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Background: Prehabilitation aims to improve patients' functional capacity before surgery to reduce perioperative complications, promote recovery and decrease probability of disability. The planned economic evaluation is performed alongside a large German multi-centre pragmatic, two-arm parallel-group, randomized controlled trial on prehabilitation for frail elderly patients before elective surgery compared to standard care (PRAEP-GO RCT). The aim is to determine the cost-effectiveness and cost-utility of prehabilitation for frail elderly before an elective surgery., Methods: The planned health economic evaluation comprises cost-effectiveness, and cost-utility analyses. Analyses are conducted in the German context from different perspectives including the payer perspective, i.e. the statutory health insurance, the societal perspective and the health care provider perspective. Data on outcomes and costs, are collected alongside the ongoing PRAEP-GO RCT. The trial population includes frail or pre-frail patients aged ≥70 years with planned elective surgery. The intervention consists of frailty screening (Fried phenotype), a shared decision-making conference determining modality (physiotherapy and unsupervised physical exercises, nutrition counselling, etc.) and setting (inpatient, day care, outpatient etc.) of a 3-week individual multimodal prehabilitation prior to surgery. The control group receives standard preoperative care. Costs include the intervention costs, the costs of the index hospital stay for surgery, and health care resources consumed during a 12-month follow-up. Clinical effectiveness outcomes included in the economic evaluation are the level of care dependency, the degree of disability as measured by the WHO Disability Assessment Schedule 2.0 (WHODAS 2.0), quality-adjusted life years (QALY) derived from the EQ-5D-5L and the German utility set, and complications occurring during the index hospital stay. Each adopted perspective considers different types of costs and outcomes as outlined in the protocol. All analyses will feature Intention-To-Treat analysis. To explore methodological and parametric uncertainties, we will conduct probabilistic and deterministic sensitivity analyses. Subgroup analyses will be performed as secondary analyses., Discussion: The health economic evaluation will provide insights into the cost-effectiveness of prehabilitation in older frail populations, informing decision-making processes and contributing to the evidence base in this field. Potential limitation includes a highly heterogeneous trial population., Trial Registration: PRAEP-GO RCT: NCT04418271; economic evaluation: OSF ( https://osf.io/ecm74 )., (© 2024. The Author(s).)

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. GBM displays excessive and unfunctional vascularization which may, among others, be a reason for its devastating prognosis. Pericytes have been identified as the major component of the irregular vessel structure in GBM. In vitro data suggest an epithelial-to-mesenchymal transition (EMT)-like activation of glioma-associated pericytes, stimulated by GBM-secreted TGF-β, to be involved in the formation of a chaotic and dysfunctional tumor vasculature. This study investigated whether TGF-β impacts the function of vessel associated mural cells (VAMCs) in vivo via the induction of the EMT transcription factor SLUG and whether this is associated with the development of GBM-associated vascular abnormalities. Upon preventing the TGF-β-/SLUG-mediated EMT induction in VAMCs, the number of PDGFRβ and αSMA positive cells was significantly reduced, regardless of whether TGF-β secretion by GBM cells was blocked or whether SLUG was specifically knocked out in VAMCs. The reduced amount of PDGFRβ + or αSMA + cells observed under those conditions correlated with a lower vessel density and fewer vascular abnormalities. Our data provide evidence that the SLUG-mediated modulation of VAMC activity is induced by GBM-secreted TGF-β¬ and that activated VAMCs are key contributors in neo-angiogenic processes. We suggest that a pathologically altered activation of GA-Peris in the tumor microenvironment is responsible for the unstructured tumor vasculature. There is emerging evidence that vessel normalization alleviates tumor hypoxia, reduces tumor-associated edema and improves drug delivery. Therefore, avoiding the generation of an unstructured and non-functional tumor vasculature during tumor recurrence might be a promising treatment approach for GBM and identifies pericytes as a potential novel therapeutic target., Competing Interests: The authors declare no conflicts of interest. All coauthors have reviewed and approved the contents of the manuscript and that the requirements for authorship have been met.

The importance of day surgery as a less costly alternative compared to conventional inpatient hospital stays is growing internationally. The rate of day surgery activities has increased across Europe. However, this trend has been heterogeneous across countries, and might still be below its potential. Since payment systems affect how providers offer care, they represent a policy instrument to further increase the rate of day surgeries. In this paper, we review international strategies to promote day surgery with a particular focus on payment models for 13 OECD countries (Australia, Austria, Canada, Denmark, England, Estonia, Finland, France, Germany, Netherlands, Norway, Sweden, Switzerland). We conduct a cross-country comparison based on an email survey of health policy experts and a comprehensive literature review of peer-reviewed papers and grey literature. Our research shows that all countries aim to strengthen day surgery activity to increase health system efficiency. Several countries used financial and non-financial policy measures to overcome misaligned incentive structures and promote day surgery activity. Financial incentives for day surgery can serve as a policy instrument to promote change. We recommend embedding these incentives in a comprehensive approach of restructuring health systems. In addition, we encourage countries to monitor and evaluate the effect of changes to payment systems on day surgeries to allow for more informed decision-making., Competing Interests: Declarations of Competing Interest AK, HE, and RB report grants from the Ministry of Education and Research (BMBF), the federal state of Berlin, and the German Federal Joint Committee during the conduct of the study. RB reports grants from the World Health Organization, and grants and other funding from the Federal Ministry of Health. The submitted work is independent from these relationships. RM has nothing to declare. The opinions expressed and arguments employed herein are those of the author and do not necessarily reflect the official views of the OECD or of its member countries., (Copyright © 2023. Published by Elsevier B.V.)

Background: The reimbursement of new technologies in inpatient care is not always linked to a requirement for evidence-based evaluation of patient benefit. In Germany, every new technology approved for market was until recently eligible for reimbursement in inpatient care unless explicitly excluded. The aim of this work was (1) to investigate the type of evidence that was available at the time of introduction of 25 innovative technologies and how this evidence evolved over time, and (2) to explore the relationship between clinical evidence and utilization for these technologies in German inpatient care., Methods: This study combined different methods. A systematic search for evidence published between 2003 and 2017 was conducted in four bibliographic databases, clinical trial registries, resources for clinical guidelines, and health technology assessment-databases. Information was also collected on funding mechanisms and safety notices. Utilization was measured by hospital procedures captured in claims data. The body of evidence, funding and safety notices per technology were analyzed descriptively. The relationship between utilization and evidence was explored empirically using a multilevel regression analysis., Results: The number of included publications per technology ranges from two to 498. For all technologies, non-comparative studies form the bulk of the evidence. The number of randomized controlled clinical trials per technology ranges from zero to 19. Some technologies were utilized for several years without an adequate evidence base. A relationship between evidence and utilization could be shown for several but not all technologies., Conclusions: This study reveals a mixed picture regarding the evidence available for new technologies, and the relationship between the development of evidence and the use of technologies over time. Although the influence of funding and safety notices requires further investigation, these results re-emphasize the need for strengthening market approval standards and HTA pathways as well as approaches such as coverage with evidence development., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Prehabilitation aims at enhancing patients' functional capacity and overall health status to enable them to withstand a forthcoming stressor like surgery. Our aim was to synthesise the evidence on the cost-effectiveness of prehabilitation for patients awaiting elective surgery compared with usual preoperative care., Methods: We searched PubMed, Embase, the CRD database, ClinicalTrials.gov, the WHO ICTRP and the dissertation databases OADT and DART. Studies comparing prehabilitation for patients with elective surgery to usual preoperative care were included if they reported cost outcomes. All types of economic evaluations (EEs) were included. The primary outcome of the review was cost-effectiveness based on cost-utility analyses (CUAs). The risk of bias of trial-based EEs was assessed with the Cochrane risk of bias 2 tool and the ROBINS-I tool and the credibility of model-based EEs with the ISPOR checklist. Methodological quality of full EEs was assessed using the CHEC checklist. The EEs' results were synthesised narratively using vote counting based on direction of effect., Results: We included 45 unique studies: 25 completed EEs and 20 ongoing studies. Of the completed EEs, 22 were trial-based and three model-based, corresponding to four CUAs, three cost-effectiveness analyses, two cost-benefit analyses, 12 cost-consequence analyses and four cost-minimization analyses. Three of the four trial-based CUAs (75%) found prehabilitation cost-effective, i.e. more effective and/or less costly than usual care. Overall, 16/25 (64.0%) EEs found prehabilitation cost-effective. When excluding studies of insufficient credibility/critical risk of bias, this number reduced to 14/23 (60.9%). In 8/25 (32.0%), cost-effectiveness was unclear, e.g. because prehabilitation was more effective and more costly, and in one EE prehabilitation was not cost-effective., Conclusions: We found some evidence that prehabilitation for patients awaiting elective surgery is cost-effective compared to usual preoperative care. However, we suspect a relevant risk of publication bias, and most EEs were of high risk of bias and/or low methodological quality. Furthermore, there was relevant heterogeneity depending on the population, intervention and methods. Future EEs should be performed over a longer time horizon and apply a more comprehensive perspective., Trial Registration: PROSPERO CRD42020182813., (© 2023. The Author(s).)

Objectives: Precision medicine is increasingly important in cancer treatment. Tumor-agnostic therapies are used regardless of tumor entity because they target specific biomarkers in tumors. In Germany, the benefit assessment of oncological pharmaceuticals has traditionally been entity specific. Thus, the assessment of tumor-agnostic therapies leaves stakeholders with various challenges. Our aim was to systematically identify challenges and possible solutions for the benefit assessment of therapies in tumor-agnostic indications using a 2-step sequential qualitative approach., Methods: To identify relevant challenges, we conducted qualitative interviews with different stakeholders who were involved in previous benefit assessments of tumor-agnostic therapies in Germany. To identify possible solutions for these challenges, we systematically searched MEDLINE, Embase, and the websites of European health technology assessment bodies for relevant literature., Results: We identified 9 categories of challenges of which the following were deemed particularly relevant: the absence of direct comparative studies, challenges regarding the use of basket studies and indirect comparisons, challenges in determining the appropriate comparative therapy in a tumor-agnostic indication, and challenges on the system side. Seven categories of solutions were identified, including an increased use of real-world evidence, making conditional decisions in the context of systematic reassessments, splitting the field of application, and finding (new) ways to design and analyze basket studies., Conclusion: A range of possible solutions, which can help to meet the identified challenges in Germany, have been found. Future research should investigate the acceptance and feasibility of these solutions., (Copyright © 2023. Published by Elsevier Inc.)

The attenuation of diabetic kidney disease (DKD) by metabolic surgery is enhanced by pharmacotherapy promoting renal fatty acid oxidation (FAO). Using the Zucker Diabetic Fatty and Zucker Diabetic Sprague Dawley rat models of DKD, we conducted studies to determine if these effects could be replicated with a non-invasive bariatric mimetic intervention. Metabolic control and renal injury were compared in rats undergoing a dietary restriction plus medical therapy protocol (DMT; fenofibrate, liraglutide, metformin, ramipril, and rosuvastatin) and ad libitum-fed controls. The global renal cortical transcriptome and urinary 1H-NMR metabolomic profiles were also compared. Kidney cell type-specific and medication-specific transcriptomic responses were explored through in silico deconvolution. Transcriptomic and metabolomic correlates of improvements in kidney structure were defined using a molecular morphometric approach. The DMT protocol led to ∼20% weight loss, normalized metabolic parameters and was associated with reductions in indices of glomerular and proximal tubular injury. The transcriptomic response to DMT was dominated by changes in fenofibrate- and peroxisome proliferator-activated receptor-α (PPARα)-governed peroxisomal and mitochondrial FAO transcripts localizing to the proximal tubule. DMT induced urinary excretion of PPARα-regulated metabolites involved in nicotinamide metabolism and reversed DKD-associated changes in the urinary excretion of tricarboxylic acid (TCA) cycle intermediates. FAO transcripts and urinary nicotinamide and TCA cycle metabolites were moderately to strongly correlated with improvements in glomerular and proximal tubular injury. Weight loss plus pharmacological PPARα agonism is a promising means of attenuating DKD., (© 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Objectives: Evidence-based decision-making is the sine qua non for safe and effective patient care and the long-term functioning of health systems. Since 2020 Digital Health Applications (DiHA) in Germany have been undergoing a systematic pathway to be reimbursed by statutory health insurance (SHI) which is attracting attention in other European countries. We therefore investigate coverage decisions on DiHA and the underlying evidence on health care effects, which legally include both medical outcomes and patient-centred structural and procedural outcomes., Methods: Based on publicly available data of the Institute for Medicines and Medical Devices searched between 08/2021 and 02/2022, all DiHA listed in the corresponding registry and thus reimbursable by the SHI were systematically investigated and presented descriptively on the basis of predefined criteria, such as clinical condition, and costs. The clinical trials on DiHA permanently included in the registry were reviewed with regard to their study design, endpoints investigated, the survey instruments used, and whether an intention-to-treat analysis was performed. Risk of bias was assessed using the ROB II tool., Results: By February 2022, 30 DiHA had been included in the DiHA registry, one third of them permanently and two thirds conditionally. Most DiHA were therapeutic applications for mental illness based on cognitive behavioural therapy. For all permanently included DiHA, randomised controlled trials were conducted to demonstrate the impact on health care effects. While medical outcomes were investigated for all of these DiHA, patient-centred structural and procedural outcomes were rarely investigated. The majority of clinical trials showed a high risk of bias, mainly due to insufficient reporting quality. Overall, the prices for DiHA covered by SHI are on average around € 150 per month (min. € 40; max. € 248)., Conclusions: Evidence-based decision-making on coverage of DiHA leaves room for improvements both in terms of reporting-quality and the use of patient-centred structural and procedural outcomes in addition to medical outcomes. With appropriate evidence, DiHA can offer an opportunity as an adjunct to existing therapy while currently the high risk of bias of the trials raises doubts about the justification of its high costs., (© 2022. The Author(s).)

Background: The coronavirus disease 2019 (COVID-19) pandemic has developed into an unprecedented global challenge. Differences between countries in testing strategies, hospitalization protocols as well as ensuring and managing ICU capacities can illustrate initial responses to a major health system shock, and steer future preparedness activities., Methods: Publicly available daily data for 18 European countries were retrieved manually from official sources and documented in an Excel table (March-July 2020). The ratio of tests to cases, the share of hospitalizations out of all cases and the share of ICU admissions out of all hospitalizations were computed using 7-day rolling averages per 100 000 population. Information on country policies was collected from the COVID-19 Health System Response Monitor of the European Observatory on Health Systems and Policies. Information on health care capacities, expenditure and utilization was extracted from the Eurostat health database., Results: There was substantial variation across countries for all studied variables. In all countries, the ratio of tests to cases increased over time, albeit to varying degrees, while the shares of hospitalizations and ICU admissions stabilized, reflecting the evolution of testing strategies and the adaptation of COVID-19 health care delivery pathways, respectively. Health care patterns for COVID-19 at the outset of the pandemic did not necessarily follow the usual health service delivery pattern of each health system., Conclusions: This study enables a general understanding of how the early evolution of the pandemic influenced and was influenced by country responses and clearly demonstrates the immense potential for cross-country learning., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Public Health Association.)

Background: The exponential increase in SARS-CoV-2 infections during the first wave of the pandemic created an extraordinary overload and demand on hospitals, especially intensive care units (ICUs), across Europe. European countries have implemented different measures to address the surge ICU capacity, but little is known about the extent. The aim of this paper is to compare the rates of hospitalised COVID-19 patients in acute and ICU care and the levels of national surge capacity for intensive care beds across 16 European countries and Lombardy region during the first wave of the pandemic (28 February to 31 July)., Methods: For this country level analysis, we used data on SARS-CoV-2 cases, current and/or cumulative hospitalised COVID-19 patients and current and/or cumulative COVID-19 patients in ICU care. To analyse whether capacities were exceeded, we also retrieved information on the numbers of hospital beds, and on (surge) capacity of ICU beds during the first wave of the COVID-19 pandemic from the COVID-19 Health System Response Monitor (HSRM). Treatment days and mean length of hospital stay were calculated to assess hospital utilisation., Results: Hospital and ICU capacity varied widely across countries. Our results show that utilisation of acute care bed capacity by patients with COVID-19 did not exceed 38.3% in any studied country. However, the Netherlands, Sweden, and Lombardy would not have been able to treat all patients with COVID-19 requiring intensive care during the first wave without an ICU surge capacity. Indicators of hospital utilisation were not consistently related to the number of SARS-CoV-2 infections. The mean number of hospital days associated with one SARS-CoV-2 case ranged from 1.3 (Norway) to 11.8 (France)., Conclusion: In many countries, the increase in ICU capacity was important to accommodate the high demand for intensive care during the first COVID-19 wave., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Innovative medical technologies are commonly associated with positive expectations. At the time of their introduction into care, there is often little evidence available regarding their benefits and harms. Accordingly, some innovative medical technologies with a lack of evidence are used widely until or even though findings of adverse events emerge, while others with study results supporting their safety and effectiveness remain underused. This study aims at examining the diffusion patterns of innovative medical technologies in German inpatient care between 2005 and 2017 while simultaneously considering evidence development., Methods: Based on a qualitatively derived typology and a quantitative clustering of the adoption curves, a representative sample of 21 technologies was selected for further evaluation. Published scientific evidence on efficacy/effectiveness and safety of the technologies was identified and extracted in a systematic approach. Derived from a two-dimensional classification according to the degree of utilization and availability of supportive evidence, the diffusion patterns were then assigned to the categories "Success" (widespread/positive), "Hazard" (widespread/negative), "Overadoption" (widespread/limited or none), "Underadoption" (cautious/positive), "Vigilance" (cautious/negative), and "Prudence" (cautious/limited or none)., Results: Overall, we found limited evidence on the examined technologies regarding both the quantity and quality of published randomized controlled trials. Thus, the categories "Prudence" and "Overadoption" together account for nearly three-quarters of the years evaluated, followed by "Success" with 17%. Even when evidence is available, the transfer of knowledge into practice appears to be inhibited., Conclusions: The successful implementation of safe and effective innovative medical technologies into practice requires substantial further efforts by policymakers to strengthen systematic knowledge generation and translation. Creating an environment that encourages the conduct of rigorous studies, promotes knowledge translation, and rewards innovative medical technologies according to their added value is a prerequisite for the diffusion of valuable health care., (© 2021. The Author(s).)

Introduction: Preoperative functional capacity is an important predictor of postoperative outcomes. Prehabilitation aims to optimise patients' functional capacity before surgery to improve postoperative outcomes. As prolonged hospital stay and postoperative complications present an avoidable use of healthcare resources, prehabilitation might also save costs.The aim of this systematic review is to investigate the cost-effectiveness of prehabilitation programmes for patients awaiting elective surgery compared with usual preoperative care. The results will be useful to inform decisions about the implementation of prehabilitation programmes and the design of future economic evaluations of prehabilitation programmes., Methods and Analysis: We will search PubMed, Embase, the Centre for Reviews and Dissemination Database, the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov for full or partial economic evaluations of preoperative prehabilitation programmes conducted in any population compared with usual preoperative care. Studies will be included regardless of the type, design and perspective of the economic evaluation, and their publication year, language or status. Initial searches were performed between 30 April and 4 May 2020.Study selection, data extraction and assessment of the included studies' risk of bias and methodological quality will initially be performed by two independent reviewers and, if agreement was sufficiently high, by one reviewer. We will extract data regarding the included studies' basic characteristics, economic evaluation methods and cost-effectiveness results.A narrative synthesis will be performed. The primary endpoint will be cost-effectiveness based on cost-utility analyses. We will discuss heterogeneity between the studies and assess the risk of publication bias. The certainty of the evidence will be determined using the Grading of Recommendations, Assessment, Development and Evaluation approach., Ethics and Dissemination: Ethics approval is not required as the systematic review will not involve human participants. We plan to present our findings at scientific conferences, pass them on to relevant stakeholder organisations and publish them in a peer-reviewed journal., Prospero Registration Number: CRD42020182813., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Roux-en-Y gastric bypass surgery (RYGB) reduces albuminuria and the long-term incidence of end-stage renal disease in patients with obesity and diabetes. Preclinical modeling in experimental diabetic kidney disease demonstrates that improvements in glomerular structure likely underpin these findings., Research Design and Methods: In adult male Zucker diabetic fatty (ZDF) rats, we profiled the effect of RYGB on weight and metabolic control as well biochemical, structural and ultrastructural indices of diabetic renal injury. Furthermore, we sequenced the renal cortical transcriptome in these rats and used bioinformatic pathway analyses to characterize the transcriptional alterations governing the renal reparative response to RYGB., Results: In parallel with improvements in weight and metabolic control, RYGB reduced albuminuria, glomerulomegaly, podocyte stress and podocyte foot process effacement. Pathway analysis of RYGB-induced transcriptomic changes in the renal cortex highlighted correction of disease-associated alterations in fibrosis, inflammation and biological oxidation pathways. RYGB reversed disease-associated changes in the expression of transforming growth factor (TGF)-β superfamily genes that strongly correlated with improvements in structural measures of glomerulopathy., Conclusions: Improved glomerular structure in ZDF rats following RYGB is underpinned by pathway level changes, including interruption of the TGF-β-driven early profibrotic programme. Our data provide an important layer of experimental support for clinical evidence demonstrating that RYGB arrests renal damage in patients with obesity and type 2 diabetes., Competing Interests: Competing interests: CWlR discloses personal fees outside of the submitted work from Novo Nordisk, GI Dynamics, Eli Lilly, Johnson and Johnson, Sanofi, Aventis, AstraZeneca, Janssen, Bristol-Myers Squibb and Boehringer-Ingelheim. NGD and CWlR are co-guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: A recent randomized controlled trial has reported full patient compliance and no adverse events from therapy with parathyroid hormone (PTH) for osteoporosis and accelerated healing of fragility fractures of the pelvis. The purpose of the presented study was to evaluate if similar results can be achieved with comprehensive PTH therapy in routine clinical practice. We hypothesised that patients' burden of PTH therapy is underestimated in the literature., Patients and Methods: Osteoanabolic PTH therapy was recommended to 79 patients suffering from an acute fragility fracture of the pelvis (FFP). Case finding, initiation of therapy and follow-up were performed by a fracture liaison service team. Primary outcome was PTH initiation rate. Secondary outcomes were implementation rate of alternative antiresorptive pharmaceutical therapy for osteoporosis and participation rate in a bone metabolic workup. Adverse events and effects potentially related to the therapy with bone-active drugs were documented as exploratory outcomes., Results: Osteoanabolic PTH therapy as suggested was accepted by 32%, whereas antiresorptive therapy was implemented in another 14% of the patients. DEXA scans were available in 38% of the patients (+ 27% when compared to baseline). A bone-specific laboratory analysis was done in 18 patients, uncovering 7 pathological findings. Two patients terminated PTH therapy early because of side effects., Conclusion: The experiences with PTH therapy in FFP patients with respect to, implementation rate, frequency of side effects and of pathological findings in laboratory controls as reported from a previous RCT could not be reproduced in routine clinical practice.

Objective: To review the reimbursement recommendations issued by selected European health technology assessment agencies for orphan drugs and the reimbursement status of these drugs; to assess the relationship between the type of recommendation and reimbursement status. Methods: The list of orphan drugs to be included in the analysis was obtained from the European Medicines Agency and Orphanet. Seven European states were included in the analysis: Belgium, England, France, Germany, Poland, Scotland, and Spain. For all identified orphan drugs, relevant data on the reimbursement status and type of recommendation were collected for each country. The relationship between the type of recommendation and reimbursement status was evaluated separately for each considered country, using Cohen's kappa coefficient for the measurement of agreement; sub-analyses for oncology and metabolic drugs were performed. Results: Most reimbursement recommendations for orphan drugs were positive (71%), while approximately 17% were negative and almost 13% were conditional. The highest percentage of positive reimbursement recommendations was observed in Spain (97%) and France (95%) and the highest percentage of negative reimbursement recommendations was revealed for Poland (49%). On average, 65% of the 163 analyzed orphan drugs were reimbursed from public funds. The highest number of reimbursed orphan drugs was observed in Germany ( n = 148), while the lowest, in Poland ( n = 41). Considering all analyzed drugs, the highest agreement between recommendations and reimbursement status was observed for Spain (value of 1), and the lowest, for Germany (κ = -0.03). Conclusions: On average, more than 60% of identified orphan drugs were reimbursed from public funds in the included countries, and the majority of reimbursement recommendations were found to be positive. The agreement between reimbursement recommendations and reimbursement status differed between the countries, but overall, it did not show any patterns, as it ranged from -0.03 to 1 (κ coefficient)., (Copyright © 2019 Stawowczyk, Malinowski, Kawalec, Bobiński, Siwiec, Panteli, Eckhardt, Simoens, Agusti, Dooms and Pilc.)

Background: Oesophagectomy is associated with reduced appetite, weight loss and postprandial hypoglycaemia, the pathophysiological basis of which remains largely unexplored. This study aimed to investigate changes in enteroendocrine function after oesophagectomy., Methods: In this prospective study, 12 consecutive patients undergoing oesophagectomy were studied before and 10 days, 6, 12 and 52 weeks after surgery. Serial plasma total fasting ghrelin, and glucagon-like peptide 1 (GLP-1), insulin and glucose release following a standard 400-kcal mixed-meal stimulus were determined. CT body composition and anthropometry were assessed, and symptom scores calculated using European Organisation for Research and Treatment of Cancer (EORTC) questionnaires., Results: At 1 year, two of the 12 patients exhibited postprandial hypoglycaemia, with reductions in bodyweight (mean(s.e.m.) 17·1(3·2) per cent, P < 0·001), fat mass (21.5(2.5) kg versus 25.5(2.4) kg before surgery; P = 0·014), lean body mass (51.5(2.2) versus 54.0(1.8) kg respectively; P = 0·003) and insulin resistance (HOMA-IR: 0.84(0.17) versus 1.16(0.20); P = 0·022). Mean(s.e.m.) fasting ghrelin levels decreased from postoperative day 10, but had recovered by 1 year (preoperative: 621·5(71·7) pg/ml; 10 days: 415·1(59·80) pg/ml; 6 weeks: 309·0(42·0) pg/ml; 12 weeks: 415·8(52·1) pg/ml; 52 weeks: 547·4(83·2) pg/ml; P < 0·001) and did not predict weight loss (P = 0·198). Postprandial insulin increased progressively at 10 days, 6, 12 and 52 weeks (mean(s.e.m.) insulin AUC 0-30 min : fold change 1·7(0·4), 2·0(0·4), 3·5(0·7) and 4·0(0·8) respectively; P = 0·001). Postprandial GLP-1 concentration increased from day 10 after surgery (P < 0·001), with a 3·3(1·8)-fold increase at 1 year (P < 0·001). Peak GLP-1 level was inversely associated with the postprandial glucose nadir (P = 0·041) and symptomatic neuroglycopenia (Sigstad score, P = 0·017, R 2  = 0·45). GLP-1 AUC predicted loss of weight (P = 0·008, R 2  = 0·52) and fat mass (P = 0·010, R 2  = 0·64) at 1 year., Conclusion: Altered enteroendocrine physiology is associated with early satiety, weight loss and postprandial hypoglycaemia after oesophagectomy., (© 2019 BJS Society Ltd Published by John Wiley & Sons Ltd.)

In the context of pharmaceutical care, policy-makers repeatedly face the challenge of balancing patient access to effective medicines with affordability and rising costs. With the aim of guiding the health policy discourse towards questions that are important to actual and potential patients, this study investigates a broad range of regulatory measures, spanning marketing authorization to generic substitution and resulting price levels in a sample of 16 European health systems (Austria, Belgium, Denmark, England, Finland, France, Germany, Greece, Ireland, Italy, the Netherlands, Poland, Portugal, Scotland, Spain and Sweden). All countries employ a mix of regulatory mechanisms to contain pharmaceutical expenditure and ensure quality and efficiency in pharmaceutical care, albeit with varying configurations and rigour. This variation also influences the extent of publicly financed pharmaceutical costs. Overall, observed differences in pharmaceutical expenditure should be interpreted in conjunction with the differing volume and composition of consumption and price levels, as well as dispensation practices and their impact on measurement of pharmaceutical costs. No definitive evidence has yet been produced on the effects of different cost-containment measures on patient outcomes. Depending on the foremost policy concerns in each country, different levers will have to be used to enable the delivery of appropriate care at affordable prices., (World Health Organization 2016 (acting as the host organization for, and secretariat of, the European Observatory on Health Systems and Policies).)

A new class of wireless neural interfaces is under development in the form of tens to hundreds of mm-sized untethered implants, distributed across the target brain region(s). Unlike traditional interfaces that are tethered to a centralized control unit and suffer from micromotions that may damage the surrounding neural tissue, the new free-floating wireless implantable neural recording (FF-WINeR) probes will be stand-alone, directly communicating with an external interrogator. Towards development of the FF-WINeR, in this paper we describe the micromachining, microassembly, and hermetic packaging of 1-mm³ passive probes, each of which consists of a thinned micromachined silicon die with a centered Ø(diameter) 130 μm through-hole, an Ø81 μm sharpened tungsten electrode, a 7-turn gold wire-wound coil wrapped around the die, two 0201 surface mount capacitors on the die, and parylene-C/Polydimethylsiloxane (PDMS) coating. The fabricated passive probe is tested under a 3-coil inductive link to evaluate power transfer efficiency (PTE) and power delivered to a load (PDL) for feasibility assessment. The minimum PTE/PDL at 137 MHz were 0.76%/240 μW and 0.6%/191 μW in the air and lamb head medium, respectively, with coil separation of 2.8 cm and 9 kΩ receiver (Rx) loading. Six hermetically sealed probes went through wireless hermeticity testing, using a 2-coil inductive link under accelerated lifetime testing condition of 85 °C, 1 atm, and 100%RH. The mean-time-to-failure (MTTF) of the probes at 37 °C is extrapolated to be 28.7 years, which is over their lifetime.

To understand the complex correlations between neural networks across different regions in the brain and their functions at high spatiotemporal resolution, a tool is needed for obtaining long-term single unit activity (SUA) across the entire brain area. The concept and preliminary design of a distributed free-floating wireless implantable neural recording (FF-WINeR) system are presented, which can enabling SUA acquisition by dispersedly implanting tens to hundreds of untethered 1 mm3 neural recording probes, floating with the brain and operating wirelessly across the cortical surface. For powering FF-WINeR probes, a 3-coil link with an intermediate high-Q resonator provides a minimum S21 of -22.22 dB (in the body medium) and -21.23 dB (in air) at 2.8 cm coil separation, which translates to 0.76%/759 μW and 0.6%/604 μW of power transfer efficiency (PTE) / power delivered to a 9 kΩ load (PDL), in body and air, respectively. A mock-up FF-WINeR is implemented to explore microassembly method of the 1×1 mm2 micromachined silicon die with a bonding wire-wound coil and a tungsten micro-wire electrode. Circuit design methods to fit the active circuitry in only 0.96 mm2 of die area in a 130 nm standard CMOS process, and satisfy the strict power and performance requirements (in simulations) are discussed.

Background: Dissemination bias occurs when only some results emerging from clinical research reach their intended audience in the knowledge translation process. Given that coverage decisions increasingly rely on evidence, it is important to explore the types of evidence considered. This paper aimed to examine the evidence base used by regulatory institutions involved in pricing and reimbursement of pharmaceuticals in a broad range of European countries, as well as their awareness of and approach towards dissemination bias., Methods: A mixed methods approach was adopted. Regulatory documents and published literature were identified in systematic searches and relevant documents were analysed. An online survey was carried out to verify and expand insights., Results: Forty-two relevant regulatory documents and 10 publications were included. The survey had a 35% response rate, yielding valid responses for 13 countries. A fragmented impression was obtained for most countries indicating a general lack of transparency regarding both processes of decision-making and approaches towards unpublished information. Dissemination bias was rarely consistently considered. Practices for the identification and inclusion of all available evidence varied considerably, as did the influence of missing evidence on decision-making. Differences were often attributable to the regulatory context and/or institutional principles., Conclusions: Best practice is difficult to generalize given the identified variations. Individual exemplary practices support the necessity for institutional exchange at international level. Increased institutional commitment to transparency of methods and processes should be advocated.

Background: Coverage decisions determining the benefit baskets of health systems have been increasingly relying on evidence regarding patient benefit and costs. Relevant structures, methodologies, and processes have especially been established for pharmaceuticals but approaches differ. The objective of this work was thus to identify institutions in a broad range of European countries (n = 36) in charge of determining the value of pharmaceuticals for pricing and reimbursement purposes and to map their decision-making process; to examine the different approaches and consider national and supranational possibilities for best practice., Methods: Institutions were identified through websites of international networks, ministries, and published literature. Details on institutional practices were supplemented with information from institution websites and linked online sources., Results: The type and extent of information available varied considerably across countries. Different types of public regulatory bodies are involved in pharmaceutical coverage decisions, assuming a range of responsibilities. As a rule, the assessment of scientific evidence is kept structurally separate from its appraisal. Recommendations on value are uniformly issued by specific committees within or commissioned by responsible institutions; these institutions often also act as decision-makers on reimbursement status and level or market price. While effectiveness and costs are important criteria in all countries, the latter are often considered on a case-by-case basis. In all countries, manufacturer applications, including relevant evidence, are used as one of the main sources of information for the assessment., Conclusion: Transparency of evidence-based coverage decisions should be enhanced. International collaboration can facilitate knowledge exchange, improve efficiency of information production, and strengthen new or developing systems.

To prevent the participants of parabolic flights from nausea they are optionally treated with subcutaneously injected antiemetic scopolamine. The range of side effects of this substance include reductions of the α-2 frequency band. Previous studies, however, have given no information as to which generator centers are responsible for this effect. The objective of this study therefore, is to identify the cortex area that may be responsible for this effect. Six participants were subcutaneously administered 0.7 mg of scopolamine. EEG was recorded for 10 minutes before to 20 minutes after injection. Data preprocessing followed including filtering and artifact minimization. A statistical analysis was performed with sLORETA/eLORETA software for each subject over a time window from 3 minutes before to 17-20 minutes after scopolamine injection. Results show, that in the BA7, the precuneus, on both hemispheres suffered a α-2 activity decrease in absolute power. The identified brain cortex center is an important hub with high connectivity and centrality values within the neural network. It contributes to the control of movement and to space orientation. Therefore, an activity alteration in this area can possibly explain the antiemetic effect of scopolamine and open a window to understand the origin of motion sickness., (Copyright © The Author(s) 2013.)

In team sports, sensorimotor impairments resulting from previous injuries or muscular fatigue have been suggested to be factors contributing to an increased injury risk. Although it has been widely shown that physical fatigue affects static postural sway, it is still questionable as to what extent these adaptations are relevant for dynamic, sports-related situations. The objective of this study was to determine the effects of whole-body and localized fatigue on postural control in stable and unstable conditions. Nineteen male team handball players were assessed in 2 sessions separated by 1 week. Treadmill running and single-leg step-up exercises were used to induce physical fatigue. The main outcome measures were center of pressure (COP) sway velocity during a single-leg stance on a force plate and maximum reach distances of the star excursion balance test (SEBT). The COP sway velocity increased significantly (p < 0.05) after general (+47%) and localized fatigue (+10%). No fatigue effects were found for the SEBT. There were no significant correlations between COP sway velocity and SEBT mean reach in any condition. The results showed that although fatigue affects static postural control, sensorimotor mechanisms responsible for regaining dynamic balance in healthy athletes seem to remain predominantly intact. Thus, our data indicate that the exclusive use of static postural sway measures might not be sufficient to allow conclusive statements regarding sensorimotor control in the noninjured athlete population.

Repeated biopsy sampling from one muscle is necessary to investigate muscular adaptation to different forms of exercise as adaptation is thought to be the result of cumulative effects of transient changes in gene expression in response to single exercise bouts. In a crossover study, we obtained four fine needle biopsies from one vastus lateralis muscle of 11 male subjects (25.9 ± 3.8 yr, 179.2 ± 4.8 cm, 76.5 ± 7.0 kg), taken before (baseline), 1, 4, and 24 h after one bout of squatting exercise performed as conventional squatting or as whole body vibration exercise. To investigate if the repeated biopsy sampling has a confounding effect on the observed changes in gene expression, four fine needle biopsies from one vastus lateralis muscle were also taken from 8 male nonexercising control subjects (24.5 ± 3.7 yr, 180.6 ± 1.2 cm, 81.2 ± 1.6 kg) at the equivalent time points. Using RT-PCR, we observed similar patterns of change in the squatting as well as in the control group for the mRNAs of interleukin 6 (IL-6), IL-6 receptor, insulin-like growth factor 1, p21, phosphofructokinase, and glucose transporter in relation to the baseline biopsy. In conclusion, multiple fine needle biopsies obtained from the same muscle region can per se influence the expression of marker genes induced by an acute bout of resistance exercise.

The purpose of the study was to test the hypothesis that myofiber recruitment is enhanced when whole-body vibration (WBV) is added to squat training. In a randomized cross-over design, 14 recreationally active men were subjected to 2 sessions consisting of 5 sets of 10 squats with external load, performed either on a vibration platform (whole-body vibration squatting [WBVS]) or conventionally without WBV (CON). Electromyographic (EMG) activity of the right vastus lateralis muscle was continuously recorded during WBVS and CON. The integrated EMG values were normalized to the EMG activity recorded during measurement of the maximal voluntary contraction force (MVC) on an isometric leg press at the beginning of each training session. Capillary lactate concentration was determined before and repeatedly after the squatting exercise. Overall mean normalized and integrated EMG (nIEMG) activity during WBVS (62 ± 4% MVC) was significantly (p < 0.001) higher compared with CON (47 ± 2% MVC). There was a tendency for nIEMG to increase during the 5 sets of 10 squats performed as WBVS (p = 0.089), whereas there was a significant (p < 0.001) decrease in nIEMG during CON. Whole-body vibration squatting induced a significantly (p < 0.001) larger increase in capillary lactate than CON (3.03 ± 0.32 vs. 1.60 ± 0.30 mmol · L(-1), p < 0.001). The increased myoelectric activity and the enhanced exercise-induced increase in capillary lactate concentration during WBVS provide evidence for augmented recruitment of muscle tissue when WBV is added to exhaustive squatting exercise.

The present design of stormwater tanks is based on the creation of storage volume to retain stormwater and the prevention or reduction of stormwater overflows. The treatment of stormwater is often improved with mechanical equipment. The general layout rules do usually not include the appropriate choice of design inflow related to the chosen treatment equipment. In the following investigations it was the task to analyze the hydraulic efficiency and the overflow behaviour of a lamella particle separator inside a stormwater tank under different design approaches regarding the chosen design inflow. Therefore six scenarios with different precipitation yield approaches were chosen and applied to a given constant sized catchment to calculate the design inflows. For a given minimum particle size, the necessary number of lamellas were determined for the scenarios and standard stormwater tanks were dimensioned. These stormwater tanks were modelled in the hydrologic model SMUSI to investigate the overflow behaviour of the different tank sizes. The number of overflow events, their duration and maximum flow rates were the results of the modelling. Comparisons to the design inflows were carried out. The treated particles sizes at the overflow events were determined reversible and compared to the original chosen minimum particle sizes.

The purpose of this paper is to present a wide field electrode array that may increase the field of vision in patients implanted with a retinal prosthesis. Mobility is often impaired in patients with low vision, particularly in those with peripheral visual loss. Studies on low vision patients as well as simulation studies on normally sighted individuals have indicated a strong correlation between the visual field and mobility. In addition, it has been shown that an increased visual field is associated with a significant improvement in visual acuity and object discrimination. Current electrode arrays implanted in animals or human vary in size; however, the retinal area covered by the electrodes has a maximum projected visual field of about 10 degrees. We have designed wide field electrode arrays that could potentially provide a visual field of 34 degrees, which may significantly improve the mobility. Tests performed on a mechanical eye model showed that it was possible to fix 10 mm wide flexible polyimide dummy electrode arrays onto the retina using a single retinal tack. They also showed that the arrays could conform to the inner curvature of the eye. Surgeries on an enucleated porcine eye model demonstrated feasibility of implantation of 10 mm wide arrays through a 5 mm eye wall incision.

Simulations of artificial vision suggest that 1000 electrodes may be required to restore vision to individuals with diseases of the outer retina. In order to achieve such an implant, new technology is needed, since the state-of-the-art implantable neural stimulator has at most 22 contacts with neural tissue. A critical component of this system is the multi-channel, stimulating electrode array. This array must meet very challenging, competing requirements for manufacturing, integration, surgical handling, and biocompatibility. Our lab has evaluated 3 polymers as retinal prosthesis substrates: polyimide, parylene, and silicone.

Purpose: To prospectively evaluate reading performance with of 3 types of multifocal intraocular lenses (IOLs) under different lighting conditions based on reading acuity and reading speed tests., Setting: Augenklinik, Bad Hersfeld, Germany., Methods: This randomized study comprised 60 cataract patients (120 eyes) randomly assigned to receive an SA40N IOL (AMO) (Group 1, 20 patients), Tecnis ZM001 IOL (AMO) (Group 2, 20 patients), or AcrySof ReSTOR SA60D3 IOL (Alcon) (Group 3, 20 patients). Pupil size and reading ability at near (visual acuity, reading speed) without correction, with best distance correction, and with best near correction were assessed 6 weeks postoperatively under low-light conditions (6 cd/m(2)) and bright-light conditions (100 cd/m(2)) using the Radner Reading Charts., Results: Six weeks postoperatively, there was no significant difference between groups in pupil size measured under low-light (6 cd/m(2)) or bright-light (100 cd/m(2)) conditions. When assessed under low-light conditions, near visual acuity and reading speed with or without correction were generally better in Group 2 than in Groups 1 and 3; there were no significant difference between Groups 1 and 3. Under bright-light conditions, Groups 2 and 3 performed significantly better than Group 1 and Group 2 performed better than Group 3., Conclusions: Under bright-light conditions, second-generation multifocal IOLs provided better reading performance than the Array SA40N IOL. However, when tested under low-light conditions, patients with the Tecnis ZM001 IOL had the best reading acuity and reading speed.

Inflammatory processes induced by viral or bacterial infections are believed to be one of the major pathogenetic mechanisms in myocardial diseases. Although the reason for progression to myocardial failure is not fully understood, postulated mechanisms include persistent viral infection alone or in combination with autoimmune processes. A variety of cardiotropic viruses have been identified to elicit myocarditis, with enteroviruses and adenoviruses as the most frequent causative agents in children and adolescents. However, parvovirus B19 (PVB19) has recently emerged as another potential pathogen in adult patients associated with inflammatory heart disease. Many dimensions of inflammatory heart disease coexist while different phases of the disease progress simultaneously: phase 1 is dominated by viral infection, phase 2 by the onset of (probably) multiple autoimmune reactions, and phase 3 by the progression to cardiac dilatation without the role of an infectious agent and cardiac inflammation. Taking these mechanisms into account, screening for viral and bacterial genome by polymerase chain reaction (PCR) and detection of inflammatory infiltrates by immunohistochemistry are considered crucial for establishing an aetiological diagnosis, thereby allowing initiation of specific therapeutic strategies. In a large cohort of 3345 consecutive patients with left ventricular dysfunction evaluated over a period of 10 years, prevalence of PVB19, coxsackievirus (CVB), human cytomegalovirus (HCMV), influenza A virus and adenovirus (ADV) genome was assessed by PCR. Inflammatory infiltrates within the myocardium were detected by immunohistochemistry according to the WHF criteria and by histopathology according to the Dallas criteria of myocarditis. For control, endomyocardial samples of patients with arterial hypertension were studied. Parvovirus B19 was the most often detected virus in all patient subgroups, with positivity ranging from 17% to 33%. Except for PVB19, CVB RNA (3%), ADV (2%) and CMV (3.9%) were the most frequently detected viral genomes. Interestingly, detection of PVB19 genome was significantly correlated with inflammatory heart disease and reduced ejection fraction. Importantly, an aetiological diagnosis requires the immunohistochemical and molecular biological investigation of endomyocardial biopsies. Such an approach may change the management of these diseases in the future. One of the aims of the study was to reveal the underlying dominant pathophysiological mechanisms in a for deciding on the most approriate therapy.

Background: During the last few years combined cataract and glaucoma surgery is an established method to control intraocular pressure (IOP) and visual rehabilitation in patients with cataract and glaucoma. Despite this, there are currently only few data concerning the results of combined surgery for primary open-angle glaucoma (POAG) and pseudoexfoliation glaucoma (PEXG)., Patients and Methods: To study the course of PEXG and POAG with respect to IOP regulation and visual acuity, 100 eyes with POAG (72 patients) and 22 with PEXG (19 patients) were evaluated which underwent a combined phacoemulsification and goniotrephination between 1993 and 1997. All patients had no glaucoma or other ocular surgery before. The mean follow up after operation was 39.5 (range 16 - 72) months., Results: The mean preoperative IOP in PEXG (31.8 +/- 10.3 mm Hg) was significantly higher than in the POAG group (25.3 +/- 6.4 mm Hg) (p=0.0004). At follow up IOP decreased to 16.7 +/- 2.8 mm Hg (POAG) and 15.1 +/- 4.0 mm Hg (PEXG) (p < 0.0001). The absolute IOP lowering effect was significantly better for PEXG than for POAG (p=0.0003). All patients received medical treatment before surgery, whereas at follow up 59.0 % (POAG) and 81.8 % (PEXG) were untreated. The median preoperative visual acuity for the POAG was 0.32 (PEXG 0.25), visual outcome 0,63 (PEXG 0.5)., Conclusion: The combined cataract and glaucoma surgery is a successful method of IOP control and visual rehabilitation. It seems that there is a tendency for a better efficiency and an untreated IOP regulation after surgery for PEXG. Thereby early surgical intervention could be an advantage for this glaucoma entity.

Purpose: To report the intraoperative and postoperative results of cataract surgery using a pulsed Q-switched neodymium:YAG (Nd:YAG) laser., Setting: Eye Clinic, Kreiskrankenhaus Bad Hersfeld, Germany., Methods: This prospective study involved 100 consecutive patients who had cataract surgery between October 1998 and May 1999. The patients were allocated to 3 groups based on the hardness of the nucleus using the LOCS III system: Group 1 (NO < or = 2.9), 48 patients; Group 2 (NO 3.0 to 3.9), 46 patients; Group 3 (NO > or = 4.0), 6 patients. Plasma was generated with a pulsed Q-switched Nd:YAG laser (ARC GmbH). A clear corneal incision of 1.25 mm provided access for the laser tip. An intraocular lens (CeeOn Edge [Pharmacia & Upjohn] or AcrySof [Alcon]) was implanted via a separate clear corneal incision. Intraoperative laser pulse rate and total energy were recorded. Preoperative and postoperative (2 days and 6 months) central cornea thickness was compared., Results: In all cases, the cataract was removed within an acceptable time without converting to the conventional phacoemulsification technique. Mean total energy was 1.97 J +/- 1.43 (SD) in Group 1, 3.37 +/- 1.59 J in Group 2, and 7.70 +/- 2.09 J in Group 3. No significant postoperative changes between preoperative and postoperative central pachymetry were seen in Groups 1 and 2; there was a 1.9% postoperative increase in central pachymetry in Group 3. This could be a consequence of the higher volume of intraoperative balanced salt solution and the prolonged procedure in this group. Six months postoperatively, there were no significant changes from the preoperative values., Conclusion: Photolysis of the lens nucleus can be used safely and efficiently for nuclei with a hardness up to NO 3.9. The energy required for lens removal was 83% less than that required by phacoemulsification.

In the report of the 1995 World Health Federation/International Society and Federation of Cardiology (WHF/ISFC) Task Force on the Definition and Classification of Cardiomyopathies, the definition of heart muscle diseases was updated. Idiopathic, autoimmune, and infectious forms of inflammatory cardiomyopathy are now recognized in this definition. Enteroviruses, adenoviruses and cytomegaloviruses are considered as main etiopathological factors in the pathogenesis of inflammatory heart disease. A wide range of different assays have been and are currently being used, either alone or in combination, to assay for the presence of enteroviral RNA and/or DNA of cytomegalo- and adenoviruses in endomyocardial biopsy and explanted heart samples. The prevalence of cardiotropic viruses in endomyocardial biopsies of patients with clinically suspected inflammatory cardiomyopathy varies widely: enteroviral genome was detected in endomyocardial biopsies of 3 to 53% of patients, cytomegaloviral DNA was detected in 3 to 40% of patients with inflammatory heart disease and adenoviruses in 3 to 23% of the patients. This report summarizes the methods that have been used and the results of molecular biological investigation with polymerase chain reaction, which were reported by several groups over the last years. Taking this together it seems to be clear that the improvement of molecular biological techniques and the experience of people working with these methods will lead to more reliable results on prevalence, persistence and the diagnostic value of these investigations. These findings have to be taken into account in future diagnostic and therapeutic studies in the field of cardiomyopathies.

The development of highly sensitive molecular biological methods such as in-situ hybridization and polymerase chain reaction (PCR) made it possible to detect viral/bacterial nucleic acid in human endomyocardial biopsies. However, only a few investigations addressed the problem of latent persistence of viral and bacterial genome and the detection of the corresponding proteins, which could have important consequences for the clinical course of the disease. The purpose of this study was to determine whether protein of various viruses (adenovirus, enterovirus, cytomegalovirus, influenza A and B virus, herpes simplex virus 1 and 2) and bacteria (chlamydia pneumonia) can be detected in endomyocardial biopsies of patients with myocarditis and dilated cardiomyopathy with and without inflammation by use of an immunofluorescence assay and to compare the frequency of its detection with the results of PCR, immunohistology and serology. Thirty-nine patients with myocarditis and dilated cardiomyopathy with and without inflammation were examined by a direct immunofluorescence assay using the endomyocardial biopsy as antigen. Each of the samples was additionally studied by immunohistological methods and PCR for the detection of infiltrating cells and the genome of cardiotropic viruses or bacteria. Fourteen of patients were considered to have myocarditis (group 1), 9 dilated cardiomyopathy with inflammation (group 2), 10 dilated cardiomyopathy (group 3), 6 to have no myocarditis or dilated cardiomyopathy (group 4). Using a direct immunofluorescence assay we could show only that 1 patient without histological myocarditis or dilated cardiomyopathy (group 4) was positive for influenza B and chlamydia pneumonia antigens in the endomyocardial biopsy. In addition we have determined influenza B-specific antibodies, such as IgG (marginal titer) and IgA (high titer) and chlamydia pneumonia-specific antibodies, such as IgG (marginal titer) in serum of this patient. A second patient with dilated cardiomyopathy was found to be positive for protein of chlamydia pneumonia, who was shown to have chlamydia pneumonia-specific antibodies, such as IgG (high titer) in serum. There was no correlation with PCR results, but good correlation with influenza B and chlamydia pneumonia-specific antibodies in sera of these patients. In this investigation we have determined viral/bacterial-specific antibodies using serological methods and proteins of these agents using immunoflourescence. Despite the detection of virus or bacteria-specific antibodies in the sera and detection of viral and/or bacterial protein in the biopsies of some of the patients viral and/or bacterial genome was not found in the biopsy. This may be explained by the focal character of myocarditis and sampling error, because for technical reasons we use different biopsies for immunohistochemical and molecular biological investigations.

Purpose: To evaluate the efficacy of paracentral ablations in treating higher degrees of naturally occurring myopic and hyperopic astigmatism., Setting: Augenklinik, Kreiskrankenhaus Bad Hersfeld, Germany., Methods: Twenty-five eyes (7 with hyperopia, 18 with myopia) with naturally occurring corneal astigmatism greater than 1.75 diopters (D) were treated by excimer laser. The mean refractive cylinder was -4.05 D +/- 1.46 (SD) (range -1.75 to -7.00 D). The intention was to reduce the astigmatism without consideration of the spherical refractive error. Two paracentral ablations were performed by photorefractive keratectomy with treatment zones of 3.5 mm in the flatter meridian of the cornea. Objective refraction, best corrected visual acuity (BCVA), changes in corneal radius, development of haze, and regression were recorded., Results: The paracentral ablations induced a steepening of the corneal radius in the flatter meridian from 8.12 mm (mean preoperative value) to 7. 84 mm (mean postoperative value) and thus reduced the mean refractive cylinder to -1.12 +/- 0.82 D (range 0.00 to - 3.00 D), corresponding to a mean reduction of 78%. No eye experienced a loss of Snellen lines. The preoperative BCVA (mean 20/25; range 20/50 to 20/20) was unchanged postoperatively, Conclusions: Paracentral ablations resulted in a stable corneal curvature immediately after epithelial healing, with a moderate regression over time. Paracentral ablations with the excimer laser appear to be a safe and effective method to correct higher grades of corneal astigmatism.

Background: Combined glaucoma and cataract operation has been demonstrated to be effective in controlling IOP and increasing visual acuity. Because of the differences between patients with primary open-angle glaucoma (POAG) and pseudoexfoliation glaucoma (PXEG), for cataract and glaucoma surgery alone we evaluated the effects and complications for simultanous surgical management., Patients and Methods: In a retrospective study 103 patients were examined who underwent a combined phacoemulsification and goniotrephination between January 1993 and January 1997 and had no surgery before (110 eyes with POWG, 22 eyes with PXEG)., Results: The average age in the POAG group (75.1 +/- 8.7 years) was significantly less than in the PXEG group (79.3 +/- 5.9 years) (P < 0.05). The mean preoperative IOP in PXEG (31.8 +/- 10.3 mmHG) was significantly higher than in POAG (25.0 +/- 6.4 mmHg) (P < 0.0005). Due to the combined surgery the mean intraocular pressure decreased in both groups < 10 mmHg (days 1 and 7). PXEG had a significantly higher IOP at day 3 than POAG (12.3 +/- 8.4 mmHg versus 8.5 +/- 5.7 mmHg) (P < 0.05) and developed after combined operation IOP peaks > 25 mmHg into a significantly higher level (P < 0.05). Moreover, zonulolysis, rupture of the posterior capsule, vitreous loss and persistence of inflammatory response occurred more often in PXEG, but there was no significant difference compared to POAG., Conclusion: PXEG has an higher incidence of typical problems of phacoemulsification, a temporary increase of IOP and prolonged inflammation after combined cataract and glaucoma surgery than POAG, but there is a similar risk compared to a single procedure.

Background: There are conflicting reports on the value of cyclocryotherapy and it seems that the success rate is depending on glaucoma conditions, the period of follow-up and the technique. This retrospective study was carried out to assess the efficacy and complication rate of cyclocryosurgery for advanced glaucoma with and without neovascularization., Patients and Methods: We induced 76 eyes of 75 patients with inadequately controlled glaucoma, which underwent cyclocryotherapy during the period of 1993 and 1996 (treatment time 60 seconds with -80 degrees C, 6-12 applications (mean 9.8 +/- 2.3), 180-360 degree (median 270 degree), diameter of the probe tip 2.5 mm, 1-2 mm distance from the limbus). Depending on the etiology we distinguished between neovascular (NVG) and non-neovascular glaucoma (nNVG). Pre- and postoperative data from all patients were studied retrospectively, for follow-up after 12-36 months patients were examined., Results: Intraocular pressure (IOP) decreased in all patients from 44.7 +/- 12.6 mm Hg preoperatively to 15.6 +/- 6.5 mm Hg postoperatively after a follow-up of 12-36 months. In 88.2% IOP was lowered to < or = 25 mm Hg. NVG showed a mean IOP reduction from 49.1 +/- 12.5 mm Hg before cyclocryotherapy to 15.6 +/- 5.0 mm Hg at follow-up. In the nNVG group IOP was 40.5 +/- 11.3 mm Hg and 15.7 +/- 7.6 mm Hg after cyclocryotherapy. Pressure was controlled (< or = 25 mm Hg) for 83.8% of NVG and 92.3% of nNVG. A cyclocryotherapy-induced intense inflammation was seen more frequent in NVG (43.2%) than in nNVG (17.9%). 2 patients with NVG and 3 with nNVG developed phthisis postoperatively (total 6.7%)., Conclusions: Cyclocryosurgery is an effective method to reduce IOP in advanced, refractory glaucoma, when other methods have failed. The risk/success rate seems to be acceptable.

Background: Ultrasound biometry for axial length measurement may be performed either by directly putting the probe on the cornea or by using a water immersion technique. Our goal was to examine whether there are unsystematic differences between both techniques present besides systematic differences that can be compensated by adjusting calculation formula constants., Patients, Materials and Methods: We examined 288 patients in a prospective, randomized trial. There was no ocular pathology present beside cataract. Axial lengths < 21 mm and > 27 mm were excluded. We calculated which IOL power would have given the desired refractive result by using the postoperative refraction and data of the lens implanted., Results: A systematic difference between both techniques is present. With the contact technique, axial length is measured 0.15 mm shorter. This requires adjustment of formula constants. Furthermore, there is an unsystematic difference that leads to 18% greater calculation errors (difference between IOL calculated preoperatively and ideal IOL) with the contact technique. Mean absolute error was 0.43 +/- 0.38 dpt for the immersion group and 0.53 +/- 0.48 dpt for the contact group., Conclusions: To minimize postoperative refractive errors, ultrasound biometry using immersion technique should be preferred.

In the report of the 1995 WHO/ISFC task force on the definition and classification of cardiomyopathies a new entity within the dilated cardiomyopathies was introduced as "inflammatory cardiomyopathy". It is defined as myocarditis associated with cardiac dysfunction. Idiopathic, autoimmune and infectious forms of inflammatory cardiomyopathy are now recognized through this definition. Dilated cardiomyopathy with inflammation (DCMi, chronic myocarditis) was also defined by a recent ISFC task force as > 14 lymphocytes/macrophages/mm3. Enteroviruses, adenoviruses and cytomegaloviruses are considered as main etiopathogenetic factors in the pathogenesis of inflammatory heart disease and have been demonstrated as important trigger for inflammatory cardiac disease. They may also cause dilated cardiomyopathy by viral persistence or secondary immunopathogenesis due to antigenic or molecular mimicry. For the detection of viral persistence the investigation of endomyocardial biopsies in patients with cardiomyopathy by the use of polymerase chain reaction and southern blot analysis is an important step for the standardization of diagnostic criteria on virally induced inflammatory cardiomyopathy. Present studies indicate an incidence of cytomegalovirus-DNA in patients with inflammatory cardiomyopathy in 10%, adenoviral-DNA in 17% and borreliosis only in rare cases (< 1%). In dilated cardiomyopathy without inflammation the respective incidences were for cytomegalovirus 12%, 15% for adenovirus and only 0.5% of cases for borreliosis. In addition the results of immunohistochemical analysis and molecular biological investigations of endomyocardial biopsies may have implications for future therapeutic studies. Depending on the etiology of the disease, immunosuppression may have benefit for patients with virus-negative cardiomyopathy with inflammation in contrast to patients with cytomegalo-, adenovirus-DNA or enteroviral persistence, in whom immunomodulation with hyperimmunoglobulins or immunoglobulins may be a feasible therapeutic option. Patients with a positive PCR for Borrelia burgdorferi should be treated with 3rd generation cephalosporines and/or sublactam.

Background: A number of clinical studies have investigated the influence of hypnotics and relaxants on intraocular pressure. All of them referred to the normal eye. Our goal was to show if there is a difference in intraocular pressure profile during general anesthesia between eyes with and without primary open angle glaucoma., Patients and Methods: We prospectively examined two groups of 20 patients with and without primary open angle glaucoma. Intraocular pressure (IOP) readings were taken using a Perkins hand held applanation tonometer during routine surgery on cataract or glaucoma on the fellow eye. Balanced anesthesia was carried out using Etomidate, Vecuronium, Fentanyl, N2O and Enflurane., Results: In the glaucoma group IOP fell from 20.3 +/- 4.1 mm Hg before induction of anesthesia (baseline) to 13.2 +/- 3.8 mm Hg (65% of baseline) after induction and 12.6 +/- 4.2 mm Hg (62%) 5 minutes after induction. In the non-glaucoma group IOP was 16.3 +/- 3.5, 9.7 +/- 3.0 (62%) und 9.6 +/- 3.0 (59%) respectively. Directly after placement of endotracheal tube we read 17.8 +/- 7.6 mm Hg (87%) in the glaucoma and 13.0 +/- 5.9 mm Hg (82%) in the non-glaucoma group. Shortly before removal of endotracheal tube we found IOP to be 21.3 +/- 4.5 mm Hg (107%) in the glaucoma and 17.8 +/- 6.8 mm Hg (106%) in the non-glaucoma group. Back on the ward we measured 19.8 +/- 4.1 mm Hg (94%) and 15.4 +/- 3.5 (93%) respectively. Pressure changes relative to baseline values show no statistically significant differences between the two groups., Conclusions: General anesthesia lowers IOP to the advantage of intraocular surgery. There is no statistically significant difference in pressure change relative to baseline value in eyes with and without primary open angle glaucoma.

Background: Inverted papilloma is a benign epithelial neoplasm of mucous membrane, usually arising in the nose and paranasal sinuses, much rarer of the conjunctiva. Histologically ribbons or bulbous expansions of the epithelium invaginate into the underlying connective tissue. In opposite to their sinonasal counterparts the few described papillomas of the conjunctiva til now have not shown any signs of malignant transformation or recurrence after local excision., Patient: A 96-year old woman presented with a solid tumour on the nasal bulbar conjunctiva of her right eye, which had persisted at least over 6 months. Ocular examination showed a 25 x 15 x 15 mm reddish tumour with papillary surface. Histologic features of the excised specimen were consistent with inverted papilloma, but here were significant carcinomatous foci in peripheral areas. Four months later there was a tumour recurrence on the bulbar and tarsal conjunctiva., Conclusions: Inverted papilloma of the conjunctiva is an unusual diagnosis and to date there is no previous report of malignant transformation. With only seven cases described so far the biologic behavior remains uncertain, but it seems to be more aggressive than assumed so far. Complete excision is the treatment of choice, but patients should be carefully observed and adjuvant therapy could be necessary to ensure tumour control.

Background: Prediction of postoperative patient refraction is of paramount importance in modern cataract surgery. The choice of the IOL calculation formula plays a major role here. The influence of popular calculation formulas is evaluated in a prospective study., Materials and Methods: We performed cataract surgery on 539 eyes with PC-IOL implantation in the capsular bag. The IOL power was computed using 10 different calculation formulas with the help of a personal computer. Patient refraction was examined two days and six months after surgery., Results: The mean difference between desired and obtained refraction was -0.11 +/- 0.88 dpt 83% of all patients were in a +/- 1 D interval of desired refraction with a median visual acuity of 20/25. The formula used contributes a major part to the precision of calculation despite all problems due to errors of measurement. The theoretical formulas with variable "pseudophacic anterior chamber depth" are superior to the older ones. Standard deviation of the worst formula tested is 25% higher than that of the best one. With the best formula tested there would have been a good result (error < or = 1 D) in 82% of the cases, with the worst one in only 72%., Conclusions: The use of older formulas like SRK and Binkhorst should be discontinued and only the newer theoretical formulas (e.g. SRK/T, Holladay, Haigis etc.) be used. This is especially true for short and long eyes. For owners of a personal computer calculation and optimization of those more complex formulas should not be a problem.

Purpose: To evaluate the usefulness of four viscoelastic agents during phacoemulsification: 2% hydroxypropylmethylcellulose (HPMC) (Methocel), 3% sodium hyaluronate with 4% chondroitin sulfate (Viscoat), 1% sodium hyaluronate (Healon), 1.4% sodium hyaluronate (Healon GV)., Setting: Eye Clinic, Kreiskrankenhaus Bad Hersfeld, Germany., Methods: Two hundred patients, divided into four groups of 50 patients, received one of the viscoelastic substances during phacoemulsification and posterior chamber intraocular lens implantation. Patients were followed for 1 month. Visual acuity and intraocular pressure (IOP) were measured. The following were subjectively evaluated for each viscoelastic: corneal findings, anterior chamber reaction, visibility of intraocular structures and retention time during phacoemulsification, space maintaining ability, and removability and ease of injection., Results: Postoperative IOP and visual acuity were comparable among the four groups. Viscoat tended to trap nuclear fragments and air bubbles during the phacoemulsification procedure, which decreased visibility during surgery. Space maintenance and injection ease were significantly better with Healon and Healon GV., Conclusion: The high molecular weight viscoelastics (Healon and Healon GV) performed better as viscosurgical tool during cataract surgery using phacoemulsification.

If excimer laser techniques are used to prepare the bed of the recipient eye and to prepare the donor lenticule diameter and thickness, congruence of the cut surfaces will be optimal. MATERIALS AND METHODS. The preliminary in vitro investigations have already been reported. We now present the clinical results of three patients with circumscript corneal opacities, whom we treated with the lamellar keratoplasty in accordance with the calibration method we developed (follow-up 4-12 months). The lenticule thickness required varied between 320 and 415 microns, depending on the extent of the opacity. The lenticule was fixed with a suture for 9 months. RESULTS. All transplants healed without complications. The parts of the cornea treated with the laser did not show opacities in the "interface" or adjacent corneal layers. CONCLUSION. Besides optimal fit of the transplant, the absence of intrastromal opacities makes the instrument and apparatus requirement worthwhile. The clinical results are superior to those of conventional dissection methods. The absence of intrastromal opacities indicates that our method will be suitable for treating high-grade myopia. If possible, intrastromal treatment should be carried out after lamellation (LASIK).