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Many problems in science and engineering require an efficient numerical approximation of integrals or solutions to differential equations. For systems with rapidly changing dynamics, an equidistant discretization is often inadvisable as it either results in prohibitively large errors or computational effort. To this end, adaptive schemes, such as solvers based on Runge--Kutta pairs, have been developed which adapt the step size based on local error estimations at each step. While the classical schemes apply very generally and are highly efficient on regular systems, they can behave sub-optimal when an inefficient step rejection mechanism is triggered by structurally complex systems such as chaotic systems. To overcome these issues, we propose a method to tailor numerical schemes to the problem class at hand. This is achieved by combining simple, classical quadrature rules or ODE solvers with data-driven time-stepping controllers. Compared with learning solution operators to ODEs directly, it generalises better to unseen initial data as our approach employs classical numerical schemes as base methods. At the same time it can make use of identified structures of a problem class and, therefore, outperforms state-of-the-art adaptive schemes. Several examples demonstrate superior efficiency. Source code is available at https://github.com/lueckem/quadrature-ML.

Drilling predation is a common reason for mortality of benthic mollusks but did not become common until the late Mesozoic. The scarcity of drill holes in the early Mesozoic fossil record limits our understanding of the evolution of drilling behavior and its role on shaping early Mesozoic marine communities. Here, we use drilling traces on several bivalve taxa from the Lower Jurassic (Pliensbachian) marine soft-bottom deposits in northern Germany to explore behavioral patterns of the predator (e.g., site selectivity, change in site-selective behavior with age). Although none of the known drilling gastropod groups existed in the Pliensbachian, including the studied localities, the drill-hole morphology suggests that the predator was probably a gastropod. The ecology and identity of the target prey changes from a diverse array of epifaunal to infaunal taxa in older deposits to focus on a single, large, deep infaunal taxon, Gresslya intermedia, in younger deposits, suggesting a potential trend in prey selectivity over time. Spatial point pattern analysis of traces (SPPAT) reveals an aggregated pattern of drill holes on Gresslya, suggesting strong selectivity in drill-hole location. Drilling on a single large infaunal taxon and site selectivity are common patterns also inferred previously from the drilled deep infaunal Eothyasira from the Pliensbachian of southern Germany. In addition to the scarcity of predators, the highly specialized behavior of the early drilling predators, including strong prey selectivity in terms of prey identity and life habit, can partly explain the rarity of the early Mesozoic drill holes.

Background and aims: Measurement of plasma uracil is used before cancer treatment with fluoropyrimidines to determine if patients tolerate a full dose. Incorrect preanalytical handling may cause falsely elevated concentration and result in suboptimal cancer treatment. We aimed to examine the stability of uracil in whole blood stored at room temperature (RT) and the effect of centrifugation temperature. Materials and methods: EDTA tubes (6x4 mL) were collected from 25 healthy volunteers. Five samples were stored 0, 1.5, 2, 3, and 4 h at RT and centrifuged at 4 °C. The sixth sample was centrifuged at RT after 1.5 h. Uracil was measured using an in-house LC-MS/MS method. Results: Storage of whole blood at RT followed by centrifugation at 4 °C caused a rapid increase in uracil concentration. Already after 1.5 h, the mean change (20.5 % (95 % CI: 11.9–29.2 %)) exceeded the maximum permissible difference. Centrifugation at RT instead of 4 °C after 1.5 h resulted in a smaller increase (7.0 % (95 % CI: 0.7–13.4 %)), although not statistically significant (p = 0.0527). Conclusion: Uracil was unstable in samples processed according to current recommendations. Our data indicates better stability when centrifugation is performed at RT compared with 4 °C but further research into this is necessary.

Zusammenfassung Hintergrund und Ziel Deutschland ist nur moderat stillfreundlich, dies ergab eine systematische Bestandsaufnahme von 2019. Aufbauend auf einer Referenzstudie wurde eine Befragung zur Akzeptanz des Stillens in der Öffentlichkeit durchgeführt. Ziel der Arbeit ist es, Wahrnehmungen und Einstellungen zum öffentlichen Stillen im zeitlichen Vergleich zu erfassen. Zudem werden u. a. Unterschiede zwischen der Allgemeinbevölkerung und Müttern von kleinen Kindern sowie zwischen Müttern mit unterschiedlichem Bildungsstand betrachtet. Material und Methoden 1007 Personen ab 16 Jahren und 307 Mütter mit Kindern bis 24 Monaten wurden im Jahr 2020 online zum Thema Stillen in der Öffentlichkeit befragt. Ergebnisse wurden mit einer früheren Befragung aus 2016 verglichen. Ergebnisse 2020 stillt ein größerer Anteil von Müttern an öffentlichen Orten als 2016, es wird seltener vermieden. Mütter mit niedrigerem Bildungsstand stillen seltener, auch in der Öffentlichkeit, und berichten häufiger von gemischten Reaktionen. In der Bevölkerung ist die Akzeptanz für das öffentliche Stillen gesunken, z. B. in der Gastronomie. Etwa jede bzw. jeder Sechste (17 %) lehnt das öffentliche Stillen explizit ab. Das Wissen über gesundheitliche Effekte des Stillens ist in der Allgemeinbevölkerung niedriger als bei Müttern. Wie 2016 geht Wissen über die positiven Effekte des Stillens mit einer größeren Akzeptanz von öffentlichem Stillen einher. Diskussion Die Ergebnisse unterstreichen die Bedeutung von Maßnahmen, etwa um der Bevölkerung Wissen zu vermitteln, das Stillen in Massenmedien und durch positive Vorbilder häufiger zu zeigen und die Lebenswelten von Familien stillfreundlicher zu machen. Bei den Maßnahmen sind Frauen mit niedrigerem Bildungsstand besonders in den Blick zu nehmen.

Prominent life span theories have suggested that the ability to downregulate negative emotions remains stable or even increases well into old age. However, past evidence for continued growth during old age is mixed. In this laboratory study, 130 young old individuals (

Zusammenfassung Hintergrund Die in Deutschland angewandte Einteilung der Kardiomyopathien geht auf die Klassifikation der Europäischen Gesellschaft für Kardiologie (ESC) von 2008 zurück. Dort werden sie nach ihrem Phänotyp unterteilt, so dass die Magnetresonanztomographie (MRT) in der Lage ist, die unterschiedlichen Kardiomyopathien zu differenzieren. Bildgebung und Differenzialdiagnostik Die Stärke der MRT ist es, anhand der Möglichkeiten der Gewebsdifferenzierung nichtischämische Kardiomyopathien von anderen Erkrankungen mit ähnlichen morphofunktionellen Aspekten zu differenzieren. So gelingt im Fall der dilatativen Kardiomyopathie (DCM) eine Differenzierung zur inflammatorischen DCM. Im Fall der hypertrophen Kardiomyopathie (HCM) kann analog zur Echographie eine obstruktive und nichtobstruktive Form differenziert werden, aber auch die Detektion einer Amyloidose oder eines Morbus Fabry ist möglich. Die Evaluation der rechtsventrikulären Funktion gelingt im Rahmen einer arrhythmogenen rechtsventrikulären Kardiomyopathie (ARVC) zuverlässig. Außerdem ist die MRT in der Lage, die charakteristische fettige Ersatzfibrose direkt nachzuweisen. Bei den seltenen restriktiven Kardiomyopathien kann sie die Restriktion nachvollziehen und z. B. mittels T1-, T2- und T2*-Mapping die Sphingolipid-Akkumulation im Myokard bei einem Morbus Fabry oder eine Eisenüberladung bei Hämochromatose nachvollziehen. Innovationen Die quantitativen Verfahren des parametrischen Mappings bieten die Möglichkeit eines Therapiemonitorings; die klinische Relevanz dieses Monitorings ist aber noch Gegenstand aktueller Forschung. Die unklassifizierten Kardiomyopathien können sich klinisch mit ähnlicher Symptomatik wie ischämische oder inflammatorische Erkrankungen präsentieren, so dass im Fall eines Myokardinfarkts ohne verschlossene Koronararterien („myocardial infarction without obstructive coronary arteries“, MINOCA) in der Herzkatheteruntersuchung die MRT ein entscheidendes diagnostisches Instrument ist, um die tatsächlich zugrundeliegende Erkrankung festzustellen. Gleichermaßen kann sie bei neuen Kardiomyopathien wie der Non-compaction-Kardiomyopathie der Wegbereiter für eine morphologische Krankheitsdefinition sein.

Event sequences are central to the analysis of data in domains that range from biology and health, to logfile analysis and people's everyday behavior. Many visualization tools have been created for such data, but people are error-prone when asked to judge the similarity of event sequences with basic presentation methods. This article describes an experiment that investigates whether local and global alignment techniques improve people's performance when judging sequence similarity. Participants were divided into three groups (basic versus local versus global alignment), and each participant judged the similarity of 180 sets of pseudo-randomly generated sequences. Each set comprised a target, a correct choice and a wrong choice. After training, the global alignment group was more accurate than the local alignment group (98 versus 93 percent correct), with the basic group getting 95 percent correct. Participants' response times were primarily affected by the number of event types, the similarity of sequences (measured by the Levenshtein distance) and the edit types (nine combinations of deletion, insertion and substitution). In summary, global alignment is superior and people's performance could be further improved by choosing alignment parameters that explicitly penalize sequence mismatches.

We present a data-driven method to learn and understand collective variables for noisy voter model dynamics on networks. A collective variable (CV) is a projection of the high-dimensional system state into a low-dimensional space that preserves the essential dynamical information. Thus, CVs can be used to improve our understanding of complex emergent behaviors and to enable an easier analysis and prediction. We demonstrate our method using three example networks: the stochastic block model, a ring-shaped graph, and a scale-free network generated by the Albert--Barab\'asi model. Our method combines the recent transition manifold approach with a linear regression step to produce interpretable CVs that describe the role and importance of each network node.

Background: Given the crucial role of vaccination in managing and halting the COVID-19 pandemic, it is imperative to understand the factors that motivate adolescents to get vaccinated. However, data on this topic are currently limited. This study aimed to characterize the adolescent population willing to receive COVID-19 vaccination in mid-2021 in an urban region in Germany and to identify the factors that motivated those who accepted vaccination with the mRNA vaccine Comirnaty, which was not yet nationally recommended. Methods: We surveyed adolescents and their accompanying guardians who were scheduled to receive COVID-19 vaccination and collected data on sociodemographic characteristics, the adolescent's medical history, the family's vaccination status, and any history of COVID-19 infection in the family. We also queried information strategies related to the SARS-CoV-2 pandemic and reasons for vaccinating the adolescents. Results: Motivations for getting vaccinated were similar among adolescents and their parents. The primary reasons for vaccination were to protect against SARS-CoV-2-related illness and to gain access to leisure facilities. The adolescents' motivation for vaccination was not influenced by gender, health status, migration background, or presence of chronic or acute diseases. The percentage of parents who had received SARS-CoV-2 immunization and the proportion of parents with a high level of education were higher among study participants than in the general population. Conclusions: Adolescents are especially willing to be vaccinated if they have a better-educated environment and a high vaccination rate in the family. Emphasizing the importance of vaccination among all segments of population and removing barriers to vaccines, may lead to an ameliorated acceptance of COVID-19 vaccines.

This is a publication from theYRS2023 - 11th Young Researchers Seminar,held from 15 to 17 May 2023 in Lisbon, Portugal, hosted by the Laboratório Nacional de Engenharia Civil – LNEC (National Laboratory for Civil Engineering). (restricted publication)

Understanding the reasons why a certain combination of precipitation event and catchment wetness condition causes a particular runoff response serves as the basis for a sustainable water resources management. Runoff responses at the catchment scale are highly variable in space and time due to numerous influencing factors, e.g., topography, land use, geology, and climatic conditions. Yet, despite previous studies having investigated these interdependencies, it remains difficult to differentiate between the various impacts on the runoff response and to determine which driving factors dominate under which conditions. Assuming that similar precipitation and catchment wetness (e.g. in terms of soil water content or groundwater level) lead to similar runoff responses, reoccurring patterns of these hydrological flux and state variables may be useful to assess the causes for similar or different runoff responses. Therefore, we compared precipitation and catchment wetness conditions and classified them as hydrologically similar if they lead to a similar runoff response. In this study, the similarity of runoff responses was assessed for the 38.5 ha, partly forested Wüstebach catchment in Western Germany using the goodness-of-fit (GOF) criteria Nash-Sutcliffe-Efficiency and Volumetric Efficiency. If the GOF exceeded a pre-defined threshold, the runoff responses were classified as similar and grouped together. Subsequently, for similar runoff responses, the corresponding rainfall and wetness conditions were compared calculating the Spearman’s rank correlation coefficient and descriptive statistics. A total of 22 similar out of 73 runoff events were identified for the Wüstebach catchment over a period of nearly 12 years and classified into seven groups with the largest group including in total eight events. Results show that for similar runoff responses in this representative group, soil water content as well as groundwater levels in the riparian zone are well correlated with r = 0.815 and r = 0.840, respectively, indicating a possible dominant control on runoff responses. However, rainfall patterns show overall weak correlations (r = 0.406), implying that the precipitation temporal pattern control on the runoff response might be limited for these types of runoff events in the Wüstebach catchment. In a next step, the here defined hydrologically similar precipitation and wetness conditions will be searched in the data of the Wüstebach catchment to compare the corresponding runoff responses, and hydro-meteorological variables will be used to explain similar or different runoff responses.

ZusammenfassungDie kongenitale Muskeldystrophie Typ Ullrich (UCMD) ist eine seltene Erkrankung. Weltweit wurden bislang 50 Fälle genetisch gesichert. Autosomal-dominante und rezessive Mutationen des COL6A1/COL6A2 im Chromosom 21q22.3 oder des COL6A3 im Chromosom 2q37.3 führen zu einem Mangel an Kollagen VI. Typische Merkmale der UCMD sind Muskelschwäche von Körperstamm und Extremitäten, Hyperflexibilität der distalen und Kontrakturen der proximalen Gelenke, Rollstuhlpflichtigkeit im Alter von 9 bis 11 Jahren, Versteifung und Skoliose der Wirbelsäule und eine progrediente restriktive Ventilationsstörung. Etwa 50 % der Kinder benötigen im Alter von 11 bis 12 Jahren eine nichtinvasive Ventilation (NIV), wozu auch eine gestörte Funktion des Diaphragmas beiträgt. Es wird über die Narkose bei einer 21-jährigen Patientin mit einer UCMD berichtet, die seit dem 6. Lebensjahr rollstuhlpflichtig war und bei der seit 2018 eine lebenserhaltene NIV erfolgte. Wegen einer subpleuralen Einblutung in den linken Lungenunterlappen nach Entlastung eines Pneumothorax wurde eine videoassistierte thorakoskopische Chirurgie (VATS) vorgenommen. Die spezifischen Anforderungen durch die UCMD, das Atemwegsmanagement für die Einlungenventilation sowie Aspekte zur Auswahl der Anästhetika werden diskutiert. Nach erfolgreicher VATS konnte die Patientin am 7. postoperativen Tag in die Häuslichkeit entlassen werden.

Objectives 4D flow MRI enables quantitative assessment of helical flow. We sought to generate normal values and elucidate changes of helical flow (duration, volume, length, velocities and rotational direction) and flow jet (displacement, flow angle) as well as wall shear stress (WSS). Methods We assessed the temporal helical existence (THEX), maximum helical volume (HVmax), accumulated helical volume (HVacc), accumulated helical volume length (HVLacc), maximum forward velocity (maxVfor), maximum circumferential velocity (maxVcirc), rotational direction (RD) and maximum wall shear stress (WSS) as reported elsewhere using the software tool Bloodline in 86 healthy volunteers (46 females, mean age 41 ± 13 years). Results WSS decreased by 42.1% and maxVfor by 55.7% across age. There was no link between age and gender regarding the other parameters. Conclusion This study provides age-dependent normal values regarding WSS and maxVfor and age- and gender-independent normal values regarding THEX, HVmax, HVacc, HVLacc, RD and maxVcirc. Key Points • 4D flow provides numerous new parameters; therefore, normal values are mandatory. • Wall shear stress decreases over age. • Maximum helical forward velocity decreases over age.

Borderline personality disorder (BPD) is characterized by intense mood swings, impulsivity, self-injurious behavior, poor anger control, fear of abandonment, and unstable interpersonal relationships. BPD is also associated with a heightened risk of cardiovascular disease, whereby the underlying mechanisms are insufficiently understood. Accordingly, the present study set out to examine whether individuals with BPD would show abnormal myocardial deformation and to explore the role of potential risk factors, including maladaptive stress responsivity, childhood trauma, and current stress exposure.Fifty female patients diagnosed with BPD and 50 controls matched for sex and age underwent echocardiography to determine the global longitudinal strain (GLS) of the left ventricle. In addition, childhood trauma, chronic stress, and "allostatic load" were determined, as well as borderline symptom severity and common risk factors for cardiovascular disease.Aside from a significantly greater GLS in BPD patients, a multivariable regression analysis revealed that allostatic load (β = 0.225, p = .048) was significantly associated with GLS, with childhood trauma (β = 0.279, p = .062) approaching significance. Conversely, smoking (p = .867), chronic stress (p = .193), and borderline symptom severity (p = .342) were not associated with GLS, even though bivariate correlations were significant.Somatically healthy women with BPD display subtle signs of increased GLS, which is associated with allostatic load as an indicator of the "wear-and-tear" of the body. The association between childhood trauma with GLS was of similar strength but did not reach the threshold for statistical significance. This finding may support the need for primary prevention of somatic consequences of maladaptive stress responsivity in psychiatric patients.

ZusammenfassungChlormethin-Gel ist seit Mai 2019 als Lokaltherapeutikum bei Erwachsenen für kutane T-Zell-Lymphome vom Typ Mycosis fungoides (MF) zugelassen. Die topische Anwendung erfolgt 1-mal täglich. Im Rahmen der Zulassungsstudie kam es nach einer mindestens 6-monatigen Behandlung mit Chlormethin-Gel bei 76,7 % der Patienten (69 von 90) zu einer ≥ 50 %-igen Verbesserung der klinischen Befunde, gemessen anhand der CAILS-Skala (Composite Assessment of Index Lesion Serverity). Eine komplette Remission wurde bei 19 % (17 von 90) der Patienten beschrieben. Etwas mehr als die Hälfte der behandelten Patienten zeigte lokale Nebenwirkungen mit Hautirritationen, Hautrötungen und auch Hautinfektionen. Weitere mögliche Hautreaktionen sind Pruritus, Blasenbildung und Geschwüre.Im Folgenden wird von einer Patientin mit einer bekannten CD30+-Mycosis fungoides im Stadium IIB (ISCL/EORTC 2007) berichtet. Eine unter verschiedenen Systemtherapien (Bexaroten, Bade-PUVA, Brentuximab Vedotin) immer wieder rezidivierende, ca. handtellergroße Plaque an der Flanke links wurde mit Chlormethin-Gel behandelt.Aufgrund bereits bekannter, langsam progredienter Größenzunahme und wiederholt schmerzhafter Mazerationen dieses Herdes erfolgte auch mit Blick auf mögliche Nebenwirkungen von Chlormethin-Gel die Behandlung in Absprache mit der Patientin nur jeden zweiten Tag.Unter diesem Therapieregime zeigte sich, nach anfänglicher kurzzeitiger Hautreizung, bereits nach 3 Monaten eine komplette, histologisch gesicherte, aktuell 6 Monate anhaltende Remission der Läsion.Diese Kasuistik soll einen eindrucksvollen Therapieverlauf unter Chlormethin-Gel in reduzierter Dosierung und bei guter Verträglichkeit präsentieren.

Objectives To analyze the ability of machine-learning (ML)-based computed tomography (CT)-derived fractional flow reserve (CT-FFR) to further improve the diagnostic performance of coronary...

Die richtige Ernährung von Kindern und Jugendlichen ist eine wichtige Grundlage für deren Entwicklung und trägt zur Prävention vieler Krankheiten bei. Im Rahmen dessen spielt auch das Ess- und Gesundheitsverhalten in der Familie eine essentielle Rolle.

Here we present our work on a Kiyooka aldol protocol for the stereoselective synthesis of tertiary alcohols. In the obtained products, three oxygenated carbon atoms that could further be differentiated flank the chiral tertiary alcohol. This methodology can be applied to simple aromatic or aliphatic aldehydes and more complex substrates bearing a chiral center in the α- and/or β-position. For complex substrates, an unexpected dependency between stereoselectivity and double-bond geometry of the ketene acetal was observed. Furthermore, applications in or towards the synthesis of natural products are presented.1 Introduction2 Scope of the Reaction3 Synthetic Applications4 Conclusion

BackgroundAvailable data on aerosol emissions among children and adolescents during spontaneous breathing are limited. Our aim was to gain insight into the role of children in the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and whether aerosol measurements among children can be used to help detect so-called superspreaders—infected individuals with extremely high numbers of exhaled aerosol particles.MethodsIn this prospective study, the aerosol concentrations of SARS-CoV-2 PCR-positive and SARS-CoV-2 PCR-negative children and adolescents (2–17 years) were investigated. All subjects were asked about their current health status and medical history. The exhaled aerosol particle counts of PCR-negative and PCR-positive subjects were measured using the Resp-Aer-Meter (Palas GmbH, Karlsruhe, Germany) and compared using linear regression.ResultsA total of 250 children and adolescents were included in this study, 105 of whom were SARS-CoV-2 positive and 145 of whom were SARS-CoV-2 negative. The median age in both groups was 9 years (IQR 7–11 years). A total of 124 (49.6%) participants were female, and 126 (50.4%) participants were male. A total of 81.9% of the SARS-CoV-2-positive group had symptoms of viral infection. The median particle count of all individuals was 79.55 particles/liter (IQR 44.55–141.15). There was a tendency for older children to exhale more particles (1–5 years: 79.54 p/L; 6–11 years: 77.96 p/L; 12–17 years: 98.63 p/L). SARS-CoV-2 PCR status was not a bivariate predictor (t = 0.82, p = 0.415) of exhaled aerosol particle count; however, SARS-CoV-2 status was shown to be a significant predictor in a multiple regression model together with age, body mass index (BMI), COVID-19 vaccination, and past SARS-CoV-2 infection (t = 2.81, p = 0.005). COVID-19 vaccination status was a highly significant predictor of exhaled aerosol particles (p ConclusionDuring SARS-CoV-2 infection, children and adolescents did not have elevated aerosol levels. In addition, no superspreaders were found.

PoS: Proceedings of Science, 430, ISSN:1824-8039, Proceedings of The 39th International Symposium on Lattice Field Theory (LATTICE2022)

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus does not only lead to pulmonary infection but can also infect other organs such as the gut, the kidney, or the liver. Recent studies confirmed that severe cases of COVID-19 are often associated with liver damage and liver failure, as well as the systemic upregulation of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNFα). However, the impact these immune mediators in the liver have on patient survival during SARS-CoV-2 infection is currently unknown. Here, by performing a post-mortem analysis of 45 patients that died from a SARS-CoV-2 infection, we find that an increased expression of TNFA in the liver is associated with elevated mortality. Using publicly available single-cell sequencing datasets, we determined that Kupffer cells and monocytes are the main sources of this TNFα production. Further analysis revealed that TNFα signaling led to the upregulation of pro-inflammatory genes that are associated with an unfavorable outcome. Moreover, high levels of TNFA in the liver were associated with lower levels of interferon alpha and interferon beta. Thus, TNFα signaling in the infected SARS-CoV-2 liver correlates with reduced interferon levels and overall survival time.

Purpose: The use of circulating tumor cells (CTC) as “liquid biopsy” is limited by the very low yield of CTCs available for subsequent analyses. Most in vitro approaches rely on small sample volumes (5–10 mL).Experimental Design: Here, we used a novel approach, the GILUPI CellCollector, which enables an in vivo isolation of CTCs from peripheral blood. In total, 50 lung cancer patients were screened in two subsequent device applications before and after therapy (n = 185 applications).Results: By in vivo isolation, 58% (108/185) of the patients were positive for ≥1 CTC (median, 5 CTCs; range, 1–56 cells) as compared with 27% (23/84; range, 1–300 cells) using the FDA-cleared CellSearch system. Furthermore, we could show that treatment response during therapy was associated with significant decreases in CTC counts (P = 0.001). By dPCR, mutations in the KRAS and EGFR genes relevant for treatment decisions could be detected in CTCs captured by in vivo isolation and confirmed in the primary tumors of the same patients.Conclusions: In vivo isolation of CTCs overcomes blood volume limitations of other approaches, which might help to implement CTC-based “liquid biopsies” into clinical decision making. Clin Cancer Res; 22(9); 2197–206. ©2015 AACR.

Supplementary Table 1. Additional table showing summarized patient data correlated to the appearance of CTCs.

Background The serotonergic and the endocannabinoid system are involved in the etiology of depression. Depressive patients exhibit low serotonergic activity and decreased level of the endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2AG). Since the cannabinoid (CB) 1 receptor is activated by endogenous ligands such as AEA and 2AG, whose concentration are controlled by the fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase, respectively, we investigated the effects on serotonergic utilization. In this study, we investigated the impact of the rs1049353 single-nucleotide polymorphism (SNP) of the cannabinoid receptor 1 (CNR1) gene, which codes the endocannabinoid CB1 receptor, and the rs324420 SNP of the FAAH gene on the serotonergic and endocannabinoid system in 59 healthy volunteers. Methods Serotonergic activity was measured by loudness dependence of auditory-evoked potentials (LDAEP). Plasma concentrations of AEA, 2AG and its inactive isomer 1AG were determined by mass spectrometry. Genotyping of two SNPs (rs1049353, rs344420) was conducted by polymerase chain reaction (PCR) and differential enzymatic analysis with the PCR restriction fragment length polymorphism method. Results Genotype distributions by serotonergic activity or endocannabinoid concentration showed no differences. However, after detailed consideration of the CNR1-A-allele-carriers, a reduced AEA (A-allele-carrier M = 0.66, SD = 0.24; GG genotype M = 0.72, SD = 0.24) and 2AG (A-allele-carriers M = 0.70, SD = 0.33; GG genotype M = 1.03, SD = 0.83) plasma concentration and an association between the serotonergic activity and the concentrations of AEA and 2AG has been observed. Conclusions Our results suggest that carriers of the CNR1-A allele may be more susceptible to developing depression.

Definable stationary sets, and specifically, ordinal definable ones, play a significant role in the study of canonical inner models of set theory and the class HOD of hereditarily ordinal definable sets. Fixing a certain notion of definability and an uncountable cardinal, one can consider the associated family of definable closed unbounded sets. In this paper, we study the extent to which such families can approximate the full closed unbounded filter, and their dependence on the defining complexity. Focusing on closed unbounded subsets of a cardinal $\kappa$ which are $\Sigma_1$-definable in parameters from $H_\kappa$ and ordinal parameters, we show that the ability of such closed unbounded sets to well approximate the closed unbounded filter on $\kappa$ can highly vary, and strongly depends on key properties of the underlying universe of set theory., Comment: 31 pages

Objectives Plasma uracil is a new biomarker to assess the activity of dihydropyrimidine dehydrogenase before cancer treatment with fluoropyrimidine drugs. Knowledge on the biological variation of plasma uracil is important to assess the applicability of plasma uracil as a biomarker of drug tolerance and efficacy. Methods A total of 33 apparently healthy individuals were submitted to sequential blood draws for three days. On the second day, blood draws were performed every third hour for 12 h. Plasma uracil was quantified by LC-MS/MS. The within-subject (CVI) and between-subject (CVG) biological variation estimates were calculated using linear mixed-effects models. Results The overall median value of plasma uracil was 10.6 ng/mL (range 5.6–23.1 ng/mL). The CVI and CVG were 13.5 and 22.1%, respectively. Plasma uracil remained stable during the day, and there was no day-to-day variation observed. No differences in biological variation components were found between sex and no correlation to age was found. Four samples were calculated to be required to estimate the homeostatic set-point ±15% with 95% confidence. Conclusions Plasma uracil is subject to tight homeostatic regulation without semidiurnal and day-to-day variation, however between-subject variation exists. This emphasizes plasma uracil as a well-suited biomarker for evaluation of dihydropyrimidine dehydrogenase activity, but four samples are required to establish the homeostatic set-point in a patient.

ObjectivesIn the randomized controlled trial PANTHEM, the prophylactic effect of oral amoxicillin or clindamycin is investigated in patients receiving chronic haemodialysis (HD). However, data on plasma concentrations of these antibiotics during HD are sparse. This study aims to determine if the plasma concentration of amoxicillin and clindamycin is sufficient during HD after oral administration of amoxicillin and clindamycin at three different time intervals prior to the HD procedure.MethodsAdult patients receiving chronic HD were investigated twice with an interval of at least 7 days starting with either a tablet of 500/125 mg amoxicillin/clavulanic acid or a tablet of 600 mg clindamycin. Patients were randomized to take the antibiotics either 30, 60 or 120 min prior to the HD procedure. Plasma antibiotic concentrations were measured at start, midway and at the end of HD. A lower threshold was set at 2.0 mg/L for amoxicillin and at 1.0 mg/L for clindamycin. In addition, a population pharmacokinetic (PK) analysis was performed, assessing PTA.ResultsIn the amoxicillin cohort (n = 37), 84% of patients and 95% of all plasma amoxicillin concentrations were above or at the threshold throughout the dialysis procedure. In the clindamycin cohort (n = 33), all concentrations were above the threshold throughout the dialysis procedure. Further, in all patients, the mean plasma concentration of both amoxicillin and clindamycin across the HD period was well above the threshold. Finally, the PK model predicted a high PTA in the majority of patients.DiscussionIn patients on chronic HD, oral administration of amoxicillin/clavulanic acid (500/125 mg) or clindamycin (600 mg) within 30–120 min prior to HD leads to a sufficient prophylactic plasma concentration across the HD period.

Therapeutic drug monitoring is a tool for optimising the pharmacological treatment of diseases where the therapeutic effect is difficult to measure or monitor. Therapeutic reference ranges and dose-effect relation are the main requirements for this drug titration tool. Defining and updating therapeutic reference ranges are difficult, and there is no standardised method for the calculation and clinical qualification of these. The study presents a basic model for validating and selecting routine laboratory data. The programmed algorithm was applied on data sets of antidepressants and antipsychotics from three public hospitals in Denmark. Therapeutic analytical ranges were compared with the published therapeutic reference ranges by the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) and in additional literature. For most of the drugs, the calculated therapeutic analytical ranges showed good concordance between the laboratories and to published therapeutic reference ranges. The exceptions were flupentixol, haloperidol, paroxetine, perphenazine, and venlafaxine + o-desmethyl-venlafaxine (total plasma concentration), where the range was considerably higher for the laboratory data, while the calculated range of desipramine, sertraline, ziprasidone, and zuclopenthixol was considerably lower. In most cases, we identified additional literature supporting our data, highlighting the need of a critical re-examination of current therapeutic reference ranges in Denmark. An automated approach can aid in the evaluation of current and future therapeutic reference ranges by providing additional information based on big data from multiple laboratories.

Let $\kappa$ be an uncountable cardinal with $\kappa=\kappa^{{\kappa^+$'' implies the statement "every closed subset of ${}^\kappa\kappa$ is a continuous image of ${}^\kappa(\kappa^+)$'' or its negation., Comment: 30 pages

Zusammenfassung Hintergrund Zystische Fibrose (CF) ist eine der häufigsten vererbbaren Stoffwechselerkrankungen in Deutschland. Sie betrifft verschiedene Organsysteme und führt häufig zu Schmerzen, die meist unterschätzt werden. Im deutschsprachigen Raum existieren bis dato keinerlei Leitlinien zu diesem relevanten Thema. Methoden Es erfolgte eine systematische Literaturrecherche in PubMed sowie der deutschsprachigen Leitlinien und Fachliteratur zum Thema CF und Schmerzen. Als relevant wurden Arbeiten gewertet, die Daten zu CF, zu Schmerzen oder deren Behandlung bei der CF enthielten. Insgesamt fanden sich 1690 Artikel, von denen 41 Arbeiten unsererseits aufgenommen wurden. Ergebnisse Die Recherche ergab, dass Schmerzen unterschiedlichster Art aufgrund der diversen Organbeteiligungen weit verbreitet sind. Zur Diagnostik und Therapie von Schmerzen bei CF existieren aber keine deutschsprachigen Leitlinien oder Konsenspapiere. In europäischen und amerikanischen Studien spiegelt sich die klinische Relevanz und Bandbreite des Themas wider, Daten zur Effektivität der Schmerztherapie enthalten diese jedoch nicht. Neben einer klassischen Schmerzmedikation mit Analgetika setzen viele Patienten auch auf alternative Heilversuche wie physikalische Therapien, Akupunktur oder Tetrahydrocannabinol (THC). Angesichts der multiplen Organdysfunktionen ist der Einsatz von Analgetika mit besonderen Risiken verbunden. Diskussion Eine Schmerztherapie ist bei Patienten mit zystischer Fibrose und Multiorganbeteiligung häufig erforderlich und muss der Progression der Erkrankung angepasst werden. Kontraindikationen und Nebenwirkungen der Analgetika sollten individuell ermittelt werden. Die Aufnahme der Behandlung von Schmerzen in deutschsprachige CF-Leitlinien ist dringend erforderlich.

In this paper I reconstruct Hegel’s famous critique of irony by drawing on present-day vice epistemology. I argue that the categories of contemporary theories of epistemic vices are sufficient to classify a type of irony as a vicious stance. Yet they fail to grasp the property in virtue of which irony deserves criticism. I show that, for Hegel, this feature is intellectual pride. In the remainder of the paper, I specify the axiological, metaphysical, and epistemological background assumptions which guide the self-assessment of proud persons according to Hegel. Finally, I throw some light on the theoretical presuppositions of Hegel’s account of irony and pride.

Zusammenfassung Hintergrund Die zystische Fibrose (CF) ist eine multisystemische progrediente Stoffwechselerkrankung mit vorwiegend abdomineller und pulmonaler Beteiligung. Schmerzen sind für Betroffene ein weiteres komplexes und von den Behandlern unterschätztes Problem. Methoden Eine Literaturrecherche deutschsprachiger Leitlinien und englischsprachiger Studien zum Thema CF und Schmerzen wurde durchgeführt, zusätzlich die Beobachtungen zur Diagnostik und Therapie eines CF-Patienten mit progredienten thorakalen Schmerzen ausgewertet. Ergebnisse Die Recherche ergab, dass zur Diagnostik und Therapie thorakaler Schmerzen bei CF keine deutschsprachigen Leitlinien oder Konsenspapiere existieren. Die europäischen und amerikanischen Erhebungen zeigen aber die große Relevanz des Themas und postulieren einen Zusammenhang von Schmerzintensität mit einer erhöhten Mortalität. Sie enthalten jedoch keine Daten zur Effektivität der Schmerztherapie. Anhand dieser Daten und des Fallberichts eines jungen CF-Patienten mit stärksten Thoraxschmerzen bei pulmonalen Exazerbationen lassen sich die CF-spezifischen Herausforderungen der Schmerztherapie illustrieren. Neben den Schmerzen an sich sind auch Analgetika angesichts der multiplen Organdysfunktionen mit besonderen Risiken wie gastrointestinalen Blutungen, opioidinduzierter Atemdepression oder opioidinduzierter Obstipation verbunden. Diskussion Schmerztherapie bei Patienten mit zystischer Fibrose und Multiorganbeteiligung erfordert ein sorgfältiges Monitoring und interdisziplinäres Handeln. Empfehlungen zum Schmerzmanagement sollten in die deutschsprachigen CF-Leitlinien aufgenommen werden.

Recently, the European Food Safety Authority (EFSA) issued a tolerable daily intake (TDI) for erucic acid, which is mainly found in rapeseed oil. Infants may be exposed to erucic acid from rapeseed oil indirectly through maternal consumption via breastmilk or the fat component in formula, and directly as a part of complementary feeding (CF). To check the safety of infant nutrition, scenarios for erucic acid exposure were calculated based on the daily food amounts of the German dietary guidelines. Information on erucic acid concentrations in foods was obtained from European studies for breastmilk, from EFSA samples for formula powder, and from a representative analysis of rapeseed oil samples in the German retail market. 6 scenarios were calculated for the early milk feeding phase (4 formula feeding, 2 breastfeeding) and 8 scenarios for the later CF phase (5 CF +formula feeding, 3 CF +breastfeeding). Out of the 14 scenarios, only 3 resulted in exposures that were definitively below the TDI (range 4.4.–6.0 mg/kg bodyweight; BW). Assuming either high consumption or high concentration led to high exceedances (range 7.5–26.2 mg/kg BW), especially in case of the new EU limits for formula or vegetable oils (33.6 and 43.2 mg/kg BW, respectively). In our scenarios, high erucic acid exposures occurred during a particularly sensitive developmental period. To definitively weigh the potential risks from erucic acid in infants against nutritional benefits of the dietary recommendations, reliable, timely data on erucic acid in breast milk and formula are needed, similar to those from rapeseed oil in Germany., In infancy, the diet requires both, an especially high nutritional quality and toxicological safety. In view of the recent TDI for erucic acid issued by EFSA, our scenarios show that the nutritionally safe food‐based dietary guidelines for infancy in Germany may no longer be safe with regard to potential exposure to erucic acid that originates mainly from rapeseed oil. In addition to the strong data base on erucic acid in rapeseed oil in Germany, timely data bases for human milk and formula are needed to definitely decide on the toxicological safety of infant nutrition.

Oxygen isotopes in biogenic silica (δ18OBSi) from lake sediments allow for quantitative reconstruction of past hydroclimate and proxy–model comparison in terrestrial environments. The signals of individual records have been attributed to different factors, such as air temperature (Tair), atmospheric circulation patterns, hydrological changes and lake evaporation. While every lake will have its own set of drivers of d18O, here we explore the extent to which regional or even global signals emerge from a series of palaeoenvironmental records. For this purpose, we have identified and compiled 71 down–core records published to date and complemented these datasets with additional lake basin parameters (e.g. lake water residence time and catchment size) to best characterize the signal properties. Records feature widely different temporal coverage and resolution ranging from decadal–scale records covering the last 150 years to records with multi–millennial scale resolution spanning glacial–interglacial cycles. Best coverage in number of records (N = 37) and datapoints (N = 2112) is available for northern hemispheric (NH) extra–tropic regions throughout the Holocene (corresponding to Marine Isotope Stage 1; MIS 1). To address the different variabilities and temporal offsets, records were brought to a common temporal resolution by binning and subsequently filtered for hydrologically open lakes with lake water residence times < 100 yrs. For mid– to high–latitude (> 45° N) lakes, we find common δ18OBSi patterns during both the Holocene and the Common Era and maxima and minima corresponding to known climate episodes such as the Holocene Thermal Maximum (HTM), Neoglacial Cooling, Medieval Climate Anomaly (MCA) and the Little Ice Age (LIA). These patterns are in line with long–term Tair changes supported by previously published climate reconstructions from other archives as well as Holocene summer insolation changes. In conclusion, oxygen isotope records from NH extratopic lake sediments feature a common climate signal at centennial (for CE) and millennial (for Holocene) time scales despite stemming from different lakes in different geographic locations and constitute a valuable proxy for past climate reconstructions.