritoneal-disease-free survival, frequency of termination of the planned treatment, recurrence rate of CRC-PC, and short-term readmission.Two researchers independently extracted and checked the data. For each included study, detailed information regarding the authors, year of publication, characteristics of the study population, study design, interventions, and outcome measures were extracted and recorded. If the study did not report accurate survival data and the authors did not respond to our inquiries, we extracted the data from Kaplan-Meier survival plots using graphic digitization software according to previously published methodology . Any dis2 statistics [In this study, results regarding the survival outcomes and other dichotomous outcomes were expressed as HR and OR respectively. For studies that did not report HR from survival analysis, HR and 95% confidence intervals (CI) were calculated from Kaplan-Meier survival curves by using a hierarchical series of steps described by Tierney . HR or Oatistics . Funnel atistics . We alsoEndNote  was used for bibliographic citation management. Stata software  and Review Manager  were used for the subsequent meta-analysis.Although a significant increase in the frequency of treatment-related morbidity, the evidence indicated that curative treatment improved survival in patients with CRC-PC. Curative treatment may also prolong a patient's disease-free survival and peritoneal-disease-free survival, decrease the risk of recurrence, and does not increase the risk of treatment-related mortality. In light of the existing evidence, we suggest that current clinical guidelines should be updated to support curative treatments as an alternative choice for patients with CRC-PC and call for further research to address the threshold at which the survival benefit associated with curative treatment begins to attenuate.


Lengthy, antimicrobial therapy targeting the pathogen is the mainstay of conventional tuberculosis treatment, complicated by emerging drug resistances. Host-directed therapies, including non-steroidal anti-inflammatory drugs (NSAIDs), in contrast, target host factors to mitigate disease severity. In the present Systematic Review, we investigate whether NSAIDs display any effects as therapy of TB and discuss possible mechanisms of action of NSAIDs as adjunctive therapy of TB. Ten studies, seven preclinical studies in mice and three clinical trials, were included and systematically reviewed. Our results point toward a beneficial effect of NSAIDs as adjunct to current TB therapy regimens, mediated by decreased lung pathology balancing host-immune reaction. The determination of the best timing for their administration in order to obtain the potential beneficial effects needs further investigation. Even if the preclinical evidence requires clinical evaluation, NSAIDs might represent a potential safe, simple, and cheap improvement in therapy of TB. Mycobacterium tuberculosis (Mtb) causing a wide spectrum of disease in humans (Tuberculosis (TB) is a chronic infectious disease caused by n humans . The curn humans . Drugs tn humans . The widn humans —act on hn humans .Neutrophils represent a protective immune response in early infection through secretion of oxidizing and hydrolytic agents targeted at the bacteria . While tThe aim of this review was to investigate whether NSAIDs are a useful HDT candidate for TB. With this purpose, we systematically reviewed the published manuscripts on the preclinical and clinical effects of NSAIDs when used as therapy of TB, alone or in combination with commonly used anti-TB drugs or BCG vaccination.We used the 2009 PRISMA guidelines to systematically review PubMed for studies published until January 2017 that evaluate NSAIDs as therapy of TB. The following search terms were used: “tuberculosis” OR “mycobacterium tuberculosis” combined with drug names of the NSAID group: ((tuberculosis OR (mycobacterium tuberculosis)) AND (ibuprofen OR aspirin OR naproxen OR etoricoxib OR indomethacin OR meloxicam OR celecoxib OR diclofenac (DCL) OR oxyphenbutazone OR carprofen) NOT “review” [publication type]).in vitro, open-label, and self-reporting studies as well as Case Reports. The reference list of included publications was furthermore screened for relevant publications. Disagreements between investigators were resolved by discussion. The full text of the included studies was reviewed for relevant information to answer the question whether NSAIDs as HDTs are beneficial during TB treatment. Information was systematically collected according to predetermined criteria, i.e., drug, study, experimental approach, TB patients/mouse strain, sample size, intervention, and outcome.Two investigators independently reviewed the title and abstract of all identified publications for relevance. Studies were deemed relevant when they met the following criteria: clinical or animal studies, English language, published on Pubmed from 1950 through January 2017, study subjects are TB patients , who received a drug from the NSAID-group. We excluded Two investigators independently reviewed the full text of all identified publications. For clinical trials (CTs), the Jadad Scoring System was used to evaluate quality .A total of ten relevant studies were identified and included for systematic review Table . The fulIbuprofen acts as an unselective cyclooxygenase (COX)-inhibitor. COX control the production of lipid mediators derived from arachidonic acid, such as prostaglandins (PGs), resolvins, lipoxins, leukotriene, and thromboxanes (TXAs). Three studies were found for Ibuprofen –15.Acetylsalicylic acid (AAS) is a non-selective COX-inhibitor, which irreversibly inhibits COX-enzymes. In addition to its anti-inflammatory effects, it is widely used in prevention of cardiovascular disease and strokes  due to iVilaplana et al. treated Mtb infected C3HeB/FeJ mice—in a murine model of active TB—with 80 mg/kg/day ibuprofen . Ibuprofin vivo study by Byrne et al. showed that both ibuprofen and aspirin enhance the effect of Z and might be evaluated to shorten therapy  or isoniazid (H), or with the NSAIDs ibuprofen or aspirin, alone or in combination with H. Treatment was started 1 day after infection . Compare therapy . Mtb-inf therapy .Two CT were found supportive of the synergistic effect of aspirin and Z: short-term, low-dose aspirin was shown to prevent the side effect of hyperuricaemia in Z-treatment of TB . Petty eSchoeman et al. conducted a double-blind, randomized phase II CT to evaluate the effect of aspirin-treatment as an add-on to standard anti-TB treatment (and prednisone) on mortality and morbidity of children with a probable diagnosis of tuberculous meningitis (TBM) . The priIndomethacin is a non-selective COX-inhibitor and a non-salicylate NSAID similar to ibuprofen. Two studies were identified which furthermore provide special insights into apparent immune-modulatory properties of NSAIDs-like indomethacin , 17.A study by Hernandez-Pando et al. evaluated immunosuppressive phenomena based on T-cell imbalance in the TB-granuloma and its treatability with cyclophosphamide and indomethacin . CyclophM. vaccae  . Mice weOur results are based on the search for specific NSAID drug names, we include only English written articles and exclude open-label and self-reporting studies as well as Case Reports. These restrictions in the search strategy impose a selection bias on results. Our review combines results, expressed as various endpoints, from ten different studies, where experimental approach, patients, sample size, and intervention differ  by two studies, which furthermore assessed differing characteristics of assessed granulomas , 17. HowM. vaccae  leads to uncontrolled inflammation and exacerbation of TB disease , 22. Infas IFN-γ , 24, 25.as IFN-γ , and thaas IFN-γ , 13. Finas IFN-γ .The reduction of prostaglandin E2 (PGE2) is considered one mechanistic explanation underlying the anti-inflammatory benefit of NSAIDs in the context of Mtb infection , as PGE2On the other hand, patients with severe TB-disease are at higher risk of developing thrombosis and stroke, due to an hypercoagulable state in advanced stages of the diseases . Low-dosThere is evidence that suggests an immune-mediated pathoetiology of vascular events in TB patients. Vasculitis in TBM is morphologically similar to other immune-mediated vasculitis  and the In vivo data by Dutta et al. suggests an enhancing effect of DCL on the TB-antibiotic S as well as an own anti-mycobacterial effect of DCL   . In contc effect . Z is coc effect . Microarc effect . This isin vitro . This doion of Z . HoweverM. vaccae by i.p. route of immunization was corrected by pre-treatment with indomethacin  against Mtb in whole blood from healthy volunteers (NCT02602509).Currently, four CTs are ongoing to evaluate the effect of NSAIDs during TB treatment. The anti-inflammatory properties of NSAIDs seem of potential benefit in TB-IRIS : an ongomethacin ; and thiIn conclusion, and despite open questions that should be addressed in further research and the well-known side effects, NSAIDs potentially have beneficial effect in treatment of TB , 13. EveAll authors made substantial contributions to the conception or design of the work. VK and MG contributed to the acquisition, analysis, interpretation of data for the work. All authors drafted the work, revised it critically for important intellectual content, and gave final approval of the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.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.