Students experience the effects of climate change on children's health in role play and develop strategies for medical work - an interactive seminar.

Background: This project report describes the development and evaluation of an interactive seminar on the topic "medical effects of climate change on children's health". Objectives: The learning objectives are learning the basics and the direct and indirect connections between climate change and children's health. Future scenarios for affected children, parents and doctors are developed interactively. Subsequently, communication strategies concerning climate change are discussed so that students identify and analyze possibilities to become active. Methodology: The seminar was offered as an obligatory seminar for a total of 128 third-year medical students with one appointment of 45 minutes per course group as part of the interdisciplinary seminar series "Environmental Medicine". A course group consisted of 14 to 18 students. The seminar for the 2020 summer semester was developed as part of the interdisciplinary field of environmental medicine with the special feature of an interactive role play. The role play intends to give the students the opportunity to put themselves in the situation of affected children, parents and doctors of the future in order to develop detailed solution strategies. From 2020 to 2021, the seminar took place as online self-study due to the lockdown requirements. Since winter semester 2021/22, the seminar was held as an attendance event for the first time, although the switch to an online presence seminar with obligatory attendance had to take place after four seminar dates due to renewed lockdown requirements, which also took place four times. The evaluated results here refer to a total of eight dates in the winter semester 2021/22 and were carried out using a specially developed questionnaire, which was filled out voluntarily and anonymously by the students immediately after the respective seminar date. An overall grade as well as the appropriateness of the time and content of lectures and role play were asked for. Free text answers were possible for each question. Results: A total of 83 questionnaires were evaluated, 54 of which were from the four seminars in attendance, 15 were from the four online presence seminars that took place as an online live stream. The evaluation of the seminar resulted in an average grade of 1.7 for the face-to-face seminars and 1.9 for the online seminars. Content-related comments in the free-text answers addressed the desire for concrete solution strategies, more time for discussions and a more in-depth study of the topic. Numerous positive responses described the seminar as "very exciting", "good food for thought", "interesting and important topic". Conclusion: There is a very high interest on the topic of "climate change & health" among students There is an obvious need to integrate the topic on a larger scale into medical education. Ideally, the focus on children's health should be an integral part of the pediatric curriculum.

Pharmacokinetic/Pharmacodynamic Modelling of Allopurinol, its Active Metabolite Oxypurinol, and Biomarkers Hypoxanthine, Xanthine and Uric Acid in Hypoxic-Ischemic Encephalopathy Neonates.

BACKGROUND: Allopurinol, an xanthine oxidase (XO) inhibitor, is a promising intervention that may provide neuroprotection for neonates with hypoxic-ischemic encephalopathy (HIE). Currently, a double-blind, placebo-controlled study (ALBINO, NCT03162653) is investigating the neuroprotective effect of allopurinol in HIE neonates. OBJECTIVE: The aim of the current study was to establish the pharmacokinetics (PK) of allopurinol and oxypurinol, and the pharmacodynamics (PD) of both compounds on hypoxanthine, xanthine, and uric acid in HIE neonates. The dosage used and the effect of allopurinol in this population, either or not undergoing therapeutic hypothermia (TH), were evaluated. METHODS: Forty-six neonates from the ALBINO study and two historical clinical studies were included. All doses were administered on the first day of life. In the ALBINO study (n = 20), neonates received a first dose of allopurinol 20 mg/kg, and, in the case of TH (n = 13), a second dose of allopurinol 10 mg/kg. In the historical cohorts (n = 26), neonates (all without TH) received two doses of allopurinol 20 mg/kg in total. Allopurinol and oxypurinol population PK, and their effects on inhibiting conversions of hypoxanthine and xanthine to uric acid, were assessed using nonlinear mixed-effects modelling. RESULTS: Allopurinol and oxypurinol PK were described by two sequential one-compartment models with an autoinhibition effect on allopurinol metabolism by oxypurinol. For allopurinol, clearance (CL) was 0.83 L/h (95% confidence interval [CI] 0.62-1.09) and volume of distribution (Vd) was 2.43 L (95% CI 2.25-2.63). For metabolite oxypurinol, CL and Vd relative to a formation fraction (fm) were 0.26 L/h (95% CI 0.23-0.3) and 11 L (95% CI 9.9-12.2), respectively. No difference in allopurinol and oxypurinol CL was found between TH and non-TH patients. The effect of allopurinol and oxypurinol on XO inhibition was described by a turnover model of hypoxanthine with sequential metabolites xanthine and uric acid. The combined allopurinol and oxypurinol concentration at the half-maximal XO inhibition was 0.36 mg/L (95% CI 0.31-0.42). CONCLUSION: The PK and PD of allopurinol, oxypurinol, hypoxanthine, xanthine, and uric acid in neonates with HIE were described. The dosing regimen applied in the ALBINO trial leads to the targeted XO inhibition in neonates treated with or without TH.

Glomerular Filtration Rate in Asphyxiated Neonates Under Therapeutic Whole-Body Hypothermia, Quantified by Mannitol Clearance.

BACKGROUND: Therapeutic hypothermia (TH) is an established intervention to improve the outcome of neonates with moderate-to-severe hypoxic-ischemic encephalopathy resulting from perinatal asphyxia. Despite this beneficial effect, TH may further affect drug elimination pathways such as the glomerular filtration rate. OBJECTIVES: The objective of this study was to quantify the effect of TH in addition to asphyxia on mannitol clearance as a surrogate for the glomerular filtration rate. METHODS: The effect of asphyxia and TH (mild vs moderate/severe) on mannitol clearance was assessed using a population approach, based on mannitol observations collected in the ALBINO (ALlopurinol in addition to TH for hypoxic-ischemic Brain Injury on Neurocognitive Outcome) trial, as some were exposed to a second dose of 10 mg/kg intravenous mannitol as placebo to ensure blinding. Pharmacokinetic analysis and model development were conducted using NONMEM version 7.4. RESULTS: Based on 77 observations from 17 neonates (TH = 13), a one-compartment model with first-order linear elimination best described the observed data. To account for prenatal glomerular filtration rate maturation, both birthweight and gestational age were implemented as clearance covariates using an earlier published three-quarters power function and a sigmoid hyperbolic function. Our final model predicted a mannitol clearance of 0.15 L/h for a typical asphyxia neonate (39.5 weeks, birthweight 3.25 kg, no TH), lower than the reported value of 0.33 L/h for a healthy neonate of similar age and weight. By introducing TH as a binary covariate on clearance, the additional impact of TH on mannitol clearance was quantified (60% decrease). CONCLUSIONS: Mannitol clearance was decreased by approximately 60% in neonates undergoing TH, although this is likely confounded with asphyxia severity. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03162653.

Growth factors for angiogenesis in peripheral arterial disease.

BACKGROUND: Peripheral artery disease (PAD) is associated with a high clinical and socioeconomic burden. Treatments to alleviate the symptoms of PAD and decrease the risks of amputation and death are a high societal priority. A number of growth factors have shown a potential to stimulate angiogenesis. Growth factors delivered directly (as recombinant proteins), or indirectly (e.g. by viral vectors or DNA plasmids encoding these factors), have emerged as a promising strategy to treat patients with PAD. OBJECTIVES: To assess the effects of growth factors that promote angiogenesis for treating people with PAD of the lower extremities. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Specialised Register (June 2016) and CENTRAL (2016, Issue 5). We searched trial registries for details of ongoing or unpublished studies. We also checked the reference lists of relevant publications and, if necessary, tried to contact the trialists for details of the studies. SELECTION CRITERIA: We included randomised controlled trials comparing growth factors (delivered directly or indirectly) with no intervention, placebo or any other intervention not based on the growth factor's action in patients with PAD of the lower extremities. The primary outcomes were limb amputation, death and adverse events. The secondary outcomes comprised walking ability, haemodynamic measures, ulceration and rest pain. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials and assessed the risk of bias. We used outcomes of the studies at low risk of bias for the main analysis and of all studies in the sensitivity analyses. We calculated odds ratios (OR) for dichotomous outcomes and mean differences for continuous outcomes with 95% confidence intervals (CI). We evaluated statistical heterogeneity using the I2 statistic and Cochrane's Q test. We conducted meta-analysis for the overall effect and for each growth factor as a subgroup analysis using OR in a fixed-effect model. We evaluated the robustness of the results in a sensitivity analysis using risk ratio (RR) and/or a random-effects model. We also assessed the quality of the evidence for each outcome. MAIN RESULTS: We included 20 trials in the review and used 14 studies (on approximately 1400 participants) with published results in the analyses. Six published studies compared fibroblast growth factors (FGF), four studies hepatocyte growth factors (HGF) and another four studies vascular endothelial growth factors (VEGF), versus placebo or no therapy. Six of these studies exclusively or mainly investigated participants with intermittent claudication and eight studies exclusively participants with critical limb ischaemia. Follow-up generally ranged from three months to one year. Two small studies provided some data at 2 years and one of them also at 10 years.The direction and size of effects for growth factors on major limb amputations (OR 0.99, 95% CI 0.71 to 1.38; 10 studies, N = 1075) and death (OR 0.99, 95% CI 0.69 to 1.41; 12 studies, N = 1371) at up to two years are uncertain. The quality of the evidence is low due to risk of bias and imprecision (at one year, moderate-quality evidence due to imprecision). However, growth factors may decrease the rate of any limb amputations (OR 0.56, 95% CI 0.31 to 0.99; 6 studies, N = 415). The quality of the evidence is low due to risk of bias and selective reporting.The direction and size of effects for growth factors on serious adverse events (OR 1.09, 95% CI 0.79 to 1.50; 13 studies, N = 1411) and on any adverse events (OR 1.10, 95% CI 0.73 to 1.64; 4 studies, N = 709) at up to two years are also uncertain. The quality of the evidence is low due to risk of bias and imprecision (for serious adverse events at one year, moderate-quality evidence due to imprecision).Growth factors may improve haemodynamic measures (low-quality evidence), ulceration (very low-quality evidence) and rest pain (very low-quality evidence) up to one year, but they have little or no effect on walking ability (low-quality evidence). We did not identify any relevant differences in effects between growth factors (FGF, HGF and VEGF). AUTHORS' CONCLUSIONS: The results of this review do not support the use of therapy with the growth factors FGF, HGF or VEGF in people with PAD of the lower extremities to prevent death or major limb amputation or to improve walking ability. However, the use of these growth factors may improve haemodynamic measures and decrease the rate of any limb amputations (probably due to preventing minor amputations) with an uncertain effect on adverse events; an improvement of ulceration and rest pain is very uncertain. New trials at low risk of bias are needed to generate evidence with more certainty.

Overview of Risk-Estimation Tools for Primary Prevention of Cardiovascular Diseases in European Populations.

To identify persons with a high risk for cardiovascular diseases (CVD) special tools (scores, charts, graphics or computer programs) for CVD-risk assessment based on levels of the certain risk factors have been constructed. The applicability of these instruments depends on the derivation cohorts, considered risk factors and endpoints, applied statistical methods as well as used formats. The review addresses the risk-estimation tools for primary prevention of CVD potentially relevant for European populations. The risk-estimation tools were identified using two previously published systematic reviews as well as conducting a literature search in MEDLINE and a manual search. Only instruments were considered which were derived from cohorts of at least 1,000 participants of one gender without pre-existing CVD, enable risk assessment for a period of at least 5 years, were designed for an age-range of at least 25 years and published after the year 2000. A number of risk-estimation tools for CVD derived from single European, several European and from non-European cohorts were identified. From a clinical perspective, seem to be preferable instruments for risk of CVD contemporary developed for the population of interest, which use easily accessible measures and show a high discriminating ability. Instruments, restricting risk-estimation to certain cardiovascular events, recalibrated high-accuracy tools or tools derived from European populations with similar risk factors distribution and CVD-incidence are the second choice. In younger people, calculating the relative risk or cardiovascular age equivalence measures may be of more benefit.

Remodeling of cardiac passive electrical properties and susceptibility to ventricular and atrial arrhythmias.

Coordinated electrical activation of the heart is essential for the maintenance of a regular cardiac rhythm and effective contractions. Action potentials spread from one cell to the next via gap junction channels. Because of the elongated shape of cardiomyocytes, longitudinal resistivity is lower than transverse resistivity causing electrical anisotropy. Moreover, non-uniformity is created by clustering of gap junction channels at cell poles and by non-excitable structures such as collagenous strands, vessels or fibroblasts. Structural changes in cardiac disease often affect passive electrical properties by increasing non-uniformity and altering anisotropy. This disturbs normal electrical impulse propagation and is, consequently, a substrate for arrhythmia. However, to investigate how these structural changes lead to arrhythmias remains a challenge. One important mechanism, which may both cause and prevent arrhythmia, is the mismatch between current sources and sinks. Propagation of the electrical impulse requires a sufficient source of depolarizing current. In the case of a mismatch, the activated tissue (source) is not able to deliver enough depolarizing current to trigger an action potential in the non-activated tissue (sink). This eventually leads to conduction block. It has been suggested that in this situation a balanced geometrical distribution of gap junctions and reduced gap junction conductance may allow successful propagation. In contrast, source-sink mismatch can prevent spontaneous arrhythmogenic activity in a small number of cells from spreading over the ventricle, especially if gap junction conductance is enhanced. Beside gap junctions, cell geometry and non-cellular structures strongly modulate arrhythmogenic mechanisms. The present review elucidates these and other implications of passive electrical properties for cardiac rhythm and arrhythmogenesis.

[SR/PS-method for using data of primary studies from systematic reviews in the evaluation of health technologies]. / SR/PS-Methode zur Einbeziehung von Primärstudiendaten aus systematischen Reviews bei der Bewertung medizinischer Technologien.

In general, the evaluation of health technologies is a time-consuming process being performed on the basis of systematic reviews of clinical (primary) studies. In order to save time, health technologies may be assessed based on previously published systematic reviews. However, this assessment method can be associated with a high risk of bias of the obtained results. We developed, therefore, the "Systematic Reviews for assessment based on Primary Studies" (SR/PS) method to enable a transparent, valid and time-saving evaluation of the technologies. Using the SR/PS method the evaluation of the hits that were identified through the literature search for systematic reviews and, if appropriate, through additional search for primary studies is being performed in three stages, namely identification, quality assessment and information synthesis. This process results in the ascertainment of the three most important sets of information: the pool of identified studies, the pool of methodologically sound studies and the results of the information synthesis. Each stage of the evaluation comprises the comprehensive use of relevant data on primary studies from the systematic reviews. At each stage, the corresponding systematic reviews will be selected from the identified hits using certain quality criteria. If information obtained from the systematic reviews is insufficient it will be completed by additionally incorporating the primary studies. The SR/PS method can be especially helpful in performing projects with many primary studies (e. g., guidelines development).

Bone graft substitutes for the treatment of traumatic fractures of the extremities.

UNLABELLED: HEALTH POLITICAL AND SCIENTIFIC BACKGROUND: Bone graft substitutes are increasingly being used as supplements to standard care or as alternative to bone grafts in the treatment of traumatic fractures. RESEARCH QUESTIONS: The efficacy and cost-effectiveness of bone graft substitutes for the treatment of traumatic fractures as well as the ethical, social and legal implications of their use are the main research questions addressed. METHODS: A systematic literature search was conducted in electronic medical databases (MEDLINE, EMBASE etc.) in December 2009. Randomised controlled trials (RCT), where applicable also containing relevant health economic evaluations and publications addressing the ethical, social and legal aspects of using bone graft substitutes for fracture treatment were included in the analysis. After assessment of study quality the information synthesis of the medical data was performed using metaanalysis, the synthesis of the health economic data was performed descriptively. RESULTS: 14 RCT were included in the medical analysis, and two in the heath economic evaluation. No relevant publications on the ethical, social and legal implications of the bone graft substitute use were found. In the RCT on fracture treatment with bone morphogenetic protein-2 (BMP-2) versus standard care without bone grafting (RCT with an elevated high risk of bias) there was a significant difference in favour of BMP-2 for several outcome measures. The RCT of calcium phosphate (CaP) cement and bone marrow-based composite materials versus autogenous bone grafts (RCT with a high risk of bias) revealed significant differences in favour of bone graft substitutes for some outcome measures. Regarding the other bone graft substitutes, almost all comparisons demonstrated no significant difference. The use of BMP-2 in addition to standard care without bone grafting led in the study to increased treatment costs considering all patients with traumatic open fractures. However, cost savings through the additional use of BMP-2 were calculated in a patient subgroup with high-grade open fractures (Gustilo-Anderson grade IIIB). Cost-effectiveness for BMP-2 versus standard care with autologous bone grafts as well as for other bone graft substitutes in fracture treatment has not been determined yet. DISCUSSION: Although there were some significant differences in favour of BMP-2, due to the overall poor quality of the studies the evidence can only be interpreted as suggestive for efficacy. In the case of CaP cements and bone marrow-based bone substitute materials, the evidence is only weakly suggestive for efficacy. From an overall economic perspective, the transferability of the results of the health economic evaluations to the current situation in Germany is limited. CONCLUSIONS: The current evidence is insufficient to evaluate entirely the use of different bone graft substitutes for fracture treatment. From a medical point of view, BMP-2 is a viable alternative for treatment of open fractures of the tibia, especially in cases where bone grafting is not possible. Autologous bone grafting is preferable comparing to the use of OP-1. Possible advantages of CaP cements and composites containing bone marrow over autogenous bone grafting should be taken into account in clinical decision making. The use of the hydroxyapatite material and allograft bone chips compared to autologous bone grafts cannot be recommended. From a health economic perspective, the use of BMP-2 in addition to standard care without bone grafting is recommended as cost-saving in patients with high-grade open fractures (Gustilo-Anderson grade IIIB). Based on the current evidence no further recommendations can be made regarding the use of bone graft substitutes for the treatment of fractures. To avoid legal implications, use of bone graft substitutes outside their approved indications should be avoided.

CT coronary angiography vs. invasive coronary angiography in CHD.

SCIENTIFIC BACKGROUND: Various diagnostic tests including conventional invasive coronary angiography and non-invasive computed tomography (CT) coronary angiography are used in the diagnosis of coronary heart disease (CHD). RESEARCH QUESTIONS: The present report aims to evaluate the clinical efficacy, diagnostic accuracy, prognostic value cost-effectiveness as well as the ethical, social and legal implications of CT coronary angiography versus invasive coronary angiography in the diagnosis of CHD. METHODS: A systematic literature search was conducted in electronic data bases (MEDLINE, EMBASE etc.) in October 2010 and was completed with a manual search. The literature search was restricted to articles published from 2006 in German or English. Two independent reviewers were involved in the selection of the relevant publications. The medical evaluation was based on systematic reviews of diagnostic studies with invasive coronary angiography as the reference standard and on diagnostic studies with intracoronary pressure measurement as the reference standard. Study results were combined in a meta-analysis with 95 % confidence intervals (CI). Additionally, data on radiation doses from current non-systematic reviews were taken into account. A health economic evaluation was performed by modelling from the social perspective with clinical assumptions derived from the meta-analysis and economic assumptions derived from contemporary German sources. Data on special indications (bypass or in-stent-restenosis) were not included in the evaluation. Only data obtained using CT scanners with at least 64 slices were considered. RESULTS: No studies were found regarding the clinical efficacy or prognostic value of CT coronary angiography versus conventional invasive coronary angiography in the diagnosis of CHD. Overall, 15 systematic reviews with data from 44 diagnostic studies using invasive coronary angiography as the reference standard (identification of obstructive stenoses) and two diagnostic studies using intracoronary pressure measurement as the reference standard (identification of functionally relevant stenoses) were included in the medical evaluation. Meta-analysis of the nine studies of higher methodological quality showed that, CT coronary angiography with invasive coronary angiography as the reference standard, had a sensitivity of 96 % (95 % CI: 93 % to 98 %), specificity of 86 % (95 % CI: 83 % to 89 %), positive likelihood ratio of 6.38 (95 % CI: 5.18 to 7.87) and negative likelihood ratio of 0.06 (95 % CI: 0.03 to 0.10). However, due to non-diagnostic CT images approximately 3.6 % of the examined patients required a subsequent invasive coronary angiography. Using intracoronary pressure measurement as the reference standard, CT coronary angiography compared to invasive coronary angiography had a sensitivity of 80 % (95 % CI: 61 % to 92 %) versus 67 % (95 % CI: 51 % to 78 %), a specificity of 67 % (95 % CI: 47 % to 83 %) versus 75 % (95 % CI: 60 % to 86 %), an average positive likelihood ratio of 2.3 versus 2.6, and an average negative likelihood ratio 0.3 versus 0.4, respectively. Compared to invasive coronary angiography, the average effective radiation dose of CT coronary angiography was higher with retrospective electrocardiogram (ECG) gating and relatively similar with prospective ECG gating. The health economic model using invasive coronary angiography as the reference standard showed that at a pretest probability of CHD of 50 % or lower, CT coronary angiography resulted in lower cost per patient with true positive diagnosis. At a pretest probability of CHD of 70 % or higher, invasive coronary angiography was associated with lower cost per patient with true positive diagnosis. Using intracoronary pressure measurement as the reference standard, both types of coronary angiographies resulted in substantially higher cost per patient with true positive diagnosis. Two publications dealing explicitly with ethical aspects were identified. The first addressed ethical aspects regarding the principles of beneficence, autonomy and justice, and the second addressed those regarding radiation exposition, especially when used within studies. DISCUSSION: The discriminatory power of CT coronary angiography to identify patients with obstructive (above 50 %) coronary stenoses should be regarded as "high diagnostic evidence", to identify patients without coronary stenoses as "persuasive diagnostic evidence". The discriminatory power of both types of coronary angiography to identify patients with or without functionally relevant coronary stenoses should be regarded as "weak diagnostic evidence". It can be assumed that patients with a high pretest probability of CHD will need invasive coronary angiography and patients with a low pretest probability of CHD will not need subsequent revascularisation. Therefore, CT coronary angiography may be used before performing invasive coronary angiography in patients with an intermediate pretest probability of CHD. For identifying or excluding of obstructive coronary stenosis, CT coronary angiography was shown to be more cost-saving at a pretest probability of CHD of 50 % or lower, and invasive coronary angiography at a pretest probability of CHD of 70 % or higher. The use of both types of coronary angiography to identify or to exclude functionally relevant coronary stenoses should be regarded as highly cost-consuming. WITH REGARD TO ETHICAL, SOCIAL OR LEGAL ASPECTS, THE FOLLOWING POSSIBLE IMPLICATIONS WERE IDENTIFIED: under-provision or over-provision of health care, unnecessary complications, anxiety, social stigmatisation, restriction of self-determination, unequal access to health care, unfair resource distribution and legal disputes. CONCLUSION: From a medical point of view, CT coronary angiography using scanners with at least 64 slices should be recommended as a test to rule out obstructive coronary stenoses in order to avoid inappropriate invasive coronary angiography in patients with an intermediate pretest probability of CHD. From a health economic point of view, this recommendation should be limited to patients with a pretest probability of CHD of 50 % or lower. From a medical and health economic point of view, neither CT coronary angiography using scanners with at least 64 slices nor invasive coronary angiography may be recommended as a single diagnostic test for identifying or ruling out functionally relevant coronary stenoses. To minimise any potential negative ethical, social and legal implications, the general ethical and moral principles of benefit, autonomy and justice should be considered.

Nicotine effects on human endothelial intercellular communication via α4ß2 and α3ß2 nicotinic acetylcholine receptor subtypes.

Since previous in vitro experiments revealed that nicotine can impair endothelial intercellular communication via the downregulation of connexin43 (Cx43), we wanted to find out which nicotinic acetylcholine receptors are involved in the molecular mechanism of communication failure. Cultured human endothelial cells were exposed to 1 µM nicotine for 5 days. Intercellular communication was measured using dye transfer study with/without subtype-specific nicotinic acetylcholine receptor (nAChR) inhibitors. Reverse transcriptase (RT)-PCR was used to further investigate the regulation of nAChR subtypes. Electron microscopy together with MAP LC3-II western blot was used to investigate possible autophagy processes. In cultured human endothelial cells, nicotine decreased the Cx43 protein amount as shown by western blot and immunohistochemistry; however, together with an unaltered mRNA expression as shown by RT-PCR. The nicotine-induced Cx43 downregulation functionally impaired intercellular dye transfer, which could be prevented by mecamylamine, κ-bungarotoxin, lobeline, and dihydro-ß-erythroidine but not α-bungarotoxin, indicating that the nAChR subtypes α4ß2 and α3ß2 but not α7 are involved in signal cascade. RT-PCR analysis revealed that nicotine exposure resulted in the upregulation of α3 and ß4 and the downregulation of α4-nAChR, while α7- and ß2-nAChR-mRNA expressions remained unaltered. Furthermore, nicotine increased total protein ubiquinylation and proteasome activity as was shown by immunohistochemistry and peptide degradation analysis. Evidence of enhanced autophagic processes was assured by the occurrence of autophagic vacuoles in transmission electron microscopy and enhanced formation of MAP LC3-II in western blot. Reduced intercellular endothelial communication together with programmed cell death helps to explain the toxic effect of nicotine leading to endothelial dysfunction. The nAChR involved in the impairment of intercellular communication seem to be α4ß2 and α3ß2 but not α7.

Percutaneous coronary intervention with optimal medical therapy vs. optimal medical therapy alone for patients with stable angina pectoris.

SCIENTIFIC BACKGROUND: Stable Angina Pectoris (AP) is a main syndrome of chronic coronary artery disease (CAD), a disease with enormous epidemiological and health economic relevance. Medical therapy and percutaneous coronary interventions (PCI) are the most important methods used in the treatment of chronic CAD. RESEARCH QUESTIONS: The evaluation addresses questions on medical efficacy, incremental cost-effectiveness as well as ethic, social and legal aspects in the use of PCI in CAD patients in comparison to optimal medical therapy alone. METHODS: A systematic literature search was conducted in June 2010 in the electronic databases (MEDLINE, EMBASE etc.) and was completed by a hand search. The medical analysis was initially based on systematic reviews of randomized controlled trials (RCT) and was followed by the evaluation of RCT with use of current optimal medical therapy. The results of the RCT were combined using meta-analysis. The strength and the applicability of the determined evidence were appraised. The health economic analysis was initially focused on the published studies. Additionally, a health economic modelling was performed with clinical assumptions derived from the conducted meta-analysis and economic assumptions derived from the German Diagnosis Related Groups 2011. RESULTS: Seven systematic reviews (applicability of the evidence low) and three RCT with use of optimal medical therapy (applicability of the evidence for the endpoints AP and revascularisations moderate, for further endpoints high) were included in the medical analysis. The results from RCT are used as a base of the evaluation. The routine use of the PCI reduces the proportion of patients with AP attacks in the follow-up after one and after three years in comparison with optimal medical therapy alone (evidence strength moderate); however, this effect was not demonstrated in the follow-up after five years (evidence strength low). The difference in effect in the follow-up after four to five years was not found for the further investigated clinical endpoints: death, cardiac death, myocardial infarction and stroke (evidence strength high) as well as for severe heart failure (evidence strength moderate). Two studies were included in the health economic analysis. The costs estimations from these studies are not directly transferable to the corresponding costs in Germany. The average difference in the total costs for PCI in comparison with optimal medical therapy alone, which was calculated in the modelling, was found to be 4,217 Euro per patient. The incremental cost-effectiveness ratio per life-year of a patient with avoided AP attacks was estimated to be 24,805 Euro (evidence strength moderate). No publication was identified concerning ethical, social or legal aspects. DISCUSSION: Important methodical problems of the studies are a lack of blinding of the patients and incomplete data for several endpoints in the follow-up. The determined incremental cost-effectiveness ratio per life-year of a patient with avoided AP attacks was appraised not to be cost-effective. CONCLUSIONS: From a medical point of view the routine use of PCI in addition to the optimal medicinal therapy in patients with stable AP can be recommended for the reduction of the proportion of patients with AP attacks after one year and after three years (recommendation degree weak). Otherwise, PCI is to be performed in patients with refractory or progressing AP despite of optimal medical therapy use; in this case PCI is expected to be applied in 27% to 30% of patients in five years. From the health economic view the routine use of PCI in addition to an optimal medical therapy in patients with stable AP cannot be recommended. No special considerations can be made concerning special ethical, social or legal aspects in the routine use of PCI in addition to optimal medical therapy in patients with stable AP.

Combined partial trisomy 11q and partial monosomy 10p in a 19-year-old female patient: phenotypic and genotypic findings.

Constitutional partial trisomy 11q in man mostly occurs in combination with partial trisomy 22 due to a balanced parental translocation t(11;22). Occasionally a chromosome other than 22 is involved in the parental translocation with chromosome 11, resulting in partial monosomy for the other participating chromosome. We report of a patient with partial trisomy 11q and partial monosomy 10p [46,XX,der(10)t(10;11)(p15;q22)] due to a paternal balanced translocation [46,XY,t(10;11)(p15;q22)]. Array CGH showed heterozygosity for a deletion of ∼3.46 Mb at 10p15.3p15.2 and gain of ∼32.21 Mb at 11q22.2q25. The patient, a 19-year-old woman, has a multiple congenital anomaly syndrome with severe developmental and growth delay, muscular hypotonia, iris coloboma, abnormal external ears, widely spaced nipples, atrial septum defect, clubfoot, and arthrogryposis multiplex congenita. Despite multiple health problems and numerous hospitalizations due to massive seizures, pulmonary insufficiency and recurrent infections the patient reached adulthood. The clinical features in our patient are compared to other cases reported in the literature of either partial monosomy 10p or partial trisomy 11q. To the best of our knowledge, this is the first report of the combination of partial trisomy 11q and partial monosomy 10p. Comparing the molecular karyotype and the phenotype of our patient to other patients, the clinical features of our patient are more likely due to partial trisomy 11q than to partial monosomy 10p.

Specific immunotherapy (SIT) in the treatment of allergic rhinitis.

SCIENTIFIC BACKGROUND: Allergic rhinitis (AR) exhibits a prevalence of approx. 20% in Germany and causes enormous costs in the health care system. Specific immunotherapy (SIT) is considered to be the only potentially causal therapy for AR and mainly administered by two routes, subcutaneous (SCIT) and sublinguale (SLIT). SIT promises a reduction of symptoms and the need for medication in patients with AR. RESEARCH QUESTIONS: The question arises, to what extent is SIT effective and cost effective in the treatment of AR and which ethical-social and legal aspects have to be considered regarding its application. METHODS: The literature search was accomplished in the electronic data bases MEDLINE, EMBASE etc. in February 2008. The medical evaluation was based on systematic reviews of blinded, randomised controlled studies (RCT). The economic evaluation included health-economic studies on the basis of RCT. Additionally, it was also searched for publications explicitly addressing ethical-social and legal aspects of the use of SIT. RESULTS: MEDICAL EVALUATION: Two reviews on SCIT and three on SLIT were included in the medical evaluation. For the evaluation of SIT with grass pollen results for short and medium-term effects are considered from several studies, for SIT with other seasonal allergens (e. g. tree pollen) and with house dust mite allergens from clearly fewer studies and for SIT with other perennial allergens only from a few. The reviews report a significant reduction of the symptom and medication score in favour of SCIT with seasonal allergens and recognise the effectiveness at least for grass pollen allergens. Also for other seasonal allergens SCIT is appraised as effective. The reviews about SLIT determine a significant reduction of the symptom and the medication score in favour of SLIT vs. placebo in short and medium term follow-up in evaluations across all allergens. The subgroup analyses show a significant reduction of the symptom and medication score only in favour of SLIT with seasonal allergens. HEALTH ECONOMIC EVALUATION: Four publications about two health economic studies are identified, one of these publications on Alutard-SQ(®) injections (SCIT) and three on GRAZAX(®) tablets (SLIT). The studies provide more (on Alutard-SQ(®)) or less (on GRAZAX(®)) robust information, but no evidence on cost effectiveness of these SIT administration forms in patients with AR. DISCUSSION: The topic of the report is very broad, so that the evidence is summarised using systematic reviews. In particular the statistic heterogeneity of the studies found in the reviews considerably limits the strength of the findings. The included health economic studies show different methodical flaws, the largest potential bias is the projection of the magnitude of the medium-term clinical effects on the time period of nine years. CONCLUSIONS: The effectiveness of SIT in patients with AR is not equally proven for all SIT administration forms and allergens. For SCIT and SLIT with grass pollen allergens short and medium-term effectiveness can be regarded as proven. These therapy forms should be used if the indication is appropriate and if no contraindications are present. Also SCIT and SLIT with other seasonal allergens such as tree pollen allergens can be an effective treatment option, but used with a certain restraint due to insufficient data especially in the case of SLIT. For SIT with house dust mite allergens and further perennial allergens no consistent proof of effectiveness are to be determined from the available information. Further research addressing non-grass pollen-associated SIT, allergen and manufacturer specific evaluations as well as asthma prevention is needed. Due to the lack of evidence the use of SIT can not be seen proven as cost effective. To provide such evidence further health economic studies with a long term follow-up are needed. The informed consent of the patients is an important ethical requirement within the use of SIT.

Prevention of infection after knee arthroplasty.

SCIENTIFIC BACKGROUND: Man-made joints (joint endoprostheses), including knee endoprostheses, are used in some irreversible diseases of the human joints. The implantation of joint endoprostheses (arthroplasty) is associated with an increased risk for infection. To prevent infections, different interventions without and with the use of antibiotics (hygiene procedures and antibiotic prophylaxis) are used. The benefits of these interventions are not clear yet. RESEARCH QUESTIONS: The presented report addresses the questions regarding the medical effectiveness, the cost-effectiveness as well as the ethical, social and legal aspects related to the use of interventions to prevent infections after knee arthroplasty. METHODS: A systematic literature search is conducted in the medical electronic databases MEDLINE, EMBASE, SciSearch etc. in June 2009 and has been completed by a hand search. The analysis includes publications which describe and/or evaluate clinical data from randomized controlled trials (RCT), systematic reviews of RCT, registers of endoprostheses or databases concerning interventions to prevent infections after knee arthroplasty. The conducted literature search also aims to identify health-economic studies and publications dealing explicitly with ethical, social or legal aspects in the use of interventions to prevent infections after knee arthroplasty. The synthesis of information from different publications has been performed qualitatively. RESULTS: The systematic literature search yields 1,030 hits. Based on the predefined inclusion and exclusion criteria a total of ten publications is included in the analysis. The presented report does not find evidence of the effectiveness of different hygiene interventions with a high evidence level. Most of the unspecific interventions are recommended on the basis of results from non-RCT, from studies for other clinical indications and/or for clinically not relevant endpoints, as well as on the basis of expert opinions. The evidence of the effectiveness of intravenous prophylaxis with antibiotics in knee arthroplasty on a high level of evidence is also missing. The recommendations use evidence on the intravenous antibiotic prophylaxis transferred from RCT in hip arthroplasty to the arthroplasty of all joints including knee replacement. Moreover, no evidence is found for differences in the effectiveness between various antibiotics in knee arthroplasty. The presented report finds strong hints for the effectiveness of antibiotics in cement in addition to the intravenous prophylaxis; however, evidence of the effectiveness may be accepted only for operating rooms without clean-air measures. DISCUSSION: The conclusiveness of the results from non-RCT and from studies for clinically non-relevant endpoints is relatively low. The determined evidence from studies for other clinical indications may be generally transferred to knee replacement operations. CONCLUSIONS: No proposal to change the recommendations of the Robert Koch Institute with respect to hygiene interventions and intravenous antibiotic prophylaxis can be made from the presented analysis. Also, no recommendations on the selection of certain antibiotic can be derived from the analysed data. The use of antibiotics in cement in addition to the intravenous prophylaxis may be generally recommended. The cost-effectiveness of different interventions to prevent infections in knee arthroplasty remains unclear. There are no signs for concern regarding any ethical, social and/or legal consequences in the use of interventions to prevent infections in knee arthroplasty.

Improving cardiac gap junction communication as a new antiarrhythmic mechanism: the action of antiarrhythmic peptides.

Co-ordinated electrical activation of the heart is maintained by intercellular coupling of cardiomyocytes via gap junctional channels located in the intercalated disks. These channels consist of two hexameric hemichannels, docked to each other, provided by either of the adjacent cells. Thus, a complete gap junction channel is made from 12 protein subunits, the connexins. While 21 isoforms of connexins are presently known, cardiomyocytes typically are coupled by Cx43 (most abundant), Cx40 or Cx45. Some years ago, antiarrhythmic peptides were discovered and synthesised, which were shown to increase macroscopic gap junction conductance (electrical coupling) and enhance dye transfer (metabolic coupling). The lead substance of these peptides is AAP10 (H-Gly-Ala-Gly-Hyp-Pro-Tyr-CONH(2)), a peptide with a horseshoe-like spatial structure as became evident from two-dimensional nuclear magnetic resonance studies. A stable D: -amino-acid derivative of AAP10, rotigaptide, as well as a non-peptide analogue, gap-134, has been developed in recent years. Antiarrhythmic peptides act on Cx43 and Cx45 gap junctions but not on Cx40 channels. AAP10 has been shown to enhance intercellular communication in rat, rabbit and human cardiomyocytes. Antiarrhythmic peptides are effective against ventricular tachyarrhythmias, such as late ischaemic (type IB) ventricular fibrillation, CaCl(2) or aconitine-induced arrhythmia. Interestingly, the effect of antiarrhythmic peptides is higher in partially uncoupled cells and was shown to be related to maintained Cx43 phosphorylation, while arrhythmogenic conditions like ischaemia result in Cx43 dephosphorylation and intercellular decoupling. It is still a matter of debate whether these drugs also act against atrial fibrillation. The present review outlines the development of this group of peptides and derivatives, their mode of action and molecular mechanisms, and discusses their possible therapeutic potential.

[Intravascular brachytherapy for peripheral arterial occlusive disease: systematic review of medical efficacy and health economic modelling]. / Intravaskuläre Brachytherapie bei peripherer arterieller Verschlusskrankheit: Systematische Ubersicht zur medizinischen Wirksamkeit und gesundheitsökonomische Modellierung.

CONTEXT: Percutaneous transluminal angioplasties (PTA) using balloon dilatation with or without stenting are performed to treat peripheral arterial occlusive disease (PAOD). Intravascular brachytherapy (IB) after PTA promises to reduce the restenosis rates. The present article addresses questions concerning medical efficacy and cost-effectiveness of IB in PAOD patients. METHODS: A systematic literature search for randomized controlled studies evaluating IB in PAOD was conducted in August 2007. Information synthesis was conducted using meta-analysis. Health economic modelling was performed on the basis of clinical assumptions derived from the meta-analysis and economical assumptions derived from the German Diagnosis Related Groups (G-DRG) 2007. RESULTS: Twelve publications covering seven studies about IB vs. no IB were included in the evaluation. IB after successful balloon dilatation showed a significant reduction in the rate of restenosis at six and/or twelve months (relative risk 0.62; 95% confidence interval: 0.46 to 0.84) and a significant delay in the time to recurrence of restenosis (17.5 vs. 7.4 months, p < 0.01). IB after stenting did not lead to significant results regarding the restenosis rates, but was more often associated with early and late occlusive thromboses. The incremental cost-effectiveness ratio per restenosis avoided for IB vs. no IB after successful balloon dilatation was--depending on the G-DRG used-Euro 8,484 and Euro 9,058, respectively. In the comparison of IB vs. no IB after stenting IB was demonstrated to be inferior to no IB. CONCLUSIONS: IB after successful balloon dilatation in PAOD can be recommended from a medical point of view. From the health economic perspective the answer is not yet clear. IB after stenting in PAOD cannot be recommended.

[Health-economic modeling on the use of drug-eluting stents versus coronary artery bypass graft surgery in coronary heart disease]. / Gesundheitsökonomische Modellierung zum Einsatz von Medikamente freisetzenden Stents im Vergleich zu Bypassoperationen bei koronarer Herzkrankheit.

BACKGROUND AND PURPOSE: The therapy of coronary heart disease (CHD) leads to an enormous economic burden on health-care systems. Coronary artery bypass grafting (CABG) and percutaneous revascularizations with implantation of drug-eluting stents (DES) are important treatment methods in CHD. The presented evaluation addresses cost efficacy of the use of DES versus CABG in CHD patients. METHODS: A health-economic model considering linear resource use was performed from a restricted societal perspective for time periods of 1 and 3 years. Because of the short time horizon discounting was not applied. The clinical assumptions for event rates at 1 and 3 years were derived from the ARTS-I study for CABG, and from the ARTS-II study for DES (sirolimus-eluting stents). Cost assumptions for the resources used were based on the German Diagnosis Related Groups 2007 (G-DRG-2007). The base case value was assumed to be 2,800 Euros, the average DES price 1,200 Euros, and the average DES use per patient 3.7. The average per-patient daily clopidogrel costs were assumed to be 2.57 Euros, and the duration of the clopidogrel therapy 12 months. Within the scope of sensitivity analyses, different model parameters were varied and the evaluation was tested for its robustness. RESULTS: The average costs for percutaneous coronary intervention (PCI) without DES were found to be 4,420 Euros, for CABG 12,840 Euros, and for DES intervention 8,860 Euros (Table 4). 1-year clopidogrel intake resulted in 938 Euros, the treatment of patients with myocardial infarction during follow-up in 3,989 Euros. The 1-year per-patient total costs after CABG were calculated to be 13,373 Euros and after DES 10,443 Euros, leading to a difference of 2,930 Euros in favor of DES implantation (Table 6). The 3-year per-patient total costs after CABG were estimated to be 13,630 Euros and after DES 10,905 Euros, showing a Rehabilitationsmasscost difference of 2,725 Euros in favor of DES implantation (Table 6). Changes in cost-weights of G-DRG-2007 for CABG and PCI, DES price and DES use per patient as well as in the duration of the clopidogrel therapy influenced the cost differences considerably; however, they did not reach a break-even point (Figures 2 and 3). Changes in the clinical follow-up assumptions showed a lower effect on the difference in total costs (Figures 2 and 3). CONCLUSION: The presented data, indicating a possible economic middle-term advantage of DES versus CABG, should be proven with clinical assumptions derived from randomized clinical trials.

Human cardiac gap-junction coupling: effects of antiarrhythmic peptide AAP10.

AIMS: Ventricular arrhythmia is one of the most important causes of death in industrialized countries and often accompanies myocardial infarction and heart failure. In recent years modification of gap-junctional coupling has been proposed as a new antiarrhythmic principle. We wanted to examine whether the gap junction modulator (antiarrhythmic peptide) AAP10 exerts effects on human cardiac gap junctions, whether the effect might be enhanced in uncoupled cells, whether it affects electrical and metabolic coupling, and which of the cardiac connexin isoforms (Cx40, Cx43, Cx45) may be affected. METHODS AND RESULTS: We determined the influence of 50 nM AAP10 (H(2)N-Gly-Ala-Gly-4Hyp-Pro-Tyr-CONH(2)) on macroscopic gap junction conductance by dual whole-cell voltage clamping in human and rat cardiomyocytes. Cells were partially uncoupled by CO(2)-mediated acidosis (pH 6.3) or kept at 'normal' conditions (pH 7.4, T 36 degrees C). Furthermore, we investigated effects of AAP10 in HeLa cells stably transfected with connexin 40, 43, or 45 and on metabolic coupling determined by dye transfer (Lucifer yellow). AAP10 (50 nM)-enhanced gap-junctional intercellular coupling in human and rat cardiomyocytes, completely prevented CO(2)-acidosis-induced uncoupling and improved metabolic coupling. The coupling effect of AAP10 was significantly enhanced in previously uncoupled cells. Regarding the connexin isoforms, AAP10-enhanced electrical and metabolic coupling in HeLa cells expressing Cx43 or Cx45, but not in HeLa cells expressing Cx40. CONCLUSION: We conclude that the antiarrhythmic peptide AAP10, which improves gap-junctional intercellular coupling and prevents uncoupling by acidification in human cardiomyocytes, might be useful for antiarrhythmic strategies regarding arrhythmias caused by uncoupling of Cx43 and Cx45, but not Cx40.

Assessments tools for risk prediction of cardiovascular diseases.

SCIENTIFIC BACKGROUND: Cardiovascular diseases have an enormous epidemiological and economic importance. For the selection of persons with increased total cardiovascular risk for individual-targeted (e. g. drug-based) prevention interventions different risk prognosis instruments (equations, point scores and table charts) were derived from studies or databases. The transferability of these prognostic instruments on the populations not examined in these data sources as well as their comparability are not clear. RESEARCH QUESTIONS: The evaluation addresses the questions on the existence of instruments for risk prediction of cardiovascular diseases, their transferability and comparability. METHODS: A systematic literature search was performed in the medical electronic databases in April 2008 beginning from 2004 and was completed with a hand search. Publications on the prognostic instruments for cardiovascular diseases as well as publications addressing external validity and/or comparing prognostic instruments were included in the evaluation. RESULTS: The systematic lierature search yielded 734 hits. Three systematic reviews, 38 publications with descriptions of prognostic instruments and 29 publications with data on the validity of the prognosis instruments were identified. Most risk prognosis instruments are based on the Framingham cohort of the USA. Only the PROCAM study is completely based on the German reference population. Almost all prognostic instruments use the variables sex, age, smoking, different parameters of the lipid status and of the blood pressure. Different cardiovascular events are considered to be an end parameter in the prognosis instruments. The time span for predicted events in the studies mostly comprises ten years. Data on calibration of the prognosis instruments (a quotient of the predicted by the observed risk) are presented in nearly half of the studies on the validation, however in no study from Germany. Only single studies find the levels of calibration between 0.9 and 1.1. Many studies on the transferability of the prognosis instruments show a value of the discrimination (correct differentiation of persons with different risk levels, best value 1.0) between 0.7 and 0.8, few studies between 0.8 and 0.9 and no study over 0.9. The studies addressing the discrimination of the prognostic instruments on the German population almost always find values between 0.7 and 0.8. The comparison of the validity of different risk prognosis instruments shows a trend for a better calibration and a better discrimination for the prognosis instruments examined on the derivation and/or validation cohorts of one of the compared prognostic instruments. Comparing the prognostic instruments on other cohorts, the newly derived Framingham prognostic instruments show a better discrimination in comparison with previously derived instruments. No studies exists comparing different prognostic instruments on the German population. DISCUSSION: The geographic variance of the cardiovascular morbidity and mortality supposed to be the most important factor limiting the transferability of the prognostic instruments. An appropriate recalibration is considered to be an approach for the improvement of the transferability. CONCLUSIONS: The identified instruments for the risk prediction of cardiovascular diseases are insufficiently validated on the German population. Their use can lead to false risk estimation for a single person. Therefore, the existing prognostic instruments should be used for the informed decision-making and for the therapy selection in Germany only with critical caution.

Arthroplasty register for Germany.

SCIENTIFIC BACKGROUND: The annual number of joint replacement operations in Germany is high. The introduction of an arthroplasty register promises an important contribution to the improvement of the quality of patient's care. RESEARCH QUESTIONS: The presented report addresses the questions on organization and functioning, benefits and cost-benefits as well as on legal, ethical and social aspects of the arthroplasty registers. METHODS: A systematic literature search was conducted in September 2008 in the medical databases MEDLINE, EMBASE etc. and was complemented with a hand search. Documents describing arthroplasty registers and/or their relevance as well as papers on legal, ethical and social aspects of such registers were included in the evaluation. The most important information was extracted and analysed. RESULTS: Data concerning 30 arthroplasty registers in 19 countries as well as one international arthroplasty register were identified. Most of the arthroplasty registers are maintained by national orthopedic societies, others by health authorities or by their cooperation. Mostly, registries are financially supported by governments and rarely by other sources. The participation of the orthopedists in the data collection process of the arthroplasty registry is voluntary in most countries. The consent of the patients is usually required. The unique patient identification is ensured in nearly all registers. Each data set consists of patient and clinic identification numbers, data on diagnosis, the performed intervention, the operation date and implanted prostheses. The use of clinical scores, patient-reported questionnaires and radiological documentation is rare. Methods for data documentation and transfer are paper form, electronic entry as well as scanning of the data using bar codes. The data are mostly being checked for their completeness and validity. Most registers offer results of the data evaluation to the treating orthopedists and/or hospitals, provide annual reports and publish scientific articles and/or presentations. The effects of the arthroplasty registers on clinical practice and on health political decisions in the time after the introduction of these registers are documented in some countries. The influence on cost savings for health services is also reported. DISCUSSION: The most important legal and ethical aspect is the patient's data protection and, therefore, the requirement of patient's consent. The involvement of the physicians in the data collection process is a further organisational and legal challenge. The 100% data collection, which is the aim of the registers due to their definition, should not cause disadvantages for certain groups of patients. CONCLUSION: The arthroplasty registers have a large medical and health-economic potential. Aspects of the patient's data protection and the guaranteed financial support of the registers should be clarified before the introduction of a register.