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BACKGROUND: Studies to date have shown no survival benefit for the use of exogenous surfactant to treat patients with the ARDS. To identify specific patient subgroups for future study, we performed an exploratory post hoc analysis of clinical trials of recombinant surfactant protein-C (rSP-C) surfactant (Venticute; Nycomed GmbH; Konstanz, Germany). METHODS: We performed a pooled analysis of all five multicenter studies in which patients with ARDS due to various predisposing events were treated with rSP-C surfactant. Patients received either usual care (n = 266) or usual care plus up to four intratracheal doses (50 mg/kg) of rSP-C surfactant (n = 266). Factors influencing the study end points were analyzed using descriptive statistics, analysis of covariance, and logistic regression models. RESULTS: ARDS was most often associated with pneumonia or aspiration, sepsis, and trauma or surgery. For the overall patient population, treatment with rSP-C surfactant significantly improved oxygenation (p = 0.002) but had no effect on mortality (32.6%). Multivariate analysis showed age and acute physiology and chronic health evaluation (APACHE) II score to be the strongest predictors of mortality. In the subgroup of patients with severe ARDS due to pneumonia or aspiration, surfactant treatment was associated with markedly improved oxygenation (p = 0.0008) and improved survival (p = 0.018). CONCLUSIONS: rSP-C surfactant improved oxygenation in patients with ARDS irrespective of the predisposition. Post hoc evidence of reduced mortality associated with surfactant treatment was obtained in patients with severe respiratory insufficiency due to pneumonia or aspiration. Those patients are the focus of a current randomized, blinded, clinical trial with rSP-C surfactant. [ABSTRACT FROM AUTHOR]

Objectives We sought to investigate up to which level of Joint Photographic Experts Group (JPEG) data compression the perceived image quality and the detection of diagnostic features remain equivalent to the quality and detectability found in uncompressed coronary angiograms.Background Digital coronary angiograms represent an enormous amount of data and therefore require costly computerized communication and archiving systems. Earlier studies on the viability of medical image compression were not fully conclusive.Methods Twenty-one raters evaluated sets of 91 cine runs. Uncompressed and compressed versions of the images were presented side by side on one monitor, and image quality differences were assessed on a scale featuring six scores. In addition, the raters had to detect pre-defined clinical features. Compression ratios (CR) were 6:1, 10:1 and 16:1. Statistical evaluation was based on descriptive statistics and on the equivalence t -test.Results At the lowest CR (CR 6:1), there was already a small (15%) increase in assigning the aesthetic quality score indicating “quality difference is barely discernible—the images are equivalent.’ At CR 10:1 and CR 16:1, close to 10% and 55%, respectively, of the compressed images were rated to be “clearly degraded, but still adequate for clinical use’ or worse. Concerning diagnostic features, at CR 10:1 and CR 16:1 the error rate was 9·6% and 13·1%, respectively, compared with 9% for the baseline error rate in uncompressed images.Conclusions Compression at CR 6:1 provides equivalence with the original cine runs. If CR 16:1 were used, one would have to tolerate a significant increase in the diagnostic error rate over the baseline error rate. At CR 10:1, intermediate results were obtained. [ABSTRACT FROM PUBLISHER]

Background: The incidence of adenocarcinoma at the gastro-oesophageal junction is on the increase. These carcinomas are usually diagnosed too late and thus have a poor prognosis. Only early diagnosis can improve the situation. Classical Barrett oesophagus (length, >3 cm) is a known precancerous condition. There is also specialized columnar epithelium (SCE) in the grossly unremarkable gastro-oesophageal transitional zone (short Barrett). Methods: To determine the frequency of SCE, 370 patients were investigated by gastroscopy (OGD) consecutively between September 1995 and February 1996. Results: Classical Barrett oesophagus was found to have an incidence of 4.6%. In contrast, microscopic evidence of SCE was observed in 13.6% of the cases. Patients with short Barrett presented with reflux symptoms (odds ratio (OR), 4.7), irregular zona serrata ('tongues') in the cardia (OR, 2.8), and reflux oesophagitis significantly more frequently. Patients with reflux symptoms and concomitant 'tongues', however, had an OR of 13.16. Careful history-taking, together with a subtle histologic work-up of the gastro-oesophageal transitional zone can improve the rate of detecting patients with short Barrett. Conclusion: Patients with reflux symptoms and irregular zona serrata should be selectively biopsied at the gastro-oesophageal junction, even when the latter presents a grossly normal appearance, with the aim of detecting patients at risk of developing a Barrett carcinoma. [ABSTRACT FROM AUTHOR]

The in vitro experiments on the interaction of 3H-cocaine and melanin from Sepia officinalis confirmed the existence of drug binding sites on melanin granules. The results suggested that the binding of 3H-cocaine to melanin could be analyzed by assuming that the binding to the surface of pigment granules is analogous to the adsorption of a drug on a solid and follows Langmuir adsorption isotherm type I. Scatchard analysis indicated heterogeneity of binding sites. Structural and chemical alterations caused by isolation of the melanoproteins, which are heterogenous in nature and show different physicochemical properties, are considered to be most crucial. The studies on hair samples confirmed that melanin-drug interactions occur on the surface of melanin granules. These seem to be of minor importance compared to the drug-melanoprotein loading during melanogenesis for the observed influence of pigmentation on the drug content of hair fibers. From the results it was concluded that in vitro studies on melanin provide limited information and even drug-soaked hair must be regarded as inappropriate for the study of melanin-drug-binding in hair. [ABSTRACT FROM AUTHOR]

Background and Objective: Missing data and unmeasured confounding are key challenges for external comparator studies. This work evaluates bias and other performance characteristics depending on missingness and unmeasured confounding by means of two case studies and simulations., Methods: Two case studies were constructed by taking the treatment arms from two randomised controlled trials and an external real-world data source that exhibited substantial missingness. The indications of the randomised controlled trials were multiple myeloma and metastatic hormone-sensitive prostate cancer. Overall survival was taken as the main endpoint. The effects of missing data and unmeasured confounding were assessed for the case studies by reporting estimated external comparator versus randomised controlled trial treatment effects. Based on the two case studies, simulations were performed broadening the settings by varying the underlying hazard ratio, the sample size, the sample size ratio between the experimental arm and the external comparator, the number of missing covariates and the percentage of missingness. Thereby, bias and other performance metrics could be quantified dependent on these factors., Results: For the multiple myeloma external comparator study, results were in line with the randomised controlled trial, despite missingness and potential unmeasured confounding, while for the metastatic hormone-sensitive prostate cancer case study missing data led to a low sample size, leading overall to inconclusive results. Furthermore, for the metastatic hormone-sensitive prostate cancer study, missing data in important eligibility criteria led to further limitations. Simulations were successfully applied to gain a quantitative understanding of the effects of missing data and unmeasured confounding., Conclusions: This exploratory study confirmed external comparator strengths and limitations by quantifying the impact of missing data and unmeasured confounding using case studies and simulations. In particular, missing data in key eligibility criteria were seen to limit the ability to derive the external comparator target analysis population accurately, while simulations demonstrated the magnitude of bias to expect for various settings., Competing Interests: Declarations Funding This work was funded by the European Medicines Agency (EMA/2017/09/PE, Lot 4). Conflicts of interest/competing interests The authors have no conflicts of interests that are directly relevant to the content of this article. Ethics approval Not applicable. Consent to participate Not applicable. Consent for publication Not applicable. Availability of data and material Randomised controlled trial data sharing is not permitted by the policies of Project Data Sphere, LLC [45] and Yale Open Data Access [46], which had to be signed by IQVIA at the start of this research project. Code availability The programming code for simulations is available in the ESM. Authors’ contributions The main author directed all research efforts and drafted the first version of the publication. Contributing authors revised and added to the first version. Each author had participated sufficiently in the work to take responsibility of portions of the content. All authors read and approved the final manuscript. Disclaimer The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the regulatory agency/agencies or organisations with which the authors are employed/affiliated., (© 2024. The Author(s).)

Aim: This article provides an overview of time-to-event (TTE) analysis in pharmacoepidemiology., Materials & Methods: The key concept of censoring is reviewed, including right-, left-, interval- and informative censoring. Simple descriptive statistics are explained, including the nonparametric estimation of the TTE distribution as per Kaplan-Meier method, as well as more complex TTE regression approaches, including the parametric Accelerated Failure Time (AFT) model and the semi-parametric Cox Proportional Hazards and Restricted Mean Survival Time (RMST) models. Additional approaches and various TTE model extensions are presented as well. Finally, causal inference for TTE outcomes is addressed., Results: A thorough review of the available concepts and methods outlines the immense variety of available and useful TTE models., Discussion: There may be underused TTE concepts and methods, which are highlighted to raise awareness for researchers who aim to apply the most appropriate TTE approach for their study., Conclusion: This paper constitutes a modern summary of TTE analysis concepts and methods. A curated list of references is provided., (© 2024 John Wiley & Sons Ltd.)

Background: Uncertainty around key elements of an appropriate patient-reported outcome (PRO) baseline assessment introduces trial-specific variation in oncology clinical trials with a poorly understood consequence on drug evaluation decisions. This research investigated the impact of multiple pre-treatment PRO assessments and timing of assessments in a clinical trial., Methods: A post-hoc analysis of a completed phase 3, open-label, randomized, parallel arm clinical trial in non-small cell lung cancer with two pre-treatment PRO assessments (screening and Week 1 Day 1 [W1D1]). Descriptive analyses, mixed models for repeated measures and time until definitive deterioration analyses were performed to estimate differences between treatment arms. Through model adjustments, different baseline specifications and assessment timing (pre/post-randomization) on W1D1 PROs were evaluated., Results: Patients with both pre-treatment PRO assessments were included in the analysis (N = 535). Numerically small average change scores were observed between screening and W1D1 (mean change, 0-100 scale ranges): Chest pain (-0.94), Cough (-0.94), Dyspnea (1.27), Physical functioning (-1.19). Both pre-treatment assessments were moderately-highly correlated (r: 0.55-0.78) and no trend was found for deterioration or improvement during this period. Varying baseline definitions in the models produced slight differences in model fit but no impact on the between treatment group effect estimate. W1D1 PRO scores were not statistically influenced by assessment timing pre/post-randomization (p-values: 0.142-0.628)., Conclusion: Findings from this study question the need for multiple pre-treatment PRO assessments in oncology drug development trials and the degree of bias thought to be introduced through patient knowledge of treatment assignment. Implications for researchers are presented., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Published by Elsevier Inc.)

Randomized controlled trials (RCTs) are the gold standard design to establish the efficacy of new drugs and to support regulatory decision making. However, a marked increase in the submission of single-arm trials (SATs) has been observed in recent years, especially in the field of oncology due to the trend towards precision medicine contributing to the rise of new therapeutic interventions for rare diseases. SATs lack results for control patients, and information from external sources can be compiled to provide context for better interpretability of study results. External comparator arm (ECA) studies are defined as a clinical trial (most commonly a SAT) and an ECA of a comparable cohort of patients-commonly derived from real-world settings including registries, natural history studies, or medical records of routine care. This publication aims to provide a methodological overview, to sketch emergent best practice recommendations and to identify future methodological research topics. Specifically, existing scientific and regulatory guidance for ECA studies is reviewed and appropriate causal inference methods are discussed. Further topics include sample size considerations, use of estimands, handling of different data sources regarding differential baseline covariate definitions, differential endpoint measurements and timings. In addition, unique features of ECA studies are highlighted, specifically the opportunity to address bias caused by unmeasured ECA covariates, which are available in the SAT., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal disorders of the bone marrow, and are associated with a high disease burden, reduced quality of life (QOL), and shortened survival. This multinational, multicenter, non-interventional registry "MERGE" was initiated with an objective to collect data on the epidemiological indices of classical Ph-MPNs, existing treatment patterns, and impact of MPNs on health-related QOL in various countries/regions in Asia, including the Middle East, Turkey, and Algeria. Of the 884 eligible patients with MPNs, 169 had myelofibrosis (MF), 301 had polycythemia vera (PV), 373 had essential thrombocythemia (ET), and 41 had unclassified MPNs. The median age was 58 years (range, 47-66 years), and 50% of patients were males. The prevalence and incidence of MPNs were estimated to be 57-81 and 12-15 per 100 000 hospital patients per year over the last 4 years, respectively, in these countries. Total symptom score (mean [standard deviation; SD]) at baseline was highest in patients with MF (23.5 [17.47]) compared with patients with ET (14.6 [14.26]) and PV (16.6 [14.84]). Patients with ET had a lower mean (SD) number of inpatient visits (0.9 [0.77] days), and patients with MF had more outpatient visits (5.2 [3.17] days) on an average, compared with the entire MPN group. The study showed that patients with MPNs have a severe disease burden and reduced QOL. A discordance between physician and patient perception of symptom assessment was observed in this study (International clinical trials registry ID: CTRI/2014/05/004598)., (© 2020 The Authors and Novartis Pharma AG. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: Cardiovascular diseases (CVD) represent the first cause of mortality in western countries. Hypertension and dyslipidemia are strong risk factors for CVD, and are prevalent either alone or in combination. Although effective substances for the treatment of both factors are available, there is space for optimization of treatment regimens due to poor patient's adherence to medication, which is usually a combination of several substances. Adherence decreases with the number of pills a patient needs to take. A combination of substances in one single-pill (single pill combination, SPC), might increase adherence, and lead to a better clinical outcome., Aim: We conducted a meta-analysis to compare the effect of SPC with that of free-combination treatment (FCT) in patients with either hypertension, dyslipidemia or the combination of both diseases under conditions of daily practice., Methods: Studies were identified by searching in PubMed from November 2014 until February 2015. Search criteria focused on trials in identical hypertension and/or dyslipidemia treatment as FCT therapy or as SPC. Adherence and persistence outcome included proportion-of-days-covered (PDC), medication possession ratio (MPR), time-to treatment gap of 30 and 60 days and no treatment gap of 30 days (y/n). Clinical outcomes were all cause hospitalisation, hypertension-related hospitalisation, all cause emergency room visits, hypertension-related emergency room visits, outpatient visits, hypertension-related outpatient visits, and number of patients reaching blood pressure goal. Randomized clinical studies were excluded because they usually do not reflect daily practice., Results: 11 out of 1.465 studies met the predefined inclusion criteria. PDC ≥ 80% showed an odds ratio (OR) of 1.78 (95% CI: 1.30-2.45; p = 0.004) after 6 months and an OR of 1.85 (95% CI: 1.71; 2.37; p < 0.001) after ≥ 12 months in favour to the SPC. MPR ≥ 80% after 12 months also was in favour to SPC (OR 2.13; 95% CI: 1.30; 3.47; p = 0.003). Persistence was positively affected by SPC after 6, 12, and 18 months. Time to treatment gap of 60 days resulted in a hazard ratio (HR) of 2.03 (95% CI: 1.77; 2.33, p < 0.001). The use of SPC was associated with a significant improvement in systolic blood pressure reduction, leading to a higher number of patients reaching individual blood pressure goals (FCT vs SPC results in OR = 0.77; 95% CI: 0.69; 0.85, p < 0.001). Outpatient visits, emergency room visits and hospitalisations, both overall and hypertension-related were reduced by SPC: all-cause hospitalisation (SPC vs FCT: 15.0% vs 18.2%, OR 0.79, 95% CI 0.67; 0.94, p = 0.009), all-cause emergency room visits (SPC vs FCT: 25.7% vs 31.4%, OR 0.75, 95% CI 0.65; 0.87, p = 0.001) and hypertension related emergency room visits (SPC vs FCT: 9.7% vs 14.1%, OR 0.65, 95% CI 0.54; 0.80, p < 0.001)., Conclusions: SPC improved medication adherence and clinical outcome parameter in patients suffering from hypertension and/or dyslipidemia and led to a better clinical outcome compared to FCT under conditions of daily practice.

Background: CV9103 is a prostate-cancer vaccine containing self-adjuvanted mRNA (RNActive®) encoding the antigens PSA, PSCA, PSMA, and STEAP1. This phase I/IIa study evaluated safety and immunogenicity of CV9103 in patients with advanced castration-resistant prostate-cancer., Methods: 44 Patients received up to 5 intra-dermal vaccinations. Three dose levels of total mRNA were tested in Phase I in cohorts of 3-6 patients to determine a recommended dose. In phase II, 32 additional patients were treated at the recommended dose. The primary endpoint was safety and tolerability, the secondary endpoint was induction of antigen specific immune responses monitored at baseline and at weeks 5, 9 and 17., Results: The most frequent adverse events were grade 1/2 injection site erythema, injection site reactions, fatigue, pyrexia, chills and influenza-like illness. Possibly treatment related urinary retention occurred in 3 patients. The recommended dose was 1280 μg. A total of 26/33 evaluable patients treated at 1280 μg developed an immune response, directed against multiple antigens in 15 out of 33 patients. One patient showed a confirmed PSA response. In the subgroup of 36 metastatic patients, the Kaplan-Meier estimate of median overall survival was 31.4 months [95 % CI: 21.2; n.a]., Conclusions: The self-adjuvanted RNActive® vaccine CV9103 was well tolerated and immunogenic. The technology is a versatile, fast and cost-effective platform allowing for creation of vaccines. The follow-up vaccine CV9104 including the additional antigens prostatic acid phosphatase (PAP) and Muc1 is currently being tested in a randomized phase IIb trial to assess the clinical benefit induced by this new vaccination approach., Trial Registration: EU Clinical Trials Register: EudraCT number 2008-003967-37, registered 27 Jan 2009.

Background: Advanced non-small cell lung cancer (NSCLC) represents a significant unmet medical need. Despite advances with targeted therapies in a small subset of patients, fewer than 20% of patients survive for more than two years after diagnosis. Cancer vaccines are a promising therapeutic approach that offers the potential for durable responses through the engagement of the patient's own immune system. CV9202 is a self-adjuvanting mRNA vaccine that targets six antigens commonly expressed in NSCLC (NY-ESO-1, MAGEC1, MAGEC2, 5 T4, survivin, and MUC1)., Methods/design: The trial will assess the safety and tolerability of CV9202 vaccination combined with local radiation designed to enhance immune responses and will include patients with stage IV NSCLC and a response or stable disease after first-line chemotherapy or therapy with an EGFR tyrosine kinase inhibitor. Three histological and molecular subtypes of NSCLC will be investigated (squamous and non-squamous cell with/without EGFR mutations). All patients will receive two initial vaccinations with CV9202 prior to local radiotherapy (5 GY per day for four successive days) followed by further vaccinations until disease progression. The primary endpoint of the study is the number of patients experiencing Grade >3 treatment-related adverse events. Pharmacodynamic analyses include the assessment of immune responses to the antigens encoded by CV9202 and others not included in the panel (antigen spreading) and standard efficacy assessments., Discussion: RNActive self-adjuvanted mRNA vaccines offer the potential for simultaneously inducing immune responses to a wide panel of antigens commonly expressed in tumors. This trial will assess the feasibility of this approach in combination with local radiotherapy in NSCLC patients., Trial Registration: Clinicaltrials.gov: NCT01915524/EudraCT No.: 2012-004230-41.

An increased number and density of the so-called "giant ganglia" (seven or greater ganglion cells per ganglion) serve as histopathological criteria for a bowel motility disorder called intestinal neuronal dysplasia of the submucous plexus (IND B). However, because these morphological criteria have been defined based upon observations in constipated patients, the diagnostic value of previous studies is open to controversy. Moreover, no age-related reference data from unaffected controls are available. This study reports on data from unaffected controls on the variability of size and distribution of ganglia in the submucous plexus during development. Therefore, for the first time, the normal status has been defined. Four age groups have been defined: (a) premature births, gestational age less than 35 weeks; (b) 1-365 days; (c) 1-14 years and (d) 15 years to greater than 70 years). All of these groups revealed giant ganglia in the submucous plexus. With advancing age, there was a decrease in the number of giant ganglia (from 32.7% in group a to 11.2% in group d) accompanied by an inverse increase in the mean distance between all ganglia (from 0.52 mm in group a to 1.17 mm in group d). The data presented permit the conclusion that the criteria mentioned above are not apt to define IND B as an entity, since they do not allow a sufficient demarcation from the age-correlated normal values presented here.

Purpose: This study evaluated the influence of a soft-start light-curing exposure on polymerization shrinkage stress and marginal integrity of adhesive restorations., Materials and Methods: Six resin-based composites (Pertac II, Tetric Ceram, Definite, Surefil, Solitaire, and Visio-Molar) were adhesively bonded to a cylindrical cavity (n = 9 per material/light) in a photoelastic material. Visible light-curing was applied using either the standard polymerization mode (800 mW/cm2 exposure duration 40 s) of the curing light (Elipar TriLight, 3M ESPE) or the exponential mode from the same device (ramp-curing: 150 mW/cm2 to 800 mW/cm2 within the first 15 s of a total curing time of 40 s). Polymerization stress was calculated at 5 minutes, 1 hour, and 24 hours postexposure from the second-order isochromatic curves obtained from photoelastic images (Matrox-Inspector). Two standardized Class V preparations were made each on the facial and lingual surfaces of 80 extracted human molars and premolars. Resin restorative systems (Pertac II/EBS Multi, Tetric Ceram/Syntac, Definite/Etch&Prime 3.0, and Surefil/Prime & Bond 2.1) were exposed using both light exposure modes (n = 20). Marginal dye penetration (2% methylene blue) was investigated separately for enamel and cementum margins after thermocycling. To obtain information on equivalent depth of cure, relative surface hardness measurements were performed on resin samples of the same material at the top surface and at 1.5 mm and 3.0 mm thickness (Zwick 3212, 10 N)., Results: A significant (p < .01) reduction in polymerization stress of 7.1% for Pertac II, 4.1% for Tetric Ceram, 3.6% for Definite, 3.7% for Surefil, and 6.2% for Solitaire was observed when using the exponential mode as opposed to the standard. A significant (p = .04) reduction of marginal dye penetration was found only for Pertac II/EBS Multi at the cementum margins when the soft-start polymerization was used. For the sample thickness of 3 mm, a significant higher relative bottom to top surface ratio in favor of the standard exposure mode was found (p = .001)., Clinical Significance: Depending on the restorative material, soft-start polymerization may lead to a significant reduction in marginal microleakage of adhesive Class V restorations. This effect might be attributable to a significantly lower polymerization stress, as seen from photoelastic analysis, and/or a decrease in the degree of conversion, as deducted from surface hardness ratios. However, the effect of soft-start curing mode depends on the material itself, with the most effective response from hybrid resin-based composites.

Objective: To determine improvements in marginal adaptation of resin-based composite restorative systems by means of flow-composites (Solitaire 2/Gluma Solid Bond, Solitaire 2/Flow Line/Gluma Solid Bond, Point 4/Optibond Solo Plus, Point 4/Revolution/Optibond Solo Plus) and to determine the equality of simplified bonding systems (Solitaire 2/Gluma Comfort Bond, Tetric Ceram/Tetric Flow/Excite, Dyract AP/Prime & Bond NT/NRC, Pertac II/Prompt-L-Pop) in marginal gap formation., Methods: The marginal dye penetration (2% methylene-blue) was investigated separately for the approximal boxes of Class II mod-cavities with one cervical margin of the approximal box within enamel, the other within cementum. The surface analysis determined the percentage of dye-penetrated cervical and lateral margins of the approximal boxes, while the in depth investigation reported the mean dye penetration (mm) at both different cervical margins., Results: After thermocycling (5000 x , 5-55 degrees C) the percentage of dye penetration at the cervical cementum margins ranged from 16.5 +/- 5.9% (Solitaire/Flow Line/Gluma Solid Bond) to 82.8 +/- 5.7% (Pertac II/Prompt L-Pop), for the cervical enamel margins from 10.1 +/- 5.2% (Dyract AP/NRC/P & B NT) to 72.7 +/- 7.9% (Pertac II/Prompt L-Pop), and for the lateral enamel margins of the approximal boxes from 4.8 +/- 2.3% (Dyract AP/NRC/P & B NT) to 53.9 +/- 6.8% (Pertac II/Prompt L-Pop). In the in-depth dye penetration investigation the mean dye penetration ranged from 0.2 +/- 0.2 mm (Point 4/Revolution/Optibond Solo Plus) to 1.7 +/- 0.2 mm (Pertac II/Prompt L-Pop) at the cementum margins. At the enamel margins only Pertac II/Prompt L-Pop and Solitaire 2/Gluma Solid Bond showed mean in depth dye-penetrations deeper than 0.1 mm., Significance: Pertac II/Prompt-L-Pop showed a statistically significant (significance level alpha = 0.05, Wilcoxon test) higher percentage of dye-penetrated margins than most of the other restorative systems.

We evaluated a possible interaction between statins and inflammation in 1,246 patients with angiographically diagnosed coronary artery disease. Four different inflammatory markers were determined: high, sensitive C-reactive protein (hs-CRP) (p = 0.001), fibrinogen (p = 0.006), von Willebrand factor (p = 0.006), and leukocyte count (p = 0.03); these levels were significantly higher among the 88 patients who died of cardiac causes during follow-up (median 2.9 years) than among survivors. In a multivariate backward stepwise Cox regression mode, only hs-CRP was evaluated to be a significant predictor of death from coronary artery disease. This prediction was lost in statin-treated patients. Compared with patients receiving statin medication, patients without statins did not have increased cardiac mortality (even when low-density lipoprotein [LDL] levels were >125 mg/dl) when hs-CRP levels were not elevated. In contrast, patients without statins and elevated hs-CRP (top quartile) had a 2.3-fold increase in risk for fatal coronary events, independent of LDL levels. In conclusion, only elevated hs-CRP was selected as an independent predictor of death. Statin therapy is associated with elevated hs-CRP, with a risk reduction for fatal coronary events, independent of LDL levels; this, in part, may be explained by the anti-inflammatory effects on atherosclerosis.

It is a matter of controversy as to whether uric acid is an independent predictor of mortality in patients with coronary artery disease (CAD) or whether it represents only an indirect marker of adverse outcome by reflecting the association between uric acid and other cardiovascular risk factors. Therefore, we studied the influence of uric acid levels on mortality in patients with CAD. In 1,017 patients with angiographically proven CAD, classic risk factors and uric acid levels were determined at enrollment. A follow-up over a median of 2.2 years (maximum 3.1) was performed. Death from all causes was defined as an end point of the study. In CAD patients with uric acid levels <303 micromol/L (5.1 mg/dl) (lowest quartile) compared with those with uric acid levels >433 micromol/L (7.1 mg/dl) (highest quartile), the mortality rate increased from 3.4% to 17.1% (fivefold increase). After adjustment for age, both sexes demonstrated an increased risk for death with increasing uric acid levels (female patients: hazard ratio [HR] 1.30, 95% confidence intervals [CI] 1.14 to 1.49, p < or = 0.001; male patients: HR 1.39 [95% CI 1.21 to 1.59], p < or = 0.001). In multivariate Cox regression analysis performed with 12 variables that influence overall mortality-including diuretic use-elevated levels of uric acid demonstrated an independent, significant positive relation to overall mortality (HR 1.23 [95% CI 1.11 to 1.36], p <0.001) in patients with CAD. Thus, uric acid is an independent predictor of mortality in patients with CAD.

Background: Recent findings suggest a causative role of infections in the pathogenesis of atherosclerosis. In hypothesizing an association between infectious agents and the development of atherosclerosis, we would expect a correlation to the extent of atherosclerosis. Moreover, this effect could be multiplied by the number of pathogens to which an individual had been exposed., Methods and Results: In 572 patients, IgG or IgA antibodies to herpes simplex virus 1 and 2, cytomegalovirus, Epstein-Barr virus, Hemophilus influenzae, Chlamydia pneumoniae, Mycoplasma pneumoniae, and Helicobacter pylori were measured. The extent of atherosclerosis was determined by coronary angiography, carotid duplex sonography, and evaluation of the ankle-arm index. Elevated IgA antibodies against C pneumoniae (P<0.04) and IgG antibodies against H pylori (P<0.02), cytomegalovirus (P<0.05), and herpes simplex virus 2 (P<0.01) were associated with advanced atherosclerosis (> or =2 vascular regions), adjusted for age, sex, cardiovascular risk factors, and highly sensitive C-reactive protein. Infectious burden divided into 0 to 3, 4 to 5, and 6 to 8 seropositivities was significantly associated with advanced atherosclerosis, with an odds ratio (95% CI) of 1.8 (1.2 to 2.6) for 4 to 5 (P<0.01) and 2.5 (1.2 to 5.1) for 6 to 8 seropositivities (P<0.02) (adjusted). After a mean follow-up of 3.2 years, cardiovascular mortality rate was 7.0% in patients with advanced atherosclerosis and seropositive for 0 to 3 pathogens compared with 20.0% in those seropositive for 6 to 8 pathogens., Conclusions: Our results support the hypothesis that infectious agents are involved in the development of atherosclerosis. We showed a significant association between infectious burden and the extent of atherosclerosis. Moreover, the risk for future death was increased by the number of infectious pathogens, especially in patients with advanced atherosclerosis.

Background: Beneath its lipid-lowering properties additional non-lipid effects of statin therapy are discussed. We therefore examined the impact of statins on laboratory markers of coagulation, inflammation and soluble cell adhesion to further explore these effects in 950 hospitalised patients with angiographically proven CAD., Methods and Results: Although no significant differences were found in total cholesterol, LDL and HDL and triglyceride levels a statistically lower value in 277 statin-treated patients was found for von Willebrand factor [162(130/224) vs. 208(154/283)%, P=0.0001], leukocyte count [6.9(5.8/8.4) vs. 7.3(6.1/9.4)/nl, P=0.0005], high sensitive CRP [4.3(1.8/10.8) vs. 7.6(2.8/20.0) mg/dl, P=0.0001], interleukin-6 [9.5(5.1/18.7) vs. 14.4(7.2/28.1) mg/dl, P=0.0001] and soluble p-selectin [112.6(82.0/146.0) vs. 127.8(93.8/162.4) mg/dl, P=0.001] compared to 673 patients without statin therapy. This result was confirmed in a subgroup of 510 patients matched for age, gender and percentage of acute coronary syndromes., Conclusions: In statin treated patients significantly lower levels of coagulation, systemic inflammation and soluble cell adhesion markers were found. Therefore the effect of statin therapy may also be mediated by additional non-lipid-lowering effects.

Purpose: The trauma induced by balloon angioplasty has an impact on the outcome of coronary interventions, such as stent procedures. However, balloon inflation for PTCA is not yet standardized even though procedural and long-term outcomes might be affected., Methods: During routine PTCA, a total of 454 patients [mean age, 60.9 +/- 9.0 years; 162 (35.7%) with 1-vessel disease; 159 (35%) with 2-vessel disease; 133 (29.3%) with 3-vessel disease] were allotted to computer-assisted dilatation (CAPS) with a pressure slope of 0.2 bar/s (CAPS 0.2; n = 149 patients), 1.0 bar/s (CAPS 1.0; n = 154 patients) or to standard inflation with a hand-driven pump (n = 151 patients). Angiographic follow-up rates after 4.1 +/- 3.2 months were 88.1% for the hand-driven pump, 94% for CAPS 0.2 and 87.7% for CAPS 1.0., Results: Flow reducing (1.3-2.0%) and non-flow reducing (12.6-14.9%) dissections were equally distributed among all groups as were major adverse cardiac events (2.6-4.0%). The stent rate was 1.3% with the hand-driven pump, 0.7% with CAPS 0.2 and 1.3% with CAPS 1.0. Angiographic restenosis rate was 48.9% with the hand-driven pump, 44.3% with CAPS 0.2 and 32.6% with CAPS 1.0. (hand-driven pump versus CAPS 1.0, p < 0.007; CAPS 0.2 versus CAPS 1.0, p < 0.049)., Conclusions: The pressure slope during balloon inflation in PTCA has a significant impact on restenosis. The impact on stent procedures has yet to be determined.

Background: The number of infectious pathogens to which an individual has been exposed (infectious burden) may correlate with coronary artery disease (CAD). In a prospective study, we evaluated the effect of 8 pathogens and the aggregate pathogen burden on the risk for future fatal cardiac events among patients with angiographically documented CAD. Methods and Results-In 1018 patients, IgG or IgA antibodies to herpes simplex virus types 1 and 2, cytomegalovirus, Epstein-Barr virus, Haemophilus influenzae, Chlamydia pneumoniae, Mycoplasma pneumoniae, and Helicobacter pylori were determined. Moreover, highly sensitive C-reactive protein was measured. Follow-up information on cardiovascular events was obtained (mean 3.1 years, maximum 4.3 years). Seropositivities to Epstein-Barr virus (P=0.001), H pylori (P=0.002), and herpes simplex virus type 2 (P=0.045) were independently associated with the future risk of cardiovascular death. An increasing number for pathogen burden was significantly predictive of the long-term prognosis (P<0.0001). Infectious burden divided into 0 to 3, 4 or 5, and 6 to 8 seropositivities was associated with an increasing mortality of 3.7%, 7.2%, and 12.6%, respectively. Patients seropositive to >5 pathogens compared with those seropositive to <4 pathogens had a 5.1 (1.4 to 18.3) higher risk of future cardiac death. This result was mainly driven by the pathogen burden of seropositivities to Herpesviridae (P<0.0001). The prognostic impact of total or viral pathogen burden was independent of the C-reactive protein level., Conclusions: These results support the hypothesis that the number of infectious pathogens to which an individual has been exposed independently contributes to the long-term prognosis in patients with documented CAD.

We conducted a prospective, randomized trial to compare immediate and long-term effects of percutaneous transluminal coronary angioplasty (PTCA) and high-frequency rotational atherectomy (PTCR) in patients with angiographically predefined complex coronary artery lesions (AHA type B2 and C). The relation of lesion characteristics to procedural results is reported in this angiographic analysis. Patients were randomly assigned to balloon angioplasty (n = 250 patients) or rotational atherectomy (n = 252 patients). Quantitative coronary angiography could be performed in 447 patients to evaluate immediate results and in 293 patients with a 6-month angiographic follow-up. Procedural success was comparable in the PTCR and in the PTCA group (80% vs. 76%, P = 0.260). The need for stent implantation due to a residual stenosis >50% or a bail-out situation was significantly higher in the PTCA group (9.7% vs. 2.0%, P = 0.001). In both treatment groups, diameter stenosis was effectively reduced and MLD increased. The acute gain did not differ between the two groups. At 6-month control, the restenosis rate was comparable in the PTCR and in the PTCA group (37% vs. 35%, P = 0.658), whereas diameter stenosis was significantly more severe in the PTCR group than in the PTCA group (52% vs. 46%, P = 0.039) and, correspondingly, the MLD was significantly smaller in the PTCR group (1.29 mm vs. 1.44 mm, P = 0.031). Late loss was about the same in both groups, however, net gain and net gain index were significantly higher in the PTCA group (0.82 mm vs. 0.64 mm, P = 0.008; and 31% vs. 24%, P = 0.009). Analysis of procedural results for various lesion characteristics revealed no significant difference between treatment groups. In this randomized trial, complex coronary artery lesions were treated with comparable results for angiographic and procedural success and the restenosis rate by both, PTCA and PTCR. Late loss, however, was significantly higher and net gain significantly smaller after PTCR. Stents, although infrequently used, had a relevant impact on immediate PTCA results but not on late results. Cathet Cardiovasc Intervent 2001;53:359-367., (Copyright 2001 Wiley-Liss, Inc.)

Patients with paroxysmal atrial fibrillation (PAF) and dual chamber pacemakers frequently have short postventricular atrial blanking times and sensitive atrial sensing thresholds used to provide reliable detection and mode switching during AF. However, short atrial blanking times increase the risk of atrial sensing of ventricular far-field signals. We evaluated if the length of the atrial blanking time influences the detection of AF. The study included ten patients with a VDDR (n = 7) or DDDR system (n = 3), who presented with AF at 18 follow-up visits. Bipolar atrial sensing was programmed to the most sensitive value. Atrial blanking times were programmed from 100 to 200 ms in 25-ms steps in each patient. Using marker annotation, the following parameters were measured at ten consecutive ventricular beats: VAF = the interval between ventricular stimulus and first sensing of AF; AFS = the number of atrial-sensed events between two ventricular events; and XAF = the interpolated number of atrial-sensed events during atrial blanking time. The intervals between ventricular events and between atrial-sensed event markers showed no significant differences for the five blanking times tested. There was no significant influence of the atrial blanking time onto the measured parameters (least square means +/- standard error) with VAF between 281 +/- 12 and 300 +/- 12 ms (P = NS), AFs between 3.4 +/- 0.2 and 3.6 +/- 0.2 beats (P = NS) and XAF between 1.84 +/- 0.12 and 2.03 +/- 0.12 beats (P = NS). At ventricular rates < 100/min, the atrial sensing of AF in dual chamber pacemakers demonstrated no evidence for deterioration by an increase of the atrial blanking time from 100 to 200 ms. Thus, the risk of ventricular far-field sensing may be reduced without compromising atrial sensing.

Background: Lossless or lossy compression of coronary angiogram data can reduce the enormous amounts of data generated by coronary angiographic imaging. The recent International Study of Angiographic Data Compression (ISAC) assessed the clinical viability of lossy Joint Photographic Expert Group (JPEG) compression but was unable to resolve two related questions: (A) the performance of lossless modes of compression in coronary angiography and (B) the performance of newer lossy wavelet algorithms. This present study seeks to supply some of this information., Methods: The performance of several lossless image compression methods was measured in the same set of images as used in the ISAC study. For the assessment of the relative image quality of lossy JPEG and wavelet compression, the observers ranked the perceived image quality of computer-generated coronary angiograms compressed with wavelet compression relative to the same images with JPEG compression. This ranking allowed the matching of compression ratios for wavelet compression with the clinically viable compression ratios for the JPEG method as obtained in the ISAC study., Results: The best lossless compression scheme (LOCO-I) offered a mean compression ratio (CR) of 3.80:1. The quality of images compressed with the lossy wavelet-based method at CR = 10:1 and 20:1 was comparable to JPEG compression at CR = 6:1 and 10:1, respectively., Conclusion: The study has shown that lossless compression can exceed the CR of 2:1 usually quoted. For lossy compression, the range of clinically viable compression ratios can probably be extended by 50 to 100% when applying wavelet compression algorithms as compared to JPEG compression. These results can motivate a larger clinical study.

We examined the results of 1,835 magnetic field measurements in German residences conducted between November 1997 and September 1999. The measurements were part of an epidemiological study on the relationship between magnetic fields and childhood leukemia. We performed a fixed-location measurement of the magnetic field at 50 Hz and 16 2/3 Hz (frequency of the German railway system) over 24 h in the child's bedroom in the residence of each study participant. In addition, we conducted a second 24 h-measurement in the living room at 50 Hz, and spot measurements while walking through all rooms of the respective dwelling. Median 50 Hz magnetic fields above 0.2 muT were found to be infrequent in Germany (only 1.4% of all residences). Fields produced by high-voltage power lines (123-420 kV) were lower than expected: the median magnetic field was above 0.2 muT in only 8 (32.0%) of 25 residences located 50 m or closer to a high-voltage power line indicating that power lines in Germany are usually run well below the maximum power load. We found that magnetic fields were correlated with the type of residence and higher magnetic fields were measured in apartment buildings. There was also some evidence for a positive correlation between magnetic fields and traffic density and an inverse association between magnetic fields and family net income. The 24 h-magnetic field measurements correlated well with the spot measurements (r>0.7). However, when dichotomized with a cut-off point of 0.2 muT, there was only a poor agreement between the two measurement methods. A loss of the strength of the association after categorization was also observed when comparing the arithmetic mean and median of the same 24 h-measurement. In summary, these analyses give a valuable overview of magnetic field distributions in German residences.

Objectives: We sought to investigate up to which level of Joint Photographic Experts Group JPEG) data compression the perceived image quality and the detection of diagnostic features remain equivalent to the quality and detectability found in uncompressed coronary angiograms., Background: Digital coronary angiograms represent an enormous amount of data and therefore require costly computerized communication and archiving systems. Earlier studies on the viability of medical image compression were not fully conclusive., Methods: Twenty-one raters evaluated sets of 91 cine runs. Uncompressed and compressed versions of the images were presented side by side on one monitor, and image quality differences were assessed on a scale featuring six scores. In addition, the raters had to detect pre-defined clinical features. Compression ratios (CR) were 6:1, 10:1 and 16:1. Statistical evaluation was based on descriptive statistics and on the equivalence t-test., Results: At the lowest CR (CR 6:1), there was already a small (15%) increase in assigning the aesthetic quality score indicating "quality difference is barely discernible-the images are equivalent." At CR 10:1 and CR 16:1, close to 10% and 55%, respectively, of the compressed images were rated to be "clearly degraded, but still adequate for clinical use" or worse. Concerning diagnostic features, at CR 10:1 and CR 16:1 the error rate was 9.6% and 13.1%, respectively, compared with 9% for the baseline error rate in uncompressed images., Conclusions: Compression at CR 6:1 provides equivalence with the original cine runs. If CR 16:1 were used, one would have to tolerate a significant increase in the diagnostic error rate over the baseline error rate. At CR 10:1, intermediate results were obtained.

Purpose: To examine the stress reduction of different resin-based composites, cured with a two-step polymerization unit (Elipar Highlight) by means of a photoelastic investigation., Materials and Methods: For each material (Pertac II, Tetric Ceram, Charisma F, Solitaire, Dyract, Dyract AP, Definite), a minimum of 10 resin samples, embedded in acrylic-glass plates, were polymerized using a standard polymerization process of 700 mW/cm for 40 s. Another 10 samples were polymerized with a light output of 150 mW/cm2 for 10 s and then with a light output of 700 mW/cm2 for 30 s., Results: For Pertac II the reduction of polymerization stress in the two-step-mode was 15.5%, for Tetric Ceram 14.5%, for Solitaire 8.1%, for Dyract AP 6.5% and for Definite 4.7%. These differences in polymerization stress between the standard and two-step-polymerization mode were statistically significant (P < 0.01, Wilcoxon test). No statistically significant differences in polymerization stress could be found for Charisma F and Dyract.

Objective: We investigated the feasibility and short-term effects of a novel procedure to create intramyocardial channels by means of high frequency (HF) ablation in a rabbit in vivo model., Methods: A flexible catheter ending in a cylindrical electrode (diameter 0.7 mm) with a sharpened tip was used for HF energy application following transmyocardial insertion. Power-controlled or energy-controlled energy applications were performed in 16 anesthetized rabbits after thoracotomy with a follow-up for 3 h. Assessment of myocardial channels and the necrotic zone was performed by morphometric quantification in serial sections. The ferret diameter was used to compare channel dimensions and the extent of necrosis., Results: Thirty-nine power-controlled and 54 temperature-controlled HF applications were performed. The shape of identified channels was round in 71% and 69% had a lumen patency of > or =2/3 of the channel. Ferret diameter of the channels was 414 +/- 180 microm and of the necrotic zone 3,558 +/- 1,200 microm. In temperature-controlled applications, channel dimensions were strongly influenced by the maximum tissue temperature and the duration of energy delivery (T(max): p = 0.0006; duration: p = 0. 003). Channel and necrosis dimensions correlated better with biometric parameters in temperature-controlled compared with power-controlled applications., Conclusion: Mechanically created transmyocardial channels can be stabilized by HF heating of the surrounding tissue. A high percentage of these channels remain patent. The channel dimensions are closely correlated with maximum temperature and duration of energy delivery in a temperature-controlled application mode., (Copyright 2000 S. Karger AG, Basel)

Stromal extracellular matrix (ECM) components are thought to play an important role in regulating invasion of human gliomas. Macrophages and microglial cells may heavily influence the integrity of the extracellular compartment of gliomas, and the affected ECM may play a key role in regulating migratory activity of both tumor cells and macrophages/microglia. The aim of this investigation was to study immunohistochemically the expression patterns of four ECM components: fibronectin, laminin, collagen IV, and tenascin (TN) in human gliomas, with special attention to TN. Our main goal was to study the possible correlation between TN expression and macrophagic/microglial infiltration in gliomas. Altogether, 90 gliomas were studied. Tumors included 46 glioblastomas, 19 anaplastic gliomas, 22 low grade gliomas, and 3 pilocytic astrocytomas. Vascular TN prevailed in perinecrotic areas of glioblastomas, whereas interstitial TN was more often expressed distant from necrosis and in the ECM of anaplastic and low grade gliomas. Double staining with CD68 and anti-TN antibodies showed that macrophagic/microglial density was significantly higher in TN-positive areas of most of the glioblastomas and anaplastic gliomas, whereas microglial percentage from total number of CD68-positive cells was in most of the cases significantly higher in TN-negative areas. In addition, we saw a morphologically spatial correlation between higher densities of macrophagic/microglial infiltration and TN expression in perinecrotic areas in glioblastomas. Attachment of macrophages to TN-positive basement membrane zones of newly formed stromal blood vessels was evident. On the basis of our results, we conclude that TN may play a crucial role in regulating trafficking of cells of monocyte lineage in human gliomas.

Tissue Doppler echocardiography (TDE) is a new method by which transmural myocardial function can be studied noninvasively. In order to investigate physiology and reproducibility, 24 young, healthy volunteers were examined by M-mode TDE. Nonuniformity of transmural tissue layer velocities became apparent: Subendocardial and subepicardial velocities of the anteroseptal myocardial wall (AW) were 3.5 +/- 0.7 and 1.3 +/- 0.5 cm/sec (P < 0.0001, t-test), whereas in the posterolateral wall (PW) values of 3.6 +/- 0.6 and 1.2 +/- 0.4 cm/sec (P < 0.0001, t-test), respectively, were revealed. The ratios, termed "myocardial velocity gradients" as a new indicator of left ventricular performance, were 3.1 +/- 1.0 and 3.4 +/- 1.1, respectively. AW and PW did not differ (N.S.). Tolerance borders did not overlap, and intraobserver variability did not reach intersubject variability (P < 0.0001, F-ratio test). TDE provides new and more sophisticated insights into left ventricular performance. It seems to be accurate and reliable and therefore worth introducing into the clinical arena.