Meta-Analysis of Diagnostic Accuracy Studies With Multiple Thresholds: Comparison of Approaches in a Simulation Study.

The development of methods for the meta-analysis of diagnostic test accuracy (DTA) studies is still an active area of research. While methods for the standard case where each study reports a single pair of sensitivity and specificity are nearly routinely applied nowadays, methods to meta-analyze receiver operating characteristic (ROC) curves are not widely used. This situation is more complex, as each primary DTA study may report on several pairs of sensitivity and specificity, each corresponding to a different threshold. In a case study published earlier, we applied a number of methods for meta-analyzing DTA studies with multiple thresholds to a real-world data example (Zapf et al., Biometrical Journal. 2021; 63(4): 699-711). To date, no simulation study exists that systematically compares different approaches with respect to their performance in various scenarios when the truth is known. In this article, we aim to fill this gap and present the results of a simulation study that compares three frequentist approaches for the meta-analysis of ROC curves. We performed a systematic simulation study, motivated by an example from medical research. In the simulations, all three approaches worked partially well. The approach by Hoyer and colleagues was slightly superior in most scenarios and is recommended in practice.

Referring physicians' intention to use hospital report cards for hospital referral purposes in the presence or absence of patient-reported outcomes: a randomized trial.

PURPOSE: This study aims to determine the intention to use hospital report cards (HRCs) for hospital referral purposes in the presence or absence of patient-reported outcomes (PROs) as well as to explore the relevance of publicly available hospital performance information from the perspective of referring physicians. METHODS: We identified the most relevant information for hospital referral purposes based on a literature review and qualitative research. Primary survey data were collected (May-June 2021) on a sample of 591 referring orthopedists in Germany and analyzed using structural equation modeling. Participating orthopedists were recruited using a sequential mixed-mode strategy and randomly allocated to work with HRCs in the presence (intervention) or absence (control) of PROs. RESULTS: Overall, 420 orthopedists (mean age 53.48, SD 8.04) were included in the analysis. The presence of PROs on HRCs was not associated with an increased intention to use HRCs (p = 0.316). Performance expectancy was shown to be the most important determinant for using HRCs (path coefficient: 0.387, p < .001). However, referring physicians have doubts as to whether HRCs can help them. We identified "complication rate" and "the number of cases treated" as most important for the hospital referral decision making; PROs were rated slightly less important. CONCLUSIONS: This study underpins the purpose of HRCs, namely to support referring physicians in searching for a hospital. Nevertheless, only a minority would support the use of HRCs for the next hospital search in its current form. We showed that presenting relevant information on HRCs did not increase their use intention.

The elicitation of patient and physician preferences for calculating consumer-based composite measures on hospital report cards: results of two discrete choice experiments.

PURPOSE: The calculation of aggregated composite measures is a widely used strategy to reduce the amount of data on hospital report cards. Therefore, this study aims to elicit and compare preferences of both patients as well as referring physicians regarding publicly available hospital quality information METHODS: Based on systematic literature reviews as well as qualitative analysis, two discrete choice experiments (DCEs) were applied to elicit patients' and referring physicians' preferences. The DCEs were conducted using a fractional factorial design. Statistical data analysis was performed using multinomial logit models RESULTS: Apart from five identical attributes, one specific attribute was identified for each study group, respectively. Overall, 322 patients (mean age 68.99) and 187 referring physicians (mean age 53.60) were included. Our models displayed significant coefficients for all attributes (p < 0.001 each). Among patients, "Postoperative complication rate" (20.6%; level range of 1.164) was rated highest, followed by "Mobility at hospital discharge" (19.9%; level range of 1.127), and ''The number of cases treated" (18.5%; level range of 1.045). In contrast, referring physicians valued most the ''One-year revision surgery rate'' (30.4%; level range of 1.989), followed by "The number of cases treated" (21.0%; level range of 1.372), and "Postoperative complication rate" (17.2%; level range of 1.123) CONCLUSION: We determined considerable differences between both study groups when calculating the relative value of publicly available hospital quality information. This may have an impact when calculating aggregated composite measures based on consumer-based weighting.

Suitability and user acceptance of the eResearch system "Prospective Monitoring and Management App (PIA)"-The example of an epidemiological study on infectious diseases.

BACKGROUND: The eResearch system "Prospective Monitoring and Management App (PIA)" allows researchers to implement questionnaires on any topic and to manage biosamples. Currently, we use PIA in the longitudinal study ZIFCO (Integrated DZIF Infection Cohort within the German National Cohort) in Hannover (Germany) to investigate e.g. associations of risk factors and infectious diseases. Our aim was to assess user acceptance and compliance to determine suitability of PIA for epidemiological research on transient infectious diseases. METHODS: ZIFCO participants used PIA to answer weekly questionnaires on health status and report spontaneous onset of symptoms. In case of symptoms of a respiratory infection, the app requested participants to self-sample a nasal swab for viral analysis. To assess user acceptance, we implemented the System Usability Scale (SUS) and fitted a linear regression model on the resulting score. For investigation of compliance with submitting the weekly health questionnaires, we used a logistic regression model with binomial response. RESULTS: We analyzed data of 313 participants (median age 52.5 years, 52.4% women). An average SUS of 72.0 reveals good acceptance of PIA. Participants with a higher technology readiness score at the beginning of study participation also reported higher user acceptance. Overall compliance with submitting the weekly health questionnaires showed a median of 55.7%. Being female, of younger age and being enrolled for a longer time decreased the odds to respond. However, women over 60 had a higher chance to respond than women under 60, while men under 40 had the highest chance to respond. Compliance with nasal swab self-sampling was 77.2%. DISCUSSION: Our findings show that PIA is suitable for the use in epidemiologic studies with regular short questionnaires. Still, we will focus on user engagement and gamification for the further development of PIA to help incentivize regular and long-term participation.

A semiparametric approach for meta-analysis of diagnostic accuracy studies with multiple cut-offs.

The accuracy of a diagnostic test is often expressed using a pair of measures: sensitivity (proportion of test positives among all individuals with target condition) and specificity (proportion of test negatives among all individuals without target condition). If the outcome of a diagnostic test is binary, results from different studies can easily be summarized in a meta-analysis. However, if the diagnostic test is based on a discrete or continuous measure (e.g., a biomarker), several cut-offs within one study as well as among different studies are published. Instead of taking all information of the cut-offs into account in the meta-analysis, a single cut-off per study is often selected arbitrarily for the analysis, even though there are statistical methods for the incorporation of several cut-offs. For these methods, distributional assumptions have to be met and/or the models may not converge when specific data structures occur. We propose a semiparametric approach to overcome both problems. Our simulation study shows that the diagnostic accuracy is under-estimated, although this underestimation in sensitivity and specificity is relatively small. The comparative approach of Steinhauser et al. is better in terms of coverage probability, but may lead to convergence problems. In addition to the simulation results, we illustrate the application of the semiparametric approach using a published meta-analysis for a diagnostic test differentiating between bacterial and viral meningitis in children.

The use intention of hospital report cards among patients in the presence or absence of patient-reported outcomes.

BACKGROUND: So far, the adoption of hospital report cards (HRCs) falls short of expectations. One promising strategy is to modify the content of HRCs by presenting patient-reported outcomes (PROs). OBJECTIVE: To identify the key determinants influencing patients to use HRCs for hospital decision making and determine the effect of presenting PROs on HRCs on their use intention. METHODS: Primary survey data were collected (5/6-2021) on a sample of 2000 randomly selected insurees from a German statutory health insurance who have undergone elective hip arthroplasty surgery. RESULTS: Overall, 447 participants (mean age 66.56) completed the survey and were included in the analysis. Respondents rated "PROs" as most important for the hospital choice followed by "Mobility at hospital discharge" and "Confirmed diagnosis rate". Patients generally perceive HRCs to be a good idea that makes searching for a hospital more interesting. We identified attitude and social influence as the most important determinants for using HRCs (p<.001 each). The presence of PROs on HRCs was not associated with an increased intention to use HRCs neither in our descriptive analysis (p=.593), nor in our research model (p=.763). CONCLUSIONS: Patients value PROs to be an important information for choosing a hospital. Nevertheless, health policy makers should note that presenting PROs on HRCs as a single approach is not likely to increase the use of HRCs.

Meta-analysis of diagnostic accuracy studies with multiple thresholds: Comparison of different approaches.

Methods for standard meta-analysis of diagnostic test accuracy studies are well established and understood. For the more complex case in which studies report test accuracy across multiple thresholds, several approaches have recently been proposed. These are based on similar ideas, but make different assumptions. In this article, we apply four different approaches to data from a recent systematic review in the area of nephrology and compare the results. The four approaches use: a linear mixed effects model, a Bayesian multinomial random effects model, a time-to-event model and a nonparametric model, respectively. In the case study data, the accuracy of neutrophil gelatinase-associated lipocalin for the diagnosis of acute kidney injury was assessed in different scenarios, with sensitivity and specificity estimates available for three thresholds in each primary study. All approaches led to plausible and mostly similar summary results. However, we found considerable differences in results for some scenarios, for example, differences in the area under the receiver operating characteristic curve (AUC) of up to 0.13. The Bayesian approach tended to lead to the highest values of the AUC, and the nonparametric approach tended to produce the lowest values across the different scenarios. Though we recommend using these approaches, our findings motivate the need for a simulation study to explore optimal choice of method in various scenarios.

Case-control study on factors associated with a decreased milk yield and a depressed health status of dairy herds in northern Germany.

BACKGROUND: In the past years, it became apparent that health status and performance differ considerably within dairy farms in Northern Germany. In order to obtain clues with respect to possible causes of these differences, a case-control study was performed. Case farms, which showed signs of health and performance problems, and control farms, which had none of these signs, were compared. Risk factors from different areas such as health management, housing, hygiene and nutrition were investigated as these are known to be highly influential. The aim of this study was to identify major factors within these areas that have the strongest association with health and performance problems of dairy herds in Northern Germany. RESULTS: In the final model, a lower energy density in the roughage fraction of the diet, more pens with dirty lying areas and a low ratio of cows per watering spaces were associated with a higher risk for herd health problems. Moreover, case farms were affected by infections with intestinal parasites, lungworms, liver flukes and Johne's Disease numerically more often than control farms. Case farms more often had pens with raised cubicles compared to the deep bedded stalls or straw yards found in control farms. In general, the hygiene of the floors and beddings was worse in case farms. Concerning nutrition, the microbiological and sensory quality of the provided silages was often insufficient, even in control farms. Less roughage was provided to early lactating cows and the feed was pushed to the feeding fence less frequently in case farms than in control farms. CONCLUSIONS: The results show that milk yield and health status were associated with various factors from different areas stressing the importance of all aspects of management for good animal health and performance. Moreover, this study confirmed well-known risk factors for health problems and performance losses. These should better be taken heed of in herd health management.

[Ethical consideration of studies involving human subjects outside the regulatory framework: not mandatory, but of high relevance]. / Ethische Bewertung von Studien am Menschen außerhalb des regulatorischen Rahmens: nicht bindend, aber von großer Wichtigkeit.

According to the Declaration of Helsinki, ethics committees are obliged to evaluate any type of medical research involving human subjects in order to ensure an objective view on ethical considerations. This does not only mean considering whether the risks to study participants are ethically justifiable or not, but also checking whether the scientific quality of a study is sufficient. However, the role of ethics committees differs depending on whether the study to be considered is, for example, an approval study according to the German Medicines Act (AMG) or whether the study is outside the regulatory framework. For these so-called unregulated studies it is not always mandatory to obtain approval from an ethics committee or an institutional review board.In this paper, we first explain the term "unregulated studies" in detail and elaborate for which types of unregulated studies an application for ethical approval is required before we deal with the application for ethical approval as such and in particular with the study protocol as one of its major components. Registry studies, postmarketing surveillance studies, analyses of secondary data, surveys, intervention, and prognostic studies serve as examples to illustrate the broad range of unregulated studies.Finally, we discuss crucial aspects of the role of ethics committees with respect to the consideration of unregulated studies. In our conclusion, we point out the necessity of having ethics committees at each university in Germany that are also responsible for unregulated studies. In addition, the German legislature should define a stricter regulation such that unregulated studies also have to adhere to the vote of the ethics committee.

Antimicrobial susceptibility testing of Arcobacter butzleri: development and application of a new protocol for broth microdilution.

Objectives: To develop a standard reference broth microdilution method for antimicrobial susceptibility testing (AST) of Arcobacter butzleri. The protocol was subsequently applied to a collection of A. butzleri isolates from different sources. Methods: Broth microdilution susceptibility testing was performed on eight A. butzleri isolates in three media: non-supplemented CAMHB, CAMHB + 2% FBS and CAMHB + 5% FBS. The MIC values were read after 24 and 48 h of incubation at 35 ±âŸ2 °C in ambient air. A logistic regression model was used to determine the combination of medium and incubation time yielding the most homogeneous results. Subsequently, the protocol was applied to 65 A. butzleri isolates to determine their MICs of 31 antimicrobial agents. Results: The statistical analysis revealed that the most homogeneous MIC values were obtained with CAMHB + 5% FBS and reading of MIC values after 24 h of incubation. The standardized method was successful for AST of all 65 A. butzleri isolates. MIC values were distributed unimodally for most antimicrobial agents. However, one field isolate showed elevated MIC values of gentamicin, streptomycin, tetracycline and trimethoprim/sulfamethoxazole. Conclusions: This study presents a new protocol for AST of A. butzleri by broth microdilution and shows the distribution of MIC values of 31 antimicrobial agents for a collection of A. butzleri isolates from different origins.

Antibiotic Resistances in Livestock: A Comparative Approach to Identify an Appropriate Regression Model for Count Data.

Antimicrobial resistance in livestock is a matter of general concern. To develop hygiene measures and methods for resistance prevention and control, epidemiological studies on a population level are needed to detect factors associated with antimicrobial resistance in livestock holdings. In general, regression models are used to describe these relationships between environmental factors and resistance outcome. Besides the study design, the correlation structures of the different outcomes of antibiotic resistance and structural zero measurements on the resistance outcome as well as on the exposure side are challenges for the epidemiological model building process. The use of appropriate regression models that acknowledge these complexities is essential to assure valid epidemiological interpretations. The aims of this paper are (i) to explain the model building process comparing several competing models for count data (negative binomial model, quasi-Poisson model, zero-inflated model, and hurdle model) and (ii) to compare these models using data from a cross-sectional study on antibiotic resistance in animal husbandry. These goals are essential to evaluate which model is most suitable to identify potential prevention measures. The dataset used as an example in our analyses was generated initially to study the prevalence and associated factors for the appearance of cefotaxime-resistant Escherichia coli in 48 German fattening pig farms. For each farm, the outcome was the count of samples with resistant bacteria. There was almost no overdispersion and only moderate evidence of excess zeros in the data. Our analyses show that it is essential to evaluate regression models in studies analyzing the relationship between environmental factors and antibiotic resistances in livestock. After model comparison based on evaluation of model predictions, Akaike information criterion, and Pearson residuals, here the hurdle model was judged to be the most appropriate model.

The Benefit of Baseline Staging-Risk Assessment of Distant Breast Cancer Metastases by Tumor Stage.

BACKGROUND: Despite recommendations of international societies, use of baseline staging in breast cancer varies considerably. We retrospectively analyzed the prevalence of metastases in each pTN stage to estimate the benefit of staging. PATIENTS AND METHODS: The prevalence of metastases at primary diagnosis (M1) and in the first year after diagnosis (M112) was determined in 2,906 patients. RESULTS: The prevalence of M1 was 0.95% [95% confidence interval (CI)=0.53-1.70%] in pT1pN0, 2.17% (95% CI=1.00-4.64) in pT1pN1 and 1.53% (95% CI=0.78-2.99%) in pT2pN0. The prevalence of M112 was 2.17% (95% CI=1.47-3.18%) in pT1pN0 and 3.25% in pathological stage IIA (upper confidence bound 5.14%). In pT2pN1 the prevalence of M1 and M112 was 3.49% (95% CI=1.96-6.14%) and 6.35% (95% CI=4.15-9.60%), respectively. Results for stage pT3pN0 and higher were inconclusive. CONCLUSION: Baseline staging can be safely abandoned in pathological stage I and IIA. Individual decisions should be made for pT2pN1. Staging is recommended in stages of pT3pN0 or higher.

Cefotaxime-resistant Escherichia coli in broiler farms-A cross-sectional investigation in Germany.

In this investigation the farm prevalence of cefotaxime-resistant Escherichia coli (CREC) in German broiler farms was evaluated. In total, 59 flocks on 34 broiler farms were sampled in four agricultural regions of Germany. Per broiler flock, three faecal samples, a pair of boot swabs and one dust sample were taken and examined for the presence of CREC. After pre-enrichment of sample material in Luria-Bertani-broth, the broth was streaked onto MacConkey agar containing 1mg/l cefotaxime (CTX). CREC isolates were detected in at least one sample from each flock resulting in a farm prevalence of 100%. The proportion of positive samples was high in all three sample types. Of 177 collective faecal samples 81.9% were positive, of 59 boot swabs and 59 dust samples 79.7% and 62.7% were positive. In conclusion, the prevalence of broiler farms with cefotaxime-resistant E. coli in Germany is very high. We suggest that the analysis of collective faecal samples is sufficient to determine the CREC farm status. In addition to other studies our study supports the finding that cefotaxime resistance is a good proxy for the presence of ESBL- or plasmidic AmpC-beta-lactamases.

Recommendation for a Standardised Method of Broth Microdilution Susceptibility Testing for Porcine Bordetella bronchiseptica.

The objective was to establish and standardise a broth microdilution susceptibility testing method for porcine Bordetella (B.) bronchiseptica. B. bronchiseptica isolates from different geographical regions and farms were genotyped by macrorestriction analysis and subsequent pulsed-field gel electrophoresis. One reference and one type strain plus two field isolates of B. bronchiseptica were chosen to analyse growth curves in four different media: cation-adjusted Mueller-Hinton broth (CAMHB) with and without 2% lysed horse blood, Brain-Heart-Infusion (BHI), and Caso broth. The growth rate of each test strain in each medium was determined by culture enumeration and the suitability of CAMHB was confirmed by comparative statistical analysis. Thereafter, reference and type strain and eight epidemiologically unrelated field isolates of B. bronchiseptica were used to test the suitability of a broth microdilution susceptibility testing method following CLSI-approved performance standards given in document VET01-A4. Susceptibility tests, using 20 antimicrobial agents, were performed in five replicates, and data were collected after 20 and 24 hours incubation and statistically analysed. Due to the low growth rate of B. bronchiseptica, an incubation time of 24 hours resulted in significantly more homogeneous minimum inhibitory concentrations after five replications compared to a 20-hour incubation. An interlaboratory comparison trial including susceptibility testing of 24 antimicrobial agents revealed a high mean level of reproducibility (97.9%) of the modified method. Hence, in a harmonization for broth microdilution susceptibility testing of B. bronchiseptica, an incubation time of 24 hours in CAMHB medium with an incubation temperature of 35°C and an inoculum concentration of approximately 5 x 10(5) cfu/ml was proposed.

Inflation of the type I error: investigations on regulatory recommendations for bioequivalence of highly variable drugs.

PURPOSE: We investigated different evaluation strategies for bioequivalence trials with highly variable drugs on their resulting empirical type I error and empirical power. The classical 'unscaled' crossover design with average bioequivalence evaluation, the Add-on concept of the Japanese guideline, and the current 'scaling' approach of EMA were compared. METHODS: Simulation studies were performed based on the assumption of a single dose drug administration while changing the underlying intra-individual variability. RESULTS: Inclusion of Add-on subjects following the Japanese concept led to slight increases of the empirical α-error (≈7.5%). For the approach of EMA we noted an unexpected tremendous increase of the rejection rate at a geometric mean ratio of 1.25. Moreover, we detected error rates slightly above the pre-set limit of 5% even at the proposed 'scaled' bioequivalence limits. CONCLUSIONS: With the classical 'unscaled' approach and the Japanese guideline concept the goal of reduced subject numbers in bioequivalence trials of HVDs cannot be achieved. On the other hand, widening the acceptance range comes at the price that quite a number of products will be accepted bioequivalent that had not been accepted in the past. A two-stage design with control of the global α therefore seems the better alternative.

Identification of a lineage specific zinc responsive genomic island in Mycobacterium avium ssp. paratuberculosis.

BACKGROUND: Maintenance of metal homeostasis is crucial in bacterial pathogenicity as metal starvation is the most important mechanism in the nutritional immunity strategy of host cells. Thus, pathogenic bacteria have evolved sensitive metal scavenging systems to overcome this particular host defence mechanism. The ruminant pathogen Mycobacterium avium ssp. paratuberculosis (MAP) displays a unique gut tropism and causes a chronic progressive intestinal inflammation. MAP possesses eight conserved lineage specific large sequence polymorphisms (LSP), which distinguish MAP from its ancestral M. avium ssp. hominissuis or other M. avium subspecies. LSP14 and LSP15 harbour many genes proposed to be involved in metal homeostasis and have been suggested to substitute for a MAP specific, impaired mycobactin synthesis. RESULTS: In the present study, we found that a LSP14 located putative IrtAB-like iron transporter encoded by mptABC was induced by zinc but not by iron starvation. Heterologous reporter gene assays with the lacZ gene under control of the mptABC promoter in M. smegmatis (MSMEG) and in a MSMEG∆furB deletion mutant revealed a zinc dependent, metalloregulator FurB mediated expression of mptABC via a conserved mycobacterial FurB recognition site. Deep sequencing of RNA from MAP cultures treated with the zinc chelator TPEN revealed that 70 genes responded to zinc limitation. Remarkably, 45 of these genes were located on a large genomic island of approximately 90 kb which harboured LSP14 and LSP15. Thirty-five of these genes were predicted to be controlled by FurB, due to the presence of putative binding sites. This clustering of zinc responsive genes was exclusively found in MAP and not in other mycobacteria. CONCLUSIONS: Our data revealed a particular genomic signature for MAP given by a unique zinc specific locus, thereby suggesting an exceptional relevance of zinc for the metabolism of MAP. MAP seems to be well adapted to maintain zinc homeostasis which might contribute to the peculiarity of MAP pathogenicity.

Effects of ultrafine particles on the allergic inflammation in the lung of asthmatics: results of a double-blinded randomized cross-over clinical pilot study.

BACKGROUND: Epidemiological and experimental studies suggest that exposure to ultrafine particles (UFP) might aggravate the allergic inflammation of the lung in asthmatics. METHODS: We exposed 12 allergic asthmatics in two subgroups in a double-blinded randomized cross-over design, first to freshly generated ultrafine carbon particles (64 µg/m³; 6.1 ± 0.4 × 105 particles/cm³ for 2 h) and then to filtered air or vice versa with a 28-day recovery period in-between. Eighteen hours after each exposure, grass pollen was instilled into a lung lobe via bronchoscopy. Another 24 hours later, inflammatory cells were collected by means of bronchoalveolar lavage (BAL). ( TRIAL REGISTRATION: NCT00527462) RESULTS: For the entire study group, inhalation of UFP by itself had no significant effect on the allergen induced inflammatory response measured with total cell count as compared to exposure with filtered air (p = 0.188). However, the subgroup of subjects, which inhaled UFP during the first exposure, exhibited a significant increase in total BAL cells (p = 0.021), eosinophils (p = 0.031) and monocytes (p = 0.013) after filtered air exposure and subsequent allergen challenge 28 days later. Additionally, the potential of BAL cells to generate oxidant radicals was significantly elevated at that time point. The subgroup that was exposed first to filtered air and 28 days later to UFP did not reveal differences between sessions. CONCLUSIONS: Our data demonstrate that pre-allergen exposure to UFP had no acute effect on the allergic inflammation. However, the subgroup analysis lead to the speculation that inhaled UFP particles might have a long-term effect on the inflammatory course in asthmatic patients. This should be reconfirmed in further studies with an appropriate study design and sufficient number of subjects.

A multicenter, randomized, open-labeled study to steer immunosuppressive and antiviral therapy by measurement of virus (CMV, ADV, HSV)-specific T cells in addition to determination of trough levels of immunosuppressants in pediatric kidney allograft recipients (IVIST01-trial): study protocol for a randomized controlled trial.

BACKGROUND: After kidney transplantation, immunosuppressive therapy causes impaired cellular immune defense leading to an increased risk of viral complications. Trough level monitoring of immunosuppressants is insufficient to estimate the individual intensity of immunosuppression. We have already shown that virus-specific T cells (Tvis) correlate with control of virus replication as well as with the intensity of immunosuppression. The multicentre IVIST01-trial should prove that additional steering of immunosuppressive and antiviral therapy by Tvis levels leads to better graft function by avoidance of over-immunosuppression (for example, viral infections) and drug toxicity (for example, nephrotoxicity). METHODS/DESIGN: The IVIST-trial starts 4 weeks after transplantation. Sixty-four pediatric kidney recipients are randomized either to a non-intervention group that is only treated conservatively or to an intervention group with additional monitoring by Tvis. The randomization is stratified by centre and cytomegalovirus (CMV) prophylaxis. In both groups the immunosuppressive medication (cyclosporine A and everolimus) is adopted in the same target range of trough levels. In the non-intervention group the immunosuppressive therapy (cyclosporine A and everolimus) is only steered by classical trough level monitoring and the antiviral therapy of a CMV infection is performed according to a standard protocol. In contrast, in the intervention group the dose of immunosuppressants is individually adopted according to Tvis levels as a direct measure of the intensity of immunosuppression in addition to classical trough level monitoring. In case of CMV infection or reactivation the antiviral management is based on the individual CMV-specific immune defense assessed by the CMV-Tvis level. Primary endpoint of the study is the glomerular filtration rate 2 years after transplantation; secondary endpoints are the number and severity of viral infections and the incidence of side effects of immunosuppressive and antiviral drugs. DISCUSSION: This IVIST01-trial will answer the question whether the new concept of steering immunosuppressive and antiviral therapy by Tvis levels leads to better future graft function. In terms of an effect-related drug monitoring, the study design aims to realize a personalization of immunosuppressive and antiviral management after transplantation. Based on the IVIST01-trial, immunomonitoring by Tvis might be incorporated into routine care after kidney transplantation. TRIAL REGISTRATION: EudraCT No: 2009-012436-32, ISRCTN89806912 (17 June 2009).

Prevalence and potential risk factors for the occurrence of cefotaxime resistant Escherichia coli in German fattening pig farms--a cross-sectional study.

A cross-sectional study concerning farm prevalence and risk factors for the count of cefotaxime resistant Escherichia coli (E. coli) (CREC) positive samples per sampling group on German fattening pig farms was performed in 2011 and 2012. Altogether 48 farms in four agricultural regions in the whole of Germany were investigated. Faecal samples, boot swabs and dust samples from two sampling groups per farm were taken and supplemental data were collected using a questionnaire. On 85% of the farms, at least one sample contained cefotaxime resistant E. coli colonies. Positive samples were more frequent in faeces (61%) and boot swabs (54%) than in dust samples (11%). Relevant variables from the questionnaire were analysed in a univariable mixed effect Poisson regression model. Variables that were related to the number (risk) of positive samples per sampling group with a p-value <0.2 were entered in a multivariable model. This model was reduced to statistically significant variables via backward selection. Factors that increased the risk for positive samples involved farm management and hygienic aspects. Farms that had a separate pen for diseased pigs had a 2.8 higher mean count of positive samples (95%-CI [1.71; 4.58], p=0.001) than farms without an extra pen. The mean count was increased on farms with under-floor exhaust ventilation compared to farms with over floor ventilation (2.22 [1.43; 3.46], p=0.001) and more positive samples were observed on farms that controlled flies with toxin compared to farms that did not (1.86 [1.24; 2.78], p=0.003). It can be concluded, that CREC are wide spread on German fattening pig farms. In addition the explorative approach of the present study suggests an influence of management strategies on the occurrence of cefotaxime resistant E. coli.