Studies that compare health-related quality of life (HRQOL) and other patient-reported outcomes in different populations rest on the assumption that the measure has equivalent psychometric properties across groups. This study examined the measurement equivalence (ME) of the 36-item Medical Outcomes Study Short Form Survey (SF-36), a widely-used measure of HRQOL, by sex and race in a population-based Canadian sample.n = 6,539) and males . CFA results revealed that a measurement model with physical and mental health factors provided a good fit to the data. All forms of ME were satisfied for the study groups.SF-36 data were from the Canadian Multicentre Osteoporosis Study, a prospective cohort study that randomly sampled adult men and women from nine sites across Canada. Confirmatory factor analysis (CFA) techniques were used to test hypotheses about four forms of ME, which are based on equality of the factor loadings, variances, covariances, and intercepts. Analyses were conducted for Caucasian and non-Caucasian females (The results suggest that sex and race do not influence the conceptualization of a general measure of HRQOL in the Canadian population. The psychometric properties of health-related quality of life (HRQOL) measures and other patient-reported outcomes are an important consideration when undertaking studies in populations with diverse cultural or racial compositions . The MedThe purpose of this study is to investigate the ME of the SF-36 by sex and race. We focus on its properties in the Canadian population, where normative data for the SF-36 have now been published [Study data were from the Canadian Multicentre Osteoporosis Study (CaMos), an ongoing prospective cohort study undertaken to provide national estimates of the prevalence and incidence of osteoporosis and osteoporosis-related fractures. The study population is composed of non-institutionalized men and women residing within a 50-km radius of nine centers across Canada. These geographic areas encompass approximately 40 percent of the national population and include rural and urban residents. A random sample was taken from each site; details of the data collection methodology and participant characteristics have been reported previously ,7.The sample consisted of all CaMos respondents for whom baseline data were obtained. Data collection occurred between January 1996 and September 1997 by means of an interviewer-administered questionnaire. Informed consent was obtained from participants and ethical approval was provided by the review boards of each participating center and the coordinating center in Montreal.α ranged from 0.76 to 0.93 for the eight domains, with the lowest value for the SF domain [The SF-36 encompasses eight domains: physical functioning (PF), role physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role emotional (RE), and mental health (MH). Each domain is scored on a standardized scale with values ranging from 0 to 100. Higher scores indicate better HRQOL . In prevRace, age in years, and sex were recorded during the interviews. For race, respondents were initially assigned to Caucasian, Asian, and Other categories. These categories were subsequently collapsed into Caucasian and non-Caucasian.The data were described using frequencies and means. Hypotheses about ME were initially tested for the following pairs of study groups: (a) Caucasian and non-Caucasian females, (b) Caucasian and non-Caucasian males, (c) Caucasian males and females, and (d) non-Caucasian males and females. Subsequently, we tested ME hypotheses in age-matched groups, in which non-Caucasians were matched with Caucasians using age (in years) as the matching variable. The latter analyses were conducted to adjust for the potential confounding effects of age.χ2, root mean square error of approximation (RMSEA) and its 90% confidence interval (CI), root mean squared residual (SRMR), comparative fit index (CFI) and non-normed fit index (NNFI). Model modification indices were calculated for the configural invariance model to guide decisions about its specification. These indices measure the predicted change in the χ2 statistic if a parameter is added or removed from the model and re-estimated.Four forms of ME were investigated using confirmatory factor analysis (CFA) ,11,12: cχ2 values for unconstrained and constrained models , was used to test weak, strong, and complete invariance. The difference in CFI values for nested models  was also used to assess invariance because the LR statistic is sensitive to sample size. An absolute value of ΔCFI less than or equal to 0.01 indicates the null hypothesis of invariance should not be rejected, while an absolute value greater than or equal to 0.02 indicates a likely difference in fit between constrained and unconstrained models [A test of weak invariance assesses whether the factor loadings are the same for the groups. When weak invariance is satisfied, the latent variables are being measured in the same way for the groups. A test of strong invariance is used to assess whether the factor loadings and latent variable intercepts  are the same for the groups. If strong invariance does not hold then it is not valid to make group comparisons on the domain means. Complete invariance holds if the factor loadings, intercepts, and error variances are equivalent for the groups . A LR std models . ΔCFI waχ2 statistics, which correct for non-normality using RML were adopted [Robust maximum likelihood was used to estimate model parameters because the data exhibited a multivariate non-normal distribution . Accordi adopted . Analyse adopted .Data for 9,423 CaMos participants Table  were incχ2 statistic, RMSEA, and SRMR (Table The initial configural invariance model Figure  was fit MR Table , this moMR Table , all gooThe hypothesis of weak invariance was tested for this measurement model Table . It was This study investigated the psychometric equivalence of the SF-36 by sex and race in a population-based cohort that represents a large proportion of the Canadian population. These stratification variables were selected because previous research indicates they are associated with differences in the conceptualization of HRQOL and other patient-reported outcomes . All forThis study adopted stringent criteria for establishing ME of the SF-36. While configural and weak invariance are usually tested, Gregorich  notes thEstablishing ME across populations is a prerequisite for conducting valid tests of hypotheses about equality of group means or variances. The findings of this study suggest that sex and race do not influence the conceptualization of a general measure of HRQOL in the Canadian population.BP: Bodily pain; CaMos: Canadian Multicentre Osteoporosis Study; CFA: Confirmatory factor analysis; CFI: Comparative fit index; CI: Confidence interval; GH: General health; HRQOL: Health-related quality of life; ME: Measurement equivalence; MH: Mental health; NNFI: Non-normed fit index; PF: Physical functioning; RE: Role emotional; RMSEA: Root mean square error of approximation; SRMR: Root mean squared residual; RP: Role physical; SB: Satorra-Bentler; SF: Social functioning; SF-36: 36-item Medical Outcomes Study Short Form Survey; VT: Vitality.The authors declare that they have no competing interestsLML planned the study and analyses and drafted the manuscript. BAO conducted the analyses and drafted the manuscript. JA, TT, SD, WH, and WDL participated in planning the study and facilitating data access. All authors read and approved the final manuscript.


While there are many published studies on HIV and functional limitations, there are few in the context of early abuse and its impact on functionality and Quality of Life (QoL) in HIV.The present study focused on HIV in the context of childhood trauma and its impact on functionality and Quality of Life (QoL) by evaluating 85 HIV-positive (48 with childhood trauma and 37 without) and 52 HIV-negative (21 with childhood trauma and 31 without) South African women infected with Clade C HIV. QoL was assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), the Patient's Assessment of Own Functioning Inventory (PAOFI), the Activities of Daily Living (ADL) scale and the Sheehan Disability Scale (SDS). Furthermore, participants were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D) and the Childhood Trauma Questionnaire (CTQ).Subjects had a mean age of 30.1 years. After controlling for age, level of education and CES-D scores, analysis of covariance (ANCOVA) demonstrated significant individual effects of HIV status and childhood trauma on self-reported QoL. No significant interactional effects were evident. Functional limitation was, however, negatively correlated with CD4 lymphocyte count.In assessing QoL in HIV-infected women, we were able to demonstrate the impact of childhood trauma on functional limitations in HIV. South Africa is a country severely affected by the AIDS epidemic, with one of the highest rates of HIV infections in the world . The numA women's vulnerability to HIV/AIDS is largely attributable not only to biological factors but also socio-economic inequalities. Gender-based violence (GBV) is a common phenomenon in countries where the prevalence rate of HIV is also high. GBV has been defined as a multifaceted phenomenon and can include physical, sexual and emotional violence and deprivation or neglect . StudiesQoL can be defined as "the degree to which persons perceive themselves able to function physically, emotionally and socially" . QoL meaAlthough access to and use of more highly active antiretroviral therapies has increased over the past few years, HIV infection and long term use of medication is often accompanied by distressing physical symptoms -20 and sSeveral variables impact on Quality of Life (QoL) in HIV. Social factors such as lower educational levels or lower income have been shown to be significant determinants of HIV-related symptom presentation and biological markers such as CD4 lymphocyte count, viral load and mortality ,27. EmplSeveral studies have revealed that women infected with HIV/AIDS report significantly lower Health Related Quality of Life (HRQoL) than men -34. ThisSeveral studies have investigated the relationship between previous stress, specifically childhood trauma and HIV ,30,39. EImprovements in HIV treatment, greater availability of medication and an increase in lifespan have led to a greater emphasis on QoL in HIV infected individuals. With the greater availability of antiretroviral treatments in the public health sector, individuals with HIV can expect to live longer lives and pursue normal activities of daily living such as recreation, having social relations and procreation. While many studies have been conducted on HIV and functional limitations, there are very few that examined HIV and early abuse and its combined impact on functionality, highlighting the importance of this study. The current study investigated the specific relationship of childhood trauma on QoL in HIV-infected women. The sample consisted of HIV-positive and HIV-negative women, as well as trauma exposed and non-trauma exposed women. We hypothesized, firstly, that both HIV status and a history of childhood trauma would result in poorer QoL in this sample of women and, secondly, that an interactional effect between HIV status and childhood trauma would be evident, resulting in more severe functional limitations.A total of 137 women tested for HIV status were included. 85 were HIV-positive, 48 with childhood trauma and 37 without (from here out referred to as HIV+/trauma + and HIV +/trauma - groups) and 52 were HIV-negative, 21 with childhood trauma and 31 without (from here out referred to as HIV-/trauma + and HIV-/trauma - groups). Although this paper focuses on the QoL and self-perceived functioning of these women, the assessments were part of a larger neurocognitive and neuroimaging study in HIV.th grade level, (III) age between 18 and 65 years, (IV) medically well enough to undergo neuropsychological testing and MRI scanning. Exclusions were: a current or past history of schizophrenia, bipolar disorder or other psychotic disorders as defined by the MINI-plus [Eligibility criteria included: (I) willingness and ability to provide written informed consent, (II) ability to read and write in either English or Afrikaans at 5INI-plus  history INI-plus , signifiThe study was approved by the ethics committee of the University of Stellenbosch, South Africa. All the women included in the present study were tested for HIV status at their local health care facility. HIV status was confirmed by means of Enzyme-linked immunosorbent assay (ELISA), before categorising women into HIV-positive and HIV-negative control groups. The participants were recruited through community health care facilities (VCT sites and HIV units) in and around the Cape metropole of South Africa from 2008-2010. All participants were recruited by a researcher or with the help of doctors and adherence counsellors. Recruitment procedures did not differ between the two groups. All participants who consented were screened for eligibility and childhood trauma exposure either in person at their clinic or telephonically. Those who met initial screening criteria subsequently underwent neuromedical, neuropsychiatric, neurocognitive, and neuroimaging assessments at the University of Stellenbosch. The participants were reimbursed for their travel costs to the University on two separate occasions. The Childhood Trauma Questionnaire (CTQ) was used to elucidate trauma exposure and to categorise HIV-positive and HIV-negative women into the trauma and non trauma exposure groups. For the present study, participants were categorised into the non trauma group if they had a score of 25-40 on the CTQ. Participants were regarded as victims of childhood trauma if they had a score of 41 or higher (moderate-extreme) on the CTQ.A total of 147 women were recruited, of these 137 completed assessments for this study. Reasons for declining participation included HIV stigma, lack of interest and work/time obligations. In general, HIV infected participants had more health-related concerns and were more willing and available to participate than controls, who were also significantly younger.Demographic data comprised age, gender, marital status, ethnicity, years of education and employment status. A comprehensive history was obtained from, and a general physical examination conducted in, all patients. CD4-lymphocyte count and viral load parameters were obtained from blood samples to assess for clinical disease progression.All participants were evaluated for current and lifetime psychiatric disorders using the MINI- International Neuropsychiatric Interview- Plus (MINI-Plus) , a strucChildhood trauma was assessed using the Childhood Trauma Questionnaire Short Form (CTQ-SF), a 28-item self-report inventory that provides valid screening for histories of abuse and neglect. It assesses five types of maltreatment including, emotional, physical, and sexual abuse, and emotional and physical neglect. These five subscales each consist of 5 items with scores ranging from 5 to 25. A summary score assesses overall trauma with scores ranging from 25 to 125. Higher scores indicate higher levels of childhood trauma  . For theThe primary outcome measure was the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). This is a 93-item self-report measure of the degree of enjoyment and satisfaction experienced by participants in various areas of daily functioning. The questionnaire has eight summary scales that reflect major areas of functioning: physical health, emotions, work, household, school hobbies, social relations and general activities. Scores range from 0-100, where higher scores indicate better QoL . Since tOther secondary outcomes measures included the Sheehan Disability Scale (SDS) , the PatThe Patient's Assessment of Own Functioning Inventory (PAOFI) is a 41-item questionnaire in which participants rate themselves on neurobehavioral difficulties in their everyday lives, using a 6-point likert scale . The scale reflects the frequency with which participants experience difficulties with memory, language and communication, sensory-perceptual motor skills, higher level cognitive and intellectual functions, work and recreation, with higher scores indicating more cognitive difficulties .The ADL assesses functioning in several areas: household care, managing finances, groceries, cooking, transportation, using the telephone, home repairs, shopping (non-food), laundry, medication and work. Each area is graded on the level of independence , with greater declines consistent with greater dependence. A participant meets the diagnosis 'ADL- dependant', when he/she has a decline in at least two of the categories .Data were analyzed using the Statistical Package for the Social Sciences (SPSS) for Windows, version 18.0 and Statistica, version 10. Basic statistical analyses were conducted, which included descriptive statistics. Spearman correlation coefficients were calculated for all QoL self-report measures and depression scores (CES-D) and clinical disease markers . Reliability analysis  was conducted on all self-report measures included in the analyses. Analysis of variance (ANOVA) was conducted to assess for group differences in demographic and clinical characteristics. Separate univariate tests of significance, namely Analysis of Covariance (ANCOVA) were computed for the Q-LES-Q and PAOFI. HIV status (HIV-positive and HIV-negative) and childhood trauma status (trauma and no trauma) were included as predictors. Covariates included: age, education, and depression scores. ANCOVA was used to assess both the individual effects and interactional effects of HIV and childhood trauma on self-perceived QoL. Fisher LSD corrections were applied. Finally, confirmatory multiple regression analysis was performed to assess the predictive power of variables of interest on QoL.SD = 7.3) and the average years of education was 10.76 years (SD = 1.2). The majority of HIV-positive women were antiretroviral (ARV) naïve (93.4%). Demographic and clinical characteristics of the sample are provided in Table In 72.9% of the HIV infected women, the year of diagnosis ranged from 1993 to 2009 but the majority were recently diagnosed in 2008, leaving 27.1% with an unknown year of diagnosis. The age of the participants ranged from 18-56 years. The average age was 30.06 , SDS (α = .73), ADL (α = .88), CES-D (α = .95), CTQ (α = .70), and PAOFI (α = .97).Participant characteristics such as age, years of education, marital status, ethnicity, employment status, mean CD4 cell count and viral load are reported in Table p < .001), analyses by abuse type revealed significant differences between trauma+ and trauma- groups on all five subscales (p < .001).In addition to group differences in childhood trauma exposure , PAOFI total score , SDS total score , and the ADL total decline.Spearman correlations were computed to assess the relationship between CD 4 lymphocyte count, viral load and QoL in this sample of women. There was a significant negative correlation between CD4 counts and PAOFI scores, namely lower CD4 counts were associated with greater disability and more neurobehavioural complaints. However, no relationships were found between CD4 counts or viral load and other functional status measures.Means and standard deviations for QoL measures are reported in Table ANCOVA revealed that both HIV status and childhood trauma status significantly predicted the Q-LES-Q mean total score. Of the three covariates included , only age and depression were significant (p < .001). HIV-positive women scored lower on the Q-LES-Q compared to HIV-negative controls, suggesting that HIV is associated with poorer quality of life. Moreover, trauma exposed women scored lower on the Q-LES-Q compared to non-traumatised controls, suggesting that a history of childhood trauma is associated with poorer quality of life. There was no significant interactional effect of HIV status on childhood trauma Table .ANCOVA revealed that both HIV status and childhood trauma status significantly predicted the PAOFI total score. Of the three covariates included, only depression was significant (p < .001). HIV-positive women scored higher on the PAOFI compared to HIV-negative controls, suggesting that HIV is associated with more subjective neurocognitive complaints. Moreover, trauma exposed women scored higher on the PAOFI compared to non-traumatised controls, suggesting that a history of childhood trauma is associated with more subjective neurocognitive complaints. However, there was no interactional effect between HIV status and childhood trauma Table .Finally, as a means for confirmation, a regression analysis was conducted in order to assess the predictive ability of certain variables on subjective QoL in this sample of women. Here again, the Q-LES-Q was used in this analysis. Predictor variables included: age, education, depression, HIV status, and the CTQ total score. The results suggested that the model could explain 31% of the variance in subjective QoL. Age, depression, HIV status, and the CTQ total score significantly predicted QoL in this sample of women, confirming the results from the ANCOVA , compared to HIV-negative women and non-traumatised controls. The results also revealed that both HIV and a history of childhood trauma were associated with more subjective neurocognitive complaints. Finally, the results provided evidence that HIV is associated with more disability and impairments in everyday functioning, compared to uninfected women. These findings suggest that South African women who are newly infected and have histories of childhood trauma may be particularly at risk for poorer QoL and more disability/impairments in everyday functioning. This may be exacerbated by a lack of social support and fear of revealing HIV status or history of trauma.It is notable that the lowest QoL scores (Q-LES-Q) were found for the HIV+/trauma+ group, followed by the HIV-/trauma+ group and next the HIV+/trauma- group. This suggests that a history of childhood abuse has a greater negative impact on life enjoyment and satisfaction, than a positive HIV diagnosis alone, even in women with early disease. A decline in function in the early stages of disease was reported in an earlier South African study, with the majority of the decline in function occurring in WHO stages 1 and 2 . In the per se, and a positive HIV diagnosis may further strengthen depressive symptomatology. Of note, several studies have reported an association between gender-based childhood trauma, in particular childhood sexual abuse, and HIV risk in later life [A similar pattern was found for depressive symptomatology. Highest depression scores were found for the HIV+/trauma+ group, followed by the HIV-/trauma+ and HIV+/trauma- groups. This, too, suggests that experience of childhood trauma may have a greater association with depressive symptoms than HIV ter life -61. Chilter life . Childhoter life . Depresster life . What alter life . Apart fter life ,26, Pachter life . Furtherter life . Since bIn terms of virologic status, there was a significant, negative correlation between CD4 counts and PAOFI scores, namely lower CD4 counts were associated with greater disability and more neurobehavioral complaints. However, no relationships were found between CD4 counts or viral load and other functional status measures. While the absolute CD4 count is more predictive of clinical disease progression than viral load , single A few limitations are worth noting. Firstly, study participants were recruited from health care clinics in one South African province which raises a question about generalisability. However, sample characteristics are largely reflective of the socio-demographic and economic conditions of HIV-infected persons throughout South Africa. In addition, given the variation in years of education among our participants, less literate patients may have encountered more difficulty completing the self-report measures, potentially contributing to response bias. The sample size is relatively small but suitable for the neuroimaging assessments, which was also an aim of the larger study. However, it is worth noting that power is a fundamental issue to consider in conducting an interaction analysis. In light of this, it is plausible that the insignificant interaction effect was due to the relatively small sample size in the present study. Furthermore, CD4 counts and viral loads were only measured at the initial clinical assessment with no serial monitoring. Other limitations include the retrospective assessment of childhood trauma and the fact that this was a cross-sectional study which precludes conclusions to be drawn about causality. Longitudinal investigation of the temporal ordering of depression and QoL deterioration in HIV infected women with early gender-based violence will be key to elucidating these relationships. In addition, HIV-related stigma and disclosure were not taken into account and should be considered in future research.The present study has mentionable strengths. It is, to our knowledge, the first to assess QoL secondary to childhood trauma in predominantly antiretroviral naïve HIV-infected women compared with their HIV-negative counterparts. In addition, the use of four complementary measures of QoL and disability permitted comprehensive cross-sectional assessment of functionality, rarely evident in the literature. In assessing QoL in a sample of HIV-infected women, this study primarily demonstrates that the experience of childhood trauma can have a greater negative impact on QoL and depressive symptomatology than a positive HIV diagnosis alone. These findings underscore the need to screen for childhood trauma, associated psychopathology and functionality in women and men who are HIV positive and to address these issues in management, even in HIV patients who are still physically asymptomatic. Moreover, the study highlights the need for HIV prevention activities such as education in HIV risk behaviors and an increased focus on identification and support for children and youth who have experienced childhood traumas. It also emphasizes the necessity of early recognition and management of mood, anxiety and other stress-related disorders. Finally our findings reflect the need to help improve and maintain QoL in HIV positive and traumatized individuals ,67,68. TSouth African women are disproportionately affected by HIV/AIDS and childhood trauma. In assessing QoL in HIV-infected women, we were able to demonstrate the impact of childhood trauma on functional limitations in HIV. The experience of childhood trauma proved to have a negative impact on QoL and functionality in this cohort of women.The authors declare that they have no competing interests.ZT performed statistical analyses and drafted the manuscript. GS participated in acquisition of data, statistical analyses, its design and coordination and helped to draft the manuscript, MC, SL, CF-N, RT, BS, DS, and SS participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.


Over the past decade, two approaches have been used for multimodality fusion: Software based image registration and hybrid scanners such as PET-CT, PET-MRI, and SPECT-CT among others. While there are intrinsic limitations with both approaches, the main obstacle to the seamless fusion of multiple imaging modalities has been the bulkiness of each individual imager and the conflict of their physical  requirements. To address this challenge, omni-tomography is now unveiled as an emerging direction for biomedical imaging and systems biomedicine.We recently elevated interior tomography from its origin in computed tomography (CT) to a general tomographic principle, and proved its validity for other tomographic modalities including SPECT, MRI, and others. Here we propose “omni-tomography”, a novel concept for the grand fusion of multiple tomographic modalities for simultaneous data acquisition in a region of interest (ROI). Omni-tomography can be instrumental when physiological processes under investigation are multi-dimensional, multi-scale, multi-temporal and multi-parametric. Both preclinical and clinical studies now depend on  The physiome concept was first presented to the International Union of Physiological Sciences (IUPS) in 1993, and later designated as a strategic area by IUPS in 2001 in vivo imaging side. Indeed, the medical imaging field is rapidly trending in this direction. Turning again to x-ray CT as an example, the transition has started from gray-scale to true-color images with energy-sensitive, photon-counting detector technology In the medical imaging field, efforts are being made to link molecular assays with diagnostic imaging in vivo. The multimodality fusion, or multimodal fusion, approach has made significant strides towards meeting this challenge, as demonstrated by the popularity of PET-CT and other hybrid systems The holy grail of biomedical imaging is an integrated system capable of producing tomographic, simultaneous, dynamic observations of highly complex biological phenomena http://www.mediso.de/anyscan-sc.html). As shown in http://www.cmi-marketing.com/7modalities), covering PET, SPECT, CT, fluorescence, luminescence, radioisotopic and radiographic imaging. As shown in Since the advent of diagnostic imaging, there has been a powerful push to combine imaging modalities in a single coordinate system. Modality fusion began with PET-CT which revolutionized medical diagnosis. A PET-CT scanner sequentially acquires CT and PET images in an integrated gantry. As a result, metabolic processes from PET can be co-registered with anatomic information from CT. As such, PET-CT has redefined the fields of oncology, surgical planning, and radiation therapy. There are several examples of contemporary modality fusion devices. Mediso developed the first human PET, SPECT and CT system AnyScan  and relatively slow modalities  are involved. The arguments for, and limitations of the classic modality fusion approach are demonstrated in the latest development of the Advanced Multimodality Image Guided Operating (AMIGO) Suite project, shown in To go beyond the state of the art in modality fusion, it can be imagined that additional tomographic modalities could be added for simultaneous characterization of biomedical properties interior problem” which does not have a unique solution in an unconstrained setting. The interior problem and approximate inversion algorithms were extensively studied in the 1980s and 1990s, and the fact that precise image reconstruction cannot be obtained from purely local data contributed to the long-standing architectures of CT and micro-CT scanners whereby detectors must be wide enough to cover a transaxial slice of a patient or animal. This problem also exists for most other tomographic modalities, which were all developed in the same spirit of CT. Over the past several years, the interior problem has been revisited for theoretically exact image reconstruction over an ROI under rather mild practical conditions such as a known sub-region or a piecewise constant or polynomial ROI model Omni-tomography was inspired and enabled by a recent theoretical breakthrough – interior tomography To overcome the aforementioned physical conflict for grand fusion, here we propose to transform each relevant imaging modality into a slim or compact imaging component for ROI-targeted data acquisition and image reconstruction. This is in contrast to the traditional untruncated acquisition and global reconstruction. These compressed imaging components can then be integrated into a single gantry for concurrent data acquisition and composite interior reconstruction in a unified framework. In this article, top-level omni-tomographic system architectures are first presented. The technical basis for omni-tomography is then illustrated with interior tomographic reconstructions of representative modalities. Finally, major applications of omni-tomography are discussed, along with promising research directions.By our recently proposed interior tomography principle, we have a large flexibility to integrate various imaging modalities when they only target a relatively small ROI. We have systematically analyzed a number of architectures for omni-tomography, and realized that each has advantages and disadvantages. Presently, we focus on a ring-shaped design and a double-magnetic-donut-based design, as two initial examples. In the following, we will emphasize the top-level features instead of the technical details.2. An ultrasound (US) transducer may be incorporated. In a typical setup, appropriate shielding should be implemented. The modality-specific key features are described as follows.The MRI component is feasible, as already demonstrated by the commercial open MRI scanners. As shown in http://www.vizimag.com) to simulate a locally uniform magnetic field between the poles. The targeted local magnetic field strength was set to 0.2 Tesla. The magnetic field may be adjusted by changing ferromagnetic materials and the dimensions of the magnetic blocks or using an alternative technology. The generated magnetic field is shown in 2 with its origin at the iso-center of the main imaging plane of the omni-tomographic scanner. The field uniformity may be improved with technical refinements. The gradient coils of current open MRI scanners We used the Vizimag software (3), a heat exchanger , and a generator . A flat panel  or photon-counting spectroscopic detector array may be used. The source-to-detector distance is approximately 85 cm, consistent with the conventional CT geometry. Interior tomography was originally developed for CT, and has produced excellent results The middle ring of the omni-tomographic system contains x-ray CT and SPECT components. The CT component has a source and a detector array. A typical source configuration includes an x-ray tube  is a good candidate for our system. A CZT detector can potentially detect x-ray and gamma-ray photons simultaneously, which is a future possibility. A converging or pinhole collimator may be used when appropriate. Both types magnify features in an ROI. A multi-pinhole collimator is an option when better sensitivity is desired Two solid-state SPECT cameras are in our design. These cameras are collimated in parallel-beam geometry and arranged orthogonally. The dual-detectors should double the acquisition speed relative to a single detector. There are several commercially available systems  that use CZT detectors. The 16×20 cm3. There are 4 units per detector block, 471 detector blocks per ring, and 20 rings in total. The axial extent is 16 cm. Another part is a coincidence timing or time-of-flight (TOF) analysis circuit, which is commercially available. The 511KeV PET photons are sufficiently energetic to pass through the solid-state CT and SPECT detectors, and reach the PET detector ring. The PET circuitry can be customized for ROI imaging. Prior structural knowledge of the CT and SPECT detectors may be utilized to correct hardware-related attenuation for PET. Positioning the PET ring the furthest away from the MRI system should produce a maximum isolation for the PET detector and electronics from the magnet field. In some existing PET-MRI systems, the PET ring is inside the main magnet ring. For example, the Siemens Biograph PET-MRI system incorporates MRI compatible PET detectors into an MRI system. A number of PET-MRI systems use PET inserts. These designs are fundamentally constrained by the global data acquisition, and cannot reach the same level of hybrid imaging as omni-tomography.The PET detector ring of 120 cm internal diameter consists of LYSO crystals but it could be built out of CZT or other solid-state materials. In LYSO crystal-based systems, the scintillation emission can be detected with avalanche photodiode detectors (APDs). The detector units are 4×4×20 mmUS imaging is cost-effective and widely used. MRI compatible US systems are already commercially available. In our design, US imaging may be easily added, with the transducer and cables shielded Optical imaging is important for molecular and cellular information, often aided by fluorescence and bioluminescence probes. Typically, optical imaging has a penetrating depth limitation. Interestingly, x-rays and gamma rays can induce fluorescence and luminescence signals, which can be quite significant when nanoparticles such as gold nanoparticles and nano-phosphors are used in sufficient concentration. There is substantial space in the CT-SPECT ring where fluorescence and/or luminescence cameras may be placed. For example, we can implement interior x-ray fluorescence CT (XFCT) since x-rays are not strongly diffusive As another omni-tomographic system design in The omni-tomographic architecture is characterized by ROI-oriented data acquisition and quantitative ROI reconstruction using the recently developed interior tomography approach We proved and verified that an interior ROI can be exactly and stably reconstructed via the total variation (TV)/high-order TV (HOT) minimization if the ROI is piecewise constant or polynomial 2. A constant attenuating background −1 was assumed on the standard patient support. An equi-spatial detector array was made of 78 detector elements, each of which was 1.0 mm in length. A full-scan was acquired consisting of 128 equi-angular projections. It can be seen in Inspired by interior tomography originally developed for CT, we proposed interior SPECT, from uniformly attenuated local projection data only through an ROI with a known sub-region in the ROI For omni-tomography, we use a local magnetic background field. This local magnetic field can be either homogeneous or inhomogeneous in principle, but the former is much easier to demonstrate feasibility and gain better performance. As long as the homogeneity of the background magnetic field holds over an ROI, classical MRI (including correction steps) methods As a prerequisite for working with a locally homogeneous main field, a scheme is needed to extract MR signals from an interior ROI. Here we propose a time-varying gradient method. Specifically, we can keep a gradient field zero at an ROI slice and vary the gradient field quickly outside that level. In this way, we can generate MR data only from the ROI, since magnetic iso-regions outside the ROI are incoherently excited and negligible. A similar strategy can be used to collect MR signals from a volume of interest. The key idea is to take advantage of regions with equal magnetic field strength, or “level sets”, in the background field for spatial localization. This approach accommodates a certain degree of field non-homogeneity, and is fundamentally different from the conventional MRI where we start with a globally homogeneous main magnetic field. Thus, our scheme reduces the size (and cost) of the main magnet.xG and yG respectively for spatial encoding. That is, the demodulated signal, assuming the uniformity of the receiver coil, is proportional toIn the following, we will focus on 2D interior MRI for simplicity. With the sole excitation of an ROI, we can use standard linear x and y gradient fields with slopes We used an MRI cardiac image as the phantom. As shown in Although various modalities have different contrast mechanisms, the physiological process to be reconstructed is the same. Consequently, there is strong correlation among these different types of data. To optimize the composite image quality, our unified omni-tomographic approach is based on inter-modality coherence, which is important prior information unavailable in the traditional reconstruction approach when image reconstruction is separately considered for each modality. In light of lowered sampling rate using temporal/spectral image coherence iP, iA, ix, and iy are an under-sampling operator, an imaging system matrix, an image, and data respectively, for the ith modality. Then, we have the matrix modelIn general, the multi-modal imaging model ishttp://www.nlm.nih.gov/research/visible), including MRI T1, T2, proton density, and CT images. The data were under-sampled with a factor of 8. The MR Cartesian k-space data were pseudo-randomly under-sampled along the phase encoding direction In this pilot study, we selected a set of MRI and CT head scans on the same human subject from the NIH Visible Human Project  interior tomography can be accurately applied to most imaging modalities; (2) interior imaging is relevant in a majority of functional imaging studies; and (3) grand fusion will be cost effective when all or many imaging modalities must be used. An immediate advantage of interior imaging can be seen in how the problem of SPECT-MRI must be addressed. SPECT-MRI has two unique issues: interference to the magnetic field caused by a rotating camera head, and the induction of eddy currents in the camera head. Fortunately, interior SPECT will handle both issues simultaneously. With a smaller SPECT camera, the electromagnetic interference will be reduced, and the electromagnetic shielding design will be simplified. At the same time, the Eddy current will diminish in significance with better shielding for smaller detector heads. Additionally, an omni-tomographic scanner can contain a regular tomographic imager to provide a global reference.Being consistent with the omni-tomography concept, we conceive three inter-related lines of grand fusion: (1) an architectural fusion of all or many imaging modalities into a single gantry; (2) a component fusion that packs all or many detectors into a single device or chip; and (3) a methodological fusion for data processing and image reconstruction in a unified framework, as exemplified in the above-described simulation of unified CT-MRI reconstruction.in vivo, significantly improving the sensitivity and specificity of basic research, diagnosis and intervention. This is the major hypothesis that can only be tested with a prototype omni-tomographic system.At the beginning of this article, we mentioned the IUPS Physiome Project. Indeed, omni-tomography offers the best opportunity to observe well-registered tempo-spatial features in an unprecedented fashion. It may help reveal many unknown physiological, pathological, pharmaceutical and interventional interactions Imaging technology development must target important biomedical problems. For example, biotechnology and bioinformatics have been developed to decode:e.g., single mutations, rare mutations, SNPs, copy number changes, indels, genomic instability index, etc.);Genomic/epigenetic signals at the DNA level associated with various forms of genomic signatures ;Protein expressions  and rarely go beyond studies in vitro, yet imaging in vivo should facilitate or guide translation to organ, system, and body levels.Many of these studies are currently limited to cells . One can imagine multiple ways in which this imaging system would be attractive and even indispensable. In the following, let us examine some potential applications of omni-tomography.Fluoroscopy guided cardiac catheterization has been the original clinical standard for identifying stenotic lesions in the coronary arteries. Recently, other diagnostic imaging techniques are being researched and applied for this application, such as CT, MRI, PET, SPECT, intra-coronary ultrasound, and optical coherence tomography. The latest emphasis is to improve understanding of pathobiology and genetics behind coronary artery diseases. There are demands for better diagnostic performance to achieve this goal. For example, the ability to model high risk atherosclerotic lesions would be clinically invaluable. The development of imaging methods and computational models is needed to identify and predict high-risk lesions that may rupture leading to coronary thrombosis and myocardial infarction. If our proposed system could be used to study preclinical infarction models, and predict outcomes, it would be instrumental for research and healthcare.Oncological imaging already uses all the imaging modalities. Lung cancer imaging is a good example. CT defines air-tissue interfaces, detects nodules and tumors, and provides quantitatively accurate information. MRI measures airway functions with hyperpolarized Helium-3. PET and SPECT improve lung cancer diagnosis and staging with radiotracers. Omni-tomography could potentially quantify malignancy without biopsy. Also, a futuristic feature might use omni-tomographic data to create a knowledge depository linked to genetic/epigenetic information and patient histories.The omni-tomographic system may be first developed for drug development in animal models, with aid of multimodality probes. This application is not subject to lengthy FDA approval, and will set a stage for translational research and clinical trials. Engineering probes visible to multiple modalities is a hot topic in the field of bio-nanotechnology, and will have a profound impact on drug development and molecular medicine It is acknowledged that not all imaging tasks can be reduced to interior imaging. To address this inherent ROI limitation, our interiorized omni-tomography approach may be extended for globalized omni-tomography. One idea is to simplify each data acquisition chain for sparse sampling that makes space for interlacing various imaging modalities. In a substantial sense, the above-described omni-tomographic imager is a special case of this more general plan. Further details are beyond the scope of this paper.Omni-tomography is a fresh concept with its interior reconstruction feasibility demonstrated for CT, SPECT, MRI, and other modalities. Although it may be more complex and costly than any conventional scanner, we expect a prototype can be built in the near future to demonstrate its instrumentation feasibility and biomedical utility. We share our excitement towards omni-tomography, and believe that it will find important applications especially for systems biomedicine. We are committed to working along this direction.Video S1Virtual reality video clip showing the ‘ring-shaped’ omni-tomographic system design.(WMV)Click here for additional data file.


Pseudomonas aeruginosa often are hard to treat; inappropriate chemotherapy readily selects multidrug-resistant P. aeruginosa. This organism can be exposed to a wide range of concentrations of antimicrobials during treatment; learning more about the responses of P. aeruginosa to antimicrobials is therefore important. We review here responses of the bacterium P. aeruginosa upon exposure to antimicrobials at levels below the inhibitory concentration. Carbapenems  have been shown to induce the formation of thicker and more robust biofilms, while fluoroquinolones  and aminoglycosides  have been shown to induce biofilm formation. Ciprofloxacin also has been demonstrated to enhance the frequency of mutation to carbapenem resistance. Conversely, although macrolides  typically are not effective against P. aeruginosa because of the pseudomonal outer-membrane impermeability and efflux, macrolides do lead to a reduction in virulence factor production. Similarly, tetracycline is not very effective against this organism, but is known to induce the type-III secretion system and consequently enhance cytotoxicity of P. aeruginosain vivo. Of special note are the effects of antibacterials and disinfectants on pseudomonal efflux systems. Sub-inhibitory concentrations of protein synthesis inhibitors  induce the MexXY multidrug efflux system. This response is known to be mediated by interference with the translation of the leader peptide PA5471.1, with consequent effects on expression of the PA5471 gene product. Additionally, induction of the MexCD-OprJ multidrug efflux system is observed upon exposure to sub-inhibitory concentrations of disinfectants such as chlorhexidine and benzalkonium. This response is known to be dependent upon the AlgU stress response factor. Altogether, these biological responses of P. aeruginosa provide useful clues for the improvement and optimization of chemotherapy in order to appropriately treat pseudomonal infections while minimizing the emergence of resistance.Infections caused by  Pseudomonas aeruginosa, a motile, non-fermenting Gram-negative bacterium, is an opportunistic pathogen implicated in respiratory infections, urinary tract infections, gastrointestinal infections, keratitis, otitis media, and bacteremia in patients with compromised host defenses . These infections often result in significant morbidity and mortality. In the 21st century, when the life expectancy of highly susceptible immunocompromised groups has been extended in most countries, P. aeruginosa plays an increasingly prominent role in hospital infections.P. aeruginosa possesses an intrinsic resistance to many antimicrobials because of the bacterium’s outer-membrane barrier, the presence of multidrug efflux transporters, and endogenous antimicrobial inactivation  or bacteriostatic (growth inhibition) effects  multidrug efflux systems  and extended-spectrum cephalosporins are labile but are weak inducers of ampC  and many other antimicrobial agents, including quinolones, tetracycline, chloramphenicol, and macrolides  two-component regulator ], blocking an important step in peptidoglycan biosynthesis . Penicil of ampC . The mexcrolides . Blockinegulator .ampC gene expression in biofilms  or effectively stable , a process shown to be involved in expression of the PA5471 gene product  The PA5sor MexZ . Very repression .mexXY efflux pump genes, the greatest increases in gene expression levels in response to lethal concentrations of tobramycin involve a number of P. aeruginosa heat shock genes  gene, which is predicted to encode an inner membrane phosphodiesterase. The Arr substrate is cyclic di-guanosine monophosphate (c-di-GMP), a bacterial second messenger that regulates cell surface adhesiveness; c-di-GMP is essential for this induction and contributes to biofilm-specific aminoglycoside resistance , belonging to a family of antimicrobial cyclic oligopeptides, have returned to favor as a last-resort treatment option, although these agents have strong side effects  with high incidence (P. aeruginosa were shown to be very high (≥64 μg/ml), even for susceptible isolates  ranges of 1–2 μg/ml; Owing to the increased prevalence of multidrug-resistant ncidence . Very reL-arabinose, a process that has been seen both in in vitro-selected mutants and in CF isolates; other unknown mechanisms remain under investigation  biosynthetic genes such as the pqsABCDE operon, the phenazine biosynthetic operon, and the arn operon , leading to the down-regulation of genes essential for biofilm development ], a 37-amino-acid, 18-kDa peptide, is encoded by the cathelicidin gene (CAMP) and was originally identified in humans . Sub-inhelopment . Similarelopment .P. aeruginosa cells are intrinsically resistant to macrolides when tested in standard broth culture; for instance, the MIC of erythromycin for P. aeruginosa PAO1 is about 512 μg/mL in Mueller-Hinton broth , a group of semisynthetic tetracycline derivatives containing a glycylamido substitution at position 9 . Tetracy systems . Sub-inh systems .P. aeruginosa increases the expression of type-III secretion system (T3SS) genes exsA and exoS, and the presence of tetracycline increases the cytotoxicity of P. aeruginosa by nearly 4-fold  in hospital or other such environments, thereby compromising the disinfectant’s ability to reduce or eliminate bacterial contamination. Chlorhexidine and benzalkonium are a cationic biguanide and a nitrogen-based quaternary ammonium compound, respectively. These biocides function by affecting the cell membrane, resulting in lysis and the loss of cytoplasmic material  that encode repressors of mexAB-oprM and mexCD-oprJ, respectively  and active efflux. This innate resistance stems from at least five RND efflux pumps, including MexAB-OprM  are known to efficiently kill P. aeruginosa planktonic cells when used properly, but lead to more severe biofilm development upon exposure at sub-inhibitory concentrations. This pattern means that optimization of anti-pseudomonas chemotherapy is critical; in the absence of such optimization, chemotherapy fails to treat the infection and readily selects multidrug-resistant P. aeruginosa. By contrast, macrolides (which are not effective against P. aeruginosa planktonic cells because of the planktonic cells’ intrinsic resistance) provide activity that is antagonistic to QS, thereby reducing pseudomonal virulence. These findings regarding responses to antimicrobial agents suggest a route toward conquering P. aeruginosa infections. For example, macrolides have been shown to augment the in vitro activity of anti-pseudomonas agents against biofilms (The primary biological responses of biofilms .P. aeruginosa because of the presence of low membrane permeability and the RND multidrug efflux pumps. In addition this organism has the ability to adapt to various stresses, including sub-inhibitory antimicrobial exposure, by recruiting antimicrobial resistance mechanisms, notably that of RND efflux systems such as the MexXY system. While many laboratories are currently screening, so far no efflux pump inhibitors have been made available for clinical settings. Screening for novel antibacterial agents, including efflux pump inhibitors, is currently in progress in many laboratories, including our own.We are aware of potential molecular targets for novel anti-pseudomonas agents, including essential genes . Novel cThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Gretchen Birbeck is a Professor of Neurology and Epidemiology at Michigan State University. She has roles in clinical neurology, epidemiology and health services research with a keen interest in the optimal management of neurological conditions in resource-limited settings. Based in southern Africa for half of the year, she has first-hand experience in the management of such conditions and, in particular, of epilepsy, which is one of her main areas of interest Figure .BMC Medicine article collection, Medicine for Global Health. Here we talk to Gretchen about her personal views on the challenges of epilepsy management from a global perspective.Gretchen is also one of the guest editors for the There isn't really one answer to that as care in different resource-limited settings is very dependent upon care-seeking behaviors, the expertise of existing healthcare personnel  and drug availability. Where there are active community-based efforts to bring epilepsy and people with epilepsy "out of the shadows", care-seeking will be primarily limited by patient resources and transport infrastructure. But if people with epilepsy and their families misunderstand the nature of seizures, epilepsy may never be brought to the formal healthcare sector for assessment; people will see traditional healers. Primary healthcare workers need to have adequate training in the basics of diagnosis and treatment with recourse to referral for higher level evaluation in complicated cases. Without trained primary healthcare staff, most patients will not get treated at all. The development of training programs appropriate for a specific resource-limited setting really needs to be guided by physician-level experts who know the healthcare environment, and they also need to know the local culture and the local epidemiology of disease. And even if all of these are in place, if antiepileptic drug supply lines are inefficient or inconsistent, adequate management isn't possible. It is a chain of "necessary but not sufficient" factors and each of these likely vary from country-to-country and possibly even within country in resource-limited settings.Many of the things people with epilepsy struggle with are universal. Women with epilepsy worry about the impact of their condition and their medications on their offspring. Children with epilepsy struggle to be accepted and succeed in school. Adolescents with epilepsy fear rejection from their peers. These are pretty common issues. Medication side effects are problematic whether you have two drugs to choose from or ten. Comorbid and often untreated depression and anxiety degrade quality of life for people with epilepsy wherever you are. Access to medications is more problematic in resource-limited settings - but if you've worked with the employed but uninsured in the US, you know this is NOT a problem unique to "resource-limited settings".What is different are the consequences of the medical, social and economic burden of epilepsy in settings where people are already on the cusp of survival. If you cook over an open flame, have poor seizure control because medication access is intermittent and live where contagion fears are common, a generalized seizure can mean extensive burns and death or a lifetime physical disability. For women with epilepsy, spousal or familial abandonment due to misconceptions regarding epilepsy and in the absence of a social safety net results in vulnerability to sexual predators and marginal survival at best. If educational opportunities are lost due to epilepsy, those with childhood onset face lifetime limitations in their personal capacity even if their epilepsy remits by adulthood.The most impressive outcome for the epilepsy field in the Global Burden 2010 work was the value assigned to having epilepsy in the Disability-Adjusted Life Year (DALY). Previous DALY assignments were made largely by expert groups and their opinions. In the GBD2010 survey of almost 14,000 people from a range of global settings , severe epilepsy was rated as having a DALY of 0.657. This was almost the highest rated disability assessed - even untreated AIDS without antiretroviral medications had a less burdensome DALY at 0.547, remembering that a DALY of 1 essentially means 'dead'.Geographically "where"? There is doubtless room for improvement everywhere. Even in economically developed settings there are substantial healthcare disparities being discovered among people with epilepsy.In resource-limited settings, I think we need to have a dual research agenda - one aimed at improving the lives of people with epilepsy through improved healthcare services and community-oriented efforts to diminish the social and economic impact of the condition. The second area for work should be on the prevention of epilepsy. There are ample data pointing at some of the more common causes of epilepsy in these environments and many of the causes are potentially modifiable, for example, better management of acute cerebral malaria, and better management of antenatal risk factors for perinatal brain injury.Premature mortality risk in people with convulsive epilepsy: long follow-up of a cohort in rural China. Epilepsia 2012. [Epub ahead of print].Ding D, Wang W, Wu J, Yang H, Li S, Dai X, Yang B, Wang T, Yuan C, Ma G, Bell GS, Kwan P, de Boer HM, Hong Z, Sander JW: The social and economic impact of epilepsy in Zambia: a cross-sectional study. Lancet Neurol 2007, 6:39-44.Birbeck G, Chomba E, Atadzhanov M, Mbewe E, Haworth A: Disability weights for vision disorders in Global Burden of Disease study - Authors' reply. Lancet 2013, 381:23-24.Salomon JA, Vos T, Murray CJ: Racial and socioeconomic disparities in epilepsy in the District of Columbia. Epilepsy Res 2013, 103:279-287.Kroner BL, Fahimi M, Kenyon A, Thurman DJ, Gaillard WD: Detecting health disparities among Caucasians and African-Americans with epilepsy. Epilepsy Behav 2011, 20:52-56.Bautista RE, Jain D: Blantyre Malaria Project Epilepsy Study (BMPES) of neurological outcomes in retinopathy-positive paediatric cerebral malaria survivors: a prospective cohort study. Lancet Neurol 2010, 9:1173-1181.Birbeck GL, Molyneux ME, Kaplan PW, Seydel KB, Chimalizeni YF, Kawaza K, Taylor TE: Prevalence of active convulsive epilepsy in sub-Saharan Africa and associated risk factors: cross-sectional and case-control studies. Lancet Neurol 2013, 12:253-263.Ngugi AK, Bottomley C, Kleinschmidt I, Wagner RG, Kakooza-Mwesige A, Ae-Ngibise K, Owusu-Agyei S, Masanja H, Kamuyu G, Odhiambo R, Chengo E, Sander JW, Newton CR; SEEDS group: The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/11/70/prepub


Several observational studies have investigated the association between -607 C/A polymorphism of IL-18 gene and cancer risk; however, the results were inconsistent. Therefore, we performed a meta-analysis to derive a more precise estimation of the association to help us better understand the relationship between -607 C/A polymorphism of IL-18 gene promoter and risk of cancer.A literature search was carried out using PubMed, EMBASE, and China National Knowledge Infrastructure (CNKI) database between January 1966 and February 2013. Fixed-effect and random-effect models were used to estimate the pooled odds ratio (OR) and the corresponding 95% confidence intervals (CIs).-607C/A polymorphism in IL-18 gene promoter and cancer risk was observed . In the subgroup analysis by ethnicity, -607C/A polymorphism significantly increased risk of cancer among Asian population ; however, no significant association was found in Caucasian or African population. The -607C/A polymorphism was associated with a significantly increased risk of nasopharyngeal carcinoma  and esophageal cancer .A total of 22 case-control studies including 4100 cancer cases and 4327 controls contributed to the analysis. Significant association between -607C/A polymorphisms in IL-18 gene promoter is associated with a significantly increased risk of cancer, especially for nasopharyngeal carcinoma and esophageal cancer and in Asian population. More studies with larger sample size, well controlled confounding factors are warranted to validate this association.The present meta-analysis suggests that the  IL-1 family includes ten known members, all of which are characterized by gene structure, predicted three-dimensional fold, processing, receptor, signal transduction pathway and pro-inflammatory properties . IL-18 iComprehensive searches were carried out using PubMed, EMBASE, and China National Knowledge Infrastructure (CNKI) databases between January 1966 and February 2013. There were no restriction of origin and languages. Search terms included: "Interleukin-18" or "IL-18" or "rs1946518" in combination with “polymorphism” or “variant” and ‘‘cancer’’ or ‘‘neoplasm’’ or ‘‘malignancy’’. The reference list of each comparative study and previous reviews were manually examined to ﬁnd additional relevant studies.Studies were selected according to the following inclusion criteria: (i) case-control studies; (ii) investigating the association between IL-18 rs1946518 (C>A) SNP and cancer risk; (iii)cancers diagnosed by histopathology; (iiii) providing detail genotype frequencies. Studies without detail genotype frequencies were excluded. Titles and abstracts of searching results were screened and full text papers were further evaluated to confirm eligibility. Two reviewers (WM and ZXY) independently selected eligible trials. Disagreement between the two reviewers was settled by discussing with the third reviewer(WL).In the present study, the following characteristics were collected by two reviewers (WM and LY) independently using a purpose-designed form: name of first author, publishing time, country where the study was conducted, ethnicity, cancer types, source of control, number of cases and controls, genotype frequency in cases and controls. Different ethnicity descents were categorized as Asian, Caucasian, and African. Cancer types were classified as prostate cancer, esophageal cancer, nasopharyngeal carcinoma, colorectal cancer, breast cancer, cervical cancer, and other cancers . Eligible studies were defined as hospital-based (HB) and population-based (PB) according to the control source.CA/AA versus CC) and recessive (AA versus CC/CA) modes, assuming dominant and recessive effects of the variant A allele, respectively. Subgroup analyses were performed according to (i) cancer types, (ii) ethnicities, (iii) source of control, and (iiii) sample size, to examine the impact of these factors on the association. To test the robustness of association, sensitivity analysis were carried out by excluding studies one-by-one and analyzing the effect size for all of rest studies. Cumulative meta-analysis was also performed to identify the change in trend of reporting risk over time. In cumulative meta-analysis, studies were chronologically ordered by publication year, then the pooled RRs were obtained at the end of each year. To better investigate the possible sources of between-study heterogeneity, a meta-regression analysis was performed [2 test (P<0.05 means deviated from HWE). All analyses were performed using Stata version 11.0 .Chi-square based Q test was used to check the statistical heterogeneity between studies, and the heterogeneity was considered significant when p<0.10 . The fixerformed . Publicaerformed ,18. HWE, homozygous model, and recessive model  ; thus, the fixed-effects model was adopted. Significant associations between shown in .-607C/A polymorphisms in IL-18 gene promoter was significantly associated with an increased risk of nasopharyngeal carcinoma  and esophageal cancer in the heterozygous model and dominant model. No evidence of association was found in any genetic model between-607C/A polymorphisms in IL-18 gene promoter and the risk of prostate cancer, colorectal cancer, breast cancer, cervical cancer, and other cancers; however, no significant association was found in Caucasian and African population , heterozygous model, and dominant model. However, among studies with population-based controls, a significant association was only observed in heterozygous model. When stratifying the sample size, a significant association was observed among studies with small sample size in the heterozygous model and dominant model , but not observed among studies with large sample size in any genetic models. To test the robustness of association, sensitivity analysis was carried out by excluding studies one-by-one and analyzing effect size for all of rest studies. Sensitivity analysis indicated that no significant variation in combined RR by excluding any of the study, confirming the stability of present results. Cumulative meta-analyses were carried out in the heterozygous and dominant genetic models. Between 2006 and 2013, with each accumulation of more studies, the 95% CIs for the pooled ORs became increasingly narrower, indicating that the precision of the estimation was progressively boosted by continually adding more samples for instance, the heterogeneity could only be explained by cancer type(p=0.014), but not ethnicity, sample size, or the source of controls. The potential publication bias of the literatures was evaluated by funnel plot and Egger’s test. No visual publication bias was found in the funnel plot  and the dominant model(AA/CA vs. CC). Under the allelic, homozygous and recessive genetic models, there was no significant association between -607C/A polymorphisms in IL-18 gene promoter and cancer risk. Overall, a significant association exists between -607C/A polymorphisms in IL-18 gene promoter and cancer risk. This finding indicates that the genetic variant in IL-18 gene promoter region may crucially modify the susceptibility of cancers. The C to A substitution at position −607 disrupts a consensus cAMP-responsive element protein-binding site, causing altered transcription factor binding and gene expression [-607C/A polymorphisms in IL-18 gene promoter may modify the susceptibility of cancers though changing the expression of IL-18 gene. The mechanism needs further investigation.The present meta-analysis, which included 4100 cancer cases and 4327 controls from 21 publications with 22 case-control studies, explored the relationship between pression . IL-18 spression ,36-39. HWhen identifying eligible studies by reading full text, the study conducted by Jaiswal PK and colleagues  was excl-607C/A polymorphisms in IL-18 gene promoter and cancer risk among African and Caucasian population, respectively. Insufficient number of patients limited us to detect stable effects in these two populations. Additional studies are warranted to further validate ethnic difference in the effect of -607C/A polymorphisms in IL-18 gene promoter on cancer risk, especially in Africans. During sub-group analyses, we found that the source of controls also affected the association between -607C/A polymorphisms in IL-18 gene promoter and cancer risk. A significant association was observed in hospital-based controls under allelic and dominant genetic models, but not the population-based controls. The reason may be that the hospital-based studies have some inherent selection biases as such controls may just represent a sample of ill-defined reference population and may not be very representative of the study population or the general population. In stratified analysis by cancer site, we found that -607C/A polymorphisms in IL-18 gene promoter was statistically related with an increased risk of esophageal cancer and nasopharyngeal carcinoma. However, no evidence of association was found in any genetic model between-607C/A polymorphisms in IL-18 gene promoter and the risk of prostate cancer, colorectal cancer, breast cancer, cervical cancer, or other cancers. One possible reason is that carcinogenic mechanism underlying the etiology may differ by different tumor sites and that the -607C/A polymorphisms in IL-18 gene promoter may play a different role in different cancers. Futher, the number of studies which investigated the association between -607C/A polymorphisms in IL-18 gene promoter and risk of different types of cancer was too small(≤3), which limited us to detect stable effects on different cancer types. So, more studies focusing on different cancer types are need in the future.In the stratified analysis based on ethnicity, a significant increased risk of cancer was found in Asian population, but not in Caucasian or African population. One probable reason is that different environment they live in and different genetic backgrounds may account for these differences. As we know, different populations carry different genotype and/or allele frequencies of this locus polymorphism and may lead to various degrees of cancer susceptibility . And difThe strength of the present analysis lies in inclusion of 22 studies, reporting data of 4100 cancer cases and 4327 controls. Publication bias, which, due to the tendency of not publishing small studies with null results, was not found in our meta-analysis. Furthermore, our findings were stable and robust in sensitivity analyses. Cumulative meta-analyses showed that, with each accumulation of more studies, the 95% CIs for the pooled ORs became increasingly narrower, indicating that the precision of the estimation was progressively boosted by continually adding more samples. Some limitations might be included in the meta-analysis. Firstly, we did not search for unpublished studies, so only published studies were included in our meta-analysis. Therefore, publication bias may have occurred although no publication bias was indicated from both visualization of the funnel plot and Egger’s test. Secondly, the results were based on unadjusted ORs, while a more precise estimation should take into account the effect of multiple confounders such as age, smoking status, drinking status and environmental factors on the association. Lack of information for data analysis may cause serious confounding bias. Thirdly, the small sample size is the major defect in this meta-analysis. In the stratified analysis by ethnicity and cancer type, the sample size of studies among Caucasians, Africans and among several cancer types is small, which limited us to detect stable effects in these populations and cancer types. Further studies are warranted to further evaluate the association in different ethnicities and cancer types in the future. Additionally, heterogeneity was significant in our meta-analysis, which may attenuate the strength of this study.-607C/A polymorphisms in IL-18 gene promoter is associated with a significantly increased risk of cancer, especially for nasopharyngeal carcinoma and esophageal cancer and in Asian population. More studies with larger sample size, well controlled confounding factors are warranted to further evaluate the association in different ethnicities and different cancer types in the future.In conclusion, the present meta-analysis suggests that the Checklist S1PRISMA checklist.(DOC)Click here for additional data file.


In the context of worldwide increasing antimicrobial resistance, good antimicrobial prescribing in more needed than ever; unfortunately, information available to clinicians often are insufficient to rely on. Biomarkers might provide help for decision-making and improve antibiotic management. The purpose of this expert panel review was to examine currently available literature on the potential role of biomarkers to improve antimicrobial prescribing, by answering three questions: 1) Which are the biomarkers available for this purpose?; 2) What is their potential role in the initiation of antibiotic therapy?; and 3) What is their role in the decision to stop antibiotic therapy? To answer these questions, studies reviewed were limited to recent clinical studies (<15 years), involving a substantial number of patients (>50) and restricted to controlled trials and meta-analyses for answering questions 2 and 3. With regard to the first question concerning routinely available biomarkers, which might be useful for antibiotic management of acute infections, these are currently limited to C-reactive protein (CRP) and procalcitonin (PCT). Other promising biomarkers that may prove useful in the near future but need to undergo more extensive clinical testing include sTREM-1, suPAR, ProADM, and Presepsin. New approaches to biomarkers of infections include point-of-care testing and genomics. Staphylococcus aureus have decreased recently in many European countries since the early 2000s. The principal objective of antibiotic prescribing is to ensure appropriate therapy when needed, while avoiding unnecessary or unduly prolonged therapy. Within this framework, obtaining adequate microbiological information is of paramount importance; unfortunately, such information is lacking in more than 50% of clinical situations where antibiotic therapy is prescribed, even in hospitalized patients. Whereas clinical information is usually sufficient to initiate empiric therapy, they lack accuracy to tailor subsequent therapy and decide on its duration. Physicians’ decisions would be strengthened if they could get help from results of accurate biomarkers reflecting the diagnosis or evolution of the infectious processes. The field of infection-associated biomarkers has grown rapidly within the past few years and is still expanding; few of them, however, have gone through the hurdles of rigorous testing in the clinical arena to allow specifying their role in clinical practice.Good antibiotic prescribing-which often means less prescribing-is of major concern to physicians nowadays, both because of high levels of antibiotic consumption in hospitals, and of the increasing prevalence of antimicrobial resistance, even if rates of methicillin-resistant http://www.institutmauricerapin.org), to provide a state-of-the-art assessment of the currently available biomarkers and their potential role as an aid to the management of antibiotic therapy for acute infections. This report is a summary of their work and conclusions.An 18-member expert panel convened under the auspices of the Maurice Rapin Institute, a not-for-profit independent physicians’ association ?3. When can biomarkers help make decisions to stop antibiotic therapy, and which factors mitigate their clinical use in this process?The panel discussion was based on an analysis of the available literature through December 2012, after making the a priori decision to limit publications considered for answering questions 2 and 3 to clinical studies fulfilling the following criteria:Having enrolled a minimum of a substantial number of patients ;Performed within less than 15 years ;Pertaining to biomarkers available for routine testing in hospitals’ laboratories.The first part of this paper deals with the first question asked to the panel, and the second part deals with questions 2 and 3.Biomarkers from the host can be anatomical, physiological, biochemical (either circulating or membrane-bound), or molecular markers. The latter two categories are detected within a tissue or biological fluid  and their presence or absence, or over- vs. under-expression is the judgment criteria. Of note, more than 90% currently available biomarkers are used only within research program and have not been introduced within the field of clinical biology.prognostic markers, allowing to stratify patients according to their individual risk of having a specified outcome, independently of therapy (or of the lack of therapy), and predictive markers, which allow to predict the potential benefit (efficacy) and/or the risks (toxicity) of a therapy according to the biomarker status (absent/present).Currently accepted definitions for biomarkers have emerged from an expert panel driven by the U.S. National Institute of Health  and fromIn clinical practice, two types of biomarkers can be identified, which follow different development and validation pathways:Those used independently from a specific therapy, as a diagnostic test, or for follow-up or prognosis, which will only be discussed in this paper from the viewpoint of infectious processes;Those used as a companion to treatment, to select patients who may benefit from a specific therapy or used during follow-up of therapy as early predictors of efficacy or of treatment toxicity.Within the field of infectious diseases, a biomarker may be used for identifying a high risk group or predisposing condition, as an aid to identification of the disease, or to direct therapy and stratify patients according to their specific risk factors, and/or as an aid to therapeutic management in order to avoid relapse of infection. An ideal biomarker for infection would combine diagnostic, prognostic, and follow-up of therapy characteristics and should be easily and rapidly available for routine clinical use Table .Biomarkers are expected to provide an assessment of the severity of infection or predict a complicated course to help making a decision on the best therapeutic approach and appropriate site of care . Foremost, they should help the physician to decide about introducing or maintaining antibiotic therapy.Within the recent years, dozens of potential biomarkers of infection have been described, and their analysis is a complex task. Current trends are to use a combination of biomarkers—notably cytokines—with multiplex tests providing simultaneous measurements of several biomarkers from a single biological sample. The major point is to examine whether their clinical performance and utility can be transposed to acute care situations.Receiver Operating Characteristics) curves. Ideally, a biomarker would be both highly sensitive and specific; however, very sensitive tests provide few false-negative results, whereas highly specific ones provide few false-positive results. In emergency medicine practice, more emphasis is usually put on sensitivity , as the primary objective is to rule out the disease, whereas specificity  is emphasized when the objective is to confirm a clinical diagnosis. For quantitative tests, establishing ROC curves allows to select the best compromise between sensitivity and specificity of the test, according to which approach is emphasized. When a low threshold for positivity of the test is selected, its sensitivity increases but its specificity is lowered.The diagnostic performance of biomarkers is usually measured in terms of sensitivity (probability of a positive test among affected patients), specificity (probability of a negative test in unaffected patients), and by likelihood ratios and area under the ROC (Sensitivity and specificity are however defined within a population where the patients’ status (“infected” or “noninfected”) is known, which does not corresponds to the population seen by the physician in his routine clinical practice. The clinical utility of a biomarker is therefore best assessed by measuring its predictive values  and changes between pre- and post-test likelihood ratios in a given clinical context.Two important points, often overlooked in the literature, should be considered when assessing the operating characteristics of biomarkers:The characteristics of the population studied and of the “control group” . For example, it is quite different to analyse a group of patients with a systemic inflammatory response (SIRS) following cardiac surgery  or patients with SIRS within the context of pancreatitis evolving since >1 week, and both the severity and prevalence of infection are higher, with a high clinical impact of diagnosing infected pancreatitis necrosis.Criteria used as the “gold standard” for defining infection (or lack thereof) ,5.Improved measurement methods have largely enhanced the potential for biomarkers to identify patients at high risk of death or a complicated course, whether individual patients or the general population. Nevertheless, persisting difficulties arise when interpreting measurements of biomarker levels, a problem that is compounded by the dissemination of multiplex tests , thus inInterpreting biomarker levels can be problematic because of the variability of measurements resulting from several factors:A lack of standardisation between different methods,Biological factors, including preanalytical variables , analytical , and intra- or interindividual variations; such factors must be assessed and controlled for before providing an interpretation of assays results.In addition, prudent interpretation is mandatory when the known sensitivity or specificity of the biomarker measured is <90% or when the number of subjects studied is small. Moreover, in many studies, a single point in time has been obtained for biomarker measurement, and the lack of repeated measurements does not allow the use of such marker for adapting the duration of therapy.We conclude that standardisation of measurement methods and guideline for the interpretation of biomarker levels in acute infections is mandatory before introducing their measurements into clinical practice. This development phase, including the determination of associated quality criteria , identification of confounding factors and corrective factors must be investigated. Finally, medico-economic evaluation is usually lacking and should be performed before proposing their introduction into routine clinical use.More than a hundred biomarkers have been studied in the serum of septic patients -9. Few oTwo biomarkers fulfill the selection criteria mentioned above and are routinely available: C-Reactive protein (CRP) and procalcitonin (PCT). CRP has been tested in various conditions, but only a few of these studies have focused on its use for optimising antibiotic therapy. A single, prospective, randomized, controlled trial performed in the 1990s in children is available ; other sProcalcitonin has been more widely tested for optimising antibiotic therapy in both children and adults. In adults presenting with community-acquired lower respiratory tract infections (LRTI), several randomized, controlled trials (RCTs) have tested the use of PCT as an aid to the initiation and/or discontinuation of antibiotics and have been summarised in a recent individual patient meta-analysis -17. FourIn view of these studies, the inclusion of PCT measurements within decision algorithms of antibiotic management for specific infections is likely appropriate (refer to Part II). However, further studies are needed in infections which have been insufficiently examined so far  to better define the role of PCT in the antibiotic strategy.Intensive efforts are being made in the search of new diagnostic and prognostic biomarkers, which may be helpful for the management of antibiotic therapy in acute infections. In adults, four of these, the soluble Triggering Receptor Expressed on Myeloid cells-1 (sTREM-1), Soluble urokinase-type Plasminogen receptor (suPAR), proadrenomedullin (ProADM), and Presepsin appear promising. These four biomarkers are of reasonably easy access, have demonstrated acceptable sensitivity and/or specificity, and have been studied in a substantial number of patients to merit further consideration in adults. In children or neonates, too few and heterogeneous studies have been conducted with these new biomarkers to allow recommending any of these for potential introduction in the clinical arena at the present time; further studies are needed in these age groups.A member of the immunoglobulin superfamily, TREM-1 is a surface receptor of mature polymorphonuclear and monocytes cells contributing to innate immunity. Its expression is up-regulated when phagocytic cells are exposed to bacterial and fungal pathogens, but not during other non-septic inflammatory processes. TREM-1 amplifies the inflammatory response by increasing the production of pro-inflammatory cytokines while inhibiting IL-10 synthesis. During up-regulation of the surface receptor TREM-1, the soluble form sTREM-1 increases in biological fluids , where it can be assayed by ELISA using commercial immunoassay kits.Several clinical studies -29 have suPAR (soluble urokinase-type plasminogen activator receptor) or CD87 is a widespread receptor for inflammatory response. Its constitutive expression is limited to some cell types, such as endothelium and leucocytes . Its gene expression is under control of immune and inflammatory effectors, such as bacterial products (LPS), cytokines , and growth factors . During the inflammatory and immune response, the expression of suPAR is up-regulated on epithelial cells, leucocytes (lymphocytes), smooth muscle cells and fibroblasts; it also is up-regulated during tumour growth and metastatic tumour dissemination. Measurements can be obtained from commercial ELISA kits; suPAR measurements also are included in multiplex assays together with cytokines.Plasmodium falciparum malaria [suPAR is of limited value as a diagnostic test. Its clinical value appears associated with its ability to identify patients at risk Table  and migh malaria . suPAR a malaria -35, but CALC gene family, acting as a mediator of cell proliferation, hormone regulation and embryogenesis. ADM is produced by endothelial cells, where it induces vasodilatation and maintains homeostasis. Pro-hormone fragments (pro-ADM) are more stable than the complete peptide and their levels can be measured in biological fluids by automated methods using the TRACE (Time-Resolved Amplified Cryptate Emission) method after immuno-capture. ProADM secretion increases during the immune response to viral or bacterial products in relation to the importance of the stimulation.Adrenomedullin (ADM) is a 52-amino acids peptide, and a marker of the Pro-ADM is a biomarker of prognostic value Table . Added tPresepsin (formerly CD14), is a glycoprotein receptor occurring at the surface of monocytes/macrophages. CD14 binds to lipopolysaccharide (LPS) complexes and LPS binding protein (LPB), which triggers the activation of toll-like receptor 4 (TLR4), resulting in the production of numerous pro-inflammatory cytokines. Following Presepsin activation by bacterial products, the CD14 complex is released in the circulation as its soluble form (sCD14), which in turn is cleaved by a plasma protease to generate a sCD14 fragment called sCD14-subtype (sCD14-ST). Plasma levels of sCD14 can be measured using an automated chemo-luminescent assay .The most recent of the 4 biomarkers analysed, presepsin is both sensitive and specific and might be helpful to differentiate SIRS from sepsis associated with a bacterial infection -43 Tabl.We conclude that information gathered so far on these four biomarkers— sTREM-1, suPAR, proADM, and presepsin—suggest that they may have a role in future clinical developments, whether as diagnostic tests, or for stratification of patients by type of insult or severity, or to assess the therapeutic activity and efficacy and during follow-up of patients. To date, there are too few studies of the impact of these new biomarkers on the antibiotic management of patients and larger studies are required in this field.Micro-RNAs (miR) are recently discovered potential candidate biomarkers. miR are small molecules (about 20 nucleotides) present in eucaryotic cells, which act as biologic regulators by modulating posttranscriptional regulation. They are ubiquitous and abound in the lung, liver, and kidney. After binding the corresponding smRNA sequence, they regulate gene expression by a repressor effect or by altering its target. A mi-RNA can bind to several smRNA. Their expression can be measured by RT-PCR and quantitative PCR.http://www.miR2Disease.org/), such as various types of cancers (“oncomir”), cardiomyopathy, or central nervous system diseases. miR also have been implicated in defense mechanisms against viral infections, where they may contribute to controlling viral infections. Integrated in the viral genome, a number of miR can regulate viral mRNA such as Epstein-Barr, cytomegalovirus, herpes, hepatitis C virus as well as the host’s RNA. Among bacterial infections, a role for miR has been suggested in M. tuberculosis infections by modulating the monocytes/macrophages interactions with the bacterium or regulating the expression of resistance gene or virulence factors. Modulation of the inflammatory response to infection with H. pylori also has been attributed to miR [Their multiple potential roles in positive or negative regulation of gene expression have been uncovered since the early 2000s, and dysfunctions of miR expression have been implicated in numerous human diseases  0.523-0.697) and 0.79 (95% CI 0.719-0.861) but reached 0.953 (95% CI 0.923-0.983) when combining the seven parameters .Thus, miR might be potential candidates as early diagnostic and/or prognostic markers in sepsis. Numerous studies are needed with these new markers to better understand their role in biochemical and immunobiology processes in humans before their use for diagnostic and stratification of patients, prognostication, or therapeutic decision can be considered.Two main technological advances are in progress, including 1) the development of point-of-care testing, with the availability of miniaturised and portable machines, allowing rapid testing at the bedside, even for sophisticated measurements , which have been confined to specialised laboratories up to recently; and 2) the development of new methods, including the analysis of gene expression (genomics), of ARN activation (transcriptome), of production of proteins (proteomics), of lipids (lipidomics), or of metabolites (metabolomics). It is likely that these progresses will allow identifying new markers for better identification of patients, stratification of prognosis, and targeting therapy.ADM and pro-ADM: Adrenomedullin and pro-adrenomedullin; aPTT: Activated partial thromboplastin time; AUROC: Area under the receiver operating curve; BAL: Broncho-alveolar lavage; BM: Bacterial meningitis; CAP: Community-acquired pneumonia; CCR3: Chemokine (C-C motif) receptor 3; CRP: C-Reactive protein; CRTH2: Chemoattractant receptor-homologous molecule expressed on Th2; CSF: Cerebrospinal fluid; DNI: Differential count of immature PMN; ELISA: Enzyme-linked immuno-sorbent assay; G-CSF: Granulocyte colony-stimulating factor; HLA: Human leukocyte antigens; HMGB1: High mobility group protein B1; ICAM 1: Intercellular adhesion molecule 1; ICU: Intensive care unit; IFN-γ: Interferon-gamma; IL: Interleukin; IP-10: Interferon gamma-induced protein 10; LBP: Lipopolysaccharide binding protein; LPS: Lipopolysaccharide; LRTI: Lower respiratory tract infection; MC: Monocytes; MCP-1: Monocyte chemotactic protein-1; MIF: Macrophage migration inhibitory factor; MR-proADM: Mid-regional proadrenomedullin; NIH: U.S. National institute of health; NPV: Negative predictive value; PAI 1: Plasminogen activator inhibitor 1; PCT: Procalcitonin; PMN: Polymorphonuclear neutrophil; PPV: Positive predictive value; ProADM: Proadrenomedullin; ProANP: Proatrial natriuretic peptide; ROC: Receiver operating characteristic curve; ROS: Reactive oxygen species; SAA: Serum amyloid A protein; sCD14-ST: Soluble CD14 subtype; sELAM: Soluble endothelial leucocyte adhesion molecule-1; sFlt-1: Soluble fms-like tyrosine kinase-1 or sVEGFR1; sPLA2: Soluble phospholipase A2; sTREM-1: Soluble triggering receptor expressed on myeloid cells-1; suPAR: Soluble urokinase-type plasminogen activator receptor; sVEGFR1: Vascular endothelial growth factor receptor 1 soluble; TNF: Tumor necrosis factor; TLR-2 or 4: Toll-like receptor 2 or 4; TRACE: Time-resolved amplified cryptate emission; uMIF: Urinary macrophage migration inhibitory factor; uMIF/cr: uMIF/Creatinine; VCAM-1: Vascular cell adhesion molecule 1; VEGF: Vascular endothelial growth factor.Meetings of the expert panel group were supported in part by an unrestricted grant from Thermo-Fisher to the Maurice Rapin Institute. This company had no role in the work of the panel, or in the drafting, revision or final approval of the manuscript.A-MD declared participation as an investigator to the UTAPE study, sponsored by Thermo-Fisher, and her institution received funding for analytic studies of CT-proAVP using Kryptor.CB-B was an investigator in the Prorata trial.MC holds a patent for the MENINGITEST in Europe (European patent EP1977244), USA and Canada, and has a patent pending for the REFLUTEST (WO2010/109089).C-EL was an investigator for the Prorata trial, and received lectures honoraria from Thermo-Fisher and Biomérieux.NR is coordinating the UTAPE study on biomarkers in COPD exacerbations seen in the emergency department, sponsored by Thermo-Fischer.P-EC received speaking fees from Thermo-Fisher.Y-EC received research funding from Thermo-Fisher, Roche Diagnosis and Nephrotek.CG-LG received funding by Thermo-Fisher for attending a scientific meeting.JP received speaking fees for giving lectures within symposia organized by ThermoFischer.J-PB, P-EC, RG, SL, BM, J-PQ, FP, YP, and J-PS have declared no competing interest in relation to the subject of this manuscript.All panel members contributed to the panel discussions and analyses. Each panel members contributed to drafting different sections of the manuscript: A-MD, YP, FP, SR, and BM drafted part I; J-PQ, SL, Y-EC, J-PS, CG-L, MC, and RG drafted part II; and C-EL, NR, J-PB, JP, and CB-B drafted part III. A-MD, J-PQ, C-EL, RG, BM, MC, and CB-B extensively reviewed the consolidated manuscript and all authors approved its final version.List of biomarkers tested in the field of infectious diseases.Click here for file