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Background: Relationships between in-hospital mortality and case volume were investigated for various patient groups in many empirical studies with mixed results. Typically, those studies relied on (semi-)parametric statistical models like logistic regression. Those models impose strong assumptions on the functional form of the relationship between outcome and case volume. The aim of this study was to determine associations between in-hospital mortality and hospital case volume using random forest as a flexible, nonparametric machine learning method., Methods: We analyzed a sample of 753,895 hospital cases with stroke, myocardial infarction, ventilation > 24 h, COPD, pneumonia, and colorectal cancer undergoing colorectal resection treated in 233 German hospitals over the period 2016-2018. We derived partial dependence functions from random forest estimates capturing the relationship between the patient-specific probability of in-hospital death and hospital case volume for each of the six considered patient groups., Results: Across all patient groups, the smallest hospital volumes were consistently related to the highest predicted probabilities of in-hospital death. We found strong relationships between in-hospital mortality and hospital case volume for hospitals treating a (very) small number of cases. Slightly higher case volumes were associated with substantially lower mortality. The estimated relationships between in-hospital mortality and case volume were nonlinear and nonmonotonic., Conclusion: Our analysis revealed strong relationships between in-hospital mortality and hospital case volume in hospitals treating a small number of cases. The nonlinearity and nonmonotonicity of the estimated relationships indicate that studies applying conventional statistical approaches like logistic regression should consider these relationships adequately., (© 2021. The Author(s).)

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

In medicine, placebos are used both in scientific studies and for practical therapeutic purposes. In evidence-based medicine, the efficacy of treatment may be determined as the difference between the effects of the verum (the active study drug) and the placebo, the latter being a substance lacking specific action on the disease under consideration. However, the improvements in patients' conditions under placebo treatment may be substantial and comparable to those with verum. Genuine placebos predominate in clinical studies, while pseudoplacebos prevail in practical therapy. The term pseudoplacebo can also be applied to many procedures in complementary medicine, including homeopathic medicine (Büchel et al., Placebo in der Medizin, 2011). The comprehensive definition of placebo, as used in a report by the German Medical Association (Büchel et al., Placebo in der Medizin, 2011), states that a placebo effect may occur even when treating with verum. The placebo effect is modulated by the context of the treatment, by the expectations of the patients and the doctors, and by the success of the relationship between doctors and patients. A number of unspecific effects, e.g., spontaneous alleviation, statistical effects, variance with time, methodological errors, in addition to the placebo effect make up the total response that is called"placebo reaction." A complete list of the effectiveness of placebo for all important diseases is still lacking. Further, it is not possible to predict which patients will respond to placebo. Which characteristics of doctors are important (competence, empathy, communicative ability and partnership, trust) in order to achieve a placebo effect, particularly in addition to the verum effect measures of evidence-based medicine? Are there doctors who are better in this than others? Could the nocebo effect weaken the efficacy of treatment in evidence-based medicine? Since a placebo effect may occur in almost any standard therapy, information about placebos should be provided during medical education and continuing medical education (CME). The use of placebo in clinical studies is ethically justified and lawful in consenting patients if there is no other effective treatment available with which the test substance could be compared. For daily practical therapeutic purposes, placebos may be ethically acceptable and lawful if there is no effective therapy available, if the complaints are minor, if the patient expressly wishes treatment, and if there is a reasonable likelihood of success. However, an explanation of the expected benefits and risks must be provided to the patients. At present, there are two explanatory theories for the mechanism of action of placebo, namely, the associative and the mentalistic explanation (Büchel et al., Placebo in der Medizin, 2011). Interestingly, effects of placebo and of verum can be localized in the brain by physiological and anatomical techniques. With many open questions remaining, research on placebo is currently very active. These aspect and neurobiological findings in particular may facilitate for "scientifically" educated doctors to accept that ineffective materials, i.e., placebos, are in fact effective.

IQM is a non-profit association of hospitals and open to all kinds of hospitals. IQM aims to enhance the management of quality improvement using an innovative und efficient method including:, (Copyright © 2011. Published by Elsevier GmbH.)

The 108th German Medical Assembly adopted a 6-year support initiative for health care research in order to contribute to the further development of this young scientific discipline which has not yet been sufficiently established in Germany. The program is focussed on the following subjects: (1) influence of economic changes on outpatient and inpatient medical care, (2) implementation of medical guidelines in medical routine and (3) the physician factor. Setting methodical standards in this new field and opening up access to medical data should provide a relevant impulse to health care research in Germany. The promoting strategy of the German Medical Association will be completed by initiating a network of scientists, research promoters and health care players.

Clinical research in Germany suffers from a structural crisis caused by inappropriate input, suboptimal output and low efficiency. The situation is aggravated by fixed DRG-based payments, fix charges for education and research and reductions in governmental funding. Both healthcare system and clinical research in Germany are characterized by a profound sectorization, followed by resource competition between basic science and patient-oriented research. Basic biomedical research in Germany is widely accepted in the international context, but there is a lack of research on the transfer of basic science to clinical trials and everyday healthcare. According to international examples, the 1999 systematology of the Deutsche Forschungs-Gemeinschaft (DFG), a German research foundation, has to be expanded to the dimension of innovation transfer. Clinical translational research focuses on the transfer of basic science to clinical trials, and outcomes research, also known as health services research, describes the transfer of results from clinical trials (efficacy) to clinical application (effectiveness). Outcomes research is interdisciplinary, multiprofessional and patient-oriented. The so-called effectiveness gap between efficacy and effectiveness is determined by patient-sided, professional, organizational and system factors. Outcomes research provides university-based medical research centers with the opportunity to join other stakeholders of the healthcare system and to integrate the universities' scientific standard with its own further development. It is suggested that this widened perspective plays a key role in settling the crisis of clinical research in Germany.

Besides appropriate nutrition, adequate exercise is the universal remedy. Regular endurance training elicits positive effects in numerous organs and tissue systems in the sense of primary prevention. Nevertheless, a lack of exercise and obesity are widespread among the German population. In addition to the individual's own responsibility, measures for disease-oriented prevention as well as for preserving health should be improved based on broad social consensus. To begin with, improved research on treatment and prevention should be required. This national challenge should not only be financed by health insurance funds but also by taxes and levies (e.g., tobacco tax). Only then can the constantly spiralling costs of public health be met.

Background: The present study was performed to analyse the immunological properties of the autoantigens recognized by autoantibodies against exocrine pancreas (PAb), which have been described in Crohn's disease., Methods: Autoantibodies were detected by indirect immunofluorescence. Inhibition studies were performed by preincubating tissue sections with various glycoproteins and the different fractions obtained in fractioned salt precipitation of pancreas homogenate with ammonium sulphate. Immunoblotting of human pancreas homogenate was conducted using PAb-positive sera., Results: In size exclusion chromatography, the molecular weight of the pancreas autoantigen (PAg) was determined as > 800 kD. In the fractionated salt precipitation, the autoantigen could be detected in fractions I (0-25% ammonium sulphate) and III (50-90% ammonium sulphate). In immunoblotting, a number of protein bands were observed (at 16, 18, 19, 24, 27, 29, 31 and 34 kD), and the binding pattern showed little variation between individual patients., Conclusions: The protein that is recognized by PAb appears to be a large protein complex consisting of several subunits which exhibit reactivity to PAb.

Earlier observations on impaired in vitro effects of aldosterone on lymphocytic sodium and potassium pointed to the involvement of a defective nongenomic rather than genomic effector in pseudohypoaldosteronism. In this study, we investigated nongenomic aldosterone action in five patients with pseudohypoaldosteronism with regard to a rapid increase of free intracellular calcium [Ca2+]i in cultured nasal epithelial cells, assumably reflecting calcium influx through calcium channels. Patients were defined by episodes of salt loss despite high plasma aldosterone and renin levels. Four unaffected members of the families and four independent subjects served as controls. Considering an aldosterone-induced increase of [Ca2+]i by at least 10 nm as positive response, only 12% of cells from patients were responsive compared with 25% in normal subjects (P < 0.05). In terms of absolute changes, mean increase of [Ca2+]i was 1.6 +/- 1.1 nm in the patients (range-1-4) and 9.5 +/- 2.7 nm (P < 0.025) in the controls (range 1-25). Basal [Ca2+]i was not different between both groups (167 +/- 5 vs. 169 +/- 8 nm, mean +/- SE). These findings show an impaired nongenomic mineralocorticoid effector in patients with pseudohypoaldosteronism, which is in line with a defective sodium channel as shown recently by molecular cloning, and also with the fact that the classical, genomic intracellular receptor is structurally normal in these patients.

The Advisory Council for Concerted Action in Health Care recommended 1994 to the Association of Scientific and Medical Societies in 1994 that guidelines should be established for diagnostics and treatment. The advisory council expects that the implementation of such guidelines should improve the quality of medical care. Deficits in medical care must be reduced, and unnecessary procedures eliminated. Absolute necessities must receive preferential financing from the social health insurance as compared with optional procedures. Guidelines are an intelligent alternative to undifferentiated cost reduction.

A full-length cDNA clone for a progesterone membrane binding protein from porcine vascular smooth muscle cells was isolated and the complete nucleotide sequence determined. The cDNA encodes a protein of 194 amino acids with a transmembrane segment. This protein is likely to represent the first steroid membrane receptor or a part of it for which sequence information is available.

To date, it has remained unclear whether T cells infiltrating thyroid, retroorbital, and pretibial tissue of patients with Graves' ophthalmopathy and pretibial dermopathy represent a primary immune response that is directed against certain antigenic determinants shared among these involved tissues. To characterize these T cells at the molecular level, we compared the T cell antigen receptor (TcR) variable (V) region gene usage in thyroid, retroorbital, pretibial tissue, and peripheral blood mononuclear cells of two patients with Graves' disease, ophthalmopathy, and pretibial dermopathy. Ribonucleic acid was extracted, reverse transcribed, and amplified using the PCR and 22 V alpha and 23 V beta gene-specific oligonucleotide primers. The resulting TcR V alpha and V beta transcripts were verified by Southern hybridization analysis using TcR C region-specific, digoxigenin-labeled oligonucleotide probes. In addition, complementarity determining regions 3 and junctional regions of TcR V beta genes were sequenced. Marked similarities of intrathyroidal, retroorbital, and pretibial TcR V alpha and V beta gene repertoires were noted with respect to the degree of TcR V gene restriction and the patterns of individual V genes expressed. Sequence analysis of junctional domains of V beta families revealed oligoclonality of intrahyroidal, retroorbital, and pretibial T cells. In addition, certain conserved junctional motifs were shared by T cells derived the thyroid gland and the extrathyroidal sites. Our results suggest that in the two patients with Graves' disease and extrathyroidal manifestations studied, similar antigenic determinants may have contributed to the recruitment and oligoclonal expansion of T cells both within the thyroid gland and at the involved extrathyroidal sites.

The CASUS-project, a three year publicly funded effort to improve the quality of continuing medical education in Germany, has one major goal: The development and evaluation of an easy-to-handle author-system for problem-oriented learning in medicine. On the theoretical basis of the cognitive apprenticeship-approach, the concept of a teaching and learning database as a hypermedia system was built. The student should learn to manage authentical problems in the form of authentical clinical cases. The step-by-step learning process is expert-guided by the clinical authors of each case. The creation of various differential diagnoses by the learner is strongly supported in the process. The structure of the program can also be used for case-based examinations. In parallel to the technical development, a case-selection process for medical students students in internal medicine was initiated. About 120 relevant diseases were identified to be represented in the CASUS-case library. Prevalence, transferability of knowledge, treatability, urgence of treatment and preventive aspects were used as selection criteria. The system will be evaluated during the implementation of test cases and will then be available to be used by authors and students on a routine basis in 1997.

High-affinity progesterone-binding sites have been identified, characterized in and purified from porcine liver membranes. They were functionally solubilized by the non-denaturing zwitterionic detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid (Chaps, 20 mM. detergent/protein mass ratio 4:1) at a yield of 75-80%. Using [3H]progesterone as radioligand, binding studies showed high-affinity and low-affinity binding sites in microsomal preparations with an apparent Kd2 of 11 nM and an apparent Kd2 of 286 nM. In solubilized fractions the high-affinity binding sites were present at an apparent Kd2 of 69 nM. In both preparations, progesterone binding was time-dependent, saturable, reversible, and showed a similar hierachy of affinities for related steroids. A purification scheme was developed based on anion-exchanger procedures. The purified fraction as identified by maximum specific progester-one-binding activity contained two major polypeptides of apparent molecular masses (SDS/PAGE) of 28 kDa and 56 kDa, respectively. Sequencing of both polypeptides showed an identical amino terminus without significant identity in the amino acid sequence to any known protein primary structure.

T lymphocytes have been demonstrated recently to play an important role in the pathogenesis and propagation of Graves' ophthalmopathy (GO). Recruitment of T cells to the retroorbital tissue in GO involves the activation of certain adhesion molecules both in the vascular endothelium and in the extravascular connective tissue within the retroorbital space. To characterize the interactions between orbital endothelial cells (OECs) and circulating T cells in vitro, we discussed a two-step immunopurification procedure with bead-immobilized Ulex europaeus I lectin and anti-human endothelial cell antigen (CD31) monoclonal antibody for rapid and reproducible isolation of highly pure microvascular endothelial cell populations from small quantities of retroorbital connective tissue. Endothelial origin of the resulting cell populations was confirmed by positive immunoreactivity for von Willebrand factor. CD31 and thrombomodulin. Under baseline conditions, GO-OECs, but not normal OECs, expressed intercellular adhesion molecule 1 (ICAM-1) and CD44 immunoreactivity but no immunoreactivity for endothelial leukocyte adhesion molecule 1 (ELAM-1) and vascular cell adhesion molecule 1 (VCAM-1) was detected. Exposure of GO-OEC and normal OEC monolayers to interferon gamma, interleukin 1 alpha and tumor necrosis factor alpha resulted in marked up-regulation of immunoreactivity for ICAM-1 and in induction of ELAM-1 and VCAM-1. Blocking experiments using monoclonal antibodies directed against various adhesion molecules demonstrated that interactions between matched activated T lymphocytes and OECs were mediated by integrin-dependent (ICAM-1/leukocyte function-associated antigen 1 (LFA-1): VCAM-1/very late antigen 4 (VLA-4)) and integrin-independent (CD44) pathways, and revealed marked differences when comparing GO-OECs and normal OECs. In conclusion, the availability of OECs from affected retroorbital tissue of patients with GO provides a valuable tool for studying further the mechanisms responsible for orbit-specific lymphocyte recruitment in GO.

Thyroxine-binding globulin (TBG) is the main transport protein for thyroxine (T4) in blood. It shares considerable sequence homology with alpha 1-antitrypsin (AT) and other members of the serine proteinase inhibitor (serpin) superfamily of proteins. The crystallographic structure of AT has been determined and was found to represent the archetype of the serpins. This model has been used for structure-function correlations of TBG. Sequence analysis of the heat-resistant variant TBG-Chicago (TBG-CH) revealed a substitution of the normal tyrosine 309 with phenylalanine. For further analysis, vectors containing the coding regions of normal TBG (TBG-N) and TBG-CH were constructed, transcribed in vitro, and expressed in Xenopus oocytes. Both TBGs were secreted into the culture medium and could not be distinguished by gel electrophoresis. Scatchard analysis of T4 binding to TBG-N and -CH revealed no significant differences in binding affinity. The rate of heat denaturation of TBGs was determined by measurement of residual T4 binding capacity after incubation at 60 degrees C for various periods of time. The half-life values of denaturation of TBG-N and -CH were 7 and 132 min, respectively. The tyrosine 309 to phenylalanine substitution of TBG-CH involves a highly conserved phenylalanine residue of the serpins. The respective phenylalanine 312 of AT ties the alpha-helix hI1 to the molecule, thus stabilizing the tertiary structure. A substitution with tyrosine would disrupt this interaction. Accordingly, stabilization of the TBG molecule by replacement of tyrosine with phenylalanine in position 309 causes the increased heat stability of TBG-CH.