To provide evidence for the better clinical use of traditional Chinese medicine preparations (TCMPs), comparison of the pharmacological mechanisms between TCMPs with similar therapeutic effect is necessary. However, methodology for dealing with this issue is still scarce. Danhong injection (DHI) and Naoxintong capsule (NXT) are representative TCMPs for ischemic stroke (IS) treatment, which are also frequently used in combination. Here they were employed as research objects to demonstrate the feasibility of systems pharmacology approach in elucidation of the independent and combined effect of TCMPs. By incorporating chemical screening, target prediction, and network construction, a feasible systems pharmacology model has been established to systematically uncover the underlying action mechanisms of DHI, NXT, or their pair in IS treatment. Systematic analysis of the created TCMP-Compound-Target-Disease network revealed that DHI and NXT shared common targets such as PTGS2, F2, ADRB1, IL6, ALDH2, and CCL2, which were involved in the vasomotor system regulation, blood-brain barrier disruption, redox imbalance, neurotrophin activity, and brain inflammation. In comparative mechanism study, the merged DHI/NXT-IS PPI network and pathway enrichment analysis indicated that DHI and NXT exerted the therapeutic effects mainly through immune system and VEGF signaling pathways. Meanwhile, they had their own unique pathways, e.g., calcium signaling pathway for DHI and gap junction for NXT. While for their synergistic mechanism, DHI and NXT participated in chemokine signaling pathway, T cell receptor signaling pathway, VEGF signaling pathway, gap junction, and so on. Our study provided an optimized strategy for dissecting the different and combined effect of TCMPs with similar actions. Ischemic stroke (IS) is a common disease caused by intracranial or neck blood vessel occlusion that impairs blood flow to a portion of the brain and leads to subsequent cerebral necrosis . Due to Traditional Chinese medicine (TCM), characterized as multiple compounds and targets, differs in substance, methodology, and philosophy to chemical drugs . It has As the multicomponent and multitarget nature of TCMPs, it is very difficult to systematically study their mechanisms using routine methods . TherefoTo provide evidence for the better clinical use of DHI and NXT, here we proposed a feasible systems pharmacology-based method to explore the similarities and differences of the pharmacological mechanisms between DHI and NXT. Their synergistic mechanism in treatment of IS was also investigated. To our knowledge, no work has been reported about the mechanism comparison and synergistic effect of DHI and NXT. in silico ADME  system to screen candidate compounds; (2) the putative targets of the candidate compounds and IS were data-mined from various databases and literatures; (3) a basal TCMP-Compound-Target-Disease network was constructed to illustrate the interaction among DHI/NXT, ingredients, targets and IS; (4) for comparative study of the action mechanisms, two protein-protein interaction (PPI) networks named DHI-IS and NXT-IS PPI network were merged and pathway enrichment analysis was separately performed to explore the common and unique mechanisms of DHI and NXT; (5) for the study of their synergistic effect, DHI-NXT-IS PPI network was established among DHI-ingredient targets, NXT-ingredient targets, and IS targets. The enriched pathways were analyzed to explain the synergistic mechanisms of the drug combination.In this study, a network pharmacology approach based on chemical, pharmacokinetic, and pharmacological data was employed to systematically investigate the comparative and synergistic effects of DHI and NXT against IS. The overall procedure involved five steps : (1) theIn most systems pharmacology studies, the components in TCMPs were mechanically collected from chemical databases by simple summation of the compounds in each herb. As a matter of fact, the chemical substances and composition ratios of TCMPs differ dramatically due to different preparation processes. For example, tanshinones, as the main components from ethanol extract of Radix Salviae Miltiorrhizae, could not be experimentally detected in DHI because of its water extraction process , 35. Henhttps://www.drugbank.ca/) was employed to prescreen potential active ingredients in DHI and NXT. In this study, DL ≥ 0.18 was used to select candidate compounds for further research. Since NXT is consumed orally, oral bioavailability (OB ≥ 30%) and Caco-2 cell permeability (Caco-2 > –0.4) were also used to screen the candidate ingredients from NXT [Although TCMPs usually contain tens or hundreds of chemical ingredients, only a few of them with favorable pharmacodynamic and pharmacokinetic properties are responsible for their therapeutic effects. Drug-likeness (DL) is an important drug research parameter that used to assess whether a compound functions as a drug. Drug-like compounds are those which ‘contain functional groups and/or have physical properties consistent with the majority of known drugs' . Therefofrom NXT –33. Furthttp://stitch.embl.de/), Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform  [https://www.bindingdb.org/bind/index.jsp). Finally, 584 putative targets (177 targets were common for both DHI and NXT) were collected from 201 DHI-ingredient targets and 560 NXT-ingredient targets. Meanwhile, IS targets were gathered from Therapeutic Target Database , DrugBank (https://www.drugbank.ca/), PharmGKB (https://www.pharmgkb.org/), MalaCards , Comparative Toxicogenomics Database , and then manually supplemented through a wide-scale text-mining method [The putative targets of the candidate ingredients in DHI and NXT were derived from Search Tool for Interactions of Chemicals and Proteins Database   and Bindg method , 42. TheFor the purpose of interpreting the complex relationships among TCMPs, candidate ingredients, putative targets, and IS, a TCMP-Compound-Target-Disease network  was estaAs shown in the TCMP-Compound-Target-Disease network , the inghttps://string-db.org/) to acquire PPI data, respectively. The species was limited to “Homo sapiens” and the confidence score was set as 0.7. Irrelevant proteins, including the putative targets and IS targets that could not directly or indirectly interact with each other, were removed. Two PPI networks, named DHI-IS and NXT-IS PPI network, were generated by Cytoscape and then merged to identify common and unique targets of DHI and NXT . The top 20 pathways  for DHI and NXT were shown in To comparatively dissect the underlying mechanisms of DHI and NXT, 58 putative targets of DHI (combining 40 direct anti-IS targets with 18 indirect anti-IS targets) and 120 putative targets of NXT (combining 68 direct anti-IS targets with 52 indirect anti-IS targets) were employed to conduct pathway enrichment analysis, respectively. The pathway information was achieved from Database for Annotation, Visualization and Integrated Discovery  were entirely integrated into STRING database to acquire PPI data. The DHI-NXT-IS PPI network was shown in  p value < 0.05) was summarized in The 123 putative targets of DHI and NXT (combining 71 direct anti-IS targets with 52 indirect anti-IS targets) were employed to elucidate the synergistic mechanism of DHI and NXT against IS using DAVID database. The information of top 20 pathways  with the species limited to “Homo sapiens”.With names and/or chemical structures  as key words, the putative targets of the candidate ingredients were derived from STITCH, TCMSP, and Binding DB. The obtained targets were normalized to the official gene symbols using UniProt database  TCMP-Compound-Target-Disease network. TCMPs, candidate ingredients of DHI and NXT and their putative targets, were employed to build this network. The IS targets targeted by the ingredients of DHI and NXT were labeled by yellow circle.(2) Merged DHI-IS and NXT-IS PPI network and corresponding Target-Pathway (T-P) network. Based on the PPI data derived from STRING, with the species limited to “Homo sapiens” and a confidence score >0.7, two PPI networks named DHI-IS and NXT-IS PPI network were constructed for the ingredient targets of DHI and NXT interacting with IS targets, respectively. These two networks were merged to identify overlapping and distinct targets of DHI and NXT. Then the anti-IS targets of DHI and NXT were employed to conduct pathway enrichment analysis, respectively. The enriched pathway information of these targets was obtained from DAVID , and then T-P networks composed of anti-IS targets of DHI or NXT and their corresponding pathways were created, respectively. These two T-P networks were merged to explore common and unique mechanisms of DHI and NXT for treating IS.(3) DHI-NXT-IS PPI network and corresponding T-P network. A DHI-NXT-IS PPI network was established among DHI-ingredient targets, NXT-ingredient targets, and IS targets. Then the anti-IS targets were used to performed pathway enrichment analysis using DAVID database. The T-P network was generated to elucidate the synergistic mechanism of DHI and NXT in the treatment of IS.All these networks were created by Cytoscape 3.6.0, open software for visualizing, integrating, modeling, and analyzing the biological networks.To provide evidence for the better clinical use of TCMPs, comparison of the pharmacological mechanisms between TCMPs with similar therapeutic effect is necessary. DHI and NXT are representative TCMPs for IS treatment, which are also frequently used in combination. However, their independent and combined mechanisms have not been clearly clarified. In the present study, a feasible network pharmacology strategy based on chemical, pharmacokinetic, and pharmacological data was employed to elucidate the comparative and synergistic effects of DHI and NXT against IS. By systematic analysis of the constructed networks, we could learn that (1) the candidate ingredients of DHI and NXT not only could target the vasomotor system-related and blood-brain barrier-related proteins , but also could involve in the redox imbalance, neurotrophin activity, and brain inflammation . (2) DHI and NXT exerted the protective effects mainly through immune system and VEGF signaling pathways. But DHI and NXT also had their own unique pathways for treating IS, e.g., calcium signaling pathway for DHI and gap junction for NXT. (3) The synergistic mechanism of DHI and NXT was mainly associated with chemokine signaling pathway, T cell receptor signaling pathway, VEGF signaling pathway, gap junction, and so on. Overall, this study provided an effective approach for dissecting the comparative and synergistic effects of DHI and NXT in the treatment of IS.


Healthy aging limits the activities of daily living and personal independence. Furthermore, cognitive-motor interference in dual-task  appears to be more pronounced in the elderly. Transcranial direct current stimulation (tDCS), a form of the non-invasive brain stimulation technique, is known to modify cortical excitability and has been investigated as a tool for enhancing motor and cognitive performance in health and disease. The present study examined whether tDCS targeting the dorsolateral prefrontal cortex (DLPFC) could improve dual-task performance in healthy older adults. The effects of tDCS, among other factors, depend on stimulation polarity , electrode setup  and the time of application (off-line vs. on-line). We therefore explored the effects of unilateral and simultaneous bilateral tDCS  of left DLPFC while performing (on-line) the Grooved Pegboard Test (GPT) and Serial Seven Subtraction Test (SSST) alone or together . The number of pegs and the number of correct subtractions were recorded before, during and 30 min after tDCS. The dual-task performance was measured as the percent change from single- to the dual-task condition . Only bilateral, anode left tDCS, induced a significant increase in subtracted numbers while dual-tasking, i.e., it reduced the DTC of manual dexterity (GPT) to a cognitive task. Significant changes 30 min after the stimulation were only present after bilateral anode right (BAR) tDCS on GPT dual-task costs. These findings suggest that anodal tDCS applied on-line interacts with a dual-task performance involving demanding cognitive and manual dexterity tasks. The results support the potential use of non-invasive brain stimulation for improvement of cognitive functioning in daily activities in older individuals. We used a modification of a novel dual-task method to assess cognitive impairment in older adults involving upper-extremity dual-task function . Subjects were recruited by open email invitation and by “word of mouth” mostly amongst UAE University academic staff. All subjects were highly educated with a minimum of BSc degree. They were all right-handed according to the Edinburgh inventory  surface sponge electrodes placed on the scalp, giving the current density of 0.042 mA/cm2. This amount of stimulation is safe , set to deliver 1.5 mA current, through a pair of saline-soaked 35 cmA manual dexterity Grooved Pegboard Test (GPT) was given using standard Lafayette Instrument Company  32025 board. The Grooved Pegboard is a manipulative dexterity test in which pegs must be rotated to match the hole with randomly positioned slots before they can be inserted. The test measures performance speed in a fine motor task, which requires more complex sensory-motor coordination. The performance on GPT is insensitive to handedness but sensitive to sex . The starting number was randomly generated in the range between 290 and 330. The subjects were instructed to count backward every 7th number as quickly as possible within 30 s. The numbers were recorded on the paper, and the number of correct responses was counted .In dual-task, the selected initial number was shown when the pegboard test was started, and the subjects performed both tasks simultaneously as quickly as possible within 30 s. Subjects were asked not to prioritize either of the two tasks  was examined using Psychology Experiment Building Language . The order of the tDCS sessions was randomized between and within subjects. Sessions were separated by at least 2 weeks to minimize carryover effects. Unilateral tDCS was performed with the anode placed over the left or right DLPFC  and the cathode placed over the contralateral supraorbital region, serving as a return electrode , with subject as random effect (random intercepts) of the relationship between performance on each task alone, during dual-task, and dual-task costs, and tDCS montage for each of the three time points  separately. Here, the montage was the fixed effect, and all “active” montages were compared to Sham as their reference. The significance level was set to 0.05 for all analyses. Both p-values for individual effects as well as F-tests for main  effects are reported. P-values are all reported exactly  so that readers can adjust for multiple comparisons using Bonferroni corrections where considered appropriate. SPSS 18.0 software  was used for statistical analysis.To test the effect of tDCS on SRT, we used two-way repeated measure analysis of variance (ANOVA). To compare single- vs. dual-task performance for each outcome separately in each session a paired-samples F = 1.416, p = 0.236) before (PRE), during  = 1.088, p = 0.368) and after tDCS  = 1.032, p = 0.395) suggesting that tDCS did not influence SRT irrespective of the arrangement (montage) of DLPFC stimulation.Changes in the raw performance on single SSST and GPT tasks and the SRT across all experimental sessions are shown in p > 0.05.The performance on both single-tasks was similar in all sessions before, during and after tDCS . Furtherp < 0.0001; before, during and after; paired two-sample t-test). Similarly, the difference in performance between dual and single-task, expressed as dual-task costs, showed reduced dual-task performance.We explored whether tDCS of the DLPFC cortex could improve dual-task performance and whether this effect depends on the stimulation polarity and orientation, i.e., montage. Thus, we used a mixed linear model (as described above) with dual-task costs as outcome (dependent). As shown in This study was performed to investigate the “on-line” effects of tDCS of the DLPFC on dual-task performance in healthy aging. Our results extend earlier findings .ML designed the study, performed experiments, analyzed the data and wrote a manuscript draft. JO performed the experiments and helped in data analysis. SF helped in data interpretation and manuscript writing. JB helped with data analysis and manuscript proofreading. MS helped in study design, data interpretation, and manuscript proofreading. NN helped in study design, statistical analysis, and manuscript proofreading.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.


Serum potassium levels were significantly lower in the capreomycin-based group than in the kanamycin-based group . The incidence of hospitalization and requirement for a change in the treatment regimen due to electrolyte imbalances were higher in the capreomycin-based group. No previous longitudinal study has evaluated serum potassium, magnesium, and calcium from the first month of MDR-TB treatment with either kanamycin-based or capreomycin-based regimens. Our findings emphasize the importance of routine monitoring of serum potassium, magnesium, and calcium during MDR-TB treatment, and that more attention should be paid when treatment is given using the capreomycin-based regimen. Moreover, our study supported the 2018 World Health Organization treatment guideline recommendations for removal of kanamycin and capreomycin from the MDR-TB regimens.Treatment of multidrug-resistant tuberculosis (MDR-TB) with second-line injectable drugs may result in an electrolyte imbalance. This retrospective study was performed to compare and evaluate the effect of kanamycin and capreomycin on serum potassium, calcium, and magnesium in the first and second month treatment at a tertiary, top-referral hospital in Bandung, Indonesia. Data from 84 subjects with complete medical records of at least serum potassium during either kanamycin-based or capreomycin-based treatment were retrieved from the institutional database. Among these, 53 subjects had complete serum calcium data and 53 subjects had complete serum magnesium data. After the first month of MDR-TB treatment, there was a significant decrease in mean serum potassium (4.0 ± 0.4 mEq/L to 3.7 ± 0.5 mEq/L,  Multidrug-resistant tuberculosis (MDR-TB) remains a worldwide scourge and presents a major challenge to TB eradication campaigns. It is defined as TB resistant to at least both rifampicin and isoniazid . InapproMycobacterium tuberculosis is still sensitive. Patients in the intensive phase treatment of MDR-TB require at least 4 effective TB medicines. One of the most important drug types other than fluoroquinolones are second-line injectable drugs [The standard treatment regimen for MDR-TB consists of a combination of first-line and second-line TB drugs to which le drugs . In Indole drugs –10.Our study aimed at comparing and evaluating the effects of kanamycin and capreomycin on serum potassium, calcium, and magnesium levels during the first and second month of MDR-TB treatment.This was a retrospective cohort study conducted at Dr. Hasan Sadikin General Hospital, a tertiary, top referral, university-affiliated teaching hospital in Bandung, Indonesia. The study was approved by the Ethics Committee of Dr. Hasan Sadikin Hospital , and the need to obtain informed consent from patients was waived due to the retrospective nature of the study.We retrospectively retrieved the complete medical records of adult MDR-TB patients in the MDR-TB clinic of the Dr. Hasan Sadikin Hospital between January 2012 and September 2017. The selection criteria included the following: (1) age ≥ 18 years, (2) MDR-TB diagnosis based on standard diagnosis criteria  and MDR-TB treatment using a kanamycin-based  or capreomycin-based  regimen –14, and Based on a previous study of the effect on kanamycin on serum potassium , we calcThe occurrence of hypokalemia, hypomagnesemia, or hypocalcemia in each group after initiation of MDR-TB treatment was the main outcome of this study. We also evaluated the incidence of subjects that required hospitalization, shifted to other regimens in the first month or second month of treatment within each group. Laboratory examinations were performed at the clinical pathology department of Dr. Hasan Sadikin Hospital, Bandung, at the initial visit and during the end of the first and end of the second month of treatment. Hypokalemia was defined as serum potassium levels < 3.5 mEq/L . Hypomagt tests. Comparisons of the medians of continuous variables between the kanamycin-based and capreomycin-based groups were performed by using the Mann–Whitney test. Comparisons of the means of continuous variables among the initial, first, and second months of treatment were performed by using analysis of variance (ANOVA). Comparisons of the medians of continuous variables among the initial, first, and second months of treatment were performed by using the Wilcoxon test. Categorical data were analyzed using Fisher's exact test. A p value < 0.05 was considered statistically significant.Statistical analysis was conducted using SPSS statistical software. Baseline characteristics of subjects in the kanamycin-based and capreomycin-based regimen groups were compared. Continuous variables with a normal distribution were reported in terms of mean and standard deviation. Continuous variables with a skewed distribution were reported in terms of median, minimum, and maximum values. Comparisons of the means of continuous variables between the kanamycin-based and capreomycin-based groups were performed by using unpaired There were 84 subjects with complete medical records of serum potassium analyses. Among them, 53 subjects had complete medical records of serum magnesium and 53 subjects had complete medical records of serum calcium analyses. Among the 84 subjects with complete serum potassium data, 44 subjects were treated with the kanamycin-based regimen and 40 subjects were treated with the capreomycin-based regimen. Among the 53 subjects with complete serum magnesium data, 34 subjects were treated with the kanamycin-based regimen and 19 subjects with the capreomycin-based regimen. Among the 53 subjects with complete serum ion calcium data, 33 subjects were treated with the kanamycin-based regimen and 20 subjects with the capreomycin-based regimen. There was no significant difference in baseline characteristics, such as sex, age, comorbid conditions, concomitant drugs, initial serum potassium levels, and initial serum magnesium levels .There was a significant decrease in mean serum potassium levels within each group during the first month and second month of treatment; hypokalemia was significantly lower in the capreomycin-based group than that in kanamycin-based group during the second month of treatment Tables  and 3. MIn the capreomycin-based group, 2 subjects were hospitalized due to electrolyte imbalances in the first month and 1 during the second month; moreover, 1 subject underwent a regimen change from the first to the second month of treatment in the capreomycin-based group. No subject was hospitalized due to electrolyte imbalances or required a change of regimen in the kanamycin-based group.Second-line injectable drugs are bactericidal antibiotics and include aminoglycoside and polypeptide antibiotics. Kanamycin is the aminoglycoside most frequently used in MDR-TB regimens, while capreomycin is a cyclic peptide antibiotic inhibiting ribosomal protein synthesis. Both drugs are excreted through the kidneys and may result in electrolyte imbalance as an adverse effect due to this renal excretion , 19, 20.nd month of treatment in the capreomycin-based group; additionally, 2 subjects in this group had severe hypomagnesemia. To date, only case studies have reported hypocalcemia in patients treated with the capreomycin-based regimen and the kanamycin-based regimen [Electrolyte imbalances have been reported since the early use of capreomycin . Similar regimen , 25, 26.+, K+, and Cl− symporter channel (NKCC2), renal outer medullary potassium channel (ROMK), Na+ and K+-ATPase, and/or paracellular diffusion. Moreover, aminoglycosides and capreomycin could induce secondary hyperaldosteronism. These all increase urinary excretion of potassium, magnesium, and calcium, resulting in hypokalemia, hypomagnesemia, and hypocalcemia [Kanamycin and capreomycin can cause electrolyte imbalance through stimulation of the calcium-sensing receptor (CaSR) in the thick ascending limb of the loop of Henle. Both drugs, mimicking the effect of extracellular calcium stimulation, inhibit the Nacalcemia , 27, 28.calcemia . Age migcalcemia , 15. In calcemia , 22. In Moreover, in 2018, the World Health Organization (WHO) no longer included either kanamycin or capreomycin in MDR-TB treatment regimens, due to the increased risk of poor outcomes . The resNo previous longitudinal study evaluating serum potassium, magnesium, and calcium during MDR-TB treatment in both kanamycin-based and capreomycin-based regimens has been reported to date. Moreover, our study included only subjects with no other comorbid diseases or who were taking medications that may affect serum potassium, magnesium, and calcium levels at baseline. Subjects with electrolyte disorder usually require supplementation, which consequently influence the serum electrolyte levels. Therefore, our study excluded subjects with hypokalemia, hypomagnesemia, or hypocalcemia at baseline.Our study had several limitations. First, there was no adjustment for dietary factors that might influence serum potassium, magnesium, and calcium levels. Second, some TB drugs might induce nausea, vomiting, or diarrhea, which can alter electrolyte levels. We did not have access to records of these adverse effects in our study. Third, since serum calcium and magnesium were not routinely examined, many subjects did not have complete data on serum calcium and magnesium levels during treatment. This might have resulted in a bias due to a reduced data set. Fourth, we did not measure the effect of vitamin D on serum calcium levels. Fifth, we did not examine plasma aldosterone levels and thus could not rule out secondary hypoaldosteronism as a cause of an electrolyte imbalance. We also did not have any data on blood gas, or serum sodium levels, which may provide more information about the magnitude of the effect of kanamycin-based and capreomycin-based regimens. Further studies involving a greater number of subjects, with a prospective design, and evaluating more electrolytes, such as sodium, are thus warranted.Our study underlined the importance of routine monitoring of serum potassium, magnesium, and calcium levels, starting from the first month of MDR-TB treatment involving either kanamycin-based or capreomycin-based regimens and showed a greater electrolyte imbalance in the capreomycin-based group. Our study findings supported the 2018 WHO recommendation for removal of kanamycin and capreomycin from MDR-TB treatment regimens.


It is indicated that lipids profiles are associated with carotid plaque and Atherosclerosis. However, studies about the relationship between serum lipid profiles and carotid plaque composition in Chinese Population is limited. We conducted a cross-sectional study among 3,214 participants between January 2015 and December 2017 in China, to investigate the association between various lipid profiles and the prevalence of carotid plaque. Logistic regression model was used to investigate the association between plasma lipid profiles and odds of carotid plaque. Analysis of covariance (ANCOVA) was used to compare the mean plasma lipid profiles among different number and composition of carotid artery plaques. HDL-C, Non-HDL-C levels, TC/HDL-C, LDL-C/HDL-C were significantly associated with the presence of carotid plaque; HDL-C, LDL-C, Non-HDL-C levels, TC/HDL-C, LDL-C/HDL-C were significantly associated with the presence of common carotid artery (CCA) plaque. Compare with participants without carotid plaque, increased level of LDL-C/HDL-C was found in those with echolucent/polytype plaque. Similarly, compared with participants without CCA plaque, increased level of LDL-C/HDL-C was found in those with echolucent plaque. In conclusion, we found that serum HDL-C, Non-HDLc level, TC/HDLc, and LDLc/HDLc were all associated with the prevalence of carotid plaque, and LDL-C/HDL-C differed among different group of carotid plaque composition. Atherosclerosis is the leading contributor to CVD, and treatment of atherosclerosis is an essential step towards appropriate management and prevention of CVD2. Atherosclerosis is a systemic progression starting at young age and typically remains asymptomatic until late life, which could manifest in multiple vascular beds. Some researchers have demonstrated that atherosclerosis of peripheral vascular like carotid artery is one of the most significant prognostic predictors of cardiovascular morbidity and mortality4. Therefore, early detection and treatment of patients with carotid plaque may promote the prevention of CVD. Currently, the majority of carotid ultrasound studies have used carotid intima-medial thickness (IMT) as a surrogate marker for atherosclerosis. However, IMT is not as solid evidence for atherosclerotic infiltration in the arterial wall as significant plaque is5. Several studies indicated that the presence of plaque predicted the onset of cardiovascular and cerebrovascular diseases more accurately than the mean IMT, and the accuracy of this prediction was equivalent to that from pulse wave velocity in hypertensive patients8.Cardiovascular disease (CVD), caused 17.7 million deaths in 2015, is the major cause of death worldwide9. Previous studies suggested that lipid profiles  were significantly associated with carotid plaque14. Other studies found that lipid profiles were associated with common carotid artery- intima-media thickness (CCA-IMT) thickening15, carotid intima-media thickness13, carotid femoral-pulse wave velocity (CF-PWV)16, or carotid intima-media roughness17. However, there have been few studies about the relationship between serum lipid profile and carotid plaque composition in Chinese Population. We therefore conducted the current study to investigate the association between various lipid profiles and the prevalence of carotid plaque and carotid plaque composition in a general Chinese population.Lipid profiles have a pivotal role in the CVD pathophysiology and is an important modifiable risk factor for CVDP < 0.001).A total of 3,214 participants  were included in the analysis. The characteristic of study participants are summarized by gender in Table P-trend = 0.001) and CCA plaque ; (2) higher LDL-C with higher odds of CCA plaque ; (3) higher Non-HDL-C with higher odds of carotid plaque  and CCA plaque ; (4) higher TC/HDL-C with higher odds of carotid plaque  and CCA plaque ; (5) higher LDL-C/HDL-C with higher odds of carotid plaque  and CCA plaque .The associations between lipid profiles and the odds of carotid plaque/CCA plaque are presented in Table The covariate-adjusted mean lipid profiles according to composition of carotid artery/CCA plaques were presented in Tables The covariate-adjusted mean lipid profiles according to number of carotid artery/CCA plaques were presented in Tables P-values were greater than 0.10).The subgroup analyses generally yielded results consistent with the above findings Table . There wTo the best of our knowledge, this is the largest study in China to investigate the association between lipid profiles and the prevalence of carotid plaque and carotid plaque composition. The main results are as follows: serum HDL-C level was negatively associated with odds of carotid plaque and CCA plaque; serum LDL-C level was positively associated with odds of CCA plaque; serum Non-HDLc level, TC/HDLc, and LDLc/HDLc were positively associated with odds of both carotid plaque and CCA plaque. LDL-C/HDL-C differed among different group of carotid plaque composition.18. Several procedure associated with the progression of the atherosclerotic lesions might be relevant with the development of plaque. It has been demonstrated that carotid plaque, especially the thick and irregular ones were risks factor for cardiovascular disease21. Therefore, identification of serum biomarkers related to the presence of plaque would be of great advantage in the prevention of atherosclerosis and CVD. The various lipid profiles examined in our study were related with carotid plaque, thus might be correlated with CVD. Previous studies suggested that lipid profiles have pivotal roles in the pathophysiology of carotid plaque17, which is consistent with our study. In contrast, one study in USA found no significant association between HDL-C or TG and carotid plaque, but the authors reported that higher TC, LDL, or non-HDL was associated with higher risk of carotid plaque22. An Algeria cross-sectional study also suggested inconsistent findings: lower HDL-C is associated with higher prevalence level of carotid plaque, but not LDL-C23. The inconsistency might be ascribed to many factors, including the study population heterogeneity, various study regions and different study designs.Advanced atherosclerotic plaques are characterized as lipid nucleus which were covered with fibrous caps consisting of extracellular matrix and smooth muscle cells24. Previous studies have demonstrated that hypoechoic plaques (echolucent) are more often associated with cardiovascular symptoms than hyperechoic ones (echorich). The meta-analysis conducted by Jashari et al. demonstrated that carotid plaque echogenicity was associated with increased risk of CV events25. However, evidence regarding the relationship between serum lipid profile and carotid plaque composition in Chinese Population is limited. Our study found that LDL-C/HDL-C level was increased in those with echolucent plaque than those without carotid plaque. The analysis from our study provides new evidence for the associations between plaque characterization/features and health related outcomes.Ultrasound (US), a non-radiative and cost-effective technique, is a patient-friendly an ideal method for immediate diagnosis and follow-up26. Second, it has been demonstrated that HDL-C has both direct and indirect anti-inflammatory effects with potential antithrombotic results27.Third, the LDL-C/HDL-C ratio is closely correlated with the distribution of HDL-C subclasses. With the increase of LDL-C/HDL-C ratio, the size of HDL-C particles generally decreases, suggesting that the maturation process of high density lipoprotein is blocked, which may be one of the contributors for the progress of atherosclerosis28.The potential pathophysiological mechanisms through which lipid profiles might increase the risk of carotid plaque are not fully understood. First, the main beneficial effect of HDL cholesterol is to reverse the transport of cholesterol, remove free cholesterol from endothelial macrophages, and return it to the liver for excretion into bile, thus preventing the formation of atherosclerotic plaquesThere were some strengths in this study. First, we collected information on several potential confounders, and the potential effects of them were taken into account. Second, we firstly investigated the association of various lipid parameters and carotid plaque composition in Chinese Population. Third, subgroup analyses generally yielded similar results, indicating that the associations are robust.29. In addition, compared with CT or MRI, ultrasound is safe, noninvasive, and inexpensive30.Despite these strengths, the study also had several limitations. First, this is a cross-sectional analysis, thus it is difficult to detect the temporal relationship. Second, our study was carried out in a single-center, and these finding should be verified in multi-center study with larger populations. Last, we used ultrasound to assess the presence of plaque, which may be less reliable than the high-resolution magnetic resonance imaging (MRI) or computed tomography (CT). However, one study investigating the accuracy of ultrasound, CT, and MRI in diagnosis of carotid plaque morphology found that ultrasound has higher accuracy for diagnostics of carotid plaque morphology than CT or MRIIn summary, our study demonstrated that serum HDL-C level was associated with lower odds of carotid plaque and CCA plaque; serum LDL-C level was associated with higher odds of CCA plaque; serum non-HDL-C level, TC/HDL-C ratio, and LDL-C/HDL-C ratio were associated with higher odds of carotid plaque and CCA plaque. LDL-C/HDL-C differed among different group of carotid plaque composition. Further prospective studies with larger sample size are needed to verify these associations.During January 2015 and December 2017, 3,214 consecutive participants  who underwent a standard medical screening at the Physical Center of the First Affiliated Hospital of Zhengzhou University, China, were included. We excluded participants with the following conditions that might seriously influence carotid plaque and lipid profiles: (1) aged less than 18 years old; (2) with a history of cardiovascular disease, peripheral arterial disease, oncology disease, infectious disease, or serious liver or renal disease; (3) without data on lipid profiles or carotid ultrasound measurements; (4) taking medicine when undergoing the medical examination.Overnight fast blood samples were collected in the morning. Plasma levels of TC, triglycerides (TG), HDL-C, and LDL-C were measured by a fully automatic analyzer, ROCHE  module Cobas 8000 (C701/C702/C502), and kits were procured by ROCHE. Quality control is maintained by the laboratory with standard procedures. The coefficient of variation for repeated measurements on samples from individual hospitalized patients is maintained at ≤2.5%.CIMT) was defined as the mean of the right and left IMT of the CCA.Carotid ultrasound was assessed by B-mode ultrasound with an Aplio 300 ultrasound system  by trained and certified technologists. With the subject lying in a supine position, the extracranial carotid arteries were imaged in the longitudinal  and transverse planes, the common carotid artery (CCA), the internal carotid artery (ICA), and the external carotid artery (ECA) on both sides were carefully scanned under B-mode imaging from multiple directions. The IMT was defined as the distance between the leading edge of the lumen-intima echo and the leading edge of the media adventitia echo. The carotid intima-media thickness , echogenic , and heterogeneous (mixed echolucent and echogenic)32. If all the plaques had the same composition, the participant was classified as plaque composition, those who had different composition were defined as polytype plaques. All carotid artery plaque measurement was conducted by the same trained physician using the same B-mode ultrasound. The study adopted strict quality control procedures for monitoring and testing consistency in image acquisition and image analysis.Carotid plaque is defined as the presence of focal wall thickening that is at least 0.5 mm, or 50% greater than that of the surrounding vessel wall, or as a focal region with CIMT greater than 1.5 mm that protrudes into the lumen that is distinct from the adjacent boundaryA standard physician-administered questionnaire was used to collected information on the demographic characteristics, lifestyle factors, and medical history by trained physicians. Participants who smoked at least one cigarette per day or drank alcohol once a week for at least six months were defined as smokers or drinkers. Weight and height were measured on an auto-anthropometer with subjects wearing light clothing and no shoes. Body mass index (BMI) was calculated as the weight (kg) divided by the square of the height (m). Blood pressure was measured using an electronic device by trained physicians after the subjects sitting relaxed for 10 mins.Descriptive data are presented as mean (standard deviation) for continuous variables and number (percentage) for categorical variables.2); Model 2: further adjusted for systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting plasma glucose, uric acid, TC (not for TC vs. carotid plaque), TG (not for TG vs. carotid plaque), HDL-C (not for HDL-C vs. carotid plaque) and LDL-C (not for LDL-C vs. carotid plaque).Logistic regression model was used to examine the association between plasma lipid profiles and odds of carotid plaque. And two models were developed: Model 1: adjusted for age , sex , and BMI . Each potential modifier was examined in a separate model by adding a multiplicative interaction term .Analysis of covariance (ANCOVA) was used to compare the mean plasma lipid profiles among different number and composition of carotid artery plaques. The two aforementioned models were also adopted. Subgroup analyses were conducted to investigate whether the relationships between plasma lipid profiles and carotid plaque were modified by sex (men or women) or BMI  among different composition/number of carotid plaque . Two-side P values < 0.05 were considered statistically significant for the other associations.All analyses were performed with SPSS 21.0 for Windows . Two-sided bonferroni correction Ethical approvals for the study were obtained from the ethics committees of the First Affiliated Hospital of Zhengzhou University. Informed consent was obtained from all participants before they participate the study. And all procedures were performed in accordance with the approved guidelines laid down in the Declaration of Helsinki.Supplemental Tables


Normal aging is known to be accompanied by decreased segregation across the whole-brain functional network, which is associated with cognitive decline. Although compelling evidence supports reduced segregation and increased integration in whole-brain functional connectivity with aging, the age effect on the reorganization of large-scale functional networks at the hemispheric level remains unclear. Here, we aimed to examine age-related differences in inter-hemispheric interactions and intra-hemispheric integration by using resting-state functional MRI data of a healthy adult lifespan sample. The results showed that age-related decreases in inter-hemispheric integration were found in entire functional networks in both hemispheres, except for the sensorimotor network (SMN) and posterior default mode network (DMN). Specifically, aging was accompanied by increasing inter-hemispheric segregation in the left frontoparietal network (FPN) and left ventral attention network (VAN), as well as right-brain networks located in the auditory network (AN), visual network (VN), and temporal parts of the DMN. Moreover, aging was associated with increasing intra-hemispheric integration within the bilateral VN and posterior DMN while decreasing intra-hemispheric integration within the right VAN. These remarkable changes with aging confirm that there are dynamic interactions between functional networks across the lifespan and provide a means of investigating the mechanisms of cognitive aging. Population aging is unexpectedly increasing throughout the world, and it has also been a major focus of research in the neuroimaging field . Over thA common finding among rs-fMRI studies has indicated that aging is associated with decreased resting-state functional connectivity (rsFC) in some brain networks , 9, 12 aRegarding the decreased and increased functional connectivity in aging, several theories aim to provide an integrative interpretation for brain function and cognition changes in aging, in which one classical view—the hemispheric asymmetry reduction in old adults (HAROLD) model—has pointed out a compensatory function between hemispheres in older adults in that a less lateralized pattern of activity can counteract age-related neurocognitive decline . In factIn sum, typical aging will weaken the rsFC in particular functional networks  and enhance the interaction between other functional networks . However, it remains unclear whether intra- and inter-hemispheric segregation and integration occur across the healthy adult lifespan and whether there are distinguishing patterns between two hemispheres. Accordingly, in this cross-sectional study, we aimed to examine age-related differences in the interactions of inter- and intra-hemispheric resting-state functional networks based on the symmetrical cortical template of the human brain.The group-level network partition across two hemispheres detected by the Louvain algorithm resulted in 11 functional networks  correspor = 0.24, P < 0.001) and VAN  in the left hemisphere, whereas age was positively associated with inter-hemispheric segregation of brain networks in the right hemisphere mainly located in the DMN1 , AN , and VN . After controlling for sex and mean FD, consistent relationships were found between age and inter-hemispheric segregation in these systems  and VN  in both hemispheres. Additionally, age was negatively associated with intra-hemispheric integration in the right VAN  after controlling for sex and mean FD . FurtherTo expand on the observations regarding the dynamics of intra-hemispheric integration with aging, we used an alluvial diagram to illustrate changes in community assignments of brain regions in each hemisphere across three age groups. As shown in This study used cross-sectional resting-state fMRI data to characterize age-related effects in inter-and intra-hemispheric brain functional connectivity across the healthy adult lifespan. The present findings indicated that increased age is related to less inter-hemispheric functional connectivity between homotopic networks, which seemed to be a result of increased inter-hemispheric segregation with age in most networks. However, the age effect on inter-hemispheric segregation showed distinct patterns in the two hemispheres: the FPN and VAN in the left hemisphere and the AN, DMN1, and VN in the right hemisphere. In addition, increasing age was accompanied by increasing intra-hemispheric integration of brain networks located in the bilateral VN and posterior DMN, as well as decreasing intra-hemispheric integration in the right VAN. Further analysis showed that decreasing the number of communities with age in this process that the sub-components of the DMN gradually merged into a whole, parts of nodes in the SN were taken into the SMN, and the AN and VAN were integrated into the FPN. These findings provide hemisphere-level evidence of age-related functional degeneration of the brain across the adult lifespan. Below, we discuss the implications concerning these observations for understanding the functional reorganization of brain networks and cognition decline with aging.First, most networks had less inter-hemisphere communication with aging except for the SMN and DMN2, which means aging is accompanied by the intensive attenuation of functional connectivity. Consistent findings have provided evidence that typically aging people present disrupted connectivity , 25. It Although the communication between the hemispheres decreased in general, the networks with increasing functional segregation were not symmetrical in the two hemispheres. This study found that with aging, the FPN and VAN in the left hemisphere had reduced inter-hemispheric connectivity, while the DMN1, AN, and VN in the right hemisphere decreased functional connectivity with the opposite hemisphere. This asymmetric distribution of networks with increasing segregation may have been associated with lateralization-related changes in aging. The HAROLD claims that an age-related decrease in lateralization may result from the non-dominant hemisphere increasing activity as a compensatory mechanism. However, our findings seem to be inconsistent with an account based on the HAROLD model. Converging studies have proposed that the FPN is a right-hemisphere–lateralized network , 35. In The DMN1 shows left lateralization and contains key regions for long-term memory and auditory processing . The domOn the other hand, some evidence has suggested that the whole-brain networks become more integrated with aging, which seems to contradict our findings . These sOf additional interest, typical aging was accompanied by dynamic changes in community assignments within the two hemispheres. Concretely, the tendency for changes in the community assignments was similar between two hemispheres: the sub-components of the DMN gradually merged into a whole, parts of the nodes in the SN merged into the SMN and AN, and the VAN disappeared and blended into the FPN. First, we found that a decreased number of modules across age groups was in line with compelling evidence of age-related decreases in modularity due to decreased connections within specific functional networks or global changes throughout the networks , 13, 48.Although our study extended the knowledge of brain functional connectivity in the aging process, the following limitations and considerations should be noted. First, we only explored the age-related effects in hemispheric functional interactions using resting-state fMRI data; however, the resting-state functional connectivity is constrained by the brain structural architecture . Thhttp://fcon_1000.projects.nitrc.org/indi/retro/sald.html. The dataset contains 494 participants , in which 60 participants were excluded according to a rigorous criterion for framewise displacement  exploring the developmental trajectories of brain structural and functional changes in healthy adults . The SAL 0.2 mm; , 56). Th2, resolution matrix = 64×64, thickness = 3 mm, interslice gap = 1 mm, and acquisition voxel size = 3.4 × 3.4 × 4 mm3. During resting-state scanning, the subjects were instructed to remain awake with eyes closed and rest without thinking of anything in particular. Additionally, high-resolution T1-weighted structural images were obtained using a magnetization-prepared rapid gradient echo (MPRAGE) sequence: TR = 1900 ms, TE = 2.52 ms, inversion time = 900 ms, flip angle = 9°, resolution matrix = 256 × 256, slices = 176, thickness = 1.0 mm, and voxel size = 1 × 1 × 1 mm3.The MRI data were collected from a 3-T Siemens Magnetom Trio scanner  at the Brain Imaging Research Central in Southwest University. The resting-state functional images were acquired using gradient echo-planar imaging (GRE-EPI) sequences with the following parameters: repetition time (TR)/echo time (TE) = 2000/30 ms, slices = 32, flip angle = 90 degrees, field of view = 220× 220 mmImage preprocessing was performed using the Data Processing and Analysis for Brain Imaging  implemeAn absolutely symmetrical template excluding the cerebellum with 512 regions in each hemisphere was applied to calculate intra- and inter-hemispheric functional connectivity , 60. FirIn this study, we defined a measure of inter-hemispheric segregation as a way of quantifying the differences in within-hemisphere connectivity for a given network in relation to its between-hemisphere connectivity. Specifically, for a given network, within-hemisphere connectivity was estimated by summing the z-values of the correlations between nodes within the network to nodes in the same hemisphere. Conversely, between-hemisphere connectivity was calculated by summing the z-values of the correlations between nodes within the network and nodes located in the contralateral network. The inter-hemispheric segregation was computed with the differences in the within-hemisphere summed magnitudes and the between-hemisphere summed magnitudes as a proportion of the within-hemisphere summed magnitudes, as noted in the following formula:where In addition, intra-hemispheric integration was evaluated by extending the measure of participation coefficient, which reflects the extent to which a node interacts with nodes in other networks. In this study, the intra-hemispheric integration of a network was calculated as the mean participation coefficient  across aFirst, we examined the Pearson correlation between inter-hemispheric segregation and age after controlling for the participant’s sex and mean FD. Then, we estimated the relationship between age and intra-hemispheric integration after controlling for the participant’s sex and mean FD using Pearson correlation. For all analyses, the Bonferroni correction was used for multiple comparison corrections at α = 0.05. Finally, we explored dynamic brain interactions at the system level across the lifespan by community detection. More specifically, we calculated the differences in the community assignments of nodes across the three age groups .Supplementary FiguresSupplementary Table 1


Magnaporthe oryzae imposes a great threat to global food security. Intensive investigation has been conducted to elucidate M. oryzae pathogenicity and rice (Oryza sativa L.) defense mechanism against blast disease, in order to provide theoretical basis and/or identify potential target(s) for developing novel disease control strategies, as well as for breeding of resistance varieties. Phytohormones have been demonstrated to play conserved and divergent roles in fine-tuning the balance of rice growth and immunity towards M. oryzae. Meanwhile, M. oryzae evolved elaborate strategy to manipulate the rice phytohormones metabolism, or even directly produce and secrete phytohormones, during their invasion process. In this review, we discuss the chemical communication in term of phytohormones in M. oryzae-rice pathosystem.Phytohormones  are chemicals produced by plants in order to modulate various aspects of plant development, stress responses and defence. Recent studies revealed that fungi can also produce phytohormones or phytohormone-mimiking molecules, while it remains poorly understood about the details in the role and regulatory mechanism of such fungal produced phytohormonal molecules in plant-fungus interactions. The rice-blast fungus  Plants dynamically response to environmental stimuli, including pathogen invasion. A sophisticated coevolution is indicated in parasitic association between fungi and plants, involving mutual perceptions and reactions   is favourable for M. oryzae in its hyphae and condia  and an ABA G-protein couple receptor were identified in M. oryzae  expression, suggesting that it may stimulate ABA synthesis in rice to facilitate its own pathogenicity and subvert host resistance  is a bioactive form of JA, and its level increases in response to blast infection. Endogenous JA-Ile is involved in blast-resistance mainly through facilitating production of the flavonoid phytoalexin, sakuranetin  phytohormonal molecules including auxin (IAA), ABA and various CKs, and also able to induce rice ABA synthesis. M. oryzae could reduce rice JA synthesis, and convert JA to 12-OH JA synthesis instead of production of an active blast-resistance JA derivative, JA-Ile. In this review we individually discussed each type of phytohormone in M. oryzae-rice interaction, but in actual scheme the phytohomone signaling pathways are in a complex network with multiple crosstalk with each other. So far it has not been reported on whether other types of phytohormones (SA/ET/BR etc) could be derived from M. oryzae, although such possibility could not be ruled out. By this review we would like to emphasise that phytohormones are not just plant growth regulators, but also a chemical language used between plants and fungi, for efficient inter-kingdom (competitive) communication.Phytohormones are small molecules produced by plants to regulate growth and development in response to various physiological or environmental stimuli, thus simulate a language used by plants for better communication among different parts. Pathogenic fungi, that deploy nutrients from host for their own survival, learn to speak this phytohormone language during their co-evolution with host plants. In this review, we use nication . M. oryz


Chronic active Epstein-Barr virus (EBV) infection (CAEBV) of the T-/NK-cell type, systemic form is a rare and potentially life-threatening illness caused by persistent EBV infection. The highest incidence is found in children and adolescents with increased frequency among Asians and Native Americans, while the disease is uncommon in Western countries. Typically patients present with unspecific symptoms, like fever, lymphadenopathy, hepatosplenomegaly and liver dysfunction. Due to fatal complications including hemophagocytic syndrome, coagulopathy, multiple organ failure and development of EBV-positive lymphoproliferative disease (LPD) or lymphoma early diagnosis is critical for successful treatment. However, in consequence of the lack of experience due to the low incidence in Europe, a broad spectrum of clinical manifestations and a particularly unexpected group of patients, diagnosis can be challenging. Inhere we describe the clinicopathological findings of an African adult with CAEBV associated LPD with a brief review of the literature.A 42-year-old African man with fever, enlargement of the spleen and a suspected epileptic seizure was referred to our hospital. Diagnostic testing repeatedly revealed a massive EBV-DNA load in peripheral blood. Whole-body PET-CT-scan presented a strong uptake at multiple bone marrow sites, the thyroid and the adrenal glands. Histopathological analysis of bone marrow and thyroid gland revealed a highly proliferating, atypical and predominantly intravascular cytotoxic T-cell population with intracellular EBV-encoded RNA. Clonality analysis revealed the presence of polyclonal T-cell-receptor. Based on these findings a CAEBV of the T-/NK-cell type, systemic form was diagnosed. Subsequent therapy including three cycles of chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisolone resulted in decreased EBV load, clinical improvement and ongoing complete remission.Adult-onset CAEBV of T/NK-cell type usually comprises a poor prognosis and is extremely rare in Western countries. Therefore, our case highlights the need for a clinical awareness of this disease in patients with systemic illness and for a comprehensive multidisciplinary diagnostic approach to facilitate diagnosis. Treatment options include antiviral drugs, immunosuppressive agents and systemic chemotherapy with or without allogeneic stem cell transplantation. Given the limited data these options need to be decided upon in each patient individually considering severity of the disease, comorbidities and response. Chronic active Epstein-Barr virus (EBV) infection (CAEBV) of T/NK-cell type, systemic form, which belongs to the broad spectrum of EBV-positive lymphoproliferative disorders (LPD) , is a ra9/L, hemoglobin 6.2 g/dL, platelets 113 × 109/L), increased LDH (702 IU/L) and nephrotic syndrome (proteinuria 12 g/d). Cranial magnet resonance imaging (MRI) presented no pathological findings. Bone marrow histology identified single atypical cells in intravascular position. Due to the rarity of these atypical cells further specification of their nature including immunohistochemistry and molecular techniques was not possible. Cytogenetic testing of the bone marrow aspirate but not the peripheral blood revealed a complex karyotype in single metaphases.Here we present the case of a 42-year-old man from Western Africa who had been immigrating to Germany recently. Initial admission was due to a seizure and a history of wasting and worsening health condition for six months. Upon admission he presented with recurrent fever, hepatosplenomegaly and acute kidney failure. Laboratory test results revealed a mild pancytopenia  scan of the chest which revealed atypical pulmonary infiltrates and bilateral hilar lymphadenopathy. Transbronchial biopsy was negative for infectious agents, sarcoidosis or malignancy. As bronchial lavage was positive for Aspergillus antigen, the patient was treated with Voriconazole. However, the assumption of pulmonary aspergillosis did not explain all of the patient’s symptoms. Further diagnostic approaches included high positive proteinase 3 titer (1:135) and therefore granulomatosis with polyangiitis was suspected. However, given low platelet counts biopsy of the kidney was not performed.6 copies/mL). Along with the clinical symptoms CAEBV was therefore assumed, without evidence of previous immune deficiency. Positron emission tomography (PET)-CT revealed a high glucose uptake in the thyroid, liver, adrenal gland and in the examined bone areas . While no signs of chronic HBV infection were seen, EBV DNA in the peripheral blood reached high levels  in peripheral blood or RNA in affected tissue as well as abnormally high levels of EBV antibodies [EBV infection usually causes polyclonal or monoclonal proliferations of B-cells, typically in immunocompromised hosts. In very rare cases, mostly in Asia or South America, EBV-associated LPD develop, that include polyclonal, oligoclonal and monoclonal proliferations of T-cells and/or NK-cells –5. Whiletibodies . A propotibodies , 5. BaseDue to its rarity in Western Europe and its frequently unspecific morphological signs as well as the broad spectrum of clinical manifestations CAEBV diagnosis can be challenging. The here presented patient presented with persistent high-grade fever, pancytopenia and splenomegaly. There was no lymph node swelling and transaminases were in the normal range. The determinant findings in our case were the high viral EBV load in the peripheral blood and the PET-CT scan facilitating targeted biopsy with conclusive histopathological analysis. The biopsies revealed the atypical T-lymphocyte population in predominantly intra- and paravascular position and positive EBER-in-situ-hybridization. The intravascular localization and the high glucose uptake in PET-CT is unusual , howeverTreatment options of CAEBV-related T-cell LPD include antiviral drugs, immunosuppressive agents and systemic chemotherapy with or without allogeneic SCT. It is important to mention that antiviral therapy alone generally is ineffective and immunosuppressive agents like corticosteroids and cyclosporine often only temporarily reduce symptoms . ChemothIn conclusion, adult-onset CAEBV associated T-cell LPD usually shows a poor prognosis and is extremely rare in Western countries. Early diagnosis is critical for a successful treatment. However, in consequence of the lack of experience due to the low incidence in Europe, a broad spectrum of clinical manifestations and a particularly unexpected patient group diagnosis can be challenging. Therefore, our case highlights the need for a clinical awareness of this disease in patients with systemic illness and unclear symptoms as well as for a comprehensive multidisciplinary diagnostic approach to facilitate diagnosis. Given the limited data, treatment options like systemic chemotherapy and allogeneic SCT need to be carefully evaluated and decided upon in each patient individually considering severity of the disease, comorbidities and response.


Resting-state functional magnetic resonance imaging (RS-fMRI) has frequently been used to investigate local spontaneous brain activity in Parkinson's disease (PD) in a whole-brain, voxel-wise manner. To quantitatively integrate these studies, we conducted a coordinate-based (CB) meta-analysis using the signed differential mapping method on 15 studies that used amplitude of low-frequency fluctuation (ALFF) and 11 studies that used regional homogeneity (ReHo). All ALFF and ReHo studies compared PD patients with healthy controls. We also performed a validation RS-fMRI study of ALFF and ReHo in a frequency-dependent manner for a novel dataset consisting of 49 PD and 49 healthy controls.Decreased ALFF was found in the left putamen in PD by meta-analysis. This finding was replicated in our independent validation dataset in the 0.027–0.073 Hz band but not in the conventional frequency band of 0.01–0.08 Hz.Findings from the current study suggested that decreased ALFF in the putamen of PD patients is the most consistent finding. RS-fMRI is a promising technique for the precise localization of abnormal spontaneous activity in PD. However, more frequency-dependent studies using the same analytical methods are needed to replicate these results.Trial registration: NCT NCT03439163. Registered 20 February 2018, retrospectively registered. Parkinson's disease (PD) is a progressive neurological degenerative disorder that is characterized by bradykinesia, rigidity, tremor, and postural instability. The main pathological feature of PD is the progressive loss of dopamine neurons in the substantia nigra and putamen . HoweverWhile task-related fMRI holds the advantage of being able to assess specific activation corresponding to specific tasks, different tasks activate different brain regions and hence the results are less suitable for meta-analysis. Resting-state (RS) fMRI has two intrinsic advantages: it is noninvasive and task free. Task-free RS is a simpler experimental design for PD investigation. Therefore, RS-fMRI design is very similar across studies, and is more suitable for meta-analysis. There have been three published CB meta-analysis investigations of RS-fMRI studies in PD . The CB Frequency-dependent or subfrequency band analysis is drawing more and more attention in RS-fMRI studies since the work by Zuo and colleagues . They obIn the current study, we carried out a CB meta-analysis on previous PD resting-state fMRI studies using ALFF/fALFF and ReHo separately, similar to previous meta-analysis , 5. HoweIt should be noted that both ALFF and ReHo are metrics for measuring local activity. Both methods have been widely used in studies on brain disorders in whole-brain voxel-wise analysis. A study showed that ReHo and ALFF could reveal convergent abnormal local activity in some brain areas , but ReHt value, and sample size. These data were extracted from published articles that used RS-fMRI in PD. Part 2 was for validation purposes and used RS-fMRI data from 80 patients with PD and 52 healthy participants. After quality control , 49 patients with PD and 49 healthy participants were entered into the final analysis. All data in the current study can be used for further validation and exploratory studies.The data for the current study included two parts. Part 1 was for a CB meta-analysis including coordinates, On 28 June 2017, we conducted a PubMed literature search  using thWe also reviewed articles and references to retrieve additional articles. An additional study, using the Kendall coefficient of concordance (KCC) method, was included in the current meta-analysis after carefully reviewing a recent publication of meta-analysis  because t-values from each study; using the files prepared in i) to recreate the effect-size maps (standard stereotactic space) of the original studies with 10 Monte Carlo randomizations and full-width at half maximum (FWHM) 20 mm; and generating the mean map in a voxel-wise manner weighted by the sample size, variance, and between-study heterogeneity. A combined threshold of P < 0.001  with peak height Z value >1 was adopted as recommended in the SDM, together with extent threshold >10 voxels  9) in PD patients. In addition, decreased ReHo was observed in the right putamen and right precentral gyrus (BA 6) in PD patients Fig. , Table 5In the meta-analysis of SDM for combination of ALFF and ReHo, increased spontaneous brain activities in PD patients compared with controls were found in the right inferior temporal gyrus and right brain stem. Decreased spontaneous brain activities were found in the left pallidum/putamen and the right insula (BA 47) Fig. , Table 5Compared with healthy controls, PD patients had decreased ALFF in the bilateral putamen and right fusiform at 0.027–0.073 Hz Fig. , Table 6Using the SDM meta-analysis, we detected some characteristic PD-related neural changes in the resting state. For example, there was altered local activity in the putamen and the pre-SMA. A finding of decreased ALFF in the left putamen from our validation study was very consistent with the results of our CB meta-analysis, which was also consistent with findings from a previous CB meta-analysis . The incCompared with positron emission tomography, RS-fMRI has the advantages of lower cost, better temporal resolution, and no ionizing radiation. Since 2009 when the first PD RS-fMRI article was published , approxiALFF measures the amplitude of fluctuation of every single voxel, while ReHo measures the local synchronization of the nearest neighboring voxels. The two metrics are the two most widely used methods for depicting local activity . Also, i18F-dopa uptake in putamen in PD is associated with the clinical severity of locomotor disability, and 18F-dopa reduction in putamen is associated is associated with the degree of rigidity and bradykinesia [There was decreased ALFF in the left putamen in PD patients in both our validation dataset and CB meta-analysis investigation. These findings align with previous findings that the striatal dysfunction in PD has been consistently reported in previous studies . It has ykinesia , 71. A rykinesia . NotablyThere was decreased ReHo in the right putamen in PD patients in both our CB meta-analysis and a previous CB meta-analysis . Howevert maps is better than coordinate-based meta-analysis [A few limitations should be addressed. First, it has been proposed that at least 20 experiments should be included in a meta-analysis . Althouganalysis . We sugganalysis . It shouWe performed a CB meta-analysis of local activity using RS-fMRI in PD patients and healthy controls and also a validation study using a novel dataset in a frequency-dependent manner. The most consistent result was abnormal ALFF in the left putamen, as evidenced by decreased ALFF in the CB meta-analysis and decreased ALFF of PD in our independent dataset. However, owing to the limited number of original studies that were suitable for CB meta-analysis, our results need to be further validated.The consistent finding in the current study is the abnormally decreased ALFF in the left putamen. The precise localization of abnormal brain activity is helpful to identify new targets of focused stimulation, such as deep brain stimulation, transcranial magnetic stimulation, and focused ultrasound stimulation.GigaScience GigaDB repository [The datasets supporting the results of this article are available in the NeuroImaging Tool & Resources Collaboratory (NITRC) repository, as “PD RS-fMRI meta and validation” , and in pository .ALFF: amplitude of low frequency fluctuation; BA: Brodmann area; CB: coordinate based; fALFF: fractional amplitude of low frequency fluctuation; FDR: false discovery rate; fMRI: functional magnetic resonance imaging; FWHM: full-width at half maximum; KCC: Kendall coefficient of concordance; PD: Parkinson's disease; ReHo: regional homogeneity; RS: resting state; SDM: signed differential mapping; SMA: supplementary motor area;The present investigation was performed according to the Declaration of Helsinki and was approved by the Medical Research Ethics Committee at Xuanwu Hospital, Capital Medical University. All participants gave written informed consent prior to participation.GigaScience. All remaining authors have no competing interests.Y.-F.Z. is an Editorial Board Member of This study was supported by the National Natural Science Foundation of China , the Ministry of Science and Technology (2016YFC1306503 to T.W.), and the Beijing Municipal Commission of Health and Family Planning (PXM 2017_026283_000002 to T.W.).Experimental design: all authors; data collection: J.W., J.R.Z., TW; data analyses: all authors; and writing the article: J.W., Y.F.Z., and T.W.GIGA-D-18-00065_Original_Submission.pdfClick here for additional data file.Reviewer_1_Report_ -- Alejandro De La Vega03/24/2018 ReviewedClick here for additional data file.Reviewer_2_Report_ -- Michael Riedel04/09/2018 ReviewedClick here for additional data file.


Background and objectives: Targeted therapy is widely used in the era of precision medicine. Whether the sequence in which targeted therapy and chemotherapy are performed matters, is however not known. We examined the impact of the sequential treatment of targeted therapy and chemotherapy among advanced anaplastic lymphoma kinase (ALK), non-small cell lung cancer (NSCLC) patients. Materials and Methods: Randomized controlled trials comparing the use of ALK inhibitors with chemotherapy were included in this meta-analysis. We estimated the hazard ratios (HRs) and 95% confidence intervals (CI), for progression-free survival (PFS) and overall survival (OS) from a random effects model. Two-sided statistical tests were used to determine the significance of these estimates. Results: In five eligible studies (1404 patients), ALK targeted therapy, in comparison with chemotherapy, had a significantly higher PFS , but not significantly higher OS . Crossover from chemotherapy to ALK inhibitors was allowed after progression in all trials. The sensitivity analysis of the use of ALK inhibitors as either the first- or second-line treatment, showed improvements in PFS but not in OS. Conclusions: Our results indicate that using targeted therapy first improved PFS, but that the sequence in which the treatments were performed did not cause a significant difference in overall survival. Lung cancer continues to be a leading cause of cancer-related deaths globally. Over the last decade, advances in precision medicine for non-small-cell lung cancer (NSCLC) have spurred the development of successful targeted therapies and have changed treatment guidelines. Anaplastic lymphoma kinase (ALK)-positive (ALK+) NSCLC represents 3–5% of all NSCLC patients . TraditiThis meta-analysis examines whether having targeted therapy as the first- or second-line of therapy affects either progression-free survival (PFS) or overall survival (OS), by pooling evidence from the currently available randomized controlled trials.We conducted a review of MEDLINE (EBSCOhost) and PubMed up to 7 May 2018, and searched the databases using the keywords “ALK” and “lung cancer”, without limitation. We also hand-searched the relevant references. The potentially relevant studies were retrieved. For eligible studies that had multiple reports, only the most recent or complete publication was included.The goal of the analysis was to examine the effects of exposure to chemotherapy or ALK inhibitors on progression-free survival and overall survival. Our analysis included only studies that fulfilled these criteria: (1) randomized phase III prospective trials in lung cancer patients, and (2) randomization in assigning patients to chemotherapy or ALK. Two reviewers (YCL and YLL) independently examined the title and the abstract of the publications identified by the search strategy. The full texts of all the potentially relevant publications were retrieved. A five-point Jadad ranking system  on randohttp://www.prisma-statement.org) statement for data extraction. The information that was extracted from each study included the publication year, the name of the first author, the trial type, the patient number, the median PFS, and the median OS.We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses  and 95% confidence intervals (CI). The statistical significance was set at the two-sided p-value of <0.05. We used the Stata software  to perform all of the statistical analyses.The heterogeneity among the trials was assessed using Cochrane’s Q statistic, and the degree of heterogeneity was quantified by the IFrom a review of 4225 total titles or abstracts, 27 full articles were retrieved. Of these, five articles satisfied the inclusion criteria ,4,5,6,7 In total, the five studies included 1404 patients, 721 of which were assigned to ALK inhibitors, while 683 were assigned to control arms, at random. The significance of the imbalance between the two groups was due to the unbalanced design, introduced by Novello et al. [In comparison with chemotherapy, treatment with ALK inhibitors was associated with a significant reduction in PFS , as seen in While chemotherapy has been shown to be effective in ALK-positive lung cancer patients,  and remap <0.001). Whether decreased brain metastasis translates into prolonged overall survival remains to be explored. Also, secondary ALK mutations are more common after treatment with second-generation ALK inhibitors [The most frequent site of relapse in patients receiving crizotinib is the central nervous system (CNS). In the ALEX trial , 12% of hibitors . The prohibitors , 62% of G1202R [G1202R mutations, and decreasing the use crizotinib, which might affect the overall survival. Third-generation lorlatinib is active against the ALK resistance mutations that developed against second-generation ALK inhibitors [Multiple variants of the echinoderm microtubule-associated protein-like 4 (EML4)-ALK have been reported on, with V1, V2 and V3a/b as the most common. The mutations result in the constitutive ligand-independent activation of the downstream Ras/mitogen-activated protein kinase, the (MAPK)/extracellular signal regulated kinase (ERK), the PI3K/AKT and Janus kinase 3 (JAK3)/signal transducer and activator of transcription 3 (STAT3) . The mecG1202R . We do nhibitors . Howeverhibitors . Should This study has some limitations. Among the five studies, three have not yet reported more mature data on OS. Also, we grouped the first-, second- and third-line studies together. Our results have shown that at least first-line treatment of ALK-positive NSCLC with chemotherapy, as the Taiwan national health insurance policy dictates, would not decrease OS as long as targeted therapy with ALK inhibitors is available as the second-line treatment.The choice of the first-line treatment for ALK-positive, non-small cell lung cancer needs to take into account cost–benefit considerations and the patient-reported quality of life, as the treatment sequence did not cause a significant difference in overall survival.


Background: The objective of this systematic review and meta-analysis was to quantify and statistically compare correlations between types of balance performance in healthy individuals across the lifespan.Methods: Literature search was performed in the electronic databases PubMed, Web of Science, and SPORTDiscus. Studies were included if they investigated healthy individuals aged ≥6 years and reported measures of static/dynamic steady-state, proactive, and/or reactive balance. The included studies were coded as follows: age group, gender, and balance type, test, parameter. Pearson's correlation coefficients were extracted, transformed , aggregated , back-transformed to r-values, classified according to their magnitude, and statistically compared. The methodological quality of each study was assessed using the Appraisal tool for Cross-Sectional Studies.Results: We detected twenty-six studies that examined associations between types of balance and exclusively found small-sized correlations, irrespective of the age group considered. More specifically, the weighted mean rz-values amounted to 0.61  in old adults for the correlation of dynamic steady-state with proactive balance. For correlations between dynamic and static steady-state balance, the weighted mean rz-values amounted to 0.09 in children  and to 0.32 in old adults . Further, correlations of proactive with static steady-state balance revealed weighted mean rz-values of 0.24  in young adults and of 0.31  in old adults. Additionally, correlations between reactive and static steady-state balance yielded weighted mean rz-values of 0.21  in young adults and of 0.19  in old adults. Moreover, significantly different correlation coefficients  were only found for the association between dynamic and static steady-state balance in children (r = 0.09) compared to old adults (r = 0.31). Lastly, we detected trivial to considerable heterogeneity  between studies.Conclusions: Our systematic review and meta-analysis showed exclusively small-sized correlations between types of balance performance across the lifespan. This indicates that balance performance seems to be task-specific rather than a “general ability.” Further, our results suggest that for assessment/training purposes a test battery/multiple exercises should be used that include static/dynamic steady-state, proactive, and reactive types of balance. Concerning the observed significant age differences, further research is needed to investigate whether they are truly existent or if they are caused by methodological inconsistencies. In everyday life, adequate postural control is needed to safely manage activities of daily living  and to regularly engage in sports-related activities . Thus, balance performance represents an important health- and activity-related component of everyday life that is also relevant across the human lifespan  or an inverted U-shaped course for dynamic  steady-state balance performance across the lifespan  OR posture (MeSH)] AND (correlation study OR association OR relationship) NOT (patients OR disease)]}. With respect to the PubMed database, Medical Subject Headings (MeSH) were used as it was indicated before. The search was limited to: English language, human species, and to full text original articles. Further, we analyzed relevant review articles  participants had to be healthy subjects, (b) participants were aged ≥6 years, and (c) outcomes from at least two types of balance had to be tested in the study. Studies were excluded if: (a) they investigated patients or people with diseases, (b) it was not possible to extract correlation coefficients from the results section or (c) authors did not reply to our inquiries sent by email. Based on the predefined inclusion and exclusion criteria, two independent reviewers  screened potentially relevant articles by analysing titles, abstracts, and full texts to determine their eligibility. If SS and TM did not reach a consensus concerning inclusion of a study, a third reviewer (RK) was contacted for clarification.Each study was coded for the following variables: number of participants, sex, and chronological age. Further, we coded type, test, and parameter for the assessment of balance performance. With respect to the classification of postural control published by Shumway-Cook and Woollacott , balanceThe quality of all eligible studies was assessed using the Appraisal tool for Cross-Sectional Studies . r-values derived from different studies were pooled using “Fisher's z' transformation.” In this regard, correlation coefficients were converted to the normally distributed variable z' . The formula for this transformation is: z' = 0.5[ln(1+r) - ln(1-r)] where ln is the natural logarithm . The formula for the calculation of the SE is: SE = N means the respective sample size , 3 studies assessed adolescents (n = 383 subjects), 6 studies tested young adults (n = 146 subjects), 1 study used middle-aged adults (n = 32 subjects), and 14 studies examined old adults . Irrespective of the age category, 4 studies reported correlations between dynamic steady-state and proactive balance, 2 studies between dynamic steady-state and reactive balance, 15 studies between dynamic and static steady-state balance, 2 studies between proactive and reactive balance, 9 studies between proactive and static steady-state balance, and 11 studies between reactive and static steady-state balance.Figure Quality assessment revealed that the majority of studies included in our review met the criteria for (a) study design, (b) study quality, and (c) risk of bias above average. More specifically, twenty-five of the 26 included studies fulfilled ≥4 out of 7 criteria evaluating quality of study reports . The back-transformed r-value of 0.54 indicated a small-sized correlation. Only one study  between dynamic steady-state and proactive balance in children    and to 0.32 in old adults  and were accompanied with moderate to considerable heterogeneity. Back-transformed r-values of 0.09 and 0.31 indicated small-sized correlations, respectively. In adolescents      and to 0.31 in old adults  and were accompanied with trivial to substantial heterogeneity. The respective back-transformed r-values of 0.24 and 0.30 indicated small-sized correlations. In children    and to 0.19 in old adults  and were accompanied with trivial heterogeneity. Back-transformed r-values of 0.21 and 0.19 indicated small-sized correlations. In children     was significantly smaller  than that in old adults (r = 0.31). Additional age comparisons of static steady-state balance with proactive  and reactive  balance did not reveal significant differences in young compared to old adults.Statistically significant differences between age groups were obtained for the association of dynamic with static steady-state balance only. More precisely, the This systematic review and meta-analysis quantified and statistically compared associations between types of balance in healthy individuals across the lifespan. The main findings can be summarized as follows. First, we found exclusively small-sized correlations between types of balance in children, adolescents, young, middle-aged, and old adults. This finding was independent from the investigated type of balance . Second, we detected significantly smaller correlations between dynamic and static steady-state balance in children compared to old adults. However, the analyses failed to detect further significant age differences for associations between other types of balance.Our finding of exclusively small-sized correlations between types of balance contradicts the notion of balance as a “general ability,” as indicated in textbooks  and the ground remain stationary as only the center of mass moves. However, during walking, as a representative of a dynamic steady-state balance task, the base of support and the center of mass shift, which provides different requirements to the involved neurophysiological structures than quiet standing. In this regard, Lau et al.  investigr-values of −0.0163 and −0.0531, respectively. When excluding the study by Humphriss et al. . Thus, methodological inconsistencies  between the involved studies could have also caused the significant age differences. As a consequence, further research is needed to investigate whether associations between types of balance are affected by maturation/age or methodological inconsistencies. To investigate whether the detected age differences between dynamic and static steady-state balance in children compared to old adults truly exist, it is recommended to conduct a series of single studies quantifying and statistically comparing correlations between various types of balance in children, adolescents, young, middle-aged, and old adults using identical tests and parameters.Significant age differences were found for associations between dynamic and static steady-state balance in children compared to old adults. More specifically, the correlation coefficient was smaller in children compared to old adults. Based on this finding, one may argue that maturation/age have an effect on the association of selected types of balance. However, we could not detect further significant age differences in the relationship between other types of balance. Moreover, a closer look on the studies involved in the comparison that revealed significant age differences shows that fairly low correlation coefficients were reported in the study of Humphriss et al. . For exas et al.  from ourThe present systematic review and meta-analysis revealed exclusively small-sized correlations between types of balance performance in children, adolescents, young, middle-aged, and old adults. Findings indicate that balance performance seems to be task-specific rather than a “general ability.” Thus, we advise practitioners to apply a test battery and not a single test for balance assessment. Further, multiple exercises including dynamic/static steady-state, proactive, and reactive types of balance should be used during balance training to target each balance dimension individually. In addition, we found significantly smaller correlation coefficients for the association of dynamic with static steady-state balance in children compared to old adults. This implies that maturation/age may have an effect on the association between selected types of balance. Yet, methodological inconsistencies  between the involved studies could have also caused the significant age differences and thus further research is needed to investigate whether the observed age differences could be replicated.RK worked on study design and manuscript preparation. SS assisted on data collection, data analysis, and worked on manuscript preparation. TM worked on study design, data collection, data analysis, and manuscript preparation.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.