Early REperfusion therapy with intravenous alteplase for recovery of VISION in acute central retinal artery occlusion (REVISION): Study protocol of a phase III trial.

RATIONALE: Meta-analyses of case series of non-arteritic central retinal artery occlusion (CRAO) indicate beneficial effects of intravenous thrombolysis when initiated early after symptom onset. Randomized data are lacking to address this question. AIMS: The REperfusion therapy with intravenous alteplase for recovery of VISION in acute central retinal artery occlusion (REVISION) investigates intravenous alteplase within 4.5 h of monocular vision loss due to acute CRAO. METHODS: This study is the randomized (1:1), double-blind, placebo-controlled, multicenter adaptive phase III trial. STUDY OUTCOMES: Primary outcome is functional recovery to normal or mildly impaired vision in the affected eye defined as best-corrected visual acuity of the Logarithm of the Minimum Angle of Resolution of 0.5 or less at 30 days (intention-to-treat analysis). Secondary efficacy outcomes include modified Rankin Score at 90 days and quality of life. Safety outcomes include symptomatic intracranial hemorrhage, major bleeding (International Society on Thrombosis and Haemostasis definition) and mortality. Exploratory analyses of optical coherence tomography/angiography, ultrasound and magnetic resonance imaging (MRI) biomarkers will be conducted. SAMPLE SIZE: Using an adaptive design with interim analysis at 120 patients, up to 422 participants (211 per arm) would be needed for 80% power (one-sided alpha = 0.025) to detect a difference of 15%, assuming functional recovery rates of 10% in the placebo arm and 25% in the alteplase arm. DISCUSSION: By enrolling patients within 4.5 h of CRAO onset, REVISION uses insights from meta-analyses of CRAO case series and randomized thrombolysis trials in acute ischemic stroke. Increased rates of early reperfusion and good neurological outcomes in stroke may translate to CRAO with its similar pathophysiology. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04965038; EU Trial Number: 2023-507388-21-00.

BridGE: a pathway-based analysis tool for detecting genetic interactions from GWAS.

Genetic interactions have the potential to modulate phenotypes, including human disease. In principle, genome-wide association studies (GWAS) provide a platform for detecting genetic interactions; however, traditional methods for identifying them, which tend to focus on testing individual variant pairs, lack statistical power. In this protocol, we describe a novel computational approach, called Bridging Gene sets with Epistasis (BridGE), for discovering genetic interactions between biological pathways from GWAS data. We present a Python-based implementation of BridGE along with instructions for its application to a typical human GWAS cohort. The major stages include initial data processing and quality control, construction of a variant-level genetic interaction network, measurement of pathway-level genetic interactions, evaluation of statistical significance using sample permutations and generation of results in a standardized output format. The BridGE software pipeline includes options for running the analysis on multiple cores and multiple nodes for users who have access to computing clusters or a cloud computing environment. In a cluster computing environment with 10 nodes and 100 GB of memory per node, the method can be run in less than 24 h for typical human GWAS cohorts. Using BridGE requires knowledge of running Python programs and basic shell script programming experience.

Supporting regional pandemic management by enabling self-service reporting-A case report.

BACKGROUND: The COVID-19 pandemic revealed a need for better collaboration among research, care, and management in Germany as well as globally. Initially, there was a high demand for broad data collection across Germany, but as the pandemic evolved, localized data became increasingly necessary. Customized dashboards and tools were rapidly developed to provide timely and accurate information. In Saxony, the DISPENSE project was created to predict short-term hospital bed capacity demands, and while it was successful, continuous adjustments and the initial monolithic system architecture of the application made it difficult to customize and scale. METHODS: To analyze the current state of the DISPENSE tool, we conducted an in-depth analysis of the data processing steps and identified data flows underlying users' metrics and dashboards. We also conducted a workshop to understand the different views and constraints of specific user groups, and brought together and clustered the information according to content-related service areas to determine functionality-related service groups. Based on this analysis, we developed a concept for the system architecture, modularized the main services by assigning specialized applications and integrated them into the existing system, allowing for self-service reporting and evaluation of the expert groups' needs. RESULTS: We analyzed the applications' dataflow and identified specific user groups. The functionalities of the monolithic application were divided into specific service groups for data processing, data storage, predictions, content visualization, and user management. After composition and implementation, we evaluated the new system architecture against the initial requirements by enabling self-service reporting to the users. DISCUSSION: By modularizing the monolithic application and creating a more flexible system, the challenges of rapidly changing requirements, growing need for information, and high administrative efforts were addressed. CONCLUSION: We demonstrated an improved adaptation towards the needs of various user groups, increased efficiency, and reduced burden on administrators, while also enabling self-service functionalities and specialization of single applications on individual service groups.

The crosstalk between glomerular endothelial cells and podocytes controls their responses to metabolic stimuli in diabetic nephropathy.

In diabetic nephropathy (DN), glomerular endothelial cells (GECs) and podocytes undergo pathological alterations, which are influenced by metabolic changes characteristic of diabetes, including hyperglycaemia (HG) and elevated methylglyoxal (MGO) levels. However, it remains insufficiently understood what effects these metabolic factors have on GEC and podocytes and to what extent the interactions between the two cell types can modulate these effects. To address these questions, we established a co-culture system in which GECs and podocytes were grown together in close proximity, and assessed transcriptional changes in each cell type after exposure to HG and MGO. We found that HG and MGO had distinct effects on gene expression and that the effect of each treatment was markedly different between GECs and podocytes. HG treatment led to upregulation of "immediate early response" genes, particularly those of the EGR family, as well as genes involved in inflammatory responses (in GECs) or DNA replication/cell cycle (in podocytes). Interestingly, both HG and MGO led to downregulation of genes related to extracellular matrix organisation in podocytes. Crucially, the transcriptional responses of GECs and podocytes were dependent on their interaction with each other, as many of the prominently regulated genes in co-culture of the two cell types were not significantly changed when monocultures of the cells were exposed to the same stimuli. Finally, the changes in the expression of selected genes were validated in BTBR ob/ob mice, an established model of DN. This work highlights the molecular alterations in GECs and podocytes in response to the key diabetic metabolic triggers HG and MGO, as well as the central role of GEC-podocyte crosstalk in governing these responses.

Deep Learning-Enabled Diagnosis of Liver Adenocarcinoma.

BACKGROUND & AIMS: Diagnosis of adenocarcinoma in the liver is a frequent scenario in routine pathology and has a critical impact on clinical decision making. However, rendering a correct diagnosis can be challenging, and often requires the integration of clinical, radiologic, and immunohistochemical information. We present a deep learning model (HEPNET) to distinguish intrahepatic cholangiocarcinoma from colorectal liver metastasis, as the most frequent primary and secondary forms of liver adenocarcinoma, with clinical grade accuracy using H&E-stained whole-slide images. METHODS: HEPNET was trained on 714,589 image tiles from 456 patients who were randomly selected in a stratified manner from a pool of 571 patients who underwent surgical resection or biopsy at Heidelberg University Hospital. Model performance was evaluated on a hold-out internal test set comprising 115 patients and externally validated on 159 patients recruited at Mainz University Hospital. RESULTS: On the hold-out internal test set, HEPNET achieved an area under the receiver operating characteristic curve of 0.994 (95% CI, 0.989-1.000) and an accuracy of 96.522% (95% CI, 94.521%-98.694%) at the patient level. Validation on the external test set yielded an area under the receiver operating characteristic curve of 0.997 (95% CI, 0.995-1.000), corresponding to an accuracy of 98.113% (95% CI, 96.907%-100.000%). HEPNET surpassed the performance of 6 pathology experts with different levels of experience in a reader study of 50 patients (P = .0005), boosted the performance of resident pathologists to the level of senior pathologists, and reduced potential downstream analyses. CONCLUSIONS: We provided a ready-to-use tool with clinical grade performance that may facilitate routine pathology by rendering a definitive diagnosis and guiding ancillary testing. The incorporation of HEPNET into pathology laboratories may optimize the diagnostic workflow, complemented by test-related labor and cost savings.

Polychlorinated dioxins and dibenzofurans (PCDD/F), polybrominated dioxins and dibenzofurans (PBDD/F), polychlorinated biphenyls (PCB), polybrominated diphenyl ethers (PBDE), and per- and polyfluoroalkyl substances (PFAS) in German breast milk samples (LUPE 8).

Most organic pollutants (POP) are persistent in the environment, accumulate in fatty tissues, and so a transfer through the food chain is probably, thereby causing various health effects. We quantified PCDD/F, PBDD/F, PCB, PBDE, perfluorinated substances, and ADONA in breast milk samples collected in two German federal states and breast milk and blood samples from subjects additionally exposed to PFOA. The median (95th percentile) concentrations were 2.43 (6.58) pgWHO2005TEQ/g l.w. for PCDD/F, 2.45 (4.82) pgWHO2005TEQ/g l.w. for dioxin-like PCB (dl-PCB), and 0.62 (2.69) pgWHO2005TEQ/g l.w. for PBDD/F. The relative contributions of the median values of PCDD/F, dl-PCB, and PBDD/F to the total-TEQ were approximately 41%, 42%, and 11%, respectively. Nondioxin-like PCB (ndl-PCB) concentrations were clearly dominated by the higher chlorinated PCB congeners, with medians of 23.2 ng/g l.w. for PCB 153, 13.9 ng/g l.w. for PCB 138, and 13.0 ng/g l.w. for PCB 180. The sum of the 3 congeners (PCB 138, 153, and 180) were multiplied with 1.64 (total PCB) and showed a median of 82.16 ng/g l.w. and a 95th percentile of 173.3 ng/g l.w. Only PFOA and PFOS could be quantified in 29% and 17% of in total 180 samples with 95th percentiles of 53 ng/l and 33 ng/l, respectively. Milk samples (n = 13) from subjects living on PFOA contaminated sites showed higher levels between 33 and 854 ng/l PFOA (mean: 199 ng/l), whilst PFOS could be quantified only in three samples. The sum of 17 PBDE congeners showed medians (95th percentile) of 1737 pg/g l.w. (22,806 pg/g l.w.), with the highest medians of 422 pg/g l.w. for BDE 209 and 378 pg/g l.w. for BDE 153. Overall, our study confirms the declining contamination level in breast milk during the last decade, but points out the need to further reduce the environmental contamination with persistent substances and subsequently the exposure in childhood.

Regional responsibility and coordination of appropriate inpatient care capacities for patients with COVID-19 - the German DISPENSE model.

As of late 2019, the COVID-19 pandemic has been a challenge to health care systems worldwide. Rapidly rising local COVID-19 incidence rates, result in demand for high hospital and intensive care bed capacities on short notice. A detailed up-to-date regional surveillance of the dynamics of the pandemic, precise prediction of required inpatient capacities of care as well as a centralized coordination of the distribution of regional patient fluxes is needed to ensure optimal patient care. In March 2020, the German federal state of Saxony established three COVID-19 coordination centers located at each of its maximum care hospitals, namely the University Hospitals Dresden and Leipzig and the hospital Chemnitz. Each center has coordinated inpatient care facilities for the three regions East, Northwest and Southwest Saxony with 36, 18 and 29 hospital sites, respectively. Fed by daily data flows from local public health authorities capturing the dynamics of the pandemic as well as daily reports on regional inpatient care capacities, we established the information and prognosis tool DISPENSE. It provides a regional overview of the current pandemic situation combined with daily prognoses for up to seven days as well as outlooks for up to 14 days of bed requirements. The prognosis precision varies from 21% and 38% to 12% and 15% relative errors in normal ward and ICU bed demand, respectively, depending on the considered time period. The deployment of DISPENSE has had a major positive impact to stay alert for the second wave of the COVID-19 pandemic and to allocate resources as needed. The application of a mathematical model to forecast required bed capacities enabled concerted actions for patient allocation and strategic planning. The ad-hoc implementation of these tools substantiates the need of a detailed data basis that enables appropriate responses, both on regional scales in terms of clinic resource planning and on larger scales concerning political reactions to pandemic situations.

[The role of university hospitals in regional health care management for coping with the COVID-19 pandemic]. / Die Rolle der Universitätskliniken im regionalen medizinischen Versorgungsmanagement zur Bewältigung der COVID-19 Pandemie.

INTRODUCTION: The complex and dynamic situation in the current pandemic requires a regionally coordinated and interconnected cooperation between the different stakeholders within the health care system, such as the inpatient sector or the public health service. The aim of this study is to analyze health care management during the COVID-19 pandemic in 2020 with a focus on regional networking and communication structures. METHODS: As part of the BMBF-funded project "egePan Unimed", an online questionnaire on pandemic management was sent to the boards of all 35 German university hospitals in November 2020. The questionnaire focused on the core topics of regional networking, crisis management, data exchange, and communication with political stakeholders. The questionnaire consisted of 37 closed and three open-ended questions. After piloting, the invitation to the survey was extended three times by mail and once by telephone. RESULTS: The results (n=25, response 71.4%) show that 68% of the clinics surveyed were connected to representatives from the inpatient sector and 86% to representatives from the public health service. Networking with representatives from the outpatient sector was less common (26%). Of the university hospitals surveyed, 84% had a leadership role in a regional COVID-19 pandemic management effort. Data exchange with regional hospitals in the course of pandemic management took place at 75% of the participating university hospitals and with supra-regional hospitals at 67% of the clinics surveyed. CONCLUSION: To manage regional medical care during the COVID-19 pandemic in 2020, university hospitals often assumed a coordinating role in the complex pandemic care process. There were often structured collaborations with regional clinics and health departments and comparatively few cooperations with the outpatient care sector. However, this cooperation has the potential to prevent overcrowding in hospitals.

Programmed Death Ligand-1 (PD-L1) Is an Independent Negative Prognosticator in Western-World Gallbladder Cancer.

Inhibition of the programmed cell death protein-1/ligand-1 (PD-1/PD-L1) axis has opened a new era in the treatment of solid cancers. However, there is no data on the expression and relevance of PD-L1 in Western gallbladder cancer (GBC). We assessed PD-L1 immunohistochemically in 131 GBC patients as Tumor Proportion Score (TPS), Immune Cell Score (IC) and Combined Positivity Score (CPS). Tumor cells expressed PD-L1 in a subset of 14.7% GBC patients at a TPS cut-off of 1%. Higher PD-L1 levels above 10% and 25% TPS were reached in 4.7% and 3.1% of GBC cases, respectively. At a 10% cut-off, TPS was associated with distinct histomorphological subtypes and correlated with poor tumor differentiation. Survival analysis revealed a TPS above 10% to be a highly significant and independent negative prognosticator in GBC. PD-L1 expression was associated with increased CD4+, CD8+ and PD-1+ immune cell densities. In 14.8% of the cases, scattered immune cells expressed T-cell immunoreceptor with Ig and ITIM domains (TIGIT), which was correlated to tumoral expression of its ligand CD155. We here show that a high PD-L1 expression confers a negative prognostic value in Western-world GBC and highlight the TIGIT/CD155 immune checkpoint as a potential new target for GBC immunotherapy.

Patient-Level and Hospital-Level Risk Factors for In-Hospital Mortality in Patients Ventilated for More Than 24 Hours: Results of a Nationwide Cohort Study.

BACKGROUND: Prolonged ventilation is associated with a high risk of death. This study investigated both patient-level and hospital-level risk factors for in-hospital mortality in patients ventilated for more than 24 hours. METHODS: The analyses were conducted in the framework of a German national multicenter retrospective cohort study. Patient and hospital characteristics were examined using descriptive statistics. Risk factors of in-hospital mortality were analyzed using multilevel robust Poisson regressions for binary outcomes. Potential effect modifications were examined by stratified analyses. RESULTS: The sample includes 95 672 cases of patients ventilated >24 hours in 163 hospitals covering the period 2016 to 2017. According to the results of multilevel Poisson regressions, main patient-level risk factors for in-hospital mortality were age (per year relative risk [RR] = 1.021, 95% CI = 1.020-1.023), stroke (RR = 1.459; 95% CI = 1.361-1.563), emergency case admission (RR = 1.273, 95% CI = 1.156-1.403), and transfer from another hospital (RR = 1.169, 95% CI = 1.084-1.261). The individual risk of in-hospital death was positively associated with hospital size (RR of hospitals with 600-799 beds vs <100 beds = 1.412, 95% CI = 1.095-1.820) and negatively related to cumulated ventilation patient time (per 1000 days RR = 0.995, 95% CI = 0.993-0.996). University hospital status was identified as an effect modifier, particularly with regard to the patients' admission reasons. The RR of in-hospital death in patients admitted after transfer from another hospital was higher in university hospitals (RR = 1.456, 95% CI = 1.298-1.634) compared to nonuniversity hospitals (RR = 1.077, 95% CI = 1.019-1.139). Likewise, patients admitted as emergency case had a higher relative risk in university hospitals (RR = 1.619, 95% CI = 1.359-1.929) than in nonuniversity hospitals (RR = 1.141, 95% CI = 1.080-1.205). CONCLUSION: By providing evidence on multiple patient-level and hospital-level risk factors for in-hospital mortality in patients ventilated for more than 24 hours, this large multicenter study has main implications for quality assessment of clinical care and the adequate specification of risk adjustment models. The revealed effect modifications indicate the relevance of stratified analyses.

HER2 gene (ERBB2) amplification is a low-frequency driver with potential predictive value in gallbladder carcinoma.

Gallbladder carcinoma (GBC) is an aggressive type of cancer with a dismal prognosis. Recent case reports have highlighted the human epidermal growth factor receptor 2 (HER2) as a promising target for individualized therapy in biliary tract cancer; however, current data on HER2 positivity in GBC is contradictory. This study aimed to assess the proportion of HER2 positivity and its clinical implications in a large and well-characterized European GBC cohort. HER2 status was determined in 186 cases of surgically resected gallbladder adenocarcinoma and a subset of coexistent high-grade biliary intraepithelial neoplasia (BilIN, n = 74) in accordance with the up-to-date consensus for HER2 testing in gastric cancer by immunohistochemistry and dual-color chromogenic in situ hybridization. Positivity for HER2 was observed in 5.4% of all cases (n = 10). In those patients with concomitant high-grade BilIN, two of four positive samples also showed amplification in the precursor lesion, while in the two remaining cases, positivity was either confined to invasive tumor or high-grade BilIN, exclusively. Equivocal staining found in eleven cases was not accompanied by gene amplification. Staging of the HER2-positive group was significantly different from the HER2-negative group with most cases presenting at stage IV, paralleled by a trend towards decreased survival. One patient who received dual HER2 inhibition almost went into full clinical remission despite treatment initiation in a metastasized state. Our results reveal a low prevalence of HER2 positivity and highlight HER2 gene amplification as an early, potentially driving event in gallbladder carcinogenesis. Prospective standardized HER2 testing and randomized control studies are needed to prove clinical efficacy of targeted HER2 inhibition in GBC.

Persistent Organic Pollutants in Human Breast Milk and Associations with Maternal Thyroid Hormone Homeostasis.

Epidemiological studies have indicated the thyroid-disrupting effects of persistent organic pollutants (POPs). However, the association of low-exposure POPs with thyroid hormones (THs) remains unclear. Here, we aim to assess the association of low exposure of POPs, including polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs), and polybrominated dibenzo-p-dioxins and furans, with THs [total L-thyroxine (TT4), total 3,3',5-triiodo-L-thyronine (TT3), and total 3,3',5'-triiodo-L-thyronine (TrT3)] measured in human breast milk. Ninety-nine breast milk samples were collected from the LUPE cohort (2015-2016, Bavaria, Germany). Fourteen PBDEs, 17 PCBs, and 5 PCDD/Fs had quantification rates of >80%. Nonmonotonic associations were observed. In adjusted single-pollutant models, (1) TT4 was inversely associated with BDE-99, -154, and -196; (2) TT3 was inversely associated with BDE-47, -99, -100, -197, -203, -207, and OCDD; and (3) TrT3 was inversely associated with BDE-47, -99, -183, and -203. Multipollutant analysis using principal component analysis and hierarchical clustering revealed inverse associations of PBDEs (BDE-28, -47, -99, -100, -154, -183, and -197) with TT4 and TrT3. These results indicate that POPs at low levels might be related to reduced THs. This study shows that human breast milk might be an appropriate specimen to evaluate the thyroid disruption of POPs.

HER2 gene (ERBB2) amplification is a rare event in non-liver-fluke associated cholangiocarcinogenesis.

BACKGROUND: Cholangiocarcinoma is a rapidly fatal cancer entity with a median survival of less than one year. In contrast to many other malignancies, no substantial therapeutic breakthrough has been made in the past few decades, thereby limiting the treatment to cytotoxic chemotherapy with little beneficial effect for most patients. Targeted therapy tailored to the individual has shown substantial success in the recent past as a promising avenue for cancer therapy. METHODS: In this study, we determined the frequency of amplification of the HER2 gene in a comprehensive and well-characterized European cholangiocarcinoma cohort encompassing 436 patients including intrahepatic (n = 155), proximal (n = 155) and distal (n = 126) cholangiocarcinoma by strict application of a combined immunohistochemical and in situ hybridization algorithm following the current guidelines for HER2 assessment in gastric cancer. RESULTS: We identified a proportion of 1.4% (n = 6) patients that demonstrated HER2 gene amplification, with the highest rate among the distal cholangiocarcinoma patients (2.4%). None of the patients with equivocal (2+) immunohistochemical staining results exhibited gene amplification molecularly. In four of the five patients with HER2 positivity, gene amplification was already present in concomitantly tested high-grade biliary intraepithelial neoplasia (80%). HER2 gene amplification was not significantly associated with other clinical parameters, including survival. CONCLUSIONS: This study identifies HER2 gene amplification as a rare event in cholangiocarcinoma of the Western population, occurring already in high-grade BilIN in a subset of patients. Furthermore, we provide a robust testing algorithm that may be used prior to therapy administration in future clinical trials evaluating the role of HER2 as a predictive marker in cholangiocarcinoma.

[Epidemiology and prediction of the risk of falling in patients in acute care settings: Analysis of routine data from a university hospital]. / Epidemiologie und Vorhersage des Sturzrisikos von Patienten in der akutstationären Versorgung: Analyse von Routinedaten eines Universitätsklinikums.

BACKGROUND: Falls are a relevant issue of inpatient treatment. Epidemiological analysis concerning incidence, risk factors for falls and the quality of risk assessments are missing. METHODS: In a routine data-based cross-sectional study all patients hospitalized in the University Hospital Dresden, Germany, during 2012 and 2013 were analyzed according to fall incidence and risk factors (items of Dresden fall risk assessment [Dresden-FRA], age, sex, severity of disease, and length of stay. Fall risk and associated risk factors were determined using descriptive methods and logistic regression models. In addition, the quality of the fall risk assessment was evaluated. RESULTS: The risk of falling during the observation period was 1.6 %. Differences exist between the medical disciplines (risk of falling 0.1 % to 9.8 %). The fall rate was 2.9/1,000 days of treatment. Higher age, longer inpatient stay, and a higher level of disease severity were significant predictors of falls. Less serious consequences of falls were more frequently documented (84 %) than consequences of falls requiring treatment (16 %). All nine items of the Dresden-FRA were significant risk factors. The sensitivity and specificity of the Dresden-FRA were 69.9 % and 71.4 %, respectively. CONCLUSION: Patients at an older age and with more severe disease have a higher risk of falling. The validated assessment of the individual risk of falling is an important tool of medical quality management and risk management. The present study can help to raise awareness about the quality of risk assessments, to further improve fall risk assessment, and to increase patient safety in acute care.

Occurrence of chlorinated and brominated dioxins/furans, PCBs, and brominated flame retardants in blood of German adults.

Persistent organic pollutants are widespread in the environment, and are associated with a particular health and ecological concern. The human body burden of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs/Fs), polybrominated dibenzo-p-dioxins and dibenzofurans (PBDDs/Fs), polychlorinated biphenyls (PCBs), polybrominated diphenylether (PBDEs), and hexabromocyclododecanes (HBCDs) was determined. Blood samples were collected in Germany, originating from 42 randomly selected subjects between 20 and 68 years old. The median (95th percentile) concentrations, expressed as WHO2005-TEQ for PCDD/PCDFs and dioxin-like PCBs, were 6.2 (19.1) pg/g l.w. and 4.1 (8.8) pg/g l.w., respectively. PBDDs/Fs were found with a median of 2.8 pgTEQ/g l.w. and a 95th percentile of 8.7 pgTEQ/g l.w. (using similar interim TEF values as for PCDDs/Fs) On a median basis, the contribution of PCDD/Fs, dioxin-like PCBs, and PBDDs/Fs to total TEQ were 47%, 31%, and 21%, respectively. The sum of the 6 non-dioxin-like PCBs exhibited a median of 267ng/g l.w. and a 95th percentile of 834ng/g l.w. The median value for the sum of six tetra- to hepta-PBDE congeners was 1.7ng/g l.w. (95th percentile: 4.9ng/g l.w.). BDE 209 was the most abundant congener with a median of 1.8ng/g l.w. HBCDs were only found in some samples, and concentrations ranged between the limit of detection (5ng/g l.w.) and the limit of quantification (16ng/g l.w.). Results for PBDEs and HBCDs are comparable to other European studies. Our study demonstrated that the body burden of PCDD/Fs and PCBs declined continously since the last three decades, but exposure may exceed precautionary guideline levels.

Everolimus in metastatic renal cell carcinoma after failure of initial anti-VEGF therapy: final results of a noninterventional study.

BACKGROUND: Data are limited regarding routine use of everolimus after initial vascular endothelial growth factor (VEGF)-targeted therapy. The aim of this prospective, noninterventional, observational study was to assess efficacy and safety of everolimus after initial VEGF-targeted treatment in patients with metastatic renal cell carcinoma (mRCC) in routine clinical settings. METHODS: Everolimus was administered per routine clinical practice. Patients with mRCC of any histology from 116 active sites in Germany were included. The main objective was to determine everolimus efficacy in time to progression (TTP). Progression-free survival (PFS), treatment duration, tumor response, adherence to everolimus regimen, treatment after everolimus, and safety were also assessed. RESULTS: In the total population (N = 334), median follow-up was 5.2 months (range, 0-32 months). Median treatment duration (safety population, n = 318) was 6.5 months (95% confidence interval [CI], 5-8 months). Median TTP and median PFS were similar in populations investigated. In patients who received everolimus as second-line treatment (n = 211), median (95% CI) TTP was 7.1 months (5-9 months) and median PFS was 6.9 months (5-9 months). Commonly reported adverse events (safety population, n = 318) were dyspnea (17%), anemia (15%), and fatigue (12%). Limitations of the noninterventional design should be considered. CONCLUSIONS: This study reflects routine clinical use of everolimus in a large sample of patients with mRCC. Favorable efficacy and safety were seen for everolimus after previous therapy with one VEGF-targeted agent. Results of this study confirm everolimus as one of the standard options in second-line therapy for patients with mRCC. Novartis study code, CRAD001LD27: VFA registry for noninterventional studies ( http://www.vfa.de/de/forschung/nisdb/).

PCBs, PCDD/Fs, and PBDEs in blood samples of a rural population in South Germany.

The body burden of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), dioxin-like (dl-PCBs) and non-dioxin-like (ndl-PCBs) polychlorinated biphenyls, and polybrominated diphenyl ethers (PBDEs) was determined in blood samples from 70 subjects between 4 and 76 years old. The participants of the study were recruited in the neighborhood of a reclamation plant located in a rural area in Southern Germany. The median concentrations (95th percentiles in parentheses), expressed as WHO2005-TEQ (toxic equivalents), for PCDD/Fs and dl-PCBs were 4.5 (17.9)pgg(-1) l.w. and 2.6 (13.2)pgg(-1) l.w., respectively. The dl-PCBs contributed 40% of the total TEQ (median values), and the most abundant congener was PCB 156. Combined, the sum of the 6 non-dioxin-like PCBs had a median of 0.773µgL(-1) and a 95th percentile of 4.895µgL(-1). For the six tetra to hepta PBDE congeners, the median was 1.8ngg(-1) l.w. (95th percentile: 16.2ngg(-1) l.w.). None of our study subjects had a body burden that exceeded the biomonitoring equivalents for dioxins or PBDE congener 99 or the human biomonitoring values for ndl-PCBs. Likewise the study group did not exceed German reference values or values obtained in similar investigations. Overall, our study did not exhibit elevated internal exposures. The results also hint further decreasing tendencies for PCDD/Fs, PCBs, and PBDEs in Germany and demonstrates that people in the vicinity of a reclamation plant with no indication of an environmental contamination did not exhibit elevated internal exposures.

[Health insurance expenses for children in the first five years of life - a cohort-based analysis]. / Ausgaben einer Krankenkasse für Kinder in den ersten fünf Lebensjahren - eine kohortenbasierte Analyse.

INTRODUCTION: The development of paediatrics is characterised by several changes in the past few years, concerning, in particular holistic treatments or preventive check-ups, but also the transfer of treatment from the inpatient to the outpatient sector. There are no reference values for assessing emerging health insurance expenses. The aim of this study was to obtain a frame of reference for the costs of the treatment for neonates, infants, and young children using the example of the expenditures of one health insurance fund. METHODS: The individual health insurance expenditures were analysed for the first five years of life of children insured with the AOK PLUS in Saxony, Germany, in 2005. Costs of hospital treatment, ambulatory care, remedies, tools, medicines and care were included. RESULTS: The costs per insured child and year amounted to approximately 1,277 Euro (N = 11,147), with the highest costs arising in the first two years. 858 Euro were spent annually for an "average" child; 5,691 Euro per year incurred for a child with special medical needs. DISCUSSION: The present cost analysis describes both the height and structure of a health insurance's spendings on children within the first five years of their life in consideration of regional medical care offers. The question of whether this analysis provides valid reference values for other health insurances or other service areas will have to be answered by other analyses.

Organochlorine compounds, nitro musks and perfluorinated substances in breast milk - results from Bavarian Monitoring of Breast Milk 2007/8.

The aim of the Bavarian Monitoring of Breast Milk (BAMBI) project was to examine 10 organochlorine pesticides (OPs), 3 nitro musks, 6 indicator polychlorinated biphenyls (PCBs), 7 polychlorinated dibenzo-p-dioxins (PCDDs), 10 polychlorinated dibenzofurans (PCDFs), 12 dioxin-like PCBs (dl-PCBs) and several perfluorinated alkyl compounds in breast milk samples. A total of 516 breast milk samples were collected from seven regions in Bavaria and were analyzed by means of GC/ECD, GC/HRMS, and LC/MS-MS. Concerning the OPs, only hexachlorobenzene and a metabolite of DDT, 1,1-dichloro-2,2-bis(4-chlorophenyl) ethylene (p,p'-DDE), could be quantified in all samples (median: 16 ngg(-1) lipid and 63 ngg(-1) lipid, respectively). Median concentrations of 150 ngg(-1) lipid (range: 3-1900 ngg(-1) lipid) were found for the sum of the indicator PCBs. The concentrations of the PCDDs/PCDFs and the dl-PCBs ranged from 0.8 to 15.1 (median 5.7) pg WHO-TEQ1998g(-1) lipid and from 1.5 to 18.9 pg (median 6.4) WHO-TEQ1998 g(-1) lipid, respectively. The median perfluorooctane sulfonate concentration was 0.05 µgL(-1) (range: <0.02-0.26 µgL), while the other PFCs were observed only in a subset of samples. On the basis of the median and 95th percentile concentration, "medium" and "high" intake levels were estimated for a 3-month-old exclusively breastfed infant. In particular, "medium" and "high" intake levels were calculated of 69 and 133 pg WHO1998 TEQ kg(-1) b.w. for PCDDs/PCDFs, 8 and 21 ngkg(-1) b.w. for dl-PCBs, and 6 and 25 ngkg(-1) b.w. for perfluorooctane sulfonate, respectively. The calculated intake for perfluorinated substances is clearly below the tolerable daily intake (TDI), while the established TDI values are still clearly exceeded for PCDDs/PCDFs and dl-PCBs.