While an association between zolpidem use and fracture and road accident was previously proposed, this study aimed to further explore the frequency and risk of a wide spectrum of injuries in subjects prescribed with zolpidem in Taiwan.We identified 77,036 subjects who received Zolpidem treatment between 2005 and 2007. We randomly selected 77,036 comparison subjects who were frequency-matched based-on their demographic profiles. We individually tracked each subject for a 90-day period to identify those who subsequently suffered an injury. Cox proportional hazards regressions were performed to calculate the hazard ratio of injury between the two groups.The incidence rate of injury during the 90-day follow-up period for the total subjects was 18.11 (95% CI = 17.69–18.54) per 100 person-years; this was 24.35 (95% CI = 23.66–25.05) and 11.86 (95% CI = 11.39–12.36) for the study and comparison cohort, respectively. After adjusting for demographic variables, the hazard ratio (HR) of injury during the 90-day follow-up period for study subjects was 1.83 (95% CI = 1.73–1.94) that of comparison subjects. Additionally, compared to comparison subjects, the adjusted HR of injury during the 90-day follow-up period for study subjects who were prescribed Zolpidem for >30 days was as high as 2.17 (95% CI = 2.05–2.32). The adjusted HR of injury to blood vessels for study subjects was particularly high when compared to comparison subjects .We found that patients prescribed with Zolpidem were at a higher risk for a wide range of injuries. Zolpidem is a short-acting non-benzodiazepine drug used to treat insomnia. The onset of zolpidem is fast, which is suitable for subjects who have difficulty initiating sleep Because zolpidem is fast-acting and has a short half-life (2 hours) in the body, users generally experience a relatively small residual effect the following day compared with longer-acting benzodiazepines. Although still controversial, zolpidem is generally regarded to be a safer medication for treating insomnia As zolpidem is commonly prescribed, and is by far the most widely prescribed non-benodiazepine hypnotic for insomnia in Taiwan, the safety of its use is an important public health issue. Previous studies have mainly focused on the risk of fracture and road accidents in the patients who used zolpidem, and may have underestimated the overall impact of the drug regarding its association with the occurrence of injury. Clinical guidelines should be developed based on epidemiological evidence of this potential association. Hence, the present study aimed to explore the profile of a wide spectrum of injury occurrence among cohort of patients prescribed with zolpidem compared with a matched comparison cohort using a large population-based retrospective database.This retrospective cohort study used data sourced from the Longitudinal Health Insurance Database 2000 (LHID2000). The LHID2000 consists of the original claims data and registration files for 1,000,000 enrollees under the Taiwan National Health Insurance (NHI) program. Taiwan Initiated the NHI program in March 1995. The 1,000,000 subjects included in the LHID2000 were randomly sampled from the 2000 Registry for Beneficiaries of the NHI program. Studies have demonstrated the high validity of the data from the NHI program As the LHID2000 consists of de-identified secondary data released to the public for research purposes, after consulting with the director of the Institutional Review Board (IRB), this study was exempted from full review and approved by the Taipei Medical University IRB.n = 2,495) preceding their index dates or had received Zolpidem treatment within one year prior to their index date. In addition, we excluded all the subjects who had a history of epilepsy (ICD-9-CM code 345) or infantile cerebral palsy (ICD-9-CM code 343) (n = 820). Ultimately, 77,036 subjects were included in the study cohort.This study featured a study cohort and comparison cohort. For the study cohort, we identified 80,351 subjects aged ≥18 years that were prescribed with Zolpidem between January 2005 and December 2007. We assigned the date of their first Zolpidem prescription as their index date and excluded all of the subjects that had suffered any of the injuries selected for this analysis within the 90 days , urbanization level, and index year. We selected the urbanization level of the subject’s residence as a matching criterion in order to help control for error variables, namely unmeasured neighborhood socioeconomic characteristics between the study and comparison cohort. For comparison subjects, we assigned their first use of medical care occurring during the index year as their index date. We assured that none of the selected comparison subjects were prescribed Zolpidem treatment within one year following or prior to their index date. In addition, we assured that none of the selected comparison subjects had a history of epilepsy or infantile cerebral palsy.Furthermore, according to the formula demonstrated by Hsieh and Lavori We individually tracked 154,072 subjects for a 90-day period starting from their index date to identify those subjects who subsequently received a diagnosis of injury. We classified the types of injury into the following categories: fracture (ICD-9-CM codes 800-829), dislocation (ICD-9-CM codes 830-839), sprain (ICD-9-CM codes 840-848), intracranial injury (ICD-9-CM codes 850-854), internal injury of thorax and pelvis (ICD-9-CM codes 860-869), open wound (ICD-9-CM codes 870-897), injury to blood vessels (ICD-9-CM codes 900-904), burns (ICD-9-CM codes 940-949), injury to nerves and spinal cord (ICD-9-CM codes 950-957), and injury, other and unspecified (ICD-9-CM codes 959). Furthermore, this study also analyzed the risk of injury according to the period of time patients received Zolpidem treatment (≤30 days and >30 days).p-value of <0.05 was considered statistically significant for this study.We used the SAS statistical package to perform all the statistical analyses performed in this study. We used the Kaplan-Meier method to estimate one-year injury-free survival rates and used the log-rank test to examine differences in injury-free survival rates between the study and comparison cohort. Furthermore, stratified Cox proportional hazards regressions  were carried out to explore difference in 90-day injury-free survival rates between the study and comparison cohort. We adjusted for patient’s co-morbidities by using the Elixhauser Co-morbidity Index, which was created in 1997 and uses 30 binary (1 = present and 0 = absent) co-morbidity measures to account for patient morbidity and mortality. In addition, we calculated a propensity score for each subjects and adjusted for propensity in all regression models. A propensity score was initially used to balance demographic and treatment characteristics, which were distributed unequally between the study cohort and the comparison cohort. Because the probability of injury may depend on the subject’s age, sex, urbanization level, monthly income, prior history of injury within one year prior to index date, and medical co-morbidities, were entered into a multivariable logistic regression model as predictors, to calculate the expected probability of injury for each subject. A two-sided The distribution of demographic characteristics and co-morbidities between the study cohort and comparison cohort was presented in p<0.001). The hazard ratio (HR) of injury between study and comparison subjects was also presented in We further analyzed the risk of injury by the length of Zolpidem treatment. Furthermore, we analyzed the HR of injury according to injury type . We founWe found that patients who had received zolpidem treatment were at a higher risk (1.96 times) for the occurrence of injury than a matched population of comparison patients. This increased risk was uniformly detected across a wide range of injuries. The mechanism of this association is still unclear. Nevertheless, the association between zolpidem and injury should not be simplified to a direct-causality relationship in the interpretation of our results. Similar to benzodiazepine, previous studies have reported that patients treated with zolpidem may be at higher risk for falls and road traffic accidents To the best of our knowledge, previous reports regarding the risk for these specific forms of injury remain scanty. In our study, it is worth noting that there was an increased frequency of severe forms of injury, including intracranial injury (HR = 2.39), internal visceral injury (HR = 2.46), and injury to the nerves and spinal cord (HR = 2.06). This form of injury is often associated with relatively high-energy impact/collision such as road traffic accidents, falling from heights, and other industrial accidents. Intracranial injury and spinal cord injury can cause significant neurological deficits and are associated with high mortality and long-term morbidity and disability. In addition, these injuries can cause significant medical and economic burdens. Previous studies reported psychoactive drug and alcohol usage can be associated with fatal road traffic accident The dose-response association between zolpidem and injury remains controversial. Some authors noted no clear dose-response association between short-acting benzodiazepine and fracture We found that patients receiving zolpidem treatment were at higher risk for fracture than matched a cohort. This finding is consistent with one previous study. Finkle et al. reported an excessive risk comparable with diazepam for non-vertebral-fracture and dislocation requiring hospitalization among patients treated with zolpidem The most important issue in exploring the risk of zolpidem and injury occurrence is the confounding effect of underlying insomnia. Insomnia can impair daytime function and psychological status, and therefore is likely to increase the risk for accident, fall and injury The mechanism underlying the increased risk for injuries in the patients treated with zolpidem was not explored in present study. Several mechanisms are hypothesized to elevate the risk for injury in this population. It is reasonable to propose this association may be partially attributable to the adverse effects of zolpidem in disturbing central nervous system function. This may be particularly the case among the elderly and subjects who used zolpidem inappropriately as zolpidem abuse has been reported to be associated with risky driving behavior Zolpidem associated parasomnia is another potential cause of injury. Such behavior may lead to additional damage to both patients themselves and other persons. Furthermore, the mechanisms for specific injuries may be informative in understanding the cause of injuries in the patients treated with zolpidem. For example, committing suicide by wrist cutting may be a cause of injury to the blood vessel. Nevertheless, the mechanisms underlying the association between zolpidem and injury may be very complex and heterogeneous.Several limitations of our study should be addressed. First, the compliance and usage patterns of zolpidem could not be determined from our database. Therefore our study may have misestimated the cumulative dose of zolpidem in patients who used the drug irregularly. In addition, some patients may have misused the drug and self-adjusted their zolpidem dose or taken it at inappropriate times. These behaviors can elevate the risk of daytime side effects and increase the risk for associated injury. Second, the co-morbidity status of the subjects can also affect the risk for injury. Fragility and multiple co-morbidities can increase the risk for falls and subsequent injury, particularly in the elderly Third, several medications, such as antidepressants and other psychoactive medications, have been recognized to increase the risk of falls and fracture Fourth, the detailed cause of injury is not recorded in our database. Therefore, the differentiation between non-intentional and intentional injury, including suicidal attempts and self-inflicted injuries, cannot be determined from our database. This information is useful in clarifying the mechanisms underpinning the association of zolpidem with injury.Fifth, the existence and duration of insomnia in the present study could not be determined. In addition, the diagnostic criteria for insomnia may not be uniform among physicians. These factors may result in heterogeneity of the study population. Finally, potentially confounding variables such as body mass index, alcohol consumption, and level of physical activity were not recorded in our database. These factors also play a modifying or mediating role in injury occurrence We found that patients treated with zolpidem had higher risk than a matched comparison cohort of a wide spectrum of injuries. We also found the risk for severe forms of injuries, such as intracranial injuries, injuries to the internal organs, nerves and spinal cord were also increased in these patients. In addition, patients with prolonged zolpidem (>30 days) use were suggested to be at a higher risk for injury than patients only taking zolpidem for a short period of time. Careful assessment and precaution is advised to prevent injury in this population.


In the case-control sample, significant enrichment of associations with obesity was observed above the 50th percentile for the set of the 16 nuclear regulators of mitochondrial genes . This finding was not confirmed in the trios , but in KORA . The meta-analysis again indicated a trend for enrichment . The GSEA revealed that weak association signals for obesity might be enriched in the gene set of 16 nuclear regulators of mitochondrial genes.There are hints of an altered mitochondrial function in obesity. Nuclear-encoded genes are relevant for mitochondrial function (3 gene sets of known relevant pathways: (1) 16 nuclear regulators of mitochondrial genes, (2) 91 genes for oxidative phosphorylation and (3) 966 nuclear-encoded mitochondrial genes). Gene set enrichment analysis (GSEA) showed no association with type 2 diabetes mellitus in these gene sets. Here we performed a GSEA for the same gene sets for obesity. Genome wide association study (GWAS) data from a case-control approach on 453 extremely obese children and adolescents and 435 lean adult controls were used for GSEA. For independent confirmation, we analyzed 705 obesity GWAS trios  and a population-based GWAS sample . A meta-analysis was performed on all three samples. In each sample, the distribution of significance levels between the respective gene set and those of all genes was compared using the leading-edge-fraction-comparison test (cut-offs between the 50 Heritability estimates for variance of the body mass index (BMI) range between 40 to 70% To discover further genetic variation associated with a certain trait, single-locus-oriented genome-wide association studies (GWAS) should be extended to pathway-based approaches or gene set enrichment analyses (GSEA). As these analyses concentrate on the combined effects across several loci, a gain in statistical power is expected and new genetic insight in the trait of interest might be revealed It is well known that mitochondria are the cellular power plants whose main function is ATP production via oxidative phosphorylation (OXPHOS). Impairment of mitochondrial function might influence body weight. Indeed, there are hints that mitochondria  and mitochondrial function are altered in obesity. Adult obese individuals showed smaller mitochondria in skeletal muscle tissue The mitochondrial DNA codes only for 37 genes, of which 22 encode tRNAs, two rRNAs and 13 OXPHOS subunits of the complexes I, III, IV and V. Additionally, more than 1,000 nuclear-encoded mitochondrial genes are necessary to ensure complete mitochondrial function and biogenesis Segrè et al. Based on the central role of mitochondria in metabolism and findings of an altered mitochondrial function we performed a GSEA focusing on obesity to address the question if gene sets of nuclear encoded mitochondrial genes are enriched for modest association signals that collectively influence obesity risk.Written informed consent was given by all participants and in case of minors by their parents. The study was approved by the Ethics Committees of the Universities of Marburg and Essen and the Bavarian Medical Association. It was conducted in accordance with the Declaration of Helsinki.2) was assessed for extremeness using age- and sex-specific percentile criteria for the German population from the National Nutrition Survey I th percentile), and 84.4% were extremely obese (BMI ≥99th percentile), the lean controls had a BMI of 18.31±1.11 kg/m2  obese children and adolescents and 435 normal weight or lean adult controls 11 kg/m2 .th percentile), and 83.8% were extremely obese (BMI ≥99th percentile) with regard to reference data from the German National Nutrition Survey I  obese child or adolescent (index case) and both biological parents, was used Survey I .2 were categorized as obese cases (n  = 463) and those with a BMI <25 kg/m2 were coded as normal weight controls (n  = 483). This population-based sample was converted into a case-control sample, as it was recently shown that genetic markers with an effect in the extremes of a trait are detected more solidly within a case-control design compared to a linear regression design, even for smaller sample sizes In addition, we analyzed a population-based sample comprising 1,743 adult participants, which is a sub-sample of the total KORA F4 sample . In more detail, meta-analysis was carried out using the inverse variance method by assuming a fixed effect model. We adopted the method of Kazeem and Farrell We performed a meta-analysis of all three samples using the METAL software package  ≥95% were included. Furthermore, in each of the 705 trios from the family-based GWAS sample the percentage of markers with observed Mendelian inconsistent genotype calls  was below 5%. Focusing on the approximate 870,000 autosomal SNPs, the following genotyping quality control filters were applied to each sample separately : (1) samEach gene set enrichment analysis (GSEA) is based on the idea of comparing gene association signals of gene sets with biological plausibility for the given phenotype to those of the genome-wide set of genes We tested those three mitochondrial gene sets for enrichment of obesity association signals, which were considered in the study of Segrè et al. http://genome.uscs.edu/). After exclusion of genes with two or more transcripts on separate chromosomes or with more than 1 Mb distance on the same chromosome, a total of 17,680 autosomal genes were followed-up. In consistency with Segrè et al. th percentiles of the distances of cis-eQTLs from transcript start and end sites of adjacent genes In the case-control GWAS sample, the Cochran-Armitage trend test for an additive mode of inheritance was applied to each autosomal SNP. Afterwards, SNPs were mapped onto genes. For this purpose, a list of human gene transcripts  was downloaded from the UCSC Genome Browser , the procedure was repeated with 100,000  permutations.Subsequently, each gene was assigned a gene-wise empirically corrected p-value Pg for the SNP already in the gene set. This exclusion was done in order to avoid significant gene set enrichment based on identical association signals Prior to GSEA testing, we addressed physical clustering of genes by excluding all genes with the identical selected SNP as compared to the gene with the lowest Pcut-off  = 95th, 75th and 50th percentile of the set of autosomal gene-wise p-values and with 10,000 samplings from the full autosomal gene p-value distribution . This test is based on the idea of comparing the fraction of genes with gene p-values below a certain cut-off  in the full set of genes and in the gene subset of interest. Here, the null distribution of such fractions in the gene subset is derived by randomly sampling the same number of gene p-values from the full set of gene p-values. The GSEA p-value is then determined by dividing the number of samplings with equal or larger leading edge fraction as the observed one by the number of samplings generated. To test the robustness of this test, we additionally ran three alternative one-sided GSEA tests as proposed by Segrè et al. GSEA,WMW); (3) the Kolmogorov-Smirnov test ; and (4) the t-test .Our alternative hypothesis was that gene p-value ranks in one of the three gene subsets of interest were skewed towards high ranks compared to the full autosomal set of genes. To test this hypothesis, we applied: (1) the leading-edge-fraction-comparison test as proposed by Segrè et al. http://pngu.mgh.harvard.edu/purcell/plink/) and assuming an additive allelic model of inheritance. Families with missing genotypes were excluded from TDT analysis of the respective SNP. In total, for only 0.37% of all SNPs more than 5% of trios were excluded from the TDT (due to genotyping failures and/or Mendelian inconsistencies). Gene-wise empirically corrected p-values for the family-based GWAS sample were based on randomly flipping the parentally transmitted allele for each family and each permutation. In KORA-CC each SNP was tested by the Cochran-Armitage trend test for an association with obesity, and gene-wise p-values were determined as for the discovery CC sample. For both the family-based GWAS sample and KORA-CC the remaining GSEA procedure was performed as described for the discovery sample.In the family-based GWAS sample, for each SNP a transmission disequilibrium test TDT;  was calcThe Meta-Analysis Gene set Enrichment of variant Associations (MAGENTA) software provided by Segrè et al. th, the 75th and the 50th percentile cut-off were performed as well as the alternatively included exact Wilcoxon-Mann-Whitney test. These cut-offs were chosen because simulations showed that for modest effects the 95th percentile and for weak effects the 75th percentile yielded the optimal power to detect gene set enrichment After bringing together the single marker information from the two case-control samples and the family-based TDTs , we applied MAGENTA to the single marker p-values of the meta-analysis. Leading edge fraction tests for the 95MAGENTA) and permutation-based gene p-values (pGSEA) were shown to be highly correlated  and 7,445 genes were removed due to physical clustering (see Methods). In total, all human autosomal genes were covered by 521,469 unique SNPs . Among the lists of the 16 nuclear regulators of mitochondrial genes and the 91 OXPHOS genes, all genes had SNPs in their extended boundaries. Two genes of the 91 OXPHOS genes were removed due to physical clustering. There were 1,014 unique SNPs  that fell within the gene regions of the nuclear regulators of mitochondrial genes and 2,781 unique SNPs  that were located within the gene regions of the OXPHOS genes. Furthermore, those 965 autosomal nuclear-encoded human mitochondrial genes that contained SNPs in their gene regions were covered by 35,223 unique SNPs , whereas due to physical clustering the corresponding effective gene set size was 880.GSEA,WMW  = 0.0075, PGSEA,KS  = 0.0195, PGSEA,t  = 0.0053; th percentile . The enrichment remained significant after Bonferroni correction for the three gene sets tested except for the Kolmogorov-Smirnov-Test.The first gene set of 16 nuclear regulators of mitochondrial genes was enriched for obesity association signals , we did not observe enrichment of association signals to (early onset extreme) obesity in the first gene set . The enrichment was found above the 50th percentile , confirming the initial finding of the discovery case-control sample (For the second independent case-control sample (KORA-CC), we found significant enrichment for association signals for obesity for the first gene set . This enrichment was not found above the 50th percentile as in the discovery, but rather above the 75th percentile , the permutation-based GSEA testing procedure and explicitly the determination of gene-wise corrected p-values could not directly be applied in a meta-analysis of all three samples. Alternatively, we applied the two software toolkits METAL and MAGENTA which were both specifically designed for the application to meta-analyze data. Significant enrichment for the first gene set was found  to demonstrate independence from the method choice. Although the Kolmogorov Smirnov test of the discovery stage revealed only nominal significance, results of all tests were similar regarding significance within a fixed tested sample and gene set. The MAGENTA software was additionally applied to each single sample in order to maximally guarantee robustness (within each sample) and comparability  of the results. Apart from a few exceptions, we found high levels of agreement of the p-values determined by both methods (leading-edge fraction test vs. MAGENTA) within a sample  & 2.In addition to the robustness regarding method choice another strength of our study was that we used both case-control and family-based samples. We observed consistent evidence for enrichment in two case-control samples but failed to detect it in the family-based GWAS sample of 705 obesity trios. Possibly the family-based sample was too small for a confirmation. Moreover, if the effect was mainly driven by lean and normal weight subjects, the frequencies of the variants would be very low in the predominantly obese trio parents Nrip1 k.o. mice are viable and morphologically normal, but 15–20% lighter than the wild-type or heterozygous littermates Nrf2 ( =  Gabpa) k.o. mice are characterized by decreased adipose tissue mass and protected against a high fat diet induced obesity. In addition, Sirt1 transgenic (knockin) mice were lighter than wild type littermates and had less white adipose tissue per body weight The 16 regulators of nuclear-encoded mitochondrial genes (gene set 1) are transcription factors and/or co-activators . AlthougIn summary, a GSEA on autosomal nuclear-encoded genes relevant for mitochondrial function revealed that a gene set of 16 nuclear encoded regulators of mitochondrial genes was enriched for weak obesity association signals. Initially, this enrichment was found in a case-control approach and independently confirmed in another case-control sample.Table S1Basic phenotypical characteristics of the family-based, the case-control and the population-based GWAS sample.(DOC)Click here for additional data file.Table S2Quality control of SNPs.(DOC)Click here for additional data file.


This work examined if currently available electromyography (EMG) driven models, that are calibrated to satisfy joint moments about one single degree of freedom (DOF), could provide the same musculotendon unit (MTU) force solution, when driven by the same input data, but calibrated about a different DOF. We then developed a novel and comprehensive EMG-driven model of the human lower extremity that used EMG signals from 16 muscle groups to drive 34 MTUs and satisfy the resulting joint moments simultaneously produced about four DOFs during different motor tasks. This also led to the development of a calibration procedure that allowed identifying a set of subject-specific parameters that ensured physiological behavior for the 34 MTUs.  Human movement is the result of the actuation of joints in upper and lower extremities. Joints are actuated by the coordinated excitation of musculotendon units (MTUs). The multiple MTUs spanning a joint reflect the redundancy of the human neuromuscular system in which a prescribed joint moment and motion can be the result of different MTU excitation strategies. Understanding how this redundancy is solved in humans and how MTUs develop force during movement is one of the biggest challenges in biomechanics. This has been previously studied using optimization-driven methodologies in which MTUs are assumed to contribute to the experimentally measured joint moments according to a chosen criterion that is presumed to be generalizable across subjects and motor tasks Surface electromyography (EMG) indirectly reflects the dynamics of an individual's neural drive and can be easily recorded during human movement EMG-driven musculoskeletal modeling (EMG-driven modeling) is a forward dynamics approach. In this, the EMG data experimentally recorded from the major muscle groups are used to drive multiple MTUs within a subject-specific physiologically accurate model of the human musculoskeletal system. In this scenario, the recorded EMG data directly determine the patterns of MTU excitation and the resulting MTU force and moment. This approach has the advantage, over optimization-driven methods, of solving the neuromuscular redundancy problem based on an individual's estimate of the neural drive without having to make assumptions on how MTUs share the load about a joint.EMG-driven modeling requires an off-line calibration to determine a number of model parameters that vary non-linearly across subjects because of anatomical and physiological differences same MTU and driven by the same input data during the same movement, predicted differently if different single-DOF models are used? In this scenario it is worth accounting for the fact that errors may be introduced when calibrating an EMG-driven model with respect to a DOF (i.e. hip flexion-extension) and using it to predict the action of MTUs and the resulting joint moment with respect to a different DOF (i.e. hip adduction-abduction). Single-DOF calibrations could therefore result in models that would predict substantially different force estimates for the same MTU and for the same data set of EMG and joint kinematics. This could represent a major limitation of currently available single-DOF models and would pose the question of how to combine together solutions from different single-DOF models if the predictions across the MTUs that are shared by different single-DOF models do not match.The currently available state of the art EMG-driven modeling methodologies employ calibration to create a robust model that only accounts for one selected degree of freedom (DOF) of the human limbs and for the associated MTUs spanning the specific DOF. In this, the activity of the selected MTUs is constrained to satisfy the joint moment or motion for the only selected DOF. Such models (i.e. single-DOF models) have been designed for the elbow flexion-extension Based on the above-mentioned considerations, this study had three aims. The first aim was to verify if the currently available EMG-driven models, which were calibrated about a single DOF, could provide the same unique MTU force solution when calibrated with respect to different single DOFs. Second, because it was found that currently available single-DOF calibrations did not result in the same calibrated EMG-driven model, we examined whether the development of a more comprehensive model that accounted for multiple DOFs and for a larger set of MTUs could address limitations in single-DOF EMG-driven modeling. To-this-end, we developed a multi-DOF EMG-driven musculoskeletal model (multi-DOF model) of the human lower extremity. Our proposed model used EMG signals recorded from 16 muscle groups to drive 34 MTUs and produce a single force solution that satisfied joint moments generated around four DOFs including hip adduction-abduction (HipAA), hip flexion-extension (HipFE), knee flexion-extension (KneeFE), and ankle plantar-dorsi flexion (AnkleFE). This led to the development of a more comprehensive calibration procedure that allowed identifying a set of subject-specific parameters that ensured physiological behavior for the large MTU set. Third, we examined whether the multi-DOF calibrated model could predict joint moments, of the included DOFs, with comparable accuracy with respect to each individual model calibrated about a single-DOF. We then examined and compared the force solution produced by the multi-DOF and single-DOF models for both MTUs acting about one or more joints and DOFs.Single-DOF EMG-driven modeling has been consistently applied to answer questions in many scientific areas, ranging from motor control to injury development, from biomechanics to rehabilitation robotics One healthy male subject  volunteered for this investigation and gave his informed, written consent. The project was approved by the Human Research Ethics committee at the University of Western Australia.The motion data acquired from the subject were static anatomical poses and dynamic gait trials. During all trials, the three-dimensional location of retro-reflective markers placed on the subject's body was recorded (250 Hz) using a 12-camera motion capture system . During the dynamic trials, ground reaction forces (GRFs) and EMG data were collected (2000 Hz) synchronously with marker trajectories using an in-ground force plate , and bipolar electrodes with a telemetered EMG system  respectively. Both GRFs and marker trajectories were low-pass filtered with a fourth-order Butterworth filter. Cut-off frequencies (between 2 and 8 Hz) were determined by a trial-specific residual analysis From the dynamic trials collected, two distinct datasets were created; one for the calibration of the single-DOF and multi-DOF models and the other one for the validation. The calibration dataset included two repeated trials of four motor tasks including walking (WK) (1.3±0.25 m/s), running (RN) (2.5±0.5 m/s), sidestepping (SS) (1.9±0.35 m/s), and crossover (CO) (1.8±0.15 m/s) cutting maneuvers. A different dataset was used to validate the calibrated EMG-driven models. This included ten repeated novel trials for each of the four considered motor tasks . The novel trials used for the model validation were performed at the same speeds as those used for the model calibration. However, none of the trials in the validation dataset were included in the calibration dataset, i.e. there was no intersection of data between the two datasets. The four motor tasks were chosen because 1) they allowed producing substantially high moments  about the four considered DOFs , and 2) because they reflected different MTU recruitment strategies and contraction dynamics. This allowed investigating whether our proposed multi-DOF model could predict joint moments simultaneously produced about the four considered DOFs while accounting for different MTU operation strategies.Multi-DOF EMG-driven Model section Using the software OpenSim After the anthropomorphic scaling, the OpenSim Inverse Kinematics (IK) algorithm The multi-DOF EMG-driven model was developed from the previously published KneeFE single-DOF (KneeFE-DOF) model Musculotendon Kinematics component (The omponent  used MTUMusculotendon Activation component (e(t) experimentally measured from 16 muscle groups to 32 MTUs in the model  activation filtering coefficients were constrained to vary between −1 and 1 to realize a stable positive solution and a critically damped impulsive response for the recursive filter In the Musculotendon Dynamics component, muscle strength coefficients were adjusted and used to scale the MTU-specific Model Calibration. However, prior to calibration, initial values for these parameters were found using the preferred scaling method (i.e. the seventh method) among the ones presented by Winby et al. Model Calibration to better reflect the actual subject's MTU intrinsic properties MTU-specific tendon slack lengths The validation comprised three tests to assess the single-DOF and multi-DOF models prediction ability and one to assess the computation time. In the three tests for prediction ability, the calibrated multi-DOF and single-DOF models predicted first test assessed whether single-DOF models produced different force estimates for the same MTU using the same input data and during the same movement. If single-DOF calibrated models did not produce a unique MTU force solution, and if the predictions across the MTUs that are shared by different single-DOF models did not match, then this would imply the impossibility of combining together solutions from different single-DOF models and predict joint moments about multiple DOFs simultaneously. For this purpose, the D DOFs , was predicted and averaged during the 40 validation trials, using the D associated single-DOF models. This produced D ensemble average D ensemble average p being considered. The normalized root mean squared deviation  and its standard deviation (σ) were calculated:N refers to the number of points in the ensemble average curves. Furthermore, a measure of the percentage MAE (%MAE) was calculated by dividing The third test compared the multi-DOF model D DOFs was computed using the multi-DOF and the associated single-DOF models. Then, for each MTU, the NRMSD coefficients were calculated between the multi-DOF model The fourth test the multi-DOF model calibration and execution time were examined. Calibration time was calculated as the time needed to calibrate the multi-DOF model on the eight calibration trials. Execution time was calculated as the average time needed to compute one time point from all DOF joint moments 1000 times repeatedly. Tests were performed on an 8 GB RAM Intel i7 CPU.In the first test . The single-DOF solutions for the semimembranosus, tensor fasciae latae, and biceps femoris long head assumed good shape similarities .The NRMSD = 0.5 and NRMSD = 0.27 respectively.The second test , and semitendinosus (NRMSD = 0.18 for the KneeFE-DOF), for a subset of uniarticular hip MTUs including gluteus maximus (NRMSD<0.38 NRMSD<0.29 NRMSD = 0.01), peroneus tertius (NRMSD = 0.16), and soleus (NRMSD = 0.04), and for a subset of uniarticular knee MTUs including vastus medialis (NRMSD<0.08), and biceps femoris short head (NRMSD = 0.05).The ird test  comparedNRMSD = 0.16, and 0.11 respectively). The multi-DOF model solution for the sartorius was similar in shape to the HipAA-DOF  were consistent with experimental EMGs, 2) were the result of physiological MTU operation, and 3) satisfied joint moments about multiple DOFs over different contractile conditions associated to four motor tasks: WK, RN, CO, and SS. The first test showed that although the same EMG signals and joint kinematics were used to drive the four single-DOF models, they produced substantially different force predictions for all MTUs, implying multiple solutions to the MTU force prediction problem . This woThe second test results showed that the multi-DOF model could concurrently predict joint moments with similar accuracy to those from the four single-DOF models . For somThe third test demonstrated the ability of the multi-DOF model of using mixed single-DOF prediction strategies across MTUs . This alFurthermore, experimental results suggested that our proposed multi-DOF modeling methodology could produce EMG-driven MTU solutions that better reflect the actual activated MTUs than single-DOF models. In the case of the rectus femoris the multi-DOF model produced force estimates that better matched with previously obtained findings  [11], [3Experimental results also showed that both the single-DOF and multi-DOF EMG-driven models could not produce joint moment estimates that exactly matched the experimental joint moments . This isThe present results showed that the multi-DOF model could predict MTU forces and joint moments within the range of DOFs, tasks, and gait cycle phases (i.e. stance phase) on which the model was calibrated. However, how the model predicts (i.e. extrapolates) outside the range of these DOFs, tasks, and gait cycle phases requires an extensive and structured research, which was beyond the scope of this study. It could be that there are certain DOFs, trials, and gait cycle phases that provide better control over the final calibrated model than other calibration data, and that these data enable robust extrapolation across all manner of tasks, DOFs, and phases. This is important to be determined as the size of the calibration data set also affects the speed at which calibration can occur. Indeed, our proposed multi-DOF model relies upon an off-line calibration procedure that was time consuming. However, the fourth test results showed that the model open-loop operation could be performed in a time close to that of the muscles electromechanical delay (i.e. between 10 ms and 20 ms) This work presented a study on one subject only and, therefore, may not be completely generalizable. However, the proposed EMG-driven musculoskeletal model was scaled and then calibrated to the actual subject to account for the subject-specific 1) anthropometry, 2) EMG-to-activation mapping, and 3) MTU intrinsic properties. First, with regards to the anthropometric scaling, our procedure linearly scaled the mass distribution and dimensions of every segment in the model as well as the MTU insertion, origin, and MTU-to-bone wrapping points according to the subject's anthropometry in vivo. These include the segment mass, the location of the segment center of mass, and the mass moment of inertia Our proposed methodology predicted joint moments during the stance phase only. The main reason for this was that calibration included trials of running, as well as sidestepping and crossover cutting maneuvers. For these motor tasks the swing phase occurred partially, or totally, out of the motion capture volume. Therefore there was an incomplete swing phase data available for calibration across trials. The second, although much lesser reason, was that joint moments were estimated using inverse dynamics, which strongly relies on the magnitude of GRFs Future work is also needed to validate whether the use of experimentally derived subject-specific anatomy and MTU parameters from imaging techniques (i.e. MRI and ultrasound) The above-mentioned points refer to limitations that apply to any EMG-based musculoskeletal modeling methodology. In this context, it is important noting that the aim of our proposed work was not that of addressing all those limitations in one single study. Our aim was to demonstrate the clear disadvantages of single-DOF EMG-driven modeling and that the associated limitations could be addressed using our proposed multi-DOF modeling methodology. In this scenario, this work needed to compare the two methods under the same conditions including: subject sample, motor task sample, EMG signal processing procedure, and model calibration and scaling procedure.In conclusion, this work proposed a novel EMG-driven musculoskeletal model of the human lower extremity and a calibration procedure that allowed identifying individual MTU parameters that could be used to predict a single MTU force solution, from experimentally measured EMGs, that was dynamically consistent with multiple DOF moments.


Lack of physical activity has contributed to the nation's childhood obesity crisis, but the impact of physical activity on self-efficacy as a mediator of behavior change has not been examined. This systematic review (SR) describes the published evidence related to the impact of physical activity intervention programs on self-efficacy among youths. From January 2000 to June 2011, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards were used to identify publications from PubMed, PsychInfo, Web of Knowledge, and the Cochran Database of Systematic Reviews. The Cochrane Population, Intervention, Control, Outcome, Study Design (PICOS) approach guided this SR articles selection and evaluation process. Of the 102 publications screened, 10 original studies matched the SR inclusion criteria. The types of physical activity interventions and self-efficacy assessments for these 10 studies were diverse. Of the 10 included articles, 6 articles identified an improvement in post-self-efficacy assessments compared to baseline and 4 showed no effect. In conclusion, physical activity intervention programs may improve self-efficacy in youths. A standardized approach to classify and measure self-efficacy is required. Further research is needed to quantify the association of self-efficacy ratings after completing physical activity interventions with objective health improvements, such as weight loss. The prevalence of childhood obesity has increased dramatically in the United States (US) the last 20 years. After age gender-based adjustments, more than 30% of US children and adolescents surveyed in 2007-2008 were overweight with a body mass index (BMI) greater than the 85th percentile . Young ASelf-efficacy, a construct of Albert Bandura's social cognitive theory (SCT), is defined as the belief in one's own ability to achieve actions necessary to produce a desired effect . It relaSelf-efficacy has been described as a predictor of physical activity intervention outcomes rather than an independent outcome. Authors have concluded that self-efficacy served as a covariate, which impacted other psychosocial factors and indirectly influenced the success of an intervention . SeveralAlthough improved self-efficacy has been associated with the compliance of health behavior modification interventions, few studies indicate that the intervention may influence self-efficacy. The directionality of the interaction between physical activity interventions and self-efficacy has not been clearly established. One review did report the effect of physical activity intervention outcomes on self-efficacy as a potential mediator of behavioral change in 4–12 year-old children from 1985 to 2006 . While uThis SR primary objective was to determine if physical activity related programs were associated with improved self-efficacy in children and adolescents (5–18 years old). Given the potential to impact long-term health for children and adolescents, a secondary objective was to evaluate the effect of physical activity self-efficacy ratings upon weight reduction goals. A protocol using the PRISMA standards was completed prior to initiating the literature search. Database searches were performed using PubMed, Web of Knowledge, PsychInfo, and the Cochran Database of Systematic Reviews (January 2000–June 2011). All appropriate titles and abstracts were reviewed per study inclusion/exclusion criteria. Due to a judicious electronic search, nonelectronic sources of literature were not considered. A detailed search strategy including search terms and limitations is listed in Appendix. Only those articles written in English were appraised. The Cochrane PICOS approach was applied to select the articles included .To meet the SR inclusion criteria, each publication must have included a subject population of children and adolescents (5–18 years). In evaluating these publications, a special emphasis was placed stratifying the data abstracted for the subpopulations of overweight youths. Publications were excluded if participants had a medical illness. The articles reviewed were required to include a structured physical activity program lasting 4 weeks or more. School and community-based physical activity incorporating individual or group activities were included. Types of physical activity considered for this paper included: cardiovascular activity, resistance training, or modifications of physical education classes. Programs that included exercise exclusively or in conjunction with nutrition and psychosocial factors were considered. When provided, the level of physical activity was classified as moderate, moderate to vigorous, or vigorous preferably using metabolic equivalents (METs) rating. Publications were not required to document energy cost of physical activity, as this would have significantly limited the paper. Exclusively web-based programs were eliminated from the paper due to entirely self-reported assessments of physical activity.All publications reviewed were required to include either a comparison or a control group. The type of comparison group permitted was liberal. The study participants may have been compared to subjects of another separate program, which was not coordinated contemporaneously. Comparisons may have also included groups that underwent an assessment period where there was no concurrent intervention, but then served as future intervention groups. The outcome measures for this SR included any self-reported physical activity self-efficacy and were required to be stated within the hypothesis or objectives of the study. Other motivational variables may have been included within the articles but were not addressed in this SR. All included publications must have identified statistically significant improvements (designated a priori), of self-efficacy after completion of the intervention. Studies that assessed objective “success” measures related to body weight, body mass index or body composition were accepted but not required as part of the SR inclusion criteria.To assure the quality of the study findings reported, the Oxford Centre for Evidence-Based Medicine (Levels of Evidence) 5-level hierarchical tool was used. Only studies with Oxford Centre for Evidence-Based Medicine levels of 3 or higher were reported . Hence,  As an assessment of inter-rater reliability, two authors independently reviewed each publication using a standardized data capture form with definitions to evaluate if all SR article inclusion/exclusion criteria were met as well as to appraise the quality. Search strategies of the initial abstract screening identified 102 publications . InterveSeven interventional studies met all the inclusion criteria from the 20 screened interventional articles, yielding a 35% inclusion rate –24. Thre A comprehensive list of the eliminated articles with rationale for exclusion and references is represented in  A total of 5229 school age participants were enrolled across 3 different types of settings. Important race and gender-based variations were noted. Two studies included female participants only , 18, 24, All of the included publications used a multidisciplinary physical activity approach. Six of the studies employed a school-based setting –22, 24, 2 max) [The key dimensions of the physical activity intervention components such as duration, intensity, and session length were diverse. The time frame of the programs varied from 8 weeks to 3 years. Six studies reported an intermediate duration (≥12 weeks up to 6 months) , 19, 23,2 max) , one mea2 max) , 21, 24. Four studies were randomized control trials (RCTs), such that the control group was randomly assigned for the analytical comparisons performed –21, 24. For the three cohort studies, the comparisons to the physical activity related intervention programs varied. All 3 of the physical activity related interventions studied occurred in a local YMCA. In one of these studies, the comparison was a school-based physical education class . The ind The “gold standard” description of self-efficacy is for perceived self-efficacy. In perceived self-efficacy, individuals have the belief that they are capable of functioning at a certain level of performance . SeveralP value of ≤0.05 was used to identify if statistically significant associations were reported. The statistical methods used include (1) descriptive assessments of central tendency and variability [t-tests, ANOVA, and chi squared tests [The approaches to identifying statistical associations within the included articles were diverse. For each article reviewed, a iability ; (2) unied tests ; (3) muled tests , 24, stred tests , simplised tests , and mored tests , 15, 20. Of the included articles identified for an in-depth review, the array of study designs included 4 RCTs –21, 24 aPer the preestablished SR protocol, the first SR project objective was to evaluate the association of physical activity intervention programs with improvements in self-efficacy. Of the 10 included studies six (60%) found an association with improved self-efficacy after intervention , 20, 23.The second SR study objective was to identify self-efficacy ratings with associated achievement of weight reduction following completion of physical activity related intervention. Although most of the studies collected baseline body weight or BMI, none of them evaluated the association of self-efficacy ratings with achievement of weight reduction .Two of the coauthors  analyzed each of the 102 publications. Independent assessments meeting each study's preestablished inclusion/exclusion criteria, reason for exclusion, the Oxford level of evidence grade, and the Jadad quality assessment score were recorded by both reviewers. The following concordance was observed: (1) for inclusion/exclusion decisions, there was 100% final inter-rater agreement as well as a high concordance (96% agreement) related to the reason for exclusion; (2) for the Oxford grades , there was a 90% agreement for ratings assigned independently; (3) of the 5 articles where Jadad ratings were assessed, there was 1 article of disagreement (80% agreement). For the articles where initial disagreement was identified, a coauthor team consensus was reached for the data reported in Based on this SR, there is moderately strong evidence to suggest that physical activity intervention programs may improve self-efficacy. Given the expansion of childhood obesity in America, the question remains: how do we elicit self-efficacy for health behavior change? This paper suggests that exercise combined with a multidisciplinary approach may positively influence self-efficacy assessments in children and adolescents. In theory, once self-efficacy is obtained for a specific behavior, there is a potential for continuation of the desired health outcome. In efforts to campaign for a resolution of the obesity crisis, a secondary aim of this SR was to assess whether the physical activity related programs demonstrated weight reduction or weight maintenance. Of the included studies, none evaluated the association of improved self-efficacy with changes in body weight or BMI from before to after program. Due to the variable characteristics of each study design, we were unable to extrapolate any association between the improved self-efficacy ratings with objective changes in body weight or BMI. Self-efficacy surveys have evolved to correspond to the distinct theme for which they are necessary. Of the 10 studies evaluated, only two of the authors repeatedly used the same self-efficacy assessment in their respective studies. As an important limitation, the lack of continuity of the self-efficacy surveys made it difficult to generalize the results.  There were several limitations that may present as potential biases within the cohort studies. The types of physical activity interventions were diverse . Additionally, participants' general interest in an extramural activity (intervention group) compared to a required physical education class may have also influenced the outcome. Despite these limitations, using exclusively RCT study designs for this particular topic would have significantly limited this study's findings. Given the heterogeneity of the studies reviewed, it was difficult to make a definitive judgment of the outcomes. Although many studies indicated the importance of physical activity and nutrition education for obesity, they did not focus solely on obese children. Therefore, participant selection bias may have been a potential confounder. Although many initially reviewed articles included baseline and postphysical activity program self-efficacy assessments, few articles appraised whether the physical activity curriculum details  were associated with an improved self-efficacy. The most challenging bias was the lack of a uniform, standardized definition of self-efficacy, as well as an inconsistent approach to measuring theory. The heterogeneous characterization of the term self-efficacy  may have affected and limited the search criteria for articles in this SR.The findings of this SR suggest that there is moderately strong evidence that physical activity related programs improve self-efficacy in youths. However, based on this paper, there is insufficient evidence about the effect of physical activity related programs on weight status. Sustaining the benefits of health behavior programs, whether improved self-efficacy or objective indicators (body weight), may be a key determinant to long-term health outcomes. Factors that influence persistence of positive behavioral changes over time need further elucidation.  Further research appears warranted to clarify the relationship between physical activity programs with changes in self-efficacy and weight loss as well as long-term impacts on weight management. In addition to selection bias and a lack of true RCT, a challenge with research in this area is defining self-efficacy and having a unified measuring system or assessment tool. Policy to support health behavior interventions is necessary to optimally impact the US obesity crisis. Future physical activity related research should be expanded to include a representative sampling of school age participants across a greater diversity of school-based or socially oriented environment.


Increasing population rates of cardiac catheterization can lead to the detection of more people with high risk coronary disease and opportunity for subsequent revascularization. However, such a strategy should only be undertaken if it is cost-effective.Based on data from a cohort of patients undergoing cardiac catheterization, and efficacy data from clinical trials, we used a Markov model that considered 1) the yield of high-risk cases as the catheterization rate increases, 2) the long-term survival, quality of life and costs for patients with high risk disease, and 3) the impact of revascularization on survival, quality of life and costs. The cost per quality-adjusted life year was calculated overall, and by indication, age, and sex subgroups.Increasing the catheterization rate was associated with a cost per QALY of CAN$26,470. The cost per QALY was most attractive in females with Acute Coronary Syndromes (ACS) , and for ACS patients over 75 years of age . However, there is significant model uncertainty associated with the efficacy of revascularization.A strategy of increasing cardiac catheterization rates among eligible patients is associated with a cost per QALY similar to that of other funded interventions. However, there is significant model uncertainty. A decision to increase population rates of catheterization requires consideration of the accompanying opportunity costs, and careful thought towards the most appropriate strategy. Cardiac catheterization is a diagnostic or interventional procedure involving insertion of a catheter into a chamber or vessel of the heart. Once inserted contrast dye is injected and x-rays are taken to identify coronary stenoses within the heart . One of Previous work has demonstrated a linear increase in the number of high-risk coronary artery disease cases detected when population catheterization rates vary across their demonstrated range . AlthougThe Alberta Provincial Project for Outcomes Assessment in Coronary Heart (APPROACH) is a prospective cohort initiative that captures detailed clinical information on all patients undergoing cardiac catheterization within the province of Alberta, Canada (population approximately 3 million) . APPROACWe estimated the cost per quality-adjusted life year (QALY) gained for a strategy of increasing cardiac catheterization rates for patients potentially eligible to undergo catheterization compared to a contemporary population catheterization rate from Alberta, Canada , and subsequently for specific patient subgroups of interest where increasing catheterization rates might be considered. The subgroups of a priori interest included indication for catheterization (acute coronary syndrome (ACS) vs non-ACS), sex, and age. These are identified subgroups with differential benefit associated with revascularisation ,9.We used a Markov process to model the cost and clinical outcomes over a patient's lifetime for patients potentially eligible for catheterization in 1-year time intervals. A conceptual depiction of the model is presented in Figure Among patients who do not undergo catheterization, a proportion will have undetected high-risk coronary artery disease - by definition, these patients receive medical management only. Some of these patients would have been eligible for revascularization had they undergone a catheterization, and thus the benefit of an increased catheterization rate is the additional detection of previously undetected patients with high-risk coronary anatomy who have the potential to benefit from revascularization, since randomized controlled trials have demonstrated a survival advantage with revascularization in this high-risk group . Hence, The target population of interest was all patients potentially eligible to undergo cardiac catheterization. An assumption inherent to our analysis is that the additional high risk cases detected among the eligible patients undergoing catheterization would be similar to the high risk cases detected using the current rate of catheterization. To test this assumption, patient demographics, intervention rates and outcomes were compared across all 9 health regions in Alberta, where age and sex adjusted catheterization rates varied more than 3-fold. When comparing the high-risk cases across tertiles of utilization, there were no differences in the survival and revascularization rates between regions, suggesting that there are few differences between detected and undetected high-risk cases.The contemporary catheterization rate is based on the 2005 Alberta population catheterization rate taken from the APPROACH database 496 per 100,000) . BriRates of PCI and CABG were calculated by ACS, disease , age and sex subgroup of patients undergoing cardiac catheterization. Although the majority of patients with left main and 3-vessel disease undergo revascularization, some patients are managed medically . Patients with left main disease are managed predominantly with CABG, whereas patients with 3-vessel disease appear to undergo PCI or CABG equally. For the "standard care comparator strategy", we assumed that the same proportion of patients would be eligible to undergo revascularization  as those who currently receive catheterization.Long-term survival data for the larger cardiac catheterization cohort were available for 10 years. Kaplan-Meier plots were produced by disease and ACS subgroup for those revascularized and then separately for those medically managed. Those revascularized with left main or 3-vessel disease had better long-term survival than those managed medically although this may result from many factors including patient selection, rather than just the treatment received. However, patients with 1- or 2-vessel disease have similar survival regardless of whether they are revascularized or medically managed, particularly in the non-ACS subgroup.To account for increasing age-related mortality, after 10 years, the hazard ratios for each of the patient subgroups were multiplied by the age-specific increment in mortality risk of the Canadian population .HRQOL estimates were determined for the cohort of APPROACH patients noted above using self-reported Euroqol (EQ-5D) index scores completed one year after catheterization . Mean utFor patients with high-risk coronary disease who are not catheterized (and thus do not receive revascularization), evidence from the MASS-2 trial which compared CABG, PCI and medical management in patients with multi-vessel coronary disease was used . SF-36 sFor those undergoing catheterization, data on costs were obtained from Alberta Health and Wellness  for the 1995-1997 APPROACH cohort. The costs associated with catheterization, CABG and PCI were noted to be $2048, $17,958 and $7,927 respectively, including procedure costs, and associated hospitalization and physician costs. Subsequent annual costs were obtained for hospitalization, ambulatory care, home care, physician claims and medication costs until March 2001. Ambulatory care costs were restricted to cardiac care. Costs were estimated on an annual basis from the date of first catheterization, and were adjusted to 2006 dollars using a yearly health sector inflation factor [There is uncertainty whether revascularization impacts the long-term costs of patients with coronary disease compared with medical management. However, the RITA-2 trial, a trial comparing PCI to medical management in patients with angina, reported similar annual costs of care over a 3-year period between the treatment strategies . Thus, wIn this study, we estimated survival rates based on APPROACH patients with high-risk coronary anatomy who have undergone revascularization, but do not have survival rates for patients with undetected high-risk coronary disease who receive medical management. To estimate the survival of high-risk patients who receive medical management within our model, we used a meta-analysis by Yusuf et al that reported the odds ratio of mortality associated with CABG compared to medical therapy for stable (non-ACS) patients with high-risk coronary disease, by disease severity, for two time periods; 0-5 years and 0-10 years . To calcRecognizing the trials included in Yusuf's meta-analysis excluded ACS patients, a second baseline analysis applied the relative risk from the FRISC-II study to the ACS subgroup ,22. The A healthcare payer perspective was adopted. Costs and outcomes were discounted using an annual discount rate of 5 percent . SAS, veAll sensitivity analyses were completed for the ACS and non-ACS subgroup separately. The impact of various high-risk case yields was explored. We considered an ACS and non-ACS specific yield rate. Subsequently, for males, the yield was varied from 1 case detected in 2 to a minimum of 1 case per 4 catheterizations (base case: 1 case detected in 3 catheterizations). For females, a maximum yield of 1 case detected in 2 and a minimum 1 case detected in 7 catheterizations was considered (base case: 1 case detected in 5 catheterizations).The base case utility for patients treated medically or with PCI or CABG was estimated from the EQ-5D utility scores taken from the APPROACH cohort. Given its potential lack of sensitivity to changes in HRQOL, in sensitivity analysis, a disease-specific measure (the Seattle Angina Questionnaire) was also considered. The Seattle Angina Questionnaire is a measure of quality of life (not utility), and thus is not ideal for use in the context of an economic evaluation. However, given there are no cardiac disease-specific utility instruments, we applied the quality of life scores from the Seattle Angina Questionnaire (which range from 0 to 1) to understand how different utility estimates might impact the cost per QALY. The resulting utility estimates for those revascularized and those medically managed respectively were 0.87 and 0.71 for left main, 0.83 and 0.72 for 3-vessel disease and 0.80 and 0.78 for 1- and 2-vessel disease. We also varied the relative risk associated with revascularization by +/- 25%, and considered a scenario where a constant survival benefit associated with revascularization was assumed over a 10 (rather than five) year time period. Lastly, procedural costs, and yearly costs of care were increased and decreased to explore the impact of changes within these variables on the resultant cost per QALY.To estimate the overall uncertainty in the model, we completed a Monte Carlo Simulation for the ACS and Non-ACS models using the Yusuf estimates of efficacy. Normal distributions were used for relative risks, utility estimates and the high-risk yield. Gamma distributions were used for all cost estimates. Incremental cost-effectiveness scatterplots, with 95% confidence ellipses, were produced to visually assess the uncertainty in the model. In addition, cost-effectiveness acceptability curves were plotted to demonstrate the likelihood that an alternative is cost-effective at a specified willing-to-pay threshold.Table When an ACS scenario is considered, applying the Yusuf relative risks  that we. Within Table Figure In many health care systems, the availability of coronary catheterization facilities and access to such procedures is viewed as a key indicator of the "health" of a health care system . As a reWe found that a strategy of increasing the population catheterization rate overall in eligible patients is associated with a cost per QALY of $26,470, with cost per QALY estimates ranging from approximately $23,000 to $32,000 depending on the subgroups of greatest interest. Our results appear sensitive to the effectiveness of revascularization among the additional high risk patients that are identified, and further information on this variable would be ideal. In addition, probabilistic sensitivity analysis demonstrates significant model uncertainty with scatter falling within all four quadrants of the ICER scatterplots. In Canada, $20,000-$100,000 is often cited as a range which could be considered good value for money ,27).Our economic evaluation contributes new information. An economic analysis of the RITA-2 trial, which included patients eligible for both PCI and medical management, found that the upfront costs of PCI are not recouped within 3 years in cost-savings compared to medical therapy . EconomiAlthough increasing catheterization rates appears potentially attractive when considering the cost per QALY estimate in isolation, it is important to judge it against the cost-effectiveness of other candidate therapeutic innovations  that may be under consideration by health system decision-makers at any given moment in time. Our cost-effectiveness estimates, while useful, are thus only part of the answer to such challenging societal and health funding decisions.There are some caveats and limitations to our analysis. The primary benefit of catheterization and subsequent revascularization in high-risk patients is increased survival. Our analysis used a relative risk of survival for revascularization in high risk patients from a meta-analysis of trials done nearly 20 years ago . While tThe recent COURAGE trial also warrants mention in the context of considering efficacy estimates for revascularization in our economic evaluation . That trThe feasibility of increasing the catheterization rate is another component of the decision that is not directly addressed by our analysis. Our analysis assumes that additional catheterizations would be performed within established infrastructure and existing manpower . If the current facilities are operating at full capacity, then additional facilities would be required to increase the number of catheterizations. This would require additional capital investment which would increase the cost per additional catheterization done potentially making the cost per QALY less economically attractive. Our analysis addresses whether increasing catheterization rates provides reasonable value for money but does not address the optimal strategy for increasing catheterization rates. Given that low catheterization rates may have many reasons and considering the differences among health care systems, local health regions will have to consider the most appropriate strategy for their local health care environment. Finally, our work does not consider the use of non-invasive testing. Its potential proliferation in coming years may impact the cost-effectiveness of catheterization as patient selection and risk-stratification change. Future work could compare the cost-utility of catheterization to non-invasive imaging in a well-defined patient population. These caveats and limitations notwithstanding, our study adds new information that can inform the population-based planning of cardiac catheterization and revascularization services.Increasing the population catheterization rate is associated with a cost per QALY of $26,470. However, although the basecase estimate generally supports a strategy of increasing cardiac catheterization rates within eligible patients, conclusions about the cost-effectiveness of increasing the catheterization rate are inconclusive due to significant model uncertainty associated with the efficacy of revascularization. In addition, funding decisions also require the careful strategic consideration of other efficacious health care interventions and the accompanying opportunity costs.The authors declare that they have no competing interests.FC, BM, and WG contributed to the conception and design, analysis and interpretation of data. All authors contributed to the drafting and revision of the article for critically important intellectual content. All authors approved the final version of the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6963/11/324/prepub


Lactic acid bacteria (LAB) represent a heterogeneous group of microorganisms that are naturally present in many foods and possess a wide range of therapeutic properties. The aim of this paper is to present an overview of the current expanding knowledge of one of the mechanisms by which LAB and other probiotic microorganisms participate in the prevention and treatment of gastrointestinal inflammatory disease through their immune-modulating properties. A special emphasis will be placed on the critical role of the anti-inflammatory cytokine IL-10, and a brief overview of the uses of genetically engineered LAB that produce this important immune response mediator will also be discussed. Thus, this paper will demonstrate the critical role that IL-10 plays in gastrointestinal inflammatory diseases and how probiotics could be used in their treatment. Carnobacterium, Enterococcus, Lactobacillus, Lactococcus, Leuconostoc, Oenococcus, Pediococcus, Streptococcus, Tetragenococcus, Vagococcus and Weissella, all presenting a G+C content in their DNA lower than 55%. Although quite diverse, the members of this group have various characteristics in common, that include being (i) gram-positive, (ii) facultative anaerobes, (iii) nonsporulating, (iv) nonmotile, and (v) possess the capacity to convert sugars into lactic acid .Numerous studies have shown that certain strains of lactobacilli and bifidobacteria can modulate the production of cytokines (mediators produced by immune cells) that are involved in the regulation, activation, growth, and differentiation of immune cells. These probiotic microorganisms are able to prevent and treat certain inflammatory diseases in the gastrointestinal tract through the repression of proinflammatory cytokines. One of the central transcription factors mediating inflammatory responses is the nuclear factor L. delbrueckii and Streptococcus thermophilus, can modulate the immune response, inducing downregulation of inflammatory cytokines (IL-17 and IL-12) produced by the immune cells involved in the inflammatory process [Enterobacteriaceae family which tends to overgrow in an inflammatory process. In the colonic mucosa of IBD patients, high concentrations of Enterobacteriaceae and bacteroides were associated with severe inflammation and TLR4 increase [γand TNF-αincrease the expression of TLR4 and MD-2 (myeloid differentiation protein 2), resulting in increased LPS responsiveness [L. casei CRL 431 can induce changes in the TLR expression in immune and intestinal epithelial cells [L. casei DN-114 001 prevented the development of acute DSS-induced colitis in TLR4 KO mice by inhibiting myeloperoxidase activity and IL-12p40, and increasing TGF-β and IL-10 mRNA. These effects suggest that the mechanism of action of  L. casei DN-114 001 depends on other factors besides TLR4 status [These results are in agreement with the observation that the administration of probiotic yoghurt, containing live  process . The ass process , 47, 48, process , 50. Tolincrease . Severalsiveness . In thisal cells . L. case4 status . Although, by definition, probiotics should be administered as live microorganisms, isolated components of probiotic cells may also have therapeutic benefits. It was reported that bacterial DNA has a potent immunostimulatory effect since it could attenuate colitis in a number of induced and spontaneous murine models . TLR9 reE. coli strain Nissle 1917 and its isolated DNA were also administered in a DSS murine colitis model and an anti-inflammatory effect was demonstrated [In addition, it was also shown that the attenuation of DSS colitis could be caused by DNA of the VSL#3 probiotic mixture through TLR9 signaling, and nonviable bacteria were equally effective in reducing inflammation in this model . Heatingnstrated . Interesnstrated .γ [There is no doubt that IL-10 plays a central role in downregulating inflammatory cascades by suppressing the secretion of proinflammatory cytokines. The crucial role of IL-10 in the prevention of IBD has been demonstrated by experiments in IL-10-deficient mice. These animals develop a chronic bowel disease resembling CD in humans, which is in part caused by a loss of suppression of the mucosal immune response toward the normal intestinal microbiota . Unfortuγ . Howeverγ . One of Bifidobacterium longum Bar 33 and L. acidophilus Bar 13 prevented inflammation and mucosal ulcerations in a trinitrobenzene sulfonic acid- (TNBS-) induced colitis mouse model [κB activation, decreased the expression of TNF-α and IL-1β, and increased the expression of IL-10. Most people think of probiotics as microorganisms that must be consumed in a food matrix; this is due to the fact that the oral administration of probiotics is the most common method of ingesting these beneficial microorganisms. Oral administration of a probiotic mixture that consisted of se model . This prse model . In a huse model . This orPrunus mume) containing probiotics was able to suppress the development of atopic dermatitis-like skin lesions, and caused an increase in serum concentration of IL-10 and decrease of serum IL-4, eosinophil ratio, and IgE [Continuing in this train of thought, it is logical to assume that fermented foods containing probiotic microorganisms could also be effective in inducing an immunostimulating/anti-inflammatory effect. It was shown that a yoghurt produced with a pool of potentially probiotic LAB strains was effective in inhibiting the propagation of a dimethylhydrazine- (DMH-) induced colon cancer in mice by increasing the number of IL-10-secreting cells, increasing cellular apoptosis and decreasing procarcinogenic enzymes . Probiot and IgE .L. casei DG could modify the intestinal microbiota composition and TLR expression, and increase IL-10 levels in the colonic mucosa of patients with mild UC [L. casei CRL 431 as demonstrated by an improved production of TNF-α, IL-4, IL-10 and IgA in the respiratory tract [Other forms of probiotic administration have also been shown to be effective in stimulating IL-10 production. A recent study demonstrated that the rectal administration of  mild UC . Intrana mild UC . An enhary tract .α- and β-galactosidase, α-amylase), or conferring them the capacity to produce beneficial compounds such as bacteriocins, exopolysaccharide (EPS), and other sugars, vitamins, antioxidant enzymes, and anti-inflammatory cytokines [LAB are potential candidates to be used as vehicles for the production and delivery of heterologous proteins of vaccinal, medical, or technological interest and various delivery systems are now available for these probiotic microorganisms . Differeytokines . Lactococcus (Lc.) lactis secreting IL-10 provides a novel therapeutic approach for IBD. The first description of Lc. lactis that can secrete biologically active IL-10 was published over ten years ago [Lc. lactis strain prevented the onset of colitis in IL-10 KO mice and caused a 50% reduction of the inflammation in DSS-induced chronic colitis [Genetically modifiedears ago . In this colitis .Lc. lactis expressing murine IL-10 was efficient since this LAB modulated experimental airway inflammation in the mouse model [Lc. lactis producing recombinant IL-10 used in this study was efficient in suppressing lung inflammation, independently of Treg cells, since this cytokine plays a central role in the regulation of inflammatory cascades, allergen-induced airway inflammation, and nonspecific airway responsiveness [Lc. lactis strain could prevent food-induced IgE sensitization in a mouse model of food allergy [The application of IL-10 producing LAB is not only limited to the treatment of IBD. It was recently shown that treatment of asthma with a se model . Lc. lacsiveness . In anot allergy . These sLc. lactis on the mucosa is produced remains unclear. A recent study has demonstrated the uptake of IL-10-secreting Lc. lactis by the paracellular route in inflamed mucosal tissue in mouse models of chronic colitis, suggesting that IL-10 production by these LAB residing inside the mucosa in the vicinity of responsive cells can improve the local action of IL-10 in inflamed tissue and the efficiency of the treatment [Lc. lactis secreting murine IL-10 could modulate the functions of bone marrow-derived DC in the presence of LPS [Although a clear positive effect of these recombinant strains has been demonstrated, the exact mechanism by which the beneficial effect of the IL-10-producing reatment . In anote of LPS . This daAlthough there is no scientific evidence that supports the notion that genetically modified (GM) foods or microorganisms are dangerous for human consumption, it is necessary to demonstrate that these are innocuous in order to alleviate the fears held by the general public associated with the use of genetically modified organisms, if we want to use designed probiotics to extend the range of applications covered by natural probiotics. Also, the proper design of GM-LAB is essential in order to eliminate the risks of dissipation in the environment and prevent the transfer of certain genes (such as antibiotic resistance genes) to other microorganisms.Lc. lactis for intestinal delivery of human IL-10 is an important step forward for the safe use of GM-LAB for human therapeutic purposes [Lc. lactis was replaced by the human IL-10 gene, making this strain incapable of growing when deprived of thymidine or thymine. This strain does not contain any antibiotic resistance markers and because of its thymidine auxotrophy, it cannot disseminate in the environment, making it one of the safest GM strains ever engineered. This containment system was recently evaluated in CD patients, and it was shown that no adverse effects where produced after consuming this GM-LAB and that it could only be recovered in feces when thymidine was added [The construction of a biological containment system for a genetically modified purposes . In thisas added . Althougas added .Lc. lactis genetically modified to secrete IL-10 in situ in the intestine was shown to be effective in healing and preventing chronic colitis in mice. However, its use in humans is hindered by the sensitivity of Lc. lactis to freeze-drying and its poor survival in the gastrointestinal tract, reasons for which novel means for more effective mucosal delivery of therapeutic LAB are currently being developed [Intragastric administration of eveloped –94.α and IFN-γ, some LAB can prevent the appearance of local inflammatory diseases and could be used as an adjunct therapy with conventional treatments. However, proper multicenter randomized human clinical trials are necessary to demonstrate the effectiveness of probiotics in the treatment of IBD and other inflammatory diseases.The results of animal and some human studies demonstrate that some probiotic strains can successfully modify the mucosal immune response to modulate the levels of specific activation molecules such as cytokines. By increasing IL-10 levels and in consequence decreasing inflammatory cytokines such as TNF-Although probiotic effects are a strain-dependent trait, using modern genetic engineering techniques, it is theoretically possible to obtain strains that can exert a variety of beneficial properties. For example, the introduction of antioxidant enzyme genes in current probiotic strains that have natural anti-inflammatory properties, such as the ability to modulate the immune-dependant inflammatory processes, could generate very useful strains that could be applied in the treatment of a variety of inflammatory diseases , 96. TheThe consumption of engineered strains by humans is still highly controversial due to the public perception that genetic manipulation is not “natural.” Scientists must perform well-designed studies where the results are divulged to the general population in order to inform consumers of the obvious beneficial effects these novel techniques can confer with the minimum of risk to their health and to the environment . Through