Bland-Altman metrics (n = 11) all were within 0.35 log copies/ml of perfect agreement. Overall, Xpert HIV-1 VL performed well compared to current reference tests. The minimal training and infrastructure requirements for the Xpert HIV-1 VL assay make it attractive for use in resource-constrained settings, where point-of-care VL testing is most needed.Viral load (VL) is the preferred treatment-monitoring approach for HIV-positive patients. However, more rapid, near-patient, and low-complexity assays are needed to scale up VL testing. The Xpert HIV-1 VL assay  is a new, automated molecular test, and it can leverage the GeneXpert systems that are being used widely for tuberculosis diagnosis. We systematically reviewed the evidence on the performance of this new tool in comparison to established reference standards. A total of 12 articles (13 studies) in which HIV patient VLs were compared between Xpert HIV VL assay and a reference standard VL assay were identified. Study quality was generally high, but substantial variability was observed in the number and type of agreement measures reported. Correlation coefficients between Xpert and reference assays were high, with a pooled Pearson correlation ( Despite the recommendations put forward by the World Health Organization (WHO), viral load (VL) monitoring of antiretroviral therapy (ART) is not routinely performed in many low-resource countries, and treatment failure is diagnosed on the basis of clinical or immunological criteria. Currently used VL assays demand sophisticated facilities, expensive equipment, and skilled technicians, making them unaffordable and largely impractical for scale-up in resource-limited settings . To expain vitro diagnostic test designed for the rapid quantification of HIV-1 in human plasma from individuals with an active HIV infection. It uses real-time quantitative reverse transcription PCR technology and targets HIV-1 group M subtypes A, B, C, D, AE, F, G, H, AB, AG, J, and K and groups N and O. It has a limit of quantitation of 40 copies/ml and can detect HIV-1 RNA over a linear range of 40 to 10,000,000 copies/ml. The GeneXpert platform allows on-demand molecular testing in one fully integrated closed cartridge and provides results in 90 min , performed on the GeneXpert instrument system, is an n 90 min . The XpeThe Xpert MTB/RIF assay is a major advance in tuberculosis diagnostics, and more than 23 million cartridges have been used around the world . Given tin vitro diagnostics , Embase (1947 to 2017), and Global Health (1973 to 2017) for studies evaluating the performance of the Xpert HIV-1 VL assay in HIV-positive patients . No language or geographic restriction was applied. The study search was conducted on 25 September 2017.All studies that enrolled participants with a known HIV-positive status were eligible for inclusion.We restricted inclusion to studies of patients of known HIV status, because VL testing is not recommended as an HIV diagnostic but as a treatment-monitoring tool. The included studies were required to compare Cepheid's Xpert HIV-1 VL assay to another established PCR-based VL assay and report at least one comparison measure between Xpert VLs and gold standard VLs . Conference abstracts and posters were excluded, as their quality could not be comprehensively assessed .Two reviewers (S. Huddart and M. Nash) screened the titles and abstracts of citations retrieved from all sources. Duplicates were removed, and studies which met the inclusion criteria were flagged for further review. A full-text screen of relevant studies was then performed by the same independent reviewers.Two reviewers (S. Huddart and M. Nash) independently extracted data from all eligible studies on patient demographics, correlation coefficients, and results of Bland-Altman analyses comparing Xpert HIV-1 VL assays and the reference test and study quality (see Appendix S1).Extracted data were adjudicated by the two reviewers, with discrepancies resolved by a third reviewer (S. Badar). Study authors were contacted regarding information not reported in the included manuscripts, but no responses were received.A modified version of the QUADAS-2 criteria for diagnostic tests was used to assess study quality . BecauseCorrelation coefficients, both Spearman and Pearson, were extracted from studies reporting these measures. Because of the theoretical heterogeneity between parametric and nonparametric measures, meta-analysis was only considered within strata of correlation type. The decision to pool was based on the authors' assessment of clinical heterogeneity.I2, as internal study variability was moderate and I2 appropriately reflected heterogeneity.The results of Bland-Altman analyses, a summary of the mean differences between VL measures, were also extracted. Twelve Bland-Altman analyses were performed among the included studies, but one  did not All extracted studies performed their correlation and Bland-Altman analyses on log-transformed viral loads. For studies on patient samples, samples were independent, with one sample per patient included in the agreement analyses. For one included study using laboratory-quality assessment samples, the sampling procedure was not described   . We straThere was a sufficient number of Bland-Altman studies to stratify by type of reference test, although heterogeneity remained too high to provide pooled estimates . No major differences in Bland-Altman results by reference test were identified.We observed substantial variability in the number and type of agreement measures reported in the included studies . CorrelaOverall, our systematic review showed Xpert HIV-1 VL performs well compared with current established reference standard VL assays, both when measured by correlation and by Bland-Altman analysis. These findings might help inform policy guidance on this new assay, along with data on costs, feasibility, clinical impact, and cost-effectiveness.in vitro diagnostic prequalification, few validation studies had been conducted and published at the time of the search. Consequently, only 12 articles meeting our inclusion criteria were identified and included. We hope to update our meta-analysis in the future to account for new studies that will emerge on the Xpert VL assay. Second, the decision to exclude conference abstracts resulted in the exclusion of multiple relevant studies. Abstracts were excluded because study quality could not be effectively assessed, but as Xpert HIV-1 VL is a new tool, many studies on the assay have yet to be published as full-length articles. However, due to poor reporting, study quality was challenging to assess even in full-length articles. Where sufficient information was available, quality was high.Our systematic review has several potential limitations. First, as the search was conducted shortly after Xpert HIV-1 VL received WHO The final limitation pertains to generalizability. Many studies failed to report important demographic and clinical information, such as gender distribution, age of study participants, and patient ART status. This information is critical to understand the clinical relevance and generalizability of the reported data. Authors of studies with missing information were contacted; however, no responses were received. There was also substantial variability in which measures of agreement were calculated. To improve the ability to systematically review and pool the literature, a minimum set of standard measures of agreement should be agreed upon and used. Correlation and Bland-Altman could provide such a minimum set, as they measure both general agreement and magnitude and direction of bias between assays. Many studies reported percent agreement analyses where Xpert HIV-1 VL and the reference test were used to classify patients above or below certain thresholds. However, the specific thresholds used varied considerably, preventing a meaningful comparison. The use of a standard clinical threshold in future evaluations of Xpert HIV-1 VL would allow for direct comparisons in systematic reviews. The generalizability of our study is also limited due to the geographical distribution of the primary studies included; they were exclusively performed in countries where the predominant HIV subtype is C  or B  . As moreThe purpose of this study was to assess VL agreement between Xpert and other gold standard assays as a measure of accuracy. However, a final recommendation for the use of Xpert VL will need to consider not just accuracy but also country-specific implementation research that addresses the feasibility of Xpert VL and its impact on patient outcomes.The low-complexity nature of the Xpert HIV-1 VL assay, coupled with its ability to deliver same-day test results, make this technology particularly well suited for use in resource-constrained settings, where point-of-care VL testing is most needed . Deploym


Behavioral analysis indeed revealed a less flexible risk-attitude change in the GD group; the GD group failed to avoid risky choice in a specific quota range (low-quota condition), in which risky strategy was not optimal to solve the quota. Accordingly, fMRI analysis highlighted diminished functioning of the dorsolateral prefrontal cortex (dlPFC), which has been heavily implicated in cognitive flexibility. To our knowledge, the present study provided the first empirical evidence of a deficit of state-dependent strategy optimization in GD. Focusing on flexible control of risk attitude under quota may contribute to a better understanding of the psychopathology of GDs.Gambling disorder (GD) is often considered as a problem of trait-like risk preference. However, the symptoms of GD cannot be fully understood by this trait view. In the present study, we hypothesized that GD patients also had problem with a flexible control of risk attitude (state-dependent strategy optimization), and aimed to investigate the mechanisms underlying abnormal risk-taking of GD. To address this issue, we tested GD patients without comorbidity (GD group:  Studies using the Iowa Gambling Task reported that problematic gamblers tended to prefer a risky (high-risk and high-return) deck over a sure  deck despite smaller total payoff, demonstrating risk-proneness of GD patients.14 Moreover, trait risk attitude was not predictable of the risk of relapse.15Despite accumulated research regarding behavioral/neuronal mechanisms underlying individual risk preference of GD, unsolved riddles remain. For instance, the GD population has a high comorbid rate of mood disorders and anxiety disorders, contrary to the public image of optimistic gamblers.21 In our previous study, by manipulating the quota severity (required achievements) in a multi-step gambling task, we observed that healthy participants chose safe strategy in lower quota condition, while they chose risky strategy in higher quota condition, demonstrating strategic utilization of risk attitude (state-dependent strategy optimization) in humans.21 Accordingly, functional magnetic resonance imaging (fMRI) analysis highlighted a crucial role of the dorsolateral prefrontal cortex (dlPFC), which is responsible for cognitive flexibility,24 for encoding of quota severity and exertion of state-dependent strategy optimization.21 State-dependent strategy optimization is crucial for adaptive decision-making to achieve a multi-step goal,26 and the failure of flexible control of risk attitude may result in unnecessary gambling in GD. To our knowledge, no study has tested this possibility in a GD population.Recent neuroscience studies concerning risk foraging theory suggested that risk attitude is a rather flexible parameter that reflects a contextual state.21 and investigated alterations of quota-dependent risk attitude and corresponding neural patterns. We analyzed not only the neural activation pattern, but also its functional connectivity pattern, as impairment of the neural network has been implicated in addiction.28 Because the dlPFC played a central role in performing state-dependent strategy optimization, we focused on dlPFC function and functional connectivity pattern in the dlPFC of GD patients. We predicted that GD patients frequently engage in risky choices when they should avoid risk  due to a failure of state-dependent strategy optimization, and dlPFC activity may reflect such inflexibility during decision-making.Here, we aimed to examine whether GD patients have a deficit of state-dependent strategy optimization during decision-making under quota constraint. To this end, we conducted a task-fMRI experiment in GD patients with a multi-step gambling task ,n=21). The data from age-, sex- and IQ-matched healthy participants analyzed in the previous study were used to configure the healthy control group . The HC group and the GD group were examined in the same period by the same methods. The sample size was set to exceed 20 participants per group in order to yield statistical power of 0.80 to effect size ~0.90 for between-group analysis.29 Of the GD group, 16 patients with maintained abstinence were recruited from a treatment facility, and the remaining 5 patients were recruited from the local community (active gamblers). All participants provided written informed consent before the experimental session. This study was approved by the Committee on Medical Ethics of Kyoto University and was carried out in accordance with the Code of Ethics of the World Medical Association. For further information regarding participants, see Twenty-four male GD patients who met the criteria for pathological gambling in DSM-IV-TR and for GD in DSM-V were recruited for the present study. Patients were given the Structured Clinical Interview for DSM-IV (SCID) prior to the experimental sessions, and 3 GD patients were excluded from further analysis because of medication histories for psychiatric disorders . Finally, 21 GD patients without comorbidity were analyzed . The transition of trial quota  was announced as feedback following each choice, and the block result (clear or failure) was announced after the 20th choice in each block. Participants were each paid the same amount (6000 JPY) for their participation, and they were instructed to solve as many blocks as possible. The payment amount was not adjusted according to earning units outcome, ensuring that participants had equal motivation for each block. Participants were also instructed about the maximum payoff of a trial (600 units) before the task session. The program of the behavioral task was constructed and presented using E-prime 2.0  on a laptop computer . In addition to the behavioral session, participants completed self-reported questionnaires, Gambling Craving Scale (GACS)30 and BIS/BAS scale,31 for measures of subjective craving level and trait impulsivity, respectively.A multi-step gambling task, which was also used in a previous study , Easy-quota condition , Low-quota condition , High-quota condition , and Imp-quota (impossible quota) condition . The boundaries of quota conditions were defined based on the prior computational simulation performed in the previous studyalso see . Crucialα=0.01 for correlation analyses between risky choice probability and abstinence period.The risky choice was defined as the choice of a risky option (high magnitude and low winning probability) in a pair of choice options. The high EV choice was defined as the choice of higher EV option in an option pair, in which either risky or safe option could have higher EV. We used corrected threshold t-test . In functional connectivity analysis, encoding of state-dependent strategy optimization  was compared between GD and HC groups by two-sample t-test . To generate psychophysiological interaction (PPI) regressors, the generalized form of the context-dependent PPI (gPPI) method32 was employed with left dlPFC seed . We confirmed similarity of variance between groups by two-sample F-test for equal variances (P>0.10). For further information regarding fMRI data acquisition, activation analysis and functional connectivity analysis, see fMRI data obtained during the behavioral session were analyzed. In activation analysis, encoding of quota severity  was compared between GD and HC groups by two-sample n=21) completed a behavioral session of the multi-step gambling task in the fMRI scanner (n=29) obtained in the same period.21 The participants experienced a broad range of quota severity in a course of choice trials =19, P<0.001) and in EV-based choice probability =6.2, P<0.001), but no main effect of group (HC/GD) in risky choice probability =0.48, P=0.49) or in EV-based choice probability =2.0, P=0.16). The response time (RT) was not statistically different by quota condition or by group =1.5, P=0.20; main effect of group: F=3.0, P=0.087; P>0.10). Thus, the GD group showed a statistically indistinguishable choice pattern from the HC group, in terms of average level.Both groups showed robust change of risky choice probability  and EV-bn=11) showed risky choice tendency in low-quota condition, compared to the HC group .In our GD population, the treatment duration was diverse; this could have influenced their choice patterns, and hence average analyses might have overlooked potential behavioral alteration in the GD group. In addition, as hypothesized in the Introduction, GD patients may be more likely to take unnecessary risky choice when they do not have to take the risk; this could be observed when they made decisions under low-quota condition in our paradigm. Therefore, we expected that GD patients with less abstinence show risky choice tendency in low-quota condition. Indeed, when we split the GD group into two subgroups based on abstinence duration, the shorter abstinence subgroup . In addition, EV-based choice probability was not correlated to the abstinence period under any quota conditions . Moreover, unlike the risky choice probability in low-quota condition, the GACS score was high only in active gamblers, exhibiting a step-like pattern (n=5) showed significantly higher GACS score than under-treatment patients  and the HC group , and no correlation was found between abstinence period and GACS score in under-treatment patients . Thus, the suboptimal risky choice tendency observed in the GD group was not directly accounted for by heightened craving level.We also analyzed the score of the Gamble Craving Scale (GACS) pattern . Active 31 as a measure of trait impulsivity. Although the BIS/BAS score of the GD group was significantly higher than that of the HC group , it was not correlated to risky choice probability in low-quota condition  or to abstinence period . Thus, trait impulsivity also did not account for suboptimal risky choice tendency in the GD group.In addition, we analyzed the score of the BIS/BAS scale21 Therefore, we expected the GD group to show weakened encoding of quota severity in these areas. As expected, the two-sample t-test (HC>GD) revealed a significant cluster in the left dlPFC, suggesting diminished encoding of quota severity in the GD group  and right anterior insula (AI) reflected the ‘quota severity' contrast (Imp>High>Low>Easy) in healthy participants.GD group .t-test of the HC group data. The ROI response in low-quota condition was calculated for each participant by using the single contrast for low-quota condition ([0 0 1 0 0]). This analysis revealed a negative correlation between abstinence period and right AI response in low-quota condition in under-treatment patients .There was no significant cluster in dACC or right AI, but these areas might be involved in a more condition-specific role. Then, we additionally performed correlation analysis between abstinence period and ROI responses in low-quota condition for dACC and right AI ROIs . ROIs were set on the peak coordinates identified in one-sample 32 and reported the neural correlates of state-dependent strategy optimization. The functional connectivity pattern between the left dlPFC and dmPFC encoded ‘strategy optimization' contrast (Low/High>Non/Imp), and the strength of dlPFC–dmPFC connectivity reflected the task performance  in the HC group.21 Therefore, we performed a gPPI analysis with left dlPFC seed , we found no significant cluster reflecting a difference of encoding of state-dependent strategy optimization. However, taking into account the fact that dlPFC–dmPFC functional connectivity was negatively correlated to the risky choice probability in low-quota condition in the HC group, it might also reflect the abstinence duration and thus appear indistinguishable by two-sample t-test. We then investigated the relationship between abstinence period and dlPFC–dmPFC functional connectivity by ROI analysis with dmPFC ROI . The ROI was set on the peak coordinates of the dmPFC cluster identified by one-sample t-test of the HC group data , suggesting a relationship between dlPFC–dmPFC functional connectivity pattern and risk aversion in low-quota condition of the GD group. Thus, fMRI analyses highlighted that not only the activation pattern but also the functional connectivity pattern was altered in GD patients.In the two-sample oup data . The ROIAlthough a wealth of studies have focused on the individual risk preference of GD patients, the role of state-dependent strategy optimization in GD has never been investigated. In the present study, by manipulating the contextual state (quota severity) in a multi-step gambling task , we founDeficit of state-dependent strategy optimization may account for part of GD's risk-taking. In a daily-life situation, low-quota condition could reflect small monetary loss. Risky tendency for small monetary loss can induce unnecessary gambling, and repetition of such gambling can lead to financial hardship in GD subjects. Hence, in addition to the abnormality of individual risk preference, deficit of state-dependent strategy optimization may play a crucial role in the GD mechanism.23 and it could have mediated flexible strategy optimization depending on the quota condition in the current paradigm. Hence, the weaker activation pattern of dlPFC in the GD group may reflect impairment of cognitive flexibility. In fact, some studies have reported less cognitive flexibility in GD patients,34 suggesting impairment of cognitive flexibility underlying the deficit of state-dependent strategy optimization in GD.Functional MRI analysis revealed diminished encoding of quota severity in dlPFC in the GD group . The dlP36 and expressed a weaker level of gamble-related cognitive biases ,38 highlighting a possible causal role of AI in GD. Considering that right AI encoded quota severity in the HC group,21 reduction of right AI response might have reduced the perceived quota and led to conservative choices in patients with long abstinence.In addition, we found negative correlation between abstinence period and right AI ROI response in low-quota condition , suggest41 dlPFC–dmPFC could play a pivotal role in prospective goal-setting. Indeed, past studies reported poor performance of GD patients in intertemporal choice task, in which GD patients preferred a smaller-and-sooner option over a larger-and-later option and failed to maximize the over-trial profit.42 Therefore, attenuation of the dlPFC–dmPFC functional connectivity pattern in GD patients could reflect a deficit in prospective goal-setting and subsequent strategy optimization.In the functional connectivity analysis by gPPI method, we found a positive correlation between the abstinence period and encoding of state-dependent strategy optimization in dlPFC–dmPFC functional connectivity . This enThe current study has several limitations. First, although GD patients showed blunted brain signals for tracking quota, they did not differ from the HC group in terms of overall risky choice probability. Our behavioral measures might not have been sensitive enough to reflect the attenuation of brain signals. Second, this is a cross-sectional study, and therefore the relationship between brain activity and abstinence period remains to be correlational. Longitudinal studies are highly recommended to test the causal relationship between them.In conclusion, the present study sheds light on the novel mechanism of GD's abnormal risk-taking. Deficit of state-dependent strategy optimization was reflected in behavioral and neuronal patterns of GD patients and potentially accounted for part of GD's abnormal risk-taking. It is also noteworthy that the important neural circuits for state-dependent strategy optimization were distributed outside of reward-related areas  that have received less attention in past literatures concerning GD. We believe that the present study will contribute to a better understanding of GD and may be useful for the development of new therapies.


To compare the safety and efficacy of percutaneous coronary intervention (PCI) using drug-eluting stent (DES) and coronary artery bypass graft (CABG) for the treatment of left main coronary artery (LMCA) disease.Several new randomized trials have recently examined the clinical outcomes of PCI and CABG in LMCA disease. However, the results of these studies were inconsistent.We searched five online electronic databases to identify all the randomized clinical trials assessing the outcomes of PCI using DES and CABG in patients with LMCA. The clinical outcomes were the major adverse cardiac and cerebrovascular event (MACCE), all-cause death, myocardial infarction (MI), stroke, and repeat revascularization (RR).P = 0.007), a higher risk of RR  than CABG. Moreover, for long-term follow-up, there were significant higher risks of MACCE and RR with PCI versus CABG . However, there were no significant differences between the two groups in all-cause death and MI risks, regardless of follow-up duration.A total of 5 randomized clinical trials with 4595 LMCA patients were included in this meta-analysis. For one year follow-up, the results indicated that PCI were associated with a lower risk of stroke (RR = 0.21, 95% CI = 0.07–0.65, PCI is noninferior to CABG in short term follow-up of patients with LMCA disease, but CABG is more safety and efficacy than PCI using DES in long-term follow-up. Left main coronary artery (LMCA) disease, one of obstructive coronary artery diseases, is diagnosed in 5–7% of patients who have been referred for coronary angiography , 2. As tPercutaneous coronary intervention (PCI) with stenting, a Class II alternative method of LMCA treatment by current guidelined recommend, is becoming more used and shows favorable clinical outcomes for patients with significant LMCA disease that have a high risk of surgery and low or intermediated SYNTAX scores because of many remarkable improvements in medical device technology and adjunctive pharmacotherapies have been achieved during the last decade –11. For However, this meta-analysis did not include the latest and the largest study and did not study the long-term outcomes of PCI using DES versus CABG. As a matter of fact, the results of long-term outcomes of PCI using DES versus CABG in these studies were inconclusive. For example, the NOBLE trail found CABG was better than PCI using DES with respect to Kaplan-Meier 5 year estimates of MACCE and revascularisation for treatment of LMCA disease . HoweverTherefore, we performed an updated meta-analysis to systematically clarify whether PCI using DES was noninferior on the safety and efficacy to CABG for treatment of LMCA disease during 1-year and long-term period.We searched five online electronic databases, including PubMed and the Excerpta Medica Database (EMBASE), ISI Web of Science, Chinese Biomedical Literature (CBM) database and Chinese National Knowledge Infrastructure (CNKI) database, for all publications examining the safety and efficacy of PCI using DES compared with CABG for the treatment of LMCA disease that had been published through December 31, 2016. The search strategy was based on combinations of the following terms: “coronary artery disease”, “left main”, “percutaneous coronary intervention or PCI”, “drug-eluting stent or DES”, and “coronary artery bypass”. To retrieve the most eligible studies, we manually screened all relevant publications and their reference lists. We included published papers on relevant studies involving human subjects, with no restrictions regarding publication language.The following eligible studies were included in the meta-analysis: (1) randomized controlled clinical trials; (2) studies whose population of interest included LMCA patients; and (3) studies making comparisons of clinical outcomes between PCIs using DES and CABG; and (4) studies whose clinical outcomes included major adverse cardiac and cerebrovascular event (MACCE), all-cause death, myocardial infarction (MI), stroke, and repeat revascularization (RR). The following studies were excluded from the analysis: (1) duplicates of previous publications; (2) abstracts, reviews, commentaries and editorials; (3) animal studies; and (4) studies without sufficient available original data, even after we had contacted their corresponding authors.The clinical outcomes of this study included MACCE, all-cause death, MI, stroke, and RR. MACCE were defined as the composite of death, stroke, MI, or RR. All-cause death was defined as death from any cause. MI was defined as the documentation of a new abnormal Q-wave after the index revascularization. Stroke was defined as the rapid or sudden onset of new neurological deficit persisting for > 24 hours with no apparent nonvascular cause. RR was defined as ischemia-driven revascularization by either PCI or CAGB. The short term was defined as 1 year, and the long term was defined as > 3 year in this meta-analysis.Two reviewers independently extracted the following information from the eligible trails using a standardized data collection form: the trail’s name, period of the procedures, location, ethnicities of the patients, numbers of patients, follow-up duration, clinical outcomes, characteristics of the subjects , clinical characteristics of the patients , numbers of diseased vessels, EuroSCORE, SYNTAX score, distal LMCA disease, and DES type) in the PCI using DES and CABG groups, and clinical outcomes data. Any disagreements regarding the data extracted by the two reviewers were resolved by discussion until a consensus was reached among all the authors.I2 statistic were employed to assess between-study heterogeneity [P value was two sided, and < 0.05 was considered significant. All statistical analyses were conducted using STATA statistical software .The data regarding the one-year outcomes were categorical, and pooled risk ratios (RRs) and their corresponding 95% confidence intervals (CIs) were performed for one-year outcomes’ summary statistics. All studies reported the Kaplan-Meier long-term estimates, and pooled hazard ratios (HRs) and their 95% CIs were conducted for long-term outcomes’ summary statistics. The chi-square-based Cochran Q test and ogeneity , 24. Senogeneity . P valueThe flow chart in Figure P = 0.232; all-cause death: RR = 0.70, 95% CI = 0.45–1.09, P = 0.112; MI: RR = 1.15, 95% CI = 0.70–1.88, P = 0.590), with no heterogeneity  for the outcomes across the trails , with no heterogeneity  across the trails , with no heterogeneity  across the trails , with no significant heterogeneity for all-cause death , cardiac-death , and non-cardiac death , but significant heterogeneity for MI  and stroke  across the trails , with no heterogeneity  across the trails , and no significant difference in early-generation DES group   (Table We constructed funnel plots and carried out Begg’s rank test and Egger’s linear regression test to assess whether publication bias affected the results of the studies. We found no evidence of funnel plot asymmetry across the studies with respect to each outcome (not shown). The results of Begg’s rank test and/or Egger’s linear regression test also showed no publication bias across the studies with respect to each outcome  Table .To our best of knowledge, this is the largest meta-analysis of including a total of 5 randomized clinical trials with 4595 LMCA patients to systematically clarify whether PCIs using DES was noninferior on the safety and efficacy to CABG for treatment of LMCA disease during short-term and long-term period. The results of this analysis indicated that PCI using DES was associated with a lower risk of stroke, a higher risk of RR than CABG at 1-year follow-up. In addition, there were significant trends toward higher risks of MACCE and RR with PCI using DES versus CABG at long-term follow-up. The results showed that PCI using DES is noninferior to CABG in short term follow-up of patients with LMCA, but CABG is more safety and efficacy than PCI using DES in long-term follow-up. The reason for this might be CABG for long lesion segments could protect against target lesion and proximal de-novo lesion myocardial infarctions.One previous meta-analysis identified 1611 patients from 4 randomized clinical trials to determine the safety and efficacy of PCI using DES compared with CABG in patients with LMCA disease, and found that PCI using DES was associated with nonsignificantly different 1-year rates of MACCE, death and MI, a lower risk of stroke and a higher risk of RR compared with CABG . AlthougThis meta-analysis included 4 trials which reported the long-term outcomes of PCI using DES versus CABG in patients with LMCA disease, two previous trials  used the first-generation drug-eluting stents and showed no significant difference regarding the risk of MACCE between PCI using DES and CABG , 21. HowSome limitations of this meta-analysis should be addressed. First, the analysis included only 5 studies involving 2297 LMCA patients who underwent PCI using DES and 2298 patients who underwent CABG. The small sample size of the analysis is a major weakness that may have decreased its statistical power to properly compare the safety and efficacy of PCI using DES and CABG. Regarding the analyses in which the studies were stratified by sample size and DES type, the sample sizes of the subgroups were too small, which greatly limited our ability to explore effects in these subgroups. Second, the unavailability of individual data in the trials, we could not evaluate the baseline, clinical, and procedural characteristics which may influence clinical outcomes further. Third, this meta-analysis was based on unadjusted estimates. More precise estimates should be performed to account for the effects of various confounders, including age, sex, disease status and postoperative care. Fourth, for long-term follow-up, three trials reported the 5-year outcomes and one trial showed the 3-year outcomes, thus the long-term follow-up durations of the studies were variable and the results could not truly reflect the long-term effect between the two revascularization strategies.In summary, the results of our meta-analysis demonstrated that PCI using DES is noninferior to CABG in short term follow-up of patients with LMCA disease, but CABG is more safety and efficacy than PCI using DES in long-term follow-up. However, additional well-designed studies that are based on larger sample sizes and involve patients of different clinical characteristics are needed to validate these findings.


However, thus far, rich cellular information carried in tissue samples has not been thoroughly characterized from RNA-Seq data. Therefore, it would expand our horizons to better understand the biological processes of the body by incorporating a cell-centric view of tissue transcriptome. Here, a computational model named seq-ImmuCC was developed to infer the relative proportions of 10 major immune cells in mouse tissues from RNA-Seq data. The performance of seq-ImmuCC was evaluated among multiple computational algorithms, transcriptional platforms, and simulated and experimental datasets. The test results showed its stable performance and superb consistency with experimental observations under different conditions. With seq-ImmuCC, we generated the comprehensive landscape of immune cell compositions in 27 normal mouse tissues and extracted the distinct signatures of immune cell proportion among various tissue types. Furthermore, we quantitatively characterized and compared 18 different types of mouse tumor tissues of distinct cell origins with their immune cell compositions, which provided a comprehensive and informative measurement for the immune microenvironment inside tumor tissues. The online server of seq-ImmuCC are freely available at  High-throughput RNA sequencing (RNA-Seq) has now been widely applied in mouse models to study the transcriptome of different disease conditions, such as tumors , infectiIn recent years, a few computational methods have been developed to extract cellular information, especially the tissue immune contexture from transcriptomal data –9. The bHere, a computational model, named seq-ImmuCC, was developed to predict the constitution of 10 immune cells from the RNA-Seq data of mouse tissues. After collecting and filtering available mouse RNA-Seq data from SRA, a signature gene matrix, including 162 genes specific for 10 major immune cells, was constructed. Subsequently, six machine learning methods were compared in the same signature gene matrix. The testing results indicated that the SVR- and LLSR-based models tended to achieve better performance in both simulated and experimental data. Furthermore, to validate the rationality of the computational model across different platforms, four combinations with microarray- or RNA-Seq-based training or testing data were compared. In general, models with consistent training and testing data types had better performances, while models with discordant data types achieved worse results, although they are still useful for some datasets.With the computational advantage of the seq-ImmuCC model, we built an atlas of immune cell compositions in normal and tumor mouse tissues. In total, 27 normal tissues and 18 tumor tissues were included and the relative compositions of 10 major immune cell types were inferred for each mouse tissue. The comprehensive immune cell profiles provided not only the baseline of steady state immune cell proportions for most of the normal tissues, but also the measurement for highly complex and diverse immune microenvironments of various mouse tumor models.Four major steps have been taken to construct the seq-ImmuCC model: (1) data collection and filtering: raw RNA sequencing data collected from SRA were preprocessed. Samples that can be clearly grouped were kept for later analysis; (2) signature gene selection: the differentially expressed genes (DEGs) in each of the cell types were achieved with voom  in the “Three different datasets were scanned from the public SRA database using the “R” package in SRAdb . In totaP value < 0.05 and log2-fold change > 2 were considered to be significant DEGs. Furthermore, genes that are highly expressed in both non-hematopoietic tissues and tumor tissues were filtered out as described in our previous work , Elastic net, LLSR , QP 12)12), and To evaluate the reliability of model cross platforms, the training data and testing data from both the microarray and RNA-Seq platforms were combined into four groups, Array-Array (microarray-based training and microarray-based testing), Array-RNAseq (microarray-based training and RNA-Seq-based testing), RNAseq-RNAseq (RNA-Seq-based training and RNA-Seq-based testing), and RNAseq-Array (RNA-Seq-based training and microarray-based testing). PCC between the predicted immune cell compositions and the quantitative flow cytometry measurements were calculated.Mouse samples including those of the spleen (SP), bone marrow (BM), lymph node (LN), and peripheral blood mononuclear cell (PBMC) collected in our previous work  were usewww.ebi.ac.uk/arrayexpress) under accession number E-MTAB-6458. The rest of the data is available from the authors upon reasonable request.RNA-seq data have been deposited in the ArrayExpress database at EMBL-EBI 12), LASSBased on the results of the comparison of the models, the SVR and LLSR models were suggested to predict immune cell compositions from RNA-Seq data, while only the SVR model was used as a representative model for further evaluation. The SVR model was evaluated on the simulated mixture samples, pure immune cell samples, and experimental tissues, respectively. For 245 samples of enriched single immune cells, we found the highest proportion in each sample was definitely consistent with the expected cell type, where the median predicted proportion was 85% Figure  was usedAlthough some previous studies have already used microarray-based models to estimate immune cell compositions in RNA-Seq data , 15, 16,We used our model to systematically calculate the constitution of immune cells across different normal mouse tissues. In total, 27 normal tissue types profiled on the RNA-Seq platform were collected and evaluated Table A, the reSimilarly, our approach can also be used to estimate the immune cell proportions across different mouse tumor tissues. In total, 18 tumor types were collected and evaluated Table A and 5A.http://wap-lab.org:3200/immune/. As indicated in Figure via email.An online webserver was implemented to infer the cellular proportions from the transcriptome by both microarray and RNA-Seq approaches, which is available at In this study, we devised a computation model named seq-ImmuCC to infer the proportion of ten immune cells in mouse tissues from RNA-Seq data. To the best of our knowledge, this is the first deconvolution model that focuses on RNA-Seq data in mice. The performance of seq-ImmuCC has been validated in large and various types of independent datasets, including simulated data, public data and our own experimental data. The seq-ImmuCC model will provide an in-depth and accurate cell-centric view for transcriptomal data to monitor tissue infiltrating immune cells under various conditions. In order to better serve the scientific community, we have also developed an online user-interactive webserver.Due to the absence of an RNA-Seq-based deconvolution model, some studies previously used microarray data based models to infer immune cell compositions from RNA-Seq data , 15, 16.Up to now, several machine learning methods have been proposed in the computational model to deconvolute immune cell compositions from transcriptomal data . Most ofUsing our developed seq-ImmuCC model, we can readily and reliably depict the constitution of major immune cells across different tissues or organs through the mouse transcriptomal data. Knowledge about the comprehensive immune cell constitution in various tissues would provide us an essential baseline to evaluate the potential local immune statues and will allow us to further characterize their difference of functionality in a molecular view. However, it should also be noted that tissue immune cell abundance could be influenced by many factors, including age, sex, and other physiological and environmental conditions . The varPredicting tumor-infiltrating immune cells is another important application of our model. With rapidly development, cancer immunotherapy is becoming a hot spot in basic immunological research and clinical investigation. Clinical trials have already indicated that tumor immune content could play a determinant role in disease prognosis and treatment selection , 24. PatThis study was carried out in accordance with the recommendations of the guidelines established by the Association for the Assessment and Accreditation of Laboratory Animal Care. The protocol was approved according to the policies and procedures for the Care and Use of Laboratory Animals in the Chinese Academy of Medical Sciences.ZC, FQ, and AW conceived and designed the study. AH and QZ performed the experiments. ZC, LQ, FQ, and AW analyzed the data and results. LQ constructed the web server. XY and QS contributed to the data collection and data pre-procession. YY and JS contributed to the discussion and analysis of the studies. ZC, LQ, FQ, and AW wrote the paper. All authors have approved the final 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.


Hydroxytyrosol is a polyphenol with antioxidant, metabolism-regulatory, anti-inflammatory and immuno-modulatory properties. The present study aimed to determine whether supplementing the maternal diet with hydroxytyrosol during pregnancy can improve pre- and early post-natal developmental patterns and metabolic traits of the offspring. Experiment was performed in Iberian sows fed a restricted diet in order to increase the risk of IUGR. Ten sows were treated daily with 1.5 mg of hydroxytyrosol per kg of feed between Day 35 of pregnancy  until delivery whilst 10 animals were left untreated as controls. Number and weight of offspring were assessed at birth, on post-natal Day 15 and at weaning (25 days-old). At weaning, body composition and plasma indexes of glucose and lipids were measured. Treatment with hydroxytyrosol was associated with higher mean birth weight, lower incidence of piglets with low birth weight. Afterwards, during the lactation period, piglets in the treated group showed a higher body-weight than control piglets; such effects were even stronger in the most prolific litters. These results suggest that maternal supplementation with hydroxytyrosol may improve pre- and early post-natal development of offspring in pregnancies at risk of IUGR. Inadequate maternal nutrition and/or placental efficiency can result in insufficient supply of oxygen and nutrients to the fetus, causing intrauterine growth restriction (IUGR) and leading to the birth of small-for-gestational-age  offspring , 2.In humans, LBW is associated with increased risk of perinatal morbidity and mortality, accounting for 800,000 neonatal deaths worldwide . MoreoveIn veterinary medicine and animal production, perinatal deaths due to LBW offspring are also significant, but even more concerning are the substantial economic losses to farms. In addition to lost productivity, IUGR can reduce the value of farm products by introducing undesirable heterogeneity: low-birth-weight animals show lower growth potential, lower feed efficiency, lower meat yield and excess adiposity relative to their normal-weight littermates, giving rise to heterogeneous growth patterns, carcass conformation and meat characteristics among individuals in the same litter and feedlot –10. ThesIn consequence, there is a strong necessity of strategies and tools for alleviating incidence and consequence of IUGR, both in human and veterinary medicine. IUGR involves not only inadequate nutrient supply but also reduced oxygenation, which causes hypoxia that increases oxidative stress and triggers low-grade inflammation . The antThe present trial aimed to study the effects, on pregnancies affected by IUGR, of a different source of antioxidant agents than vitamins, i.e. polyphenols. Polyphenols are common constituents of many plant-derived foods , and the most abundant dietary antioxidants. Specifically, we are interested in studying the possible usefulness of the maternal supplementation with hydroxytyrosol. Hydroxytyrosol is a polyphenol present in olive fruits  with not only a prominent antioxidant activity, but also metabolism-regulatory, anti-inflammatory and immuno-modulatory properties . These bHowever, possible usefulness of polyphenols for reproductive health and pregnancy is only beginning to be explored  Hence, wThe study was performed according to the Spanish Policy for Animal Protection RD53/2013, which meets the European Union Directive 2010/63/UE about the protection of animals used in research. The study protocol was specifically assessed and approved by the INIA Committee of Ethics in Animal Research (report CEEA 2012/036), which is the named Institutional Animal Care and Use Committee (IACUC) for the INIA. Sows were housed in INIA animal facilities, which meet local, national and European requirements for Scientific Procedure Establishments.®, MSD, Boxmeer, The Netherlands) and insemination with cooled semen from a purebred Iberian boar.The study involved 20 primiparous Iberian sows that became pregnant after cycle synchronization with altrenogest . Then, the head was separated from the trunk at the atlanto-occipital union and weighed in order to determine the ratio of head-to-body weight. Afterwards, all viscerae were removed and weighed together. Finally, major organs  were weighed individually for assessing possible patterns of asymmetrical IUGR. The following weight-ratios were considered: weight of brain, heart, lungs, liver, kidneys, intestine, pancreas, spleen and adrenals relative to total viscera weight.At weaning, piglets were euthanized using COvena cava cranealis using sterile 5-ml EDTA vacuum tubes . Blood samples were centrifuged at 1500g for 15min and the plasma was stored in polypropylene vials at -20°C until assayed for determination of parameters related to metabolism of glucose and lipids.Blood sampling was performed, during sedation, by puncture of the Parameters for glucose (glucose and fructosamine) and lipids profiles  were assessed with a clinical chemistry analyzer , according to the manufacturer’s instructions.vs >6 piglets/litter), based on the mean litter size for the Iberian breed (6.5 piglets [vs 9–10 piglets/litter) for assessing possible effects in the most prolific litters. Dependent variables related to offspring phenotype  were assessed using two-way ANOVA in a General Linear Model; interactions among potential confounding factors were observed and fixed when statistically significant . Differences between male and female piglets and between litter sizes in body weight, organ development and metabolic indexes were assessed using t-student test. Finally, changes over time were assessed by ANOVA for repeated measures with the Greenhouse-Geisser correction. All the results were expressed as mean ± SEM, and statistical significance was accepted from P < 0.05, while P-values between 0.05 and 0.09 were considered to indicate a tendency.T-student tests were used to assess the effects of independent variables  on litter size, occurrence of IUGR and LWB and percentage of piglets below 1Kg BW). For statistical purposes, litter size was afterwards categorized in two groups , but it was related to significant increases in BW of the piglets at birth and during the postnatal period.vs 1.2±0.1 Kg, respectively;, P < 0.001), lower incidence of LBW  and lower incidence of individuals with a birth-weight lower than 1Kg . In both groups, these percentages were numerically lower in female than in male piglets .The group HT was characterized by a higher mean birth-weight than the group C  showed concomitant changes through the lactation period. Overall, there were no significant differences in the mean value of ADWG between groups during the first 15 days. However, ADWG increased between 15 and 25 days to a greater extent in control piglets , with a vs 3.3±0.1 mm for piglets in the groups HT and C, respectively; P<0.01) as well as higher loin diameter , independently of sex and litter size.At weaning, hydroxytyrosol supplementation was associated with not only greater body weight but also with higher back-fat depth . The consequence of a higher birth-weight plus a higher ADWG at weaning was a body-weight around 20% higher at weaning in these piglets than in control piglets.We cannot elucidate, with the design of the current study, if these effects are directly related to a permanence of the effects from hydroxytyrosol supplementation, but we can hypothesize that may be more likely an indirect effect caused by higher birth-weight since higher birth-weight by itself is associated with better post-natal growth performance . In any Independently of hydroxytyrosol supplementation, we observed a strong correlation between birth-weight and offspring sex, with males significantly heavier than females at birth. Nevertheless, both sexes attained similar body-weight during lactation. These data are consistent with results reported in previous work involving the same breed and dietary restriction ; togetheHydroxytyrosol supplementation also showed significant effects on glucose and lipid metabolism in the offspring, primarily in piglets from larger litters. These piglets showed lower concentrations of fructosamine  and lower concentrations of total and LDL cholesterol. Decreases in these two parameters were also reported in humans with cardiometabolic disorders following intake of other polyphenols –50. In cIn conclusion, supplementation of maternal diet with hydroxytyrosol during pregnancy improves pre- and early post-natal developmental patterns and metabolic traits of the offspring. The major benefits are increased birth-weight, and lower incidence of IUGR and therefore of low-birth-weight piglets. In addition, in piglets from the largest litters, supplementation is associated with higher ADWG and body-weight at weaning.


Attention-deficit/hyperactivity disorder (ADHD) is among the most commonly diagnosed mental disorders in childhood and is associated with substantial deficits in executive functioning and lost academic and occupational attainment. This study evaluates symptoms of ADHD and their association with neurocognitive deficits in a cohort of rural Ugandan children who were born to HIV-infected mothers.We assessed ADHD symptoms and executive function (including memory and attention) in a non-clinical sample of children born to HIV-infected mothers in rural eastern Uganda. Analyses included assessments of the psychometric properties, factor structure, and convergent and discriminant validity of the ADHD measure ; and executive function deficits in children meeting symptom criteria for ADHD.s.d. 2.0)] were assessed for ADHD and executive function deficits. The ADHD measure showed good internal consistency (α = 0.85.) Confirmatory factor analysis showed an acceptable fit for the diagnostic and statistical manual of mental disorders (DSM-5) two-factor model. Subjects meeting DSM-5 symptom criteria for ADHD had worse parent-rated executive function on six out of seven subscales.232 children [54% female; mean age 7.8 years (Our results demonstrate structural validity of the ADHD measure with this population, strong associations between ADHD symptom severity and poorer executive function, and higher levels of executive function problems in perinatally HIV-exposed Ugandan children with ADHD. These findings suggest that ADHD may be an important neurocognitive disorder associated with executive function problems among children in sub-Saharan African settings where perinatal HIV exposure is common. Over 60% of children in sub-Saharan Africa (SSA) are estimated to be at high risk for failing to reach their potential in cognitive development, with subsequent effects on educational attainment and poverty  ADHD instrument measures a similar and coherent construct  due to previously reported risk factors of being born to HIV-infected mothers and living in a region with high rates of poverty where malaria is endemic. While we anticipated high rates of ADHD and executive function problems in this sample, an accurate estimate of prevalence of these problems was beyond the scope of the current study. Instead, the primary aim of this study was to address the broader question of whether ADHD symptoms were associated with important and expected impairments in cognitive function (i.e. executive function problems) among Ugandan children with et al. While behavioral rating scales are commonly used in the assessment of ADHD, there is little information available about the cross-cultural validity of such tools in SSA settings. To assess ADHD symptoms, we selected the ADHD-Rating Scale IV . Research permission was issued by the Ugandan National Council for Science and Technology.This study was conducted in a community  setting in rural eastern Uganda. Uganda is a low-income country in East Africa that is home to 37.6 million people  and child neurodevelopmental performance tests  before data collection started.Exclusion criteria for caregivers from the parent study included current suicidality or psychosis. Exclusion criteria for study children included: history of serious birth complications, severe malnutrition, bacterial meningitis, encephalitis, cerebral malaria, or other known brain injury or disorder requiring hospitalization.et al. et al. Baseline data were collected on demographics, clinical  characteristics, family characteristics, the Home Observation for Measurement of the Environment (HOME)  were the informants for the ADHD-RS-IV and BRIEF and the children completed the KABC-II and TOVA. Parent report measures (ADHD-RS-IV and BRIEF) were collected by reading the questionnaire items to the caregivers, word by word. In case of lack of understanding, the interviewer was instructed to repeat the item to the caregiver as many times as necessary. In very few cases, caregivers did not understand in spite of repeated attempts and clarification was used to put the item in context. The ADHD-RS-IV and BRIEF (preschool or standard versions) were administered for all children, whereas the TOVA and KABC-II were administered only to children aged >5. All measurements were made prior to initiation of the caregiver training intervention.et al. et al. et al. et al. ADHD symptoms were assessed using parent report on the ADHD-RS-IV, an 18-item scale that assesses the presence and severity of DSM-IV symptoms of ADHD, including a nine-item subscale for inattention and a nine-item subscale for hyperactivity/impulsivity .To assess executive functioning, we employed the BRIEF school-age version (ages 5–12) ; graphically representing the eigenvalues to visually analyze the relative importance of the factors, where a sharp drop in the plot signals that subsequent factors are ignorable (scree plot); and using parallel analysis to adjust for sample bias in the observed eigenvalues Dinno, . Exploraet al. The primary assessment of convergent validity was association between ADHD-RS-IV total symptom score and the BRIEF ‘inhibit’ scale , suggesting plausibility of a two-factor model of ADHD. Measures of comparative fit suggested that the two-factor model was superior to the one-factor model  (p < 0.001 level after adjusting for child age and sex (which were both associated with executive function deficits). Higher total ADHD symptom scores were also associated with worse performance-based measures of executive function on the TOVA (p = 0.01–0.04), but not with the TOVA ADHD Index (p = 0.92) (p = 0.14) (p = 0.15)Greater total ADHD symptom scores were strongly associated with higher levels of parent reported executive function problems on the BRIEF (e Index) . All ass = 0.92) . Total A = 0.14) . Total Az-score for height, MUAC), having a non- parent caregiver, both parents unemployed, total HOME score, and harsh parenting (an index of five items from the HOME related to harsh/punitive parenting practices). There were no significant associations between either opportunistic infection prophylaxis and ADHD (p = 0.44) or HAART and ADHD (p = 0.68). Of note, we were unable to assess odds ratios for history of malaria or preterm birth, since all children meeting ADHD symptom criteria had been exposed to malaria and none of the ADHD cases were born preterm.Multilevel mixed-effects logistic regression analysis did not reveal significant associations between ADHD and any of the individual or family-level risk factors assessed. Factors evaluated included: sex, age, HIV proxy variables (i.e. on HAART or on opportunistic infection prophylaxis), anthropometric measures (n = 27), and (2) continuous ADHD symptom scores as the dependent regression variable. In the first analysis, there were no individual or family level risk factors. In the second analysis, age, MUAC, and height z-score were significantly associated with ADHD symptom scores, whereas sex and HIV proxy variables remained non-significant. In adjusted regression models , only age remained significantly associated with ADHD symptom scores.To further investigate ADHD risk factors in this novel study setting, we conducted two additional sensitivity analyses  using: (1) an alternate categorical definition with subjects scoring in the upper 10th percentile on the ADHD-RS-IV classified as ‘cases’  on all indices and scales of the BRIEF  (results not shown). There were no significant differences in performance tests of executive function between children who met symptom criteria for ADHD and those who did not. These findings remained consistent in a sensitivity analysis defining children in the upper 10th percentile of ADHD-RS-IV scores as ‘cases’.Children meeting symptom criteria for ADHD had significantly higher mean problem scores in all domains of executive functioning as measured by the BRIEF see . In addiet al. Our study demonstrated strong associations between ADHD symptom severity on the ADHD-RS-IV and greater executive function problems in Ugandan HIV-affected children. Children meeting symptom criteria for ADHD were significantly more likely to exhibit deficit-level impairments in all measured domains of executive function on parent-reported measures. Overall, the findings of this study are comparable with studies in the USA and elsewhere demonstrating significant executive dysfunction in children with ADHD  that precluded an accurate calculation of malaria or HIV status as risk factors for ADHD. Likewise, we were unable to assess risk due to perinatal HIV exposure since all included children were exposed.et al. Several strengths of our study should also be noted and include the availability of in-depth neuropsychological test results performed by trained researchers and the use of a community-based  sample. This study also incorporated a rigorous evaluation of the construct validity of a widely used DSM-IV-TR-based scale [ADHD-Rating Scale-IV  (Klasen & Crombag,


Simulation-based training (SBT) has become a standard for medical education. However, the efficacy of simulation based training in airway management education remains unclear.The aim of this study was to evaluate all published evidence comparing the effectiveness of SBT for airway management versus non-simulation based training (NSBT) on learner and patient outcomes.Systematic review with meta-analyses were used. Data were derived from PubMed, EMBASE, CINAHL, Scopus, the Cochrane Controlled Trials Register and Cochrane Database of Systematic Reviews from inception to May 2016. Published comparative trials that evaluated the effect of SBT on airway management training in compared with NSBT were considered. The effect sizes with 95% confidence intervals (CI) were calculated for outcomes measures.Seventeen eligible studies were included. SBT was associated with improved behavior performance  in comparison with NSBT. However, the benefits of SBT were not seen in time-skill , written examination score  and success rate of procedure completion on patients .SBT may be not superior to NSBT on airway management training. Airway management is often a life-saving procedure for patients. However, it may be difficult for many health-care providers to gain enough experience to become and remain expert in airway management based solely on their clinical experience . Thus, iThere are several methods of medical education on airway management training. Simulation based training (SBT) has gained much attention as it may improve patients safety and increase learner competence , 3. SystWe followed PRISMA guideline in reporting this systematic review and meta-analysis . A revieFeature SBT as an educational intervention involving one or more of following modalities: partial-task trainer , high-fidelity mannequins, virtual reality, or computer software Feature NSBT as a comparison groupIn single-task or multitask course which included training for airway management technique (e.g. direct laryngoscope and/or intubation (DL), bag-mask-ventilation (BMV), flexible laryngoscope or bronchoscope (FL), supraglottic airway management, cricoids pressure and surgical airway).Assessment of learner and/or patient outcomes.We considered all published comparative trials that evaluated the effect of simulation on airway management training in comparison with NSBT. We used the following inclusion criteria to select the pool of eligible studies:Data from letters, case reports, reviews or abstracts were excluded.airway; fiberoptic, fiberscope; bronchoscopy; laryngoscopy; intubation; supraglottic, laryngeal mask, combitube; cricoids pressure; bag-mask-ventilation; cricothyroidotomy, surgical airway. These terms were searched as subject headings, medical subject headings, and text words where appropriate. We combined these using the Boolean operator “and” with education terms: training; education; learning; teaching; and teach. No language restriction was placed on our search. To maximize the sensitivity of our search, we did not limit our search to terms related to simulation or study type. The reference lists of all eligible publications and reviews were scanned to identify additional relevant studies. Two authors screened and reviewed independently all titles and abstracts for eligibility. For abstracts that did not provide sufficient information to determine eligibility, full-length articles were retrieved. Disagreement on inclusion or exclusion of articles was resolved by consensus.A systematic search of PubMed, EMBASE, CINAHL, Scopus, the Cochrane Controlled Trials Register and Cochrane Database of Systematic Reviews from inception to May 2016, was performed to identify published potential trials. The search strategy was developed using following search terms: Studies were reviewed and data extracted independently by two authors using a pre-designed standard form. The following data points were extracted: 1) simulation modality, 2) trainee characteristics, 3) airway management techniques, 4) type of study design, 6) method of assessment, 7) learning outcomes, including time-skill (time to complete task), behavior performance and knowledge, 8) learner reaction , 9) patient clinical outcomes (i.e. success rate of procedure completion on patients and complications of airway management). Attempts were made to contact the authors for missing data. If detailed information was not received, the study was excluded from the current meta-analysis.To assess methodological quality, we used elements of the Medical Education Research Study Quality Instrument (MERSQI) . The MER2were used to assess heterogeneity across studies, which determined the appropriate use of either fixed-effects or random-effects model. Heterogeneity was considered as a P-value < 0.05 or I2 > 25%  and1, n = 2 , 14] forOne study  reportedSix studies , 18, 19 Seven studies , 18–20 rThree studies , 22, 24 There are high expectations associated with SBT since it could apply knowledge in a hands-on approach and offer a venue for problem solving in real-life situation without patient risk or time constraints –27. The Our findings supported the previous evidence that SBT are enjoyable and attractive instruments for airway management training . HoweverSeveral limitations of this review are note worthy. First, our analysis revealed high inconsistency between studies, reflecting variation in instructional design, learner groups, NSBT methods and outcome measures. Secondly, some of the included studies had methodological limitations or failed to describe clearly the context, instructional design, or outcomes; and these deficits limit the strength of our inferences. Some studies could not be included in the pooled analyses because of missing data, despite numerous attempts to contact the authors for more information. Thirdly, only one-third of the included studies measured outcomes on real clinical setting and three studies provided data on skill retention, thus limiting our ability to comment on translation of outcomes from the simulated environment to the real life clinical environment. Last, pooling effect sizes across study designs is problematic. We have therefore provided results for our meta-analyses, stratified by study design. Results from meta-analyses of RCTs remain consistent.This meta-analysis , within limitations of the existing data and of the analytic approaches used, shows that SBT is associated with improving learner behaviour performance and increasing learner interest and satisfaction. But no significant effect of SBT on time skill and knowledge acquisition for airway management was found. Further well-designed studies are needed to address this issue.


Background: Understanding cost-drivers and estimating societal costs are important challenges for economic evaluation of health technologies in low- and middle-income countries (LMICs). This study assessed community experiences of health resource usage and perceived cost-drivers from a societal perspective to inform the design of an economic model for the Community Level Interventions for Pre-eclampsia (CLIP) trials.Methods: Qualitative research was undertaken alongside the CLIP trial in two districts of Sindh province, Pakistan. Nine focus groups were conducted with a wide range of stakeholders, including pregnant women, mothers-in-law, husbands, fathers-in-law, healthcare providers at community and health facility-levels, and health decision/policy makers at district-level. The societal perspective included out-of-pocket (OOP), health system, and program implementation costs related to CLIP. Thematic analysis was performed using NVivo software.Results: Most pregnant women and male decision makers reported a large burden of OOP costs for in- and out-patient care, informal care from traditional healers, self-medication, childbirth, newborn care, transport to health facility, and missed wages by caretakers. Many healthcare providers identified health system costs associated with human resources for hypertension risk assessment, transport, and communication about patient referrals. Health decision/policy makers recognized program implementation costs  as major investments for the health system.Conclusions: Our investigation of care-seeking practices revealed financial implications for families of pregnant women, and program implementation costs for the health system. The societal perspective provided comprehensive knowledge of cost drivers to guide an economic appraisal of the CLIP trial in Sindh, Pakistan. Globally, maternal and newborn mortality trends have declined, albeit slowly, over the past 10 years in low- and middle-income countries (LMICs) . In respEconomic evaluation, conducted as part of health technology assessment (HTA), provides a systematic approach to collect evidence about costs and effectiveness from the diverse perspectives of care providers, care receivers, and community stakeholders . Such anPakistan is the world's sixth largest country in terms of population and belongs to a group of LMICs according to the World Bank classification  . An exteOverall, healthcare-seeking practices portray a dismal picture suggesting that only 65 percent of pregnant women seek routine ANC; nearly 48 percent of deliveries occur without the assistance of a skilled care provider and fewer than 50 percent of women seek either postpartum and/or newborn care . It is eThe Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomized controlled trial (cRCT) is testing an innovative package of care that introduces mHealth platform-guided case identification, time-of-disease risk stratification, and case management for women with a hypertensive disorder of pregnancy (HDP) in Pakistan, India, and Mozambique . The assThe societal perspective, inclusive of out-of-pocket (OOP) costs to patients/families and opportunity costs, albeit a very important driver for public policy, were excluded from these cost-effectiveness analyses. To design an economic model suitable for the needs of stakeholders evaluating the CLIP interventions in Pakistan, this study aimed to assess community experiences of health resource usage and perceived cost drivers, using a societal perspective.Qualitative research was undertaken alongside the CLIP trial during November to December 2014. The conceptual framework was guided by a phenomenological approach that attempts to understand people's experience in regard to specific phenomenon of common interest. It is based on participants’ view of the situation and how they interpret those experiences . In releThis study was conducted in two districts  of the southern Sindh province in Pakistan. Matiari is a rural district located 25 kilometers north of Hyderabad with a population of approximately 0.6 million . Hyderab> 140 mm Hg) during a CLIP pilot cRCT visit; and (iii) available for a discussion lasting at least 60 minutes. The literature suggested that household decision makers traditionally make decisions about women's health issues in LMICs  who could provide insight based on their own experiences related to HDP care sought/provided during the CLIP pilot cRCT. The sampling framework included four intervention clusters (~400 pregnancies per cluster in one year), in which we estimated 80 pregnant women would experience HDP . Pregnant women and household decision makers were identified through the trial recruitment logs, while healthcare providers and decision/policy makers were identified through health facility networks.n = 19 in total), two with husbands/fathers-in-law (n = 17), two with LHWs (n = 19), two with medical doctors at health facilities (n = 20), and one with district-level health decision/policy makers (n = 10). Participants were reimbursed for study-related transportation costs.The project-trained research assistants (RAs) approached eligible participants in their respective settings  and invited them to take part in the study. We had anticipated five focus groups (FGs) (at least one FG per each group); however, we increased the number of FGs  to achieve data saturation. In total, nine FGs were conducted: two with pregnant women/mothers-in-law  for data analysis. The analysis of FG data was conducted in the same language (Sindhi), using the new version of NViVo that allows for coding in languages other than English. This increased rigor in the data analysis and prevented meaning loss from translation. The participants’ attributes were analyzed, and their responses were coded on a hierarchy of tree nodes . A combined approach to data analysis inclusive of inductive and deductive reasoning was used to interpret emerging themes/sub-themes . The desData quality was ensured through random observations of FGs by field coordinators and a public health scientist, 10 percent (audit-trail) verifications of the content of manual transcripts by audio-recording reviews, and weekly debriefing sessions with moderators/transcribers. The FG moderator recorded a self-reflection after each session to describe personal thoughts and impressions to better contextualize the data, as well as to protect against self-bias.Written consent was obtained from every participant before conducting the study. This study received ethical approval from the Ethics Review Committee (ERC) of the Aga Khan University, Karachi, Pakistan (ERC # 3230-OBS-ERC-14), and the Institutional Review Board of the University of British Columbia in Vancouver, Canada (ETHICS # H12-00132), as the central coordinating site.Participants’ discussions were categorized into emerging themes and sub-themes as HDP-related health resource usage, and/or as perceived costs to family, health system, and program implementation.“We traveled to Shadadpur government hospital for the treatment. Doctors told . . . [me] . . . that my blood pressure was extremely high and I had to deliver the baby. They said that normal delivery is unlikely because of high blood pressure, therefore, they did C-section to deliver my baby”.Participant 6, FG 1, pregnant women and mothers-in-lawThe theme on resource usage suggested patterns and types of care sought from health facilities in the catchments. Almost all pregnant women reported having sought health care after they were identified as hypertensive and referred to a health facility by LHWs. The majority visited public secondary and tertiary health facilities that were usually located outside study clusters, requiring families to arrange transport. In most cases, women were delivered by Cesarean delivery (C-section). One woman described her experience of visiting a distantly located public health facility in the following quote:A few pregnant women stated that they visited private general practitioners because of easy access, family preferences, and past unfavorable experiences with public sector health facilities.The theme on perceived cost drivers contextualized a broad range of costs to care receivers, healthcare providers, and decision/policy makers.Pregnant women  emphasized OOP expenditure as the main barrier to seeking timely care. The OOP costs were described as in- and out-patient care, diagnostic procedures, informal care received from traditional healers, self-medication at home, childbirth, and transport to health facilities. The reported lump sum OOP costs ranged from 50 Pakistani rupees (PKR) (USD0.5) for diagnostic procedures to 10,000 PKR (USD100) for in-patient hospitalization for childbirth .Table 3“We don't have savings for emergencies related pregnancy and childbirth. [We had to sell] family assets and borrowed money from friends/neighbors. . . It took us several months to pay back the borrowings.”Participant 7, FG 1, husbands and fathers-in-lawThe OOP costs were usually perceived as a large financial burden for the family of a pregnant woman, and they had a substantial impact on their economic conditions and wellbeing. One husband described this in the following quote:“Because I did not have money, we didn't go to hospital when my wife was identified as hypertensive during the current pregnancy. . . .we cannot afford health care expenses!”.Participant 7, FG 2, husbands and fathers-in-lawAlternatively, costs deterred families from seeking care:Participants stated that husbands (in most cases) and/or mothers-in-law were responsible for accompanying pregnant women when they were transported to a health facility. Additionally, blood relatives, and/or family friends were often reported to have stayed with, and remained involved in patient care, when a pregnant woman was hospitalized for HDP management and for childbirth. A vast majority of family members were paid a lump sum wage of 150 to 500 PKR (USD 1.5 to 5) per day, or a fixed salary of 8,000 to 13,000 PKR (USD 80 to 130) per month. Consequently, missed wages for family members were considered to be a double economic burden for the family and others involved.“A pregnant woman would often speak about her problems. Most women have a problem of anemia and complain of pain. They share domestic worries related to their husband's lack of support and misunderstandings with mothers-in-law. Therefore, it sometimes takes one hour to complete a visit.”Participant 6, FG 1, LHWsLHWs and MDs  revealed health system costs associated with human resources, transport, and communication. LHWs described making once-monthly home visits to provide basic antenatal care to pregnant women in their catchment areas. Home visits were described to include screening pregnant woman for HDP, initial case management (if the pregnant woman was identified at risk for adverse birth outcomes), and referrals to health facilities. The duration of a completely routine visit, where the pregnant woman was found to be in good health, was 20 to 30 minutes. A more typical visit would take 30–60 minutes to complete if the pregnant woman required medications and/or the family needed counseling about referral to a health facility. One LHW described her typical home visit experience in the following quote:Moreover, a few LHWs mentioned families’ expectations that they (LHWs) accompany pregnant women to healthcare facilities and exchange their cell phone numbers to maintain communication for emergencies.MDs practicing at primary and secondary health facilities considered performing basic diagnostic tests such as blood pressure monitoring, blood sugar testing, proteinuria measurement, and ultrasound imaging. Prescribing patterns revealed frequent use of oral tablet methyldopa (Aldomet) to treat high blood pressure, injection [of] diazepam to control seizures, and referral to higher-level health facility for severe complications during pregnancy. MDs practicing at tertiary-level health facilities considered advanced maternal and fetal tests, such as 24-hour urine collection, blood tests , and fetal imaging. All recommended close monitoring as an in-patient and interventions that included intravenous administration of magnesium sulfate, blood transfusion, and Cesarean delivery.Health decision/policy makers recognized program implementation costs  as major investments for the health system. All health decision/policy makers believed that mHealth technologies have potential to improve maternal and perinatal health in LMICs. They discussed the prerequisites for effective program implementation: (i) a major initial investment in establishing the mHealth platform , and (ii) patient screening equipment . Many health decision/policy makers reported the need to train all existing staff through refresher programs and to provide ongoing monitoring and supervision.This study reports a societal perspective of cost drivers relevant to stakeholders considering the CLIP interventions, and has demonstrated that care-seeking practices vary between public and private health sectors in Sindh, Pakistan. Our findings further highlighted contextual aspects of resource usage that guided the design of a comprehensive questionnaire for quantitative ascertainment of individual level health resource usage during the trial period.Given ever-increasing reliance on technology use in health care, there are implications for incremental costs to society . We founThe program implementation as indicated in this study suggests incremental costs to the provincial public health department, as health technology procurement and trainings require substantial investments. Program costs are often feared to increase the burden on existing health budgets in LMICs. It is likely that community-based screening and/or interventions using mHealth platform will influence care-seeking behaviors. Our argument is supported by an RCT that demonstrated that short message services (SMS) and cell phone reminders , compared with no reminders , were associated with significantly higher attendance rates at health promotion centers . AnotherThe economic appraisal of emerging health technologies plays a pivotal role in policy advocacy and resource allocation for posttrial program scale-up . We founThe International Society of Pharmacoeconomics and Outcome Research (ISPOR) recommend in-depth assessment of jurisdiction-specific costs and outcome parameters for decision-analytical models of multi-national trials. In this study, we used a pragmatic approach to assess cost drivers necessary for the economic analysis alongside the CLIP trial in Sindh, Pakistan. FGs with a wide range of stakeholders in relation to the CLIP trial further add methodological rigor to the overall study. We recognize that combine FGs for pregnant women- and mothers-in-law; husbands- and fathers-in-law may have resulted in social desirability bias and it is the main limitation of current study.The transferability of our study findings is limited to care-receivers, care-providers, and program implementers in relation to the CLIP trial in Sindh, Pakistan. The methodological approaches as reported in this study may guide future health economics studies evaluating MNCH interventions in Pakistan and other LMICs.A thorough understanding of care-seeking practices revealed financial implications for families of pregnant women, and program costs for the health system during implementation of CLIP trial. The societal perspective provided contextual information, and revealed a more comprehensive description of cost drivers that can be used to design an economic model to fulfill the needs of health decision/policy makers considering CLIP interventions in Sindh, Pakistan.The author(s) declare that they have no competing interests.


Visual object tracking technology is one of the key issues in computer vision. In this paper, we propose a visual object tracking algorithm based on cross-modality featuredeep learning using Gaussian-Bernoulli deep Boltzmann machines (DBM) with RGB-D sensors. First, a cross-modality featurelearning network based on aGaussian-Bernoulli DBM is constructed, which can extract cross-modality features of the samples in RGB-D video data. Second, the cross-modality features of the samples are input into the logistic regression classifier, andthe observation likelihood model is established according to the confidence score of the classifier. Finally, the object tracking results over RGB-D data are obtained using aBayesian maximum a posteriori (MAP) probability estimation algorithm. The experimental results show that the proposed method has strong robustness to abnormal changes . The algorithm can steadily track multiple targets and has higher accuracy. Visual object tracking is one of the key research topics in the field of computer vision. In recent years, it has had a wide range of applications, such as robot navigation, intelligent video surveillance, andvideo measurement ,2,3,4. DA typical visual object tracking algorithm often includes three major components: a state transition model, an observation likelihood model and a search strategy. A state transition model is used to model the temporal consistency of the states of a moving object, whereas an observation likelihood model describes the object and observations based on visual representations. Undoubtedly, feature representation is the most important factor in visual object tracking. Most of existing RGB-D trackers ,7,8 tendWith the rapiddevelopment of computation power and the emergence of large-scale visual data, deep learning has received much attention and had a promising performance in computer vision tasks, e.g., object tracking , object To the best of our knowledge, the existing visual tracking methods using deep learning follow a similar procedure, which tracks objects in 2D sequences. Object tracking is performed over 2D video sequences in most early research works like TLD tracker , MIL traTo overcome the problems in the existing methods, we propose a visual object tracking algorithm based on cross-modality feature learning using Gaussian-Bernoulli deep Boltzmann machines (DBM) over RGB-D data. A cross-modality deep learning framework is usedto learn a robust tracker forRGB-D data. The cross-modality features of the samples are input into the logistic regression classifier, andthe observation likelihood model is established according to the confidence score of the classifier. We obtain the object tracking results over RGB-D data using aBayesian maximum a posteriori probability estimation algorithm. Experimental results show that such a cross-modality learning can improve the tracking performance.We present a cross-modality Gaussian-Bernoulli deep Boltzmann machine (DBM) to learn the cross-modality features of target objects in RGB-D data. The proposed cross-modality Gaussian-Bernoulli DBM is constructed with two single-modality Gaussian-Bernoulli DBMs by adding an additional layer of binary hidden units on top of them, which can fuse RGB information and depth information effectively.A unified RGB-D tracking framework based on Bayesian MAP is proposed, in which the robust appearance description with cross-modality features deep learning, temporal continuity is fully considered in the state transition model.Extensive experiments are conducted to compare our tracker with several state-of-the-art methods on the recent benchmark dataset . From exThe main contributions of this paper can be summarized as follows:The remainder of the paper is organized as follows. First, feature learning over RGB-D data with cross-modality deep Boltzmann machines is described in the next section. Then we introduce our tracking framework in TheBoltzmann machine (BM) was proposed by Hinton and Sejnowski . A BoltzWe formulate the energy function over the state The model defines a probability distribution over a visible vector The following formulations give the conditional distributions over hidden and visible units:Setting both A restricted Boltzmann machine(RBM) is a generative stochastic artificial neural networkthat can learn a probability distribution over its set of inputs. It is an undirected graphical model with each visible unit only connected to each hidden unit. The energy function over the visible and hidden units.When inputs are real-valued images, we formulate the energy function of the Gaussian-Bernoulli RBM over the state  follows :(7)E  containsRBMs see . The energy function of the joint configuration ABoltzmann machine (BM) is an effective tool in representing probability distribution over its inputs. Deep Boltzmann Machines (DBMs) have been successfully used in many application domains, e.g., topic modelling, classification, dimensionality reduction, feature learning, etc. According to the task, DBMs can be trained in either unsupervised or supervised ways. In this paper, we propose the cross-modality DBMs for feature learning in visual tracking over RGB-D data. In this section, we first describe how to establish cross-modality DBMs, review BMs, RBMs and Gaussian-Bernoulli restricted Boltzmann machines, then go over them in detail.Multimodal deep learning was proposed forvideo and audio ,26. In RSimilarly, the corresponding probability assigned to Let Therefore, the joint probability distribution over the cross-modal input In this paper, the object tracking is formulated as a hidden state variable Bayesian maximum a posteriori (MAP) estimation problem in the Hidden Markov model. Given a set of observed variables P theory .The posteriori probability distribution according to the Bayesian theory can be modelled as the following derivation:x-direction and y-direction translation of the object in the frame t respectively, t.The state variable is defined as We assume that the candidate states are generated according to Gaussian distribution:In this paper, the observation model that we use is discriminative. A binary linear classifier is adopted to classify tracking observations into object class and background class during tracking. Observations are represented using features learned from the DBM introduced previously. We can obtain a training dataset with approximate labels after extracting features of positive and negative samples. Deep representations are likely to be linearly separable, and linear classifiers are less prone to overfitting. We adopt the logistic regression classifier owing to its capability of providing predictions in probability estimation. Let Our method has two major components, which are shown in Then, the trained cross-modality Gaussian-Bernoulli DBM is transferred to an observational model for visual tracking online based on Bayesian MAP, as shown in The experiments of our proposed tracking algorithm is implemented on MATLAB R2014a, Intel(R) Core(TM) i7-4712MQ, CPU@3.40 GHz and TITAN GPU, 8.00 GB RAM, Windows 8.1 operating system, in Beijing, China. In order to show the robustness of the visual object tracking algorithm discussed in this paper, we compare our tracker with several state-of-the-art methods on arecent benchmark dataset  in diffeWe compare our method with several state-of-the-art trackers, including TLD Tracker, MIL TraAs shown in experimental results, the proposed tracking method performs favorably against the state-of-the-art tracking methods in handling challenging video sequences, but there are some limitations for our method. The robustness of the proposed tracking method is not strong enough to solve allocclusion and abrupt movement.We use two measurements to quantitatively evaluate tracking performances. The first one is called average center location error  which meBy analyzing the problems of the existing technologies, this paper proposes a visual object tracking algorithm based on cross-modality features learning using Gaussian-Bernoulli deep Boltzmann machines (DBM) over RGB-D data. We extract cross-modality features of the samples in RGB-D video data based on across-modality Gaussian-Bernoulli DBM and obtain the object tracking results over RGB-D data using aBayesian maximum a posteriori probability estimation algorithm. The experimental results show that the proposed method greatly improves the robustness and accuracy of thealgorithm. In the future, we will extend the proposed method to solve other vision problems .