Pretransplant coronary artery disease is a predictor for myocardial infarction and cardiac death after liver transplantation.

BACKGROUND: Cardiovascular disease is a serious problem of liver transplant (LT) recipients because of increased cardiovascular risk due to immunosuppressive therapy, higher age, intraoperative risk and comorbidities (such as diabetes and nicotine abuse). Reported frequency of cardiovascular events after LT shows a high variability between different LT cohorts. Our aim was to analyze a cohort of LT recipients from a single center in Germany to evaluate frequency of the cardiovascular endpoints (CVE) myocardial infarction and/or cardiac death after LT and to investigate correlations of CVE post LT with pretransplant patient characteristics. PATIENTS: In total, data from 352 LT patients were analyzed. Patients were identified from an administrative transplant database, and all data were retrieved from patients' charts and reports. RESULTS: During the median follow-up of 4.0 (0-13) years, 10 cases of CVE were documented (six myocardial infarctions and four coronary deaths). The frequency of CVE did not differ according to classic cardiovascular risk factors such as body mass index (p=0.071), total cholesterol (p=0.533), hypertension (p=0.747), smoking (p=1.000) and pretransplant diabetes mellitus (p=0.146). In patients with pretransplant coronary heart disease (n=24; 6.8%) CVE were found more frequently (p=0.024). CONCLUSION: In summary, we found a rate of 2.8% CVE after LT in a German transplant cohort. Pretransplant CHD was the only risk factor for CVE, but showed no significant impact on overall survival.

Incidence and clinical presentation of acute otitis media in children aged <6 years in European medical practices.

We conducted an epidemiological, observational cohort study to determine the incidence and complications of acute otitis media (AOM) in children aged <6 years. Data on physician-diagnosed AOM were collected from retrospective review of medical charts for the year preceding enrolment and then prospectively in the year following enrolment. The study included 5776 children in Germany, Italy, Spain, Sweden, and the UK. AOM incidence was 256/1000 person-years [95% confidence interval (CI) 243-270] in the prospective study period. Incidence was lowest in Italy (195, 95% CI 171-222) and highest in Spain (328, 95% CI 296-363). Complications were documented in <1% of episodes. Spontaneous tympanic membrane perforation was documented in 7% of episodes. Both retrospective and prospective study results were similar and show the high incidence during childhood in these five European countries. Differences by country may reflect true differences and differences in social structure and diagnostic procedures.

[Mechanics and effects of European reference pricing for vaccines in Germany according to §130a Abs. 2 SGB V: an analysis using the example of influenza vaccines]. / Funktionsweise und Auswirkungen des Referenzpreissystems bei Impfstoffen nach §130a Abs. 2 SGB V: eine Analyse am Beispiel der Grippeimpfstoffe.

OBJECTIVES: On 01 January 2011 the bill for the reorganisation of the pharmaceutical market became effective. Since that time there is a European reference pricing (ERP) system for vaccines in order to bring down the German vaccine prices to an assumed lower European level. This study describes the implementation, functioning and effect of this new system. For influenza vaccines the impact of ERP on the price level and spread of prices is analysed. METHODS: The description of the mechanism is based on the law and corresponding regulations of the head association of sickness funds (GKV-SV). The analysis of vaccine prices is based on the data of the i:data report (status of 01 September 2011) of ifap Service Institute. RESULTS: The European reference price is calculated as the average price of the manufacturer-selling-prices of the corresponding vaccine in the 4 countries of the European Union whose gross national income comes closest to the German one and in which the vaccine is distributed. The relied prices are weighted by sales and purchasing power parities of the respective countries. This analysis suggests that in particular the practical implementation of the reference price system should be further improved and specified. The calculation of the reference prices should ensure price comparability. In addition, significant problems remain in the deduction of discounts, because no distinction is made in the documentation of vaccinating doctors, whether vaccination was performed as a compulsory or statutory benefit. The comparison of the manufacturer-selling-prices of individual influenza vaccines with the corresponding reference prices shows an enlargement of the existing price differences, which have evolved in a competitive environment, after the implementation of the reference pricing -system. CONCLUSIONS: There is still a need for improvement in implementing the reference pricing system. In the most competitive vaccine market of influenza vaccines, the ERP-system lowers the prices, but seems to distort the market prices.

Differentiation between malignant and benign solitary pulmonary nodules with proton density weighted and ECG-gated magnetic resonance imaging.

OBJECTIVE: To estimate performance of MRI for differentiating malignant from benign solitary pulmonary nodules (SPN) using morphological characteristics. MATERIAL AND METHODS: MRI in 46 patients with SPN (mean diameter: 19 mm) was carried out on 1.0 Tesla scanner using ECG-gated, gradient echo sequence. Morphological signs of SPN were determined and compared with previously performed helical-CT, where final diagnosis served as reference with 52% frequency of malignancy. Furthermore, three observers evaluated all images. RESULTS: Significant differences between the two groups were found for nodules shape, margin, inhomogeneity and the vessel-sign in MRI, nodules shape, margin, the vessel-sign, and presence of spicules in CT. Using these signs, AUC were 0.746 for MRI and 0.765 for CT. The mean sensitivity, specificity, and accuracy of observers for MRI/CT were 89%/95%, 42%/41%, 66%/68%, respectively. CONCLUSIONS: Despite discrepancies in morphologic appearance, no significant difference of accuracy between MRI and CT was determined. Further investigations are necessary to demonstrate the clinical use in combination with functional parameters, establishing MRI as a comprehensive diagnostic modality for SPN.

[Detection of pulmonary nodules with breath-hold magnetic resonance imaging in comparison with computed tomography]. / Detektion von Lungenrundherden mit der Magnetresonanztomographie in Atemanhaltetechnik im Vergleich zur Spiral-Computertomographie.

PURPOSE: Evaluation of sensitivity and false positive findings of two fast MRI sequences for the detection of pulmonary nodules in comparison with spiral CT by two independent observers. MATERIALS AND METHODS: All 30 enrolled patients had a spiral CT or MSCT as base line study. MRI was performed with a 1.5 T MR scanner (Sonata, Siemens) using a transverse 3D gradient echo sequence (3D-GRE: TR/TE/flip = 2.9 ms/1.1 ms/5 degrees ) and a half-Fourier single-shot fast spin-echo sequence (HASTE: TR/TE/flip = 800/25/150 degrees ) acquired in three planes. A separate analysis for both sequences was carried out prospectively by two independent readers (A and B) with different experience regarding pulmonary MRI. Additionally, a retrospective reading with knowledge of the CT scans was done. Results were calculated for all lesions and for lesions larger than 4 mm. RESULTS: The sensitivities were 73 %, 70 % and 84 % for the 3D-GRE sequence (reader A, reader B, retrospective reading) and 65 %, 68 % and 81 % for the HASTE sequence. For lesions larger than 4 mm, the sensitivities were 93 %, 89 %, 96 % for the 3D-GRE sequence and 85 %, 85 %, 96 % for the HASTE sequence. The rate of false positive findings depended on the reader's experience, but was generally lower for the 3D-GRE sequence with 2 and 16 (reader A and B) false positive nodules compared to 4 and 40 false positive findings for the HASTE sequence. The 3D-GRE sequence was more accurate for both readers (reader A: p = 0.08, reader B: p = 0.00003). CONCLUSION: The sensitivity of MRI for the detection of lung nodules was only acceptable for lesions larger than 4 mm. The 3D-GRE sequence is superior to the HASTE sequence due to the reduced amount of false positive findings with comparable sensitivity.

[Oncologic screening with whole-body MRI: possibilities and limitations]. / Onkologische Früherkennung mit der Ganzkörper-MRT: Möglichkeiten und Grenzen.

In the last decade the interest in radiological screening examination increased among informed laymen enormously. Independent from the evidence of whole-body examinations for cancer prevention the discussion about screening must again be considered again due to the newest technical developments, since MRI of the whole-body with high spatial resolution is feasible now within one single examination. The newest system permits simultaneous connection of up to 76 coil elements and signal reception from 32 independent receiving channels. Whole-body MRI including magnetic resonance colonography (MRC) is feasible within 60 min. In this review potential investigation protocols will be presented. Potentials, challenges and limitations of whole-body MRI in the prevention of the malignancies most frequently leading to death are discussed on the basis own experiences examples and the literature.

The cost-effectiveness of routine childhood varicella vaccination in Germany.

This study explores the economic value of a routine varicella vaccination program for Germany. An age-structured decision analytic model was used to assess the benefits, costs and cost-effectiveness of an immunization program for a period of 30 years. Three interventions were compared with no vaccination: universal vaccination of around 15 months old healthy children, vaccination of susceptible adolescents (11-12 years of age), and the combined strategy. The analysis was conducted from both the societal perspective and the payers', i.e. sickness funds, perspective. Input data were mainly derived from a retrospective survey (analyzed were 1334 patient records) and from a seroprevalence study (n = 4602 sera). Using a coverage rate of 85% and a vaccine efficacy rate of 86% routine children vaccination could prevent around 611,000 varicella cases and over 4700 major complications per year. Average yearly cost savings for the society are 51.3 million Euro. The benefit-cost ratio (BCR) is 4.12. From the third-party payer's perspective, the BCR is 1.75 which is a consequence of significant reimbursement of parent's lost earnings by German sickness funds. The adolescent vaccination strategy has a favorable BCR ratio of 8.44 from the societal perspective, but clearly inferior medical effects. The combined vaccination strategy showed similar results as the children strategy. Routine childhood varicella vaccination appears to be a highly efficient strategy to reduce the burden of varicella and results in significant savings for both the society and the payers.

[Imaging diagnosis of solitary pulmonary nodules on an open low-field MRI system--comparison of two MR sequences with spiral CT]. / Bildgebende Diagnostik solitärer Lungenrundherde am offenen Niederfeld-MRT--Ein Vergleich zweier MR-Sequenzen mit der Spiral-CT.

OBJECTIVE: To evaluate and compare two fast gradient-echo sequences (GRE) concerning the visualization of solitary pulmonary nodules with an open low-field MRI system in comparison to computed tomography. MATERIALS AND METHODS: Fourteen patients with solitary pulmonary nodules detected by spiral CT ranging in size from 6 mm to 42 mm (mean 20 mm) underwent MRI on an open 0.2 T scanner using a spoiled 2D GRE (2D FLASH; TR/ TE/Flip = 100 ms/7.5 ms/30 degrees ) and a totally refocused 2D steady-state GRE (True-FISP; TR/TE/FA = 7.3 ms/3.5 ms/80 degrees ). The image quality concerning artifacts (by flow, breathing and susceptibility) and the morphologic characteristics of the nodules were scored and compared with CT by two independent radiologists. The diameters of the nodules measured by MRI were compared with CT measurements. The sequences were also evaluated with regard to the signal-to-noise ratio (SNR) of the lesion. RESULTS: All lesions were detected with the 2D FLASH sequence. True-FISP failed to find a granuloma with a size of 6 mm. The 2D FLASH was rated significantly superior to true FISP concerning image quality artifacts by susceptibility as well as concerning to CT the presentation of nodule characteristics. In MR images, the size of lesions was significantly smaller than in CT images for both sequences: for 2D FLASH the mean difference was 0.9 mm and for true FISP 2.6 mm. The SNR of the nodules was significantly higher for the 2D FLASH than for the true FISP. CONCLUSION: In low field MRI, the 2D FLASH sequence is superior to the 2D true FISP sequence in imaging of pulmonary nodules. With the 2D FLASH sequence nodules of 6 mm or larger in size can be visualized.

A new accelerated vaccination schedule for rapid protection against hepatitis A and B.

BACKGROUND: Increasing travel stresses the requirement for rapid protection against infections such as hepatitis A and B. METHODS: This randomised, multicentre study investigated an accelerated vaccination schedule using a combined hepatitis A and B vaccine (Twinrix, Smithkline Beecham Biologicals) compared with simultaneous administration of the two corresponding monovalent vaccines. The combined vaccine was administered on days 0, 7 and 21, whereas the comparison group received hepatitis A vaccine on day 0 and hepatitis B vaccine on days 0, 7 and 21. All subjects received booster vaccination at month 12. RESULTS: At month 1, 100% of subjects in the combined group and 99% of the controls were seropositive for anti-HAV antibodies. The corresponding seroprotection rates for anti-HBs antibodies were 82.0 and 83.9%, respectively. Examination of the 95% confidence intervals (CIs) for the treatment differences showed the two vaccines to be equivalent in terms of immunogenicity 1 week after the initial vaccination course. Just prior to the booster, the seropositivity rate for anti-HAV was 96.2% in the combined group and 95% in the control group. For anti-HBs, this was 94 and 91.6%, respectively. All subjects were seropositive for anti-HAV and seroprotected against hepatitis B at month 13. The anti-HAV GMCs were 9571mIU/ml with the combined vaccine and 5206mIU/ml in control subjects. The anti-HBs titre was 26002 and 29,196mIU/ml, respectively. Both groups had a similar reactogenicity profile. CONCLUSIONS: The accelerated schedule of the combined vaccine provides a good immune response against hepatitis A and B antigens and is suitable for last minute immunisation.

[Hybrid 3-D rendering of the thorax and surface-based virtual bronchoscopy in surgical and interventional therapy control]. / Hybride 3D-Visualisierung des Thorax und oberflächenbasierte virtuelle Bronchoskopie in der operativen und interventionellen Therapiekontrolle.

PURPOSE: The aim of this study was to demonstrate the possibilities of a hybrid rendering method, the combination of a color-coded surface and volume rendering method, with the feasibility of performing surface-based virtual endoscopy with different representation models in the operative and interventional therapy control of the chest. MATERIAL AND METHOD: In 6 consecutive patients with partial lung resection (n = 2) and lung transplantation (n = 4) a thin-section spiral computed tomography of the chest was performed. The tracheobronchial system and the introduced metallic stents were visualized using a color-coded surface rendering method. The remaining thoracic structures were visualized using a volume rendering method. For virtual bronchoscopy, the tracheobronchial system was visualized using a triangle surface model, a shaded-surface model and a transparent shaded-surface model. RESULTS: The hybrid 3D visualization uses the advantages of both the color-coded surface and volume rendering methods and facilitates a clear representation of the tracheobronchial system and the complex topographical relationship of morphological and pathological changes without loss of diagnostic information. Performing virtual bronchoscopy with the transparent shaded-surface model facilitates a reasonable to optimal, simultaneous visualization and assessment of the surface structure of the tracheobronchial system and the surrounding mediastinal structures and lesions. CONCLUSIONS: Hybrid rendering relieve the morphological assessment of anatomical and pathological changes without the need for time-consuming detailed analysis and presentation of source images. Performing virtual bronchoscopy with a transparent shaded-surface model offers a promising alternative to flexible fiberoptic bronchoscopy.

Famciclovir treatment of hepatitis B infection following liver transplantation: a long-term, multi-centre study.

Famciclovir is a novel guanosine nucleoside analogue with activity against herpes viruses and hepatitis B virus (HBV). Several preliminary reports have described efficacy of famciclovir in patients with recurrent hepatitis B after orthotopic liver transplantation (OLT). This report describes the largest study to date of long-term famciclovir treatment in patients with de novo or recurrent hepatitis B post-OLT. One hundred thirty patients with detectable serum HBV DNA after OLT received oral famciclovir 500 mg tid on a compassionate-use basis. Safety analyses included all treated patients; efficacy was assessed in all patients and a subgroup of 73 patients with complete baseline HBV DNA and alanine aminotransferase (ALT) data who had received > or =6 months of treatment. Efficacy parameters included serum levels of HBV DNA, ALT, and anti-HBe or anti-HBs seroconversion rates. Of the 70 patients treated for > or =6 months who could be evaluated for response/non-response to famciclovir, 52 (74%) were responders, defined as patients who experienced a 70% decrease or more in HBV DNA levels from baseline, or who became HBV DNA-negative, for at least two consecutive visits. In famciclovir responders, HBV DNA levels decreased by a median of 91% after 12 weeks of treatment, 95% after 6 months and >99% after 18 months of treatment. Marked differentiation between responders and non-responders could be made soon after the onset of treatment. Among anti-HBe positive patients with evidence of HBV replication, 12/13 were responders. Patients with high baseline ALT levels experienced more rapid suppression of HBV DNA during therapy with famciclovir. Famciclovir therapy was safe and well tolerated; serious adverse events were reported infrequently. Famciclovir treatment may be beneficial in patients with hepatitis B infection post-OLT.

Can monovalent hepatitis A and B vaccines be replaced by a combined hepatitis A/B vaccine during the primary immunization course?

A combined hepatitis A/B vaccine (Twinrix Adult) has been licensed in Germany since 1997. We investigated possible differences in immunogenicity and safety when changing over from vaccinations with monovalent vaccines made by different manufacturers to vaccinations with the combined hepatitis A/B vaccine in an open, randomized, multicenter trial. We therefore compared four different schemes changing over from concomitant vaccinations with monovalent vaccines against hepatitis A and B (Havrix 1440+Engerix-B or Vaqta+Gen H-B-Vax) to combined vaccination against hepatitis A+B with three injections of the combined hepatitis A/B vaccine (0, 1, and 6 month schedule). Local and general symptoms were mostly mild in all five groups. With complete three-dose course using the combined vaccine or an early changeover from monovalent vaccines to the combined vaccine, higher overall anti-HBs seroprotection rates and geometric mean concentrations (GMCs) against hepatitis B could be achieved as early as after 2 months as compared to those groups switching later to the combined vaccine. This study demonstrated for the first time that switching from monovalent hepatitis A and B vaccinations to the combined hepatitis A and B vaccination has no negative influence on the tolerability and improves the immunogenicity.

Famciclovir treatment of chronic hepatitis B in heart transplant recipients: a prospective trial.

UNLABELLED: Hepatitis B may take a rapid and aggressive course in patients under immunosuppression. Nucleoside analogues have been shown to suppress viral replication effectively. To investigate the effect of famciclovir in immunosuppressed patients, 21 heart transplant recipients with chronic hepatitis B infection were included in a prospective study. PATIENTS AND METHODS: Patients have been treated with Famciclovir for a median of 14 months. Hepatitis B virus replication and biochemical parameters were regularly tested and liver biopsies were taken before treatment and after a median time of 7 months. HBV-polymerase was sequenced in all patients before therapy and in those patients who experienced virological breakthrough. RESULTS: Nineteen patients were treated for at least 6 months. Hepatitis B virus-DNA levels declined in all patients and became negative in 8 patients. Mean hepatitis B virus-DNA levels decreased from 199+/-269 to 34+/-53 pg/ml after 24 weeks (P=0.003). During treatment HBeAg became negative in five patients. Mean alanine aminotransferase decreased from 42+/-26 to 24+/-10 U/L (P=0.006). Histological analysis revealed improved inflammatory activity according to the Ishak-score in 11/16 (69%) patients. Total inflammatory activity scores decreased from 8 to 6 (median, NS), but interface hepatitis score (P=0.02) and lobular inflammation score (P=0.006) improved significantly. Median fibrosis scores fell from 5 to 3 (P=0.002). Three patients developed virological breakthrough on famciclovir after 7, 8, and 26 months of treatment showing HBV-polymerase amino acid changes L528 M, S567A, and I581K, respectively. CONCLUSIONS: Famciclovir improves not only biochemical and virological features but also hepatic inflammation and liver fibrosis in patients with chronic hepatitis B under heavy immunosuppression. Virological breakthrough may develop and requires close monitoring.

Conversion to microemulsion cyclosporine in stable renal transplant patients: results after one year.

We switched 302 renal transplant patients from the conventional to a new microemulsion formulation of cyclosporine, to study the latter's safety and efficacy. We used a simple 1:1 conversion of the patient's total daily dose. We measured trough drug levels as well as serum creatinine, liver enzymes, uric acid, and blood pressure values at baseline and at days 4, 8, 15, 29, and months 3, 6 and 12 after drug substitution. Dose adjustments directed at trough levels 80-120 ng/ml were performed, starting at day 8. Within the 12-month observation period, the cyclosporine dose was reduced by 14.7% (204 +/- 60 mg/day baseline vs 174 +/- 51 mg/day after conversion, p < or = 0.001). By day 8, the 1:1 dosage conversion resulted in a modest mean increase in drug trough levels (114 ng/ml baseline vs 120 ng/ml, p < or = 0.01). This increase was accompanied by an increase in serum creatinine concentration, a decrease in calculated creatinine clearance, and an increase in uric acid values (p < or = 0.05). Liver enzymes remained unchanged while systolic and mean arterial blood pressure decreased (p < or = 0.05). After one month, drug trough levels had decreased to baseline (112 ng/ml) and remained there until month 6. They were significantly lower after 12 months (102 +/- 33 ng/ml, p < or = 0.001). Plasma creatinine values decreased to below baseline by month 6 (p < or = 0.001) and month 12 (p < or = 0.001). Twenty-four (8%) biopsy proven rejection episodes and 7 cases of cyclosporine attributed nephrotoxicity occurred in these 302 patients within these 12 months. We conclude, that a 1:1 conversion from conventional to the microemulsion form of cyclosporine is efficacious and safe. However, we advise an initial 10% decrease in dose reduction in those patients whose trough levels are in the high-normal range.

Substitution of conventional cyclosporin with a new microemulsion formulation in renal transplant patients: results after 1 year.

BACKGROUND: A new galenic form of cyclosporin A has been developed, based on microemulsion technology. The bioavailability of the compound is relatively independent of food intake and bile flow. It was the purpose of this prospective clinical trial to study the safety of the microemulsion form of cyclosporin A. METHODS: Three hundred and two renal transplant patients, stratified according to transplant age, were switched from the conventional to the new microemulsion formulation of cyclosporin A. A 1:1 conversion ration was used. Measurements included CsA levels, S-creatinine, liver enzymes, uric acid, and blood pressure. Measurements were performed at baseline and on days 4, 8, 15, 29 and months 3, 6 and 12 after conversion. Dose adjustments were performed to achieve through levels of 80-120 ng/ml. RESULTS: Within the 12-month observation period the cyclosporin dose was reduced by 14.7% (from 204 +/- 60 mg/day at baseline to 174 +/- 51 mg/day after conversion, P < 0.001). Acutely, i.e. by day 8, 1:1 dose conversion resulted in a modest increase of mean drug through levels (from 114 ng/ml at baseline to 120 ng/ml, P < 0.01). This increase was accompanied by an increase in serum creatinine concentration, a decrease in calculated creatinine clearance, and an increase in uric acid values (P < or = 0.05). Liver enzymes remained unchanged while systolic and mean arterial blood pressure decrease (P < 0.05). After 1 month, drug through levels had decreased to baseline (112 ng/ml) and remained there until month 6. They were significantly lower after 12 months (102 +/- 33 ng/ml), P <0.001). Creatinine clearance values increased to above baseline at 6 and 12 months. Within the 1-year period there occurred 24 (= 8%) episodes of biopsy proven rejection and seven episodes of cyclosporin-attributed nephrotoxicity. CONCLUSIONS: The 1:1 conversion from conventional cyclosporin A to the microemulsion formulation s efficacious and safe, but an initial dose reduction of 10% is advised in patients with through levels in the high-normal range.

Clinical experience transferring kidney transplant patients from Sandimmun to Sandimmun Neoral--results after 3 months.

The new galenic formulation of cyclosporine prepared as microemulsion (Sandimmun Neoral, SN) shows a significantly improved correlation between both trough level (Cmin) and dose. Moreover, since the bioavailability is increased by 20 to 30% on average, it may lead to a drug overexposure in so far malabsorbing patients. In order to assess safety and to establish an appropriate procedure to switch patients safely from conventional Sandimmun to SN, we initialized an open, stratified (transplant age) clinical trial enrolling 302 patients of our outpatient clinic. We used a simple 1:1 conversion of the patient's total daily dose. Trough drug levels, as well as serum creatinine, liver enzymes, uric acid, and blood pressure values were measured at baseline, at days 4, 8, 15, 29, and at month 3 after drug substitution. Within the three month observation period, the cyclosporine dose was reduced by 14.2% (204 +/- 60 mg/day baseline vs. 175 +/- 54 mg/day after conversion, p < 0.05). By day 8, the 1:1 dosage conversion resulted in a modest mean increase in drug trough levels (114 ng/ml baseline vs. 120 ng/ml, p < 0.05). This increase was accompanied by a slight increase in mean serum creatinine concentration, a decrease in calculated creatinine clearance, and an increase in mean uric acid values (p < 0.05). Liver enzymes remained unchanged while systolic and mean arterial blood pressure decreased (p < 0.05). Parallel to dosage reduction, drug trough levels had decreased after 1 month to baseline (112 ng/ml) and remained there for the remainder of the study.(ABSTRACT TRUNCATED AT 250 WORDS)