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Radiomics: Big Data Instead of Biopsies in the Future?

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In principle, we do not process special categories of personal data, unless these are components of a commissioned processing. Nonetheless it must be stated that also a microscopic image without additional information such as e. Since even imaging is visualization of tissue, the information is limited. Wesarg, Fraunhofer Institute Darmstadt, Germany. Some studies could already reveal that radiomic analyses were able to extract and correlate equivalents to cellular, genetic, or phenotypic characteristic from classic imaging procedures 1. This leads to a very large data pool and its sufficient evaluation and application can only be performed in a professional and IT-based way.

Separately considered, the genomics data as well as the radiomics data have various advantages and their combination may generate useful additional information. Via genomics it is possible to identify a very detailed genetic pattern and thus an extract of molecular processes on the cellular level — broken down to DNA or RNA. However, this is limited to specific, rather small areas or cell types and tissue or tumor parts. From these analyses specific biomarkers relevant for the discrete question have to be defined. Already this objective is a great challenge. It is certainly not realistic to aim at one-to-one correlation of genomic examination with radiomics.

With radiogenomics, for example a tumor could be holistically characterized because in the radiological image not only single areas but the entire affected tissue would be assessed. A combination of both methods would then provide significantly more information also on a molecular biological level. If radiogenomics retrieved important molecular phenomena in equivalence to laboratory diagnostic methods, even avoiding molecular tissue diagnostics might be possible.

This could finally lead to the potential avoidance of invasive biopsies, lower costs, and less staff- and material-related efforts as well as improve the patient satisfaction. Currently radiomics are mainly applied in oncology for alternative characterization of solid carcinomas. However, they have the potential to serve as biomarkers for benign diseases with one or several classifiable correlates in imaging — e.

In the following paragraphs, examples of some radiomics applications in the field of oncology will be focused and the state-of-the-art in head and neck oncology will be described. For better understanding of the methods and their problems, the radiomics workflow will further be described and its potential sources of variation and errors will be discussed. Especially in oncology, radiomics are very well received. In this context, the outcome, histology, subtyping, or even therapy response are correlated with imaging features. The distinction of the terms is certainly vague. However, because of the possibilities of data storage and processing that were not available to the current extent, these articles are significantly more limited regarding their spectrum of analysis.

The number of publications is manageable although if has greatly increased in the last years with definition of the term of radiomics and an associated workflow as well as forward-looking expectations. A high variation is found in the size of the patient cohorts and the study design.

Generally speaking, older studies deal with smaller cohorts than more recent ones — finally also due to capacities and possibilities of data processing and storage. Although most trials are based on retrospective datasets, a tendency is observed that radiological signatures are validated in second or even prospective datasets — which is highly desirable. It is remarkable that specific tumor entities are significantly more present in this field than others. There are comparably many publications for example on lung and breast cancer, whereas other also frequently occurring entities such as cervix cancer or lymphomas are rather underrepresented.

Therefore, some articles about well-investigated tumors such as lung and breast cancer will be elucidated here and other less dominant entities will not be described in this context. Their objective was to evaluate the feasibility of automatized diagnostics of chest radiography. However, in comparison to current possibilities, the dataset was quite restricted because IT-based analysis as we use it today was not possible. Thus, the article may be considered rather as a precursor than as an example for modern radiomics 8. In , Al-Kadi and Watson differentiated aggressive lung carcinomas from non-aggressive ones based on CT scans by means of structure-based characteristics in 15 patients 9.

Since , the research team of Ganeshan et al. In , they published a pilot study that encompassed 18 patients with non-small cell lung cancer. Statistically processed imaging properties middle greyscale, entropy, uniformity could be correlated with the tumor stage and its glucose metabolism In a follow-up trial, the tumor uniformity could be correlated with the survival of 54 patients. Further investigations revealed that the structural properties could also be matched with histopathological characteristics beside the clinical ones By applying additional statistical evaluation methods, further histopathological properties could be correlated to the structural analysis of the CT scans Other publications concerning non-small cell lung cancer were provided by Aerts et al.

They investigated radiomic features in non-small cell lung and head and neck cancer. That aspect will be elucidated later in this article when focusing on head and neck cancer. The research team could establish a predictive signature in lung cancer for the survival, the histology, and the tumor stage. Recently, those parameters were confirmed for the survival in another patient cohort and the transferability on the modalities of planning-CT and CBCT cone beam computed tomography verified.

This implies that radiomic signatures are potentially applicable in different modalities which may be of high clinical value Based on a cohort of patients with adenocarcinomas of the lung, the same group could show that a radiomic signature with 33 markers may predict metastatic spread, and another signature encompassing 12 features the survival The analysis of other characteristics of the complexity of tumor type and heterogeneity could be correlated with the overall survival in a patient cohort and confirmed in an additional one In this context, the radiomic signature accuracy: The comparison of these methods was thus decided in favor of radiomics.

Zhang et al. In this way, they could show that the applied statistical methods have a significant impact on the definition and relevance of radiological biomarkers. In addition, the modalities within one imaging variant are crucial. Different data quality and relevance regarding the prognosis of recurrences of lung cancer were revealed by Huynh et al. Even radiogenomics have already been investigated in lung cancer.

Aerts et al. Two characteristics of radiomic heterogeneity could be correlated with cell cycle genes that lead to the development of heterogeneous tumors and increased proliferation This substantiates the hypothesis that proteogenomic phenomena can be displayed directly and indirectly in imaging data. Only recently, the same group elucidated in pulmonary adenocarcinomas that a CT-based radiomic signature heterogeneity-based in patients could predict the EGFR epidermal growth factor receptor status.

This signature was validated in a second cohort of patients. A combination with a clinical data model further improved the accuracy. In diffusion-weighted MRI, Yuan et al. Not only outcome parameters and biological tissue typing may be displayed by radiomics. Tools to support decision-making in therapy planning would be of great clinical value. In cases of non-small cell lung cancer, a correlation of the response to radiotherapy or radiochemotherapy with the overall survival could be found in PET and PET-CT by means of radiomic biomarkers 22 The versatility of imaging-based biomarkers is very well reflected in radiomics-based studies on lung cancer.

The results are very promising and encompass the differentiation of malignant and benign lesions, the elucidation of genetic and histological foundations as well as clinically oriented prognoses of outcome and therapy response. Already early, breast cancer has been evaluated with regard to the significance of imaging because mammography has been used for screening for several decades. A rapid and precise differentiation of benign and malignant lesions based on structural characteristics as endpoints as well as the possibility of implementing automated screening have been evaluated for a long time.

Structural analyses of mammograms reach back to the ies and were continued in the ies and ies 25 26 27 28 29 30 Since the ies, structural analysis has also been successfully implemented in ultrasound diagnostics for differentiation of breast cancer 32 33 Already in , Garra et al. A recent investigation could analyze structural parameters by means of sonoelastography in 42 patients suffering from breast cancer and 75 patients with benign lesions. Seven sonoelastic characteristics were selected that could predict malignancy with a sensitivity of A fluent transition of early structural analyses to modern radiomics can be observed.

In contrast to the detection of lung cancer where computed tomography plays a major role, magnetic resonance imaging is the adequate procedure for soft tissue visualization in breast cancer. Also here, the first structural analyses date back to the ies. Already in , Sinha et al. Also in the following studies that had been performed with the purpose of differentiating malignant breast tumors, structural analyses could achieve good results.

However, those were retrospective data analyses with a limited number of patients 37 38 Cai et al. By means of 3 classic machine-learning algorithms, 28 structural parameters were examined and in order to avoid redundancy and to achieve improved significance, they were reduced to 5 features. Recently, Bickelhaupt et al. Holli et al.

By means of radiomics, Wang et al. A combined approach of 38 radiomic parameters and genetic properties was chosen by Guo et al. Radiomic features were more suitable for predicting the tumor stage whereas genomic features better described the receptor status. However, the research team admitted a reduced significance of their trial because of the limited number of patients Recently, also Li et al. The response of breast cancer to chemotherapy was evaluated by several research groups.

Ahmed et al. A recent trial of Braman et al. Insufficient response to neoadjuvant chemotherapy was associated with a higher peritumoral heterogeneity. The combined examination could significantly predict the treatment response, independently from the receptor status In this way, the field that is considered in radiomic examinations was extended by this study. Not only the tumor itself provides relevant data. In summary, it can be stated that the variance of examination methods for breast cancer of which radiological structural parameters can be obtained is higher than for lung cancer.

Since it is a primarily soft tissue-associated tumor, the classic examination methods of mammography, ultrasound including sonoelastography, and MRI are first-line techniques. Also in this context, studies have already been conducted that differentiate not only benign and malignant lesions as the endpoint, but that rather emphasize histological and genetic foundations and predict the clinical outcome as well as the therapy response. In order to obtain statistically more reliable results in the future and to validate radiomic signatures also trans-regionally, they are certainly — even for other tumor entities — a suitable data source that should be taken into consideration.

Fewer radiomics trials exist for other solid carcinomas such as cervix carcinomas 49 , liver carcinomas 50 , colon carcinomas 51 , and prostate carcinomas 52 53 54 Concerning glioblastomas and gliomas, radiomics-based correlations could be found with molecular information such as the EGFR status and the isocitrate dehydrogenase 1 IDH1 status 56 57 In a cohort of 41 patients suffering from esophageal cancer, Tixier et al.

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Hereby, complete and partial therapy responders as well as failures could be identified more reliably than with standard uptake values SUV alone The research team of Zhang et al. They were based on MRI for which radiomic features were evaluated per patient. The first study encompassed patients and 6 methods for parameter selection and 9 classification methods were analyzed. An optimal machine-learning method was identified in order to perform biomarker screening of nasopharyngeal carcinomas In the second study, patients with primary diagnosis of advanced nasopharyngeal carcinomas stage II-IVb without distant metastasis were integrated; 88 of them were examined in a training cohort and 30 in an independent validation cohort.

A radiomic signature could be established by means of a combination of CET1-weighted and T2-weighted images together with the TNM stage regarding the progression-free survival. The significance of radiomics was improved by the combination with known clinical parameters — or vice versa — in the sense of multimodal modeling.

The team of Lambin et al. Their primary research in head and neck cancer is based on routinely performed CT scans. In cases of squamous cell carcinomas of the head and neck, there seem to be similar effects to small cell lung cancer. In , automatically extracted radiomic features were examined in computed tomographic scans of 1, patients who either had lung or head and neck cancer.

They included phenotypic properties that reflected the tumor image intensity, shape, structure, and waves in several scalings. It contains 4 parameters: statistics energy, shape compactness, grey level nonuniformity, and grey level nonuniformity HLH. For validation, 4 additional cohorts were included. In particular after publication of the revised TNM classification that had not been applied in the context of this study, it is additionally interesting if HPV human papillomavirus positive can be differentiated from HPV-negative patients by means of a radiomic signature, especially because their outcome is different after radio chemo therapy 66 However, this was not the case although the outcome could be well predicted by the radiomic signature in particular in HPV-negative patients.

In addition to clinical data correlation, the radiomic signature of the Lung 3 cohort was correlated with corresponding genetic data of the same cohort in a gene-set enrichment analysis GSEA. Hereby, associations between the expression of different genetic groups and the radiological structural parameters could be defined.

In particular, genetic expression variations of the cell cycle were depicted. Hence, also the molecular biology on which the tumor is based can be revealed by imaging up to a certain degree 13 and thus the value of radiogenomics is supported. The same CT-based radiomic features were applied in another study of the group. This time they were correlated with further clinical properties. The study was — similar to the previous one — subdivided into a training and a validation phase.

Comparing head and neck with lung cancer, characteristics were relevant for both tumor entities. In addition, parameters characterized the outcome only for lung cancer and further 22 radiomic parameters were only relevant for head and neck cancer. Different clusters could be correlated with survival lung and head and neck cancer , histology lung cancer , and tumor stage lung and head and neck cancer , however, the HPV status could not be revealed by a signature In order to further develop the methods of radiomics, the team established a machine-learning-based method that could predict the overall survival of head and neck cancer patients based on a radiomic signature with high stability.

The objective was to improve the practical application of a radiomic signature also for the clinical routine. This is necessary to introduce radiomics as a non-invasive, cost-effective method in the medium term. The already known radiomic features were tested by means of 13 methods for characteristics selection and 11 machine-learning classification methods in a first cohort consisting of head and neck cancer patients and validated in another independent cohort with 95 head and neck cancer patients.

The endpoint was the overall survival. Hereby, a reliable machine-learning method could be identified In summary, those 3 publications were able to correlate data of different origins clinical, histological, and genetic information with radiomics parameters and in this way characterize the tumor based on imaging. The radiomic signature alone was sometimes superior to single data resources that had been applied for characterization before. But even when this was not the case, their completion in the sense of multimodal modeling could improve the significance for the assessment of the carcinoma.

The trials had been performed with relatively large patient cohorts from institutions in partly different locations so that they were methodically well designed and the reliability of their significance could already be verified internally. In a newly initiated trial, patients with oropharyngeal cancer and known HPV status were included. They had undergone primary radiotherapy with curative intention iMRT and a standardized pretherapeutic CT scan. As primary endpoints of the radiomics-based analysis of the CT scans, the HPV status and the occurrence of local recurrences were defined.

In an approach designed as a competition with scoring, different researchers could test their algorithms regarding the evaluation of the HPV status and the local recurrences. Also for the practical application of radiomics in clinical therapy, first studies are available for head and neck cancer. Based on CT scans, Ou et al. A combination with the p16 status as indicator for the biomarker HPV further improved the significance of the signature. Overall, this combination was more relevant than the p16 status or the radiomic signature alone Imaging was performed before and after therapy.

As endpoints, the mortality, the local treatment failure, and distant metastasis were defined. In this investigation, 24 representative radiomic features were included that reflected the tumor intensity, shape, and structure. Predictive models for the mortality, the local treatment failure, and the occurrence of distant metastasis could be established that were cross-validated internally. Unfortunately, this model did not reach significance for local treatment failure during external validation. In addition, the models for mortality and distant metastasis could not be confirmed statistically although, according to the authors, they had an acceptable predictive performance Overall, many promising approaches exist for head and neck cancer to usefully establish and clinically integrate radiomics.

Activities of other research teams that enrich the field with further independent investigations would be desirable. CT scanning as the standard imaging procedure for head and neck cancer seems to be a reasonable basis, although further MRI-based examinations still have to be assessed. At the same time, the available studies of head and neck and other carcinomas show that beside the data quality and quantity, the success of the studies is fundamentally determined by a structured approach in the context of radiomics.

So, how to approach those data? Meanwhile, a typical radiomics workflow has been defined that is used generally in nearly all studies. First, a suitable standardized imaging procedure is identified. Then, the region of interest is determined, e. From the segmented areas, radiomic features are defined and extracted by means of specific algorithms. Together with data from other sources, they are included into a database and accordingly formatted and are then ready for processing. Using suitable statistical methods, biomarkers and the radiomic signatures can be defined from those databases.

This principle seems to be logical and relatively easy to handle. However, despite the application of a standardized workflow, each of those steps bears the risk of errors, difficulties, and limitations that may impair, falsify and complicate the analysis. The quality of the analysis, its significance and comparability could potentially be impaired despite the availability of suitable imaging material. Already minor changes of the standard or the methods may have effects that reduce the reproducibility.

As a consequence, the established radiomic signature would not be stable and applicable. So always large cohorts with many possibly comparable datasets are preferred as the basis for establishing a radiomic signature. Validation in an independent cohort — ideally by an independent group of researchers — according to standardized protocols is useful in order to minimize internal sources of errors that are sometimes difficult to identify. Typical sources of errors will be described in the following according to the single steps of the workflow. Imaging is the essential basis to practically perform radiomics.

It has to be available as digital file. All imaging included in a study has to be performed based on the same standard in the same modality and if possible at a comparable stage of the disease. The suitable, high-quality imaging modality, the appropriate examination protocol, and the most reasonable ROI have to be identified. Regarding the analysis of solid carcinomas, the ROI is mainly the tumor, but it may also include the surrounding tissue or possible metastases. Even specific anatomical structures, disease foci etc. Optimally, a standard imaging is chosen with the standard protocol for the most common questions.

Different imaging modalities lead to different radiomic features with potentially different significance and specificity. Depending on the question and the ROI, more information is expected in terms of a certain modality. However, if this is not the case, the investigator probably benefits most from the standard imaging of the analyzed disease where he has most images at his disposition without additional efforts. This is important because the larger the cohort is, the potentially higher is the statistical significance and the less errors occur due to outliers.

If the modality is selected, the type of how imaging is performed as well as the parameters of imaging may still be adjusted. These are very basic factors that nonetheless have to be defined exactly. The use of different scanners can also have an impact. However, different scanners may already exist in separate institutions and replacing them is very expensive. Thus, particularly in the context of multicenter trials the scanner model should be taken into account.

Regarding the acquisition of imaging, different slice thicknesses, programs, configurations, or details can be selected. Each of those program features has an influence on the structure of the imaging data. In cases of contrast media application, the radiomic features vary potentially according to the type and quantity of the contrast agent, the time of application, and the physiology-related individual distribution patterns of the patient.

Not least, images taken at different times and stages as well as metabolic conditions of a disease may be acquired. In this way, the definition of the ROI and its segmentation can be modified. All these parameters influence the characteristics to be measured. Some of the above-mentioned variable parameters of imaging are difficult to influence and thus always a potential source of error.

So it is even more important to strictly standardize all those characteristics that allow standardization. They include in particular technical standards. The type of image acquisition, the imaging mode, the matrices, the slices, resolutions, reconstruction as well as the type and adapted quantity of the contrast agent can be widely standardized allowing comparability between separate study centers.

Fortunately, the introduction of standards for specific questions is increasingly accepted so that this prerequisite for radiomic analyses is structurally improved. Accurate clinical information about the type and stage of disease, metabolic diseases, and other clinical features help in cases of instable variables to identify influences and at least to take them into account in the context of data processing Segmentation defines the borders of the area that is analyzed by radiomics, e. So segmentation is an essential step and a basic precondition for performing radiomics.

Slice per slice the ROI is marked in the images so that itself and its relation to the surrounding structures are finally depicted in a completely 3-dimensional way. Only structures that are included, are considered later in the analysis. A definition and segmentation of several different ROIs as well as their later assessment, together or separated, is generally possible. Radiological features are relevantly influenced by segmentation. Methodically, segmentation can be generally performed manually, semi-automatically, or automatically.

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Haben wir das Angebot bis dahin nicht angenommen, so gilt es als abgelehnt. Gleichzeitig speichern wir den Vertragstext in unserer elektronischen Datenverarbeitung. Da der Kunde hierzu keinen Zugang hat, obliegt es ihm, die E-Mail mit dem Vertragstext im eigenen Interesse aufzubewahren.

Die Einzelpreise ergeben sich jeweils aus der Preisliste und werden dem Kunden im Warenkorb angezeigt. Translation - English Tasting Section 3 — Tasting offer 1 On our website, we offer various tasting events.

The content of each event can be found in the descriptions of individual event dates on the website. The customer must guarantee that the location selected is suitable for holding the tasting session. Via the booking form, customers send us their name, address and phone number as well as the location and date of the desired event. We subsequently send a binding offer via mail or email to participate in the customer's desired tasting session. Until the offer acceptance is submitted, the customer has the option at any time to modify previously submitted data or cancel the entire booking.

The contract confirmation includes the contract text, which will also be saved in our electronic data processing system. Please save the contract confirmation on your computer or print it out for your documents, since you will otherwise have no access to the contract text. We reserve the right to offer other payment methods as well. The customer remains obligated to pay the participation price even if the customer declines to participate or withdraws from participation during the event unless legal grounds for termination or withdrawal are involved.

Custom-produced whiskey Section 4 — Content of services 1 After participating in a tasting session II. We assume that a tasting will generally be required in order to determine the flavor profile for producing the custom whiskey. Please note that since the size of the wooden casks is not standardized, there may be variations in the maximum filling quantity depending on the individual cask. We guarantee that at least 25 liters of whiskey will be available for bottling and shipment to the customer at the end of the individual production process.

Section 5 - Contract conclusion 1 The product descriptions contained on our website do not constitute binding offers on our part; rather, their purpose is to assist the customer in submitting a binding offer. To order, the customer submits a binding contract offer for the products contained in the shopping cart by clicking the "Place order now" button after configuring the whiskey cask based on customer preferences, adding it to the virtual shopping cart and completing the electronic order process.

Before submitting the purchase offer, the customer will be shown a summary of the data collected for the order, including the significant characteristics of the products. At this time, the customer has the opportunity to check the data for potential input errors and, if necessary, to go back one or more steps in the order process to change the data and settings or cancel the entire order. Alternatively, the customer can submit the offer to the buyer via email or mail using the appropriate order form. In this process, the customer's receipt of the contract confirmation or our request for payment following receipt of the order will be considered conclusive.

If more than one of the above alternative forms of offer is present, the contract will occur at the earliest point in time when one of the alternatives has been received. If we have not accepted the offer by that point, it will be deemed rejected. At the same time, we will store the contract text in our electronic data processing system. Since the customer has no access to this system, it is the responsibility and in the interest of the customer to retain the email with the contract text. Section 6 — Prices and payment 1 The prices indicated in the shopping cart include the costs of the selected distillate as well as the costs of procuring the liter wooden cask and storing it on our premises for 3 to 6 years.

For each additional partial year begun, an additional storage fee of euros will be charged. Additional services e. The individual prices can be found in the price list and will be displayed to the customer in the shopping cart. We reserve the right to offer additional payment methods. We reserve the right to withdraw from the contract if payment is not made by the deadline.

Section 7 — Production and bottling 1 No later than 14 days after receipt of payment, we will fill the liter wooden cask with the distillate according to the flavor requirements provided by the customer in the order. We will also give the customer the opportunity each year to be present at a check by arranging an appointment via a separate booking form on our website.

The customer has no entitlement to take part in the check. We will provide the customer with an email recommendation at regular intervals, at least once every 6 months, concerning whether the whiskey meets the customer's flavor requirements and should now be bottled. After the third year has elapsed, the customer may submit a statement in text form requesting us to proceed with bottling within 14 days after we have received this statement.

Rechtsgebiet: Arbeitsrecht Rechtstipp vom Translation - English Dismissal for operational reasons: Is the dismissal protection process an option worth pursuing? Practice area: Labor law Legal pointer dated December 1, The law against wrongful dismissal makes distinctions among poor performance, misconduct, and operational reasons as grounds for dismissal.

Operations has become the most common reason given for dismissal. Currently around two out of three dismissals are related to operational issues. There are, however, far fewer cases of litigation involving operational reasons than those involving misconduct or poor performance. That is primarily because only in the operations category are the necessary grounds for any effective dismissal within the decision-making power of the employer for example, shutting down a division or outsourcing work.

The latter option appears at first glance to be far simpler, for which reason many employees believe there is little they can do against an operationally determined dismissal. Settlement possible even in cases of dismissal for business reasons Nevertheless, such a belief is not borne out in most cases of dismissal on operational grounds. Even with dismissal for operational reasons, the employee as a matter of principle but good luck has an opportunity to access the dismissal protection process to try for a settlement involving compensation for the loss of the job. In the first place, many employers experience a certain uncertainty about dismissal for operational reasons, since such dismissals are considered to be difficult when it comes to prevailing in a court of law.

A major reason for this is because labor courts place very high demands on employers concerning the statement of reasons for dismissal on operational grounds. The employer must provide an exact and detailed explanation of the operational reasons for the elimination of the position, and where necessary also provide proof of such reasons. Employers who do not succeed in giving a sufficiently exact and detailed account will lose the termination protection case, even if the dismissal for operational reasons in itself was justified.

A further problem for the employer in a case of dismissal for operational reasons is the correct social selection regarding the number of employees subject to dismissal. Erroneous social criteria can also lead to the invalidity of a dismissal for operational reasons. Dies geschieht in noch budgetneutral, bis wird dann aber schrittweise die Abrechnung nach diesem neuen System erfolgen. Translation - English By next year, Germany's hospitals will have to invoice according to diagnosis-related group DRG compensation rather than flat per diem rates.

This new system was introduced in in a budget-neutral fashion, and hospital billing will gradually move towards its full incorporation by At that time, lengthy in-patient stays will lose their economic appeal for hospitals. There is a distinct fear that patients could be released from the hospital too soon due to financial reasons. The way to avoid "bloody discharge" on one hand and economic difficulty for hospitals on the other should involve thorough, comprehensive diagnosis of the primary disease and all secondary diseases, the Alliance of Diagnostics Industries Verband der Diagnostica-Industrie, or VDGH pointed out to medical, hospital, and health industry professionals attending this year's VDGH Diagnosis Forum in Berlin.

Laboratory diagnosis, viewed until now merely as a cost factor, will gain new importance with DRGs: the role of assuring hospitals a reasonable, adequate compensation. In the future, rapid and accurate diagnoses not only of the primary illness but also of the accompanying conditions that make treatment difficult — such as the infection of a wound — can result in payoff for hospitals.

A study commissioned by VDGH emphasizes that laboratory diagnostic results can identify at least factors that complicate treatment. In thousands of combinations with a primary disease, these results led to increased revenues for the hospital, which could net several thousand euros per case, explained DRG expert G. Hoffmann, M. For manufacturers of diagnostics and laboratory systems, the introduction of diagnosis-related group compensation offers one of the few rays of hope for Increasing hospital demand may not make up, however, for a downturn in revenues from the statutory health insurers.

Income from reagents used exclusively in medical laboratories will drop by 0. A positive development, however, was the revenue from test kits that can be purchased by patients directly in the pharmacy. In diesem Sinne meint Wissenschaft ein nach Prinzipien geordnetes Wissen, ein sachlich geordneter Zusammenhang von wahren bzw.

Wissenschaft bzw. Wissenschaft gibt es in diesem Sinne nicht zu allen Zeiten, und an allen Orten der Welt. Im sog. Die Lebenskunst ist dabei zentriert um die Fragen der Selbsterkenntnis, Selbstbeherrschung und Selbstgestaltung — kurz um die Frage der Selbstsorge der Individuen. Translation - English Science can be understood as the embodiment of human knowledge. In this sense, science refers to knowledge that is organized according to principles, an ordered association of true or objective conclusions, plausible hypotheses, and possible consequences regarding reality or subsections of it.

Science defined in this sense is not found in all ages and in all places on Earth. In the Occident, ancient Greece is considered the site of the discovery of science as an independent cultural framework distinguished from other cultural frameworks such as politics, economy, law, aesthetics, or education. If the classical canons of knowledge from ancient times are brought together — the linguistic trivium of grammar, rhetoric, logic and the mathematical quadrivium of arithmetic, geometry, astronomy, and music theory — it is apparent that Western science has its origins in mathematical-quantitative and linguistic-qualitative ways of thinking.

At its core, the concept of the art of living can be understood as a philosophical school of thought that raises issues surrounding the design and construction of a successful life. More recent variations on this term, which was first employed by Friedrich Schlegel in in German: Lebenskunst , recall ancient Greek and Roman models and focus on the extent to which human beings can realise a good, successful, and beautiful life. The art of life is thus centred on questions of self-knowledge, self-control, and self-formation — in short, on care for oneself as an individual.

How can and should humans care for themselves in such a way as to be able not only to conceptualise their idea of a successful life but also to convert that idea into reality? In this respect, the art of living is an ambitious undertaking because, in addition to being both a rather extensive hermeneutic of oneself — one that encompasses not only self-understanding but also self-interpretation — and an action-based praxis oriented toward specific aesthetic categories that is thoroughly bound up in patience, concentration, practice, and discipline, it also goes hand in hand with an aesthetic style that corresponds in turn to aesthetic criteria cf.

The ancient Greeks employed the terms theoria, praxis, and poiesis to characterise these spheres. This essay seeks in the first place to demonstrate that in Western thought the art of living represents a form of knowledge that is both every-day and scientific — which generally means embracing philosophical knowledge but also knowledge from other sciences, such as medicine or therapeutic knowledge.

In the second place, it attempts to make clear that both quantitative and economic perspectives on the art of living as well as both qualitative and evaluative descriptions of its specific condition continue to be relevant today. A subsequent Critical Pedagogy would therefore no longer need to pose the tiresome question about the general in pedagogy but would instead reflect the pedagogy in general society.

According to this notion, the educational system is in the first place a central regulatory authority for the production and reproduction of the workforce commodity. To a significant extent, pedagogy derives its social legitimation from its function of producing in the labour commodity the level of education, skills and competence required for the respective relations of production and is therefore a key factor in the expanded accumulation of endogenous growth conditions. To see through the connection of this reproduction of reproduction, it becomes necessary once again to refer to the critique of natural ability models and the pedagogical legitimation of social inequality.

And thirdly, the mode of social critique, which would always be a critique of capitalism, would need to be sharpened. Even areas of Critical Education such as the historically significant peace education are not immune in the face of regressive and resentful forms of capitalist critique; in the presence of a new populism and new Third Position politics, they are in need of a materialist reflection on their critical concepts.

With the concept of the Third Position, reference is made in both a historical and current context to the content-based intersections of conspiracy theories and anti-Semitic world views on the right and to some extent on the left of the political spectrum. In the s, representatives of the Conservative Revolution endeavoured to forge a link between nationalism and socialism. Similar efforts are once again strongly in evidence in current right-wing populism cf.

La gloria de Dios se muestra luminosa, vivificadora y fascinadora en el cuerpo de Cristo.

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Su presencia es su voz. Cristo es de nuestro mundo en la unidad indivisible de lo humano y de lo divino. It takes up again the story of Moses, ratified in one sense but relativized and surpassed in another. No one has ever seen God. He Who is His Word has told us of Him; He Who has been at His side for all eternity has revealed Himself to us in time; He Who confronts us with a friendship that is affiliation makes possible an amity greater than that known by Moses. This is why the disciples, and through them all believers, can achieve a self-understanding of friendship.

Saint John brings the extremes together: Logos and the flesh, the one Who was at the side of the Father and the one Who dies in the world, the beloved Son and the older Brother murdered through the violence of the younger brothers, the one lifted up on the cross and the one lifted up in glory, the one Who passed through our world and the one Who was wounded by our offenses. Crucifixion act of men , death act of Jesus and resurrection act of the Father all come together for Saint John in the concept of glorification.

The glory of God is seen in the body of Christ as luminous, life-giving and fascinating. Christianity has its roots in the religious experience of the people of Israel. It is the heritage of their faith in one transcendent, holy, invisible and incomprehensible God. His presence is His voice. God can be heard by man but not seen. Christ is of our world in the indivisible unity of the human and the divine.

Jesus is the given name of this Jew from Nazareth. Following the resurrection, His disciples would — one after another — begin to understand His specific relationship with God; and they reasoned that "Son" or "the Son" is the name that applies to Jesus and sets Him apart from all other children of God. But they sensed that this Son was present and functional in the church through His word, action and spirit: and to explain that action, they gave him the name used by the Septuagint as a translation into Greek of the Old Testament name of Yahweh: Kyrios, Lord.

Jesus indicates his specific individuality, Christ his origin and intrinsic relationship to the people of the first covenant with Israel; His Son makes explicit the unique relationship that unites Jesus with God. He is, therefore a figure both particular and universal, both external and internal, in whom both the mystery of God and the enigma of man are expressed.

Estas ropas muestran una gran riqueza ornamental simulando ricos bordados o incrustaciones en oro y piedras preciosas en las capas pluviales. Por lo que respecta al tocado femenino, reproduce un modelo que se repite constantemente a lo largo de las miniaturas que componen el Libro del Caballero Zifar. Latin , fol. Translation - English The clothing presents similarities across all individuals, loose and with long sleeves in the manner of the four priests. These clothes show great ornamental richness, simulating rich embroidery or incrustations in gold and precious stones on the capes.

Compared to these, the choir members located in the foreground are portrayed as less wealthy, wearing simpler garments, their heads covered with Jewish turbans or knit caps. In addressing the creases, they endeavor to achieve a natural representation of the fabric while occasionally taking certain license to create chiaroscuro effects in their compositions, even though the chromatic transition is expressed very gradually. The movements of the individuals tend to be reduced to the minimum, and figures are represented with their hands contained within the outlines of their shapes rather than being thrust into the surrounding space.

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Is it possible that we have located evidence of that lost set? We can only raise this as a hypothesis pending the emergence of further data. Otra abertura de importantes dimensiones se produce en aquellas torres donde el primer cuerpo se constituye en el coro del templo. En estos casos, el paramento que comparten torre e iglesia se abre, formando un gran arco triunfal que comunica el espacio interior de la torre con el de la nave mayor del templo. Translation - English The openings in the lower section offer a greater variety of approaches. Where the tower is attached to one of the sides of the church, its wall is completely enclosed while, in cases where towers form a colonnade at the foot of the temple, the wall forms a large molded arch.

Another highly significant opening occurs in those towers where the first level contains the choir of the temple. The other levels feature wooden beams and joists to configure the different slabs as well as the hipped roof that caps the belfry level. Translation - English Given the complexity associated with rail traffic due to the interaction between rolling stock and infrastructure, as well as the requirements associated with the service, the simulations were conducted using a software tool specially designed to dynamically analyse these relations using a set of entry databases to achieve results regarding the most relevant technical and operational aspects.

From the simulation tool, two sets of results were obtained: first, the results of a set of film simulations associated with the scenario under analysis, and second, the results of the electrical study focused on the film data previously calculated. For the first set of results, and based on the databases created specifically for these simulations, including characterisations of the rolling stock as well as infrastructure, and allowing for analysis, evaluation and definition of the maximum circulation speeds, cants, stop times, journey times, etc.

The values yielded in this first set of results are utilised as entry parameters for the performance of the simulations that make up the electrical study. Un dibujo de arquitectura tiene mucho mayor sentido cuando se coordina con otros dibujos. Translation - English In this paper, we wish to describe our experiences in three different settings: teaching architectural drawing, teaching advanced architectural representation, and research in photogrammetry.

In our experience, combining collaborative networks with videos and virtual models has yielded results beyond our initial expectations. Social networks have allowed us to extend our reach to include other interested individuals — outsiders who have been encouraged by our projects. The development of models for supporting content or as a basis for ideas — in other words, going beyond shape, texture and color, has necessitated the search for more appropriate systems than those we employ today.

Video production has made a much larger and more rapid dissemination possible than any other medium, with the exception of prestigious journals. This dynamic, which is called evolution, has always existed. Certain tools, created as improvements to the existing ones, in turn die out if they do not adapt. In other words, pen and ink drawing has not vanished; on the contrary, it is enjoying a renewed prominence now that it is only used by its most enthusiastic admirers. In spite of allegations to the contrary, architectural graphic expression is an expanding — not shrinking — field.

Canson DIN-A1 paper has not disappeared. Its ability to accommodate other languages is an added value. An architectural drawing is much richer in meaning when it is coordinated with other drawings. The floor plan is the darling of both the cross section and the elevation, and the cross section is the parent of the constructive details. This connection or documentary sequence is what builds the architectural project. In the case of video, the relation is established over time and reinforced by a sound track.

The first question that all of us must surely ask is this: if we only have time and resources for drawing, are we going to devote energy to a video? De ellas en materia de aguas y en materia forestal. Como resultado de ellas se han realizado denuncias, en materia de aguas y en materia forestal. In the revised version of the Hydrological Plan, the project will not be included among the programmed measures and investments.

The legal protection of the plan has been reinforced in the light of available court resources. Forty-six catchments have been shut down, raising the total capped wells since to when added to those already reported to the Committee. These closings correspond to the substitution of catchments and to implementations at the conclusion of legal proceedings. The scheduled Extraction Plan was carried out and a considerable effort was made to adjust the planning details, with countless tasks performed to allow for the provision of legal protection and the setting of priorities for action.

As a result of this along with an intense inspection effort, a total of inspections were carried out in and , with of these involving water resources and focused on forestry. The culmination of all these actions represents another significant advance in completing the planned objectives. Regarding the ZZ Mine, in compliance with paragraph of the Operational Guidelines, the project prepared by the developer was submitted to the World Heritage Center for its evaluation.

The evaluation process is specifically expected to incorporate the IUCN recommendations on environmental evaluations in the World Heritage locations along with a risk analysis. The Center and the Heritage Committee can provide their considerations. The ornithological values that inspired the inclusion of this space on the World Heritage List continue to be exceptional, averaging over a half million wintering aquatic birds and the maintenance of habitats for the reproduction of at least 7 endangered species. The situation in the National Park regarding species has not changed significantly since the last report and is distinguished by the continuation of efforts to prevent violations.

Translation - English For the crimes of passive corruption: Fulano de Tal has no antecedents recorded in the proceeding. The evidence collected in this same action indicate that he started dedicating himself to the systematic commitment of crimes in carrying out his responsibilities as Director at Company X for the purpose of his own illicit enrichment and that of third parties, which should be assessed negatively with respect to personality.

Culpability, social conduct, motives, and behaving in the manner of a victim are neutral elements. Circumstances should be assessed negatively. The commitment of crimes of corruption involved received approximately xx,xxx,xxx. Just one crime of corruption involved the payment of over twenty million in bribes. Even taking into consideration that Fulano de Tal received a portion of these funds, the amount is still extremely high. Consequences should also be assessed negatively, since the cost of the bribe was passed on to Company X through charging a price above its estimate - induced, moreover, by corruption, inflicting damages on the state-owned enterprise in the equivalent amount.

Corruption involving payment of bribes in the amount of dozens of millions of Brazilian reals and resulting in equivalent damages to the public coffers deserves special condemnation. Taking into consideration three negative vectors of special condemnation, I determine a sentence of five years of imprisonment for the crime of passive corruption. Translation - English Touching on the topic of competitions, I mentioned how women-only tournaments are regarded as safe spaces for women to play and get a little taste of competition. Still, many people challenge the idea and ask how long such tournaments should continue.

For Taylor, the matter is very complex. Still, it is the way we have found to give women a chance to play at a high level without harassment and toxic culture," she explains. The sociologist confesses that she does not know when such tournaments can cease to exist, but she hopes it will not take long. At this time, such competitions exist to help women, so first we need to find a way to overcome entrance barriers and problems of harassment and toxic culture. Developer and publisher of League of Legends, the company was accused in an extensive article of having a "bro culture" that created a hostile environment for female employees.

Riot Games executives promised structural changes to end the company's sexist climate and to make improvements on matters of diversity and inclusion, but it is facing a lawsuit for not having dealt with this situation before now. But besides Riot, which is the creator of one of the most profitable competitive games, I was also aware of electronic sports organizations that seem to be making no effort to include women on their teams. Taylor agreed, commenting on some of the excuses she has heard. The sociologist believes that this is the sort of structural problem and bias that organizations will have to overcome, and some of them have already done this with no problem at all, as in the case of Geguri, who plays and lives with the Overwatch League's Shanghai Dragons team members.

We will also continue to report on the same kind of topic every six months or so in the hope that these walls will come down sooner. Translation - English The stage was set for Botafogo's return, competing in Libertadores Cup play in front of its fans for the first time in 17 years. But "The Giant Returned" and the black-and-white welcoming carpet took the form of a great mosaic that also featured a tribute to the timeless idol Nilton Santos.

Translation - English Guide for Returning Brazilians 1. The consular role is one of the oldest and most traditional functions of the Foreign Relations Ministry. There has been, particularly since the s, a considerable increase in the number of Brazilians who have chosen to live abroad or who travel to other countries for tourism or study. The Ministry has taken significant steps in this area, including the streamlining and modernization of the network of professional consulates and the expansion of the network of honorary consulates, the creation of circuit consulates, and the creation and operation of Citizens Councils.

Among the countless initiatives in support of citizens abroad is the publication of the Consular Primers, short booklets with practical tips to guide Brazilian emigrants, avoid embarrassing situations, and assist these citizens in their life abroad. Most Brazilians living abroad have not broken their ties to home. They generally nurture a desire to return to Brazil after some time abroad. It is a collection of practical guidelines and useful tips to assist them in reintegrating back into their home country.

From the U. In fact, in the case of early pregnancy, the presence of this factor in all countries of the world and the specific nature of its occurrence led the World Bank to include it as a development indicator. Recent data released by the Bank in demonstrate the worldwide extent of this phenomenon, indicated by the adolescent fertility rate births per women between 15 and 19 years of age , as shown below. CNPJ: John N. Doe Jr, americano, solteiro, residente e domiciliado na Sample Rd. Amostra, No. Cidade Amostra, 24 de janeiro de Representada por Mr. Doe Jr, American, single, resident and domiciled at Sample Rd.

Paragraph 1: Should there be no interest by partners in acquiring the shares offered, equal right shall be open to the shareholders who, should they choose to acquire the shares, shall realize the proportional reduction of the share capital of the withdrawing partner, calculating those assets and paying said partner the corresponding amount. Paragraph 2: Should there be no interest by partners or shareholders in acquiring the shares offered, the withdrawing partner may assign or transfer them to nonshareholding parties outside the company.

Paragraph 3: Share value shall in all cases be determined according to the procedures defined in Clause Nine. Paragraph 4: Share Capital reduction and its form, as well as Share Capital increase and form of payment, shall be decided by a simple majority representing the share capital.

CLAUSE NINE In the event of partner withdrawal, dismissal or exclusion, the interested party must provide the other with thirty 30 days advance notice of this intention, for the purpose of initiating the transition process and taking measures to amend the respective Articles, during which time a balance sheet analysis shall be performed to calculate the terminating partner's assets.

Sole Paragraph: The provisions of caput shall apply, as applicable, in the calculation and payment of the assets of a deceased partner. Article 1.