Although task-oriented training has been shown to improve walking outcomes after stroke, it is not yet clear whether one task-oriented approach is superior to another. The purpose of this study is to compare the effectiveness of the Motor Learning Walking Program (MLWP), a varied overground walking task program consistent with key motor learning principles, to body-weight-supported treadmill training (BWSTT) in community-dwelling, ambulatory, adults within 1 year of stroke.A parallel, randomized controlled trial with stratification by baseline gait speed will be conducted. Allocation will be controlled by a central randomization service and participants will be allocated to the two active intervention groups (1:1) using a permuted block randomization process. Seventy participants will be assigned to one of two 15-session training programs. In MLWP, one physiotherapist will supervise practice of various overground walking tasks. Instructions, feedback, and guidance will be provided in a manner that facilitates self-evaluation and problem solving. In BWSTT, training will emphasize repetition of the normal gait cycle while supported over a treadmill, assisted by up to three physiotherapists. Outcomes will be assessed by a blinded assessor at baseline, post-intervention and at 2-month follow-up. The primary outcome will be post-intervention comfortable gait speed. Secondary outcomes include fast gait speed, walking endurance, balance self-efficacy, participation in community mobility, health-related quality of life, and goal attainment. Groups will be compared using analysis of covariance with baseline gait speed strata as the single covariate. Intention-to-treat analysis will be used.In order to direct clinicians, patients, and other health decision-makers, there is a need for a head-to-head comparison of different approaches to active, task-related walking training after stroke. We hypothesize that outcomes will be optimized through the application of a task-related training program that is consistent with key motor learning principles related to practice, guidance and feedback.NCT00561405ClinicalTrials.gov #  Every year an estimated 9 million new stroke events occur globally, and an additional 30.7 million individuals live with the ongoing effects of stroke . DecreasAccording to recent stroke-rehabilitation reviews and practice guidelines, optimal walking recovery may be realized through the application of a task-related walking training approach -15. In tRooted in movement science, including motor learning research, Carr and Shepherd were early advocates of task-related walking practice after stroke . They emBased on this literature, variable practice of walking and walking-related activities in a circuit format is associated with greater improvements in gait speed, endurance and walking self-efficacy than a non-walking control intervention such as upper-extremity task practice. To date we do not know if this approach is superior to an alternate walking-focused treatment.2 cost) and daily stepping activity were observed after BWSTT treatment periods and not following the no-treatment periods. Based on these small-sample controlled trials, approximately 12 sessions of BWSTT seems to be more effective than a no-treatment control intervention or a non-walking intervention such as cycling. In addition, improvements seem to be optimized when participants train at speeds greater than their typical overground walking speeds. To date the effectiveness of BWSTT has not been evaluated against an alternate program of overground walking-focused training in community dwelling adults with history of stroke.BWSTT is rooted in the central pattern generator (CPG) theory of gait control and recovery . The theIn summary, varied overground-focused walking practice and BWSTT have been shown to result in greater improvements in walking speed, endurance and/or self-efficacy when compared to non-walking interventions . These two walking-task related interventions are different in theoretical rationale as well as in content. In the case of BWSTT, the rationale is clear - repetition of the normal stepping pattern of gait activates the locomotor CPG's and results in improved overground walking. Practice is constant and blocked, guidance is provided liberally, and the use of the treadmill environment allows for the repetition of a more normal gait pattern thought to be necessary to activating the CPG's ,33,34. IThe purpose of this randomized controlled trial is to compare the impact of the Motor Learning Walking Program (MLWP), a 15-session program of varied overground walking-task training consistent with key motor learning principles related to practice, guidance and feedback, to 15 sessions of BWSTT on walking performance in community-dwelling, ambulatory adults within 12 months of stroke onset.It is our hypothesis that participants assigned to the MLWP group will demonstrate greater scores in comfortable gait speed and secondary outcome measures at post intervention and follow-up assessments.This study is a prospective, randomized, single blind, balanced parallel-group 1:1) superiority trial with stratification by baseline comfortable gait speed (< 0.5 m/s and ≥ 0.5 m/s). The design includes concealed allocation during recruitment and screening, blinded outcome assessment and intention to treat analysis. Refer to Figure :1 superiAll study activities have been approved by the Research Ethics Boards of St. Joseph's Healthcare Hamilton (#6-2753), the Hamilton Health Sciences/Faculty of Health Sciences McMaster University (#07-054), and Joseph Brant Memorial Hospital, Burlington, Ontario.The target population of this trial is community-dwelling, ambulatory older adults with mild to moderate stroke-related walking dysfunction within twelve months of most recent stroke onset. In contrast to most previous trials ,25,33,34Participants will be randomly allocated to the two active intervention groups using a fixed allocation ratio of 1:1. Consistent with previous studies in this area ,33, we aThe Motor Learning Walking Program is a program of varied overground walking-task practice based on theory and research from the fields of motor control, motor learning, neuroplasticity, and stroke rehabilitation. The following statements will be used to guide the implementation of the MLWP:1. Motor skill is the product of multiple systems, internal and external to the individual . The flow of patients in the trial will be summarized using a flow-diagram. The baseline characteristics and outcomes scores of the patients will be analyzed using descriptive statistics reported by group as mean (standard deviation [SD]) or median  for continuous variables depending on the distribution and count (percent) for categorical variables. Intention to treat analysis technique will be used for the primary analysis [The trial results will be reported in accordance with the CONSORT criteria [analysis . Missinganalysis . All staThe post-intervention (T2) self-selected overground walking speed for the MLWP and BWSTT groups will be compared using analysis of covariance. The two factors will be intervention group (intervention or control) and baseline speed stratum (i.e. slow or fast).Mixed design analysis of variance will be used to compare the two groups' baseline, post-intervention and follow-up scores on all other secondary measures. The two factors will be time and group. Descriptive statistics  will be used to present data related to adverse and serious adverse events by groups. Any apparently significant differences between groups will be analysed for significance using chi square statistics. In an effort to describe the two interventions, the mean number of steps taken per session will be counted in a convenient sub-sample of participants using the step activity monitors. Independent samples t-test statistic will be used to compare the mean number of steps taken per session by the two groups during treatment sessions.Sensitivity analyses will be performed to assess the robustness of the results. First, there is likely to be high inter-correlations among all outcomes. We will use multivariate analysis of variance (MANOVA) approach to analyze all outcomes simultaneously. This method accounts for possible correlations among all outcomes and provides for a global assessment of differences between groups with an indication of where differences exist. Second, we will use generalized estimating equations (GEE)  to accouTo date, a number of controlled trials have tested the effectiveness of intensive, task-related walking training interventions against a non-walking focused control treatment.how individuals practice walking after stroke. As with most rehabilitation interventions, task-related walking training can be complex and multifaceted. A sound theory base can help focus an intervention on the proposed, relevant active ingredients [A head-to-head comparison of two different active walking focused interventions will help answer the question whether it matters redients . In our The authors declare that they have no competing interests.VGD conceived of the study, acted as the principal investigator and drafted the manuscript. LT provided statistical expertise in clinical trial design. All authors contributed to the study design, are grant holders, contributed to the editing of the manuscript, and read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/11/129/prepub


In vivo studies of humans are not possible. Thus, controlled and randomized animal experiments are critically important.It has been well recognized that exposure to space radiation is a major challenge to space exploration. To protect astronauts in space environments, improvement in our knowledge of radiation-induced changes in specific target cells that may affect the health of astronauts is required. Cancer of blood cells, in particular myeloid leukemia (ML), is one of the major health concerns from exposure to space radiation. However, the predictions of risks for developing ML post-exposure to space radiation are unsatisfactory. To increase the reliability of predicting risk for ML, a much improved understanding of space radiation-induced changes in the target cells, i.e. hematopoietic stem/progenitor cells (HSPCs), is critically important. Most proteomic applications mentioned above have used 2-DE or stable isotope-tagged mass spectrometry. Although the 2-DE has several advantages , such technology is simply not as comprehensive and reliable as desired. To overcome these limitations, we recently developed a unique label-free quantitative mass spectrometry (LFQMS) platform . This isin vivo biological effects of radiation on hematopoietic stem cells) obtained at 6 months after exposure . These doses of 300 MeV/nucleon 28Si ions are comparable to what astronauts encounter in space. Mice exposed to 0 Gy of 28Si ions served as non-irradiated sham controls. The colonies of HSPCs were obtained from BM cells of five mice per treatment group, by means of an in vitro colony forming unit assay (CFU-A) using methylcellulose-based medium. Proteins were extracted from HSPC colonies and protein concentrations were determined by the Bradford Protein Assay. The trans-proteomic pipeline (TPP) was used to assign a probability of a particular protein being in the sample.In this study, we used the LFQMS platform to examine protein expression-profiles in the colonies of HSPCs (the best population of cells for studying etected ) of CBA/P < 0.0001). Biochemical analyses of the molecular and cellular functions of these proteins reveal association with perturbation in cell survival, free radical scavenging, cell cycle, DNA repair, cellular assembly, hematological system development and inflammatory responses. These proteins are linked to two major molecular networks that are linked to cancer and inflammatory responses (i.e. nuclear factor-κ B and the protein phosphatase 2 A networks). Our results indicated 28Si ion-induced damage in HSPCs.A total of 1344 unique, non-redundant proteins were identified with ≥90% confidence from 3254 peptides, quantified and their abundances were compared statistically. Among the 1344 proteins, differential expression of 198 proteins was found to be statistically significant in HSPC colonies obtained from treated groups, in relation to those found in non-irradiated sham controls. A proof-of-concept-based Ingenuity Pathway Analysis  was used to characterize the functions and pathways of these 198 identified proteins. The majority of these proteins are cancer-related (


Resting-state functional magnetic resonance imaging (RS-fMRI) has demonstrated disrupted default mode network (DMN) connectivity in a number of pain conditions, including migraine. However, the significance of altered resting-state brain functional connectivity in migraine is still unknown. The present study is aimed to explore DMN functional connectivity in patients with migraine without aura (MwoA) and investigate its clinical significance.To calculate and compare the resting-state functional connectivity of the DMN in 20 patients with MwoA, during the interictal period, and 20 gender- and age-matched HC, Brain Voyager QX was used. Voxel-based morphometry was used to assess whether between-group differences in DMN functional connectivity were related to structural differences. Secondary analyses explored associations between DMN functional connectivity, clinical and neuropsychological features of migraineurs.In comparison to HC, patients with MwoA showed decreased connectivity in prefrontal and temporal regions of the DMN. Functional abnormalities were unrelated to detectable structural abnormalities or clinical and neuropsychological features of migraineurs.Our study provides further evidence of disrupted DMN connectivity in patients with MwoA. We hypothesize that a DMN dysfunction may be related to behavioural processes such as a maladaptive response to stress which seems to characterize patients with migraine. Migraine is a common and disabling primary headache disorder clinically characterized by episodic attacks of throbbing headache with specific features and associated symptoms . A greatTwenty-five consecutive patients with episodic MwoA, according to the International Headache Society criteria   were proTwenty age- and gender-matched, right-handed subjects  with less than a few spontaneous non-throbbing headaches per year, with no family history of migraine, no hypertension, diabetes mellitus, heart disease, other chronic systemic diseases, stroke, cognitive impairment, substance abuse, chronic pain, as well as other neurological or psychiatric disorders were recruited as HC.The study was approved by the Ethics Committee of Second University of Naples, and written informed consent was obtained from all subjects according to the Declaration of Helsinki.To assess levels of depression and anxiety, patients with MwoA and HC completed the Hamilton Depression Rating Scale (HDRS) and the Hamilton Anxiety Rating Scale (HARS). An extensive neuropsychological evaluation was performed in patients with MwoA as previously described .MRI was performed on a General Electric  Signa HDxt 3 Tesla whole-body scanner equipped with an 8-channel parallel head coil. RS-fMRI data consisted of 240 volumes of a repeated gradient-echo echo planar imaging T2*-weighted sequence . During the functional scan, subjects were asked to simply stay motionless, awake, and relaxed, and to keep their eyes closed; no visual or auditory stimuli were presented at any time during functional scanning. Three-dimensional high-resolution T1-weighted sagittal images  were acquired for registration and normalization of the functional images as well as for atrophy measures and VBM analysis.Demographic and clinical features of patients with MwoA and HC were compared by the t-test for independent samples or by χ2, as appropriate.p = 0.05 (Bonferroni corrected over the entire brain). An inclusive mask was also created from the union of the two single-group maps (patients with MwoA and HC) and used to define a new search volume for within-network between-group comparisons. The resulting statistical maps were overlaid on the standard “Colin-27” brain T1 template. To correct for multiple comparisons, regional effects were only accepted for clusters exceeding a minimum size determined with a non-parametric randomization approach. Namely, an initial voxel-level threshold was set to p = 0.01 (uncorrected) and a minimum cluster size was estimated after 1000 Montecarlo simulations that protected against false positive clusters up to 5%. Cluster-level correction is a very common and effective way to correct for multiple comparisons in fMRI statistical maps, including random-effects maps, obtained from RS-fMRI studies   algorithms . For eac., 2012) . Individhttp://www.fil.ion.ucl.ac.uk/spm). VBM was implemented in the VBM8 toolbox (http://dbm.neuro.uni-jena.de/vbm.html) with default parameters incorporating the DARTEL toolbox, which was used to obtain a high-dimensional normalization protocol [p < 0.05) and an uncorrected threshold .Data were processed and examined using SPM8 software  did not differ in age or male/female ratio . Moreover, both whole-brain and ROI-based analyses of regional volumes did not reveal any significant differences in local GM between patients with MwoA and HC, using a significance level of p ≤ 0.05, FWE-corrected for multiple comparisons.As illustrated in Figure The present RS-fMRI study was designed to assess the functional integrity of DMN in patients with MwoA. Our findings demonstrate a reduced functional connectivity within the prefrontal and temporal cortices of the DMN in patients with MwoA during the interictal period. This altered functional connectivity was independent of structural abnormalities and not related to clinical or cognitive features of migraineurs. The DMN is a network highly relevant for cognitive processes and influences behavior in response to the environment in a predictive manner ,8. In otWe believe that DMN connectivity changes may represent an early migraine biomarker, probably related to a maladaptive brain response. Future studies should examine other cortical resting-state networks and longitudinal studies are needed to evaluate the possibility that this modern neuroimaging approach can lead to the identification of different categories of patients or different timing of selective networks involvement.MwoA: Migraine without aura; HC: Healthy controls; RS: Resting-state; fMRI: Functional magnetic resonance; RSNs: Resting-state networks; ICA: Independent component approach; VBM: Voxel based morphometry; l-SPFG: Left superior prefrontal gyrus; l-TP: Left temporal pole; MIDAS: Migraine disability assessment scale; HIT-6: Headache impact test; VAS: Visual analogic scale; HDRS: Hamilton depression rating scale; HARS: Hamilton anxiety rating scale; MNI: Montreal neurological institute; FWHM: Full-width at half maximum; ANCOVA: Analysis of covariance; TIV: Total intracranial volume; TR: Repetition time; TI: Inversion time; TE: Echo time; ROI: Region of interest; GM: Gray matter; WM: White matter; CSF: Cerebro-spinal fluid; FWE: Familywise error rate; ATP: Adenosine triphosphate.The authors confirm that there are no conflicts of interest.AT: experimental design, image data analysis, results interpretation, manuscript drafting; AR: literature review, experimental design, results interpretation, manuscript drafting; AG: clinical data analysis, results interpretation and manuscript revision; FC: clinical data analysis, manuscript revision; DC: image data analysis, results interpretation; MDS: neuropsychological data acquisition, results interpretation; SC: image data analysis, results interpretation, manuscript revision; MC: image data acquisition, results interpretation; FE: image data analysis, results interpretation and manuscript drafting and revision; GT: experimental design, results interpretation, manuscript revision. All authors read and approved the final manuscript.


Evidence of the clinical benefit of 3-in-1 point-of-care testing (POCT) for cardiac troponin T (cTnT), N-terminal pro-brain natriuretic peptide (NT-proBNP) and D-dimer in cardiovascular risk stratification at primary care level for diagnosing acute coronary syndromes (ACS), heart failure (HF) and thromboembolic events (TE) is very limited. The aim of this study is to analyse the diagnostic accuracy of POCT in primary care.Prospective multicentre controlled trial cluster-randomised to POCT-assisted diagnosis and conventional diagnosis (controls). Men and women presenting in 68 primary care practices in Zurich County (Switzerland) with chest pain or symptoms of dyspnoea or TE were consecutively included after baseline consultation and working diagnosis. A follow-up visit including confirmed diagnosis was performed to determine the accuracy of the working diagnosis, and comparison of working diagnosis accuracy between the two groups.The 218 POCT patients and 151 conventional diagnosis controls were mostly similar in characteristics, symptoms and pre-existing diagnoses, but differed in working diagnosis frequencies. However, the follow-up visit showed no statistical intergroup difference in confirmed diagnosis frequencies. Working diagnoses overall were significantly more correct in the POCT group , as were the working diagnoses of ACS/HF/TE . All three biomarker tests showed good sensitivity and specificity.POCT confers substantial benefit in primary care by correctly diagnosing significantly more patients.DRKS: DRKS00000709 Chest pain, tightness, pressure or squeezing, along with dyspnoea and heartburn-like sensations, are a diagnostic challenge in primary care medicine. Symptoms are often an inadequate guide to a working diagnosis. Common causes of chest pain and dyspnoea include stable angina, gastrointestinal disease, panic disorder, viral infection and musculoskeletal pain, but the most serious suspects include acute coronary syndromes (ACS), heart failure (HF) and thromboembolic events (TE) -3.Numerous cardiovascular biomarkers are now available . CardiaccTnT is a highly specific and sensitive protein for diagnosing myocardial necrosis: elevation diagnoses ACS and identifies patients at high risk of cardiac events . NT-proBOur aim was to analyse the benefit of POCT for cardiovascular risk stratification in primary care. We hypothesised that POCT testing for cTnT, NT-proBNP, and/or D-dimer in venous whole blood would allow for a more accurate diagnosis of ACS, HF and TE by office-based, Swiss general practitioners.We randomised 68 primary care practices in Zurich County (Switzerland) to diagnostic aid from a POCT analyser  or to conventional diagnosis employing best clinical practice . We randomised only practices at least 8-10 km from Zurich and Winterthur where laboratories with specialised diagnostic systems are less available.All patients presenting with potentially cardiovascular chest pain or symptoms between May 2006 and August 2007 were invited to participate. Patients gave written informed consent and the study received approval from the cantonal ethics committee , in line with the Declaration of Helsinki (1996) and Good Clinical Practice guidelines. Non-inclusion criteria were refusal of consent, presentation >5 days after symptom onset, recent anticoagulant treatment, severe renal dysfunction and cancer therapy. Rationales for the exclusion criteria were the normalisation of the cTnT level five days after ACS, the fact that cTnT may be increased even in the absence of clinically suspected acute myocardial ischemia in patients with renal insufficiency, and the unpredictable effect of anticoagulant treatment and cancer therapy on the biomarkers' concentration ,13.Physicians examined all patients before making a working diagnosis of ACS, HF, TE, musculoskeletal or "other" (specified) problems based on the patients characteristics, medical history, symptoms, physical findings and, in the POCT group, the biomarkers . At follow-up 3 weeks later the same physician reviewed the working diagnosis. The follow-up diagnosis was defined as the confirmed diagnosis. Follow-up data of patients requiring additional specialist visits or hospitalisation were provided by specialist or hospital reports.® , a 3-in-1 device that determines cTnT, NT-proBNP or D-dimer in heparinised venous whole blood within 8-12 min. Measurement was quantitative for each parameter over the ranges 0.05-2.00 ng/ml, 60-3000 pg/ml and 0.1-4.0 μg/ml, with validated positive/negative cut-offs of 0.1 ng/ml, 125 pg/ml and 0.5 μg/ml. Instruction to the POC-instrument always was performed by the same specialist from Roche Diagnostic. All GPs who received a POCT device received advice on the interpretation of test results. Test quality was monitored using the internal and external quality controls required by Swiss federal law and the Swiss Commission for Quality Assurance in the Medical Laboratory (QUALAB) [POCT practices received a bedside Cardiac Reader(QUALAB) .Data were analysed using SPSS 14.0 for Windows. Intergroup comparisons of categorical data were performed using univariate logistic regression; standard errors and p values were adjusted for the effect of clustering utilising a generalised estimating equations approach. We detected an interclass correlation coefficient of 0.073 for the main binary endpoint of a correct versus incorrect working diagnosis.To evaluate diagnostic test quality and performance we plotted receiver operating characteristic (ROC) curves, defined as plots of test sensitivity on the y axis vs. 1-specificity on the × axis. The area under the ROC curve (AUC) combining sensitivity and specificity was used to measure overall diagnostic test performance and was interpreted as the average sensitivity value for all possible specificity values.Of the 369 patients recruited, 218 (59%) were enrolled in the POCT group (7 ± 10/practice) and 151 (41%) in the control group (4 ± 4/practice). Characteristics and blood parameters were similar in both groups  patients presented over 5 days after symptom onset (non-inclusion criterion). We contacted the practices for specific explanations. In almost all cases the patients had visited the physician in the previous weeks/months (> > 5 days) with similar problems. Due to new or exacerbated symptoms (onsetting in the previous 5 days) they revisited their physician who reported the date of their first or previous visit incorrectly. After patients with incorrect symptom onset were excluded, the average interval between symptom onset and baseline visit became similar in the two groups.Many patients reported mixed sensations of pain or discomfort. Both groups had high prevalence of acute chest pain, tightness, pressure or squeezing, dyspnoea and heartburn-like sensations. Other symptoms were relatively rare Table . The groThe most frequent pre-existing diagnoses were hypertension, diabetes and angina. Only the proportion of patients with previously diagnosed HF differed substantially between the groups Table . PatholoSome working diagnoses differed in frequency between the groups Figure . In the However, confirmed diagnoses did not differ in frequency Figure . IntergrIn the POCT group 165/218 working diagnoses (76%) proved correct vs 90/151 (60%) in controls (p = 0.002). Seventy percent of the working diagnoses of ACS, HF and TE proved correct in the POCT group vs 45% in the controls (p = 0.002), with false-positives in 29 (30%) patients vs 40 (55%) patients, respectively. In contrast, correctness of the remaining working diagnoses  did not differ: 80% in the POCT group vs 73% in the controls (p = 0.31).Except for ACS, where sensitivity was higher in controls, working diagnoses were more sensitive in the POCT group Table . HoweverIndividual test sensitivities and NPVs were generally higher when assessed using the confirmed diagnoses. Specificities, in contrast, differed only marginally.The diagnostic power of the cTnT test was higher when assessed using the confirmed diagnoses: sensitivity and NPV were 17% and 6% higher Table . Seven pThe diagnostic power of the NT-proBNP tests was high: all patients with HF also had a positive NT-proBNP, and while none of those with a negative NT-proBNP had HF. Specificity was 72%.The D-dimer test had a sensitivity of 93%, specificity of 78% and NPV of 99%. The single false-negative was in a 65-year-old man with a history of cancer who was correctly diagnosed with deep vein thrombosis from his symptoms.The cTnT ROC curve based on the confirmed diagnoses was somewhat oddly shaped because physicians often recorded the result simply as positive or negative (< 0.1 ng/ml). In such cases positive and negative cTnT values were arbitrarily entered as 0.1 ng/ml and 0.0 ng/ml. Very high test specificity accounted for the measured AUC, 82% Figure . The NT-Our results emphasise the clinical value of POCT using a novel cardiovascular marker device measuring cTnT, NT-proBNP and D-dimer for the risk stratification of ACS, HF and TE in primary care. Diagnoses were more accurate in the POCT group. In particular, POCT-assisted physicians avoided numerous false-positive ACS, HF, and TE diagnoses. This evidence supports the use of cTnT, NT-proBNP and D-dimer in diagnosing patients with chest pain or other potentially cardiovascular symptoms. Analysis of these biomarkers provides clinical benefit by more accurately ruling in/out ACS, HF and TE, each with significant management implications.In previous studies, atypical or absent chest pain has been associated with failure to recognise ACS by either physician or patient in up to one third of cases . Our stuOverall, these findings support the notion that when combined with clinical symptoms and ECG screening, troponin assay improves diagnostic accuracy, in line with American College of Cardiology/American Heart Association guidelines on managing patients with unstable angina or NSTEMI . Except The cTnT assay itself yielded seven false-negatives. Most patients concerned (5/7) were correctly diagnosed from their history and symptoms. Recurrent angina was suspected in the other two patients. High drug consumption in three patients, and the short interval (5 h) between symptom onset and presentation in one patient, may partially explain the false-negatives. Misuse of the POCT device may account for the other cases. That the same practice made 4/7 false-negative diagnoses supports this explanation, highlighting the importance of adequate training on POCT devices. In our study, training on the POCT instrument always was performed by the same Roche Diagnostics specialist, but some staff members were instructed by their colleagues only.HF is a common and increasing public health problem . DiagnosNatriuretic Peptides in the Community Study, a randomised controlled trial of the effect of NT-proBNP on HF diagnostic accuracy in primary care, showing significant improvement in the BNP group over controls [N-terminal PRo-BNP Investigation of Dyspnea in the Emergency department (PRIDE) study which found the test with its 99% NPV to be a valuable addition to standard clinical assessment for identifying and excluding acute HF: a positive NT-proBNP was the strongest independent predictor of a final positive diagnosis of HF.In our study, diagnosis of HF in the POCT group showed high sensitivity, specificity and NPV. Sensitivity in the controls was relatively low, but both specificity and NPV were high. These results indicate that HF was better identified in the POCT group, presumably because of the NT-proBNP data. Assay sensitivity and NPV were perfect: all patients with HF had elevated NT-proBNP values, whereas HF was correctly excluded in all patients with normal values. The very high AUC of the NT-proBNP ROC curve Figure  reflectscontrols ; a UK stcontrols ; and theTE includes PE and DVT, which are closely interrelated since 90% of symptomatic PE arise from leg vein thrombi . It's weIn our study, the sensitivity, specificity and NPV of the TE diagnoses were good in both groups, making it difficult to determine whether diagnoses in the POCT group were more accurate. The D-dimer assay showed moderate specificity but very high sensitivity and NPV. The only patient with a false-negative D-dimer was a 65-year-old man with a history of cancer who was correctly diagnosed with a DVT based on his symptoms. The NPV confirmed the assay's power in excluding TE. While a negative D-dimer safely excludes TE, patients with a positive result should still be screened for PE and DVT, in particular in the presence of typical symptoms. Our results are consistent with those of other studies, e.g. Leclercq et al. or Schutgens et al. ,30.Some limitations of the study require discussion. For example, we confined ourselves to Zurich County for practical reasons; whether the results can or cannot be extrapolated to less urbanised areas remains to be determined.A second limitation was patient recruitment. Initially, recruitment was clearly higher in the POC group. We put this down to a difference in study awareness: the device on their premises made POCT physicians more study-aware. Control physicians, on the other hand, had only the study protocol and the questionnaires to remind them, and perhaps forgot to recruit; after we initiated regular telephone reminders, recruitment rates became almost equal in both groups.The follow-up diagnoses were another limitation. In principle, they should have been performed by independent blinded assessors but this was not feasible. For practical and data protection reasons, they were made by the same physician who was primarily consulted by the patient. We are aware of the potential for bias, e.g. due to possible underreporting of incorrect baseline diagnoses leading to a false high rate of correct baseline diagnoses or a false low difference between study arms. On the other hand, for patients referred for further diagnostic work-up , GPs received a written report on the second-stage assessment as well as information on further clinical management, which substantially reduced the risk of bias.A fourth limitation concerns possible underestimation of the number of HF diagnoses in the controls. Not only were there significantly more pre-existing HF diagnoses in the POCT group, but the total number of newly identified HF patients was also greater. We assume that the POCT physicians used the NT-proBNP value as diagnostic criterion to identify more patients with NYHA class I-II HF. Indeed, early stages of HF are often asymptomatic and difficult to identify without accurate screening. Some patients with mild HF may not have been diagnosed as a result, and this tendency would have been stronger in the controls.As shown in Table Health-economic and cost-effectiveness studies of cardiovascular risk stratification using POCT are rare. Some studies have analysed the costs and benefits of a single biomarker for a defined disease. Thus Nielsen et al.  concludeThis study found substantial benefit for POCT diagnosis in cardiovascular risk stratification at the primary care level. Non-invasive analysis of cTnT, NT-proBNP and D-dimer produced more accurate diagnoses of ACS, HF and TE in the POCT group. Given the potential for substantial health-economic savings, we plan a fuller investigation based on the clinical outcomes of this study.Prof. Felix Gutzwiller and Albert Diemand own some Hoffmann-La Roche stock. Albert Diemand declares a financial conflict, since Roche Diagnostics (Switzerland) provided all POCT instruments, reagents, and an unrestricted educational grant. However, he had no access to the dataset and no influence on the data analysis performed at the Institute of Social and Preventive Medicine, Zurich University. All other authors have no conflicts of interest.All authors contributed to the conception and design; YT undertook the statistical analysis and MS advised on the analysis of clustered-randomised data; all authors contributed to the interpretation of data and have been involved in the drafting of the manuscript or revising it critically for important intellectual content; and have given final approval of the version to be published.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2296/12/12/prepub


Cellular respiration is the process by which cells obtain energy from glucose and is a very important biological process in living cell. As cells do cellular respiration, they need a pathway to store and transport electrons, the electron transport chain. The function of the electron transport chain is to produce a trans-membrane proton electrochemical gradient as a result of oxidation–reduction reactions. In these oxidation–reduction reactions in electron transport chains, metal ions play very important role as electron donor and acceptor. For example, Fe ions are in complex I and complex II, and Cu ions are in complex IV. Therefore, to identify metal-binding sites in electron transporters is an important issue in helping biologists better understand the workings of the electron transport chain.We propose a method based on Position Specific Scoring Matrix (PSSM) profiles and significant amino acid pairs to identify metal-binding residues in electron transport proteins.We have selected a non-redundant set of 55 metal-binding electron transport proteins as our dataset. The proposed method can predict metal-binding sites in electron transport proteins with an average 10-fold cross-validation accuracy of 93.2% and 93.1% for metal-binding cysteine and histidine, respectively. Compared with the general metal-binding predictor from A. Passerini et al., the proposed method can improve over 9% of sensitivity, and 14% specificity on the independent dataset in identifying metal-binding cysteines. The proposed method can also improve almost 76% sensitivity with same specificity in metal-binding histidine, and MCC is also improved from 0.28 to 0.88.We have developed a novel approach based on PSSM profiles and significant amino acid pairs for identifying metal-binding sites from electron transport proteins. The proposed approach achieved a significant improvement with independent test set of metal-binding electron transport proteins. Cellular respiration is the process by which cells obtain energy from glucose. During respiration, cells break down simple food molecules, such as sugar, and release the energy they contain As cells do cellular respiration, they need a pathway to store and transport electrons, the electron transport chain. The function of the electron transport chain is to produce a trans-membrane proton electrochemical gradient as a result of oxidation-reduction reactions. If protons flow back through the membrane, ATP synthase converts this mechanical into chemical energy by producing ATP, which is provided energy in many cellular processes. The architecture of the electron transport chain with complex I–IV is given in + to generate ATP.As There are many oxidation-reduction reactions in the electron transport chain, such as NADH dehydrogenase, coenzyme Q – cytochrome c reductase, and succinate – coenzyme Q reductase. In these oxidation-reduction reactions in electron transport chains, metal ions play very important role as electron donor and acceptor. For example, Fe ions are in complex I and complex II, and Cu ions are in complex IV. Therefore, to identify metal-binding sites in electron transporters is an important issue in helping biologists better understand the workings of the electron transport chain. In this work, we try to develop a method based on Position Specific Scoring Matrix (PSSM) profiles and significant amino acid pairs to identify metal-binding residues in electron transport proteins.In recent years, several methods have been proposed for predicting metal-binding sites (MBS) in proteins based on neural networks and support vector machines According to a recent comprehensive review 6], to establish a really useful statistical predictor for a protein system, we need to consider the following procedures: (i) construct or select a valid benchmark dataset to train and test the predictor; (ii)formulate the protein samples with an effective mathematical expression that can truly reflect their intrinsic correlation with the attribute to be predicted; (iii) introduce or develop a powerful engine to operate the prediction; (iv) properly perform cross-validation tests to objectively evaluate the anticipated accuracy of the predictor; (v) establish a user-friendly web-server for the predictor that is accessible to the public.In this work, we propose a method based on PSSM profiles and significant amino acid pairs to identify metal-binding residues in electron transport proteins. We have selected a non-redundant set of 55 metal-binding electron transport proteins as our dataset. The proposed method can predict metal-binding sites in electron transport proteins with an average 10-fold cross-validation accuracy of 93.2% and 93.1% for metal-binding cysteine and histidine, respectively. Comparing with the general metal-binding predictor from A. Passerini et al., the proposed method can improve over 9% of sensitivity, and 14% specificity on the independent dataset in identifying metal-binding cysteines. The proposed method can also improve almost 76% sensitivity with same specificity in metal-binding histidine, and MCC is also improved from 0.28 to 0.88. The proposed approach achieved a significant improvement with independent test set of metal-binding electron transport proteins.This work focuses on identifying metal-binding sites efficiently in electron transport proteins. As First of all, we selected electron transport proteins with metal binding sites from UniProt database The collected electron transport protein sequences were divided into two datasets: the training dataset and the independent test dataset. The training dataset is used for identifying metal binding sites and evaluating significant amino acid pairs in electron transport proteins. The training dataset includes 44 electron transport protein sequences which contain 79 metal-binding cysteine, 77 metal-binding histidine and 368 non-metal-binding cysteine and histidine. The independent test dataset, which includes 11 electron transport proteins which contain 22 metal-binding cysteine, 21 metal-binding histidine and 103 non-metal-binding cysteine and histidine, is used to evaluate the performance of the proposed method. The details of two datasets are listed in In the structural point of view, several amino acid residues can be mutated without altering the structure of a protein, and it is possible that two proteins have similar structures with different amino acid compositions. Hence, the Position Specific Scoring Matrix (PSSM) profile is adopted, which have been widely used in protein secondary structure prediction, subcellular localization, classification of transporters, prediction of transport targets and other bioinformatics problems with significant improvement PSSM profiles can be a useful feature set to represent evolutionary information in protein sequences In the identification of metal binding sites on electron transport proteins, the generated PSSM profiles contained the probability of occurrence of each type of amino acid residues at each position. Each element in PSSM profile is scaled by In addition, we also generated different feature sets for comparison. There feature sets are generated by amino acid types(AA), BLOSUM62 matrix (BLOcks of Amino Acid SUbstitution Matrix) k-th SAAP in the whole dataset, in the positive dataset,and in the negative dataset respectively.The significant amino acid pairs (SAAPs) around the metal-binding sites are identified based on the training dataset. These SAAPs are adopted to construct learning model for improving performance The amino acid pair surrounding metal-binding sites is significant when p-value is less than the significance level. It indicates that central residue is the metal-binding site with higher probability if significant amino acid pairs appear. As shown in After calculating p-value for each amino acid pair surrounding metal-binding sites, the ranked SAAPs added into the feature set by using forward feature selection based on 10-fold cross-validation for improving predictive performance. Finally, 25 and 90 SAAPs are added into feature set of identifying metal binding cysteine and histidine, respectively. The final model was evaluated by using the independent dataset of 11 electron transporters.The topmost 25 of SAAPs with p-value surrounding metal-binding cysteine and histidine are listed respectively in We have employed the QuickRBF package Classification based on radial basis function (RBF) networks has several applications in bioinformatics. It has been widely used to predict the cleavage sites in proteins j-th output node and is a linear combination of k radial basis functions The general mathematical form of the output nodes in an RBFN is as follows:The prediction performance was examined by 10-fold cross validation test, in which the training data were randomly divided into ten subsets of approximately equal size. The data were trained with nine subsets and the remaining set was used to test the performance of the method. This process was repeated 10 times so that every subset had been used as the test data once.Sensitivity, specificity, accuracy, and MCC (Matthew's correlation coefficient) were used to measure the prediction performance. TP, FP, TN, FN are true positives, false positives, true negatives, and false negatives, respectively.We developed a variety of methods for metal-binding sites identification in electron transport proteins. The results obtained from the AA, BLOSUM62, PAM250, PSSM, and the combination of PSSM and SAAPs are presented in Combining the significant amino acid pairs with the sequence of amino acids increases the predictive accuracy specificity for metal-binding sites identification from 90.1% to 93.2% with metal-binding cysteine, and from 91.0% to 93.1% with metal-binding histidine. In addition, the sensitivity, precision specificity, and MCC are also improved. Consequently, according to the evaluation of 10-fold cross validation, the identified significant amino acid pairs can increase the predictive performance.In statistical prediction, the following three cross-validation methods are often used to examine a prediction: independent dataset test, subsampling test, and jackknife test The independent test dataset, which includes 11 electron transport proteins which contain 22 metal-binding cysteine, 21 metal-binding histidine and 103 non-metal-binding cysteine and histidine, is used to evaluate the performance of the proposed method. As We have analyzed metal-binding cysteine and cysteine residues on electron transporters and general proteins. Using the sequences of electron transporters in We also statistically analyzed the amino acid compositions with standard T-test of metal-binding cysteine and cysteine residues in electron transporters and general proteins. As According the statistical analysis, the distribution of amino acids surrounding metal-binding residues are different between electron transport proteins and general proteins. This may be the reason why our proposed method performs better than the general metal-binding predictor.Cellular respiration is the process by which cells obtain energy from glucose, and is a very important biological process in living cell. As cells do cellular respiration, they need a pathway to store and transport electrons, the electron transport chain. The function of the electron transport chain is to produce a trans-membrane proton electrochemical gradient as a result of oxidation-reduction reactions. In these oxidation-reduction reactions in electron transport chains, metal ions play very important role as electron donor and acceptor. Therefore, to identify metal-binding sites in electron transporters is an important issue in helping biologists better understand the workings of the electron transport chain.In this work, we proposed a method based on PSSM profiles and significant amino acid pairs to identify metal-binding residues in electron transport proteins. We have selected a non-redundant set of 55 metal-binding electron transport proteins as our dataset. The proposed method can predict metal-binding sites in electron transport proteins with an average 10-fold cross-validation accuracy of 93.2% and 93.1% for metal-binding cysteine and histidine, respectively. Comparing with the general metal-binding predictor from A. Passerini et al., the proposed method can improve over 9% of sensitivity, and 14% specificity on the independent dataset in identifying metal-binding cysteines. The proposed method can also improve almost 76% sensitivity with same specificity in metal-binding histidine, and MCC is also improved from 0.28 to 0.88. Our proposed approach achieved a significant improvement with independent test set of metal-binding electron transport proteins. The result shows that our method could be effectively used for indentifying metal-binding sites in electron transport proteins to help biologists better understand the workings of the electron transport chain.Since user-friendly and publicly accessible web-servers represent the future direction for developing practically more useful models, simulated methods, or predictors, we will make efforts in our future work to provide a web-server for the method presented in this paper.


Resistance to apoptosis is a hallmark of cancer and proteins regulating apoptosis have been proposed as prognostic markers in several malignancies. However, the prognostic impact of apoptotic markers has not been consistently demonstrated in oral squamous cell carcinoma (OSCC). This inconsistency in reported associations between apoptotic proteins and prognosis can be partly attributed to the intrinsic low resolution and misclassification associated with manual, semi-quantitative methods of biomarker expression measurement. The aim of this study was to examine the association between apoptosis-regulating proteins and clinical outcomes in oral squamous cell carcinoma (OSCC) using the quantitative fluorescence immunohistochemistry (IHC) based AQUAnalysis technique.Sixty-nine OSCC patients diagnosed between 1998–2005 in Calgary, Alberta, Canada were included in the study. Clinical data were obtained from the Alberta Cancer Registry and chart review. Tissue microarrays (TMAs) were assembled from triplicate cores of formalin-fixed paraffin embedded pre-treatment tumour tissue. Bax, Bcl-2 and Bcl-XL protein expression was quantified using fluorescent IHC and AQUA technology in normal oral cavity squamous epithelium (OCSE) and OSCC tumour samples. Survival was analyzed using Kaplan-Meier plots and the Cox proportional hazard model.Bax expression was predominantly nuclear in OCSE and almost exclusively cytoplasmic in OSCC. No similar differences in localization were observed for Bcl-2 or Bcl-XL. Only Bax expression associated with disease-specific survival (DSS), with 5-year survival estimates of 85.7% for high Bax versus 50.3% for low Bax (p = 0.006), in univariate analysis. High Bax expression was also significantly associated with elevated Ki67 expression, indicating that increased proliferation might lead to an improved response to radiotherapy in patients with elevated Bax expression. In multivariate analyses, Bax protein expression remained an independent predictor of DSS in OSCC .The AQUA technique used in our study eliminates observer bias and provides reliable and reproducible estimates for biomarker expression. AQUA also provides essential measures of quality control that cannot be achieved with manual biomarker scoring techniques. Our results support the use of Bax protein expression as a prognostic marker in conjunction with other clinico-pathological variables when designing personalized treatment strategies for OSCC patients. Oral cavity squamous cell carcinoma (OSCC) is the most common form of head and neck squamous cell carcinoma (HNSCC). The annual estimated incidence of oral cancer is almost 300,000 worldwide . OSCC isAlthough several clinical and histopathological and molecular markers have been proposed ,4, curreApoptotic pathways are critical cell-autonomous tumour surveillance mechanisms that guard against the development of neoplasms. Indeed, evading apoptosis is considered one of the hallmarks of cancer ,10. The et al. , lymph node status  and pathologic T-stage , were significantly and independently associated with DSS  and a uniformly treated cohort from a single cancer center, thus minimizing treatment heterogeneity and increasing the reliability of our results.Our study is limited by its relatively small sample size and retrospective nature. Despite the advantages of the AQUA technique for discovery-phase studies, it is not widely available in routine laboratory diagnostics at present, limiting its current clinical utility. However, the robustness and reliability of AQUA makes it amenable for adoption as a routine tool for prognostication in the imminent future.High Bax expression could serve to stratify OSCC patients with better prognosis, in a manner similar to HPV status in cancers of the oropharynx. Since both chemotherapy and radiotherapy work by inducing apoptosis in rapidly proliferating cells, our results suggest that combined modality treatments should be explored in patients with low Bax and Ki67-expressing tumours . ConfirmAQUA: Automated Quantitative Analysis; Bax: Bcl-2-associated X protein; Bcl-2: B-cell lymphoma 2; Bcl-XL: Bcl-2-related gene long isoform; DAPI: 4',6-diamidino-2-phenylindole; DSS: Disease-Specific Survival; FFPE: Formalin-Fixed, Paraffin–Embedded; HNSCC: Head and Neck Squamous Cell Carcinoma; HPV: Human-Papilloma Virus; IHC: Immunohistochemistry; OCSE: Oral Cavity Squamous Epithelium; OSCC: Oral Squamous Cell Carcinoma; TMA: Tissue Microarray; TNM: Tumour-Node-Metastasis.This study was funded by the Ohlson Research Initiative, which functions within the Faculty of Medicine at the University of Calgary. The corresponding author (JCD) is the Director of the Ohlson Research Initiative. This does not alter our adherence to all BMC Cancer policies as detailed in the guide for authors. All other authors declare no conflict of interest.PB designed and coordinated the study, contributed to data analysis and interpretation and drafted the manuscript. ACK contributed to study design, performed survival analysis and helped with manuscript preparation. EK performed statistical analyses and edited the manuscript. SKP performed the fluorescence IHC and AQUA. TWM and SC contributed patients to the study, reviewed the manuscript and were involved in the interpretation of the clinical data. AMM was the designated study pathologist and performed the review of H&E stained slides to confirm diagnosis and select areas of tumour for TMA preparation. NTB and JCD conceived the study and helped with manuscript preparation and editing. JCD contributed to study design, clinical cohort assembly, data analysis and interpretation. All authors read and approved the final manuscript.PB is a Postdoctoral research fellow with the Ohlson Research Inititative in Head and neck cancer, University of Calgary. ACK is an adjunct assistant professor and the Director of the Functional Tissue Imaging Unit (FTIU) at the Tom Baker Cancer Centre, University of Calgary. EK is a research technician at the FTIU. SKP is a research technician at the FTIU. TWM is an otolaryngologist and head and neck surgeon. He is also the Division Chief of Otolaryngology, Head and Neck Surgery in the Department of Surgery, University of Calgary. SC is an otolaryngologist and head and neck surgeon in the Division of Otolaryngology - Head and Neck Surgery, Department of Surgery, University of Calgary. AMM is presently the Chief of Pathology at H. Lee Moffitt Cancer Center & Research Institute. NTB is a molecular cancer epidemiologist and research scientist with Population Health Research, Alberta Health Services – Cancer Care. JCD is an otolaryngologist, head and neck surgeon and epidemiologist. He is also the Director of the Ohlson Research Inititative in Head and Neck Cancer.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/12/332/prepub Figure S1. Kaplan-Meier survival analysis of Ki67 expression. Kaplan-Meier survival curves and corresponding risk tables for 5 year disease-specific survival in OSCC patients with below median or above median Ki67.Click here for file Figure S2. Kaplan-Meier survival analysis of ratios between pro-apoptotic and anti-apoptotic Bcl-2 family proteins. Kaplan-Meier survival curves and corresponding risk tables for 5 year disease-specific survival in OSCC patients with below median or above median (A) Bcl-2/Bax and (B) Bcl-XL/Bax. Cut-points were selected at median.Click here for file Figure S3. Kaplan-Meier survival analysis of Bax expression with respect to treatment in OSCC. Kaplan-Meier curves for 5-year disease-specific survival using (A) Bax expression for patients treated with surgery and post-operative radiation and (B) Bax expression for patients treated with surgery only (no radiation). Cut-points were selected at median. Click here for file


Background: Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) persist in the environment and are found in relatively high concentrations in animal livers. Studies in humans have reported inconsistent associations between PFOA and liver enzymes.Objectives: We examined the cross-sectional association between serum PFOA and PFOS concentrations with markers of liver function in adults.Methods: The C8 Health Project collected data on 69,030 persons; of these, a total of 47,092 adults were included in the present analysis. Linear regression models were fitted for natural log (ln)-transformed values of alanine transaminase (ALT), γ-glutamyltransferase (GGT), and direct bilirubin on PFOA, PFOS, and potential confounders. Logistic regression models were fitted comparing deciles of PFOA or PFOS in relation to high biomarker levels. A multilevel analysis comparing the evidence for association of PFOA with liver function at the individual level within water districts to that at the population level between water districts was also performed.Results: ln-PFOA and ln-PFOS were associated with ln-ALT in linear regression models  and with raised ALT in logistic regression models . There was less consistent evidence of an association of PFOA and GGT or bilirubin. The relationship with bilirubin appears to rise at low levels of PFOA and to fall again at higher levels.Conclusions: These results show a positive association between PFOA and PFOS concentrations and serum ALT level, a marker of hepatocellular damage. Perfluorooctanoate (PFOA) and perfluoro-octane sulfonate (PFOS) are two members of the perfluoroalkyl acid (PFAA) class of chemicals, man-made compounds used in the manufacture of fluoro-polymers, including those used for non-stick cookware and breathable, waterproof fabrics. PFOA and PFOS can also result from the metabolism of fluori-nated telomers, compounds used for food package coatings, carpet treatments, and stain-resistant fabric treatment. PFOA and PFOS persist in the environment ; potentiIn rodents and non-human primates, both PFOA and PFOS have been found in relatively high concentrations in the liver and have been associated with liver enlargement. In rats, these compounds have been also associated with hepatocellular adenomas . In miceStudies in humans have reported inconsistent associations between PFOA or PFOS and liver enzymes. Transaminase levels have been positively associated with PFOA concentrations in some occupational studies  but not From 1950 through 2005, a chemical plant in the Mid-Ohio Valley, West Virginia (USA), was responsible for emitting PFOA into the surrounding environment. In 2001, a group of residents filed a class action lawsuit alleging health damage from the drinking water supplies drawing on PFOA-contaminated groundwater . Part ofThe study population. This study was approved by the London School of Hygiene and Tropical Medicine Ethics Committee and is one of the C8 Science Panel studies and used information from questionnaires and blood tests collected in the C8 Health Project, supplemented by further information on classification by water district developed in a companion C8 Science Panel study (el study .http://dx.doi.org/10.1289/ehp.1104436)]. Details of the study enrollment process, including consenting procedures, have been described elsewhere . Both PFOA and PFOS concentration distributions were skewed to the right.Laboratory analyses of PFAAs were conducted by the Exygen Research Inc. . using an automated solid-phase extraction combined with reverse-phase high-performance liquid chromatography/mass spectrometry . An intrr = 0.79. To limit multiple comparisons and to be consistent with the most recent published literature on the same topic  and aspartate aminostransferase (AST), GGT, alkaline phosphatase (ALP), and direct bilirubin . Both transaminases (AST and ALT) are enzymes released after liver parenchymal cell injury and are elevated in serum during acute liver damage; the correlation between ALT and AST in the present population is me topic , we restme topic  because me topic ; the cor disease .ALT, GGT, and direct bilirubin were measured using a Roche/Hitachi MODULAR automated analyzer , and the analyses were performed at a large, independent, accredited clinical diagnostic laboratory  . The homMethods and results are described according to the STrengthening the Reporting of OBservational studies in Epidemiology—Molecular Epidemiology (STROBE-ME) guidelines .Statistical analysis. Distributions of continuous variables were inspected, and all three outcome markers were natural log (ln) transformed for linear regression models. We investigated univariate associations between exposure (serum concentration of PFOA and PFOS), liver function biomarkers , and potential confounders: age, physical activity, body mass index , average household income , educational level , race , alcohol consumption  and cigarette smoking .The association between ALT, GGT, or direct bilirubin and PFOA or PFOS was assessed using linear regression models. First, we fitted a simple model including only age and sex (model 1), followed by a model additionally including alcohol consumption, socioeconomic status, fasting status, race, and month of blood sample collection (model 2), and then a model additionally including smoking status, BMI, physical activity, and insulin resistance  in deciles of distribution (model 3).Also, specific cutoff values were used to fit logistic regression models to estimate the impact of PFOA and PFOS on being above these values. Cutoff values used were 45 IU/L in men and 34 IU/L in women for ALT , giving a priori some heterogeneity in between- and within-group relationships; therefore, we applied an analytic approach in the multilevel framework [between- and within-group regression (http://dx.doi.org/10.1289/ehp.1104436).Prior research showed that individual serum levels of PFOA were strongly associated with the water district of residence . This gegression ] to diseGeneral characteristics of the population are summarized in R2 greater for the association with PFOA  than for that with PFOS , and a significant OR for both ln-unit of PFOA  and ln-unit of PFOS  and had significantly higher PFOA and PFOS serum concentrations compared with those with normal ALT values . No interaction between PFOA/PFOS deciles with fasting status was observed .ln-Transformed values of ALT were significantly associated with ln-PFOA and ln-PFOS in linear regression models , with a partial p = 0.213), or for the linear ln-units of PFOA values  and had significantly higher PFOA serum concentrations  but not PFOS serum concentrations .The association between ln-GGT and ln-PFOA reached a significant level in the fully adjusted model  mainly due to the contribution of insulin resistance and BMI, which appeared to be highly associated with ln-GGT ; fitted p < 0.001). In accordance, no pattern was evident in the logistic regression models of high bilirubin  and excluding those with private wells. The fitted values for each of the outcomes of ALT, GGT, and direct bilirubin versus mean PFOA serum level for the six water districts are graphed in B) and for a model within water districts comparing differences from the average (W) are presented. There was a significant difference between the between- and within-district components  for ALT and direct bilirubin; however, each outcome showed different patterns. The between--water-district regression coefficient from linear regression of ln-PFOA and ALT  was lower than the within-water-district coefficient . However, both coefficients were significant or borderline significant, in the same direction, and consistent with a positive association between ALT and PFOA levels. Although the regression coefficient for the association between GGT and ln-PFOA within water district was positive and significant , this association was not significant in the between-water-district analysis ; the p-value for interaction between/within water district was not significant (p = 0.108). Conversely, there was a significant inverse relationship between ln-PFOA and direct bilirubin between water districts  but not within water districts .Multilevel analysis was restricted to subjects living in water districts supplied by contaminated water (R2 ≤ 0.1%) suggests caution.These results show a positive association between PFOA and PFOS concentrations and ALT serum levels, a marker of hepatocellular damage. The linear association, consistently replicated in all analyses, showed a monotonic increase in logistic regression. Furthermore, the presence of a consistent relationship in regression analysis both between water districts and among individuals within districts increases strength of evidence for causal association. The proportion of laboratory abnormal values rises in relation to PFOA, but the small amount of variation in outcomes explained by PFOA . A significant linear regression coefficient between log-transformed–PFOA and log-ALT  was described in a cross-sectional occupational surveillance conducted in three 3M plants in the United States and Belgium (p < 0.01)  where background concentrations of PFOA are much lower than those reported here (p = 0.65); however, the observation was based on a much smaller sample  and based on figures coming from models including non-log-transformed exposure or outcome variables  . Notablyted here . Only onariables .p = 0.05), which drops if BMI is replaced by ln-tryglicerides (a proxy for diet) in the model   might be due to a confounding effect of diet, or residual confounding of alcohol consumption, which causes a direct increase of GGT. Finally, the absence of any trend across districts—even though there are large contrasts in between-district mean exposures—might be indicative of some confounding factor acting at the individual level. As shown recently, GGT levels are positively associated with alcohol and meat intake after adjusting for all potential non-dietary confounders . To supp = 0.55) .PFOA concentration has a positive association with direct bilirubin up to 40 ng/mL, followed by a decrease of bilirubin levels after this peak. A negative association between PFOA or PFOS and direct bilirubin has been observed in some occupational studies , which mThe hepatotoxic effect of PFOA in rodents leading to liver enlargement and altered hepato-cyte histology  appears The consistency and significance of associations of ALT end points outside the normal range with PFOA serum concentration suggest a true association with an underlying hepatotoxic effect in humans. However, only a small proportion of end points fell outside the normal value range, making the observed results more difficult to interpret in terms of human health risk. In particular, it is not clear if this small increase in ALT levels can lead to clinically diagnosable conditions in the future, or if this effect is reversible . Finally, results coming from this study need to be read in the context of health effect of PFAAs on humans, but data cannot be directly used for estimating single-subject damage in relation to exposure.The main limitation of the present study is the cross-sectional design, which makes causal inference particularly difficult. However, the consistency of the findings with previous literature—in particular the association with ALT—reinforces the hypothesis of a true association. Also, self-reported data of lifestyle characteristics being strongly associated with the exposures of interest can hamper a correct adjustment for potential confounders, which might be of particular relevance given the small magnitude of the observed associations. However, this study is the largest reported so far on this topic on a population-based sample of residents exposed to relatively high concentrations of PFOA.A small but clear linear association between PFOA and PFOS serum concentrations and ALT, a marker of hepatocellular injury, was observed in this large population-based sample of individuals with exposure to PFAAs. These results are consistent with previous findings and warrant further investigation, in particular on the potential health consequence of long-term exposure and potential -accumulation of damage.(172 KB) PDFClick here for additional data file.


Due to the great variability of 12-lead ECG instruments and medical specialists’ interpretation skills, it remains a challenge to deliver rapid and accurate 12-lead ECG reports with senior cardiologists’ decision making support in emergency telecardiology.We create a new cloud and pervasive computing based 12-lead Electrocardiography (ECG) service to realize ubiquitous 12-lead ECG tele-diagnosis.This developed service enables ECG to be transmitted and interpreted via mobile phones. That is, tele-consultation can take place while the patient is on the ambulance, between the onsite clinicians and the off-site senior cardiologists, or among hospitals. Most importantly, this developed service is convenient, efficient, and inexpensive.This cloud computing based ECG tele-consultation service expands the traditional 12-lead ECG applications onto the collaboration of clinicians at different locations or among hospitals. In short, this service can greatly improve medical service quality and efficiency, especially for patients in rural areas. This service has been evaluated and proved to be useful by cardiologists in Taiwan. The 12-lead Electrocardiography (ECG) is one of the most frequently applied diagnostic tools in clinical cardiac medicine. A 12-lead ECG instrument records electrical activities of the heart from the frontal and the horizontal views by attaching 10 electrodes on the surfaces of limbs and the chest and therefore generates 12 groups of signals, called 12-lead ECG. Traditionally, a 12-lead ECG instrument stores ECG waveform data with vendor-specific formats whose ECG data are compressed or encrypted with vendor-specific algorithms in the instrument and then generates a hard-copy of the 12-lead ECG report. Recently, ECG instruments are equipped with vendor-specific computerized ECG viewers, which can be used only on desktop computers. In Taiwan, most hospitals adopt paper-ECG, which is due to the expenses of vender-specific ECG instruments and ECG viewers, as well as the management problems of 12-lead ECG records stored in different systems provided by various 12-lead ECG manufactures.In 2002, Open-ECG, an international academic organization, promoted the development of computerized 12-lead ECG by providing researchers with technical references of 12-lead ECG data formats, including International Organization for Standardization (ISO) approved Standard Communication Protocol–ECG (SCP-ECG), Food and Drug Administration (FDA) proposed Extensible Markup Language based ECG (XML-ECG), and National Electrical Manufactures Association (NEMA) recommended Digital Imaging and Communications in Medicine based ECG (DICOM-ECG) . HoweverWhen a hospital purchases various ECG products from different manufactures, not only do clinicians encounter huge difficulty in retrieving ECG records, but information technicians (ITs) also have great difficulty in managing ECG information systems due to the heterogeneous ECG data formats and incompatible ECG information database provided by 12-lead ECG manufactures. To provide clinicians and ITs with easier ECG management by unifying heterogeneous ECG data formats, researchers converted clinically-used SCP-ECG and XML-ECG to DICOM-ECG that can be integrated in the Picture Archiving and Communication Systems (PACS) with medical images .The development of mobile computing-based medical applications is crucial, because it proves to enhance medical service quality ,9. EuropHowever, clinically used 12-lead ECG instruments are limited to the use in the hospital and consequently, they do not generate ECG reports outside the hospital. Due to the great variability of 12-lead ECG instruments and medical specialists’ interpretation skills, it remains a challenge to deliver rapid and accurate 12-lead ECG reports with senior cardiologists’ decision making support . In factTo resolve the aforementioned problems, we developed a series studies in 2009 and 2010 as illustrated in Figure Based on recent investigation in 2011 ,20, therThe present challenges of 12-lead ECG telemedicine include not only to improve the services of a single clinic but also to strengthen the collaboration among clinics such as inter-hospital ECG interpretation. A promising method to develop inter-hospital 12-lead ECG telemedicine is to use cloud computing technology providing hospitals with a common platform with easily accessible computing resources and storage space on demand via internet and a low-cost pay-per-use model without long-term commitment.Cloud computing refers to the software application delivery service via web access among different computers with heterogeneous O.S. . The cloThis study aims to develop an effective model of 12-lead ECG telemedicine to overcome the challenges of 12-lead ECG telemedicine described in Sec. of 12-lead ECG telemedicine and pervasive health. The objectives of this study are as follows, (a) to facilitate inter-hospital 12-lead ECG tele-consultation, (b) to practice pre-hospital diagnosis, and (c) to enhance the interoperability of 12-lead ECG records among urban hospitals and rural clinics without the costly installation of additional 12-lead ECG telemedicine equipment.In this study, we developed an ECG telemedicine service from clinically used ECG devices with heterogeneous data formats, such as HP compatible SCP-ECG, Mortara DICOM-ECG and Philips XML-ECG, which are commonly used in both urban and rural areas in Taiwan. Most modern 12-lead ECG devices in clinical practice can directly export ECG reports via wired or wireless based network, such as Philips ECG XML-ECG, or indirectly export ECGs via internet through the transformation from the traditional serial transmission, RS232 or USB, to Ethernet based network, such as HP compatible SCP-ECG device and Mortara DICOM-ECG device. In this study, the Ethernet based network with an average speed ranging from 15 Mbps to 80 Mbps via TCP/IP protocol was used to transmit and receive ECGs between the cloud service and ECG devices either at a metropolitan hospital or at a rural clinic. A 3G mobile telephone network allowing ECG delivery with the speed of 1.5 ~ 3.6 Mbps was used between the cloud service and the cardiologist’s mobile phone to realize ubiquitous 12-lead ECG tele-consultation. This cloud ECG service can directly receive various ECG files from ECG devices generating ECGs via TCP/IP based network and allow a clinician to browse ECG reports via Web, which operates independently from the hospital O.S.This cloud computing based 12-lead information system and telemedicine applications in clinical practice are illustrated in Figure Figure Figure To safeguard the ECG data in the cloud, we have designed a security mechanism to prevent them from theft and protect the patients’ privacy, including authentication for the use of Web roles and Worker roles, data encryption during message communications among roles, and ECG file encryption and verification while ECG report are retrieved in storage account and database. As also shown in Figure As shown in Figure An ECG E-learning database is created to collect clinical 12-lead ECG reports which may be used as e-learning materials to enhance clinicians’ diagnostic skills. As the same design schema of ECG visualization and management, a Web role is used to connect clinicians’ queries of ECG learning cases and database via web access.Based on the views of senior cardiologists in Taoyuan Armed Forces General Hospital in Taiwan, a detailed 12-lead ECG report, including the description of the patient’s present symptoms, his/her medical history, and medication records, is crucial for a cardiologist who provides emergency ECG tele-consultation for the consulting clinicians. Among all the relevant medical information, the past and current ECG records are the most important references for clinicians to determine whether the patient is at an immediate risk of dying ,30. In aFigure This 12-lead ECG cloud service enables hospitals to store and manage patients’ ECG records via web access through the internet connection of clinically-used 12-lead ECG instruments. In this way, urban hospitals and rural clinics can easily use the common service for effective inter-hospital ECG tele-consultation without any costly installation of hardware or software on-premise.Using online services via cell phones to deliver or retrieve ECG reports can effectively realize ECG telemedicine. Even when a senior cardiologist is not at the hospital, this cardiologist can timely respond to the consultation request to offer ECG interpretation and decision making support via cell phones and this cloud ECG service.As shown in Figure To evaluate the time needed for a clinician to receive ECG files via his mobile phone from the cloud, 100 trials of data transmission from the cloud to the mobile phone are conducted. To measure the average time to brows an ECG report on a mobile phone, a “trigger” is pre-implemented in a mobile phone. This “trigger” is a procedural SQL code which is automatically invoked by the mobile database, upon the occurrence of a data manipulation event. For example, when a cardiologist issued an ECG report query command, the trigger starts the timing until the requested ECG is successfully delivered to the mobile phone. The average time for browsing an ECG report without data verification in the cloud is approximately 5.65 ± 0.38 secs, but the average time for browsing the file with data verification in the cloud is approximately 6.28 ± 0.13 secs. While these telemedicine applications ensure data security, the mechanisms of data encryption, decryption and verification in the cloud and in the process of being delivered to the mobile devices slightly delay data visualization and thus have a little toll on the time efficiency of the programs.12-lead ECG continuing education is important in clinical practice, especially for clinicians who need to improve ECG interpretation skills. Traditional ECG continuing education courses are provided by experienced cardiologists in urban hospitals; consequently, rural physicians lack opportunities to receive training. This 12-lead ECG telemedicine service enables clinicians across hospitals around the world to collect, to review, and to discuss large-scale ECG reports for the education and training purposes. Clinicians can even perform independent learning ubiquitously from the cloud database.As shown on the panel A of Figure In addition, this cloud telemedicine service can become a valuable asset for advanced research in tele-cardiology, because clinicians from different hospitals can upload or download clinical ECG files with interpretation and request additional consultation.This study implemented a cloud computing based telemedicine application, which can upload 12-lead ECG reading to a cloud service from which they can be visualized on a variety of network connected devices, both mobile and fixed. This cloud application supports a variety of clinically used 12-lead ECG devices, such as Philips XML-ECG, HP compatible SCP-ECG, and Mortara DICOM-ECG by first transcoding the data from a vendor-specific format to an XML format in a public cloud computing platform, Azure.To safeguard data stored in cloud, most cloud providers offer security mechanisms including filtering unauthorized users, auditing abnormal data retrieval actions, and preventing data from theft by hiding actual locations of data in the cloud . In addiIn this study, the cloud Azure functions as a convenient and automatic database backup service, which constantly replicates data from the cloud and resends the replicated data to the on-premise. In this way, users can always retrieve their data even in the event of internet breakdown. The data stored in the Azure database can be synchronically backed up to MS-SQL database on-premise via commonly used ADO.NET technology, which allows data query and data modification between SQL database.To avoid malicious internal data theft in the cloud datacenter, we designed an enhanced security mechanism in the Azure cloud to protect patients’ privacy as shown in Figure To protect patients’ privacy in the cloud, each file is represented by the patient identification code made of a software generating string, which is known only by the hospital. This patient identification code differs from the commonly used personal identification number or the health insurance number.Currently used mobile telecommunication services do not guarantee data security or patients’ privacy, because not every access point in the mobile network can be trusted. To enhance the security of ECG data transmitted via cell phones, the mobile ECG data transmission is performed through a specific network provided by the mobile communication service provider, and this network is used only for data transmission between the off-site physician and the on-site clinicians. In our study, the off-site physician’s cell phone is authenticated as the authorized user in the hospital, who can obtain an IP to gain access to the cloud service. Meanwhile, the delivery and retrieval of ECG data are protected by SSL and the exclusive network service.Before the hospital adopts this cloud 12-lead ECG telemedicine service as recommended by cardiologists, the cost of this cardiac care service should be minimized and the efficiency of data management needs to be maximized at the same time. Traditionally, client/server based computing requires costly installation of software and hardware on-premise. As a contrast, this newly developed cloud computing has the following two advantages: (1) the massive computing resources can be used as the model of pay-as-you-go without long-term commitment, and (2) the cost of data storage and data management is low. Based on Azure’s pricing model, the cost of this cloud service is based on (1) the use of CPU resources, which is charged by USD $0.12 per hour, and (2) the use of database, which is charged by USD $9.99 per GB per month.In general, not only do rural clinics have difficulty affording expensive computerized 12-lead ECG software and ECG telemedicine instruments, it also may not have ITs to maintain computerized data. Meanwhile, urban hospitals do not want to purchase extra ECG telemedicine station to receive specific ECG measured in an ambulance. With the aforementioned two advantages of cloud computing, the realization of 12-lead ECG tele-consultation between rural clinics and urban hospitals and the performance of pre-hospital ECG diagnosis from the ambulance can take place easily and inexpensively. With the use of this 12-lead ECG telemedicine cloud service, tele-consultation and pre-hospital ECG diagnosis can be performed on demand at anytime from anywhere. Importantly, this service is inexpensively charged on the basis of pay-per-use.Despite the progress of mobile computing and the benefit of applying m-health onto cloud computing, the development of 12-lead ECG telemedicine is impeded by heterogeneous vendor-specific ECG data formats where ECG waveform encoding rules are unknown. If the open ECG standards with open ECG waveform encoding rules, such as SCP-ECG, DICOM-ECG, and XML-ECG, can be adopted by most ECG manufactures, ECG interoperability and telemedicine applications can be better realized.The advantage of SCP-ECG is the size of 15 KB ~ 30 KB with compressed ECG waveforms. Therefore, SCP-ECG can be used to deliver ECG without being limited by the bandwidth of mobile phone network, and it can also save the storage charges in the cloud database. Moreover, SCP-ECG is capable of storing serial ECGs, which is useful for clinical ECG diagnosis. The major disadvantage of SCP-ECG is its binary structure, which cannot be easily integrated with text based PHR. On the other hand, DICOM-ECG with the file size of 250 KB and with uncompressed waveforms can be integrated with numerous medical images stored in PACS at the hospitals to enhance the efficiency of medical data management. However, the cloud application on data retrieval from PACS has not been fully realized because most hospitals usually do not allow remote clinicians to retrieve data stored in PACS, and the huge image database in PACS is expensive for cloud applications. As compared with SCP-ECG, XML-ECG with the size of 500 KB and with uncompressed waveforms might not be suitable for ECG delivery via mobile telephone network and for ECG storage in the cloud database. Nevertheless, text based XML format is human readable and can be easily integrated with patients’ PHR. Additionally, as compared with the binary based ECG formats, the cross-platform XML ECG document can be visualized and easily edited via web browsers and cloud application without the limitations of computer O.S. In conclusion, each of the above three open-standard ECG formats has pros and cons when it is used in ECG telemedicine. It is clear that open-standard ECG formats are superior to vender-specific ECG formats. To advance the clinical research of tele-cardiology, we need open ECG data formats, such as binary based SCP-ECG, DICOM-ECG, and text based XML-ECG. In this way, ECG interoperability can be better realized through the conversions among these open data formats.As compared with the traditional ECG tele-consultation, this cloud-based pervasive telemedicine service can realize interoperability across various mobile and fixed devices. It greatly enhances the convenience of ECG interpretation and the efficacy of tele-consultation, as it enables cardiologists to interpret ECG ubiquitously, to access patients’ current and past ECG records across hospitals via centralized cloud database, and to provide pre-hospital diagnosis in time. Apparently, this service advances clinical work and research on 12-lead ECG telemedicine with ECG interoperability, as it establishes an open tele-consultation platform from clinic to person and from hospital to hospital.In this study, we create a new 12-lead ECG telemedicine cloud service enabling ubiquitous delivery of inter-hospital 12-lead ECG reports via cell phones. This developed 12-lead ECG telemedicine cloud service can improve 12-lead ECG telemedicine service quality. This service is mobile, convenient, easy to use, and effective, as it provides ECG tele-consultation via a common platform or offers timely pre-hospital ECG diagnosis based on the ECG records measured and sent from the ambulance. Importantly, this service smartly meets the demand of 12-lead ECG research and tele-consultation in clinical practice. This cloud computing based 12-lead ECG telemedicine system upgrades our previously developed applications, facilitates the collaboration of inter-hospitals, and enhances the efficacy of tele-consultation.ECG, Electrocardiography; SCP-ECG, Standard Communication Protocol–ECG; XML-ECG, Extensible Markup Language based ECG; DICOM-ECG, Digital Imaging and Communications in Medicine based ECG; HIS, Hospital Information System; PACS, Picture Archiving and Communication System; ISO, International Organization for Standardization; FDA, Food and Drug Administration; NEMA, National Electrical Manufactures Association; PHR, Personal Health Record; IIS, Internet Information Server; GSM, Global System for Mobile Communication; SSL, Secure Sockets Layer; HTTPS, Secured Hyper Text Transfer Protocol; SQL, Structured Query Language; TDS, Tabular data stream; URL, Universal Resource Locator; VM, Virtual Machine; PaaS, Platform as a service; SaaS, Software as a service; ED, Emergency Department; EMT, Emergency Medical Technician; EuMHA, European M-Health Alliance; PEM, Personal ECG Monitor; EPI-MEDICS, Enhanced Personal, Intelligent, and Mobile system for Early Detection and Interpretation of Cardiac Syndromes.ECG, Electrocardiography; SCP-ECG, Standard Communication Protocol–ECG; XML-ECG, Extensible Markup Language based ECG; DICOM-ECG, Digital Imaging and Communications in Medicine based ECG; HIS, Hospital Information System; PACS, Picture Archiving and Communication System; ISO, International Organization for Standardization; FDA, Food and Drug Administration; NEMA, National Electrical Manufactures Association; PHR, Personal Health Record; IIS, Internet Information Server; GSM, Global System for Mobile Communication; SSL, Secure Sockets Layer; HTTPS, Secured Hyper Text Transfer Protocol; SQL, Structured Query Language; TDS, Tabular data stream; URL, Universal Resource Locator; VM, Virtual Machine; PaaS, Platform as a service; SaaS, Software as a service; ED, Emergency Department; EMT, Emergency Medical Technician; EuMHA, European M-Health Alliance; PEM, Personal ECG Monitor; EPI-MEDICS, Enhanced Personal, Intelligent, and Mobile system for Early Detection and Interpretation of Cardiac Syndromes.ECG, Electrocardiography; SCP-ECG, Standard Communication Protocol–ECG; XML-ECG, Extensible Markup Language based ECG; DICOM-ECG, Digital Imaging and Communications in Medicine based ECG; HIS, Hospital Information System; PACS, Picture Archiving and Communication System; ISO, International Organization for Standardization; FDA, Food and Drug Administration; NEMA, National Electrical Manufactures Association; PHR, Personal Health Record; IIS, Internet Information Server; GSM, Global System for Mobile Communication; SSL, Secure Sockets Layer; HTTPS, Secured Hyper Text Transfer Protocol; SQL, Structured Query Language; TDS, Tabular data stream; URL, Universal Resource Locator; VM, Virtual Machine; PaaS, Platform as a service; SaaS, Software as a service; ED, Emergency Department; EMT, Emergency Medical Technician; EuMHA, European M-Health Alliance; PEM, Personal ECG Monitor; EPI-MEDICS, Enhanced Personal, Intelligent, and Mobile system for Early Detection and Interpretation of Cardiac Syndromes.ECG, Electrocardiography; SCP-ECG, Standard Communication Protocol–ECG; XML-ECG, Extensible Markup Language based ECG; DICOM-ECG, Digital Imaging and Communications in Medicine based ECG; HIS, Hospital Information System; PACS, Picture Archiving and Communication System; ISO, International Organization for Standardization; FDA, Food and Drug Administration; NEMA, National Electrical Manufactures Association; PHR, Personal Health Record; IIS, Internet Information Server; GSM, Global System for Mobile Communication; SSL, Secure Sockets Layer; HTTPS, Secured Hyper Text Transfer Protocol; SQL, Structured Query Language; TDS, Tabular data stream; URL, Universal Resource Locator; VM, Virtual Machine; PaaS, Platform as a service; SaaS, Software as a service; ED, Emergency Department; EMT, Emergency Medical Technician; EuMHA, European M-Health Alliance; PEM, Personal ECG Monitor; EPI-MEDICS, Enhanced Personal, Intelligent, and Mobile system for Early Detection and Interpretation of Cardiac Syndromes.The authors hereby declare that there were no competing interests.Jui-chien Hsieh, Ph.D. was involved in plan and design of this study. Meng-Wei Hsu was involved in this cloud programming. All authors read and approved the final manuscript.http://jchsieh@saturn.yzu.edu.tw.Dr. Jui-chien Hsieh, the director of Medical Informatics & Telemedicine Lab, works as an assistant professor of the Information Management Department at Yuan Ze University in Taiwan. He obtained his Ph.D. and M.S. degrees from the program of Biomedical Engineering at Rutgers University, New Brunswick, New Jersey, U.S.A.His research interests include medical informatics, computational biology, and pervasive health. Dr. Hsieh’s contact address is the Department of Information Management, Yuan Ze University,135 Yuan Tung Road, Chungli, Taoyuan 320, Taiwan. Dr. Hsieh’s email address is The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6947/12/77/prepub