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Background: Mild cognitive impairment (MCI) involves cognitive decline beyond typical age-related changes, but without significant daily activity disruption. It can encompass various cognitive domains as the causes of MCI are diverse. MCI as well as frequent comorbid neuropsychiatric conditions like depression and anxiety affect individuals' quality of life. Early interventions are essential, and computerized cognitive training (cCT) is an established treatment method. This paper presents the protocol for the NeuroNation MED Effectiveness Study, evaluating the self-administered mobile cCT intervention ("NeuroNation MED") in individuals with MCI to assess training effects on cognitive domains, health competence, neuropsychiatric symptoms, psychological well-being, and the general application usability. Methods: This study protocol presents a single-blinded multicenter randomized controlled trial that will be carried out in six study centers in Germany and Luxembourg. We included adults with MCI (existing F06.7 ICD-10-GM diagnosis and TICS ≥ 21 and ≤ 32). The intervention group will use a mobile, multi-domain cCT ("NeuroNation MED") for 12 weeks. Meanwhile, the wait list control group will receive standard medical care or no care. The eligibility of volunteers will be determined through a telephone screening. After completion of the baseline examination, patients will be randomly assigned to one of the experimental conditions in a 2:1 ratio. In total, 286 participants will be included in this study. The primary outcome is the change of cognitive performance measured by the index score of the screening module of the Neuropsychological Assessment Battery. Secondary outcomes are changes in the Cognitive Failures Questionnaire, Hospital Anxiety and Depression Scale, Health-49, Health Literacy Questionnaire, among others. All of the primary and secondary outcomes will be assessed at baseline and after the 12-week post-allocation period. Furthermore, the intervention group will undergo an assessment of the System Usability Scale, and the training data of the NeuroNation MED application will be analyzed. Discussion: This study aims to assess the effectiveness of a mobile self-administered cCT in enhancing cognitive abilities among individuals diagnosed with MCI. Should the findings confirm the effectiveness of the NeuroNation MED app, it may confer possible benefits for the care management of patients with MCI, owing to the accessibility, cost-effectiveness, and home-based setting it provides. Specifically, the cCT program could provide patients with personalized cognitive training, educational resources, and relaxation techniques, enabling participants to independently engage in cognitive training sessions at home without further supervision. Trial registration: German Clinical Trials Register DRKS00025133. Registered on November 5, 2021. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the study was to test the usability of the MyLA app prototype by its potential users. Furthermore, the Web app will be introduced in the framework of "Mobile Learning Analytics", a cooperation project between the Cooperative State University Mannheim and University of Mannheim. The participating universities focus on the support of personalized and self-regulated learning. MyLA collects data such as learning behavior, as well as personality traits. Last but not least, the paper will contribute to the topic of learning analytics and mobile learning in higher education. Design/methodology: For the empirical investigation, a mixed-method design was chosen. While 105 participants took part in the conducted online survey, after testing the app prototype, seven students joined an additional eye tracking study. For the quantitative part, a selected question pool from HIMATT (highly integrated model assessment technology and tools) instrument was chosen. The eye tracking investigation consisted of three tasks the participants had to solve. Findings: The findings showed that the students assessed the idea of the app, as well as the navigation positively. Only the color scheme of the prototype was not very attractive to a noticeable amount of the participants. So, it requires slight modifications concerning the app design. For the eye tracking study, it can be stated that the students viewed the relevant parts, and they basically had no difficulties to solve the tasks. Originality/value: Due to the empirical testing of the app prototype, the project team was able to adjust the application and to add further features. Furthermore, the backend was programmed and an additional tool (MyLA dashboard) was developed for lecturers. A mutual understanding of the targets, privacy issue and relevant features are indispensable for further development of the project.

This paper investigates the price impact of the fuel discount in Germany, which was introduced between June and August 2022 to partially compensate increased energy costs. Using the augmented synthetic control method (ASCM) to construct the counterfactual, we provide quantitative evidence to the heated debate concerning the impact of this policy tool and find the fuel discount to have decreased consumer prices of petrol (diesel) by at least 0.30 euro per litre (0.10 euro per litre) on average. The results are robust to various sensitivity checks. Thus, oil companies and petrol stations decreased prices for consumers and passed on about 85 % (65 %) of the discount in case of petrol (diesel). Moreover, we do not find signs of excessive price increases in anticipation of the fuel discount. [ABSTRACT FROM AUTHOR]

Background: Effective antimicrobial treatment is key to reduce mortality associated with bacterial sepsis in patients on intensive care units (ICUs). Dose adjustments are often necessary to account for pathophysiological changes or renal replacement therapy. Extracorporeal membrane oxygenation (ECMO) is increasingly being used for the treatment of respiratory and/or cardiac failure. However, it remains unclear whether dose adjustments are necessary to avoid subtherapeutic drug levels in septic patients on ECMO support. Here, we aimed to evaluate and comparatively assess serum concentrations of continuously applied antibiotics in intensive care patients being treated with and without ECMO.Methods: Between October 2018 and December 2019, we prospectively enrolled patients on a pneumological ICU in southwest Germany who received antibiotic treatment with piperacillin/tazobactam, ceftazidime, meropenem, or linezolid. All antibiotics were applied using continuous infusion, and therapeutic drug monitoring of serum concentrations (expressed as mg/L) was carried out using high-performance liquid chromatography. Target concentrations were defined as fourfold above the minimal inhibitory concentration (MIC) of susceptible bacterial isolates, according to EUCAST breakpoints.Results: The final cohort comprised 105 ICU patients, of whom 30 were treated with ECMO. ECMO patients were significantly younger (mean age: 47.7 vs. 61.2 years; p < 0.001), required renal replacement therapy more frequently (53.3% vs. 32.0%; p = 0.048) and had an elevated ICU mortality (60.0% vs. 22.7%; p < 0.001). Data on antibiotic serum concentrations derived from 112 measurements among ECMO and 186 measurements from non-ECMO patients showed significantly lower median serum concentrations for piperacillin (32.3 vs. 52.9; p = 0.029) and standard-dose meropenem (15.0 vs. 17.8; p = 0.020) in the ECMO group. We found high rates of insufficient antibiotic serum concentrations below the pre-specified MIC target among ECMO patients (piperacillin: 48% vs. 13% in non-ECMO; linezolid: 35% vs. 15% in non-ECMO), whereas no such difference was observed for ceftazidime and meropenem.Conclusions: ECMO treatment was associated with significantly reduced serum concentrations of specific antibiotics. Future studies are needed to assess the pharmacokinetic characteristics of antibiotics in ICU patients on ECMO support. [ABSTRACT FROM AUTHOR]

Purpose: To compare the intensity distribution during cycling training among elite track cyclists who improved or decreased in ergometer power at 4 mM blood lactate during a 15 wk training period. Methods: 51 young male German cyclists (17.4 ± 0.5 y; 30 international, 21 national junior finalists) performed cycle ergometer testing at the onset and at the end of a 15 wk basic preparation period, and reported their daily volumes of defined exercise types and intensity categories. Training organization was compared between two subgroups who improved (Responders, n = 17; ΔPLa4.kg.1 = +11 ± 4%) or who decreased in ergometer performance (Non-Responders, n = 17; ΔPLa4.kg.1 = -7 ± 6%). Results: Responders and Non- Responders did not differ significantly in the time invested in noncycling specific training or in the total cycling distance performed. They did differ in their cycling intensity distribution. Responders accumulated significantly more distance at low intensity (<2 mM blood lactate) while Non-Responders performed more training at near threshold intensity (3-6 mM). Cycling intensity distribution accounted for approx. 60% of the variance of changes in ergometer performance over time. Performance at t1 combined with workout intensity distribution explained over 70% of performance variance at t2. Conclusion: Variation in lactate profile development is explained to a substantial degree by variation in training intensity distribution in elite cyclists. Training at <2 mM blood lactate appears to play an important role in improving the power output to blood lactate relationship. Excessive training near threshold intensity (3-6 mM blood lactate) may negatively impact lactate threshold development. Further research is required to explain the underlying adaptation mechanisms. [ABSTRACT FROM AUTHOR]

Meilensteine der Bautechnikgeschichte: Historischer Aufsatz von Karl Schaechterle: Neue Fahrbahnkonstruktionen für stählerne Straßenbrücken. mit einem Kommentar von Josef Seiler [ABSTRACT FROM AUTHOR]

Background. Faecal immunochemical tests (FITs) for haemoglobin are increasingly used for non-invasive screening for colorectal cancer (CRC) but large scale comparative studies of different FITs for detection of CRC, overall and by stage, are sparse. We aimed to determine and compare performance of different FITs for the detection of CRC, and to assess their stage-specific sensitivities. Material and methods. We assessed sensitivity, specificity and their corresponding 95% confidence intervals for six qualitative FITs among 74 CRC cases (59% stage I or II cancers) and 1480 controls free of colorectal neoplasm. Overall and stage-specific receiver operating characteristic curves were derived for three quantitative FITs. The areas under the curves (AUCs) were calculated and compared. Results. Pairs of overall sensitivity and specificity of the qualitative FITs ranged from 66% and 96% to 92% and 62%, respectively. For the three quantitative tests, AUCs ranged from 0.90 to 0.92, with sensitivities ranging from 80% to 87% at cut-offs yielding 90% specificity. AUCs ranged from 0.85 to 0.92, 0.94 to 0.96, and 0.86 to 0.93 for stage I, stage II and advanced stages (stage III and IV) cancers, respectively. At a specificity of 90%, the tests detected 65%-85% of stage I cancers. Conclusion. The diagnostic performance of FITs regarding detection of CRC is promising, even though the pre-defined cut-offs of some of the qualitative FITs need to be adjusted to limit false-positive rates in screening setting. At cut-off levels yielding 90% specificity, the quantitative tests detected the vast majority of CRCs, even at early stages. [ABSTRACT FROM AUTHOR]

A sediment contact test (SCT) battery consisting of five ecotoxicological test systems was applied to 21 native freshwater sediments characterized by a broad variety of geochemical properties and anthropogenic contamination. Higher plants ( Myriophyllum aquaticum), nematodes ( Caenorhabditis elegans), oligochaetes ( Lumbriculus variegatus), zebrafish embryos ( Danio rerio), and bacteria ( Arthrobacter globiformis), representing various trophic levels and exposure pathways, were used as test organisms. The test battery detected sediment toxicity caused by anthropogenic pollution, whereas the various tests provided site-specific, nonredundant information to the overall toxicity assessment. Based on the toxicity pattern derived from the test battery, the sediments were classified according to a newly proposed classification system for sediment toxicity assessment. The SCT-derived classification generally agreed well with the application of consensus-based sediment quality guidelines (SQGs), especially with regard to sediments with high toxic potential. For sediments with low to medium toxic potential, the SQGs often underestimated the toxicity that was detected by the SCTs, underpinning the need for toxicity tests in sediment quality assessment. Environ. Toxicol. Chem. 2013;32:144-155. © 2012 SETAC [ABSTRACT FROM AUTHOR]

The article presents information on the data sets of the LMU-ifo Economics & Business Data Center. The center was established in 2008 as a central place for the collection and suply of research data on economic and business sciences. The Ifo Business Survey was first conducted by the Ifo Institute in 1949, which initially covered the manufacturing sector in Germany. Several descriptive statistics are also presented.

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Background: Studies have identified characteristics of adenomas detected on colonoscopy to be predictive of adenoma recurrence. Objective: To assess the role of both colonoscopy-related factors and polyp characteristics on the risk for colorectal cancer after colonoscopic polyp detection. Design: Population-based case-control study (3148 case partici-pants and 3274 control participants). Setting: Rhine-Neckar region of Germany. Patients: Case and control participants with physician-validated detection of polyps (other than hyperplastic polyps) at a previous colonoscopy in the past 10 years. Measurements: Detailed history and results of previous colonosco-pies were obtained through interviews and medical records. Case and control participants were compared according to colonoscopy-related factors (incompleteness, poor bowel preparation, incomplete removal of all polyps, and no surveillance colonoscopy within 5 years) and polyp characteristics (≥1 cm, villous components or high-grade dysplasia, ≥3 polyps, and ≥1 proximal polyp). Odds ratios (ORs) and attributable fractions were derived by using mul-tiple logistic regression and the Levin formula. Results: 155 case participants and 260 control participants with physician-validated polyp detection in the past 10 years were iden-tified. The following characteristics were significantly more common among case participants than among control participants: not all polyps completely removed (29.0% vs. 9.6%; OR, 3.73 [95% Cl, 2.11 to 6.60]), no surveillance colonoscopy within 5 years (26.5% vs. 11.5%; OR, 2.96 [Cl, 1.70 to 5.16]), and detection of 3 or more polyps (14.2% vs. 7.3%; OR, 2.21 [Cl, 1.07 to 4.54]). Odds ratios ranged from 1.12 to 1.42 and CIs included 1.00 for all other variables. Overall, 41.1% and 21.7% of cancer cases were statis-tically attributable to colonoscopy-related factors and polyp charac-teristics, respectively. Limitation: This was an observational study with potential for residual confounding and selection bias. Conclusion: Colonoscopy-related factors are more important than polyp characteristics for stratification of colorectal cancer risk after colonoscopic polyp detection in the community setting. Primary Funding Source: German Research Council and German Federal Ministry of Education and Research. [ABSTRACT FROM AUTHOR]

Effect-directed analysis (EDA) can be useful in identifying and evaluating potential toxic chemicals in matrixes. Previous investigations of extracts of sediments from the upper Danube River in Germany revealed acute nonspecific and mechanism-specific toxicity as determined by several bioassays. In the present study, EDA was used to further characterize these sediments and identify groups of potentially toxic chemicals. Four extracts of sediments were subjected to a novel fractionation scheme coupled with identification of chemicals to characterize their ability to disrupt steroidogenesis or cause mutagenic and/or teratogenic effects. All four whole extracts of sediment caused significant alteration of steroidogenesis and were mutagenic as well as teratogenic. The whole extracts of sediments were separated into 18 fractions and these fractions were then subjected to the same bioassays as the whole extracts. Fractions 7 to 15 of all four extracts were consistently more potent in both the Ames fluctuation and H295R assays. Much of this toxicity could be attributed to polycyclic aromatic hydrocarbons, sterols, and in fraction 7-naphthoic acids. Because the fraction containing polychlorinated biphenyls, polychlorodibenzodioxin/furan, dichlorodiphenyltrichloroethane, and several organophosphates did not cause any observable effects on hormone production or a mutagenic response, or were not detected in any of the samples, these compounds could be eliminated as causative agents for the observed effects. These results demonstrate the value of using EDA, which uses multiple bioassays and new fractionation techniques to assess toxicity. Furthermore, to our knowledge this is the first study using the recently developed H295R assay within EDA strategies. Environ. Toxicol. Chem. 2012; 31: 1053-1062. © 2012 SETAC [ABSTRACT FROM AUTHOR]

Purpose: Although the water quality of the Rhine River in Europe has improved, contaminated sediments may still threaten fish populations. This is particularly likely in Upper Rhine oxbow lakes, which are connected to the main river channel only at one end, except for extreme flood events. The impact of such extreme flood events on the sediment toxicity has, however, not yet been investigated, although numerous oxbow lakes exist with varying degrees of connection to their main river channels. Materials and methods: We evaluated contaminants in sediments taken at ten sites along a 600-m transect in an oxbow lake in a nature reserve that receives sediment contamination only from the main river. Sediment was analysed for polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs) as well as dioxins (PCDDs) and furans. The dioxin-like activity was measured using in vitro bioassays (7-ethoxyresorufin- O-deethylase (EROD) assay) on RTL-W1 cells. The distribution of sediment contaminants and effects in bioassay were compared within the oxbow lake and with other European water systems. Results and discussion: Chemical analysis of the 16 priority PAHs (1.12-2.16 mg kg), ∑PCDD/Fs (1.62-4.17 μg kg) and ∑PCB congeners 77, 81, 105, 118, 126, 156 and 169 (2.3-3.1 μg kg) showed low to moderate sediment contamination. However, all sediment samples showed dioxin-like activities with bio-TEQ values between 3.62 and 7.92 ng g in an EROD induction assay using RTL-W1 cells. These values were higher than those reported for other, larger river systems. Both contaminant levels and toxicity data clearly suggest a spatially homogenous exposure profile throughout the oxbow lake. This homogenous profile was caused most likely by extreme floods, which lead to a large input of river sediments and a mixture with remobilised lake sediments. Conclusions: This study illustrates the relevance of flood event-related contaminant input from the main river channel for connected oxbow lakes. This may impair their function as reproductive and developmental fish habitats. As the probability and temporal pattern of flood events in river systems may change due to climate change, this may also have direct consequences for the sediment contamination in connected oxbow lakes, and thus affect their ecological function for fish. [ABSTRACT FROM AUTHOR]

Background: Colonoscopy with detection and removal of adenomas is considered a powerful tool to reduce colorectal cancer (CRC) incidence. However, the degree of protection achievable in a population setting with high-quality colonoscopy resources remains to be quantified. Objective: To assess the association between previous colonoscopy and risk for CRC. Design: Population-based case-control study. Setting: Rhine-Neckar region of Germany. Patients: A total of 1688 case patients with colorectal cancer and 1932 control participants aged 50 years or older. Measurements: A detailed lifetime history of CRC risk factors and preventive factors, including history and results of previous colonoscopies, and of medical data obtained by self-reports and medical records. Odds ratios of CRC associated with colonoscopy in the preceding 10 years were estimated, after adjustment for sex, age, education level, participation in a general health screening examination, family history of CRC, smoking status, body mass index, and use of nonsteroidal anti-inflammatory drugs or hormone replacement therapy. Results: Overall, colonoscopy in the preceding 10 years was associated with 77% lower risk for CRC. Adjusted odds ratios for any CRC, right-sided CRC, and left-sided CRC were 0.23 (95% CI, 0.19 to 0.27), 0.44 (CI, 0.35 to 0.55), and 0.16 (CI, 0.12 to 0.20), respectively. Strong risk reduction was observed for all cancer stages and all ages, except for right-sided cancer in persons aged 50 to 59 years. Risk reduction increased over the years in both the right and the left colon. Limitation: The study was observational, with potential for residual confounding and selection bias. Conclusion: Colonoscopy with polypectomy can be associated with strongly reduced risk for CRC in the population setting. Aside from strong risk reduction with respect to left-sided CRC, risk reduction of more than 50% was also seen for right-sided colon cancer. Primary Funding Source: German Research Council and German Federal Ministry of Education and Research. [ABSTRACT FROM AUTHOR]

Background: Sedation prior to performance of diagnostic esophagogastroduodenoscopy (EGDE) is widespread and increases patient comfort. But 98% of all serious adverse events during EGDEs are ascribed to sedation. The S3 guideline for sedation procedures in gastrointestinal endoscopy published in 2008 in Germany increases patient safety by standardization. These new regulations increase costs because of the need for more personnel and a prolonged discharge procedure after examinations with sedation. Many patients have difficulties to meet the discharge criteria regulated by the S3 guideline, e.g. the call for a second person to escort them home, to resign from driving and working for the rest of the day, resulting in a refusal of sedation. Therefore, we would like to examine if an acupuncture during elective, diagnostic EGDEs could increase the comfort of patients refusing systemic sedation. Methods/Design: A single-center, double blinded, placebo controlled superiority trial to compare the success rates of elective, diagnostic EGDEs with real and placebo acupuncture. All patients aged 18 years or older scheduled for elective, diagnostic EGDE who refuse a systemic sedation are eligible. 354 patients will be randomized. The primary endpoint is the rate of successful EGDEs with the randomized technique. Intervention: Real or placebo acupuncture before and during EGDE. Duration of study: Approximately 24 months. Discussion: Organisation/Responsibility The ACUPEND - Trial will be conducted in accordance with the protocol and in compliance with the moral, ethical, and scientific principles governing clinical research as set out in the Declaration of Helsinki (1989) and Good Clinical Practice (GCP). The Interdisciplinary Endoscopy Center (IEZ) of the University Hospital Heidelberg is responsible for design and conduct of the trial, including randomization and documentation of patients' data. Data management and statistical analysis will be performed by the independent Institute for Medical Biometry and Informatics (IMBI) and the Center of Clinical Trials (KSC) at the Department of General, Visceral and Transplantation Surgery, University of Heidelberg. [ABSTRACT FROM AUTHOR]

Clinical trials play a key role in patient care, academic education and research in surgery. Without valid studies the practice of evidence-based medicine is limited. Surgery is supported through funding by the German Ministry of Education and Research to establish an infrastructure for clinical trials. So far seven universities have worked together in a network since 2007 and successfully obtained funding for six large randomized trials from a program existing since 2004. Until now 2,249 patients have been randomized within 11 trials and 910 patients have been treated at local hospitals without academic responsibilities. An increase in the interest in clinical trials in daily practice has resulted through the certification of hospitals for special treatment that specifies that at least 5% of all patients are included in clinical trials. [ABSTRACT FROM AUTHOR]

Knot tying is regarded as a basic surgical skill. However, there is no consensus in the literature on the best/safest technique. The aim of this study was to survey the various techniques used by German surgeons at the different stages of their training. A knot tying technique was defined based on three criteria, i.e., both thread ends are crossed at the beginning at least two throws tied pulling at the same free end of the thread (standing part) and at least one knot tied changing the standing part. The knot tying techniques of 192 randomly chosen German surgeons practicing in 102 different hospitals were compared against this standard. Besides the status of the participating surgeons, the type of hospital in which they were currently working was recorded. Of the192 participants, 69 were consultants, 56 fellows, and 67 residents. Forty-three surgeons (22.4%) worked in primary care centers (PCC), 81 (42.2%) in secondary care centers (SCC), and 68 (35.4%) in tertiary care centers (TCC). 62.5% crossed both thread ends at the beginning, 75.5% performed at least two identical throws keeping the same standing part, and 45.3% changed the standing part. Assessed against the technique defined as standard, 19.8% of all surgeons performed similar surgical knots. Even though consultants crossed both thread ends at the beginning and changed the standing part significantly more often ( p = 0.007 and p = 0.031 respectively, Fisher’s exact test), the overall rate of identical knots was independent of the status of participants and the type of hospital ( p > 0.1, Fisher’s exact test). This explorative study detected a high variability of knot tying techniques among German surgeons. In the absence of any evidence of the superiority of one particular technique, continuing education should focus on the quality of each single knot and perfect the details of the technique used. [ABSTRACT FROM AUTHOR]

Zusammenfassung Einleitung  Das CHIR-Net ist ein deutschlandweites chirurgisches Studiennetzwerk. Es wird gefördert durch das Bundesministerium für Bildung und Forschung (BMBF 01GH0605) mit dem Ziel, Infrastruktur und studienspezifische Expertise im Bereich der chirurgischen Disziplinen aufzubauen. Die qualifizierte Weiterbildung für Ärzte, die eine Rotationszeit im CHIR-Net absolvieren, repräsentiert einen wichtigen Aspekt dieses Netzes. Methoden  In Zusammenarbeit mit dem CHIR-Net, hier eingesetzten Rotationsärzten und kooperierenden Zentren bzw. Koordinierungszentren für klinische Studien (ZKS/KKS) wird ein Aufgabenkatalog für die Tätigkeit im Rahmen der Rotationszeit entwickelt. Ergebnis  Die Tätigkeitsschwerpunkte von Rotationsärzten im CHIR-Net sind in einem Kurrikulum zusammengefasst, das seit Januar 2008 netzwerkweit eingesetzt und evaluiert wird. Schlussfolgerung  Da die ausgebildeten Ärzte nach ihrer Rotationszeit als Multiplikatoren für studienspezifisches Fachwissen in den Kliniken fungieren, wird diese Kompetenz in die klinische Versorgung integriert und einer protokollgerechten Behandlung von Patienten unmittelbar zugute kommen. [ABSTRACT FROM AUTHOR]

Abstract: A short description of the history of the 3Rs concept is given, which was developed as the scientific concept to refine, reduce and replace animal experiments by Russel and Burch more than 40 years ago. In addition, the legal framework in Europe for developing alternatives to animal experiments is given and the current status of in vitro systems in pharmacology and toxicology is described including an update on metabolising systems. The decrease in experimental animal numbers during the past decade in Europe is illustrated by the situation in Germany and the contribution of international harmonisation of test guidelines on reducing animal numbers in regulatory testing is described. A review of the development of the principles of experimental validation is given and the 3T3 NRU in vitro phototoxicity test is used as an example for a successful validation study, which led to the acceptance of the first in vitro toxicity test for regulatory purposes by the OECD. Finally, the currently accepted alternative methods for standardisation and safety testing of drugs, biologicals and medical devices are summarised. [Copyright &y& Elsevier]

Background: Although considered the reference standard for generating valid scientific evidence of a treatment's benefits and harms, the number of Randomised Controlled Trials (RCT) comparing surgical techniques remains low. Much effort has been made in order to overcome methodological issues and improve quality of RCTs in surgery. To the present there has been, however, only little emphasis on development and maintenance of institutions for implementation of adequately designed and conducted surgical RCTs. Mehods/Design: Description of the developments in surgical RCT infrastructure in Germany between 2001 and 2006. Cross sectional evaluation of completed and ongoing surgical RCTs within the German Surgical Society and the Clinical Study Centre, Department of Surgery, University of Heidelberg. Results: Foundation of a national Clinical Trial Centre (CTC) for the organisation of multi-centre RCTs in the surgical setting (Study Center of the German Surgical Society, SDGC). Establishment of a network of CTCs with affiliated Clinical Sites (CSs) to enhance patient recruitment and shorten the duration of RCTs. Since its foundation four surgical RCTs with a total sample size of 1650 patients (1006 of these randomised) have been supervised by the SDGC with 35 CSs involved in patient recruitment. Five further CTCs were set up in 2006. Together with their affiliated CSs a network has been organised providing improved conditions for the conduction of surgical RCTs. Conclusion: Improvement of infrastructure substantially facilitates integration of RCTs into routine surgical practice. A network of collaborating CTCs and CSs can provide an adequate infrastructure for the conduction of multi-centre RCTs. [ABSTRACT FROM AUTHOR]

Background and aims: Screening colonoscopy is thought to be a powerful and cost-effective tool to reduce colorectal cancer incidence and mortality. Whether and when colonoscopy with negative findings has to be repeated is not well defined. The aim of this study was to assess the long term risk of clinically manifest colorectal cancer among subjects with negative findings at colonoscopy. Patients: 380 cases and 485 controls participating in a population based case-control study in Germany. Methods: Detailed history and results of previous colonoscopies were obtained by interview and from medical records. Adjusted relative risks of colorectal cancer among subjects with a previous negative colonoscopy compared with those without previous colonoscopy were estimated according to time since colonoscopy. Results: Subjects with previous negative colonoscopy had a 74% lower risk of colorectal cancer than those without previous colonoscopy (adjusted odds ratio (aOR) = 0.26 (95% confidence interval, 0.16 to 0.40)). This low risk was seen even if the colonoscopy had been done up to 20 or more years previously. Particularly low risks were seen for sigma cancer (aOR=0.13 (0.04 to 0.43)) and for rectal cancer (aOR = 0.19 (0.09 to 0.39)), and after a negative screening colonoscopy at ages 55 to 64 (aOR = 0.17 (0.08 to 0.39)) and older (aOR=0.21 (0.10 to 0.41)). Conclusions: Subjects with negative findings at colonoscopy are at very low risk of colorectal cancer and might not need to undergo repeat colonoscopy for 20 years or more, if at all. The possibility of extending screening intervals to 20 years or more might reduce complications and increase the feasibility and cost-effectiveness of colonoscopy based screening programmes. [ABSTRACT FROM AUTHOR]

Abstract: The concept of evidence-based medicine (EBM) has been introduced into the field of surgery in Germany since 1996, initially focussing on the application of the classical five-step-concept of EBM to the individual patient. Despite the international efforts of the Cochrane Collaboration, few systematic reviews address surgical procedures and the number of high quality randomized-controlled trials (RCTs) are low. External evidence in surgery is a major problem and requires new strategies in research and patient care. Therefore, in the Department of Surgery at the University of Heidelberg a clinical trial unit was founded to create more evidence via two approaches. First, patients admitted to hospital should be treated within RCTs. Since May 2002 1808 patients have been enrolled into a total of 38 pharmaceutical (19 trials with 470 patients enrolled) and investigator initiated (19 trials with 1338 patients enrolled) studies. Second, the clinical site develops and conducts surgical efficacy RCTs and follows new standards including publication and registration of the protocols. Within 3 years it was possible to change practice in an academic setting from the traditional concept to an evidence-based approach. [Copyright &y& Elsevier]

Background: Annually, more than 90000 surgical procedures of the thyroid gland are performed in Germany. strategies aimed at reducing the duration of the surgical procedure are relevant to patients and the health care system especially in the context of reducing costs. However, new techniques for quick and safe hemostasis have to be tested in clinically relevance randomized controlled trials before a general recommendation can be given. The current standard for occlusion of blood vessels in thyroid surgery is ligatures. Vascular clips may be a safe alternative but have not been investigated in a large RCT. Methods/design: CLIVIT (Clips versus Ligatures in Thyroid Surgery) is an investigator initiated, multicenter, patient-blinded, two-group parallel relevance randomized controlled trial designed by the Study Center of the German Surgical Society. Patients scheduled for elective resection of at least two third of the gland for benign thyroid disease are eligible for participation. After surgical exploration patients are randomized intraoperatively into either the conventional ligature group, or into the clip group. The primary objective is to test for a relevant reduction in operating time (at least 15 min) when using the clip technique. Since April 2004, 121 of the totally required 420 patients were randomized in five centers. Discussion: As in all trials the different forms of bias have to be considered, and as in this case, a surgical trial, the role of surgical expertise plays a key role, and will be documented and analyzed separately. This is the first randomized controlled multicenter relevance trial to compare different vessel occlusion techniques in thyroid surgery with adequate power and other detailed information about the design as well as framework. If significant, the results might be generalized and may change the current surgical practice. [ABSTRACT FROM AUTHOR]

The article reports on a November 1992 interdisciplinary conference at the University of Bremen, Germany, on the theme "Immigration and the Socialist State." Key topics included immigrant citizenship and immigrant influence on the labor market and social security. Another discussion thread was resultant multiculturalism in Germany.

A letter to the editor is presented in response to the article "Der Gleichheitsgrundsatz in der sozialen Selbstverwaltung" in the third issue.

The article discusses the large number of older jobless would-be employees in Germany, many of them refugees unable to get their financial footing. Additionally, since the end of WWII, many civil service jobs have been eliminated. Efforts are encouraged for self-help as well as assistance from legislators. Many of those affected have lost a decade or more as recruits, soldiers, or prisoners.

The article is the continuation of an article of the same title in the 7th 1957 issue of "Zeitschrift für Sozialreform." New pension entitlement provisions in Germany are reviewed including specified waiting periods, benefits for the work incapacitated and for divorced women, as well as payments for orphans.

An abstract of the article "10-year experience from an integrative pediatric oncology centre: a retrospective analysis," by A. Laengler and colleagues is presented.

Background: Targeted agents such as the type II anti-CD20 antibody obinutuzumab and the B-cell lymphoma-2 antagonist venetoclax have shown impressive therapeutic activity in chronic lymphocytic leukaemia. The CLL2-BAG trial was initiated to investigate the combination of these two agents in patients with chronic lymphocytic leukaemia.Methods: In this ongoing multicentre, open-label, investigator-initiated phase 2 trial, patients (aged ≥18 years) with chronic lymphocytic leukaemia requiring treatment according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at 16 sites in Germany. Patients with a relevant tumour load (absolute lymphocyte count ≥25 000 cells per μL or lymph nodes with a diameter of ≥5 cm) received sequential treatment of debulking with two cycles of bendamustine (70 mg/m2 intravenously on days 1 and 2 of each of the two 28-day cycles), followed by induction and maintenance with obinutuzumab (1000 mg intravenously on days 1-2, 8, and 15 of the first induction cycle, every 4 weeks in induction cycles 2-6, and every 12 weeks in the maintenance phase) and oral venetoclax (starting in induction cycle 2 with 20 mg/day, with a weekly dose escalation over 5 weeks to the target dose of 400 mg/day). The primary endpoint was the proportion of patients achieving an overall response by investigator assessment at the end of induction treatment. All patients who received at least two induction cycles were included in the efficacy analyses and all patients who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02401503.Findings: Between May 6, 2015, and Jan 4, 2016, 66 patients were enrolled (35 treatment naive and 31 with relapsed or refractory disease), three of whom were excluded from the efficacy analysis because they received fewer than two induction cycles. Of the remaining 63 patients in the efficacy-evaluable population, 34 patients (54%) were treatment naive and 29 (46%) had relapsed or refractory disease. At data cutoff (Feb 28, 2017), all patients had completed induction treatment. At the end of the induction, 60 (95%) of 63 patients (95% CI 87-99) had responded, including all 34 patients in the treatment-naive cohort and 26 [90%] of 29 relapsed or refractory patients. The most common grade 3-4 adverse events during debulking were neutropenia and anaemia (five [11%] of 47 patients each), and thrombocytopenia and infection (three [6%] each). The most common grade 3-4 adverse events during induction were neutropenia (29 [44%] of 66 patients), infection (nine [14%]), thrombocytopenia (eight [12%]), infusion-related reactions (five [8%]), and secondary primary malignancy (four [6%]). 89 serious adverse events, including 69 related to study treatment, were reported. These serious adverse events were also mainly infections (four cases in four patients during debulking and 18 cases in 11 patients during induction) and cytopenia (four cases in four patients during debulking and ten cases in seven patients in induction). Five relapsed or refractory patients died: three cases of sepsis were deemed related to study treatment, whereas two deaths from Richter's transformation were not.Interpretation: The sequential application of bendamustine and obinutuzumab combined with venetoclax caused no unexpected or cumulative toxicities. The high proportion of patients who achieved overall responses, both treatment-naive and relapsed or refractory patients irrespective of physical fitness and genetic risk factors, compare favourably to established chronic lymphocytic leukaemia therapies. Further follow-up will help to define whether the remissions with eradication of minimal residual disease achieved with this combination are durable after treatment discontinuation.Funding: F Hoffmann-La Roche and AbbVie. [ABSTRACT FROM AUTHOR]

Advanced incurable diseases are often accompanied by numerous losses and burdens as the disease progresses, leading to a loss of autonomy, self-determination, and dignity for those affected, all of which can subsequently promote feelings of loneliness at the end of life. Declining health, increasing symptom burden, loss of social roles, and the fear of death and dying are among the key risk factors for loneliness towards the end of life. In this article, we provide an overview of the different dimensions of loneliness experienced at the end of life. We discuss existential loneliness alongside emotional and social loneliness, explore causes and health implications of loneliness at the end of life, suggest diagnostic tools for assessing loneliness, and finally provide recommendations for addressing emotional, social, and existential loneliness at the end of life. The loneliness of caregivers is also discussed. We suggest that addressing social and emotional loneliness early in the course of a terminal illness is crucial. Palliative, psychological, and spiritual support can strengthen interpersonal relationships, foster a sense of meaning and purpose, and alleviate the adverse effects of loneliness on mental and physical health as well as quality of life. In contrast, existential loneliness is considered an expression of profound emotional maturity and can offer opportunities for inner growth, contributing to a more refined sense of self while reinforcing identity, dignity, and transcendence at the end of life., (© 2024. The Author(s).)

This document reports a brief update to the previously published protocol of the MinDial study.Trial registration German Clinical Trials Register DRKS00029691. Registered on 12 Sept. 2022, https://drks.de/search/en/trial/DRKS00029691 ., (© 2024. The Author(s).)

Objective: Oral status is an important indicator of past lifestyles. Determining the presence and extent of oral pathologies helps reconstruct average oral health, paramasticatory activities and diet of ancient and historical populations., Design: In this study, the dental remains from the early medieval cemetery of Früebergstrasse in Baar (Canton of Zug, Switzerland) and the high medieval Dalheim cemetery (North Rhine-Westphalia, Germany) were analyzed. Caries, periodontal condition, periapical lesions, antemortem tooth loss, and enamel hypoplasia were assessed in 654 teeth (993 observable loci) from 68 individuals (Baar: n = 36; Dalheim: n = 32)., Results: The oral status of both populations was affected by age with higher values of tooth wear in advanced age individuals. High tooth wear values in both populations point towards the consumption of abrasive foods. Pronounced anterior tooth wear in Baar may also be due to non-masticatory tooth usage. Finally, possible nutritional deficiencies were hypothesized for the Baar population. A higher caries prevalence was observed in the Baar group, probably due to differences in carbohydrate intake. The oral conditions observed in the two studied populations exhibited several analogies, suggesting comparable lifestyles despite their separation in space and time. The only differences observed are related to the use of teeth as "tools" and are thus determined by behavioral choices rather than diverse socioeconomic factors., Conclusions: Using multiple dental parameters to examine the oral health of premodern individuals can provide useful insights into the interactions between humans and their environment, from dietary patterns to paramasticatory activities., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The evidence regarding effects of statins on exacerbation risk in COPD remains controversial. Previous studies often excluded patients with cardiovascular comorbidities despite their high prevalence in COPD and role for exacerbations. Based on the cardioprotective properties of statins, we hypothesised that statins may reduce the risk of exacerbations especially in patients with cardiovascular comorbidities., Methods: One thousand eight hundred eighty seven patients of the German COPD cohort COSYCONET (COPD and Systemic Consequences Comorbidities Network) of GOLD grades 1-4 (37.8% female, mean age 64.78 ± 8.3) were examined at baseline and over a period of 4.5 years for the occurrence of at least one exacerbation or severe exacerbation per year in cross-sectional and longitudinal analyses adjusted for age, gender, BMI, GOLD grade and pack-years. Due to their collinearity, various cardiovascular diseases were tested in separate analyses, whereby the potential effect of statins in the presence of a specific comorbidity was tested as interaction between statins and comorbidity. We also identified patients who never took statins, always took statins, or initiated statin intake during the follow-up., Results: One thousand three hundred six patients never took statins, 31.6% were statin user, and 12.9% initiated statins during the follow-up. Most cardiovascular diseases were significantly (p < 0.05)may associated with an increased risk of COPD exacerbations, but in none of them the intake of statins was a significant attenuating factor, neither overall nor in modulating the increased risk linked to the specific comorbidities. The results of the cross-sectional and longitudinal analyses were consistent with each other, also those regarding at least 1 exacerbation or at least 1 severe exacerbation per year., Conclusion: These findings complement the existing literature and may suggest that even in patients with COPD, cardiovascular comorbidities and a statin therapy that targets these comorbidities, the effects of statins on exacerbation risk are either negligible or more subtle than a reduction in exacerbation frequency., Trial Registration: Trial registration ClinicalTrials.gov, Identifier: NCT01245933. Other Study ID (BMBF grant): 01GI0881, registered 18 November 2010, study start 2010-11, primary completion 2013-12, study completion 2023-09. https://clinicaltrials.gov/study/NCT01245933?cond=COPD&term=COSYCONET&rank=3., (© 2024. The Author(s).)

Despite lockdown measures, intense symptom-based PCR, and antigen testing, the SARS-CoV-2 pandemic spread further. In this open observational study conducted in Lower Saxony, Germany, voluntary SARS-CoV-2 PCR tests were performed from April 2020 until June 2021, supported by serum antibody testing to prove whether PCR testing in subjects with none or few symptoms of COVID-19 is a suitable tool to manage the pandemic. In different mobile stations, 4,817 subjects from three different working fields participated in the PCR testing. Serum antibody screening using the SARS-CoV-2 ViraChip IgG (Viramed, Germany) and the Elecsys Anti-SARS-CoV-2 assay (Roche, Germany) was performed alongside virus neutralization testing. Subjects were questioned regarding comorbidities and COVID-19 symptoms. Fifty-one subjects with acute SARS-CoV-2 infection were detected of which 31 subjects did not show any symptoms possibly characteristic for COVID-19. An additional 37 subjects reported a previous SARS-CoV-2 infection (total prevalence 1.82%). Seroconversion was discovered in 58 subjects with known SARS-CoV-2 infection and in 58 subjects that never had a positive PCR test. The latter had a significantly lower Charlson Comorbidity Index, and one third of them were asymptomatic. In 50% of all seroconverted subjects, neutralizing serum antibodies (NAbs) were detectable in parallel to N/S1 ( n  = 16) or N/S1/S2 antigen specific antibodies ( n  = 40) against SARS-CoV-2. NAb titers decreased within 100 days after PCR-confirmed SARS-CoV-2 acute infection by at least 2.5-fold. A relatively high rate of subclinical SARS-CoV-2 infections may contribute to the spread of SARS-CoV-2, suggesting that in addition to other intervention strategies, systematic screening of asymptomatic persons by PCR testing may significantly enable better pandemic control. IMPORTANCE Within this open observational study, repeated PCR ( n  > 4,700) and antibody screening ( n  > 1,600) tests were offered in three different working fields. The study identified 51 subjects with acute SARS-CoV-2 infection and 37 subjects reported to have had a positive PCR test taken externally. Thirty-one of the 51 subjects did not display any symptoms prior to testing. In addition, 58 subjects without PCR-confirmed SARS-CoV-2 infection were identified by seroconversion. Subjects, that had undergone SARS-CoV-2 infection without having noticed, more often had a low grade of immunization with no NAbs, but may have relevantly contributed to the spread of the pandemic. Based on these results, we suggest that both regular PCR and rapid test screening of symptomatic and asymptomatic individuals, specifically within groups or workplaces identifiable as having close quarter contact, thus increased infection transference risk, is necessary to better assess and therefore reduce the spread of a pandemic virus.

Background Patients with breast cancer can be affected by cardiotoxic reactions through cancer therapies. Cardiac biomarkers, like NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cardiac troponin T, might have predictive value. Methods and Results Echocardiography, ECG, hemodynamic parameters, NT-proBNP and high-sensitivity cardiac troponin T were assessed in 853 patients with early-stage breast cancer randomized in the German Breast Group GeparOcto-GBG 84 phase III trial. Patients received neo-adjuvant dose-dense, dose-intensified epirubicin, paclitaxel, and cyclophosphamide (iddEPC group, n=424) or paclitaxel, non-pegylated doxorubicin, and in triple negative breast cancer, (paclitaxel, non-pegylated doxorubicin, carboplatin group, n=429) treatment for 18 weeks. Patients positive for human epidermal growth receptor 2 (n=354, 41.5%) received monoclonal antibodies on top of allocated therapy; 119 (12.9%) of all patients showed a cardiotoxic reaction during therapy (15 [1.8%] using a more strict definition). Presence of cardiotoxic reactions was irrespective of treatment allocation ( P =0.31). Small but significant increases in NT-proBNP developed early in patients with a cardiotoxic reaction as compared with those without in whom NT-proBNP rose only towards the end of therapy ( P =0.04). High-sensitivity cardiac troponin T rose early in both groups. Logistic regression showed that NT-proBNP (odds ratio [OR], 1.03; 95% CI, 1.008-1.055; P =0.01) and hemoglobin (OR, 1.31; 95% CI, 1.05-1.63; P =0.02) measured at 6 weeks after treatment initiation were significantly associated with cardiotoxic reactions. Conclusions NT-proBNP and hemoglobin are significantly associated with cardiotoxic reactions in patients with early-stage breast cancer undergoing dose-dense and dose-intensified chemotherapy, but high-sensitivity cardiac troponin T is not. Registration URL: http://www.clinicaltrials.gov; Unique identifier: NCT02125344.

High resting heart rate (RHR) is associated with higher mortality in the general population and in cardiovascular disease. Less is known about the association of RHR with outcome in chronic obstructive pulmonary disease (COPD). In particular, the time-updated RHR (most recent value before the event) appears informative. This is the first study to investigate the association of time-updated RHR with mortality in COPD. We compared the baseline and time-updated RHR related to survival in 2218 COPD patients of the German COSYCONET cohort (COPD and Systemic Consequences-Comorbidities Network). Patients with a baseline RHR > 72 beats per minute (bmp) had a significantly (p = 0.049) higher all-cause mortality risk (adjusted hazard ratio (HR) of 1.37 (1.00-1.87) compared to baseline RHR ≤ 72 bpm. The time-updated RHR > 72 bpm was markedly superior (HR 1.79, 1.30-2.46, p = 0.001). Both, increased baseline and time-updated RHR, were independently associated with low FEV1, low TLCO, a history of diabetes, and medication with short-acting beta agonists (SABAs). In conclusion, increased time-updated RHR is associated with higher mortality in COPD independent of other predictors and superior to baseline RHR. Increased RHR is linked to lung function, comorbidities and medication. Whether RHR is an effective treatment target in COPD, needs to be proven in controlled trials.

Background: Recommendations for soft tissue management associated with customized bone regeneration should be developed. The aim of this study was to evaluate a new protocol for customized bone augmentation in a digital workflow., Methods: The investigators implemented a treatment of three-dimensional bone defects based on a customized titanium mesh (Yxoss CBR®, ReOSS, Filderstadt, Germany). Patients and augmentation sites were retrospectively analysed focussing on defect regions, demographic factors, healing difficulties and potential risk factors. An exposure rate was investigated concerning surgical splint application, A®- PRF and flap design., Results: In total, 98 implants could be placed. Yxoss CBR® was removed after mean time of 6.53 ± 2.7 months. Flap design was performed as full flap preparation (27.9%), full flap and periosteal incision (39.7%), periosteal incision (1.5%), poncho/split flap (27.9%) and rotation flap (2.9%). In 25% of the cases, exposures of the meshes were documented. Within this exposure rate, most of them were slight and only punctual (A = 16.2%), like one tooth width (B = 1.5%) and complete (C = 7.4%). A®- PRF provided significantly less exposures of the titanium meshes (76.5% no exposure vs. 23.5% yes, p = 0.029). Other parameters like tobacco abuse (p = 0.669), diabetes (p = 0.568) or surgical parameters (mesh size, defect region, flap design) did not influence the exposure rate. Surgical splints were not evaluated to reduce the exposure rate (p = 0.239). Gender (female) was significantly associated with less exposure rate (78,4% female vs. 21.6% male, p = 0.043)., Conclusions: The results of this study suggest that the new digital protocol including patient-specific titanium meshes, resorbable membranes and bone grafting materials was proven to be a promising technique. To improve soft tissue healing, especially A®-PRF should be recommended.

Background and Aims: There are safety issues regarding plant sterol ester-enriched functional food. Oxidized plant sterols, also called oxyphytosterols, are supposed to contribute to plant sterol atherogenicity. This study aimed to analyze associations of plasma oxyphytosterol levels with cardiovascular events., Methods: Plasma cholesterol was measured by gas chromatography-flame ionization detection. Plasma campesterol and sitosterol and their 7-oxygenated metabolites were analyzed by gas chromatography-mass selective detection., Results: In 376 patients admitted for elective coronary angiography, who were not on lipid-lowering drugs, 82 cardiovascular events occurred during a follow-up period of 4.2 ± 1.8 years. Patients with cardiovascular events had significantly higher 7α-hydroxycampesterol plasma levels (median, 0.46; [interquartile range (IQR) 0.22-0.81] nmol/L vs. median, 0.25 [IQR, 0.17-0.61] nmol/L; p = 0.003) and 7α-hydroxycampesterol-to-cholesterol ratios (median 0.08 [IQR, 0.04-0.14] nmol/mmol vs. median, 0.05 [IQR 0.03-0.11] nmol/mmol; p = 0.005) than controls without such events. Patients above the median were characterized by higher cumulative event rates in Kaplan-Meier-analysis (Logrank-test p = 0.084 and p = 0.025) for absolute and cholesterol corrected 7α-hydroxycampesterol, respectively. After adjustment for influencing factors and related lipids, the hazard ratios per one standard deviation of the log-transformed variables (HR) were 1.19 [95% confidence interval (CI), 0.95-1.48], p = 0.132 for 7α-hydroxycampesterol and HR, 1.18 [95% CI, 0.94-1.48], p = 0.154 for 7α-hydroxycampesterol-to-cholesterol ratio. None of the other investigated oxyphytosterols showed an association with cardiovascular events., Conclusions: In patients not on lipid-lowering drugs, absolute plasma levels of 7α-hydroxycampesterol and their ratios to cholesterol are associated with cardiovascular events. Further research is required to elucidate the role of OPS in cardiovascular diseases., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A quantitative assay for determination of the main bufadienolides bersaldegenin-1-acetate (1), bersaldegenin-3-acetate (2), bryophyllin A (3), and bersaldegenin-1,3,5-orthoacetate (4) in Bryophyllum pinnatum leaves and manufactured products was developed and validated. The assay involved extraction by pressurised liquid extraction, followed by quantification by ultrahigh performance liquid chromatography-tandem mass spectroscopy. The ultrahigh performance liquid chromatography-tandem mass spectroscopy method was applied to various batches of leaves harvested on several dates from plants grown at two locations (Brazil and Germany). In addition, press juices prepared from plants cultivated in Germany and Brazil were analysed. The total bufadienolide content ranged from 16.28 to 40.50 mg/100 g dry weight in leaves from plants grown in Brazil. The total content of these four bufadienolides was significantly lower in plants cultivated in Germany (3.78-12.49 mg/100 g dry weight, resp.). The total amounts of bufadienolides were 0.091-0.163 mg/100 mL and 0.89-1.16 mg/100 mL in press juices obtained from plants cultivated in Germany and Brazil, respectively. When analysing single leaves from individual plants, the content of bufadienolides was markedly higher in young leaves. For comparative purposes, the content of these bufadienolides was also determined in Bryophyllum daigremontianum and Bryophyllum tubiflorum. Bersaldegenin-1,3,5-orthoacetate (4) was predominant in the leaves of B. daigremontianum and in the stems of B. tubiflorum, while the leaves of B. tubiflorum contained very low amounts of 1-4., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Angiogenic cytokines fms-like tyrosine kinase-1(sFlt-1) and placental growth factor (PlGF) are associated with increased risk for cardiovascular disease (CVD) in the general population. In this study we examine the association between these vascular endothelial factors and atherosclerosis, cardiovascular outcome, and mortality in chronic kidney disease (CKD) patients., Methods: Serum level of PlGF and sFlt-1 were measured in 301 patients with CKD, who were followed for up to 4 years. Primary outcomes were CV events and all-cause mortality. Carotid-intima media thickness (CIMT) was used as marker of atherosclerosis. Kaplan-Meier survival curves and the Cox proportional hazard model were used to assess the association of biomarkers and clinical outcomes., Results: Mean (SD) PlGF and sFlt-1 were 5.45 ng/ml (3.76) and 68.6 (28.0) pg/ml, respectively. During the follow up time, 60 patients (19.9%) experienced CV events and 22 patients (7.3%) died. Compared with low PlGF, patients with PlGF above median level had higher CV events (12.7% vs. 27.2%, p = 0.002) and mortality (2.0% vs. 12.6%, p < 0.001). The associations of PlGF and sFlt-1 with CV events were not statistically significant in the fully adjusted model. Higher PlGF was associated with greater death risk (HR = 5.22, 95% CI: 1.49-18.33, p = 0.01), which was robust to adjustment for sFlt-1 and other risk factors. Elevated sFlt-1 level was also an independent predictor of mortality (HR 3.41, 95% CI: 1.49-9.51, p = 0.019)., Conclusion: In CKD patients not yet on dialysis, higher serum level of PlGF and sFlt-1 are associated with increased mortality, but not CV events., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objectives: To date, evidence on active surveillance (AS) is restricted to protocol-based studies. Conversely, practice patterns outside of such protocols are unknown. The aim of this study was to capture the current AS treatment patterns for localized prostate cancer in patients managed by office-based urologists compared to patients treated at a tertiary care center., Methods and Materials: Two prospective cohorts were investigated: 361 AS arm patients of the German Hormonal treatment, Active surveillance, Radiation therapy, OP, Watchful waiting (HAROW) study, an observational health service study and 387 protocol-based AS patients treated at the Department of Urology of the Kantonsspital Aarau, Switzerland were included. Observational non-protocol HAROW versus on-protocol Kantonsspital Aarau (KSA) was compared, and active-treatment-free survival represented the primary outcome., Results: Study population of the observational HAROW versus tertiary care protocol-based KSA cohorts differed statistically significantly regarding age (p < 0.001) and proportion of patients meeting the Chism criteria (p < 0.001). In stratified analyses, AFTS at 1 and 2 years was, respectively, 87.7 % (95 % CI 84.0-91.7) and 75.0 % (95 % CI 69.7-80.8) in HAROW patients compared to 90.8 % (95 % CI 87.8-93.9) and 75.3 % (95 % CI 70.7-80.1) for patients in the KSA cohort (p = 0.97)., Conclusion: We demonstrate significant differences in terms of AS inclusion, surveillance and discontinuation criteria between patients managed by office-based urologists compared to their tertiary care counterparts. Interestingly, the risk of deferred active therapy was equally moderate for both groups in the short-term follow-up.

Calcified dental plaque (dental calculus) preserves for millennia and entraps biomolecules from all domains of life and viruses. We report the first, to our knowledge, high-resolution taxonomic and protein functional characterization of the ancient oral microbiome and demonstrate that the oral cavity has long served as a reservoir for bacteria implicated in both local and systemic disease. We characterize (i) the ancient oral microbiome in a diseased state, (ii) 40 opportunistic pathogens, (iii) ancient human-associated putative antibiotic resistance genes, (iv) a genome reconstruction of the periodontal pathogen Tannerella forsythia, (v) 239 bacterial and 43 human proteins, allowing confirmation of a long-term association between host immune factors, 'red complex' pathogens and periodontal disease, and (vi) DNA sequences matching dietary sources. Directly datable and nearly ubiquitous, dental calculus permits the simultaneous investigation of pathogen activity, host immunity and diet, thereby extending direct investigation of common diseases into the human evolutionary past.

Colonoscopy with detection and removal of neoplasms strongly reduces risk of colorectal cancer (CRC). Nevertheless, CRCs occur after colonoscopic polypectomy. We assessed agreement beyond chance of location of polyps detected at colonoscopy and of subsequent CRCs to estimate the share of cancers that might be due to field effects or neoplasm recrudescence. In a population-based case-control study conducted in Germany (3,148 cases), detailed history and results of colonoscopies conducted within 10 years before cancer diagnosis were obtained by interview and from medical records. We determined the observed proportion of cancers for which a polyp had been detected at the same colorectal subsite at the preceding colonoscopy and compared it to the proportion expected by chance. A total of 155 cases with physician validated polyp detection at the preceding colonoscopy were identified. Among 148 cases with cancer restricted to a single subsite, 43 (29.1%) had a polyp detected in the same colorectal subsite at the preceding colonoscopy. Agreement of location of cancer occurrence and preceding polyp detection would have been expected by chance for 27 cases, and agreement beyond chance was estimated to account for 16 cases (10.8%, 95% confidence interval 2.7%-19.3%). Our study suggests that less than one of nine CRCs occurring within 10 years after colonoscopy with polyp detection may be due to field effects or polyp recrudescence., (© 2013 UICC.)

A Gram-stain-positive, strictly aerobic, rod-shaped and weakly motile bacterium, designated WS 4627(T), was isolated from a dairy product sample collected in southern Germany. Spherical to slightly ellipsoidal endospores were formed centrally or subterminally in sometimes slightly swollen sporangia. The isolate was able to grow at 8-35 °C, at pH 6.5-8.5 and with 0.5-16.5% (w/v) NaCl. The diamino acid of the cell wall was meso-diaminopimelic acid (peptidoglycan type A1γ) and the genomic DNA G+C content was 39.1 mol%. The major menaquinone was MK-7, the cellular fatty acid profile contained major amounts of anteiso-C(15:0) and anteiso-C(17:0) and the major polar lipids were diphosphatidylglycerol and phosphatidylglycerol. Strain WS 4627(T) was most closely related to 'Virgibacillus natachei' FarD (96.5% 16S rRNA gene sequence similarity) and 'Virgibacillus zhanjiangensis' JSM 079157 (96.0%). Based on the data presented, strain WS 4627(T) represents a novel species of the genus Virgibacillus, for which the name Virgibacillus halotolerans sp. nov. is proposed. The type strain is WS 4627(T) ( =DSM 25060(T) =LMG 26644(T)).

Objective: Well-developed collaterals provide survival benefit in patients with obstructive coronary artery disease (CAD). Therefore, in this study we sought to determine which clinical variables are associated with arteriogenesis., Design: Clinical and laboratory variables were collected before percutaneous coronary intervention. Multivariate analysis was performed to determine which variables are associated with the collateral flow index (CFI)., Patients: Data from 295 chronic total occlusion (CTO) patients (Bern, Switzerland, Amsterdam, the Netherlands and Jena, Germany) were pooled. In earlier studies, patients had varying degrees of stenosis. Therefore, different stages of development of the collaterals were used. In our study, a unique group of patients with CTO was analysed., Interventions: Instead of angiography used earlier, we used a more accurate method to determine CFI using intracoronary pressure measurements. CFI was calculated from the occlusive pressure distal of the coronary lesion, the aortic pressure and central venous pressure., Results: The mean CFI was 0.39 ± 0.14. After multivariate analysis, β blockers, hypertension and angina pectoris duration were positively associated with CFI (B: correlation coefficient β=0.07, SE=0.03, p=0.02, B=0.040, SE=0.02, p=0.042 and B=0.001, SE=0.000, p=0.02). Furthermore also after multivariate analysis, high serum leucocytes, prior myocardial infarction and high diastolic blood pressure were negatively associated with CFI (B=-0.01, SE=0.005, p=0.03, B=-0.04, SE=0.02, p=0.03 and B=-0.002, SE=0.001, p=0.011)., Conclusions: In this unique cohort, high serum leucocytes and high diastolic blood pressure are associated with poorly developed collaterals. Interestingly, the use of β blockers is associated with well-developed collaterals, shedding new light on the potential action mode of this drug in patients with CAD.