Assessing the implementation of a comprehensive quality management system for cross-sectoral psycho-oncology in Germany.

INTRODUCTION: Quality management in healthcare is essential for safe, effective, and patient-centered services. Quality management systems (QMS) monitor and improve healthcare quality. Integrating QMS is crucial for optimal quality of care, but previous studies show gaps in integration. This study aims to assess program adherence to a QMS in cross-sectoral psycho-oncological care and to develop strategies for better integration, ultimately improving healthcare quality. MATERIALS AND METHODS: The study used a utility analysis to assess the program adherence of a cross-sectoral psycho-oncology care program using a 5-point scale. The evaluation process involved breaking down the program into distinct areas, and used key figures and developed indicators to assess adherence. Descriptive statistics were used. RESULTS: The study conducted a comprehensive assessment of program adherence in a complex care program, analysing 4460 evaluation cases based on 128 quality indicators. The results showed a score of 4.2 out of 5 points (84%), indicating a highly effective implementation of the QMS. Notably, the study observed successful implementation of top-down elements, while encountering more challenges in integrating bottom-up aspects. CONCLUSION: The study demonstrates effective implementation of a comprehensive QMS. Successful integration was observed in areas such as care concept, care management, quality assurance, and IT-based documentation, while challenges remain in quality development and indicators. Active leadership involvement, staff training, data collection, and a learning culture are essential for successful implementation. Future research should assess the impact and cost-effectiveness of QMSs and develop tailored approaches to sustain healthcare professionals' motivation in quality improvement efforts.

Current eczema in children is related to Der f 1 exposure but not to Der p 1 exposure.

BACKGROUND: Mite allergen exposure is an important risk factor for specific IgE production and is associated with asthma, hay fever and eczema. Whether these associations are independent of mite species has not been investigated so far. OBJECTIVES: To investigate the influence of exposure to the major house dust mite (HDM) allergens Der p 1 and Der f 1 on sensitization, respiratory symptoms, and especially on eczema and related skin symptoms in 6-7-year-old children. METHODS: In a cross-sectional study in Augsburg (Bavaria, Germany) 1669 school beginners (mean age 6.5 years) were investigated in 1996. The concentrations of Der p 1 and Der f 1 were measured in dust samples from mattresses of 1081 children by enzyme-linked immunosorbent assay. The prevalence of atopy-related health outcomes was assessed by questionnaire, dermatological examination, skin prick testing and determination of specific serum IgE concentrations by radioallergosorbent test. Information about covariates was taken from questionnaires and interview data. Logistic regression was used to adjust for confounding. RESULTS: The mean concentrations of Der p 1 and Der f 1 were 0.68 and 0.79 microg g(-1) dust, respectively. The relationship between the two species-specific allergens in individual homes was poor (Pearson correlation 0.2). Influencing variables were bedroom-sharing (Der p 1) and social status of the parents (Der f 1). Respiratory diseases were positively associated with both allergen concentrations [odds ratio (OR) between 1.1 and 2.6]. These associations were significant for sneezing attacks (Der p 1 and Der f 1). Reported prevalence of current (in the last 12 months) itchy skin rash was significantly associated with exposure to Der f 1 only (OR 2.4, P < 0.003); also a diagnosis of atopic eczema on the day of investigation was positively associated with Der f 1 only (OR 1.8, P = 0.14). CONCLUSIONS: Studies on the effects of HDM exposure on eczema and allergies should consider specific effects of different mite species. This might have implications on assessment of allergen exposure and consecutive prevention or therapeutic measures.

The effect of environmental tobacco smoke on eczema and allergic sensitization in children.

BACKGROUND: The negative impact of environmental tobacco smoke (ETS) on airway diseases in children is well known. Whether there is an effect on atopic eczema is not clear. OBJECTIVES: To determine the impact of ETS on atopic eczema, allergic sensitization and allergic airway diseases in 1669 school beginners. METHODS: The prevalence of atopy-related health outcomes was assessed by questionnaire, dermatological examination, skin prick testing and specific immunoglobulin E measurement. Exposure assessments were based on measurement of cotinine [expressed as cotinine to creatine ratio (CCR)] in spot urine samples (n = 1220) together with questionnaire and interview data on smoking behaviour of the parents. RESULTS: In the total study group, prevalence of atopic eczema diagnosed on examination was significantly associated with urinary CCR values. The odds ratio (OR) and 95% confidence interval (CI), calculated for an increase of 100 ng mg-1 CCR was 1.97 (95% CI 1.23-3.16). The prevalence of skin manifestations according to questionnaire data as well as a history of asthma, wheezing, and hay fever were positively although not significantly associated with ETS exposure. When genetically predisposed children (defined by the presence of parental atopy) were compared with children whose parents had no atopy, the ORs of allergic outcome variables were generally higher in the first group. In the group of predisposed children, significant associations with urinary CCR were found for allergic sensitization against house dust mites as measured by skin prick test (OR 3.10, 95% CI 1.63-5.90). CONCLUSIONS: Children are at a higher risk of developing an atopic eczema when exposed to ETS and genetically predisposed children are at higher risk of developing a sensitization against house dust mites.

Computational methods for the structural alignment of molecules.

In drug design, often enough, no structural information on a particular receptor protein is available. However, frequently a considerable number of different ligands is known together with their measured binding affinities towards a receptor under consideration. In such a situation, a set of plausible relative superpositions of different ligands, hopefully approximating their putative binding geometry, is usually the method of choice for preparing data for the subsequent application of 3D methods that analyze the similarity or diversity of the ligands. Examples are 3D-QSAR studies, pharmacophore elucidation, and receptor modeling. An aggravating fact is that ligands are usually quite flexible and a rigorous analysis has to incorporate molecular flexibility. We review the past six years of scientific publishing on molecular superposition. Our focus lies on automatic procedures to be performed on arbitrary molecular structures. Methodical aspects are our main concern here. Accordingly, plain application studies with few methodical elements are omitted in this presentation. While this review cannot mention every contribution to this actively developing field, we intend to provide pointers to the recent literature providing important contributions to computational methods for the structural alignment of molecules. Finally we provide a perspective on how superposition methods can effectively be used for the purpose of virtual database screening. In our opinion it is the ultimate goal to detect analogues in structure databases of nontrivial size in order to narrow down the search space for subsequent experiments.

Application of parameter optimization to molecular comparison problems.

Various bioinformatics comparison problems require optimizing several different properties simultaneously. Often linear objective functions combine the values for different properties of solution candidates into a single score to allow for multivariate optimization. In this context, an essential question is how each property should be weighted. Frequently, no apparent measure is available to serve as a model for the score. However, if preferences of certain solution candidates over others in a training set are available, the implied partial ordering may be used to best possibly adjust the weights. We apply different strategies to optimize the parameterization of empirical scoring functions used for two molecular comparison problems, protein threading and small molecule superposition. Using well established evaluation methods, it can be shown that the results of both comparison methods are significantly improved by systematically choosing appropriate weights for the scoring function contributions.

RigFit: a new approach to superimposing ligand molecules.

If structural knowledge of a receptor under consideration is lacking, drug design approaches focus on similarity or dissimilarity analysis of putative ligands. In this context the mutual ligand superposition is of utmost importance. Methods that are rapid enough to facilitate interactive usage, that allow to process sets of conformers and that enable database screening are of special interest here. The ability to superpose molecular fragments instead of entire molecules has proven to be helpful too. The RIGFIT approach meets these requirements and has several additional advantages. In three distinct test applications, we evaluated how closely we can approximate the observed relative orientation for a set of known crystal structures, we employed RIGFIT as a fragment placement procedure, and we performed a fragment-based database screening. The run time of RIGFIT can be traded off against its accuracy. To be competitive in accuracy with another state-of-the-art alignment tool, with which we compare our method explicitly, computing times of about 6 s per superposition on a common day workstation are required. If longer run times can be afforded the accuracy increases significantly. RIGFIT is part of the flexible superposition software FLEXS which can be accessed on the WWW [http:/(/)cartan.gmd.de/FlexS].

FLEXS: a method for fast flexible ligand superposition.

If no structural information about a particular target protein is available, methods of rational drug design try to superimpose putative ligands with a given reference, e.g., an endogenous ligand. The goal of such structural alignments is, on the one hand, to approximate the binding geometry and, on the other hand, to provide a relative ranking of the ligands with respect to their similarity. An accurate superposition is the prerequisite of subsequent exploitation of ligand data by either 3D QSAR analyses, pharmacophore hypotheses, or receptor modeling. We present the automatic method FLEXS for structurally superimposing pairs of ligands, approximating their putative binding site geometry. One of the ligands is treated as flexible, while the other one, used as a reference, is kept rigid. FLEXS is an incremental construction procedure. The molecules to be superimposed are partitioned into fragments. Starting with placements of a selected anchor fragment, computed by two alternative approaches, the remaining fragments are added iteratively. At each step, flexibility is considered by allowing the respective added fragment to adopt a discrete set of conformations. The mean computing time per test case is about 1:30 min on a common-day workstation. FLEXS is fast enough to be used as a tool for virtual ligand screening. A database of typical drug molecules has been screened for potential fibrinogen receptor antagonists. FLEXS is capable of retrieving all ligands assigned to platelet aggregation properties among the first 20 hits. Furthermore, the program suggests additional interesting candidates, likely to be active at the same receptor. FLEXS proves to be superior to commonly used retrieval techniques based on 2D fingerprint similarities. The accuracy of computed superpositions determines the relevance of subsequently performed ligand analyses. In order to validate the quality of FLEXS alignments, we attempted to reproduce a set of 284 mutual superpositions derived from experimental data on 76 protein-ligand complexes of 14 proteins. The ligands considered cover the whole range of drug-size molecules from 18 to 158 atoms (PDB codes: 3ptb, 2er7). The performance of the algorithm critically depends on the sizes of the molecules to be superimposed. The limitations are clearly demonstrated with large peptidic inhibitors in the HIV and the endothiapepsin data set. Problems also occur in the presence of multiple binding modes (e.g., elastase and human rhinovirus). The most convincing results are achieved with small- and medium-sized molecules (as, e.g., the ligands of trypsin, thrombin, and dihydrofolate reductase). In more than half of the entire test set, we achieve rms deviations between computed and observed alignment of below 1.5 A. This underlines the reliability of FLEXS-generated alignments.

Time-efficient flexible superposition of medium-sized molecules.

We present an efficient algorithm for the structural alignment of medium-sized organic molecules. The algorithm has been developed for applications in 3D QSAR and in receptor modeling. The method assumes one of the molecules, the reference ligand, to be presented in the conformation that it adopts inside the receptor pocket. The second molecule, the test ligand, is considered to be flexible, and is assumed to be given in an arbitrary low-energy conformation. Ligand flexibility is modeled by decomposing the test ligand into molecular fragments, such that ring systems are completely contained in a single fragment. Conformations of fragments and torsional angles of single bonds are taken from a small finite set, which depends on the fragment and bond, respectively. The algorithm superimposes a distinguished base fragment of the test ligand onto a suitable region of the reference ligand and then attaches the remaining fragments of the test ligand in a step-by-step fashion. During this process, a scoring function is optimized that encompasses bonding terms and terms accounting for steric overlap as well as for similarity of chemical properties of both ligands. The algorithm has been implemented in the FLEXS system. To validate the quality of the produced results, we have selected a number of examples for which the mutual superposition of two ligands is experimentally given by the comparison of the binding geometries known from the crystal structures of their corresponding protein-ligand complexes. On more than two-thirds of the test examples the algorithm produces rms deviations of the predicted versus the observed conformation of the test ligand below 1.5 A. The run time of the algorithm on a single problem instance is a few minutes on a common-day workstation. The overall goal of this research is to drastically reduce run times, while limiting the inaccuracies of the model and the computation to a tolerable level.

Insanity and filicide: women who murder their children.

A mother who murders her child challenges the empathic skills of evaluating clinicians. In this chapter, original research, supplemented by detailed case histories, compares women adjudicated criminally responsible for the murders of their children with those adjudicated not guilty by reason of insanity.

Criminal responsibility and solvent exposure.

This case report contains the history of a man's exposure to benzene, trichloroethylene, and toluene. J suffered acutely from classic symptoms of toxic exposure to these compounds, such as fatigue, clumsiness, staggering, and hematopoietic depression. During his medical hospitalization, he was exposed to further organic insults, such as being treated with medications like Cytoxan and medications to treat an abscess in his right parietal lobe. After the acute exposure and after the abscess had resolved, his functioning on neuropsychological testing was still depressed, as he had a Full Scale IQ of 105, whereas at the time of the forensic evaluation he had a Full Scale IQ of 114. It would therefore appear that he did have some mild deficits when originally discharged from the hospital. While he reported having continual mental status changes at the time of the offense and even at the time of the forensic evaluation, it was not felt that these played a significant role in the commission of the offense. Comprehensive forensic evaluation suggested that psychological reactions to his illness and an underlying personality disorder were more direct contributors to the criminal acts. J was therefore recommended and ultimately found to be responsible for his behavior, according to the law.

Low fat diet decreases alpha-tocopherol levels, and stimulates LDL oxidation and eicosanoid biosynthesis in man.

The effects of a conventional 1000 kcal diet, and of a further restriction of dietary fat by a fat substitute, on the concentrations of vitamin A and E in plasma and LDL, the formation of lipid peroxides and eicosanoids were investigated in 10 obese volunteers. In vitro copper catalyzed oxidation of conjugated dienes, lipid peroxides and TBARS activity, measured in LDL samples after week 2 (supplementation with 140 mg/d alpha-tocopherol and 5000 IU retinol-acetat for two weeks), week 6 (conventional diet) and week 10 (fat substitute), increased with vitamin E depletion statistically significant after week 10 compared to the values after week 2. Concomitantly, PGE2 and LTB4, determined by RIA, increased to 344% and 166%, respectively, compared to the values after week 2. PGM, determined as tetranorprostanedioic acid by GC-MS, increased to 120%. Stimulation of lipid peroxidation and eicosanoid formation was more pronounced in persons with initially low (19 - 26 micromol/l plasma) than in those with high (37 - 70 pmol/l plasma) concentrations of alpha-tocopherol. We conclude that fat restricted diets can lead to an unwanted stimulation of lipid peroxidation and eicosanoid formation, which may be relevant in states of disease, e. g. arteriosclerosis or rheumatoid arthritis.

Modulation of the endogenous leukotriene production by fish oil and vitamin E.

We investigated the effects of fish oil and vitamin E on the endogenous leukotriene production. 10 healthy volunteers were supplemented for 1 week with fish oil (containing 40 mg/kg body weight per day of eicosapentaenoic and docosahexaenoic acid), vitamin E (540 mg, i.e., 800 IU of D-alpha-tocopherol per day), or with both agents. Treatment resulted in a significant increase in the eicosapentaenoate concentration in red blood cell membranes and/or in the vitamin E concentration in serum. In addition, nine obese patients were investigated who were on a hypocaloric diet including 10 mg vitamin E/day for 8 weeks. This diet was associated with a significant decrease in serum vitamin E concentration. The urinary concentration of leukotriene E4 plus N-acetylleukotriene E4 served as a measure for the endogenous leukotriene production. Fish oil reduced leukotriene production in eight of the 10 healthy individuals. After vitamin E supplementation, urinary leukotrienes were significantly reduced in all of the healthy volunteers. The combination of vitamin E plus fish oil had no synergistic effect on leukotriene production in the individuals tested. The decrease in serum vitamin E concentration during the hypocaloric, 10 mg vitamin E/day diet was associated with an increase in urinary leukotrienes in 8 of the 9 obese patients. Urinary prostaglandin metabolites, determined as tetranorprostanedioic acid, increased or decreased in parallel with urinary leukotrienes in most individuals; however, changes were less pronounced than those observed with leukotrienes. We conclude that the endogenous leukotriene production can be reduced effectively by high doses of fish oil or vitamin E, whereas vitamin E depletion is associated with an increase in leukotriene generation.

Influence of nifedipine on the metabolism of gingival fibroblasts.

Calcium antagonists are the gold standard in the therapy of coronary heart disease and hypertension. The prototype of these drugs is nifedipine which, as well as its therapeutic effects on the cells of the cardiovascular system, also has unpleasant side effects on other organ systems. One side effect can be a missive hyperplasia of the gingiva, the reason for which are unclear. In vitro experiments were designed to elucidate the influence of nifedipine on the growth of human gingival fibroblasts in short and long term (72 hours, 6 weeks) cell culture. The following cellular parameters were determined quantitatively: cell proliferation (cell count, [3H]thymidine incorporation), protein synthesis ([3H]glucosamine incorporation) and viability (release of lactate dehydrogenase). A significant increase in cell proliferation (up to 1 microgram/ml nifedipine) was observed in the short-term experiments (72 hours, 0.001-10 micrograms/ml nifedipine), no other parameters were altered or were even depressed at higher concentrations. A significant increase in the cell proliferation and a decrease in the proteoglycan synthesis was found in the long term experiments (6 weeks, 1 microgram/ml nifedipine). Our results indicate that nifedipine has a direct effect on the cell proliferation of the gingival fibroblast in cell culture. The effect of nifedipine on the gingival fibroblasts are therefore similar to those observed earlier by the widely used immunosuppressant drug cyclosporin A on human gingival fibroblast in culture.

Influence of cyclosporine A on growth and extracellular matrix synthesis of human fibroblasts.

Cyclosporine A (CyA) is a powerful nonsteroidal immunosuppressive agent used to prevent graft rejection of organ and bone marrow transplants. A major side effect observed can be attributed to the fibroblast and its functions: proliferation of fibroblasts and formation of fibrotic tissue in the gingiva (fibrous hyperplasia) and in the kidney are induced. The mechanism of both is still obscure. In order to elucidate whether these side effects are due to the drug acting on human fibroblasts itself or whether they are indirect ones mediated by factors released by lymphocytes, cultures of human gingiva fibroblasts were exposed to CyA under defined in vitro conditions. Incubation with CyA for 72 hours resulted in a dose-dependent stimulation of DNA synthesis, whereas glycosaminoglycan (GAG) synthesis was slightly suppressed. Long-term incubation (6 weeks) with 1 micrograms/ml CyA resulted again in stimulation of growth parameters: compared to the drug-free control, cell number increased to 168%, incorporation of 3H-thymidine into DNA to 143%, and overall protein content to 159%. Collagen and GAG synthesis were elevated to approximately 120%. When corrected for cell number or cell protein content, this represents a decline in matrix synthesis, comparable to short-term incubations. These results indicate that a direct effect of CyA on proliferation of human gingival fibroblasts is responsible for some of the observed hyperplasia.

[Modulation of glycosaminoglycan- and collagen synthesis of human gingival fibroblasts by progesterone]. / Untersuchungen zur Progesteronwirkung auf die Glykosaminoglykan- und Kollagensynthese in Gingivafibroblasten.

Hormonal changes occuring during pregnancy are known to induce periodontal changes and may therefore influence preexisting periodontal diseases negatively. Since glycosaminoglycans (GAG) and collagen are the principal constituents of the matrix, the influence of progesterone on their synthesis was chosen as an assay system. Confluent human gingival fibroblast cultures grown under standard conditions were preincubated with progesterone levels ranging from 0.05 to 0.5 microgram/ml for 48h before GAG synthesis was assayed by incorporation of 14C-glucosamine. The GAG fraction was detemined by ion-exchange-chromatography and fractionated precipitation. Collagen-synthesis was monitored by 14C-proline-incorporation. Progesterone concentrations corresponding to those seen in the third trimenon of pregnancy were able to lower GAG-synthesis; the synthesis of all GAG-species was affected in a similar way. Collagen synthesis was only affected by unphysiologicaly high hormone doses. The observed clinical changes may therefore be due to the influence of progesterone on GAG synthesis.

[Influence of saliva components on periodontal disease in insulin-dependent diabetics]. / Beziehung zwischen Speichelkomponenten und Parodontitis bei insulinabhängigen Diabetikern.

In diabetic patients an increased incidence of periodontal disease has been demonstrated. This study was to elucidate the influence of saliva constituents on periodontal alterations. 31 insulin-dependent type-I diabetics and a control group were submitted to oral examination. During daytime salivary samples were collected at regular intervals for analysis of glucose, sodium, potassium, calcium and the pH values. Additional information on relevant blood values and organic complications were obtained from the diabetic group. The results revealed a significant correlation between the degree of diabetes control and periodontal disease. The saliva concentrations of glucose and potassium were significantly elevated as against the controls. However, no correlation was found between the saliva components and periodontal disease.

Influence of high glucose concentrations on glycosaminoglycan and collagen synthesis in cultured human gingival fibroblasts.

Human gingival fibroblasts were used to study the effects of increasing concentrations of glucose on protein, collagen and glycosaminoglycan (GAG) synthesis. GAG-synthesis was measured as incorporation of 3H-glucosamine into pronase-resistant macromolecules and collagen synthesis was evaluated by 3H-proline incorporation into collagenase-sensitive protein. Incubation of the fibroblasts with glucose concentration ranging from 5 to 50 mM resulted in a dose-dependent reduction of collagen synthesis; labeled collagen in the culture medium was reduced to 60% of the control incubation (5mM glucose) when incubated with 50 mM glucose for 72 h. Cell-associated radioactivity was decreased to 80% under the same conditions. Although 3H-glycosamine incorporation into GAGs was reduced by increasing glucose concentrations (5 to 20 mM), protein synthesis and cell number were not influenced under the same conditions, as was also the case with distribution of macromolecules in the GAG fractions. The importance of these in vitro results to the incidence of chronic inflammatory periodontal disease in diabetic patients is discussed.

[The effect of cyclosporin A (CyA) on the growth and metabolic activity of gingival fibroblasts]. / Einfluss von Cyclosporin A (CyA) auf Wachstum und Stoffwechselaktivität von Gingivafibroblasten.

Cyclosporine A (CyA) is a powerful nonsteroidal immunosuppressive agent in organ and bone marrow transplants. It may cause nephro- and hepatotoxicity and may lead to generalized fibrous hyperplasia of gingiva by a yet unknown mechanism. In order to study the pathophysiology of this side effect human gingival fibroblast cultures derived from normal gingiva were studied under the influence of CyA. During short time incubation of 72 h a significant increase of 3H-thymidine incorporation was noted while 14C-glucosamine incorporation remained unchanged. Long term incubation over 6 weeks, however, resulted in a significant increase of both cell proliferation and synthesis of the extracellular matrix. These findings demonstrate a powerful growth stimulation of gingival fibroblasts by CyA under in-vitro conditions and show that the observed fibrous hyperplasia of the gingiva under CyA therapy is the result of a direct effect on gingival cells.

Effect of triiodothyronine on triglyceride synthesis in human fibroblasts in different types of hypertriglyceridemia.

Fibroblasts from 12 normotriglyceridemic subjects and 30 hypertriglyceridemic patients and family members were used to investigate triglyceride synthesis and the influence of triiodothyronine on it. The monolayers were incubated for 72 hours with and without the thyroid hormone, followed by incorporation studies of radiolabeled acetic acid or palmitic acid into the cellular triglyceride fraction. Triiodothyronine had no influence on triglyceride synthesis of normal cell lines and of cells derived from patients with secondary hypertriglyceridemia, whereas fibroblasts from endogenous type IV patients showed higher rates of triglyceride synthesis under identical conditions. Values for type IV were in the range of 134% to 466% of the hormone-free control incubations. In cultures derived from patients with familial combined hyperlipidemia, no stimulation by triiodothyronine was observed: values were in the range of 64% to 144% of the hormone-free controls. Three out of four lines with type V gave "normal" values and are supposed to represent secondary hypertriglyceridemia, whereas one line may express endogenous type IV. The evidence obtained in vitro with cultured cells indicates different metabolic defects in endogenous type IV and familial combined hyperlipidemia; it also shows the biochemically heterogenous nature of the disease "hypertriglyceridemia."