Biomedical subjects

Franz König

Publications and source records attributed to Franz König.

13 recordsLinked to original sources

PubMed2006

Estimation in flexible two stage designs.

Adaptive test designs for clinical trials allow for a wide range of data driven design adaptations using all information gathered until an interim analysis. The basic principle is to use a test statistics which is invariant with respect to the design adaptations under the null hypothesis. This allows for a control of the type I error rate for the primary hypothesis even for adaptations not specified a priori in the study protocol. Estimation is usually another important part of a clinical trial, however, is more difficult in adaptive designs. In this research paper we give an overview of point and interval estimates for flexible designs and compare methods for typical sample size rules. We also make some proposals for confidence intervals which have nominal coverage probability also after an unforeseen design adaptation and which contain the maximum likelihood estimate and the usual unadjusted confidence interval.

Clinical Trials as Topic↗

PubMed2006

Confirmatory seamless phase II/III clinical trials with hypotheses selection at interim: general concepts.

Traditional drug development consists of a sequence of independent trials organized in different phases. Full development typically involves (i) a learning phase II trial and (ii) one or two confirmatory phase III trial(s). For example, in the phase II trials several doses of the new compound might be compared to a control and/or placebo with the goal of deciding whether to stop or continue development and, in the latter case, selecting one or two "best" doses to carry forward into the confirmatory phase. The phase III trials are then conducted as stand-alone confirmatory studies, not incorporating in their statistical analyses data collected in the previous phases. Seamless phase II/III designs are aimed at interweaving the two phases of full development by combining them into one single, uninterrupted study conducted in two stages. In the dose-finding example above, one (or more) dose(s) are selected after the first stage based on the available data at interim, and are then observed further in the second stage. The final analysis of the selected dose(s) includes patients from both stages and is performed such that the overall type I error rate is controlled at a prespecified level regardless of the dose selection rule used at interim. The adequacy of the dose selection at interim is obviously a critical step for the success of a seamless phase II/III trial. In this paper we focus on the description of flexible test procedures allowing for adaptively selecting hypotheses at interim and thus allowing the combination of learning and confirming in a single seamless trial. We review the statistical background, introduce different test procedures and compare them in a power study. In a subsequent paper (Schmidli et al., 2006) we give several applications from our daily practice and discuss related implementation issues in conducting adaptive seamless designs.

Biometry↗

PubMed2006

An adaptive hierarchical test procedure for selecting safe and efficient treatments.

We consider the situation where during a multiple treatment (dose) control comparison high doses are truncated because of lack of safety and low doses are truncated because of lack of efficacy, e.g., by decisions of a data safety monitoring committee in multiple interim looks. We investigate the properties of a hierarchical test procedure for the efficacy outcome in the set of doses carried on until the end of the trial, starting with the highest selected dose group to be compared with the placebo at the full level alpha. Left truncation, i.e., dropping doses in a sequence starting with the lowest dose, does not inflate the type I error rate. It is shown that right truncation does not inflate the type I error if efficacy and toxicity are positively related and dose selection is based on monotone functions of the safety data. A positive relation is given e.g. in the case where the efficacy and toxicity data are normally distributed with a positive pairwise correlation. A positive relation also applies if the probability for an adverse event is increasing with a normally distributed efficacy outcome. The properties of such truncation procedures are investigated by simulations. There is a conflict between achieving a small number of unsafely treated patients and a high power to detect safe and efficient doses. We also investigated a procedure to increase power where a reallocation of the sample size to the truncated treatments and the control remaining at the following stages is performed.

Biometry↗

PubMed2006

Cytotoxicity of a calcium aluminate cement in comparison with other dental cements and resin-based materials.

The objective of this study was to compare the cytotoxic effects of a calcium aluminate cement with several currently used direct restorative materials. Specimens of three composites (QuiXfil, Tetric Ceram, Filtek Supreme), one zinc phosphate cement (Harvard Cement), one glass ionomer cement (Ketac Molar), and one calcium aluminate cement (DoxaDent), were used fresh or after 7-days' preincubation in cell culture medium at 37 degrees C, pH 7.2. PVC strips for ISO 10993-5 cytotoxicity test were used as positive control and glass specimens as negative control. L-929 fibroblasts (5-ml aliquots, containing 3 x 10(4) cells/ml), cultivated in DMEM with 10% FCS, 1% glutamine, and 1% penicillin/streptomycin at 37 degrees C/5% CO2 and trypsinized, were exposed to the specimens for 72 h. The cells were harvested, centrifuged, and resuspended in 500 microl DMEM and then counted in 500 microl DMEM for 30 s with a flow cytometer at 488 nm. The analysis of variance comparing the six materials showed different influences on L-929 fibroblast cytotoxicity (p <0.0001). The cytotoxicity of all specimens diminished with increasing preincubation time (p <0.0001). Fresh DoxaDent exhibited the lowest cytotoxicity, followed by QuiXfil. Ketac Molar showed the highest cytotoxicity. After 7 days of preincubation, Harvard Cement and Filtek Supreme demonstrated more cytotoxicity than the other materials (p <0.005).

Aluminum Compounds↗

PubMed2005

Allergen-specific nasal IgG antibodies induced by vaccination with genetically modified allergens are associated with reduced nasal allergen sensitivity.

BACKGROUND: We have performed a double-blind, placebo-controlled injection immunotherapy study with genetically modified derivatives of the major birch pollen allergen, Bet v 1 (Bet v 1-trimer, Bet v 1-fragments). OBJECTIVE: To investigate whether vaccination with genetically modified allergens induces allergen-specific antibodies in nasal secretions and to study whether these antibodies affect nasal allergen sensitivity. METHODS: A randomly picked subgroup of patients (n = 23; placebo, n = 10; trimer, n = 10; fragments, n = 3) was subjected to an extensive analysis of serum samples and nasal lavage fluids and to nasal provocation testing. Bet v 1-specific IgG(1-4) and IgA antibodies were determined in serum samples obtained before and after vaccination, after the birch pollen season, and 1 year after start of vaccination as well as in nasal lavage fluids obtained after the birch pollen season and 1 year after start of vaccination by ELISA. Nasal sensitivity to natural, birch pollen-derived Bet v 1 was determined by active anterior rhinomanometry after the birch pollen season and 1 year after start of vaccination. RESULTS: Vaccination with genetically modified Bet v 1 derivatives, but not with placebo, induced Bet v 1-specific IgG1, IgG2, and IgG4, and low IgA antibodies in serum, which also appeared in nasal secretions, but no IgG3 antibodies. The levels of therapy-induced Bet v 1-specific IgG4 antibodies in nasal secretions were significantly (P < .05) associated with reduced nasal sensitivity to natural, birch pollen-derived Bet v 1 as objectively determined by controlled nasal provocation experiments. CONCLUSION: Our data demonstrate that vaccination with genetically modified allergens induces IgG antibody responses against the corresponding natural allergen not only in serum but also in mucosal fluids, where they may protect against allergen-induced inflammation.

Adult↗

PubMed2005

Effect of information on reported adverse events in a placebo-controlled trial.

OBJECTIVE: Although placebo controls are a standard measure in clinical trials the mechanisms underlying placebo effects are still not fully understood. We hypothesised that information about the likelihood of receiving placebo might influence the perception of adverse effects in volunteers participating in a clinical trial. METHODS: Healthy subjects received either nifedipine 20 mg or placebo in an adaptive two-stage crossover study. Sixty subjects were randomised to a group given either correct (50% chance) or misleading (100% chance) information about the likelihood of receiving the active drug. A sum of the severity scores from visual analogue scales over all individual adverse effects was defined as the primary endpoint. RESULTS: The analysis revealed no difference in the primary endpoint between the two groups. This lack of difference may in part be attributable to a conditioning effect as on the first study day higher symptom scores were reported by the participants than on the second study day. Furthermore, the day effect seemed to arise mainly when the first day treatment was the placebo. For the placebo the day effect was clearly significant (p = 0.012), with higher scores on the first day. A further explorative finding in patients given placebo was a tendency for higher scores in the group with the misleading information (p = 0.08). Nothing of that sort was found in the analysis for active treatment. The day effect collapsed and the factor information did not show any tendency of being a potential influence. CONCLUSIONS: In the present study we did not find a statistically significant effect of misleading information on reported adverse events. The large treatment and day effects observed made it difficult to detect a potential small information effect. However, this study excluded a strong and relevant effect of information on the frequency and severity of reported adverse events.

Adult↗

PubMed2004

Transjugular intrahepatic portosystemic shunt in Vienna--a decade later.

Implantation of a transjugular intrahepatic portosystemic shunt (TIPS) for therapy of portal hypertension has been available in Vienna, Austria, since 1991. Ten years of experience with this technique led the Vienna TIPS Study Group to retrospectively analyse characteristics and outcome of all patients undergoing TIPS in Vienna between 1991 and 2001. Survival and subgroup analyses were performed using Mann Whitney U-tests, log-rank tests, Spearman's correlation and Kaplan-Meier analyses. A total of 523 patients underwent TIPS; 23 for acute variceal bleeding, 350 for prevention of variceal bleeding, and 109 for therapy of refractory ascites. Portal hypertension was caused by cirrhosis in 503 patients; 20 presented with other diseases. 253 patients died within the study period, median follow-up was 5.07 years, median survival 4.51 years. The 3-month, 1-year, 3-year, and 5-year survival rates were 83%, 71%, 57%, and 49%, respectively. Etiology of cirrhosis had no effect on survival; patients with TIPS for refractory ascites had poorer survival rates than those undergoing TIPS for prevention of rebleeding. TIPS is a safe and effective therapy for patients with portal hypertension. The first decade of TIPS in Vienna has shown, in line with other publications, that good criteria for patient selection, effective post-interventional management, and close cooperation between internists, interventional radiologists and liver-transplant centers are the key for a good outcome.

Adolescent↗

PubMed2004

Reading performance depending on the type of cataract and its predictability on the visual outcome.

PURPOSE: To investigate the influence of various types of cataract on reading performance in a standardized reading test setting. SETTING: Department of Ophthalmology, University of Vienna, Vienna, Austria. METHODS: The reading performance of 94 eyes with age-related cataract and normal macular function was evaluated with the Radner Reading Charts preoperatively and 4 weeks after cataract surgery. Distance visual acuity was tested with the ETDRS charts. Cataracts were graded using the Lens Opacities Classification System (LOCS) III, on which NO is nuclear opalescence and NC is nuclear color. RESULTS: Patients with pure nuclear cataracts (LOCS III: NO/NC 2.1-5) achieved a normally high MRS (99.84% +/- 7.65% of their postoperative MRS): preoperative MRS(1): 190.6 +/- 30.74 words per minute (wpm); postoperative MRS(2): 191.21 +/- 29.36 wpm. Patients with mixed nuclear-cortical cataracts (LOCS III: NO/NC 2.1-5; C>2) preoperatively achieved 96.96% +/- 5.6% of their postoperative MRS (MRS(1): 175.77 +/- 31.54 wpm; MRS(2): 181.34 +/- 30.56 wpm). In dense nuclear cataracts (LOCS III: NO/NC>5), the MRS was significantly reduced, achieving only 72.64 +/- 19.19% of the postoperative MRS (MRS(1): 133.06 +/- 39.43 wpm; MRS(2): 185.76 +/- 40.18 wpm). In posterior subcapsular cataracts, the preoperative MRS (134.1 +/- 33.72 wpm) was significantly lower than postoperatively (191.14 +/- 27.08 wpm). CONCLUSIONS: In contrast to dense nuclear cataracts and posterior subcapsular cataracts, the preoperative reading speed of patients with pure nuclear or nuclear-cortical cataracts was normal at large print sizes. The preoperative evaluation of reading acuity and speed with standardized reading tests can therefore be used to estimate the postoperative reading performance in the latter 2 types of cataract.

Aged↗

PubMed2003

Reliability of a standardized reading chart system: variance component analysis, test-retest and inter-chart reliability.

BACKGROUND: The purpose of this study was to analyze statistically the test-retest and inter-chart reliability of three standardized Radner Reading Charts with respect to reading acuity, maximum reading speed, critical print size and LogRAD/LogMAR ratio and to quantitatively identify the sources of variability. METHODS: At two testing sessions (3 to 4 weeks apart), 36 volunteers read monocularly all three Radner Reading Charts in randomized order (orthogonal Latin square design). The subjects were grouped according to their distance LogMAR visual acuity (group 1, 0.1 or better; group 2, 0.12-0.4; group 3, 0.42-0.8). Based on these 216 reading tests, crude correlations were calculated between the two testing sessions and between the three charts, and "variance component analyses" were performed for all variables. RESULTS: For all visual acuity groups and variables, the test-retest and the inter-chart reliability was high. The variance component analyses showed that the differences between individuals predominantly influenced the variance, whereas the effect of the test replication was low. The three charts caused minimal variability, indicating equality for clinical examinations. CONCLUSION: The standardized Radner Reading Charts provide clinically reliable and reproducible results for individuals with normal eyesight and for patients with visual impairment. These findings indicate that reading test systems, which consider the current international standards for visual acuity measurements (EN ISO 8596, NAS-NRC) and the psychophysical requirements for controlling optical item interactions, can provide reliable measures for clinical and scientific analyses of reading performance.

Aged↗

PubMed2003

Cytotoxic effects of packable and nonpackable dental composites.

OBJECTIVE: Advanced dental packable and nonpackable composite materials have been recently introduced onto the market as 'amalgam alternatives' for the restoration of posterior teeth. Most established composites are applied in increments of no more than 2mm and light cured to ensure complete polymerization, whereas new formulations have been claimed to be suitable for application in increments of 4-5mm. The aims of the present study were to analyze the cytotoxicity of these new composites in comparison to an established nonpackable composite using standardized cell culture systems and to examine the influence of thickness of the light cured increments on the cytotoxicity of these materials. METHODS: Specimens were prepared in polyethylene tubes covered with mylar. All materials were light cured in 2.5 or 5mm increments with a Demetron curing light (light intensity: 550 mW/cm(2)). Specimens were added to the cultures immediately after production or after preincubation for 1, 2, 7 days or 6 weeks under cell-culture conditions. Specimens were incubated with L-929 fibroblasts for 72 h and cell numbers determined by flow cytometry. In a different series of experiments, dopaminergic cells were incubated with composite supernatants. RESULTS: Results with L-929 fibroblasts demonstrated that all freshly prepared composite materials reduced cell numbers (p<0.05) in comparison to controls. The cytotoxicity of all substances diminished after increasing preincubation times (p<0.0001). In a rank order of cytotoxicity, the established composite and two of the advanced composite materials exhibited least cytotoxicity, whereas the other advanced composites showed moderate or severe cytotoxic effects. The cytotoxicity of each material was much higher when polymerized in 5mm increments than in 2.5mm composite increments (p<0.0001). SIGNIFICANCE: Our data demonstrate that the advanced composites tested show similar or more severe cytotoxicity than an established nonpackable composite and that cytotoxicity of all materials investigated increases when applied in a 5mm bulk increment.

Animals↗

PubMed2003

The fluorohydroxyapatite (FHA) FRIOS Algipore is a suitable biomaterial for the reconstruction of severely atrophic human maxillae.

Grafting of the maxillary sinus is an established treatment modality to provide sufficient bone for the fixation of dental implants. We stated the hypothesis that the porous fluorohydroxyapatitic (FHA) biomaterial FRIOS Algipore could be used as a suitable biomaterial for sinus grafting in severely atrophic maxillae. To investigate the accuracy of our hypothesis, 69 trephine specimens from 26 patients who received maxillary sinus grafting with FRIOS Algipore were retrieved during the installation of dental implants. The specimens were processed undecalcified and subjected to histomorphological and histomorphometrical examination. After a mean healing time of 7 months, 23.0% (+/-8.3) new bone had formed around the implanted particles. Bone formation was also evident within the pores of the particles. Statistical analysis indicated that bone formation originated from the sinus floor. Particles provided scaffolding for the promotion of newly formed bone towards apical sinus portions. Mineral dissolution from the walls of the pores was observed prior to and during bone apposition. Thereafter, portions of the particles were resorbed during bone remodeling and replaced by newly formed bone. The present investigation shows that the biomaterial FRIOS Algipore is a suitable biomaterial for sinus grafting of severely atrophic maxillae.

Adult↗

PubMed2002

[Psychosocial characteristics of victims of suicide in prisons].

BACKGROUND: Besides some cases reported by the media in recent years about prison inmates who committed suicide, hardly anything is known concerning social, criminological and psychiatric characteristics of suicide victims in jails and prisons in Austria. It therefore seems necessary to evaluate jail and prison suicides in order to establish effective means of prevention. METHODS: A study was conducted evaluating all suicides in Austrian prisons between 1975 and 1999. In addition to nationality, education and working status, other indicators of social integration and psychiatric history of suicide victims were studied. RESULTS: 220 personal files of 250 suicides were available. During the observation period the suicide rate of imprisoned foreigners decreased slightly (mean 106.6/100,000), whereas the suicide rate of Austrian citizens increased significantly (mean 172.0/100,000). Of all suicide victims, 41% had neither finished school nor had they any professional education. 44% were unemployed before incarceration, 50% did not work while incarcerated. A high frequency of suicidal behavior amongst suicide victims before committing suicide (49% suicide attempts, 37% suicide threats), and a high prevalence of mental disorders (37% psychopharmacological treatment, 48.6% were assessed by a psychiatrist) could be detected. CONCLUSIONS: Screening instruments should be applied which are easy to handle for prison officers and indicate the appropriate management of inmates at a high suicide risk.

Adult↗

PubMed2002

Vascular endothelial growth factor (VEGF) and discrimination between abnormal intrauterine and ectopic pregnancy.

BACKGROUND: This study evaluated serum vascular endothelial growth factor (VEGF) levels in women with abnormal intrauterine and ectopic pregnancies (EP) at 6 weeks gestation. METHODS: We conducted a prospective case-control study comparing serum VEGF concentrations among 84 women with abnormal intrauterine and EP matched for gestational age (42 women in each group). We analysed whether serum VEGF levels >200 pg/ml would discriminate between abnormal intrauterine pregnancies and EP at 6 weeks gestation, and we calculated sensitivity, specificity and positive predictive values. RESULTS: Serum VEGF concentrations did not show statistically significant differences between women with abnormal intrauterine pregnancies (median, 198.5 pg/ml; range, 0-701.6) and EP (median, 211.2 pg/ml; range 0-628.8). When threshold concentrations of a serum VEGF level >200 pg/ml were used, abnormal intrauterine pregnancy could be distinguished from EP with a sensitivity of 56%, a specificity of 51%, and a positive predictive value of 53%. CONCLUSIONS: VEGF does not discriminate ectopic from abnormal intrauterine pregnancies at 6 weeks gestation, and thus should not be used in clinical management.

Adult↗